**Meet the editors**

Dr Nishtha Sareen is a female Interventional Cardiologist board certified in Echocardiography, Nuclear Medicine, Interventional Cardiology and Endovascular Interventions. After completing her medical school in India with gold medals in 10 out of 13 medical subjects and first position in the University of Rajasthan comprising of 13 medical colleges, Dr Sareen completed her

sub-internship with "High Honors" at Harvard Medical School, Boston. Following this, she completed her training in Internal Medicine at LIJ Medical Center in New York and Cardiology at St Joseph Mercy Oakland, Michigan. She trained in Interventional Cardiology at the coveted Mount Sinai Medical Center, New York. With more than 118 publications and presentations, and numerous National and International awards, Dr Sareen is dedicated to enthusiastic academic teaching of medical students, residents, fellows and fellow physicians as part of many frontline associations in the US. Dr Sareen is passionate about Women Heart Health and nurtures the revolution "Women-hood without Stents".

Dr Abhishek Ojha is a graduate of Rabindra Nath Tagore Medical College in India. With a glorious academic career that includes the highest division in medical college subjects, academic position in the top 0.1% of students in the country and gold and silver medals, Dr Ojha has completed more than 100 publications and presentations. Dr Ojha completed his sub-internship at Harvard

Medical School, Boston and Yale School of Medicine, New Haven. He has since been involved in active clinical research, which encompasses cardiac physiology, medical pharmacology, quality improvement projects in NSTE ACS patients and projects to study and improve the current educational infrastructure in cardiology fellowships. Dr Ojha has extensively studied the epidemiological medical issues in various communities in varied age groups and their impact on dispensing quality care. Dr Ojha is passionate about teaching and contributing to the ever-fascinating field of Cardiology and Research.

Contents

**Preface VII**

**Section 1 Superficial Femoral Artery and Popliteal Artery 1**

Chapter 2 **Interventional Strategies for the Superficial**

**Section 2 Risk Assessment Peripheral Arterial Disease 47**

**Ischemia before Vascular Surgery 49**

Chapter 5 **Risk Factors in the Patients with Extracranial Carotid**

Chapter 6 **The Role of Imaging in Peripheral Arterial Disease 85**

**Femoral Artery 9** Rudin Gjeka

**and Iliac Arteries 27**

**Atherosclerosis 73**

Stacy Willner

Mohamed Abdusalam Elwaifa

**Section 3 Diagnosis of Peripheral Arterial Disease 83**

Omer Tanyeli

Chapter 1 **Introductory Chapter: Superficial Femoral Arterial Disease 3** Yashwant Agrawal, Abhishek Ojha and Nishtha Sareen

Chapter 3 **Percutaneous Reconstruction Techniques: Popliteal Artery**

Chapter 4 **Cardiovascular Risk Evaluation in Patients with Critical Leg**

Diana Larisa Hognogi Mocan and Roxana Chiorescu

**Approach for Chronic Total Occlusion of Superficial Femoral**

Mirela-Anca Stoia, Mihaela Mocan, Cerasela Mihaela Goidescu,

Mei-Ling Sharon Tai, Julia Sien Yuin Liew, Sheun Yu Mo and

## Contents

#### **Preface XI**


Stacy Willner

#### **Section 4 Extracranial Carotid Disease 91**

#### Chapter 7 **Extracranial Carotid Atherosclerosis in the Patients with Transient Ischemic Attack 93** Mei-Ling Sharon Tai, Jun Kit Khoo and Mohamed Abdusalam Elwaifa

Preface

ing interventional cardiologists.

about this book in its current form.

Warmly,

"Peripheral Arterial Disease - A Practical Approach" is an attempt to summarize and dis‐ cuss the most pertinent practical aspects of peripheral vascular disease, its clinical implica‐ tions, diagnostic testing, therapeutic interventions and innovations. This book is an honest effort to provide a clinically relevant approach to the management plan in patients present‐ ing with peripheral vascular symptoms. We intend to provide our readers with additional ground-breaking strategies, which may evolve as vital interventions as this ever-fascinating field continues to progress. We have incorporated an Introductory chapter on the diagnostic modalities in peripheral atherosclerotic disease and additional chapters ranging from super‐ ficial femoral stenosis, approach to superficial femoral and popliteal chronic total occlusions, risk factors in carotid stenosis, cardiovascular risk evaluation in leg ischemia to the evolving field of genetics in peripheral arterial disease. By providing this diverse array of topics to our readers, we hope this book serves as a clinical guide for cardiology fellows and practic‐

I would like to thank the authors for their time and effort in bringing about the character of this publication. I extend sincere gratitude to my co-editor Dr. Abhishek Ojha for his relent‐ less work in reviewing the chapters. I would also like to thank the publishers for bringing

> **Nishtha Sareen and Abhishek Ojha** Michigan State University, USA

I hope you enjoy reading this book as much as we enjoyed working on it.

#### **Section 5 Genetics in Peripheral Arterial Disease 105**

#### Chapter 8 **Genetics in Peripheral Artery Disease 107** Amir-Houshang Shemirani, Katalin Szilvia Zsóri, András Jávor and Zoltán Csiki

## Preface

**Section 4 Extracranial Carotid Disease 91**

Elwaifa

**VI** Contents

Zoltán Csiki

**Transient Ischemic Attack 93**

**Section 5 Genetics in Peripheral Arterial Disease 105**

Chapter 8 **Genetics in Peripheral Artery Disease 107**

Chapter 7 **Extracranial Carotid Atherosclerosis in the Patients with**

Mei-Ling Sharon Tai, Jun Kit Khoo and Mohamed Abdusalam

Amir-Houshang Shemirani, Katalin Szilvia Zsóri, András Jávor and

"Peripheral Arterial Disease - A Practical Approach" is an attempt to summarize and dis‐ cuss the most pertinent practical aspects of peripheral vascular disease, its clinical implica‐ tions, diagnostic testing, therapeutic interventions and innovations. This book is an honest effort to provide a clinically relevant approach to the management plan in patients present‐ ing with peripheral vascular symptoms. We intend to provide our readers with additional ground-breaking strategies, which may evolve as vital interventions as this ever-fascinating field continues to progress. We have incorporated an Introductory chapter on the diagnostic modalities in peripheral atherosclerotic disease and additional chapters ranging from super‐ ficial femoral stenosis, approach to superficial femoral and popliteal chronic total occlusions, risk factors in carotid stenosis, cardiovascular risk evaluation in leg ischemia to the evolving field of genetics in peripheral arterial disease. By providing this diverse array of topics to our readers, we hope this book serves as a clinical guide for cardiology fellows and practic‐ ing interventional cardiologists.

I would like to thank the authors for their time and effort in bringing about the character of this publication. I extend sincere gratitude to my co-editor Dr. Abhishek Ojha for his relent‐ less work in reviewing the chapters. I would also like to thank the publishers for bringing about this book in its current form.

I hope you enjoy reading this book as much as we enjoyed working on it.

Warmly,

**Nishtha Sareen and Abhishek Ojha** Michigan State University, USA

**Section 1**

**Superficial Femoral Artery and Popliteal Artery**

**Superficial Femoral Artery and Popliteal Artery**

**Chapter 1**

**Provisional chapter**

**Introductory Chapter: Superficial Femoral Arterial**

**Introductory Chapter: Superficial Femoral Arterial** 

DOI: 10.5772/intechopen.81097

Superficial femoral artery, traditionally grouped together with the popliteal artery, as femoral popliteal segment, is the most common localization of peripheral artery disease (70%). Atherosclerotic disease of superficial femoral artery is deemed high risk to present with diffuse distribution, frequent calcification, large plaque burden, and high progression rate to total occlusion [1]. Additionally, femoral popliteal segment is exposed to significant flexion, bending, and compression forces. Hence, unique anatomical features, along with nonfavorable atherosclerotic plaques characterize in this region, contributes to a significant challenge, when treating this disease. Apart from the variation in the anatomy and the presentation of the pathology in superficial femoral artery area, there are many unique features in the presentation and diagnosis as well. These in concert with the downstream areas of supply at risk, can present with pain on exertion, pain at rest, or/and with nonhealing ulcers extending anywhere from thigh to feet area. It is crucial to understand that while these issues could arise from focal stenosis at the presentation level, consideration should always be given to an inflow lesion.

Superficial femoral artery arises, at the level of the femoral head, as the continuation of the common femoral artery, medially and anteriorly to profunda femoral artery. After the origin, superficial femoral artery enters the femoral triangle, coursing toward the abductor canal. Subsequently, it leaves the abductor canal through abductor hiatus to enter the popliteal fossa.

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Disease**

**Disease**

Nishtha Sareen

**1. Introduction**

**2. Anatomy**

and Nishtha Sareen

Yashwant Agrawal, Abhishek Ojha and

Yashwant Agrawal, Abhishek Ojha

http://dx.doi.org/10.5772/intechopen.81097

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

#### **Introductory Chapter: Superficial Femoral Arterial Disease Introductory Chapter: Superficial Femoral Arterial Disease**

DOI: 10.5772/intechopen.81097

Yashwant Agrawal, Abhishek Ojha and Nishtha Sareen Yashwant Agrawal, Abhishek Ojha and Nishtha Sareen

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.81097

#### **1. Introduction**

Superficial femoral artery, traditionally grouped together with the popliteal artery, as femoral popliteal segment, is the most common localization of peripheral artery disease (70%). Atherosclerotic disease of superficial femoral artery is deemed high risk to present with diffuse distribution, frequent calcification, large plaque burden, and high progression rate to total occlusion [1]. Additionally, femoral popliteal segment is exposed to significant flexion, bending, and compression forces. Hence, unique anatomical features, along with nonfavorable atherosclerotic plaques characterize in this region, contributes to a significant challenge, when treating this disease. Apart from the variation in the anatomy and the presentation of the pathology in superficial femoral artery area, there are many unique features in the presentation and diagnosis as well. These in concert with the downstream areas of supply at risk, can present with pain on exertion, pain at rest, or/and with nonhealing ulcers extending anywhere from thigh to feet area. It is crucial to understand that while these issues could arise from focal stenosis at the presentation level, consideration should always be given to an inflow lesion.

#### **2. Anatomy**

Superficial femoral artery arises, at the level of the femoral head, as the continuation of the common femoral artery, medially and anteriorly to profunda femoral artery. After the origin, superficial femoral artery enters the femoral triangle, coursing toward the abductor canal. Subsequently, it leaves the abductor canal through abductor hiatus to enter the popliteal fossa.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

At this level, the artery name is changing to the popliteal artery, which usually bifurcates into the anterior tibial artery and tibioperoneal trunk. One of the unique features of superficial femoral artery is lack of the major branches. The only named branch is the descending genicular branch, contributing to collateral flow of the knee when there is a stenosis in the area. Additionally, when discussing the superficial femoral artery disease, profunda femoral branch deserves a special attention, as the potential source of significant collateral flow, which should be evaluated before decision-making about the intervention on superficial femoral artery [2].

artery is characterized by diffuse distribution, significant plaque burden, frequent calcification, and the high risk of progression to total occlusion, which is likely dictated by distinguishable anatomical features, including significant length of the segment, measuring about 50 cm in an average adult patient. The management is dictated by the extent, location, and intensity of the stenosis and calcification. It can range from medical therapy alone to aggressive interventional approaches. The interventional approaches can range from percutaneous interventions to surgical interventions, again based upon the extent of pathology and patient clinical risk factors.

Introductory Chapter: Superficial Femoral Arterial Disease

http://dx.doi.org/10.5772/intechopen.81097

5

Clinically, intermittent claudication is the classic symptom of peripheral arterial disease (PAD). Usually, patients with SFA disease endorse pain in the upper two-thirds of the calf. Nevertheless, approximately only 10% of patients report these symptoms. About half of them complain about atypical leg pain and about 40% remain asymptomatic. Acute limb ischemia

Usually, the diagnosis of PAD is made clinically based upon symptoms and signs. Physical examination typically reveals diminished peripheral pulses and skin changes over the poorly supplied area. Elevation pallor and dependent rubor are signs of advanced PAD. Physical examination may be helpful in localizing the segment of obstruction. Intact femoral pulses, diminishing peripherally and vascular bruit over the SFA are suggestive about this vessel involvement. Ankle brachial index (ABI) is a useful confirmatory test for PAD (ABI ratio < 0.9). Pursuing topography is justified in case of potential intervention. The approach to the patient with suspected PAD and information about testing modalities were outlined in detail

Clinical symptoms are the fundaments of Fontaine classification. This is a widely used system, encompassing four stages of PAD, ranging from asymptomatic disease to apparent necrosis of the limb (**Table 1**). Similarly, Rutherford classification included patient's symptoms, but was

Anatomically, SFA has been grouped together with neighboring arterial vessels as the femoral popliteal segment. This facilitates the management even more significantly. Further anatomical details about the lesion, including the disease pattern and the number of changes, were incorporated into Trans-Atlantic Inter-Society Consensus (TASC II). This classification distinguishes type A, B, C, and D type. Accordingly, lesions vary from relatively short stenosis or occlusion to more diffuse changes. This dictates the management plan from medical therapy to revascularization. Importantly, TASC II additionally provides guidelines regarding the treatment strategy, based on intervention success rate. Detailed classification, in relation to

enriched by objective data, not requiring invasive measures (**Table 2**) [4].

femoral popliteal segment was presented in **Table 3** [5].

is an uncommon presentation (1–2%) [3]. However, it can be limb threatening.

**4. Clinical symptoms and diagnosis**

in the chapter dedicated to aortoiliac disease.

**5. Classification**

Anatomy is especially important when evaluating the superficial femoral arterial stenosis in patients with concerning clinical presentation on abdominal aiortogram with run-off. In cardiac catheterization laboratory, we place a pigtail in the abdominal aorta above the level of iliac bifurcation. There is an option of performing stepped digital subtraction views with 100 ml contrast at the rate of 10–15 ml/sec. The alternative option is to cross over the iliac artery of the affected lower extremity and then use 50 ml contrast at the flow rate of 10 ml/sec for the imaging. Adequate images can be obtained if patient does not move the lower extremities.

#### **3. Pathophysiology of superficial femoral arterial (SFA) disease**

While the pathology can range from atherosclerosis to thrombosis, the majority is attributed to atherosclerosis in the lower extremities. The detailed pathophysiology has been described in the chapter of aortoiliac disease. As outlined above, atherosclerotic disease of superficial femoral artery is characterized by diffuse distribution, significant plaque burden, frequent calcification, and the high risk of progression to total occlusion, which is likely dictated by distinguishable anatomical features, including significant length of the segment, measuring about 50 cm in an average adult patient. The management is dictated by the extent, location, and intensity of the stenosis and calcification. It can range from medical therapy alone to aggressive interventional approaches. The interventional approaches can range from percutaneous interventions to surgical interventions, again based upon the extent of pathology and patient clinical risk factors.

### **4. Clinical symptoms and diagnosis**

Clinically, intermittent claudication is the classic symptom of peripheral arterial disease (PAD). Usually, patients with SFA disease endorse pain in the upper two-thirds of the calf. Nevertheless, approximately only 10% of patients report these symptoms. About half of them complain about atypical leg pain and about 40% remain asymptomatic. Acute limb ischemia is an uncommon presentation (1–2%) [3]. However, it can be limb threatening.

Usually, the diagnosis of PAD is made clinically based upon symptoms and signs. Physical examination typically reveals diminished peripheral pulses and skin changes over the poorly supplied area. Elevation pallor and dependent rubor are signs of advanced PAD. Physical examination may be helpful in localizing the segment of obstruction. Intact femoral pulses, diminishing peripherally and vascular bruit over the SFA are suggestive about this vessel involvement. Ankle brachial index (ABI) is a useful confirmatory test for PAD (ABI ratio < 0.9). Pursuing topography is justified in case of potential intervention. The approach to the patient with suspected PAD and information about testing modalities were outlined in detail in the chapter dedicated to aortoiliac disease.

#### **5. Classification**

At this level, the artery name is changing to the popliteal artery, which usually bifurcates into the anterior tibial artery and tibioperoneal trunk. One of the unique features of superficial femoral artery is lack of the major branches. The only named branch is the descending genicular branch, contributing to collateral flow of the knee when there is a stenosis in the area. Additionally, when discussing the superficial femoral artery disease, profunda femoral branch deserves a special attention, as the potential source of significant collateral flow, which should be evaluated before decision-making about the intervention on superficial femoral artery [2]. Anatomy is especially important when evaluating the superficial femoral arterial stenosis in patients with concerning clinical presentation on abdominal aiortogram with run-off. In cardiac catheterization laboratory, we place a pigtail in the abdominal aorta above the level of iliac bifurcation. There is an option of performing stepped digital subtraction views with 100 ml contrast at the rate of 10–15 ml/sec. The alternative option is to cross over the iliac artery of the affected lower extremity and then use 50 ml contrast at the flow rate of 10 ml/sec for the imaging. Adequate images can be obtained if patient does not move the lower extremities.

4 Peripheral Arterial Disease - A Practical Approach

**3. Pathophysiology of superficial femoral arterial (SFA) disease**

While the pathology can range from atherosclerosis to thrombosis, the majority is attributed to atherosclerosis in the lower extremities. The detailed pathophysiology has been described in the chapter of aortoiliac disease. As outlined above, atherosclerotic disease of superficial femoral Clinical symptoms are the fundaments of Fontaine classification. This is a widely used system, encompassing four stages of PAD, ranging from asymptomatic disease to apparent necrosis of the limb (**Table 1**). Similarly, Rutherford classification included patient's symptoms, but was enriched by objective data, not requiring invasive measures (**Table 2**) [4].

Anatomically, SFA has been grouped together with neighboring arterial vessels as the femoral popliteal segment. This facilitates the management even more significantly. Further anatomical details about the lesion, including the disease pattern and the number of changes, were incorporated into Trans-Atlantic Inter-Society Consensus (TASC II). This classification distinguishes type A, B, C, and D type. Accordingly, lesions vary from relatively short stenosis or occlusion to more diffuse changes. This dictates the management plan from medical therapy to revascularization. Importantly, TASC II additionally provides guidelines regarding the treatment strategy, based on intervention success rate. Detailed classification, in relation to femoral popliteal segment was presented in **Table 3** [5].


**6. Treatment**

**7. Revascularization**

**Author details**

Yashwant Agrawal<sup>1</sup>

**References**

All patients with PAD should be treated initially the same way with pharmacotherapy, including antiplatelet medications and high-intensity statin, risk factors control, and exercise program, irrespectively of the localization of the lesion. Medical therapy is paramount in the management and should be instituted. Revascularization is a modality reserved for selected cases, including no adequate symptoms control despite appropriate conservative treatment and acute limb ischemia [6]. Detailed information regarding conservative management based

Introductory Chapter: Superficial Femoral Arterial Disease

http://dx.doi.org/10.5772/intechopen.81097

7

Revascularization, as mentioned above, is a treatment option only for selected patients with SFA disease. Traditionally, femoral popliteal segment used to be treated with vein bypass surgery. Nevertheless, over the last decades, a rapid evolution of endovascular techniques revolutionized the treatment of PAD. Admittedly, endovascular treatment of SFA disease appears to be specifically complex due to unique biophysical forces over his body area along with often diffuse and calcified atherosclerotic lesions, leading to suboptimal endovascular treatment results and stent restenosis as the significant problem affecting long-term outcome. However, the tendency is pointing toward improving morbidity and mortality index after endovascular treatment [7]. Currently, according to TASC II Update (2015), endovascular approach is the preferred method of treating femoropopliteal lesion up to 10 cm in length [5].

Different modalities of invasive treatment have been presented in a separate chapter.

and Nishtha Sareen<sup>1</sup>

[1] Klein AJ, Chen SJ, Messenger JC, et al. Quantitative assessment of the conformational change in the femoropopliteal artery with leg movement. Catheterization and Cardio-

[2] Casserly IP, Sachar R, Bajzer C, Yadav JS. Utility of IVUS-guided transaccess catheter in the treatment of long chronic total occlusion of the superficial femoral artery.

Catheterization and Cardiovascular Interventions. 2004;**62**(2):237-243

\*

, Abhishek Ojha<sup>2</sup>

1 St Joseph Mercy Oakland, Pontiac, Michigan, USA

vascular Interventions. 2009;**74**:787-798

2 Rabindranath Tagore Medical College, Udaipur, India

\*Address all correspondence to: nishtha.sareen01@gmail.com

on the most recent trials was outlined in the chapter of aortoiliac disease.

**Table 1.** PAD classification system by Fontaine.


**Table 2.** PAD classification system by Rutherford.

Type A lesion

Solitary stenosis <10 cm in length Solitary occlusion <5 cm in length Type B lesion Solitary, severally calcified stenosis <5 cm in length Many lesions, each <5 cm in length Solitary lesion <15 cm in length Type C lesion Multiple lesions totaling >15 cm in length Recurring lesions after treatment failure Type D lesion Chronic total occlusion of SFA > 20 cm in length.

**Table 3.** SFA lesions – TASC II classification system.

#### **6. Treatment**

All patients with PAD should be treated initially the same way with pharmacotherapy, including antiplatelet medications and high-intensity statin, risk factors control, and exercise program, irrespectively of the localization of the lesion. Medical therapy is paramount in the management and should be instituted. Revascularization is a modality reserved for selected cases, including no adequate symptoms control despite appropriate conservative treatment and acute limb ischemia [6]. Detailed information regarding conservative management based on the most recent trials was outlined in the chapter of aortoiliac disease.

#### **7. Revascularization**

**Grade Category Presentation Objective measures**

III 5 Minor tissue loss, focal gangrene,

Stage IIa – Intermittent claudication >200 m walking distance Stage IIb – Intermittent claudication <200 m walking distance

Stage IV – Ulceration/gangrene due to ischemia

6 Peripheral Arterial Disease - A Practical Approach

**Table 1.** PAD classification system by Fontaine.

**Table 2.** PAD classification system by Rutherford.

Solitary, severally calcified stenosis <5 cm in length

Type A lesion

Type B lesion

Type C lesion

Type D lesion

Solitary stenosis <10 cm in length Solitary occlusion <5 cm in length

Many lesions, each <5 cm in length Solitary lesion <15 cm in length

Multiple lesions totaling >15 cm in length Recurring lesions after treatment failure

Chronic total occlusion of SFA > 20 cm in length.

**Table 3.** SFA lesions – TASC II classification system.

Stage I – No symptoms Stage II – Mild claudication

Stage III – Pain at rest

any longer

and ischemic ulceration

6 Tissue loss spreading above metatarsal

level, extremity cannot be preserved

0 0 No symptoms Treadmill test and reactive hyperemia test

I 2 Moderate intermittent claudication Between mild and severe claudication

II 4 Symptoms at rest Ankle pressure <40 mmHg at rest. Toe

1 Mild intermittent claudication Can complete treadmill test. Ankle pressure

3 Severe claudication Unable to complete treadmill test. Ankle

within normal limits

lower than at rest

pressure <30 mmHg

pressure <40 mmHg

Same as above

post exertion >50 mmHg, but ≥20 mmHg

pressure post exertion <50 mmHg

Ankle pressure <60 mmHg at rest. Toe

Revascularization, as mentioned above, is a treatment option only for selected patients with SFA disease. Traditionally, femoral popliteal segment used to be treated with vein bypass surgery. Nevertheless, over the last decades, a rapid evolution of endovascular techniques revolutionized the treatment of PAD. Admittedly, endovascular treatment of SFA disease appears to be specifically complex due to unique biophysical forces over his body area along with often diffuse and calcified atherosclerotic lesions, leading to suboptimal endovascular treatment results and stent restenosis as the significant problem affecting long-term outcome. However, the tendency is pointing toward improving morbidity and mortality index after endovascular treatment [7]. Currently, according to TASC II Update (2015), endovascular approach is the preferred method of treating femoropopliteal lesion up to 10 cm in length [5]. Different modalities of invasive treatment have been presented in a separate chapter.

#### **Author details**

Yashwant Agrawal<sup>1</sup> , Abhishek Ojha<sup>2</sup> and Nishtha Sareen<sup>1</sup> \*

\*Address all correspondence to: nishtha.sareen01@gmail.com

1 St Joseph Mercy Oakland, Pontiac, Michigan, USA

2 Rabindranath Tagore Medical College, Udaipur, India

#### **References**


[3] Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;**286**:1317-1324

**Chapter 2**

Provisional chapter

**Interventional Strategies for the Superficial Femoral**

DOI: 10.5772/intechopen.76724

The incidence of peripheral arterial disease (PAD) is rising due to significant increase in metabolic disease such as diabetes mellitus, increase in aging population, and tobacco use. Superficial femoral artery (SFA) disease is the leading cause of peripheral artery disease and claudication. In the last decades, several technologies/techniques have been developed for the treatment of SFA atherosclerotic disease including balloon angioplasty, balloon expanding stents, self-expanding stents, drug-eluting balloon, and atherectomy. The advances made in technology have significantly improved the quality of the balloons, but they have limitations especially in long and calcified lesions. While the initial studies using stainless steel stents failed to show any significant difference in outcomes, understanding the pathophysiology and improvement in stent technologies has shown significant reduction of restenosis by five- to sevenfold when compared to angioplasty alone. Atherectomy is another modality of plaque modification and treatment, which can be done as a stand-alone treatment or more commonly combined with PTA and/or stenting. Finally, several randomized studies and registries have showed that with improvement in technology, there is significant improvement in long-term outcomes of SFA atherosclerotic

Keywords: superficial femoral artery angioplasty, superficial femoral artery stenting, SFA rotational atherectomy, SFA laser atherectomy, SFA directional atherectomy

The incidence of peripheral arterial disease (PAD) is rising due to significant increase in metabolic diseases such as diabetes mellitus, increase in aging population and tobacco use.

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Interventional Strategies for the Superficial Femoral

**Artery**

Artery

Rudin Gjeka

Rudin Gjeka

Abstract

disease.

1. Introduction

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76724


#### **Interventional Strategies for the Superficial Femoral Artery** Interventional Strategies for the Superficial Femoral Artery

DOI: 10.5772/intechopen.76724

#### Rudin Gjeka Rudin Gjeka

[3] Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection,

[4] Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, et al. Recommended standards for reports dealing with lower extremity ischemia: Revised version. Journal of

[5] Michael R, Jaff DO, Christopher J, White MD, William R, Hiatt MD, et al. An update on methods for revascularization and expansion of the TASC lesion classification to include below-the-knee arteries: A supplement to the inter-society consensus for the management of peripheral arterial disease (TASC II): The TASC steering committee. Journal of

[6] Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): A report of the American College of Cardiology Foundation/American Heart Association

[7] Diehm NA, Hoppe H, Do DD. Drug eluting balloons. Techniques in Vascular and

awareness, and treatment in primary care. JAMA. 2001;**286**:1317-1324

Task Force on Practice Guidelines. Circulation. 2013;**127**(13):1425-1443

Vascular Surgery. 1997;**26**(3):517-538

8 Peripheral Arterial Disease - A Practical Approach

Endovascular Therapy. 2015;**22**:657-671

Interventional Radiology. 2010;**13**:59-63

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76724

#### Abstract

The incidence of peripheral arterial disease (PAD) is rising due to significant increase in metabolic disease such as diabetes mellitus, increase in aging population, and tobacco use. Superficial femoral artery (SFA) disease is the leading cause of peripheral artery disease and claudication. In the last decades, several technologies/techniques have been developed for the treatment of SFA atherosclerotic disease including balloon angioplasty, balloon expanding stents, self-expanding stents, drug-eluting balloon, and atherectomy. The advances made in technology have significantly improved the quality of the balloons, but they have limitations especially in long and calcified lesions. While the initial studies using stainless steel stents failed to show any significant difference in outcomes, understanding the pathophysiology and improvement in stent technologies has shown significant reduction of restenosis by five- to sevenfold when compared to angioplasty alone. Atherectomy is another modality of plaque modification and treatment, which can be done as a stand-alone treatment or more commonly combined with PTA and/or stenting. Finally, several randomized studies and registries have showed that with improvement in technology, there is significant improvement in long-term outcomes of SFA atherosclerotic disease.

Keywords: superficial femoral artery angioplasty, superficial femoral artery stenting, SFA rotational atherectomy, SFA laser atherectomy, SFA directional atherectomy

#### 1. Introduction

The incidence of peripheral arterial disease (PAD) is rising due to significant increase in metabolic diseases such as diabetes mellitus, increase in aging population and tobacco use.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PAD is the third cardiovascular cause of morbidity following the coronary artery disease and stroke.

Indications to intervene upon the lower extremities depend on the severity of disease and symptoms with absolute indications in cases with limb-threatening ischemia with resting pain and tissue loss (including Rutherford classification class 4–6). Relative indications are not limb threatening but significantly debilitating and often a reason to intervene upon and include

Interventional Strategies for the Superficial Femoral Artery

http://dx.doi.org/10.5772/intechopen.76724

11

Once intervention is indicated, the decision to intervene via endovascular approach rather than open surgical approach is mainly based upon the Trans-Atlantic inter-Society Consensus

Like all endovascular interventions, SFA interventions begin with vascular access. The most common vascular access is the common femoral artery (CFR). In selected cases, brachial artery can be used as well. For safety purposes and in attempting to reduce complications, the recommended technique is the ultrasound (US)-guided technique and if possible micropunc-

Using the ultrasound permits direct visualization of the artery and its branches. US-guided access reduces multiple punctures and as such reduces the incidence of arteriovenous fistulas. US-guided technique is an excellent choice in patients with no palpable pulse, heavily diseased

Puncture using anatomical landmarks is another approach several operators use. The point of maximal pulsation correlates with the midpoint of the CFA in over 92% of the cases. When the pulse is difficult to palpate, the midpoint between the anterior superior iliac spine and pubic tubercle by palpation is used. The groin crease is an unreliable marker and is located distal to the CFA bifurcation and is located distal to the CFA bifurcation in about three out of four patients. Fluoroscopy-guided puncture can be used as well, aiming the inner lower third of the femoral head. The femoral head provides a solid surface for firm compression of the CFA

Arterial access can be obtained on either side with the contralateral side being the preferred in most cases. The contralateral access remains the preferred choice as it allows an adequate working length to image and treat the sequential lesions within the entire target extremity. Once the access is obtained, a guide wire is introduced with size 0.018–0.035-in depending on if it is a micropuncture or not. Sheath sizes used for the SFA intervention range from 4 to 7 French. Sheaths protect the access vessel during the catheter intervention and wire exchanges during a procedure. The smallest size sheath to complete the intervention should be used. A reverse curved catheter and a 0.035-in guide wire are usually used to crossover the aortic bifurcation. The guide wire is then advanced to the level of the CFA and at that point allows to advance a catheter to the distal external iliac artery. At this point, serial lower extremity angiograms can be performed at the target extremity. Patency of the runoff vessels is very important to assess prior to intervention. Clinically assessing the presence of pulses is very important because distal vessels can be occluded secondary to embolization from the SFA

common femoral artery (CFR), obese patients, and high bifurcation [9].

necessary for hemostasis following arterial puncture [10–12].

mainly patients with intermittent claudication (Rutherford class 2 and 3), [8] (Table 1).

II Classification (TASCII) recommendations [7] (Table 2).

2. Vascular access technique

ture needle can be used as well.

Superficial femoral artery (SFA) disease is the leading cause of peripheral artery disease and claudication. According to current estimates, there are over 8 million people affected with PAD and the numbers are rising. Nearly half of the patients affected from PAD are asymptomatic and about 20% have claudication [1–4]. Regardless if the patients are symptomatic or not, patients with PAD have worse quality of life and worse outcomes when compared to people that do not [5].

Nearly 50 years after the first endovascular intervention of the SFA performed by Charles Dotter, endovascular intervention of the lower extremity has increased significantly [6]. The relatively low risk for morbidity and mortality and improvement in technology have seen a high success rate making the endovascular intervention of the SFA the preferred choice, particularly in short-segment disease [7]. Nevertheless, the unique biochemical, anatomical, and hemodynamic forces the SFA is exposed to, makes the endovascular intervention quite challenging.


Table 1. Rutherford classification of chronic limb ischemia.



Table 2. Trans-Atlantic inter-society consensus II (TASC II). Classification of the femoropopliteal disease.

Indications to intervene upon the lower extremities depend on the severity of disease and symptoms with absolute indications in cases with limb-threatening ischemia with resting pain and tissue loss (including Rutherford classification class 4–6). Relative indications are not limb threatening but significantly debilitating and often a reason to intervene upon and include mainly patients with intermittent claudication (Rutherford class 2 and 3), [8] (Table 1).

Once intervention is indicated, the decision to intervene via endovascular approach rather than open surgical approach is mainly based upon the Trans-Atlantic inter-Society Consensus II Classification (TASCII) recommendations [7] (Table 2).

#### 2. Vascular access technique

PAD is the third cardiovascular cause of morbidity following the coronary artery disease and

Superficial femoral artery (SFA) disease is the leading cause of peripheral artery disease and claudication. According to current estimates, there are over 8 million people affected with PAD and the numbers are rising. Nearly half of the patients affected from PAD are asymptomatic and about 20% have claudication [1–4]. Regardless if the patients are symptomatic or not, patients with PAD have worse quality of life and worse outcomes when compared to people

Nearly 50 years after the first endovascular intervention of the SFA performed by Charles Dotter, endovascular intervention of the lower extremity has increased significantly [6]. The relatively low risk for morbidity and mortality and improvement in technology have seen a high success rate making the endovascular intervention of the SFA the preferred choice, particularly in short-segment disease [7]. Nevertheless, the unique biochemical, anatomical, and hemodynamic forces the SFA is exposed to, makes the endovascular intervention quite challenging.

Rutherford category Characteristic Asymptomatic Mild claudication Moderate claudication Severe claudication

4 Pain at rest 5 Minor tissue loss 6 Major tissue loss

Type lesion Stenosis or occlusion pattern Procedure A Single stenosis less or equal to 10 cm or occlusion less or equal to 5 cm. Endovascular

Single stenosis or occlusion of 15 cm or less, not involving below the knee popliteal

Single or multiple lesions in conjunction with occluded proximal infra-geniculate vessels

Endovascular

Endovascular or Surgical bypass

Surgical bypass

B Multiple stenosis or occlusion less or equal to 5 cm or a single severely calcified occlusion

C Multiple stenosis or occlusion adding to more than 15 cm irrespective of calcification.

D Chronic occlusions of the CFA, more than 20 cm of SFA stenosis, popliteal artery or

Table 2. Trans-Atlantic inter-society consensus II (TASC II). Classification of the femoropopliteal disease.

Two failed attempts for endovascular revascularization.

Trans-Atlantic Inter-Society Consensus II classification of femoropopliteal disease

Table 1. Rutherford classification of chronic limb ischemia.

to improve inflow for distal bypass. Single popliteal artery stenosis.

proximal trifurcation vessels.

CFA = Common Femoral Artery. SFA = Superficial Femoral Artery.

of 5 cm or less.

artery.

stroke.

10 Peripheral Arterial Disease - A Practical Approach

that do not [5].

Like all endovascular interventions, SFA interventions begin with vascular access. The most common vascular access is the common femoral artery (CFR). In selected cases, brachial artery can be used as well. For safety purposes and in attempting to reduce complications, the recommended technique is the ultrasound (US)-guided technique and if possible micropuncture needle can be used as well.

Using the ultrasound permits direct visualization of the artery and its branches. US-guided access reduces multiple punctures and as such reduces the incidence of arteriovenous fistulas. US-guided technique is an excellent choice in patients with no palpable pulse, heavily diseased common femoral artery (CFR), obese patients, and high bifurcation [9].

Puncture using anatomical landmarks is another approach several operators use. The point of maximal pulsation correlates with the midpoint of the CFA in over 92% of the cases. When the pulse is difficult to palpate, the midpoint between the anterior superior iliac spine and pubic tubercle by palpation is used. The groin crease is an unreliable marker and is located distal to the CFA bifurcation and is located distal to the CFA bifurcation in about three out of four patients. Fluoroscopy-guided puncture can be used as well, aiming the inner lower third of the femoral head. The femoral head provides a solid surface for firm compression of the CFA necessary for hemostasis following arterial puncture [10–12].

Arterial access can be obtained on either side with the contralateral side being the preferred in most cases. The contralateral access remains the preferred choice as it allows an adequate working length to image and treat the sequential lesions within the entire target extremity. Once the access is obtained, a guide wire is introduced with size 0.018–0.035-in depending on if it is a micropuncture or not. Sheath sizes used for the SFA intervention range from 4 to 7 French. Sheaths protect the access vessel during the catheter intervention and wire exchanges during a procedure. The smallest size sheath to complete the intervention should be used. A reverse curved catheter and a 0.035-in guide wire are usually used to crossover the aortic bifurcation. The guide wire is then advanced to the level of the CFA and at that point allows to advance a catheter to the distal external iliac artery. At this point, serial lower extremity angiograms can be performed at the target extremity. Patency of the runoff vessels is very important to assess prior to intervention. Clinically assessing the presence of pulses is very important because distal vessels can be occluded secondary to embolization from the SFA intervention. In presence of single-vessel runoff, an embolic protection filter can be used prior to intervention to minimize distal embolic occlusion. Prior to starting intervention, the patient should be heparinized with an activated clotting time (ACT) of 250 seconds or more [13].

When planning on performing only angioplasty without stent placement, longer balloon inflation times are used to stabilize the luminal surface of the arterial segment being treated. The longer inflation times may reduce a flow-limiting dissection. After the intervention, angiography is performed; if there is any vessel recoil, persistent stenosis, or a flow-limiting dissection, repeat angioplasty is recommended. In these circumstances, increase of inflation times is recommended

Interventional Strategies for the Superficial Femoral Artery

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13

Conventional balloons are associated with a high rate of uncontrolled dissections that may require bailout stenting, particularly in more complex and diffuse SFA lesions. Cutting balloons are reinforced with microtomes that provide a leading edge to cut through stiff fibrotic lesions at lower pressures. These types of balloons are suggested instead of using larger diameter balloons and may be associated with less hemodynamically significant dissections. Studies have shown that use of cutting balloons have shown better long-term patency in peripheral artery interventions. When there is a persistent residual stenosis of more than 50% or a flow-limiting dissection

With improvement in technology, development of newer balloons, such as drug-coated balloons (DCB), have significantly improved outcomes in percutaneous interventions of the peripheral arteries including the SFA disease. Tepe G et al. conducted a randomized controlled study of 331 patients with symptomatic femoropopliteal artery disease up to 18 cm in length. At 24 months, outcomes from the trial revealed a durable and superior treatment effect of the DCB versus percutaneous transluminal angioplasty (PTA) with significantly higher primary patency, lower clinically driven target lesion revascularization (TLR), and similar functional

Drug-coated balloons have been also studied in complex stenosis such as in-stent restenosis (ISR). Brodmann et al. performed a study to assess the effectiveness and safety of the use of paclitaxel-coated drug-coated balloon (DCB) in patients with de novo in-stent restenosis (ISR). A total of 131 patients were enrolled. Procedural success was achieved in 98.5% of subjects. Primary patency estimate was 88.7% in the ISR cohort at 12 months. Freedom from clinically

The efficacy of stenting over the balloon angioplasty failed to show any significant advantage in the early randomized trials where mainly stainless steel bare-metal stents were used [7, 23, 24]. However, with the advancement in stent technology, further newer studies compared primary angioplasty to Nitinol stents in the SFA. Interestingly, these studies revealed that angioplasty alone results in equivalent patency rates when compared to primary stenting in patients with short lesions. On the other hand, longer stenosis are best treated with primary

The FAST trial, a multicenter randomized controlled trial, compared the SFA PTA and nitinol stenting in 244 patients. The indication to treat was claudication in 97% of patients in both groups. The mean lesion length was relatively short, 4.4 cm in the stenting group and 4.5 cm in

driven target lesion revascularization (CD-TLR) estimated at 92.9% at 12 months [22].

after the PTA, provisional stenting is performed [20].

status improvement with fewer repeat interventions [21].

stenting and that offers longer time patency (Table 3).

[17, 19].

4. Stenting

After the patient is anticoagulated, the target SFA lesion must be crossed. This is achieved using a directional catheter and a 0.035-in wire, usually a hydrophilic wire. The catheter is usually positioned just proximal to the target lesion providing wire support and pushability to cross the stenosis. Remaining intraluminal is the preferred technique to cross the lesion, but it is not possible with a 0.035-in wire. Therefore, an attempt can be made by using a 0.018-inch or a 0.014-inch guide wire and catheter. If there are still difficulties in crossing the lesion, then a subintimal approach can be attempted. When the reentry with a hydrophilic wire is not possible, then the use of a reentry device is recommended. Subintimal angioplasty can be performed effectively with excellent technical success and acceptable patency [14–16].

#### 3. Balloon angioplasty

Balloon angioplasty remains the most frequently used technique in the treatment of SFA disease as either primary or adjunctive therapy for stents and other devices. After crossing the lesion, an appropriate balloon must be selected. There are several balloons that can be used in different scenarios as we describe later [20].

The noncompliant balloons inflate to a uniform diameter regardless of the amount of pressure introduced in the balloon. As such, the noncompliant balloons are often preferred because they are less likely to cause injury to the native vessel and are more effective in treating atherosclerotic lesions. Balloon catheters can be over the wire, and they offer more pushability and often times are better in crossing tight lesions. Furthermore, these balloons can be used as catheters as well. Monorail or the rapid exchange balloons are less cumbersome and easier to handle as they use shorter wires. However, these advantages come at the expense of the pushability, and crossing a tight lesion with a monorail balloon can be more challenging. The diameter of a normal SFA segment distal to the lesion is used as a reference to size the angioplasty. To size the length of the balloon, a radiopaque external ruler is used. The proper length of the balloon must treat the target lesion without disruption of the normal segment proximal and distal to the lesion [17].

The nominal pressure of a balloon is the pressure at which the balloon will achieve the manufacturer's stated diameter. With noncompliant balloon, increasing the pressure will not result in increase in diameter, while with compliant or semi-compliant balloons, an increase in pressure will result in balloon overinflation to a larger diameter. Overinflation and over-sizing the balloon can cause trauma to the artery or significant dissection. The burst pressure is the pressure at which 99.9% of the balloon will not rupture. This pressure should not be exceeded. Balloon can rupture due to overinflation or if the atherosclerotic plaque is heavily calcified. Balloon rupture can cause embolization of balloon fragments or air embolization if the balloon is not properly prepped [17, 18].

When planning on performing only angioplasty without stent placement, longer balloon inflation times are used to stabilize the luminal surface of the arterial segment being treated. The longer inflation times may reduce a flow-limiting dissection. After the intervention, angiography is performed; if there is any vessel recoil, persistent stenosis, or a flow-limiting dissection, repeat angioplasty is recommended. In these circumstances, increase of inflation times is recommended [17, 19].

Conventional balloons are associated with a high rate of uncontrolled dissections that may require bailout stenting, particularly in more complex and diffuse SFA lesions. Cutting balloons are reinforced with microtomes that provide a leading edge to cut through stiff fibrotic lesions at lower pressures. These types of balloons are suggested instead of using larger diameter balloons and may be associated with less hemodynamically significant dissections. Studies have shown that use of cutting balloons have shown better long-term patency in peripheral artery interventions. When there is a persistent residual stenosis of more than 50% or a flow-limiting dissection after the PTA, provisional stenting is performed [20].

With improvement in technology, development of newer balloons, such as drug-coated balloons (DCB), have significantly improved outcomes in percutaneous interventions of the peripheral arteries including the SFA disease. Tepe G et al. conducted a randomized controlled study of 331 patients with symptomatic femoropopliteal artery disease up to 18 cm in length. At 24 months, outcomes from the trial revealed a durable and superior treatment effect of the DCB versus percutaneous transluminal angioplasty (PTA) with significantly higher primary patency, lower clinically driven target lesion revascularization (TLR), and similar functional status improvement with fewer repeat interventions [21].

Drug-coated balloons have been also studied in complex stenosis such as in-stent restenosis (ISR). Brodmann et al. performed a study to assess the effectiveness and safety of the use of paclitaxel-coated drug-coated balloon (DCB) in patients with de novo in-stent restenosis (ISR). A total of 131 patients were enrolled. Procedural success was achieved in 98.5% of subjects. Primary patency estimate was 88.7% in the ISR cohort at 12 months. Freedom from clinically driven target lesion revascularization (CD-TLR) estimated at 92.9% at 12 months [22].

#### 4. Stenting

intervention. In presence of single-vessel runoff, an embolic protection filter can be used prior to intervention to minimize distal embolic occlusion. Prior to starting intervention, the patient should be heparinized with an activated clotting time (ACT) of 250 seconds or more [13].

After the patient is anticoagulated, the target SFA lesion must be crossed. This is achieved using a directional catheter and a 0.035-in wire, usually a hydrophilic wire. The catheter is usually positioned just proximal to the target lesion providing wire support and pushability to cross the stenosis. Remaining intraluminal is the preferred technique to cross the lesion, but it is not possible with a 0.035-in wire. Therefore, an attempt can be made by using a 0.018-inch or a 0.014-inch guide wire and catheter. If there are still difficulties in crossing the lesion, then a subintimal approach can be attempted. When the reentry with a hydrophilic wire is not possible, then the use of a reentry device is recommended. Subintimal angioplasty can be performed effectively with excellent technical success and acceptable

Balloon angioplasty remains the most frequently used technique in the treatment of SFA disease as either primary or adjunctive therapy for stents and other devices. After crossing the lesion, an appropriate balloon must be selected. There are several balloons that can be used

The noncompliant balloons inflate to a uniform diameter regardless of the amount of pressure introduced in the balloon. As such, the noncompliant balloons are often preferred because they are less likely to cause injury to the native vessel and are more effective in treating atherosclerotic lesions. Balloon catheters can be over the wire, and they offer more pushability and often times are better in crossing tight lesions. Furthermore, these balloons can be used as catheters as well. Monorail or the rapid exchange balloons are less cumbersome and easier to handle as they use shorter wires. However, these advantages come at the expense of the pushability, and crossing a tight lesion with a monorail balloon can be more challenging. The diameter of a normal SFA segment distal to the lesion is used as a reference to size the angioplasty. To size the length of the balloon, a radiopaque external ruler is used. The proper length of the balloon must treat the target lesion without disruption of the normal segment proximal and distal to

The nominal pressure of a balloon is the pressure at which the balloon will achieve the manufacturer's stated diameter. With noncompliant balloon, increasing the pressure will not result in increase in diameter, while with compliant or semi-compliant balloons, an increase in pressure will result in balloon overinflation to a larger diameter. Overinflation and over-sizing the balloon can cause trauma to the artery or significant dissection. The burst pressure is the pressure at which 99.9% of the balloon will not rupture. This pressure should not be exceeded. Balloon can rupture due to overinflation or if the atherosclerotic plaque is heavily calcified. Balloon rupture can cause embolization of balloon fragments or air embolization if the balloon

patency [14–16].

the lesion [17].

is not properly prepped [17, 18].

3. Balloon angioplasty

12 Peripheral Arterial Disease - A Practical Approach

in different scenarios as we describe later [20].

The efficacy of stenting over the balloon angioplasty failed to show any significant advantage in the early randomized trials where mainly stainless steel bare-metal stents were used [7, 23, 24]. However, with the advancement in stent technology, further newer studies compared primary angioplasty to Nitinol stents in the SFA. Interestingly, these studies revealed that angioplasty alone results in equivalent patency rates when compared to primary stenting in patients with short lesions. On the other hand, longer stenosis are best treated with primary stenting and that offers longer time patency (Table 3).

The FAST trial, a multicenter randomized controlled trial, compared the SFA PTA and nitinol stenting in 244 patients. The indication to treat was claudication in 97% of patients in both groups. The mean lesion length was relatively short, 4.4 cm in the stenting group and 4.5 cm in


maximal walking distance was significantly less in the PTA group at 6 and 12 months (267 vs.

Interventional Strategies for the Superficial Femoral Artery

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15

Another study that showed significant superiority of stenting versus PTA is the RESILIANT trial. A multicenter randomized controlled trial (RCT) comparing the PTA to nitinol stenting in 206 patients [27]. Indication for treatment was claudication and the lesion length was in the moderate range (7.7 cm in the stent group and 6.4 cm in the PTA group). The 6-month primary patency was worse in the PTA group when compared with primary stenting (47.4 vs. 94.2%, p = 0.0001). Patients were followed up at 12 months and results remained statistically significant in the stenting group (36.7% in the PTA group vs. 81.3% in the stenting group, p = 0.0001). Even longer term, 3-year follow-up, patients randomized to primary stent placement had significantly higher freedom from target lesion revascularization (75.5 vs. 41.8%) [28]. The earlier-mentioned studies provided strong evidence favoring the primary stenting as the

Based on recent registry studies, current-generation nitinol self-expanding stents have improved primary patency, with low to zero rates of stent fractures [29, 30]. The SUMMIT study was a prospective multicenter registry study of the Epic stent, which is a laser-cut nitinol selfexpanding stent [29]. At 1-year follow-up, the restenosis rate was 15.7%, with a freedom from the target lesion revascularization (TLR) rate of 92%. No stent fractures were noted on follow-up

COMPLETE SE trial is a prospective multicenter, single-arm study that evaluated the selfexpanding stent in SFA and proximal popliteal for de novo and/or restenotic lesions in patients with symptomatic PAD [30]. At 1-year follow-up, the primary patency rate was 72.6%, with a

Technology continues to undergo significant improvement in SFA stents with the goal to increase durability and conformability with better long-term patency. The Supera stent (Abbott Vascular) is a recently approved stent with a novel woven design that results in improved radial strength, flexibility, and resistance to fracture. The SUPERB study reported a primary patency rate of 86% in the pivotal registry [31]. Other stent designs under investigation include the Tigris stent (Gore and Associates), which has a nitinol wire frame with Extended polytetrafluoroethylene (ePTFE) coating and interconnecting ePTFE-linking regions. The SMART Flex stent (Flexible Stent Solutions) has a helical strut bands and flex bridges that provide flexibility while maintaining longitudinal integrity. The BioMimics 3D stent (Veryan Medical) has a

Considering the success of the drug-eluting stents over the bare-metal stents in the coronary arterial disease, similar stent technology was developed for the peripheral arterial disease hoping for similar results. Several early studies failed to demonstrate clinical superiority when

387 m, p = 0.04).

treatment choice for moderate-length SFA lesions.

5. Recent development in SFA stents

helical design that may promote laminar flow.

patients with available X-rays.

clinically driven.

Table 3. Landmark trials for PAD and stenting.

the PTA group. Results revealed comparable amputation and mortality rates. No significant differences were noted in the restenosis rates (38.6% in the PTA group vs. 31.7% in the stent group) or change in clinical status between the two groups. The ankle-brachial index remained the same at 12 months [25].

The Vienna-ABSOLUTE study was the first randomized study to show superiority of primary stenting over balloon angioplasty for the treatment of moderate-length SFA lesions, 13.2 cm in the stenting group, and 12.7 in the PTA group. In this study, 104 patients were included, and patients were randomized 1:1 to a Dynalink or Absolute stent versus balloon angioplasty. The indication for treatment was claudication in the majority of cases, 88% in the stent group and 87% in the PTA group. The groups did not defer in limb salvage or mortality. The restenosis rate was greater in the PTA group (43 vs. 24%, p = 0.05). Duplex ultrasound at 12 months also demonstrated a greater restenosis rate in the PTA group (63 vs. 37%, p = 0.01). Furthermore, the maximal walking distance was significantly less in the PTA group at 6 and 12 months (267 vs. 387 m, p = 0.04) [26]. The groups did not defer in limb salvage or mortality. The restenosis rate was greater in the PTA group (43 vs. 24%, p = 0.05). Duplex ultrasound at 12 months also demonstrated a greater restenosis rate in the PTA group (63 vs. 37%, p = 0.01). Furthermore, the maximal walking distance was significantly less in the PTA group at 6 and 12 months (267 vs. 387 m, p = 0.04).

Another study that showed significant superiority of stenting versus PTA is the RESILIANT trial. A multicenter randomized controlled trial (RCT) comparing the PTA to nitinol stenting in 206 patients [27]. Indication for treatment was claudication and the lesion length was in the moderate range (7.7 cm in the stent group and 6.4 cm in the PTA group). The 6-month primary patency was worse in the PTA group when compared with primary stenting (47.4 vs. 94.2%, p = 0.0001). Patients were followed up at 12 months and results remained statistically significant in the stenting group (36.7% in the PTA group vs. 81.3% in the stenting group, p = 0.0001). Even longer term, 3-year follow-up, patients randomized to primary stent placement had significantly higher freedom from target lesion revascularization (75.5 vs. 41.8%) [28]. The earlier-mentioned studies provided strong evidence favoring the primary stenting as the treatment choice for moderate-length SFA lesions.

Based on recent registry studies, current-generation nitinol self-expanding stents have improved primary patency, with low to zero rates of stent fractures [29, 30]. The SUMMIT study was a prospective multicenter registry study of the Epic stent, which is a laser-cut nitinol selfexpanding stent [29]. At 1-year follow-up, the restenosis rate was 15.7%, with a freedom from the target lesion revascularization (TLR) rate of 92%. No stent fractures were noted on follow-up patients with available X-rays.

COMPLETE SE trial is a prospective multicenter, single-arm study that evaluated the selfexpanding stent in SFA and proximal popliteal for de novo and/or restenotic lesions in patients with symptomatic PAD [30]. At 1-year follow-up, the primary patency rate was 72.6%, with a clinically driven.

#### 5. Recent development in SFA stents

the PTA group. Results revealed comparable amputation and mortality rates. No significant differences were noted in the restenosis rates (38.6% in the PTA group vs. 31.7% in the stent group) or change in clinical status between the two groups. The ankle-brachial index remained

The Vienna-ABSOLUTE study was the first randomized study to show superiority of primary stenting over balloon angioplasty for the treatment of moderate-length SFA lesions, 13.2 cm in the stenting group, and 12.7 in the PTA group. In this study, 104 patients were included, and patients were randomized 1:1 to a Dynalink or Absolute stent versus balloon angioplasty. The indication for treatment was claudication in the majority of cases, 88% in the stent group and 87% in the PTA group. The groups did not defer in limb salvage or mortality. The restenosis rate was greater in the PTA group (43 vs. 24%, p = 0.05). Duplex ultrasound at 12 months also demonstrated a greater restenosis rate in the PTA group (63 vs. 37%, p = 0.01). Furthermore, the maximal walking distance was significantly less in the PTA group at 6 and 12 months (267 vs. 387 m, p = 0.04) [26]. The groups did not defer in limb salvage or mortality. The restenosis rate was greater in the PTA group (43 vs. 24%, p = 0.05). Duplex ultrasound at 12 months also demonstrated a greater restenosis rate in the PTA group (63 vs. 37%, p = 0.01). Furthermore, the

the same at 12 months [25].

Trial Device Sample

14 Peripheral Arterial Disease - A Practical Approach

Dynalink/Absolute vs.

Sirolimus coated vs.

Sirolimus coated vs.

Sirolimus coated vs.

PTA

SMART

SMART

SMART

Table 3. Landmark trials for PAD and stenting.

Bare metal stents

Krachenberk et al.

Drug-eluting stents SIROCCO I Duda et al. [34]

SIROCCO II Duda et al. [55]

SIROCCO Long term Duda et al. [56]

Zilver PTX Drake et al. [34]

Resiliant Laird et al. [27]

FAST

[25]

[26]

Absolute Schillinger et al. size

LifeStent versus PTA 206 71 44 BMS

Bard Luminexx vs. PTA 244 53.4 29.5

Zilver PTX vs. PTA 479 66.4 38.9

Average lesion length (mm)

64 41 PTA

127 55 PTA

88.6 BMS

76.3 46 BMS

81 52 BMS

63.2 40.5

BMS 51.1 24 PTA

104 132 71 BMS

36 82.9 DES

57 86.5 37 DES

93 85 44 DES

Primary end point Stent patency

TLR at I year 81/37, 1 year

Binary restenosis at

Binary restenosis at 6 months

In-stent luminal stenosis at 6 months

In-stent luminal stenosis at 6 months

In-stent luminal stenosis at 6 months

patency

Event free survival and

1 year

rate %

(p = 0.0001)

68/62, 1 year (p = 0.377)

75/55, 6 months (p = 0.05) 63/37, 1 year (p = 0.01)

100/77, 6 months (P = 0.10)

100/93, 6 months (p = 0.46)

77/79, 2 years (p > 0.05)

83/33, 1 year (p < 0.001) 75/27, 2 years (p < 0.01)

> Technology continues to undergo significant improvement in SFA stents with the goal to increase durability and conformability with better long-term patency. The Supera stent (Abbott Vascular) is a recently approved stent with a novel woven design that results in improved radial strength, flexibility, and resistance to fracture. The SUPERB study reported a primary patency rate of 86% in the pivotal registry [31]. Other stent designs under investigation include the Tigris stent (Gore and Associates), which has a nitinol wire frame with Extended polytetrafluoroethylene (ePTFE) coating and interconnecting ePTFE-linking regions. The SMART Flex stent (Flexible Stent Solutions) has a helical strut bands and flex bridges that provide flexibility while maintaining longitudinal integrity. The BioMimics 3D stent (Veryan Medical) has a helical design that may promote laminar flow.

> Considering the success of the drug-eluting stents over the bare-metal stents in the coronary arterial disease, similar stent technology was developed for the peripheral arterial disease hoping for similar results. Several early studies failed to demonstrate clinical superiority when

Figure 1. There is an example of retrograde approach of the SFA CTO (chronic total occlusion) intervention with PTA and two Zilver PTA self expanding drug eluting stents (pre intervention).

compared to bare-metal stents in the SFA. These early studies included both sirolimus-eluting and everolimus-eluting designs using an earlier-generation platform [32, 33].

6. Atherectomy

define the best therapy.

increase in size of more than 20 cm.

and/or stenting has shown increased benefit [35].

two Zilver PTA self expanding drug eluting stents (post intervention).

Treatment options for the PAD have significantly increased in number, but they remain limited in scope, as they are lacking substantial scientific data and large-scale randomized trials to help

Figure 2. There is an example of retrograde approach of the SFA CTO (chronic total occlusion) intervention with PTA and

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17

The majority of interventionalists use balloon expansion as a principal therapy which can or may not be followed by the stenting depending on weather the results of the angioplasty are satisfactory. This can be associated with vascular barotrauma leading to increase in incidence of restenosis and the need for re-interventions as the lesions are longer and heavily calcified. Stent use in SFA disease has shown significant improvement in vessel patency after intervention. [27, 28, 34]. However, the success rate of intervention decreases significantly as the lesions

Changing arterial compliance through debulking specifically highly calcified plaques has been shown to be of benefit. Recent data suggest that atherectomy with or without adjunctive PTA

With subsequent development of DES technology, paclitaxel-eluting stent has shown significant benefit in the SFA treatment when compared to both balloon angioplasty and placement of a bare-metal stent. The Zilver-PTX is a nitinol scaffold stent with a polymer-free coating that elutes paclitaxel [34]. In the ZILVER PTX study, patients were randomized to placement of a paclitaxel-eluting Zilver stent versus balloon angioplasty. A second arm of the study randomized patients to Zilver PTX versus bare-metal stenting in cases of failure of balloon angioplasty. At 1 year, the primary patency rate was 83% in the DES group versus 32% in the PTA group. In the second-arm randomization, 1-year primary patency with Zilver PTX was superior to the Zilver BMS (89.9% vs. 73%). These results showed significant superiority of the Zilver PTX to both angioplasty alone and the Zilver bare-metal stent (Figures 1 and 2).

Based in the above results, DES use in SFA provides significant promise for improving patency and long-term outcomes. In the years to come, further improvement in technology of the stent scaffolds and refinement of drug-eluting technology will further improve outcomes in endovascular interventions.

Interventional Strategies for the Superficial Femoral Artery http://dx.doi.org/10.5772/intechopen.76724 17

Figure 2. There is an example of retrograde approach of the SFA CTO (chronic total occlusion) intervention with PTA and two Zilver PTA self expanding drug eluting stents (post intervention).

#### 6. Atherectomy

compared to bare-metal stents in the SFA. These early studies included both sirolimus-eluting

Figure 1. There is an example of retrograde approach of the SFA CTO (chronic total occlusion) intervention with PTA and

With subsequent development of DES technology, paclitaxel-eluting stent has shown significant benefit in the SFA treatment when compared to both balloon angioplasty and placement of a bare-metal stent. The Zilver-PTX is a nitinol scaffold stent with a polymer-free coating that elutes paclitaxel [34]. In the ZILVER PTX study, patients were randomized to placement of a paclitaxel-eluting Zilver stent versus balloon angioplasty. A second arm of the study randomized patients to Zilver PTX versus bare-metal stenting in cases of failure of balloon angioplasty. At 1 year, the primary patency rate was 83% in the DES group versus 32% in the PTA group. In the second-arm randomization, 1-year primary patency with Zilver PTX was superior to the Zilver BMS (89.9% vs. 73%). These results showed significant superiority of the Zilver PTX to

Based in the above results, DES use in SFA provides significant promise for improving patency and long-term outcomes. In the years to come, further improvement in technology of the stent scaffolds and refinement of drug-eluting technology will further improve outcomes in

and everolimus-eluting designs using an earlier-generation platform [32, 33].

two Zilver PTA self expanding drug eluting stents (pre intervention).

16 Peripheral Arterial Disease - A Practical Approach

both angioplasty alone and the Zilver bare-metal stent (Figures 1 and 2).

endovascular interventions.

Treatment options for the PAD have significantly increased in number, but they remain limited in scope, as they are lacking substantial scientific data and large-scale randomized trials to help define the best therapy.

The majority of interventionalists use balloon expansion as a principal therapy which can or may not be followed by the stenting depending on weather the results of the angioplasty are satisfactory. This can be associated with vascular barotrauma leading to increase in incidence of restenosis and the need for re-interventions as the lesions are longer and heavily calcified. Stent use in SFA disease has shown significant improvement in vessel patency after intervention. [27, 28, 34]. However, the success rate of intervention decreases significantly as the lesions increase in size of more than 20 cm.

Changing arterial compliance through debulking specifically highly calcified plaques has been shown to be of benefit. Recent data suggest that atherectomy with or without adjunctive PTA and/or stenting has shown increased benefit [35].

Atherectomy devices remove plaque by physically shaving, drilling, or pulverizing by sanding the plaque resulting in modification of the vessel and its compliance. Atherectomy usually causes minimal trauma to the vessel and as such the incidence of acute complications including dissection and acute vessel occlusion may be reduced [36].

6.2. Rotational atherectomy

Coronary Lesions (COBRA) [45].

respectively [47].

6.3. Orbital atherectomy

is cleared by the reticuloendothelial system [41–43].

is not deliverable, or it cannot be properly expand [42].

Rotablator system was first used in 1988 and it is currently available as Rotablator System and consists of an elliptical, nickel-plated, brass burr which is coated with 2000–3000 microscopic diamond crystals on the leading edge, and the burr rotates at 140,000–190,000 RPM. There are several available burr sizes available ranging from 1.25 to 2.5 mm. The majority of the debris, approximately 98%, is smaller than 10 micrometer, which traverses the microvasculature and

Interventional Strategies for the Superficial Femoral Artery

http://dx.doi.org/10.5772/intechopen.76724

19

Clinical data currently lack any benefit in preventing restenosis in native and restenotic lesions. Rotational atherectomy is used to prepare a calcified lesion for stenting when a stent

In a single-center Excimer Laser, Rotablator Atherectomy, and Balloon Angioplasty study (ERBAC), a total of 685 patients were randomized to various atherectomy methods. RA had the greatest initial success, 89% in RA, 77% in Excimer laser, and 80% in balloon angioplasty. No differences were observed in major complications at the hospital and at 6 months followup. Revascularization of the original target lesion was performed more frequently in the RA group (42.4%) and the Excimer laser group (46.0%) than the angioplasty group (31.9%, p = 0.0013) [44]. Similar results were replicated in a multicenter, prospective trial of 502 patients, Comparison of Balloon Angioplasty versus Rotational Atherectomy in Complex

Pathway Jetstream PV Atherectomy system consists of a single-use catheter with control pod and a reusable console. The system is indicated for both thrombectomy and rotational atherectomy. The catheter is advanced over a 0.014<sup>00</sup> with a maximum rate of 1 mm/sec to avoid significant drops in rotational speeds; it has a front-cutting tip that makes it go through tight lesions. The electric motor spins catheters at 60–70 krpm, and for every 40 sec of treatment, a 10-sec pause is recommended. Jetstream expandable catheters 2.1/3.0 mm and 2.4/3.4 mm have a catheter tip that remains at a defined nominal diameter (2.1 or 2.4 mm) when spinning clockwise but expands to a maximum diameter when rotating counterclockwise. These sizes are recommended for larger-diameter arteries, typically above the knee.

Clinical data are not very robust for the Pathway Jetstream atherectomy device as there are only small-sized studies performed. The largest study was conducted by Zeller et al. where 172 patients were included with femoropopliteal and popliteal lesions. The success rate was excellent (99%). Patients were followed up at 1 year and the restenosis rate as per arterial duplex ultrasound was 38.2%. Target lesion revascularization at 6 and 12 months were 15 and 26%,

Orbital atherectomy is an atherectomy device used for plaque modification to reduce the total atheroma burden, to change the arterial compliance, and to decrease vessel-wall trauma [48].

During atherectomy, the device offers a continuous active aspiration [46].

Initially, atherectomy devices were used in coronary artery disease without much success when compared to the contemporary bare-metal stents. Potential complication of atherectomy is the embolization of the debris distally. Shammas NW et al. performed a small study of 40 patients. In all patient that underwent atherectomy with SilverHawk device macro-embolization occurred. The study concluded that distal embolic filter protection is very effective in capturing macro debris and that is associated with good angiographic outcome. To determine the clinical outcome more randomized controlled studies need to be performed in the future [37].

Currently, there are several atherectomy devices available including directional, rotational, orbital, and laser atheroablative.

#### 6.1. Laser atheroablative technique

Laser therapy received the FDA approval with the Laser Angioplasty for Critical Limb Ischemia (LACI) trial, where a total of 145 patients were enrolled. The diseased segments were equally distributed involving superficial femoral artery and infrapopliteal segments (41%) with 15% who had popliteal lesions. In this study, a 308-nm Excimer laser was used to ablate the plaque and thrombus, restoring the flow in diseased segments. Laser was delivered through a flexible fiberoptic catheter using short bursts of ultraviolet energy, which vaporized the plaque into small particles with minimal thermal injury in the surrounding tissues and lower chance for distal embolization [38].

In the CliRpath Excimer Laser System to Enlarge Lumen Openings (CELLO), Dave RM et al. evaluated the safety and efficacy of a modified laser catheter designed for the endovascular treatment of the PAD including the SFA and proximal popliteal artery. The study included 65 patients with intermediate claudication and stenotic lesion of more than 70% by visual assessment. Results revealed that laser ablation reduced the diameter stenosis from 77% to 34.7%. Patency rates were 59% and 54% at 6 and 12 months, respectively. There was significant functional status improvement with increased walking distance that was hemodynamically significant [39].

Laser atherectomy has shown to be effective also in patients with in-stent restenosis. Dippel EJ et al. conducted a multicenter, prospective, randomized controlled trial to assess the safety and efficacy of the Excimer laser atherectomy (ELA) in addition to PTA alone in patients who developed in-stent restenosis. The primary efficacy end point was TLR at 6 months follow-up. The primary safety end point was major adverse event (death, amputation or TLR) at 30-day post procedure. A total of 250 patient were included in the study, Rutherford class 1–4 and target lesion length was >4 cm. The lesion length was approximately 20 cm in both groups. ELA + PTA subjects demonstrated superior procedural success (93.5 vs. 82.7%; p = 0.01) with significantly fewer procedural complications and less target lesion revascularization (73.5 vs. 51.8%, p < 0.005) [40].

#### 6.2. Rotational atherectomy

Atherectomy devices remove plaque by physically shaving, drilling, or pulverizing by sanding the plaque resulting in modification of the vessel and its compliance. Atherectomy usually causes minimal trauma to the vessel and as such the incidence of acute complications includ-

Initially, atherectomy devices were used in coronary artery disease without much success when compared to the contemporary bare-metal stents. Potential complication of atherectomy is the embolization of the debris distally. Shammas NW et al. performed a small study of 40 patients. In all patient that underwent atherectomy with SilverHawk device macro-embolization occurred. The study concluded that distal embolic filter protection is very effective in capturing macro debris and that is associated with good angiographic outcome. To determine the clinical outcome

Currently, there are several atherectomy devices available including directional, rotational,

Laser therapy received the FDA approval with the Laser Angioplasty for Critical Limb Ischemia (LACI) trial, where a total of 145 patients were enrolled. The diseased segments were equally distributed involving superficial femoral artery and infrapopliteal segments (41%) with 15% who had popliteal lesions. In this study, a 308-nm Excimer laser was used to ablate the plaque and thrombus, restoring the flow in diseased segments. Laser was delivered through a flexible fiberoptic catheter using short bursts of ultraviolet energy, which vaporized the plaque into small particles with minimal thermal injury in the surrounding tissues and

In the CliRpath Excimer Laser System to Enlarge Lumen Openings (CELLO), Dave RM et al. evaluated the safety and efficacy of a modified laser catheter designed for the endovascular treatment of the PAD including the SFA and proximal popliteal artery. The study included 65 patients with intermediate claudication and stenotic lesion of more than 70% by visual assessment. Results revealed that laser ablation reduced the diameter stenosis from 77% to 34.7%. Patency rates were 59% and 54% at 6 and 12 months, respectively. There was significant functional status improvement with increased walking distance that was hemodynamically significant [39].

Laser atherectomy has shown to be effective also in patients with in-stent restenosis. Dippel EJ et al. conducted a multicenter, prospective, randomized controlled trial to assess the safety and efficacy of the Excimer laser atherectomy (ELA) in addition to PTA alone in patients who developed in-stent restenosis. The primary efficacy end point was TLR at 6 months follow-up. The primary safety end point was major adverse event (death, amputation or TLR) at 30-day post procedure. A total of 250 patient were included in the study, Rutherford class 1–4 and target lesion length was >4 cm. The lesion length was approximately 20 cm in both groups. ELA + PTA subjects demonstrated superior procedural success (93.5 vs. 82.7%; p = 0.01) with significantly fewer procedural complications and less target lesion revascularization (73.5 vs.

ing dissection and acute vessel occlusion may be reduced [36].

orbital, and laser atheroablative.

18 Peripheral Arterial Disease - A Practical Approach

6.1. Laser atheroablative technique

lower chance for distal embolization [38].

51.8%, p < 0.005) [40].

more randomized controlled studies need to be performed in the future [37].

Rotablator system was first used in 1988 and it is currently available as Rotablator System and consists of an elliptical, nickel-plated, brass burr which is coated with 2000–3000 microscopic diamond crystals on the leading edge, and the burr rotates at 140,000–190,000 RPM. There are several available burr sizes available ranging from 1.25 to 2.5 mm. The majority of the debris, approximately 98%, is smaller than 10 micrometer, which traverses the microvasculature and is cleared by the reticuloendothelial system [41–43].

Clinical data currently lack any benefit in preventing restenosis in native and restenotic lesions. Rotational atherectomy is used to prepare a calcified lesion for stenting when a stent is not deliverable, or it cannot be properly expand [42].

In a single-center Excimer Laser, Rotablator Atherectomy, and Balloon Angioplasty study (ERBAC), a total of 685 patients were randomized to various atherectomy methods. RA had the greatest initial success, 89% in RA, 77% in Excimer laser, and 80% in balloon angioplasty. No differences were observed in major complications at the hospital and at 6 months followup. Revascularization of the original target lesion was performed more frequently in the RA group (42.4%) and the Excimer laser group (46.0%) than the angioplasty group (31.9%, p = 0.0013) [44]. Similar results were replicated in a multicenter, prospective trial of 502 patients, Comparison of Balloon Angioplasty versus Rotational Atherectomy in Complex Coronary Lesions (COBRA) [45].

Pathway Jetstream PV Atherectomy system consists of a single-use catheter with control pod and a reusable console. The system is indicated for both thrombectomy and rotational atherectomy. The catheter is advanced over a 0.014<sup>00</sup> with a maximum rate of 1 mm/sec to avoid significant drops in rotational speeds; it has a front-cutting tip that makes it go through tight lesions. The electric motor spins catheters at 60–70 krpm, and for every 40 sec of treatment, a 10-sec pause is recommended. Jetstream expandable catheters 2.1/3.0 mm and 2.4/3.4 mm have a catheter tip that remains at a defined nominal diameter (2.1 or 2.4 mm) when spinning clockwise but expands to a maximum diameter when rotating counterclockwise. These sizes are recommended for larger-diameter arteries, typically above the knee. During atherectomy, the device offers a continuous active aspiration [46].

Clinical data are not very robust for the Pathway Jetstream atherectomy device as there are only small-sized studies performed. The largest study was conducted by Zeller et al. where 172 patients were included with femoropopliteal and popliteal lesions. The success rate was excellent (99%). Patients were followed up at 1 year and the restenosis rate as per arterial duplex ultrasound was 38.2%. Target lesion revascularization at 6 and 12 months were 15 and 26%, respectively [47].

#### 6.3. Orbital atherectomy

Orbital atherectomy is an atherectomy device used for plaque modification to reduce the total atheroma burden, to change the arterial compliance, and to decrease vessel-wall trauma [48].

The orbital atherectomy device has an eccentrically mounted diamond-coated crown. The crown sizes include 1.25, 1.5, 2.0, and 2.25 mm. As the crown rotates, the centrifugal forces press the crown against the calcified lesion that is less compliant, while the healthy segment complies and moves away from the device reducing the risk for complications such as perforation. The small particles are so small that distal protection is not necessary. Short and slow runs are recommended of approximately 1–10 mm/sec to increase the efficacy and reduce the number of passages. Another advantage of orbital atherectomy over other atherectomy devices is the bidirectional treatment capability [49].

OA efficacy was assessed in critical limb ischemia by Kandzari et al. where 69 patients were treated and prospectively followed for 6 months. Procedural success rate was very high (99%)

Interventional Strategies for the Superficial Femoral Artery

http://dx.doi.org/10.5772/intechopen.76724

21

In conclusion, endovascular therapy has become increasingly common in the treatment of obstructive SFA disease. With the advance in technology, PAD interventions can be performed with high success rate and relatively low clinical risk. New-generation drug-eluting stents have shown very promising results with better long-term patency. However, more random-

[1] Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: A systematic review and analysis.

[2] White C. Clinical practice. New England Journal of Medicine—Intermittent Claudication.

[3] Stoffers HE, Rinkens PE, Kester AD, Kaiser V, Knottnerus JA. The prevalence of asymptomatic and unrecognized peripheral arterial occlusive disease. International Journal of

[4] Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection,

[5] McDermott MM, Fried L, Simonsick E, Ling S, Guralnik JM. Asymptomatic peripheral arterial disease is independently associated with impaired lower extremity functioning:

[6] Dotter CT, Judkins MP. Transluminal treatment of atherosclerotic obstructions: Description of a new technique and preliminary report of its applications. Circulation. 1964;30:

[7] Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). Journal of Vascular Surgery. 2007;45(Suppl S):S5-S67

awareness, and treatment in primary care. JAMA. 2001;286:1317-1324

The women's health and aging study. Circulation. 2000;101:1007-1012

with very low rates of target lesion revascularization (4%) [54].

ized clinical trials are needed to prove the durability and safety.

Department of Cardiology, St. Joseph Mercy Oakland, Pontiac, MI, USA

Address all correspondence to: rudingjeka@gmail.com

Author details

Rudin Gjeka

References

Lancet. 2013;382:1329-1340

Epidemiology. 1996;25:282-290

2007;356:1241-1250

654-670

Clinical evidence for the orbital atherectomy use in peripheral artery disease has been shown in a serial of studies called CONFIRM registry series. A total of 3135 patient were included from over 200 centers in the Unites States from October 2009 to June 2011.

Results revealed that treatment with orbital atherectomy (OA) reduced pre-procedural stenosis from 88 12% s to an average of 10% with adjunctive treatments, such as low-pressure BA. Further analysis showed that shorter spin times and smaller crown sizes significantly reduced procedural complications, which included slow flow, embolism, and spasm [50].

Orbital atherectomy can properly treat a calcified lesion, improving lesion compliance. OA also increases the luminal gain and by doing so decreases the need for high-pressure balloon inflation as demonstrated in COMPLIANCE 360trial [51].

#### 6.4. Directional atherectomy

There are two FDA-approved directional atherectomy devices, SilverHawk and TurboHawk. Both these devices are approved for peripheral vasculature use. SilverHawk is a forwardcutting directional atherectomy device. The device consists of rotating blade inside a tubular housing with a collection area. The TurboHawk device is similar in function but has four inner blades. Both devices come in various sizes to enable atherectomy in vessels with diameters of 1.5–7 mm as the device is advanced and though the lesion plaque is excised and packed in the nosecone. These devices have the advantages to remove eccentric lesions due to the advantage of directional control. Distal embolization remains a major disadvantage and the use of distal protection is recommended, especially in large and heavily plaques.

There is significant clinical data supporting the directional atherectomy devices in peripheral artery disease. In the TALON registry, a total of 601 patients were included with complaints of claudication and acute limb ischemia. The procedural success rates were high (over 97%), and a significant decrease in requirement for stent placement was noted after atherectomy (6.3%). One-year outcomes correlated well with angioplasty and stenting with free of target lesion revascularization in the 80% range. Cautious interpretation of the results is advised as this is an observational registry [52].

A serial of prospective randomized trials were done to assess efficacy of the directional atherectomy. McKinsey et al. enrolled 275 patients with femoropopliteal disease. Nearly twothirds of patients had critical limb ischemia (63%). Limb salvage ischemia was over 90% at 1.5 year follow-up with a small percentage of patients (4.4%) requiring bypass [53].

OA efficacy was assessed in critical limb ischemia by Kandzari et al. where 69 patients were treated and prospectively followed for 6 months. Procedural success rate was very high (99%) with very low rates of target lesion revascularization (4%) [54].

In conclusion, endovascular therapy has become increasingly common in the treatment of obstructive SFA disease. With the advance in technology, PAD interventions can be performed with high success rate and relatively low clinical risk. New-generation drug-eluting stents have shown very promising results with better long-term patency. However, more randomized clinical trials are needed to prove the durability and safety.

#### Author details

Rudin Gjeka

The orbital atherectomy device has an eccentrically mounted diamond-coated crown. The crown sizes include 1.25, 1.5, 2.0, and 2.25 mm. As the crown rotates, the centrifugal forces press the crown against the calcified lesion that is less compliant, while the healthy segment complies and moves away from the device reducing the risk for complications such as perforation. The small particles are so small that distal protection is not necessary. Short and slow runs are recommended of approximately 1–10 mm/sec to increase the efficacy and reduce the number of passages. Another advantage of orbital atherectomy over other atherectomy

Clinical evidence for the orbital atherectomy use in peripheral artery disease has been shown in a serial of studies called CONFIRM registry series. A total of 3135 patient were included

Results revealed that treatment with orbital atherectomy (OA) reduced pre-procedural stenosis from 88 12% s to an average of 10% with adjunctive treatments, such as low-pressure BA. Further analysis showed that shorter spin times and smaller crown sizes significantly reduced

Orbital atherectomy can properly treat a calcified lesion, improving lesion compliance. OA also increases the luminal gain and by doing so decreases the need for high-pressure balloon

There are two FDA-approved directional atherectomy devices, SilverHawk and TurboHawk. Both these devices are approved for peripheral vasculature use. SilverHawk is a forwardcutting directional atherectomy device. The device consists of rotating blade inside a tubular housing with a collection area. The TurboHawk device is similar in function but has four inner blades. Both devices come in various sizes to enable atherectomy in vessels with diameters of 1.5–7 mm as the device is advanced and though the lesion plaque is excised and packed in the nosecone. These devices have the advantages to remove eccentric lesions due to the advantage of directional control. Distal embolization remains a major disadvantage and the use of distal

There is significant clinical data supporting the directional atherectomy devices in peripheral artery disease. In the TALON registry, a total of 601 patients were included with complaints of claudication and acute limb ischemia. The procedural success rates were high (over 97%), and a significant decrease in requirement for stent placement was noted after atherectomy (6.3%). One-year outcomes correlated well with angioplasty and stenting with free of target lesion revascularization in the 80% range. Cautious interpretation of the results is advised as this is

A serial of prospective randomized trials were done to assess efficacy of the directional atherectomy. McKinsey et al. enrolled 275 patients with femoropopliteal disease. Nearly twothirds of patients had critical limb ischemia (63%). Limb salvage ischemia was over 90% at 1.5-

year follow-up with a small percentage of patients (4.4%) requiring bypass [53].

from over 200 centers in the Unites States from October 2009 to June 2011.

procedural complications, which included slow flow, embolism, and spasm [50].

devices is the bidirectional treatment capability [49].

20 Peripheral Arterial Disease - A Practical Approach

inflation as demonstrated in COMPLIANCE 360trial [51].

protection is recommended, especially in large and heavily plaques.

6.4. Directional atherectomy

an observational registry [52].

Address all correspondence to: rudingjeka@gmail.com

Department of Cardiology, St. Joseph Mercy Oakland, Pontiac, MI, USA

#### References


[8] Rutherford RB, Baker JD, Johnston KW, Porter JM, et al. Recommended standarts for reports dealing with lower extremity ischemia: Revised version. Journal of Vascular Surgery. 1997;26:517-538

[21] Gunnar T, John L, Peter S, Marianne B, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and/or popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial.

Interventional Strategies for the Superficial Femoral Artery

http://dx.doi.org/10.5772/intechopen.76724

23

[22] Marianne B, Koen K, Dierk S, et al. Drug-coated balloon treatment for Femoropopliteal artery disease: The IN.PACT global study De novo in-stent restenosis imaging cohort.

[23] Grimm J, Müller-Hülsbeck S, Jahnke T, Hilbert C, Brossmann J, et al. Randomized study to compare PTA alone versus PTA with Palmaz stent placement for femoropopliteal lesions.

[24] Muradin GS, Bosch JL, Stijnen T, Hunink MG. Balloon dilation and stent implantation for treatment of femoropopliteal arterial disease: Meta-analysis. Radiology. 2001;221:137-145

[25] Krankenberg H, Schlüter M, Steinkamp HJ, Bürgelin K, Scheinert D, et al. Nitinol stent implantation versus percutaneous transluminal angioplasty in superficial femoral artery lesions up to 10 cm in length: The femoral artery stenting trial (FAST). Circulation. 2007;

[26] Schillinger M, Sabeti S, Loewe C, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. The New England Journal of Medicine. 2006;354:

[27] Laird JR, Katzen BT, Scheinert D, et al. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: Twelve-month results from the RESILIENT randomized trial. Circulation: Cardiovascular Interventions.

[28] Laird JR, Katzen BT, Scheinert D, et al. Nitinol stent implantation vs balloon angioplasty for lesions in the superficial femoral and proximal popliteal arteries of patients with claudication: Three-year follow-up from the RESILIENT randomized trial. Journal of

[29] Werner M, Piorkowski M, Thieme M, et al. SUMMIT registry: One-year outcomes after implantation of the EPIC self-expanding nitinol stent in the femoropopliteal segment.

[30] Laird JR, Jain A, Zeller T, et al. Nitinol stent implantation in the superficial femoral artery and proximal popliteal artery: Twelve-month results from the complete SE multicenter

[31] Supera Periperal Stent System. Available at http://www.abbottvascular.com/static/cms\_ workspace/pdf/ifu/peripheral\_intervention/eIFU\_Supera.pdf [Accessed: September 23, 2014]

[32] Duda SH, Bosiers M, Lammer J, et al. Drug-eluting and bare nitinol stents for the treatment of atherosclerotic lesions in the superficial femoral artery: Long-term results from

the SIROCCO trial. Journal of Endovascular Therapy. 2006;13:701-710

Circulation. 2018 Feb 3;131(5):495-502

116:285-292

1879-1888

2010;3:267-276

Endovascular Therapy. 2012;19:1-9

Journal of Endovascular Therapy. 2013;20:759-766

trial. Journal of Endovascular Therapy. 2014;21:202-212

JACC: Cardiovascular Interventions. 2017;10(20):2113-2123

Journal of Vascular and Interventional Radiology. 2001;12:935-942


[21] Gunnar T, John L, Peter S, Marianne B, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and/or popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation. 2018 Feb 3;131(5):495-502

[8] Rutherford RB, Baker JD, Johnston KW, Porter JM, et al. Recommended standarts for reports dealing with lower extremity ischemia: Revised version. Journal of Vascular Sur-

[9] Marcus AJ, Lotzof K, Howard A. Access to the superficial femoral artery in the presence of a "hostile groin": A prospective study. Cardiovascular and Interventional Radiology.

[10] Grier D, Hartnell G. Percutaneous femoral artery puncture: Practice and anatomy. The

[11] Louvard Y, Lefèvre T, Allain A, Morice M. Coronary angiography through the radial or the femoral approach: The CARAFE study. Catheterization and Cardiovascular Interven-

[12] Lechner G, Jantsch H, Waneck R, Kretschmer G. The relationship between the common femoral artery, the inguinal crease, and the inguinal ligament: A guide to accurate angiographic puncture. Cardiovascular and Interventional Radiology. 1988;11(3):165-169

[13] Jin Wook C, Deuk Young N, Jun Ho B. Percutaneous transluminal angioplasty of contralateral iliac and superficial femoral arteries via graft vessel in a patient with

[14] Boufi M, Dona B, Orsini B, Auquier P, Hartung O, et al. A comparison of the standard bolia technique versus subintimal recanalization plus Viabahn stent graft in the management of femoro-popliteal occlusions. Journal of Vascular Surgery. 2010;52:1211-1217

[15] Markose G, Miller FN, Bolia A. Subintimal angioplasty for femoro-popliteal occlusive

[16] London NJ, Srinivasan R, Naylor AR, Hartshorne T, Ratliff DA, et al. Subintimal angioplasty of femoropopliteal artery occlusions: The long-term results. European Journal of

[17] A review of superficial femoral arter angioplasty and stenting Rami O Tadros\*, Ageliki G Vouyouka, Windsor Ting, Victoria Teodorescu, Sung Yup Kim, Michael L Marin, Peter L

[18] Shehab M, Michalis LK, Rees MR. Balloon angioplasty optimization: Should we measure balloon volume as well as pressure? Cardiovascular and Interventional Radiology. 2008;

[19] Niels Z, Christoph M, Markus L, et al. Peripheral arterial balloon angioplasty: Effect of short versus long balloon inflation times on the morphologic results. Journal of Vascular

[20] Cotroneo AR, Pascali D, Iezzi R. Cutting balloon versus conventional balloon angioplasty in short femoropopliteal arterial stenoses. Journal of Endovascular Therapy. 2008;15:

FemoroFemoral bypass graft. Korean Circulation Journal. 2013 Apr;43(4):265-268

gery. 1997;26:517-538

22 Peripheral Arterial Disease - A Practical Approach

2007;30(3):351-354

tions. 2001;52(2):181-187

British Journal of Radiology. 1990;63(752):602-604

disease. Journal of Vascular Surgery. 2010;52:1410-1416

and Intervention Radiology. April 2002;13(4):355-359

Vascular Surgery. 1994;8:148-155

Faries ISSN: 2329-6925

31(1):149-157


[33] Lammer J, Bosiers M, Zeller T, et al. First clinical trial of nitinol self-expanding everolimuseluting stent implantation for peripheral arterial occlusive disease. Journal of Vascular Surgery. 2011;54:394-401

[46] Zeller T, Krankenberg H, Rastan A, et al. Percutaneous rotational and aspiration atherectomy in infrainguinal peripheral arterial occlusive disease: A multicenter pilot

Interventional Strategies for the Superficial Femoral Artery

http://dx.doi.org/10.5772/intechopen.76724

25

[47] Hassan AH, Ako J, Waseda K, et al. Mechanism of lumen gain with a novel rotational aspiration atherectomy system for peripheral arterial disease: Examination by intravascu-

[48] Staniloae CS, Korabathina R. Orbital atherectomy: Device evolution and clinical data. The

[49] Chambers JW, Diage T. Evaluation of the diamondback 360 coronary orbital atherectomy system for treating de novo, severely calcified lesions. Expert Review of Medical Devices.

[50] Das T, Mustapha J, Indes J, et al. Technique optimization of orbital atherectomy in calcifed peripheral lesions of the lower extremities: The CONFIRM series, a prospective multicen-

[51] Dattilo R, Himmelstein SI, Cuff RF. The COMPLIANCE 360 trial: A randomized, prospective, multicenter, pilot study comparing acute and long-term results of orbital Atherectomy to balloon angioplasty for Calcifed Femoropopliteal disease. The Journal of Invasive Cardi-

[52] Ramaiah V, Gammon R, Kiesz S, et al. Midterm outcomes from the TALON registry: Treating peripherals with SilverHawk: Outcomes collection. Journal of Endovascular

[53] McKinsey JF, Goldstein L, Khan HU, et al. Novel treatment of patients with lower extremity ischemia: Use of percutaneous atherectomy in 579 lesions. Annals of Surgery. 2008;

[54] Kandzari DE, Kiesz RS, Allie D, et al. Procedural and clinical outcomes with catheterbased plaque excision in critical limb ischemia. Journal of Endovascular Therapy. 2006;13:

[55] Duda SH, Pusich B, Richter G, et al. Sirolimus-eluting stents for the treatment of obstructive superficial femoral artery disease: Six-month results. Circulation. 2002;106:1505-1509

[56] Duda SH, Bosiers M, Lammer J, et al. Sirolimus-eluting versus bare nitinol stent for obstructive superficial femoral artery disease: The SIROCCO II trial. Journal of Vascular

ter registry. Catheterization and Cardiovascular Interventions. 2014;83(1):115-122

lar ultrasound. Cardiovascular Revascularization Medicine. 2010;11(3):155-158

study. Journal of Endovascular Therapy. 2007;14(3):357-364

Journal of Invasive Cardiology. 2014;26(5):215-219

2014;11:457-466

ology. 2014;26(8):355-360

Therapy. 2006;13:592-602

and Interventional Radiology;16:331-338

248(4):519-528


[46] Zeller T, Krankenberg H, Rastan A, et al. Percutaneous rotational and aspiration atherectomy in infrainguinal peripheral arterial occlusive disease: A multicenter pilot study. Journal of Endovascular Therapy. 2007;14(3):357-364

[33] Lammer J, Bosiers M, Zeller T, et al. First clinical trial of nitinol self-expanding everolimuseluting stent implantation for peripheral arterial occlusive disease. Journal of Vascular

[34] Dake MD, Ansel GM, Jaff MR, et al. Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease: Twelve-month Zilver PTX randomized study results. Circulation: Cardiovascular Interventions. 2011;4:495-504 [35] Shammas NW, Lam R, Mustapha J, et al. Comparison of orbital atherectomy plus balloon angioplasty vs. balloon angioplasty alone in patients with critical limb ischemia: Results of the CALCIUM 360 randomized pilot trial. Journal of Endovascular Therapy. 2012;19(4):

[36] Ahn SS, Concepcion B. Current status of atherectomy for peripheral arterial occlusive

[37] Shammas NW, Dippel EJ, Coiner D, Shammas GA, Jerin M, Kumar A. Preventing lower extremity distal embolization using embolic filter protection: Results of the PROTECT

[38] Laird JR, Zeller T, Gray BH, et al. Limb salvage following laser-assisted angioplasty for critical limb ischemia: Results of the LACI multicenter trial. Journal of Endovascular

[39] Dave RM, Patlola R, Kollmeyer K, Bunch F, Weinstock BS, Dippel E, Jaff MR, Popma J, Weissman N. Excimer laser recanalization of femoropopliteal lesions and 1-year patency: Results of the CELLO registry. Journal of Endovascular Therapy. 2009;16(6):665-675 [40] Dippel EJ, Makam P, Kovach R, George JC, et al. Randomized controlled study of excimer laser atherectomy for treatment of femoropopliteal in-stent restenosis: Initial results from the EXCITE ISR trial (EXCImer laser randomized controlled study for treatment of FemoropopliTEal in-stent restenosis). JACC. Cardiovascular Interventions. 2015:92-101

[41] Spencer B, Yeung AC. Rotational Atherectomy: Concepts and practice. In: Interventional

[42] Tran T, Brown M, Lasala J. An evidence-based approach to the use of rotational and directional coronary atherectomy in the era of drug-eluting stents: When does it make

[43] Tomey MI, Kini AS, Sharma SK. Current status of rotational atherectomy. JACC. Cardio-

[44] Rinfart N, Vandormeal M, Krajcar M, et al. Randomized comparison of angioplasty of complex coronary lesions at a single center. Excimer laser, rotational Atherectomy, and

[45] Dill T, Dietz U, Hamm CW, et al. A randomized comparison of balloon angioplasty versus rotational atherectomy in complex coronary lesions (COBRA study). European Heart

sense? Catheterization and Cardiovascular Interventions. 2008;72(5):650-662

balloon angioplasty comparison (ERBAC) study. Circulation. 1997;96:91-98

disease. World Journal of Surgery. 1996;20(6):635-643

registry. Journal of Endovascular Therapy. 2008;15(3):270-276

Cardiology. New York: McGraw-Hill; 2007. pp. 333-347

vascular Interventions. 2014;7(4):345-353

Journal. 2000;21:1759-1766

Surgery. 2011;54:394-401

24 Peripheral Arterial Disease - A Practical Approach

Therapy. 2006;13(1):1-11


**Chapter 3**

**Provisional chapter**

**Percutaneous Reconstruction Techniques: Popliteal**

Peripheral artery disease (PAD) is one of the most common diseases affecting quality of life. Claudication is the most frequent sign. If left untreated, PAD may cause serious daily life disturbances and may cause extremity losses, especially in elderly and diabetic patients. Restoration of blood flow from the aorta to the femoral arteries and from the femoral arteries to the popliteal arteries necessitates complex operational procedures. Most of these patients have concomitant coronary diseases. In such patients, open surgical repair with vascular grafts by the aid of general anesthesia increases both mortality and morbidity. Although femoral arteries are the most common site for PAD, iliac impairment is not so rare. In patients with combined iliac and femoral artery diseases, popliteal artery approach is a safe and effective technique for percutaneous revascularization. In this chapter, we share our experience with interventional percutaneous revascularization through popliteal approach, mainly using drug eluting balloons and stents, by the aid of mechanical thrombectomy devices with the highlights of current literature review. **Keywords:** peripheral artery disease, popliteal artery approach, stenting, balloon

PAD is third most common cause of cardiovascular mortality and mortality worldwide, following coronary artery disease and stroke [1]. Although the exact number of patients suffering from PAD is unknown, it is commonly agreed that there is a global increase in the amount of patients mainly by increased age and life expectancy of the populations, mainly

**Percutaneous Reconstruction Techniques: Popliteal** 

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.78045

**Artery Approach for Chronic Total Occlusion of**

**Artery Approach for Chronic Total Occlusion of** 

**Superficial Femoral and Iliac Arteries**

angioplasty, mechanical atherectomy, total occlusion

**Superficial Femoral and Iliac Arteries**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.78045

Omer Tanyeli

**Abstract**

**1. Introduction**

Omer Tanyeli

#### **Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion of Superficial Femoral and Iliac Arteries Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion of Superficial Femoral and Iliac Arteries**

DOI: 10.5772/intechopen.78045

Omer Tanyeli Omer Tanyeli

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.78045

#### **Abstract**

Peripheral artery disease (PAD) is one of the most common diseases affecting quality of life. Claudication is the most frequent sign. If left untreated, PAD may cause serious daily life disturbances and may cause extremity losses, especially in elderly and diabetic patients. Restoration of blood flow from the aorta to the femoral arteries and from the femoral arteries to the popliteal arteries necessitates complex operational procedures. Most of these patients have concomitant coronary diseases. In such patients, open surgical repair with vascular grafts by the aid of general anesthesia increases both mortality and morbidity. Although femoral arteries are the most common site for PAD, iliac impairment is not so rare. In patients with combined iliac and femoral artery diseases, popliteal artery approach is a safe and effective technique for percutaneous revascularization. In this chapter, we share our experience with interventional percutaneous revascularization through popliteal approach, mainly using drug eluting balloons and stents, by the aid of mechanical thrombectomy devices with the highlights of current literature review.

**Keywords:** peripheral artery disease, popliteal artery approach, stenting, balloon angioplasty, mechanical atherectomy, total occlusion

#### **1. Introduction**

PAD is third most common cause of cardiovascular mortality and mortality worldwide, following coronary artery disease and stroke [1]. Although the exact number of patients suffering from PAD is unknown, it is commonly agreed that there is a global increase in the amount of patients mainly by increased age and life expectancy of the populations, mainly

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

in underdeveloped countries. Fowkes et al. reported that there were 202 million people estimated to suffer from PAD, with a stronger change in the prevalence of low- and middleincome countries [1].

according to gender, associated disease, especially diabetes mellitus (DM) and the age group. Motsumi et al. reported that diabetic patients have severe occlusive disease involving the tibioperoneal segment [5]. Diabetic patients also have diffuse nature of PAD. Patients with DM, hypertension, dyslipidemia and smoking habits have significant occlusive disease of the femoropopliteal arterial segment. Smoking obviously increases the severity of arterial occlusive disease in the femoropopliteal segment or more proximal arterial segments. Diehm et al. reported that smoking had a higher relative risk ratio for severe involvement of the aortoiliac segment [6]. Interestingly, aortoiliac involvement in female diabetic patients was uncommon, irrespective of risk factor grouping and they had relative sparing of the arterial foot arch

Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion…

http://dx.doi.org/10.5772/intechopen.78045

29

When the frequency of the involved arterial segment in PAD was analyzed, researchers found that femoropopliteal location was the most common [6–8]. The involvement of femoropopliteal arterial segment varied between 47.3% and 77% in these studies. On the contrary, there are also a few studies reporting different results, mainly in the younger age groups. A study mainly focused on relatively younger age groups (<50 years) with early-onset PAD demonstrated that these patients had 65% aortoiliac disease [9]. In another study, common femoral arteries (CFA) were more commonly affected than the distal arterial segment (57.6% and 42.9%, respectively) [10]. In this study, older age, male sex, diabetes, heart failure and critical limb ischemia were more significantly associated with distal disease, whereas female sex, smoking, hypertension, dyslipidemia, coronary heart disease, cerebrovascular disease and chronic obstructive pulmonary disease were more significantly associated with proximal

PAD resulting from atherosclerosis is a multisegmental disease in about two-thirds of symptomatic patients [11]. About 25–50% of patients have stenoses and/or occlusions in two or more segments [7, 12]. Knowing the fact that multisegmental disease affects about one in every 2–4 patients, determining the access site before any interventional procedure is very

Patients with PAD may have different symptoms depending on the anatomical location of the diseased arterial segments, onset of disease (acute or chronic) or presence/absence of the collateral circulation. Since the disease is progressive in nature, the patients may remain asymptomatic for years until the luminal obstruction is >50%. During this period, patients may have IC in strenuous exercise or may remain completely asymptomatic as stated earlier. As the disease progresses, and the luminal obstruction is >50%, patients may have progressively worsening IC, and the walking distance becomes to decrease. In following years, if the patient is left untreated symptoms intensify to rest pain, arterial ulceration, tissue loss or amputation.

There is a significant correlation between the severity of limb ischemia and the distribution of PAD. IC is usually associated with proximal lesions, and critical limb ischemia is associated with crural involvement. Proximal aortoiliac disease may cause thigh, hip, or buttock pain while walking and they are usually preceded by calf pain. Distal tibial or peroneal obstructions may result in ankle or foot pain while walking [13]. PAD patients with more severe and

**2.2. Characteristics of Iliofemoral peripheral artery disease**

limb-threatening ischemia usually have multisegment involvement.

compared to their male counterparts [5].

disease.

important.

Elderly patients with diabetes mellitus and smoking habits are under great risk for PAD. Hyperlipidemia or hypertension is less likely to be the predisposing factors for the development of PAD.

Intermittent claudication (IC) is the most common symptom factor affecting quality of life. In order to improve walking distance, and prevent extremity losses, a wide variety of treatment strategies are offered including lifestyle changes, medical therapy, supervised exercise therapy, interventional procedures and surgical revascularization.

Ever since Seldinger discovered the needle-in, wire-in, needle-out, catheter in, interventional radiologists and cardiologists gained a favorable expertise not only in diagnosis of cardiovascular diseases, but also for treatment of vascular lesions. Over the past decade, with improvement of diagnostic procedures, catheter-based treatment strategies also increased and now almost became the first-line treatment strategy in almost all vascular diseases, mainly being performed by new generation qualified vascular surgeons and interventionists. Balloon angioplasty or stenting for a stenotic segment of the superficial femoral artery (SFA) became a routine process and endovascular procedures for complex chronic total occlusions (CTO) are more commonly being treated with interventional procedures using mechanical thrombectomy/atherectomy devices, which put the common surgical revascularization techniques in second order. In this chapter, we aimed to discuss the treatment of iliofemoral PAD, using combined endovascular treatment strategies, mainly focusing on the retrograde popliteal artery (PA) approach.

#### **2. Peripheral artery disease**

On the basis of anatomical and functional considerations, lower extremity occlusive PAD can be defined as atherosclerotic arterial disease and arterial narrowing, causing a mismatch between the blood supply and demand. Whatever is the cause, this mismatch results in symptoms including IC, exercise limitations, rest pain or tissue loss. These two definitions help divide the PAD patients into asymptomatic or symptomatic disease states [2]. About 10% of men at the age of 65 years are affected by atherosclerotic PAD. This ratio increases to 20% in men and women ≥75 years [3]. Besides its common nature, most of the patients remain asymptomatic and the disease is underdiagnosed. For every symptomatic patient with PAD, up to six patients are asymptomatic and miss the diagnosis. In a study of patients with PAD including 60-year-old men and women, Schroll et al. found that only 19% of patients were symptomatic [4].

#### **2.1. The frequency of PAD location**

Determining the location of PAD is crucial for decision-making and planning the treatment. The PAD may be classified according to the location of the involved arterial segment as aortoiliac, femoropopliteal and tibioperoneal segment. Location of PAD segment may vary according to gender, associated disease, especially diabetes mellitus (DM) and the age group. Motsumi et al. reported that diabetic patients have severe occlusive disease involving the tibioperoneal segment [5]. Diabetic patients also have diffuse nature of PAD. Patients with DM, hypertension, dyslipidemia and smoking habits have significant occlusive disease of the femoropopliteal arterial segment. Smoking obviously increases the severity of arterial occlusive disease in the femoropopliteal segment or more proximal arterial segments. Diehm et al. reported that smoking had a higher relative risk ratio for severe involvement of the aortoiliac segment [6]. Interestingly, aortoiliac involvement in female diabetic patients was uncommon, irrespective of risk factor grouping and they had relative sparing of the arterial foot arch compared to their male counterparts [5].

When the frequency of the involved arterial segment in PAD was analyzed, researchers found that femoropopliteal location was the most common [6–8]. The involvement of femoropopliteal arterial segment varied between 47.3% and 77% in these studies. On the contrary, there are also a few studies reporting different results, mainly in the younger age groups. A study mainly focused on relatively younger age groups (<50 years) with early-onset PAD demonstrated that these patients had 65% aortoiliac disease [9]. In another study, common femoral arteries (CFA) were more commonly affected than the distal arterial segment (57.6% and 42.9%, respectively) [10]. In this study, older age, male sex, diabetes, heart failure and critical limb ischemia were more significantly associated with distal disease, whereas female sex, smoking, hypertension, dyslipidemia, coronary heart disease, cerebrovascular disease and chronic obstructive pulmonary disease were more significantly associated with proximal disease.

PAD resulting from atherosclerosis is a multisegmental disease in about two-thirds of symptomatic patients [11]. About 25–50% of patients have stenoses and/or occlusions in two or more segments [7, 12]. Knowing the fact that multisegmental disease affects about one in every 2–4 patients, determining the access site before any interventional procedure is very important.

#### **2.2. Characteristics of Iliofemoral peripheral artery disease**

in underdeveloped countries. Fowkes et al. reported that there were 202 million people estimated to suffer from PAD, with a stronger change in the prevalence of low- and middle-

Elderly patients with diabetes mellitus and smoking habits are under great risk for PAD. Hyperlipidemia or hypertension is less likely to be the predisposing factors for the develop-

Intermittent claudication (IC) is the most common symptom factor affecting quality of life. In order to improve walking distance, and prevent extremity losses, a wide variety of treatment strategies are offered including lifestyle changes, medical therapy, supervised exercise

Ever since Seldinger discovered the needle-in, wire-in, needle-out, catheter in, interventional radiologists and cardiologists gained a favorable expertise not only in diagnosis of cardiovascular diseases, but also for treatment of vascular lesions. Over the past decade, with improvement of diagnostic procedures, catheter-based treatment strategies also increased and now almost became the first-line treatment strategy in almost all vascular diseases, mainly being performed by new generation qualified vascular surgeons and interventionists. Balloon angioplasty or stenting for a stenotic segment of the superficial femoral artery (SFA) became a routine process and endovascular procedures for complex chronic total occlusions (CTO) are more commonly being treated with interventional procedures using mechanical thrombectomy/atherectomy devices, which put the common surgical revascularization techniques in second order. In this chapter, we aimed to discuss the treatment of iliofemoral PAD, using combined endovascular treatment strategies, mainly focusing on the retrograde popliteal

On the basis of anatomical and functional considerations, lower extremity occlusive PAD can be defined as atherosclerotic arterial disease and arterial narrowing, causing a mismatch between the blood supply and demand. Whatever is the cause, this mismatch results in symptoms including IC, exercise limitations, rest pain or tissue loss. These two definitions help divide the PAD patients into asymptomatic or symptomatic disease states [2]. About 10% of men at the age of 65 years are affected by atherosclerotic PAD. This ratio increases to 20% in men and women ≥75 years [3]. Besides its common nature, most of the patients remain asymptomatic and the disease is underdiagnosed. For every symptomatic patient with PAD, up to six patients are asymptomatic and miss the diagnosis. In a study of patients with PAD including 60-year-old men and women, Schroll et al. found that only 19% of patients were

Determining the location of PAD is crucial for decision-making and planning the treatment. The PAD may be classified according to the location of the involved arterial segment as aortoiliac, femoropopliteal and tibioperoneal segment. Location of PAD segment may vary

therapy, interventional procedures and surgical revascularization.

income countries [1].

28 Peripheral Arterial Disease - A Practical Approach

artery (PA) approach.

symptomatic [4].

**2. Peripheral artery disease**

**2.1. The frequency of PAD location**

ment of PAD.

Patients with PAD may have different symptoms depending on the anatomical location of the diseased arterial segments, onset of disease (acute or chronic) or presence/absence of the collateral circulation. Since the disease is progressive in nature, the patients may remain asymptomatic for years until the luminal obstruction is >50%. During this period, patients may have IC in strenuous exercise or may remain completely asymptomatic as stated earlier. As the disease progresses, and the luminal obstruction is >50%, patients may have progressively worsening IC, and the walking distance becomes to decrease. In following years, if the patient is left untreated symptoms intensify to rest pain, arterial ulceration, tissue loss or amputation.

There is a significant correlation between the severity of limb ischemia and the distribution of PAD. IC is usually associated with proximal lesions, and critical limb ischemia is associated with crural involvement. Proximal aortoiliac disease may cause thigh, hip, or buttock pain while walking and they are usually preceded by calf pain. Distal tibial or peroneal obstructions may result in ankle or foot pain while walking [13]. PAD patients with more severe and limb-threatening ischemia usually have multisegment involvement.

Patients with distal disease had poorer prognosis compared with patients without distal disease, independent of age, sex, comorbid conditions, medication (lipid-lowering and aspirin) use and resting ankle-brachial index (ABI), whereas patients with proximal disease showed no difference in prognosis after similar adjustment compared with patients without proximal disease. These findings suggest PAD is complex and heterogeneous and not a uniform entity [10].

exercise is considered diagnostic for PAD. Climbing stairs, walking in the highway or 6-min walking test can also be performed not only for differentiation of claudication from pseudoclaudication, but also objectively assess the limitations of the patients and help to prescribe patient specific exercise programs. They are also important for patient follow-ups and disease

Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion…

http://dx.doi.org/10.5772/intechopen.78045

31

Pulse volume recordings and Doppler waveform techniques are other techniques that can provide accurate information even in patients with noncompressible vessels. The normal waveform is triphasic. Loss of triphasic pattern and analysis of the peak velocity can localize the area of stenosis. They may be used to establish the initial diagnosis, assess the location and severity of PAD as well as follow-up of patients after any revascularization procedures [17].

Although they are not the first diagnostic test of choice in diagnosis of PAD, computed tomography angiography (CTA), magnetic resonance angiography (MRA) and digital subtraction angiography (DSA) are the other techniques that allow direct visualization of the vasculature

CTA may be used with either intra-venous or intra-arterial contrast agents. The sensitivities and specificities are >95% for identifying stenosis >50% and for correctly identifying occlusions [22]. CTA produces images of vascular structures in cross-sectional slices that can be reformatted into three-dimensional angiographic-like images. CTA not only shows the intraluminal space, but also shows the surrounding tissue. For this reason, it visualizes calcification well, which is advantageous when considering revascularization strategies [23]. The main disadvantage is radiation exposure and the use of large volumes of iodinated contrast media, which limits its use in acute renal failure patients or patients with borderline renal function.

MRA is a useful diagnostic method in determining the location and stenosis severity in PAD patients. MRA may identify outflow vessels which may not be visualized by conventional angiography [24]. MRA has a high sensitivity and specificity for detecting acute occlusive disease when compared with DSA [25]. It is very useful for preoperative evaluation of the PAD patient in order to make a road-map, whether surgical or endovascular revasculariza-

MRA may also be used for postoperative follow-up of patients. A meta-analysis comparing MRA with catheter angiography demonstrated that sensitivity and specificity of MRA for detection of stenoses >50% were both in the range of 90–100% [26]. The main limitation of MRA is that it tends to overestimate the degree of stenosis because of turbulence; it cannot scan patients with pacemakers or defibrillators; metal stents or clips can obscure vascular flow; and use of gadolinium rarely may cause renal toxicity and nephrogenic systemic fibrosis

In our daily practice, there are some patients who are planned for endovascular interventions for critical stenoses, but not critically stenotic by DSA. Also, patients with previous stent in iliac/SFAs may also be misdiagnosed as occluded by MRA; that is why each patient needs a careful physical examination before MRA including comparative ABI. Duplex ultrasound

Contrast angiography provides detailed information about the vasculature, including minor collateral vessels, run-off and the flow speed, and is recommended as 'gold standard' method

tion. **Figure 1** shows MRA of two different patients showing total occlusion of SFA.

progress [21].

in PAD patients.

in patients with elevated creatinine [17].

scanning (DUS) may also give supportive data in these patients.

The mortality for asymptomatic PAD is similar to that of mild to moderately symptomatic patients. Besides its beneficial effect on diagnosis of the disease, ankle-brachial index is also shown to correlate with the overall mortality of the disease [14]. The majority of these patients die of vascular causes such as cardiac, cerebrovascular, or other vascular diseases. The main reason for morbidity or mortality is either myocardial infarction or stroke. All-cause mortality is approximately 30% at 5 years, 50% at 10 years and 70% at 15 years [15]. In a population study, large-vessel involvement in PAD patients was significantly predictive of all-cause mortality in both genders with a relative risk of 4–5, independent of other cardiovascular risk factors. Isolated small-vessel PAD was unrelated to mortality. In that study, large-vessel PAD involved all arteries above the level of ankle [16]. Ogt et al. also found that the relative risk of mortality was elevated from 2- to 7-fold in men and women with multi- and unisegmental disease involving the aortoiliac and femoropopliteal segments. In the same study, the presence of tibioperoneal disease did not significantly increase mortality [8].

#### **2.3. Diagnosis of iliofemoral peripheral artery disease**

Depending on basic medical rules, the initial evaluation should include a careful history and physical examination. Knowing the fact that almost half of patients with PAD remain asymptomatic, suspicion of PAD for a clinician is very important. Shoes and socks should be removed for assessment of distal perfusion. Any signs of peripheral ischemia, peripheral pulses, skin color, toe nails, hair loss and trophic skin changes should be noted. Every sign of physical examination should be compared to the contralateral extremity. Abdomen should also be palpated for any potential abdominal aortic aneurysm. The blood pressure should be measured in both arms.

Upon suspicion and physical examination findings, referral to the vascular laboratory should be the initial step. The diagnostic tests should start by noninvasive methods. These noninvasive tests are also important for the follow-up of patients or disease progress.

The ABI is the single best initial screening test to perform in a patient suspected for PAD. A ratio of <0.90 is considered abnormal, with mild obstruction defined as a ratio of 0.71–0.90, moderate as 0.41–0.70 and severe when the ABI is <0.40. The higher arm blood pressure is used for the ABI ratio calculation [17]. The overall accuracy of the ABI to establish the diagnosis of lower extremity PAD has been validated with a sensitivity of 79–95% and a specificity of 96–100%, based on different studies [18, 19]. It is a reproducible technique, cheap and can also be used for screening and initial evaluation of target population, as well as assessment of disease progression. In patients with noncompressible arteries due to medial calcification such as elderly, diabetes and end-stage renal disease, toe-brachial index calculation may be helpful and values <0.7 are considered diagnostic for lower extremity PAD [20].

Treadmill exercise testing can be helpful, especially in patients with normal ABI during resting, such as in patients with isolated iliac artery stenosis. A decrease in ABI of 15–20% with exercise is considered diagnostic for PAD. Climbing stairs, walking in the highway or 6-min walking test can also be performed not only for differentiation of claudication from pseudoclaudication, but also objectively assess the limitations of the patients and help to prescribe patient specific exercise programs. They are also important for patient follow-ups and disease progress [21].

Patients with distal disease had poorer prognosis compared with patients without distal disease, independent of age, sex, comorbid conditions, medication (lipid-lowering and aspirin) use and resting ankle-brachial index (ABI), whereas patients with proximal disease showed no difference in prognosis after similar adjustment compared with patients without proximal disease. These findings suggest PAD is complex and heterogeneous and not a uniform entity [10]. The mortality for asymptomatic PAD is similar to that of mild to moderately symptomatic patients. Besides its beneficial effect on diagnosis of the disease, ankle-brachial index is also shown to correlate with the overall mortality of the disease [14]. The majority of these patients die of vascular causes such as cardiac, cerebrovascular, or other vascular diseases. The main reason for morbidity or mortality is either myocardial infarction or stroke. All-cause mortality is approximately 30% at 5 years, 50% at 10 years and 70% at 15 years [15]. In a population study, large-vessel involvement in PAD patients was significantly predictive of all-cause mortality in both genders with a relative risk of 4–5, independent of other cardiovascular risk factors. Isolated small-vessel PAD was unrelated to mortality. In that study, large-vessel PAD involved all arteries above the level of ankle [16]. Ogt et al. also found that the relative risk of mortality was elevated from 2- to 7-fold in men and women with multi- and unisegmental disease involving the aortoiliac and femoropopliteal segments. In the same study, the pres-

ence of tibioperoneal disease did not significantly increase mortality [8].

Depending on basic medical rules, the initial evaluation should include a careful history and physical examination. Knowing the fact that almost half of patients with PAD remain asymptomatic, suspicion of PAD for a clinician is very important. Shoes and socks should be removed for assessment of distal perfusion. Any signs of peripheral ischemia, peripheral pulses, skin color, toe nails, hair loss and trophic skin changes should be noted. Every sign of physical examination should be compared to the contralateral extremity. Abdomen should also be palpated for any potential abdominal aortic aneurysm. The blood pressure should be

Upon suspicion and physical examination findings, referral to the vascular laboratory should be the initial step. The diagnostic tests should start by noninvasive methods. These noninva-

The ABI is the single best initial screening test to perform in a patient suspected for PAD. A ratio of <0.90 is considered abnormal, with mild obstruction defined as a ratio of 0.71–0.90, moderate as 0.41–0.70 and severe when the ABI is <0.40. The higher arm blood pressure is used for the ABI ratio calculation [17]. The overall accuracy of the ABI to establish the diagnosis of lower extremity PAD has been validated with a sensitivity of 79–95% and a specificity of 96–100%, based on different studies [18, 19]. It is a reproducible technique, cheap and can also be used for screening and initial evaluation of target population, as well as assessment of disease progression. In patients with noncompressible arteries due to medial calcification such as elderly, diabetes and end-stage renal disease, toe-brachial index calculation may be

Treadmill exercise testing can be helpful, especially in patients with normal ABI during resting, such as in patients with isolated iliac artery stenosis. A decrease in ABI of 15–20% with

sive tests are also important for the follow-up of patients or disease progress.

helpful and values <0.7 are considered diagnostic for lower extremity PAD [20].

**2.3. Diagnosis of iliofemoral peripheral artery disease**

30 Peripheral Arterial Disease - A Practical Approach

measured in both arms.

Pulse volume recordings and Doppler waveform techniques are other techniques that can provide accurate information even in patients with noncompressible vessels. The normal waveform is triphasic. Loss of triphasic pattern and analysis of the peak velocity can localize the area of stenosis. They may be used to establish the initial diagnosis, assess the location and severity of PAD as well as follow-up of patients after any revascularization procedures [17].

Although they are not the first diagnostic test of choice in diagnosis of PAD, computed tomography angiography (CTA), magnetic resonance angiography (MRA) and digital subtraction angiography (DSA) are the other techniques that allow direct visualization of the vasculature in PAD patients.

CTA may be used with either intra-venous or intra-arterial contrast agents. The sensitivities and specificities are >95% for identifying stenosis >50% and for correctly identifying occlusions [22]. CTA produces images of vascular structures in cross-sectional slices that can be reformatted into three-dimensional angiographic-like images. CTA not only shows the intraluminal space, but also shows the surrounding tissue. For this reason, it visualizes calcification well, which is advantageous when considering revascularization strategies [23]. The main disadvantage is radiation exposure and the use of large volumes of iodinated contrast media, which limits its use in acute renal failure patients or patients with borderline renal function.

MRA is a useful diagnostic method in determining the location and stenosis severity in PAD patients. MRA may identify outflow vessels which may not be visualized by conventional angiography [24]. MRA has a high sensitivity and specificity for detecting acute occlusive disease when compared with DSA [25]. It is very useful for preoperative evaluation of the PAD patient in order to make a road-map, whether surgical or endovascular revascularization. **Figure 1** shows MRA of two different patients showing total occlusion of SFA.

MRA may also be used for postoperative follow-up of patients. A meta-analysis comparing MRA with catheter angiography demonstrated that sensitivity and specificity of MRA for detection of stenoses >50% were both in the range of 90–100% [26]. The main limitation of MRA is that it tends to overestimate the degree of stenosis because of turbulence; it cannot scan patients with pacemakers or defibrillators; metal stents or clips can obscure vascular flow; and use of gadolinium rarely may cause renal toxicity and nephrogenic systemic fibrosis in patients with elevated creatinine [17].

In our daily practice, there are some patients who are planned for endovascular interventions for critical stenoses, but not critically stenotic by DSA. Also, patients with previous stent in iliac/SFAs may also be misdiagnosed as occluded by MRA; that is why each patient needs a careful physical examination before MRA including comparative ABI. Duplex ultrasound scanning (DUS) may also give supportive data in these patients.

Contrast angiography provides detailed information about the vasculature, including minor collateral vessels, run-off and the flow speed, and is recommended as 'gold standard' method

therapeutic options are to improve symptoms and quality of life, at the same time decrease

Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion…

http://dx.doi.org/10.5772/intechopen.78045

33

Since cardiovascular events are the major cause of death in patients with PAD, modification of atherosclerotic risk factors should be the mainstay of risk factor modification. Smoking cessation and aggressive glycemic control in diabetic patients, both represent the most dominant risk factors for PAD, are very important [17]. Smoking cessation among patients with symptomatic PAD does not improve walking capacity, but may reduce the severity of claudication

In addition to smoking cessation and glycemic control in PAD patients, hyperlipidemia should be treated to reduce the risk of cardiovascular events in patients with atherosclerosis. Statin treatment is shown to have beneficial effects in reducing pain-free walking distance in

Hypertension is associated with a two- to three-fold increased risk for PAD. Hypertension guidelines support the aggressive treatment of blood pressure in patients with atherosclerosis, indicating PAD. In this high-risk group the current recommendation is a goal of <140/90 mmHg and < 130/80 mmHg if the patient also has diabetes or renal insufficiency [29]. Regarding drug choice, all drugs that lower blood pressure are effective at reducing the risk of cardiovascular events. Most patients will require multiple agents to achieve desired blood pressure goals [21]. The angiotensin-converting enzyme (ACE) inhibitor drugs have also shown benefit in PAD, possibly beyond blood-pressure lowering in high-risk groups [30]. Beta-adrenergic blocking drugs have previously been discouraged in PAD because of the possibility of worsening IC symptoms. However, this concern has not been supported by randomized trials, especially for cardioselective beta-blockers; therefore, beta-adrenergic

In patients with claudication, there is a considerable body of evidence to support the clinical benefits of a supervised exercise program in improving exercise performance and communitybased walking ability [21]. Apart from medical therapy, exercise significantly improves walking time and overall walking ability in patients with IC and should be considered as a primary efficacious treatment in PAD. Several studies have suggested that some level of supervision is necessary to achieve optimal results (general, unstructured recommendations to exercise by the physician do not result in any clinical benefit). In prospective studies of supervised exercise conducted for 3 months or longer, there are clear increases in treadmill exercise performance and a lessening of claudication pain severity during exercise [32]. Current ACC/AHA guidelines recommend a supervised exercise therapy as a first-line treatment for IC, as it is equally effective as endovascular revascularization in the treatment of patients with IC [33]. Whether asymptomatic or symptomatic, any patients taking support for PAD (either medical or surgical/interventional), exercise therapy (namely structured exercise therapy) should be considered, not only to improve IC, but also for motivation and promote risk factor modification.

cardiovascular event rates.

**3.1. Risk factor modification**

and the risk of developing critical limb ischemia [27].

patients with PAD, so that there is a positive effect on IC [28].

blocking drugs can be safely used in patients with claudication [31].

**3.2. Exercise and cardiovascular rehabilitation**

**Figure 1.** Contrast enhanced MR angiography, showing total occlusion of superficial femoral artery and well developed collateral circulation.

for evaluation of patients with PAD, especially when revascularization is considered. Image quality is enhanced by digital subtraction. The major advantage of DSA is the ability to selectively evaluate individual vessels, to obtain physiologic information such as pressure gradients and to serve as a platform for percutaneous intervention [23]. Angiography carries risk of any interventional procedure such as bleeding, infection, vascular damage, dissection, pseudoaneurysm formation and atheroembolism. Any of these factors can be reduced by experience of the interventionist [17]. As seen with other techniques, the use of contrast agent carries risk of contrast induced nephropathy, as well as anaphylactoid reactions. Angiography should not only be thought solely as a diagnostic method; at the same time, it also offers therapeutic options that are discussed later in this chapter.

Angiography, either noninvasive or invasive, should not be performed for the anatomic assessment of patients with PAD without leg symptoms because delineation of anatomy will not change treatment for this population.

#### **3. Treatment options for iliofemoral peripheral artery disease**

The management of lower extremity PAD is one of the most challenging problems for vascular surgeons/interventionists. As the population age increases and diagnostic tools improve, it is not surprising that the amount of patients seeking for treatment of PAD also increase day by day.

Treatment of any PAD, including iliofemoral PAD, can be classified into four categories including risk factor modification, exercise and cardiovascular rehabilitation, pharmacologic therapy, and invasive methods including surgery and interventional procedures [2]. Patients should not only be aware of their PAD, but also be informed and searched for other related diseases, including cerebrovascular and cardiovascular diseases. All the goals of these therapeutic options are to improve symptoms and quality of life, at the same time decrease cardiovascular event rates.

#### **3.1. Risk factor modification**

for evaluation of patients with PAD, especially when revascularization is considered. Image quality is enhanced by digital subtraction. The major advantage of DSA is the ability to selectively evaluate individual vessels, to obtain physiologic information such as pressure gradients and to serve as a platform for percutaneous intervention [23]. Angiography carries risk of any interventional procedure such as bleeding, infection, vascular damage, dissection, pseudoaneurysm formation and atheroembolism. Any of these factors can be reduced by experience of the interventionist [17]. As seen with other techniques, the use of contrast agent carries risk of contrast induced nephropathy, as well as anaphylactoid reactions. Angiography should not only be thought solely as a diagnostic method; at the same time, it also offers thera-

**Figure 1.** Contrast enhanced MR angiography, showing total occlusion of superficial femoral artery and well developed

Angiography, either noninvasive or invasive, should not be performed for the anatomic assessment of patients with PAD without leg symptoms because delineation of anatomy will

The management of lower extremity PAD is one of the most challenging problems for vascular surgeons/interventionists. As the population age increases and diagnostic tools improve, it is not surprising that the amount of patients seeking for treatment of PAD also increase day

Treatment of any PAD, including iliofemoral PAD, can be classified into four categories including risk factor modification, exercise and cardiovascular rehabilitation, pharmacologic therapy, and invasive methods including surgery and interventional procedures [2]. Patients should not only be aware of their PAD, but also be informed and searched for other related diseases, including cerebrovascular and cardiovascular diseases. All the goals of these

**3. Treatment options for iliofemoral peripheral artery disease**

peutic options that are discussed later in this chapter.

not change treatment for this population.

by day.

collateral circulation.

32 Peripheral Arterial Disease - A Practical Approach

Since cardiovascular events are the major cause of death in patients with PAD, modification of atherosclerotic risk factors should be the mainstay of risk factor modification. Smoking cessation and aggressive glycemic control in diabetic patients, both represent the most dominant risk factors for PAD, are very important [17]. Smoking cessation among patients with symptomatic PAD does not improve walking capacity, but may reduce the severity of claudication and the risk of developing critical limb ischemia [27].

In addition to smoking cessation and glycemic control in PAD patients, hyperlipidemia should be treated to reduce the risk of cardiovascular events in patients with atherosclerosis. Statin treatment is shown to have beneficial effects in reducing pain-free walking distance in patients with PAD, so that there is a positive effect on IC [28].

Hypertension is associated with a two- to three-fold increased risk for PAD. Hypertension guidelines support the aggressive treatment of blood pressure in patients with atherosclerosis, indicating PAD. In this high-risk group the current recommendation is a goal of <140/90 mmHg and < 130/80 mmHg if the patient also has diabetes or renal insufficiency [29]. Regarding drug choice, all drugs that lower blood pressure are effective at reducing the risk of cardiovascular events. Most patients will require multiple agents to achieve desired blood pressure goals [21]. The angiotensin-converting enzyme (ACE) inhibitor drugs have also shown benefit in PAD, possibly beyond blood-pressure lowering in high-risk groups [30]. Beta-adrenergic blocking drugs have previously been discouraged in PAD because of the possibility of worsening IC symptoms. However, this concern has not been supported by randomized trials, especially for cardioselective beta-blockers; therefore, beta-adrenergic blocking drugs can be safely used in patients with claudication [31].

#### **3.2. Exercise and cardiovascular rehabilitation**

In patients with claudication, there is a considerable body of evidence to support the clinical benefits of a supervised exercise program in improving exercise performance and communitybased walking ability [21]. Apart from medical therapy, exercise significantly improves walking time and overall walking ability in patients with IC and should be considered as a primary efficacious treatment in PAD. Several studies have suggested that some level of supervision is necessary to achieve optimal results (general, unstructured recommendations to exercise by the physician do not result in any clinical benefit). In prospective studies of supervised exercise conducted for 3 months or longer, there are clear increases in treadmill exercise performance and a lessening of claudication pain severity during exercise [32]. Current ACC/AHA guidelines recommend a supervised exercise therapy as a first-line treatment for IC, as it is equally effective as endovascular revascularization in the treatment of patients with IC [33]. Whether asymptomatic or symptomatic, any patients taking support for PAD (either medical or surgical/interventional), exercise therapy (namely structured exercise therapy) should be considered, not only to improve IC, but also for motivation and promote risk factor modification.

#### **3.3. Pharmacologic therapy**

Apart from medical therapies used to modify risk factors for PAD (antihypertensive, antidiabetic and antihyperlipidemic drugs), there are some drugs that are shown to improve IC or prevent occlusion-reocclusion after surgery/interventional procedures.

When the aortoiliac disease is the concern, endovascular procedures are effective as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant aortoiliac occlusive disease (class of recommendation IA) [33]. The CLEVER trial enrolled only patients with aortoiliac disease and compared endovascular therapy to supervised exercise therapy and to medications alone. At 6-month follow-up, both the endovascular therapy and supervised exercise groups had improved peak walking time compared with medication alone, with a greater improvement in the supervised exercise group [38]. The ERASE trial randomized patients with claudication and aortoiliac (as well as femoropopliteal) disease to endovascular revascularization plus supervised exercise or supervised exercise alone. After 1 year, patients in both groups had significant improvements in walking distances and health-related QoL, with greater improvements in the combined-therapy group [39].

Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion…

http://dx.doi.org/10.5772/intechopen.78045

35

When the femoropopliteal disease is the concern, endovascular procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant femoropopliteal disease (class of recommendation IIa) [33]. There are a number of randomized clinical trials that showed short-term beneficial effects with endovascular treatment of femoropopliteal disease for claudication versus supervised exercise training or medical therapy, with benefit that diminishes by 1 year [40]. In a systematic review that included randomized clinical trials that enrolled patients with femoropopliteal disease, authors reported that endovascular treatment of claudication improved walking parameters and quality of life [41]. The durability of endovascular treatment for claudication is directly related to vessel patency. Long-term patency is greater in the iliac artery than in the femoropopliteal segment [33].

Since SFA and popliteal arteries are the most common sites of obstruction in PAD patients, when the surgery is the concern, femoropopliteal bypass is one of the most widely performed surgical processes in these patients with claudication. There is a clear and consistent primary patency benefit for autogenous vein versus to prosthetic grafts for popliteal artery bypass [42]. PTFE grafts should be preferred over Dacron grafts for femoropopliteal bypass when

In this chapter, apart from the surgical revascularization, mainly endovascular treatment

Among those with appropriate indications for intervention, the procedure of choice, whether surgical or endovascular, depends on surgeon's/interventionist's experience, localization of the diseased arterial segment, anatomical suitability of disease and patient related factors, such as comorbid diseases. Most of the endovascular procedures are performed using local

Although the radiologists and cardiologists were the main pioneers of endovascular procedures, in the last decade, by the formation of hybrid operating rooms, vascular and cardiovascular surgeons became the leader of these interventional procedures. As a cardiovascular surgeon, in the last decade, we shared our patients with radiologists and cardiologists only for the reason that they had cath labs. The only way to re-face the patient was at the end of an unsuccessful attempt for percutaneous procedure, or a complication, such as rupture of the

there is lack of autogenous grafts.

anesthesia on an outpatient manner.

options for iliofemoral PAD and access sites will be discussed.

**4. Endovascular management of iliofemoral lesions**

Based on the currently available literature, all patients with PAD should receive antiplatelet therapy to reduce cardiovascular risk with a slight preference for clopidogrel monotherapy. Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke and vascular death in patients with symptomatic PAD [33]. The CAPRIE (clopidogrel versus aspirin in patients at risk of ischemic events) trial demonstrated a benefit of clopidogrel as compared with aspirin in cardiovascular risk reduction and bleeding events in a population of patients with symptomatic atherosclerotic vascular disease, including a subgroup of patients with symptomatic PAD [34]. However, there are two important subgroups that benefit from a different medical regime. Those receiving a venous bypass graft will have the most benefit when treated with a vitamin K antagonist and those receiving a below-knee prosthetic bypass graft will benefit the most when dual antiplatelet therapy (ASA and clopidogrel) [35].

Probably, the most effective pharmacologic treatment proven to be effective in relief of symptoms and improving IC in patients with PAD is cilostazol. ACC/AHA guideline strongly recommends the use of cilostazol in patients with PAD (class of recommendation IA) [33]. In a Cochrane review including 15 double-blind RCTs with a total of 3718 participants, cilostazol was associated with improvement in claudication symptoms but no changes in cardiovascular deaths or quality of life when compared with placebo [36]. The main limitation of the drug is congestive heart failure. Pentoxifylline is a xanthine and also acts as a nonselective inhibitor of phosphodiesterases, which causes an increase in intracellular cyclic AMP and decreased synthesis of tumor necrosis factor alpha and leukotrienes. It acts by improving red blood cell deformability, thus reducing blood viscosity as well as decreasing platelet aggregation and thrombus formation. By these properties, it was one of the agents used in PAD treatment. In a multicenter randomized control trial of pentoxifylline, cilostazol, or placebo for patients with moderate-to-severe claudication, there was no difference between pentoxifylline and placebo in the primary endpoint of maximal walking distance [37]. Therefore, pentoxifylline is not recommended as a treatment for claudication [33].

#### **3.4. Invasive methods**

An individualized approach to revascularization for claudication is recommended for each patient to optimize outcome. If a strategy of revascularization for claudication is undertaken, the revascularization strategy should be evidence based and can include endovascular revascularization, surgery, or both [33]. When deciding for an invasive method for treatment of PAD, patient's symptoms, localization of the affected arterial segment, patient specific factors including age, co-morbid diseases should be taken into consideration with a favorable risk– benefit ratio, with all combination therapies listed earlier.

In the last decade-or-two, endovascular procedures became one of the most popular concerns for treatment of PAD. There are numerous randomized clinical trials that compared endovascular procedures to various combinations of medical treatment with or without exercise programs.

When the aortoiliac disease is the concern, endovascular procedures are effective as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant aortoiliac occlusive disease (class of recommendation IA) [33]. The CLEVER trial enrolled only patients with aortoiliac disease and compared endovascular therapy to supervised exercise therapy and to medications alone. At 6-month follow-up, both the endovascular therapy and supervised exercise groups had improved peak walking time compared with medication alone, with a greater improvement in the supervised exercise group [38]. The ERASE trial randomized patients with claudication and aortoiliac (as well as femoropopliteal) disease to endovascular revascularization plus supervised exercise or supervised exercise alone. After 1 year, patients in both groups had significant improvements in walking distances and health-related QoL, with greater improvements in the combined-therapy group [39].

**3.3. Pharmacologic therapy**

34 Peripheral Arterial Disease - A Practical Approach

Apart from medical therapies used to modify risk factors for PAD (antihypertensive, antidiabetic and antihyperlipidemic drugs), there are some drugs that are shown to improve IC or

Based on the currently available literature, all patients with PAD should receive antiplatelet therapy to reduce cardiovascular risk with a slight preference for clopidogrel monotherapy. Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke and vascular death in patients with symptomatic PAD [33]. The CAPRIE (clopidogrel versus aspirin in patients at risk of ischemic events) trial demonstrated a benefit of clopidogrel as compared with aspirin in cardiovascular risk reduction and bleeding events in a population of patients with symptomatic atherosclerotic vascular disease, including a subgroup of patients with symptomatic PAD [34]. However, there are two important subgroups that benefit from a different medical regime. Those receiving a venous bypass graft will have the most benefit when treated with a vitamin K antagonist and those receiving a below-knee prosthetic bypass graft will benefit the most when dual

Probably, the most effective pharmacologic treatment proven to be effective in relief of symptoms and improving IC in patients with PAD is cilostazol. ACC/AHA guideline strongly recommends the use of cilostazol in patients with PAD (class of recommendation IA) [33]. In a Cochrane review including 15 double-blind RCTs with a total of 3718 participants, cilostazol was associated with improvement in claudication symptoms but no changes in cardiovascular deaths or quality of life when compared with placebo [36]. The main limitation of the drug is congestive heart failure. Pentoxifylline is a xanthine and also acts as a nonselective inhibitor of phosphodiesterases, which causes an increase in intracellular cyclic AMP and decreased synthesis of tumor necrosis factor alpha and leukotrienes. It acts by improving red blood cell deformability, thus reducing blood viscosity as well as decreasing platelet aggregation and thrombus formation. By these properties, it was one of the agents used in PAD treatment. In a multicenter randomized control trial of pentoxifylline, cilostazol, or placebo for patients with moderate-to-severe claudication, there was no difference between pentoxifylline and placebo in the primary endpoint of maximal walking distance [37]. Therefore, pentoxifylline is not

An individualized approach to revascularization for claudication is recommended for each patient to optimize outcome. If a strategy of revascularization for claudication is undertaken, the revascularization strategy should be evidence based and can include endovascular revascularization, surgery, or both [33]. When deciding for an invasive method for treatment of PAD, patient's symptoms, localization of the affected arterial segment, patient specific factors including age, co-morbid diseases should be taken into consideration with a favorable risk–

In the last decade-or-two, endovascular procedures became one of the most popular concerns for treatment of PAD. There are numerous randomized clinical trials that compared endovascular procedures to various combinations of medical treatment with or without exercise programs.

prevent occlusion-reocclusion after surgery/interventional procedures.

antiplatelet therapy (ASA and clopidogrel) [35].

recommended as a treatment for claudication [33].

benefit ratio, with all combination therapies listed earlier.

**3.4. Invasive methods**

When the femoropopliteal disease is the concern, endovascular procedures are reasonable as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant femoropopliteal disease (class of recommendation IIa) [33]. There are a number of randomized clinical trials that showed short-term beneficial effects with endovascular treatment of femoropopliteal disease for claudication versus supervised exercise training or medical therapy, with benefit that diminishes by 1 year [40]. In a systematic review that included randomized clinical trials that enrolled patients with femoropopliteal disease, authors reported that endovascular treatment of claudication improved walking parameters and quality of life [41]. The durability of endovascular treatment for claudication is directly related to vessel patency. Long-term patency is greater in the iliac artery than in the femoropopliteal segment [33].

Since SFA and popliteal arteries are the most common sites of obstruction in PAD patients, when the surgery is the concern, femoropopliteal bypass is one of the most widely performed surgical processes in these patients with claudication. There is a clear and consistent primary patency benefit for autogenous vein versus to prosthetic grafts for popliteal artery bypass [42]. PTFE grafts should be preferred over Dacron grafts for femoropopliteal bypass when there is lack of autogenous grafts.

In this chapter, apart from the surgical revascularization, mainly endovascular treatment options for iliofemoral PAD and access sites will be discussed.

#### **4. Endovascular management of iliofemoral lesions**

Among those with appropriate indications for intervention, the procedure of choice, whether surgical or endovascular, depends on surgeon's/interventionist's experience, localization of the diseased arterial segment, anatomical suitability of disease and patient related factors, such as comorbid diseases. Most of the endovascular procedures are performed using local anesthesia on an outpatient manner.

Although the radiologists and cardiologists were the main pioneers of endovascular procedures, in the last decade, by the formation of hybrid operating rooms, vascular and cardiovascular surgeons became the leader of these interventional procedures. As a cardiovascular surgeon, in the last decade, we shared our patients with radiologists and cardiologists only for the reason that they had cath labs. The only way to re-face the patient was at the end of an unsuccessful attempt for percutaneous procedure, or a complication, such as rupture of the artery, pseudoaneurysm formation, bleeding, or emboli and so on. All the interventions can be of-course performed by different departments, but any department should be capable of fixing their own complications, related to their interventions. In this decade, probably one of the most important advancement in PAD diseases was involvement of vascular surgeons in the world of endovascular and hybrid procedures.

atherectomy and subsequent drug-coated balloon application has been implemented. Drugcoated balloons are proved to be an effective treatment option that does not require a perma-

Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion…

http://dx.doi.org/10.5772/intechopen.78045

37

Atherosclerotic iliac artery disease is increasingly being treated with endovascular techniques. A number of new stent technologies can be utilized with high long-term patency, including self-expanding stents, balloon-expandable stents and covered stents, but comparative data on these stent types and in more complex lesions are lacking. Iliac stent choice can be largely categorized into choosing either a balloon-expandable or self-expanding stent based on lesion characteristics (i.e., calcified, fibrous, soft, eccentric, concentric, focal, diffuse, etc.), access site,

For the last few years, our main strategy in treating iliac and femoropopliteal lesions are endo-first, if the lesion has suitable anatomy. For the patients with long segment stenosis and calcified lesions, we prefer rotational atherectomy for debulking of atherosclerotic plaque and then dilatation with drug-coated balloons. If there is a residual dissection, stenting is preferred. Mainly balloon inflatable stents are preferred for proximal iliac lesions, since the plaque over the iliac segments are generally stiff and prone to re-occlusion. For common and SFAs, our main preference is self-expanding nitinol stents, unless the problem is not solved by drug-coated balloons. As surgeons, we always should think of a possibility of reocclusion in these patients and that is why, stenting in the popliteal and distal CFAs should be avoided

To go inside a building, we should open the door first with the right key and in order to perform complex interventions, choosing the right access site is mandatory. There are several access sites described in the literature for endovascular procedures including ipsilateral retrograde common femoral access, ipsilateral antegrade common femoral access, superficial femoral access, contralateral common femoral access, retrograde popliteal access, pedal access, aortic access, radial access and so on. Whatever is the access site, the main goal is to approach stenotic/occluded arterial segments and perform endovascular interventions with success avoiding complications. Since PAD is not a uniform disease, and coexistence of femoral and iliac lesions are present in favorable amount of patients, retrograde contralateral common femoral access can result in procedural failure, especially in patients with unfavorable

The SFA occlusions are generally managed by antegrade ipsilateral or retrograde contralateral femoral approach ending in intraluminal or subintimal recanalization of the vessel lumen [49].

The retrograde popliteal approach is a type of subintimal arterial flossing with antegraderetrograde intervention; it was first described by Tonnesen et al. in 1988 [51]. The main indications for this technique are a short SFA stump, flush occlusion or tandem common/ SFA lesions and failure of antegrade approach. Also, coexistence of femoral and iliac lesions necessitates contralateral femoral approach; crossover in the abdominal aorta may complicate

In case of failure, a retrograde popliteal access is considered a valid alternative [50].

**4.1. Retrograde popliteal artery approach for femoral and iliac arterial lesions**

introducer size, vessel tortuosity and lesion location [48].

nent stent [47].

for alternative surgical sites.

anatomy of the aortic bifurcation.

Given the widespread availability of percutaneous procedures, major vascular society guidelines recommend initial percutaneous revascularization. The endovascular techniques for the treatment of patients with lower extremity ischemia include balloon angioplasty, stents, stent-grafts and plaque debulking procedures. Although long segment stenosis/occlusions, multifocal stenoses, eccentric and calcified lesions are more prone to surgical revascularization, use of total occlusion catheters, rotational thrombectomy/atherectomy devices made these complex lesions also treatable with endovascular procedures.

In general, the outcomes of revascularization depend upon the extent of the disease in the subjacent arterial tree (inflow, outflow and the size and length of the diseased segment). IN TASC-II guideline, 'A' lesions represent those which yield excellent results from, and should be treated by, endovascular means; 'B' lesions offer sufficiently good results with endovascular methods that this approach is still preferred first, unless an open revascularization is required for other associated lesions in the same anatomic area; 'C' lesions produce superior enough long-term results with open revascularization that endovascular methods should be used only in patients at high risk for open repair; and 'D' lesions do not yield good enough results with endovascular methods to justify them as primary treatment [21]. For treatment of TASC A lesions, the choice of treatment is endovascular, whereas it is surgery for TASC D lesions. Endovascular treatment is the preferred treatment for type B lesions and surgery is the preferred treatment for good-risk patients with type C lesions, which should be decided on a patient basis. The same is also recommended for femoropopliteal lesions.

The technical and clinical success rate of percutaneous transluminal angioplasty (PTA) of femoropopliteal artery stenoses in all series exceeds 95% [43]. Device developments such as hydrophilic guide wires and technical developments, such as subintimal recanalization, provide high recanalization rates in total occlusions of more than 85% [44]. The technique of subintimal angioplasty is not as dependent on length, but rather on the presence of normal vessel above and below the occlusion to allow access [45]. There is general agreement that for acute failure of PTA of an SFA lesion, stent placement is indicated.

The mechanism of endovascular treatment using balloon angioplasty and stenting is based on plaque disruption and displacement within the arterial wall. By this way, the atheroma is not removed but pressed or crushed by the balloon and redistributed inside and along the arterial wall. Endovascular atherectomy may be performed under local anesthesia using standard caliber arterial sheaths, ranging from 4 to 8 Fr, and provides the theoretical advantage over balloon angioplasty that plaque is removed rather than pressed against the arterial wall, and subsequent balloon dilation is optional depending on the debulking effect. This contributes to substantial luminal gain with less barotrauma even if postdilation is performed, decreasing the risk of dissection and/or neointimal hyperplasia, while avoiding stent placement [46]. In order to improve patency, the combination of lesion debulking using percutaneous atherectomy and subsequent drug-coated balloon application has been implemented. Drugcoated balloons are proved to be an effective treatment option that does not require a permanent stent [47].

artery, pseudoaneurysm formation, bleeding, or emboli and so on. All the interventions can be of-course performed by different departments, but any department should be capable of fixing their own complications, related to their interventions. In this decade, probably one of the most important advancement in PAD diseases was involvement of vascular surgeons in

Given the widespread availability of percutaneous procedures, major vascular society guidelines recommend initial percutaneous revascularization. The endovascular techniques for the treatment of patients with lower extremity ischemia include balloon angioplasty, stents, stent-grafts and plaque debulking procedures. Although long segment stenosis/occlusions, multifocal stenoses, eccentric and calcified lesions are more prone to surgical revascularization, use of total occlusion catheters, rotational thrombectomy/atherectomy devices made

In general, the outcomes of revascularization depend upon the extent of the disease in the subjacent arterial tree (inflow, outflow and the size and length of the diseased segment). IN TASC-II guideline, 'A' lesions represent those which yield excellent results from, and should be treated by, endovascular means; 'B' lesions offer sufficiently good results with endovascular methods that this approach is still preferred first, unless an open revascularization is required for other associated lesions in the same anatomic area; 'C' lesions produce superior enough long-term results with open revascularization that endovascular methods should be used only in patients at high risk for open repair; and 'D' lesions do not yield good enough results with endovascular methods to justify them as primary treatment [21]. For treatment of TASC A lesions, the choice of treatment is endovascular, whereas it is surgery for TASC D lesions. Endovascular treatment is the preferred treatment for type B lesions and surgery is the preferred treatment for good-risk patients with type C lesions, which should be decided

The technical and clinical success rate of percutaneous transluminal angioplasty (PTA) of femoropopliteal artery stenoses in all series exceeds 95% [43]. Device developments such as hydrophilic guide wires and technical developments, such as subintimal recanalization, provide high recanalization rates in total occlusions of more than 85% [44]. The technique of subintimal angioplasty is not as dependent on length, but rather on the presence of normal vessel above and below the occlusion to allow access [45]. There is general agreement that for

The mechanism of endovascular treatment using balloon angioplasty and stenting is based on plaque disruption and displacement within the arterial wall. By this way, the atheroma is not removed but pressed or crushed by the balloon and redistributed inside and along the arterial wall. Endovascular atherectomy may be performed under local anesthesia using standard caliber arterial sheaths, ranging from 4 to 8 Fr, and provides the theoretical advantage over balloon angioplasty that plaque is removed rather than pressed against the arterial wall, and subsequent balloon dilation is optional depending on the debulking effect. This contributes to substantial luminal gain with less barotrauma even if postdilation is performed, decreasing the risk of dissection and/or neointimal hyperplasia, while avoiding stent placement [46]. In order to improve patency, the combination of lesion debulking using percutaneous

the world of endovascular and hybrid procedures.

36 Peripheral Arterial Disease - A Practical Approach

these complex lesions also treatable with endovascular procedures.

on a patient basis. The same is also recommended for femoropopliteal lesions.

acute failure of PTA of an SFA lesion, stent placement is indicated.

Atherosclerotic iliac artery disease is increasingly being treated with endovascular techniques. A number of new stent technologies can be utilized with high long-term patency, including self-expanding stents, balloon-expandable stents and covered stents, but comparative data on these stent types and in more complex lesions are lacking. Iliac stent choice can be largely categorized into choosing either a balloon-expandable or self-expanding stent based on lesion characteristics (i.e., calcified, fibrous, soft, eccentric, concentric, focal, diffuse, etc.), access site, introducer size, vessel tortuosity and lesion location [48].

For the last few years, our main strategy in treating iliac and femoropopliteal lesions are endo-first, if the lesion has suitable anatomy. For the patients with long segment stenosis and calcified lesions, we prefer rotational atherectomy for debulking of atherosclerotic plaque and then dilatation with drug-coated balloons. If there is a residual dissection, stenting is preferred. Mainly balloon inflatable stents are preferred for proximal iliac lesions, since the plaque over the iliac segments are generally stiff and prone to re-occlusion. For common and SFAs, our main preference is self-expanding nitinol stents, unless the problem is not solved by drug-coated balloons. As surgeons, we always should think of a possibility of reocclusion in these patients and that is why, stenting in the popliteal and distal CFAs should be avoided for alternative surgical sites.

#### **4.1. Retrograde popliteal artery approach for femoral and iliac arterial lesions**

To go inside a building, we should open the door first with the right key and in order to perform complex interventions, choosing the right access site is mandatory. There are several access sites described in the literature for endovascular procedures including ipsilateral retrograde common femoral access, ipsilateral antegrade common femoral access, superficial femoral access, contralateral common femoral access, retrograde popliteal access, pedal access, aortic access, radial access and so on. Whatever is the access site, the main goal is to approach stenotic/occluded arterial segments and perform endovascular interventions with success avoiding complications. Since PAD is not a uniform disease, and coexistence of femoral and iliac lesions are present in favorable amount of patients, retrograde contralateral common femoral access can result in procedural failure, especially in patients with unfavorable anatomy of the aortic bifurcation.

The SFA occlusions are generally managed by antegrade ipsilateral or retrograde contralateral femoral approach ending in intraluminal or subintimal recanalization of the vessel lumen [49]. In case of failure, a retrograde popliteal access is considered a valid alternative [50].

The retrograde popliteal approach is a type of subintimal arterial flossing with antegraderetrograde intervention; it was first described by Tonnesen et al. in 1988 [51]. The main indications for this technique are a short SFA stump, flush occlusion or tandem common/ SFA lesions and failure of antegrade approach. Also, coexistence of femoral and iliac lesions necessitates contralateral femoral approach; crossover in the abdominal aorta may complicate the procedure in patients with angled iliac arteries and aorta. Also, in chronic total occlusions (TASC D), it may be rather difficult to crossover the aorta by the atherectomy devices, even if the patient had normal anatomy in the aortic segment. In SFA lesions, the access over the inguinal region may rather be hard, especially in obese patients.

For the abovementioned patients, popliteal access is a useful method for interventional procedures. The procedure begins in prone position. Prone position has the advantage of contralateral popliteal artery use, either for proximal visualization of the totally occluded artery, or crossover if the retrograde access is not successful. Puncture of the artery and replacement of sheath should always be made by the aid of an ultrasonography, since the popliteal vein is in close proximity to the popliteal artery and sometimes lies over the artery. Visualization of the vein and artery avoids iatrogenic AV fistula formation (**Figure 2**). Since majority of the patients have absent/weak popliteal artery pulses, ultrasonography aided catheterization should always be part of routine practice. After placement of 6–8 Fr sheath, a hydrophilic 0.0035 wire is advanced, and supported either by a slightly angled diagnostic catheter or total occlusion catheter. In total occlusions, the lesion is usually crossed intimally/subintimally by the aid of 6 Fr total occlusion catheter. Confirming that the guidewire is in the patent true lumen proximally, verification is made by angiography. In total occlusion of femoral/iliac arteries, our strategy is to make debulking of atherosclerotic plaque with rotational atherectomy devices and then use drug-coated balloons, or stents according to type and localization of the lesions (**Figure 3**).

A good preoperative evaluation is important before the procedure. Minimum popliteal artery diameter should be at least 4 mm. Local anesthesia should not be made too much in amount

not to cause compression of the vasculature and obtain a clear image of ultrasound. Just a little amount of local anesthesia is usually enough; after insertion of the needle and guidewire,

**Figure 3.** Rotational mechanical atherectomy catheter inserted through the 8F sheath over the popliteal artery in a

Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion…

http://dx.doi.org/10.5772/intechopen.78045

39

Popliteal access is also advantageous in patients with occluded femoropopliteal artery bypass grafts. The atherectomy/thrombectomy can be made either from the native artery or the occluded graft, which usually results in high operational success in our cases. Videos (https://mts.intechopen.com/download/index/process/195/authkey/b9bb94b883d527ae-1b201a3ea2901c84) shows pre- and post-procedural angiograms showing total opening of

Subintimal guidewire extension and atherectomy usually results in residual dissection in the entry area; but since the direction of dissection is opposite to the direction of flow, in our opinion, this access becomes advantageous. As mentioned before, vascular surgeons should always leave a potential area for future surgical revascularization in the popliteal and com-

The main disadvantage of this process is mainly based on the prone position of the patient. In complex cases, prolonged procedural times may disturb patients, especially if the patient has chronic obstructive pulmonary disease. Direct cannulation of the artery needs experience of ultrasonography and a learning curve in the very first few cases. Hematoma and post-procedural lack of compression may be overcome by routine use of vascular closure devices (**Figure 4**). Vascular closure devices are especially important when 6F or 8F sheaths are used for vascular access in the popliteal region; because, after the interventional procedure is completed, external compression may cause runoff failure, leading acute obstruction

additional local anesthetic provides comfort of the patient.

of the popliteal artery.

retrograde fashion.

SFA after rotational mechanical atherectomy and drug-coated balloons.

mon femoral arteries (CFA), after an eventful reocclusion of these segments.

**Figure 2.** Popliteal artery access using ultrasonography probe after application of minimal local anesthesia.

Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion… http://dx.doi.org/10.5772/intechopen.78045 39

the procedure in patients with angled iliac arteries and aorta. Also, in chronic total occlusions (TASC D), it may be rather difficult to crossover the aorta by the atherectomy devices, even if the patient had normal anatomy in the aortic segment. In SFA lesions, the access over the

For the abovementioned patients, popliteal access is a useful method for interventional procedures. The procedure begins in prone position. Prone position has the advantage of contralateral popliteal artery use, either for proximal visualization of the totally occluded artery, or crossover if the retrograde access is not successful. Puncture of the artery and replacement of sheath should always be made by the aid of an ultrasonography, since the popliteal vein is in close proximity to the popliteal artery and sometimes lies over the artery. Visualization of the vein and artery avoids iatrogenic AV fistula formation (**Figure 2**). Since majority of the patients have absent/weak popliteal artery pulses, ultrasonography aided catheterization should always be part of routine practice. After placement of 6–8 Fr sheath, a hydrophilic 0.0035 wire is advanced, and supported either by a slightly angled diagnostic catheter or total occlusion catheter. In total occlusions, the lesion is usually crossed intimally/subintimally by the aid of 6 Fr total occlusion catheter. Confirming that the guidewire is in the patent true lumen proximally, verification is made by angiography. In total occlusion of femoral/iliac arteries, our strategy is to make debulking of atherosclerotic plaque with rotational atherectomy devices and then use drug-coated balloons, or stents according to type and localization

A good preoperative evaluation is important before the procedure. Minimum popliteal artery diameter should be at least 4 mm. Local anesthesia should not be made too much in amount

**Figure 2.** Popliteal artery access using ultrasonography probe after application of minimal local anesthesia.

inguinal region may rather be hard, especially in obese patients.

38 Peripheral Arterial Disease - A Practical Approach

of the lesions (**Figure 3**).

**Figure 3.** Rotational mechanical atherectomy catheter inserted through the 8F sheath over the popliteal artery in a retrograde fashion.

not to cause compression of the vasculature and obtain a clear image of ultrasound. Just a little amount of local anesthesia is usually enough; after insertion of the needle and guidewire, additional local anesthetic provides comfort of the patient.

Popliteal access is also advantageous in patients with occluded femoropopliteal artery bypass grafts. The atherectomy/thrombectomy can be made either from the native artery or the occluded graft, which usually results in high operational success in our cases. Videos (https://mts.intechopen.com/download/index/process/195/authkey/b9bb94b883d527ae-1b201a3ea2901c84) shows pre- and post-procedural angiograms showing total opening of SFA after rotational mechanical atherectomy and drug-coated balloons.

Subintimal guidewire extension and atherectomy usually results in residual dissection in the entry area; but since the direction of dissection is opposite to the direction of flow, in our opinion, this access becomes advantageous. As mentioned before, vascular surgeons should always leave a potential area for future surgical revascularization in the popliteal and common femoral arteries (CFA), after an eventful reocclusion of these segments.

The main disadvantage of this process is mainly based on the prone position of the patient. In complex cases, prolonged procedural times may disturb patients, especially if the patient has chronic obstructive pulmonary disease. Direct cannulation of the artery needs experience of ultrasonography and a learning curve in the very first few cases. Hematoma and post-procedural lack of compression may be overcome by routine use of vascular closure devices (**Figure 4**). Vascular closure devices are especially important when 6F or 8F sheaths are used for vascular access in the popliteal region; because, after the interventional procedure is completed, external compression may cause runoff failure, leading acute obstruction of the popliteal artery.

**Author details**

University, Konya, Turkey

Address all correspondence to: otanyeli@gmail.com

DOI: 10.1016/S0140-6736(13)61249-0

Department of Cardiovascular Surgery, Meram Medicine Faculty, Necmettin Erbakan

[1] Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: A systematic review and analysis. Lancet. 2013;**382**:1329-1340.

Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion…

http://dx.doi.org/10.5772/intechopen.78045

41

[2] Dieter RS, Chu WW, Pacanowski JP, McBride PE, Tanke TE. The significance of lower

[3] Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevelance of peripheral arterial disease in a defined population. Circulation. 1985;**71**:

[4] Schroll M, Munck O. Estimation of peripheral arteriosclerotic disease by ankle blood pressure in a population study of 60-year-old men and women. Journal of Chronic

[5] Motsumi MJ, Naidoo NG. Pattern and distribution of peripheral arterial disease in diabetic patients with critical limb ischemia (Rutherford clinical category 4-6). South

[6] Diehm N, Shang A, Silvestro A, Dick F, Schmidli J, Mahler F, et al. Association of cardiovascular risk factors with pattern of lower limb atherosclerosis in 2659 patients undergoing angioplasty. European Journal of Vascular and Endovascular Surgery. 2006;**31**:59-63

[7] Haltmayer M, Mueller T, Horvath W, Luft C, Poelz W, Haidinger D. Impact of atherosclerotic risk factors on the anatomical distribution of peripheral arterial disease.

[8] Vogt MT, Wolfson SK, Kuller LH. Segmental arterial disease in the lower extremities: Correlates of disease and relationship to mortality. Journal of Clinical Epidemiology.

[9] Barretto S, Ballman KV, Rooke TW, Kullo IJ. Early-onset peripheral arterial occlusive disease: Clinical features and determinants of disease severity and location. Vascular

[10] Chen Q, Smith CY, Bailey KR, Wennberg PW, Kullo IJ. Disease location is associated with survival in patients with peripheral artery disease. Journal of the American Heart

extremity peripheral artery disease. Clinical Cardiology. 2002;**25**:3-10

Omer Tanyeli

**References**

510-515

Diseases. 1981;**34**:261-269

1993;**46**:1267-1276

Medicine. 2003;**8**:95-100

Association. 2013;**2**:e000304

African Journal of Surgery. 2017;**55**:48-54

International Angiology. 2001;**20**:200-207

**Figure 4.** At the end of the endovascular procedure, popliteal artery is closed by vascular closure device to avoid compression.

Retrograde transpopliteal approach is an innovative technique that allows complex endovascular procedures, and should be a part of every vascular interventinal's skill set. Proper case selection, operator experience and appropriate technique are essential for clinical and procedural success.

#### **5. Conclusions**

PAD is one of the most common diseases affecting quality of life, especially in the elderly population. Since most of these patients are asymptomatic, a careful physician should always be suspicious about the diagnosis. Symptomatic patients should be encouraged to structured exercise therapy, in combination with risk factor modification, pharmacological treatment and invasive treatment strategies when needed.

Endovascular treatment options and the number of procedures dramatically increased in the last decade. A careful preoperative evaluation and plan should be made to achieve success in interventional procedures. Although femoral arteries are the most common site for PAD, iliac impairment is not so rare. In patients with combined iliac and femoral artery diseases, popliteal artery approach is a safe and effective technique for percutaneous revascularization. Interventionists should always have an alternative plan and access site in their reserve for the success of complex procedures.

#### **Conflict of interest**

None.

#### **Notes/Thanks/Other declarations**

Thanks Prof. Dr. Niyazi Gormus, for his expert opinion, patience and excellent guidance in our practice.

### **Author details**

Omer Tanyeli

Address all correspondence to: otanyeli@gmail.com

Department of Cardiovascular Surgery, Meram Medicine Faculty, Necmettin Erbakan University, Konya, Turkey

#### **References**

Retrograde transpopliteal approach is an innovative technique that allows complex endovascular procedures, and should be a part of every vascular interventinal's skill set. Proper case selection, operator experience and appropriate technique are essential for clinical and procedural success.

**Figure 4.** At the end of the endovascular procedure, popliteal artery is closed by vascular closure device to avoid

PAD is one of the most common diseases affecting quality of life, especially in the elderly population. Since most of these patients are asymptomatic, a careful physician should always be suspicious about the diagnosis. Symptomatic patients should be encouraged to structured exercise therapy, in combination with risk factor modification, pharmacological treatment

Endovascular treatment options and the number of procedures dramatically increased in the last decade. A careful preoperative evaluation and plan should be made to achieve success in interventional procedures. Although femoral arteries are the most common site for PAD, iliac impairment is not so rare. In patients with combined iliac and femoral artery diseases, popliteal artery approach is a safe and effective technique for percutaneous revascularization. Interventionists should always have an alternative plan and access site in their reserve for the success of complex procedures.

Thanks Prof. Dr. Niyazi Gormus, for his expert opinion, patience and excellent guidance in

**5. Conclusions**

compression.

40 Peripheral Arterial Disease - A Practical Approach

**Conflict of interest**

None.

our practice.

and invasive treatment strategies when needed.

**Notes/Thanks/Other declarations**


[11] Aboyans V, Desormais I, Lacroix P, Salazar J, Criqui MH, Laskar M. The general prognosis of patients with peripheral arterial disease differs according to the disease localization. Journal of the American College of Cardiology. 2010;**55**:898-903

infra-popliteal runoff in patients with peripheral arterial occlusive disease. European

Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion…

http://dx.doi.org/10.5772/intechopen.78045

43

[26] Nelemans PJ, Leiner T, de Vet HC, van Engelshoven JM. Peripheral arterial disease: Metaanalysis of the diagnostic performance of MR angiography. Radiology. 2000;**217**:105-114

[27] Girolami B, Bernardi E, Prins MH, Ten Cate JW, Hettiarachchi R, Prandoni P, et al. Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl: A meta-analysis. Archives of Internal Medicine. 1999;**159**:337-345

[28] Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90056

[29] Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the joint National Committee on prevention, detection, evaluation, and treat-

[30] Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The heart outcomes prevention evaluation study investigators. The New England Journal of

[31] Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized

[32] Hiatt W, Wolfel E, Meier R, Regensteiner J. Superiority of treadmill walking exercise vs. strength training for patients with peripheral arterial disease. Implications for the

[33] Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. AHA/ACC guideline on the Management of Patients with Lower Extremity Peripheral Artery Disease: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Journal of the American

[34] CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;**348**:1329-1339

[35] Vos C, Vahl AC. Anticoagulation and antiplatelet therapy in patients with peripheral arterial disease of the femoropopliteal arteries. The Journal of Cardiovascular Surgery.

[36] Bedenis R, Stewart M, Cleanthis M, Robless P, Mikhailidis DP, Stansby G. Cilostazol for intermittent claudication. Cochrane Database of Systematic Reviews. 2014:CD003748

[37] Dawson DL, Cutler BS, Hiatt WR, Hobson RW 2nd, Martin JD, Bortey EB, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. The

participants in 14 randomised trials of statins. Lancet. 2005;**366**:1267-1278

ment of high blood pressure. Hypertension. 2003;**42**:1206-1252

controlled trials. Archives of Internal Medicine. 1991;**151**:1769-1776

mechanism of the training response. Circulation. 1994;**90**:1866-1874

College of Cardiology. 2016, 2017;**69**:e71-e126

American Journal of Medicine. 2000;**109**:523-530

Journal of Radiology. 2008;**66**:519-525

Medicine. 2000;**342**:145-153

2018;**59**:164-171


infra-popliteal runoff in patients with peripheral arterial occlusive disease. European Journal of Radiology. 2008;**66**:519-525

[26] Nelemans PJ, Leiner T, de Vet HC, van Engelshoven JM. Peripheral arterial disease: Metaanalysis of the diagnostic performance of MR angiography. Radiology. 2000;**217**:105-114

[11] Aboyans V, Desormais I, Lacroix P, Salazar J, Criqui MH, Laskar M. The general prognosis of patients with peripheral arterial disease differs according to the disease localiza-

[12] Weinberg I, Giri J, Calfon MA, Hawkins BM, Weinberg MD, Margey R, et al. Anatomic correlates of supra-normal ankle brachial indices. Catheterization and Cardiovascular

[13] Halperin JL. Evaluation of patients with peripheral vascular disease. Thrombosis Research.

[14] Crique MH, Langer R, Fronek A, Feigelson H, Klauber M, McCann T, et al. Mortality over a period of 10 years in patients with peripheral artery disease. The New England

[15] TASC Working Group. Management of peripheral arterial disease. Journal of Vascular

[16] Criqui MH, Coughlin SS, Fronek A. Noninvasively diagnosed peripheral arterial disease as a predictor of mortality: Results from a prospective study. Circulation. 1985;**72**:768-773

[17] Kasapis C, Gurm HS. Current approach to the diagnosis and treatment of femoral-popliteal arterial disease. A systematic review. Current Cardiology Reviews. 2009;**5**:296-311

[18] Fowkes FG. The measurement of atherosclerotic peripheral arterial disease in epidemio-

[19] Lijmer JG, Hunink MG, van den Dungen JJ, Loonstra J, Smit AJ. ROC analysis of noninvasive tests for peripheral artery disease. Ultrasound in Medicine & Biology.

[20] Carter SA, Tate RB. Value of toe pulse waves in addition to systolic pressures in the assessment of the severity of peripheral arterial disease and critical limb ischemia.

[21] Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Intersociety concensus for the management of peripheral arterial disease (TASC II). European

[22] Sun Z. Diagnostic accuracy of multislice CT angiography in peripheral artery disease.

[23] Chen Q, Shi Y, Wang Y, Li X. Patterns of disease distribution of lower extremity periph-

[24] Carpenter JP, Baum RA, Holland GA, Barker CF. Peripheral vascular surgery with magnetic resonance angiography as the sole preoperative imaging modality. Journal of

[25] Huegli RW, Thalhammer C, Jacob AL, Jaeger K, Bilecen D.Intra-arterial MR-angiography on an open-bore MR-scanner compared to digital-subtraction angiography of the

logical surveys. International Journal of Epidemiology. 1988;**17**:248-254

Journal of Vascular and Endovascular Surgery. 2007;**33**(Suppl 1):1-75

Journal of Vascular and Interventional Radiology. 2006;**17**:1915-1921

tion. Journal of the American College of Cardiology. 2010;**55**:898-903

Interventions. 2013;**81**:1025-1030

42 Peripheral Arterial Disease - A Practical Approach

Journal of Medicine. 1992;**326**(6):381

Journal of Vascular Surgery. 1996;**24**:258-265

eral artery disease. Angiology. 2015;**66**:211-218

Vascular Surgery. 1994;**20**:861-869

2002;**106**:303-311

Surgery. 2000;**31**:1-296

1996;**22**:391-398


[38] Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER, Cohen DJ, Reynolds MR, et al. Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: The CLEVER study. Journal of the American College of Cardiology. 2015;**65**:999-1009

[49] Dumantepe M. Retrograde popliteal access to percutaneous peripheral intervention for chronic total occlusion of superficial femoral arteries. Vascular and Endovascular

Percutaneous Reconstruction Techniques: Popliteal Artery Approach for Chronic Total Occlusion…

http://dx.doi.org/10.5772/intechopen.78045

45

[50] Narins CR. Access strategies for peripheral arterial intervention. Cardiology Journal.

[51] Tonnesen KH, Sager P, Karle A, Henriksen L, Jorgensen B. Percutaneous transluminal angioplasty of the superficial femoral artery by retrograde catheterization via the popli-

teal artery. Cardiovascular and Interventional Radiology. 1988;**11**:127-131

Surgery. 2017;**51**:240-246

2009;**16**:88-97


[49] Dumantepe M. Retrograde popliteal access to percutaneous peripheral intervention for chronic total occlusion of superficial femoral arteries. Vascular and Endovascular Surgery. 2017;**51**:240-246

[38] Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER, Cohen DJ, Reynolds MR, et al. Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: The CLEVER study. Journal of the American College

[39] Fakhry F, Spronk S, van der Laan L, Wever JJ, Teijink JA, Hoffmann WH, et al. Endovascular revascularization and supervised exercise for peripheral artery disease and intermittent claudication: A randomized clinical trial. Journal of the American Medical

[40] Nordanstig J, Taft C, Hensäter M, Perlander A, Osterberg K, Jivegard L. Improved quality of life after 1 year with an invasive versus a noninvasive treatment strategy in claudicants: Oneyear results of the invasive revascularization or not in intermittent clau-

[41] Vemulapalli S, Dolor RJ, Hasselblad V, Subherwal S, Schmit KM, Heidenfelder BL, et al. Comparative effectiveness of medical therapy, supervised exercise, and revascularization for patients with intermittent claudication: A network meta-analysis. Clinical

[42] Pereira CE, Albers M, Romiti M, Brochado-Neto FC, Pereira CA. Meta-analysis of femoropopliteal bypass grafts for lower extremity arterial insufficiency. Journal of Vascular

[43] Muradin G, Bosch J, Stijnen T, Hunink M. Balloon dilation and stent implantation for treatment of femoropopliteal arterial disease: Metaanalysis. Radiology. 2001;**221**:137-145

[44] London N, Srinivasan R, Naylor A, Hartshorne T, Ratliff D, Bell P, et al. Subintimal angioplasty of femoropopliteal artery occlusions: The long-term results. European

[45] Desgranges P, Boufi M, Lapeyre M, Tarquini G, van Laere O, Losy F, et al. Subintimal angioplasty: Feasible and durable. European Journal of Vascular and Endovascular

[46] Katsanos K, Spiliopoulos S, Reppas L, Karnabatidis D. Debulking atherectomy in the peripheral arteris: Is there a role and what is the evidence? Cardiovascular and

[47] Katsanos K, Spiliopoulos S, Karunanithy N, Krokidis M, Sabharwal T, Taylor P. Bayesian network meta-analysis of nitinol stents, covered stents, drug-eluting stents, and drug-coated balloons in the femoropopliteal artery. Journal of Vascular Surgery.

[48] Aggarwall V, Waldo SW, Armstrong EJ. Endovascular revascularization for aortoiliac atherosclerotic disease. Vascular Health and Risk Management. 2016;**12**:117-127

of Cardiology. 2015;**65**:999-1009

44 Peripheral Arterial Disease - A Practical Approach

Association. 2015;**314**:1936-1944

Cardiology. 2015;**38**:378-386

Surgery. 2006;**44**:510-517

Surgery. 2004;**28**:138-141

2014;**59**:1123-1133

Journal of Vascular Surgery. 1994;**8**:148-155

Interventional Radiology. 2017;**40**:964-977

dication (IRONIC) trial. Circulation. 2014;**130**:939-947


**Section 2**

**Risk Assessment Peripheral Arterial Disease**

**Risk Assessment Peripheral Arterial Disease**

**Chapter 4**

**Provisional chapter**

**Cardiovascular Risk Evaluation in Patients with Critical**

**Cardiovascular Risk Evaluation in Patients with Critical** 

Assessment of the role and investigation particularities (comparative and complementary aspects, hierarchies, preferential indication) adapted to the context of a global cardiovascular (CV) evaluation, including clinical elements, non-invasive and invasive imagistic examination in order to estimate the cardiovascular risk (CVR) and to define the revascularization therapeutic strategy in patients with critical leg ischemia (CLI). Complete and accessible evaluation involves accessible means of investigation like clinical exam, electrocardiogram, cardiac biomarkers, arterial, cardiac, and carotid ultrasonography which could be affordable in all cardiovascular departments. Non-invasive stress tests, coronary and arterial cervical angiography imaging leads in selected cases and where is possible to the identification of significant coronary and/or carotid lesions potential responsible for cardiac and cerebrovascular events after vascular surgery. The evaluation algorithm allows better risk stratification of patients with CLI in high and intermediate CVR. The "poly-arterial" status in patients with CLI changes the intervention management with a more intensive pre-operative medical treatment, while the coronary and the carotid arteries revascularization might precedes the peripheral arterial revascularization

**Keywords:** critical leg ischemia (CLI), cardiovascular risk (CVR), poly-arterial (multi-arterial sites lesions), perioperative evaluation, non-invasive stress tests,

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.78046

**Leg Ischemia before Vascular Surgery**

**Leg Ischemia before Vascular Surgery**

Diana Larisa Hognogi Mocan and Roxana Chiorescu

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

procedures, in order to reduce the CV risk status.

Mirela-Anca Stoia, Mihaela Mocan,

Diana Larisa Hognogi Mocan and

Mirela-Anca Stoia, Mihaela Mocan,

http://dx.doi.org/10.5772/intechopen.78046

Cerasela Mihaela Goidescu,

Roxana Chiorescu

**Abstract**

cardiac biomarkers

Cerasela Mihaela Goidescu,

#### **Cardiovascular Risk Evaluation in Patients with Critical Leg Ischemia before Vascular Surgery Cardiovascular Risk Evaluation in Patients with Critical Leg Ischemia before Vascular Surgery**

DOI: 10.5772/intechopen.78046

Mirela-Anca Stoia, Mihaela Mocan, Cerasela Mihaela Goidescu, Diana Larisa Hognogi Mocan and Roxana Chiorescu Mirela-Anca Stoia, Mihaela Mocan, Cerasela Mihaela Goidescu, Diana Larisa Hognogi Mocan and Roxana Chiorescu

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.78046

#### **Abstract**

Assessment of the role and investigation particularities (comparative and complementary aspects, hierarchies, preferential indication) adapted to the context of a global cardiovascular (CV) evaluation, including clinical elements, non-invasive and invasive imagistic examination in order to estimate the cardiovascular risk (CVR) and to define the revascularization therapeutic strategy in patients with critical leg ischemia (CLI). Complete and accessible evaluation involves accessible means of investigation like clinical exam, electrocardiogram, cardiac biomarkers, arterial, cardiac, and carotid ultrasonography which could be affordable in all cardiovascular departments. Non-invasive stress tests, coronary and arterial cervical angiography imaging leads in selected cases and where is possible to the identification of significant coronary and/or carotid lesions potential responsible for cardiac and cerebrovascular events after vascular surgery. The evaluation algorithm allows better risk stratification of patients with CLI in high and intermediate CVR. The "poly-arterial" status in patients with CLI changes the intervention management with a more intensive pre-operative medical treatment, while the coronary and the carotid arteries revascularization might precedes the peripheral arterial revascularization procedures, in order to reduce the CV risk status.

**Keywords:** critical leg ischemia (CLI), cardiovascular risk (CVR), poly-arterial (multi-arterial sites lesions), perioperative evaluation, non-invasive stress tests, cardiac biomarkers

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **1. Introduction**

Atherosclerosis (ATS) is a systemic pathological process that affects coronary, cerebral and peripheral arterial circulation. Peripheral arterial disease (PAD) is a distinct athero-thrombotic syndrome marked by stenosis and occlusion of arterial beds [1]. A large proportion of PAD patients are not diagnosed before having a major ischemic cardiovascular (CV) event (MACE), which limits the use of medical therapies with recognized evidence of cardiovascular risk (CVR) reduction [2]. Even if claudication can remain stable over 10 years in 70–80% of patients, the prevalence of myocardial infarction (MI), stroke and CV death is high. PAD patients triple their risk of mortality from any other cause and have a six fold higher risk of death by coronary artery disease (CAD) than those without this ATS lesions. All these problems lead to repeated hospitalizations, low quality of life for patients and increased CV morbidity [3].

The major objective of CVR stratification is the reduction of perioperative global morbidity and mortality. Clarifying the patient's risk status allows the clinician as well as the surgeon to consent to a better informed patient. From a socio-economic point of view, reducing postoperative complications allowed to reduce perioperative care and treatment costs. The main impediment of perioperative risk stratification procedure is the duration, the cost and the number of investigational tests, which implicitly leads to postponing the intervention moment [4, 7, 8, 10]. And that could be done in elective surgery, but it seems to be quite

Cardiovascular Risk Evaluation in Patients with Critical Leg Ischemia before Vascular Surgery

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51

Retrospective clinical studies have shown that a history of coronary artery bypass surgery (CABG), percutaneous transluminal coronary angioplasty intervention (PCI) or coronary angiography without significant lesions indicates a low risk for perioperative cardiac events. The risk is similar to that of patients without clinical signs of significant CAD. The term "protection" given by the presence of a coronary graft cannot be specified. Many studies in large groups of patients have shown the independent predictors of perioperative CVR: the history of MI, angina pectoris (AP), and ischemic ST-T changes on the electrocardiogram (ECG/EKG),

The revised cardiac risk index (RCRI) is used by anesthesiologists and surgeons to assess the perioperative CVR in patients who undergo noncardiac surgery. Parameters included in the evaluation are age over 70 years, estimated risk of surgery, history or presence of IHD (MI or history of AP), congestive heart failure (HF), HT with signs of left ventricular hypertrophy (LVH), presence of Q waves or ischemic ST changes on resting electrocardiogram (ECG) cerebrovascular disease (CVD), the presence of DM (treated with insulin, additional risk) and renal failure (e.g., **Table 1**) [4, 12, 13]. The presence of more than one of these six independent predictors of cardiac complications following surgery is mandatory for further investigation. Patients who do not have active cardiac conditions are stratified into three groups by the RCRI: low (0 risk factor), intermediate (1–2 risk factors) and high (≥3 risk factors) [14, 15]. In a meta-analysis of 24 studies that reported the association of the RCRI with MACE or death in the hospital or within 30 days of surgery, the RCRI discriminated moderately well between

patients at low versus high risk for cardiac events after mixed noncardiac surgery.

However, its performance was considerably diminished when it was used in patients who underwent vascular surgery and emphasized the necessity of development and validation of a suitable CRI for use in vascular surgery patients [14, 16, 17]. The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database derived from general and other specialty surgery patients have allowed the development of another risk model, in which five risk factors (basically the same from RCRI) were determined to be associated with MI/cardiac arrest following an operation [13]. In the VSG-RCI assessment (published in 2010 by Vascular Study Group of New England (VSGNE), additional

difficult to be done in emergencies interventions.

*2.3.1. Overview*

**2.3. Clinical elements of perioperative cardiovascular risk**

as well as the clinical symptoms of congestive heart failure (HF) [9–11].

*2.3.2. Several clinical risk assessment scores for postoperative cardiac events*

#### **2. Predictors of perioperative cardiovascular risk**

#### **2.1. The risk of PAD patients in noncardiac vascular surgery**

It is estimated that more than 200 million patients suffer a surgery intervention every year worldwide, and the proportion might increase up to 300 million in time. Most of these patients are elderly men, 25% of them having a high or intermediate CVR. The rate of MACE ranges from 11% in patients with one CV risk factor (CVRF) up to 33% in patients with four CVRFs. Perioperative mortality ranges from 0.9% in patients with one CVRF to 11% in patients with four CVRFs. Approximately 60% of patients with PAD have coronary artery disease (CAD), up to 25% of PAD patients have carotid-cerebrovascular atherosclerotic lesions, and the rate of MACE (MI, stroke and CV death) reaches 7% per year. The main causes of mortality in patients with PAD are due to cardiac events, coronary MI (60%) first of all, followed by major or fatal stroke (35%) and only a small proportion (15%) of these patients dies due to complications of critical peripheral arterial ischemia (by gangrene, septicemia and multiorgan failure) [4]. Along with coronary and/or cerebrovascular disease, the type of surgery is an independent predictive risk factor for death of PAD patients with multisite arterial lesions [5, 6]. This is why, patients undergoing vascular surgery have a higher risk of MI (31%), CV death (5%) than general surgery patients (3%) [4, 7, 8]. A good diagnostic and management strategy for PAD patients reduces vital CVR in terms of short outcomes and identifies patients with coronary and/or cervical arterial lesions at risk for long-term CV events. noninvasive tests can provide both diagnostic information (by revealing coronary ischemic heart disease (IHD) or cervical arterial lesions) and CVR prognosis in patients who undergo noncardiac surgery [4, 9, 10].

#### **2.2. Benefits and limits of perioperative risk stratification**

Cardiac risk stratification separates patients for vascular surgery into high-risk, intermediate and low-risk categories, adapting the management of perioperative therapy to their needs. Low-risk patients will be further investigated by completing noninvasive and invasive tests, while for high-risk patients, perioperative management primordially changes. The major objective of CVR stratification is the reduction of perioperative global morbidity and mortality. Clarifying the patient's risk status allows the clinician as well as the surgeon to consent to a better informed patient. From a socio-economic point of view, reducing postoperative complications allowed to reduce perioperative care and treatment costs. The main impediment of perioperative risk stratification procedure is the duration, the cost and the number of investigational tests, which implicitly leads to postponing the intervention moment [4, 7, 8, 10]. And that could be done in elective surgery, but it seems to be quite difficult to be done in emergencies interventions.

#### **2.3. Clinical elements of perioperative cardiovascular risk**

#### *2.3.1. Overview*

**1. Introduction**

50 Peripheral Arterial Disease - A Practical Approach

Atherosclerosis (ATS) is a systemic pathological process that affects coronary, cerebral and peripheral arterial circulation. Peripheral arterial disease (PAD) is a distinct athero-thrombotic syndrome marked by stenosis and occlusion of arterial beds [1]. A large proportion of PAD patients are not diagnosed before having a major ischemic cardiovascular (CV) event (MACE), which limits the use of medical therapies with recognized evidence of cardiovascular risk (CVR) reduction [2]. Even if claudication can remain stable over 10 years in 70–80% of patients, the prevalence of myocardial infarction (MI), stroke and CV death is high. PAD patients triple their risk of mortality from any other cause and have a six fold higher risk of death by coronary artery disease (CAD) than those without this ATS lesions. All these problems lead to repeated

It is estimated that more than 200 million patients suffer a surgery intervention every year worldwide, and the proportion might increase up to 300 million in time. Most of these patients are elderly men, 25% of them having a high or intermediate CVR. The rate of MACE ranges from 11% in patients with one CV risk factor (CVRF) up to 33% in patients with four CVRFs. Perioperative mortality ranges from 0.9% in patients with one CVRF to 11% in patients with four CVRFs. Approximately 60% of patients with PAD have coronary artery disease (CAD), up to 25% of PAD patients have carotid-cerebrovascular atherosclerotic lesions, and the rate of MACE (MI, stroke and CV death) reaches 7% per year. The main causes of mortality in patients with PAD are due to cardiac events, coronary MI (60%) first of all, followed by major or fatal stroke (35%) and only a small proportion (15%) of these patients dies due to complications of critical peripheral arterial ischemia (by gangrene, septicemia and multiorgan failure) [4]. Along with coronary and/or cerebrovascular disease, the type of surgery is an independent predictive risk factor for death of PAD patients with multisite arterial lesions [5, 6]. This is why, patients undergoing vascular surgery have a higher risk of MI (31%), CV death (5%) than general surgery patients (3%) [4, 7, 8]. A good diagnostic and management strategy for PAD patients reduces vital CVR in terms of short outcomes and identifies patients with coronary and/or cervical arterial lesions at risk for long-term CV events. noninvasive tests can provide both diagnostic information (by revealing coronary ischemic heart disease (IHD) or cervical arterial lesions) and CVR prognosis in patients who undergo noncardiac surgery [4, 9, 10].

Cardiac risk stratification separates patients for vascular surgery into high-risk, intermediate and low-risk categories, adapting the management of perioperative therapy to their needs. Low-risk patients will be further investigated by completing noninvasive and invasive tests, while for high-risk patients, perioperative management primordially changes.

hospitalizations, low quality of life for patients and increased CV morbidity [3].

**2. Predictors of perioperative cardiovascular risk**

**2.1. The risk of PAD patients in noncardiac vascular surgery**

**2.2. Benefits and limits of perioperative risk stratification**

Retrospective clinical studies have shown that a history of coronary artery bypass surgery (CABG), percutaneous transluminal coronary angioplasty intervention (PCI) or coronary angiography without significant lesions indicates a low risk for perioperative cardiac events. The risk is similar to that of patients without clinical signs of significant CAD. The term "protection" given by the presence of a coronary graft cannot be specified. Many studies in large groups of patients have shown the independent predictors of perioperative CVR: the history of MI, angina pectoris (AP), and ischemic ST-T changes on the electrocardiogram (ECG/EKG), as well as the clinical symptoms of congestive heart failure (HF) [9–11].

#### *2.3.2. Several clinical risk assessment scores for postoperative cardiac events*

The revised cardiac risk index (RCRI) is used by anesthesiologists and surgeons to assess the perioperative CVR in patients who undergo noncardiac surgery. Parameters included in the evaluation are age over 70 years, estimated risk of surgery, history or presence of IHD (MI or history of AP), congestive heart failure (HF), HT with signs of left ventricular hypertrophy (LVH), presence of Q waves or ischemic ST changes on resting electrocardiogram (ECG) cerebrovascular disease (CVD), the presence of DM (treated with insulin, additional risk) and renal failure (e.g., **Table 1**) [4, 12, 13]. The presence of more than one of these six independent predictors of cardiac complications following surgery is mandatory for further investigation. Patients who do not have active cardiac conditions are stratified into three groups by the RCRI: low (0 risk factor), intermediate (1–2 risk factors) and high (≥3 risk factors) [14, 15]. In a meta-analysis of 24 studies that reported the association of the RCRI with MACE or death in the hospital or within 30 days of surgery, the RCRI discriminated moderately well between patients at low versus high risk for cardiac events after mixed noncardiac surgery.

However, its performance was considerably diminished when it was used in patients who underwent vascular surgery and emphasized the necessity of development and validation of a suitable CRI for use in vascular surgery patients [14, 16, 17]. The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database derived from general and other specialty surgery patients have allowed the development of another risk model, in which five risk factors (basically the same from RCRI) were determined to be associated with MI/cardiac arrest following an operation [13]. In the VSG-RCI assessment (published in 2010 by Vascular Study Group of New England (VSGNE), additional


procedures for low- and higher-risk patients. VSG-CRI risk model predicted more accurately the risk of cardiac complications in vascular surgery patients than the RCRI, which underestimated in-hospital cardiac events in patients undergoing vascular surgery and that new VSGNE index was more accurate than the RCRI in predicting postoperative cardiac event. It should be noted that in this recent study only 45% of patients were evaluated by stress

Cardiovascular Risk Evaluation in Patients with Critical Leg Ischemia before Vascular Surgery

http://dx.doi.org/10.5772/intechopen.78046

53

Generally, the type and the conditions of planned surgery cannot be fundamentally changed and can influence the postoperative CVR of patients. Urgent, prolonged (more than 5 h) and long hemodynamic stress (in major vascular interventions, intraabdominal and intrathoracic surgery) increase the risk of perioperative cardiac events. Peripheral vascular procedures present the highest risk (13%); the incidence of postoperative CV events could reach 10–15% [4, 7, 19].

Cardiac biomarkers have been studied for years in prediction of CV long-term outcomes, but less so for preoperative prediction. The most important and evaluated four biomarkers troponinI (TNI), N-terminal brain natriuretic peptide (NT-BNP), cystatin C, and C-reactive protein (CRP) significantly affected the prediction of death from CV causes. The statistical significance increased when the four biomarkers were incorporated into a model with established risk factors [20]. From six risk markers of interest (coronary artery calcium (CAC), carotid intima-media thickness (IMT), ankle-brachial index (ABI), brachial flow-mediated dilation (BFMD), CRP and family history of CAD, at a median follow up of 7.6 years, the CAC (had the highest predictive value), ABI, CRP and family history of CAD were independently associated with incident CAD [21, 22]. The addition of the degree of stenosis measured with computed tomography coronary angiography (CTCA), the presence of significant coronary artery stenosis (>50%) and/ or multivessel CAD in completion with the CAC value and the RCRI significantly improved the predictive model for postoperative CV events [23]. Addition of CTCA determines a slight improvement in discrimination for CV death or MI. When added to the RCRI, information from CTCA is five times more likely to overestimate risk in low-risk individuals than to identify a previously misclassified high-risk individual. Thus, current data do not support CTCA as

a first-line preoperative screening test for CAD in PAD patients (e.g., **Table 2**) [4, 24].

pared with a 32% rate in those with a baseline CRP < 5 mg/L (**Table 2**) [25].

High CRP levels are positively associated with PAD, independent of smoking, and multiple other cofounders, demonstrating the important role of inflammation in ATS. High levels of inflammatory markers would identify vascular surgery patients at increased risk for adverse events (graft failure, MACE) after lower extremity bypass surgery. Among patients with an elevated CRP (>5 mg/L) before surgery, major postoperative MACE occurred in 60%, com-

High preoperative NT-BNP or CRP are independent predictors of perioperative MACE in noncardiac surgery; the addition of these two markers to the RCRI improves its predictive power for adverse events. There is a statistically significant association between an elevated preoperative NT-BNP level and various CV adverse outcomes within 30 days of surgery (composite of cardiac death, nonfatal MI and atrial fibrillation). NT-BNP concentrations of 99.5 pg./mL predicted cardiac events and 448 pg./mL predicted cardiac death (all-cause

myocardial scintigraphy, the accessibility of the method still being limited [13, 18].

**2.4. Noninvasive cardiovascular parameters (biomarkers, coronary artery** 

**calcification)**

**Table 1.** Clinical risk factor to predict MACE and active cardiac conditions to be evaluated and to be treated before

noncardiac surgery.

risk factors were introduced: CVRF (increasing age, DM insulin-dependent, HT, smoking), clinical features (presence of aortic aneurysm, peripheral arterial ischemic symptoms, CAD, congestive HF, chronic obstructive pulmonary disease, elevated creatinine, abnormal cardiac stress test), previous CV medication administered (β-blockers long-term therapy, antiplatelet, statins) and revascularization interventions (carotid endarterectomy, peripheral arterial bypass, endovascular/surgical interventions for aortic aneurysm). The RCRI predicted risk after carotid endarterectomy reasonably well, but substantially underestimated the other procedures for low- and higher-risk patients. VSG-CRI risk model predicted more accurately the risk of cardiac complications in vascular surgery patients than the RCRI, which underestimated in-hospital cardiac events in patients undergoing vascular surgery and that new VSGNE index was more accurate than the RCRI in predicting postoperative cardiac event. It should be noted that in this recent study only 45% of patients were evaluated by stress myocardial scintigraphy, the accessibility of the method still being limited [13, 18].

Generally, the type and the conditions of planned surgery cannot be fundamentally changed and can influence the postoperative CVR of patients. Urgent, prolonged (more than 5 h) and long hemodynamic stress (in major vascular interventions, intraabdominal and intrathoracic surgery) increase the risk of perioperative cardiac events. Peripheral vascular procedures present the highest risk (13%); the incidence of postoperative CV events could reach 10–15% [4, 7, 19].

#### **2.4. Noninvasive cardiovascular parameters (biomarkers, coronary artery calcification)**

Cardiac biomarkers have been studied for years in prediction of CV long-term outcomes, but less so for preoperative prediction. The most important and evaluated four biomarkers troponinI (TNI), N-terminal brain natriuretic peptide (NT-BNP), cystatin C, and C-reactive protein (CRP) significantly affected the prediction of death from CV causes. The statistical significance increased when the four biomarkers were incorporated into a model with established risk factors [20]. From six risk markers of interest (coronary artery calcium (CAC), carotid intima-media thickness (IMT), ankle-brachial index (ABI), brachial flow-mediated dilation (BFMD), CRP and family history of CAD, at a median follow up of 7.6 years, the CAC (had the highest predictive value), ABI, CRP and family history of CAD were independently associated with incident CAD [21, 22]. The addition of the degree of stenosis measured with computed tomography coronary angiography (CTCA), the presence of significant coronary artery stenosis (>50%) and/ or multivessel CAD in completion with the CAC value and the RCRI significantly improved the predictive model for postoperative CV events [23]. Addition of CTCA determines a slight improvement in discrimination for CV death or MI. When added to the RCRI, information from CTCA is five times more likely to overestimate risk in low-risk individuals than to identify a previously misclassified high-risk individual. Thus, current data do not support CTCA as a first-line preoperative screening test for CAD in PAD patients (e.g., **Table 2**) [4, 24].

High CRP levels are positively associated with PAD, independent of smoking, and multiple other cofounders, demonstrating the important role of inflammation in ATS. High levels of inflammatory markers would identify vascular surgery patients at increased risk for adverse events (graft failure, MACE) after lower extremity bypass surgery. Among patients with an elevated CRP (>5 mg/L) before surgery, major postoperative MACE occurred in 60%, compared with a 32% rate in those with a baseline CRP < 5 mg/L (**Table 2**) [25].

risk factors were introduced: CVRF (increasing age, DM insulin-dependent, HT, smoking), clinical features (presence of aortic aneurysm, peripheral arterial ischemic symptoms, CAD, congestive HF, chronic obstructive pulmonary disease, elevated creatinine, abnormal cardiac stress test), previous CV medication administered (β-blockers long-term therapy, antiplatelet, statins) and revascularization interventions (carotid endarterectomy, peripheral arterial bypass, endovascular/surgical interventions for aortic aneurysm). The RCRI predicted risk after carotid endarterectomy reasonably well, but substantially underestimated the other

Adapted from [4, 13]. CCS, Canadian Cardiovascular Society; MI, myocardial infarction; HF, heart failure; NYHA,

**Table 1.** Clinical risk factor to predict MACE and active cardiac conditions to be evaluated and to be treated before

**Clinical risk factors Clinical elements Active cardiac** 

Previous MI

on stress test Use of nitroglycerin Typical angina pectoris

ECG Q waves

edema

Previous positive result

Previous PCI or CABG

Previous pulmonary

Evidence of heart failure on chest radiograph

Previous TIA disease Previous stroke

preoperative insulin

therapy

mg/dL

Third heart sound Bilateral rales

History of ischemic heart

52 Peripheral Arterial Disease - A Practical Approach

History of compensated previous congestive heart

History of cerebro-vascular

Diabetes mellitus (DM) With or without

Renal failure Creatinine level > 2

New York Heart Association; HR, heart rate.

noncardiac surgery.

disease (IHD)

failure (HF)

disease (CVD)

**condition**

Unstable coronary syndromes

De-compensated

Significant arrhythmias

Severe valvular disease

HF

**Clinical presentation**

Recent MI (7–30 days)

NYHA functional class IV worsening or new-onset HF

High-grade atrioventricular block Symptomatic ventricular arrhythmias Supraventricular arrhythmias (including atrial fibrillation) with uncontrolled ventricular rate (HR

Severe aortic stenosis (mean pressure gradient > 40 mm Hg, aortic valve

Symptomatic mitral stenosis (progressive dyspnea on exertion, exertional presyncope, or HF)

or symptomatic)

> 100 bpm at rest) Symptomatic bradycardia Newly recognized ventricular

tachycardia

area < 1.0 cm2

III–IV)

Unstable or severe angina (CCS class

High preoperative NT-BNP or CRP are independent predictors of perioperative MACE in noncardiac surgery; the addition of these two markers to the RCRI improves its predictive power for adverse events. There is a statistically significant association between an elevated preoperative NT-BNP level and various CV adverse outcomes within 30 days of surgery (composite of cardiac death, nonfatal MI and atrial fibrillation). NT-BNP concentrations of 99.5 pg./mL predicted cardiac events and 448 pg./mL predicted cardiac death (all-cause


An isolated peak cardiac biomarker elevation (preferably Tn) with or without correlation with ischemia may be the most sensitive tool to detect perioperative ischemic events that are clinically important [29]. A peak postoperative TnT (>0.02 ng/ml) measured within the first 3 days after surgery is the strongest predictor of 30 days mortality and explained 41.8% of the deaths in population [30]. The current data suggest that the absolute postoperative threshold of Tn is a stronger independent predictor of postoperative MI and intermediate-term survival than the increase in the Tn level between the preoperative and postoperative period. Current data therefore suggest that a raised preoperative Tn level may identify patients who are at risk of increased short-term CV morbidity, mortality and long-term mortality (1 year after surgery, but no longer) due to his high sensitivity, but it may be an inappropriate additional test for

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55

improving preoperative risk stratification due to its poor specificity (**Table 2**) [26].

**2.5. Cardiac evaluation**

*2.5.1. Investigation of inducible myocardial ischemia*

increases if the cardiac Tn serum level reaction is associated [7].

Preoperative cardiac biomarkers (especially BNP and Tn) evaluation adds incremental value to the risk stratification (by RCRI) for MACE (i.e. MI, pulmonary edema, CV death) and for in-hospital mortality [26]. While the body of evidence for the use of cardiac biomarkers for risk stratification is not extensive, the utility of assessing certain biomarkers in high-risk vascular surgical patients is suggested. A pharma-economic analysis of routine Tn surveillance in all patients who fulfilled the VISION study, based on a 25% relative risk reduction for vascular mortality and perioperative MI following the introduction of statin and aspirin therapy in highrisk patients who were Tn positive, found routine Tn surveillance to be cost-effective [30, 31].

An ECG should be obtained in all moderate to high-risk vascular surgery patients and confers well-accepted prognostic information [11]. The two most common forms of stress testing are exercise ECG (not often feasible due to debility of many vascular surgery patients) and exercise or pharmacologic stress testing combined with imaging (e.g. dobutamine/dipyridamole stress echocardiography (DSE) and myocardial perfusion imaging scintigraphy (MPI)). There is an association between a positive test (ST depression) and the likelihood of postoperative cardiac complications [15]. Outpatient ECG monitoring is relatively affordable, but requires manual interpretation from the investigator, being time-consuming. The automatic or manual interpretation of the ischemic score depends on the correctness and the accuracy of the recorded ECG path. At a very variable percentage of patients (12–73%), recording irregularities are an obstacle to correct interpretation [32]. A study involving both noncardiac (general and vascular) surgery patients has not shown benefits in performing this type of ECG screening in preoperative monitoring [33]. Other studies focused only on patient groups in vascular surgery demonstrated both the positive and negative predictive value of the results of ECG monitoring of silent ischemia, but under the significance of the values provided by MPI. However, the combination of the two tests does not increase the predictive value [7, 28]. Ischemia and/or intra- and postintervention endocardial lesions (T-negative or ST-segment elevation) are more predictive for perioperative cardiac events (up to 85% of perioperative MI may also be preceded by episodes of ischemia-lesion on ECG), and the prognostic value

**Table 2.** Indications and characteristics of various markers in preoperative cardiac risk stratification.

mortality in the short-, intermediate- and long-term postoperative periods). Over the threshold value of 448 pg./mL, NT-BNP had a positive predictive value of 100% and suggested that, if a preoperative NT-BNP level is in this vicinity, then it may be preferable to delay or cancel the procedure. Patients with high preintervention values of both CRP and NT-BNP are 10.6 times more likely to experience MACE than patients with normal CRP and NT-BNP values. Patients with a postoperative BNP ≥245 pg./ml or NT-proBNP ≥718 pg./ml had a significantly elevated risk for 30-day CV mortality, nonfatal MI, and cardiac failure. In addition, these postoperative elevations are able to predict long-term outcomes (i.e. ≥ 180 days after surgery) (e.g., **Table 2**) [26, 27].

Similar to postoperative troponin (Tn) levels, the current data for postoperative BNP suggest that it is the absolute postoperative threshold, rather than the increase in the BNP between the preoperative and postoperative period, that is associated with postoperative morbidity and mortality. Natriuretic peptides act as a cumulative marker of myocardial damage sustained during the perioperative period, possibly as a result of ischemic injury, volume overload or both. However, it remains unclear what the exact temporal relationship between postoperative BNP and Tn elevations is. In certain circumstances, it is possible that BNP elevation may precede Tn elevation, as may occur during fluid overload. In such cases, BNP elevations may identify patients at risk of subsequently developing myocardial injury and postoperative Tn elevation. Identification of patients at risk may provide a window for therapeutic intervention. It is likely that the more common scenario is postoperative BNP elevation that occurs together with, or shortly after, a postoperative Tn elevation. In these cases, elevated postoperative BNP may reflect the severity of myocardial injury and may prognosticate short- and long-term outcomes (e.g., **Table 2**) [26, 27].

In the perioperative period, it is clear that any Tn elevation is associated with an increased risk of death, even in the absence of a defining features (e.g., ischemic symptoms and ECG changes, evidence of MI on echocardiography) necessary for the diagnosis of MI. Owing to the effects of anesthesia, and widespread use of narcotics, the majority of perioperative ischemic events are clinically silent. In the Perioperative Ischemic Evaluation (POISE) trial, 65% of patients with a perioperative ischemic event did not experience ischemic symptoms [28]. The risk of death at 30 days was 9.7% in patients with a symptomatic MI and 12.5% in patients with an asymptomatic MI. Thus, the universal definition of MI may not be as sensitive in the perioperative period to detect ischemic events that are associated with poor, intermediate and long-term outcomes. An isolated peak cardiac biomarker elevation (preferably Tn) with or without correlation with ischemia may be the most sensitive tool to detect perioperative ischemic events that are clinically important [29]. A peak postoperative TnT (>0.02 ng/ml) measured within the first 3 days after surgery is the strongest predictor of 30 days mortality and explained 41.8% of the deaths in population [30]. The current data suggest that the absolute postoperative threshold of Tn is a stronger independent predictor of postoperative MI and intermediate-term survival than the increase in the Tn level between the preoperative and postoperative period. Current data therefore suggest that a raised preoperative Tn level may identify patients who are at risk of increased short-term CV morbidity, mortality and long-term mortality (1 year after surgery, but no longer) due to his high sensitivity, but it may be an inappropriate additional test for improving preoperative risk stratification due to its poor specificity (**Table 2**) [26].

Preoperative cardiac biomarkers (especially BNP and Tn) evaluation adds incremental value to the risk stratification (by RCRI) for MACE (i.e. MI, pulmonary edema, CV death) and for in-hospital mortality [26]. While the body of evidence for the use of cardiac biomarkers for risk stratification is not extensive, the utility of assessing certain biomarkers in high-risk vascular surgical patients is suggested. A pharma-economic analysis of routine Tn surveillance in all patients who fulfilled the VISION study, based on a 25% relative risk reduction for vascular mortality and perioperative MI following the introduction of statin and aspirin therapy in highrisk patients who were Tn positive, found routine Tn surveillance to be cost-effective [30, 31].

#### **2.5. Cardiac evaluation**

mortality in the short-, intermediate- and long-term postoperative periods). Over the threshold value of 448 pg./mL, NT-BNP had a positive predictive value of 100% and suggested that, if a preoperative NT-BNP level is in this vicinity, then it may be preferable to delay or cancel the procedure. Patients with high preintervention values of both CRP and NT-BNP are 10.6 times more likely to experience MACE than patients with normal CRP and NT-BNP values. Patients with a postoperative BNP ≥245 pg./ml or NT-proBNP ≥718 pg./ml had a significantly elevated risk for 30-day CV mortality, nonfatal MI, and cardiac failure. In addition, these postoperative elevations are able to predict long-term outcomes (i.e. ≥ 180 days after surgery)

**Biomarker Indication Sensitivity Specificity**

75–88% NA 97%

79% 61%

62–100% NA 54%

Obtain preoperatively in high surgical risk patients scheduled to

**Table 2.** Indications and characteristics of various markers in preoperative cardiac risk stratification.

undergo non-emergent vascular surgery

54 Peripheral Arterial Disease - A Practical Approach

CAC Evidence is currently lacking to recommend preoperative risk stratification with routine measurement

Similar to postoperative troponin (Tn) levels, the current data for postoperative BNP suggest that it is the absolute postoperative threshold, rather than the increase in the BNP between the preoperative and postoperative period, that is associated with postoperative morbidity and mortality. Natriuretic peptides act as a cumulative marker of myocardial damage sustained during the perioperative period, possibly as a result of ischemic injury, volume overload or both. However, it remains unclear what the exact temporal relationship between postoperative BNP and Tn elevations is. In certain circumstances, it is possible that BNP elevation may precede Tn elevation, as may occur during fluid overload. In such cases, BNP elevations may identify patients at risk of subsequently developing myocardial injury and postoperative Tn elevation. Identification of patients at risk may provide a window for therapeutic intervention. It is likely that the more common scenario is postoperative BNP elevation that occurs together with, or shortly after, a postoperative Tn elevation. In these cases, elevated postoperative BNP may reflect the severity of myocardial injury and may prognosticate short- and

In the perioperative period, it is clear that any Tn elevation is associated with an increased risk of death, even in the absence of a defining features (e.g., ischemic symptoms and ECG changes, evidence of MI on echocardiography) necessary for the diagnosis of MI. Owing to the effects of anesthesia, and widespread use of narcotics, the majority of perioperative ischemic events are clinically silent. In the Perioperative Ischemic Evaluation (POISE) trial, 65% of patients with a perioperative ischemic event did not experience ischemic symptoms [28]. The risk of death at 30 days was 9.7% in patients with a symptomatic MI and 12.5% in patients with an asymptomatic MI. Thus, the universal definition of MI may not be as sensitive in the perioperative period to detect ischemic events that are associated with poor, intermediate and long-term outcomes.

(e.g., **Table 2**) [26, 27].

NT-BNP CRP TnT

Adapted from [13].

long-term outcomes (e.g., **Table 2**) [26, 27].

#### *2.5.1. Investigation of inducible myocardial ischemia*

An ECG should be obtained in all moderate to high-risk vascular surgery patients and confers well-accepted prognostic information [11]. The two most common forms of stress testing are exercise ECG (not often feasible due to debility of many vascular surgery patients) and exercise or pharmacologic stress testing combined with imaging (e.g. dobutamine/dipyridamole stress echocardiography (DSE) and myocardial perfusion imaging scintigraphy (MPI)). There is an association between a positive test (ST depression) and the likelihood of postoperative cardiac complications [15]. Outpatient ECG monitoring is relatively affordable, but requires manual interpretation from the investigator, being time-consuming. The automatic or manual interpretation of the ischemic score depends on the correctness and the accuracy of the recorded ECG path. At a very variable percentage of patients (12–73%), recording irregularities are an obstacle to correct interpretation [32]. A study involving both noncardiac (general and vascular) surgery patients has not shown benefits in performing this type of ECG screening in preoperative monitoring [33]. Other studies focused only on patient groups in vascular surgery demonstrated both the positive and negative predictive value of the results of ECG monitoring of silent ischemia, but under the significance of the values provided by MPI. However, the combination of the two tests does not increase the predictive value [7, 28]. Ischemia and/or intra- and postintervention endocardial lesions (T-negative or ST-segment elevation) are more predictive for perioperative cardiac events (up to 85% of perioperative MI may also be preceded by episodes of ischemia-lesion on ECG), and the prognostic value increases if the cardiac Tn serum level reaction is associated [7].

#### *2.5.2. Noninvasive clinical imaging tests for cardiac perioperative risk assessment*

The American College of Cardiology (ACC) and the American Heart Association (AHA) as well as European Society of Cardiology (ESC) introduced guidelines to detect and manage perioperative cardiac risk and to prevent cardiac complications after vascular surgery [15, 19]. For preoperative noninvasive stress testing (NIST), the guidelines recommended that patients with active cardiac conditions should be evaluated and treated. NIST may be considered for patients with high or intermediate risk, if it will change management.

anemia, anesthetic and surgical stress. Noninvasive clinical screening (via ECG, cardiac, carotid-vertebral and peripheral arterial ultrasound and where possible by NIST) coupled with cardiac Tn serum levels dosing increases the safety of postoperative evolution and

Cardiovascular Risk Evaluation in Patients with Critical Leg Ischemia before Vascular Surgery

Although available in many cardiology centers, stress tests could not be performed systematically in all presurgery intervention patients. Due to the pain caused by critical leg ischemia (CLI), 30–70% of PAD patients could not perform the exercise test; they are added to those who could not do it the same because of obesity, degenerative diseases of the hip and knee or postvascular sequelae. In this context, the results of the effort tests were inconclusive in several studies [7, 36]. For these patients, stress tests using pharmacological agents that increase consumption and demand for oxygen represent an alternative for detecting coronary ischemia. These stress tests are dipyridamole-coupled ECG, thallium myocardial scintigraphy and echocardiography coupled with dobutamine or dipyridamole. The presence of "reversible" segmental infiltration defects fixation, or alterations in segmental parietal kinetics has a predictive sensitivity with positive value greater than the presence of "fixed" defects (e.g.,

Stress echocardiography with dobutamine (DSE) (or dipyridamole) has the theoretical advantage for evaluating both segmental ventricular parietal kinetics and altered LVF as determined by inducible myocardial ischemia. Most echocardiography stress studies conducted on vascular surgery patients suggested that DSE had a good negative predictive value, but the positive

**Advantages Disadvantages**

If pharmacologic stress testing is necessary, may be preferred in patients with known bronchospastic lung disease or significant carotid stenosis. Preferable choice when any additional information about left ventricular function and/or valvular heart disease is desired. Shorter testing time with results

If pharmacologic stress testing is necessary, may be preferred in patients with known arrhythmias and symptomatic or large aortic aneurysms. Preferable for the assessment of myocardial viability in patients with known left ventricular dysfunction, where the extent and severity of inducible ischemia

available sooner. No ionizing radiation.

Unable to use in many vascular surgery patients that suffer from claudication and poor functional capacity, as target heart rates cannot be achieved. No additional information about cardiac function that can be seen with cardiac imaging is

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Dobutamine has the ability to induce arrhythmias and increases in blood pressure and/or myocardial contractility;

Dipyridamole may induce bronchospasm or decreases in blood pressure; avoid in patients with bronchospastic lung disease or significant carotid stenosis. Longer testing time and delay for results to be available. Ionizing radiation. Failure to

avoid in patients with known arrhythmias and symptomatic or large

aortic aneurysms

detect global ischemia

provided

Stress ECG Most affordable of the common testing modalities

Widely available

is of importance.

**Table 4.** Comparison of noninvasive stress testing modalities.

improves the prognosis [34, 35].

**Table 4**) [28].

**Non-invasive stress** 

**tests**

Stress echocardiography (dobutamine) DSE

Myocardial perfusion imaging or scintigraphy (MPI with dipyridamole/ thallium)

Adapted from [13].

NIST include left ventricular (LV) function evaluation and inducible myocardial ischemia through ECG holter monitoring, ECG, echocardiography or scintigraphy coupled with exercise trial or pharmacological stress methods (**Table 3**). These noninvasive assessment tests should be able to detect cardiac abnormalities not revealed by clinical scores. The simple observation of some cardiac abnormalities does not necessarily means augmenting perioperative cardiac risk [32, 33].

NIST requires logistical and financial support. The PAD patients have less accessibility to MPI when compared to CAD patients. The interpretation of the investigation results in these studies is quite variable, which decreases the predictive accuracy. The explanations of these variable interpretations could be related to differences between the definition of fixed objectives, the follow-up strategies and the heterogeneity of the evaluated groups. Even though NIST are available and can be performed, they do not provide a "guarantee" for the perioperative period, as long as postoperative events have multifactorial causes that could not be accurately predicted [32, 33].

The perioperative period is characterized by myocardial ischemia due to hypercoagulability, increased consumption and oxygen demand, caused by catecholamine discharges, pain,


Adapted from [15].\*Uncertain utility may be considered. CAD indicates coronary artery disease; CVD, cerebrovascular disease; HF, heart failure; MET, metabolic equivalents; PAD, peripheral arterial disease.

**Table 3.** Recommendations for preoperative cardiac investigations in vascular surgery.

anemia, anesthetic and surgical stress. Noninvasive clinical screening (via ECG, cardiac, carotid-vertebral and peripheral arterial ultrasound and where possible by NIST) coupled with cardiac Tn serum levels dosing increases the safety of postoperative evolution and improves the prognosis [34, 35].

*2.5.2. Noninvasive clinical imaging tests for cardiac perioperative risk assessment*

patients with high or intermediate risk, if it will change management.

tive cardiac risk [32, 33].

56 Peripheral Arterial Disease - A Practical Approach

predicted [32, 33].

Non-invasive stress test

(NIST)

Electrocardiogram (ECG) None in prior 3 months

Echocardiogram Potential to change management

exercise capacity

The American College of Cardiology (ACC) and the American Heart Association (AHA) as well as European Society of Cardiology (ESC) introduced guidelines to detect and manage perioperative cardiac risk and to prevent cardiac complications after vascular surgery [15, 19]. For preoperative noninvasive stress testing (NIST), the guidelines recommended that patients with active cardiac conditions should be evaluated and treated. NIST may be considered for

NIST include left ventricular (LV) function evaluation and inducible myocardial ischemia through ECG holter monitoring, ECG, echocardiography or scintigraphy coupled with exercise trial or pharmacological stress methods (**Table 3**). These noninvasive assessment tests should be able to detect cardiac abnormalities not revealed by clinical scores. The simple observation of some cardiac abnormalities does not necessarily means augmenting periopera-

NIST requires logistical and financial support. The PAD patients have less accessibility to MPI when compared to CAD patients. The interpretation of the investigation results in these studies is quite variable, which decreases the predictive accuracy. The explanations of these variable interpretations could be related to differences between the definition of fixed objectives, the follow-up strategies and the heterogeneity of the evaluated groups. Even though NIST are available and can be performed, they do not provide a "guarantee" for the perioperative period, as long as postoperative events have multifactorial causes that could not be accurately

The perioperative period is characterized by myocardial ischemia due to hypercoagulability, increased consumption and oxygen demand, caused by catecholamine discharges, pain,

Adapted from [15].\*Uncertain utility may be considered. CAD indicates coronary artery disease; CVD, cerebrovascular

CAD, PAD, CVD Significant arrhythmia Structural heart disease Document baseline\*

within 1 year\*

HF with worsening symptoms Dyspnea of unknown origin

assessment or validated tool

Clinical suspicion of structural heart disease HF or structural heart disease and no prior test

Unable to perform >4 METs based on subjective

**Tests Prerequisites Recommended indications**

Perioperative risk death/MI >1%

Not for prognosis or as surrogate for

Perioperative risk death/MI >1% Elevated risk or known CAD Potential to change management

disease; HF, heart failure; MET, metabolic equivalents; PAD, peripheral arterial disease.

**Table 3.** Recommendations for preoperative cardiac investigations in vascular surgery.

Although available in many cardiology centers, stress tests could not be performed systematically in all presurgery intervention patients. Due to the pain caused by critical leg ischemia (CLI), 30–70% of PAD patients could not perform the exercise test; they are added to those who could not do it the same because of obesity, degenerative diseases of the hip and knee or postvascular sequelae. In this context, the results of the effort tests were inconclusive in several studies [7, 36]. For these patients, stress tests using pharmacological agents that increase consumption and demand for oxygen represent an alternative for detecting coronary ischemia. These stress tests are dipyridamole-coupled ECG, thallium myocardial scintigraphy and echocardiography coupled with dobutamine or dipyridamole. The presence of "reversible" segmental infiltration defects fixation, or alterations in segmental parietal kinetics has a predictive sensitivity with positive value greater than the presence of "fixed" defects (e.g., **Table 4**) [28].

Stress echocardiography with dobutamine (DSE) (or dipyridamole) has the theoretical advantage for evaluating both segmental ventricular parietal kinetics and altered LVF as determined by inducible myocardial ischemia. Most echocardiography stress studies conducted on vascular surgery patients suggested that DSE had a good negative predictive value, but the positive


**Table 4.** Comparison of noninvasive stress testing modalities.

predictive value was moderate. This does not increase the discriminatory value of the clinical criteria and does not change the appropriate risk group ranking after the RCRI score. In patients with one or two positive cardiac markers, the negative value of DSE was confirmed by the absence of postoperative cardiac events, while a positive result was followed by an incidence of up to 5% of cardiac events postoperative (MI, sudden death), so preoperative DSE offered no incremental value for determining postoperative adverse cardiac outcomes [7, 28, 37]. The second multicenter Dutch Echocardiographic Cardiac Risk Evaluation study showed no difference between the intermediate risk patients with positive NIST results group and negative results group in cardiac death or MI at 30 days after surgery (1.8 vs. 2.3%) (e.g., **Table 4**) [38].

treatment [40]. Widespread use of NIST in assessing the risk of perioperative CV complications remains controversial due to the low predictive value that affects the accuracy of the information. Therefore, the implications for CV risk stratification remain unclear. Even with the reported subtle differences between MPI and DSE, the fact remains that current guidelines do not distinguish between one or the other NIST for the preoperative workup of surgical patients. In line with current joint guidelines, we would recommend that surgeons take into account the availability and expertise in interpretation of the varying modalities and patients specifics at their respective institutions when deciding which test to obtain (e.g., **Figure 1**) [13]. A reversible defect on NIST is considered a predictor of postoperative MACE, and possible revascularization might be recommended. Some authors have suggested coronary angiography as a routine screening test, due to the significant prevalence of coronary involvement in vascular patients. Because coronary angiography is an invasive method with a risk of up to 0.05%, it was not used in studies as a routine examination in perioperative RCV assessment in noncardiac surgery patients. Last data suggested perioperative MI is quite common in

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**Figure 1.** Suggested algorithm for preoperative optimization in vascular surgical patients. AP—Antiplatelet therapy;

HTN—Hypertension. Adapted from [13].

Myocardial perfusion imaging (MPI) scintigraphy combined with pharmacokinetic stress test and EKG with dipyridamole are most used today in centers that benefit from this availability. Despite the initial expectations of better characterization and stratification of patients, especially from groups initially assessed as having intermediate or low risk for postoperative cardiac events, the results were not what they expected. Stress MPI has a relatively high sensitivity for the prediction of cardiac complications, but the specificity of this method is less satisfactory. Preoperative MPI has a high negative predictive value, but it has not proven to be sufficiently sensitive, and the benefit of MPI was unproven in low-risk patients and probably not cost-effective. There was no association between reversible defects on dipyridamole stress MPI and adverse cardiac events in moderate-risk patients undergoing elective vascular surgery. Based on the scintigraphy results, previously patients in the low-risk group switched to the intermediate risk group, but the rate of postsurgery intervention cardiac events do not change significantly, indicating the limited positive predictive value of these tests and proving no independent prognostic value superior to clinically stratified risk [7, 28]. Information about myocardial perfusion does not accurately predict adverse cardiac outcomes (e.g., as prolonged myocardial ischemia, MI, congestive HF and severe ventricular tachyarrhythmia) following univariate and multivariate analyses. The best correlates of cardiac complications were documented evidence of CAD and age greater than 65 years (e.g., **Table 4**) [12, 24, 39].

Two important questions remain unanswered related to the patient at risk: which stress test is best for which patient and what interventions outside of best medical management are of benefit to reducing perioperative ischemia events. No large head-to-head analyses of DSE versus MPI have been performed, although two well-known meta-analyses have compared the different modalities. DSE showed a positive trend toward better diagnostic performance than the other tests. Relative to MPI, DSE had a similar sensitivity, but significantly greater specificity (70% vs. 49%) (e.g., **Table 3**). Comparison with summary receiver operating characteristic analysis between all modalities revealed a trend toward better performance with DSE, but this was only significant when compared with MPI. DSE has better negative predictive value characteristics than MPI. In addition, a moderate-to-large perfusion defect by either DSE or MPI predicts postoperative MI and death, but DSE is slightly superior to MPI in predicting postoperative cardiac events [24, 39].

A typical pattern has emerged with stress testing for risk stratification prior to surgery; the positive predictive value is usually very low, and the negative predictive value is typically high. Routine preoperative NIST is not necessary in all patients undergoing revascularization for CLI, especially for patients in the low-risk group and for those undergoing endovascular treatment [40]. Widespread use of NIST in assessing the risk of perioperative CV complications remains controversial due to the low predictive value that affects the accuracy of the information. Therefore, the implications for CV risk stratification remain unclear. Even with the reported subtle differences between MPI and DSE, the fact remains that current guidelines do not distinguish between one or the other NIST for the preoperative workup of surgical patients. In line with current joint guidelines, we would recommend that surgeons take into account the availability and expertise in interpretation of the varying modalities and patients specifics at their respective institutions when deciding which test to obtain (e.g., **Figure 1**) [13]. A reversible defect on NIST is considered a predictor of postoperative MACE, and possible revascularization might be recommended. Some authors have suggested coronary angiography as a routine screening test, due to the significant prevalence of coronary involvement in vascular patients. Because coronary angiography is an invasive method with a risk of up to 0.05%, it was not used in studies as a routine examination in perioperative RCV assessment in noncardiac surgery patients. Last data suggested perioperative MI is quite common in

predictive value was moderate. This does not increase the discriminatory value of the clinical criteria and does not change the appropriate risk group ranking after the RCRI score. In patients with one or two positive cardiac markers, the negative value of DSE was confirmed by the absence of postoperative cardiac events, while a positive result was followed by an incidence of up to 5% of cardiac events postoperative (MI, sudden death), so preoperative DSE offered no incremental value for determining postoperative adverse cardiac outcomes [7, 28, 37]. The second multicenter Dutch Echocardiographic Cardiac Risk Evaluation study showed no difference between the intermediate risk patients with positive NIST results group and negative results group in cardiac death or MI at 30 days after surgery (1.8 vs. 2.3%) (e.g., **Table 4**) [38]. Myocardial perfusion imaging (MPI) scintigraphy combined with pharmacokinetic stress test and EKG with dipyridamole are most used today in centers that benefit from this availability. Despite the initial expectations of better characterization and stratification of patients, especially from groups initially assessed as having intermediate or low risk for postoperative cardiac events, the results were not what they expected. Stress MPI has a relatively high sensitivity for the prediction of cardiac complications, but the specificity of this method is less satisfactory. Preoperative MPI has a high negative predictive value, but it has not proven to be sufficiently sensitive, and the benefit of MPI was unproven in low-risk patients and probably not cost-effective. There was no association between reversible defects on dipyridamole stress MPI and adverse cardiac events in moderate-risk patients undergoing elective vascular surgery. Based on the scintigraphy results, previously patients in the low-risk group switched to the intermediate risk group, but the rate of postsurgery intervention cardiac events do not change significantly, indicating the limited positive predictive value of these tests and proving no independent prognostic value superior to clinically stratified risk [7, 28]. Information about myocardial perfusion does not accurately predict adverse cardiac outcomes (e.g., as prolonged myocardial ischemia, MI, congestive HF and severe ventricular tachyarrhythmia) following univariate and multivariate analyses. The best correlates of cardiac complications were documented evidence of CAD and age greater than 65 years (e.g., **Table 4**) [12, 24, 39].

58 Peripheral Arterial Disease - A Practical Approach

Two important questions remain unanswered related to the patient at risk: which stress test is best for which patient and what interventions outside of best medical management are of benefit to reducing perioperative ischemia events. No large head-to-head analyses of DSE versus MPI have been performed, although two well-known meta-analyses have compared the different modalities. DSE showed a positive trend toward better diagnostic performance than the other tests. Relative to MPI, DSE had a similar sensitivity, but significantly greater specificity (70% vs. 49%) (e.g., **Table 3**). Comparison with summary receiver operating characteristic analysis between all modalities revealed a trend toward better performance with DSE, but this was only significant when compared with MPI. DSE has better negative predictive value characteristics than MPI. In addition, a moderate-to-large perfusion defect by either DSE or MPI predicts postoperative MI and death, but DSE is slightly superior to MPI

A typical pattern has emerged with stress testing for risk stratification prior to surgery; the positive predictive value is usually very low, and the negative predictive value is typically high. Routine preoperative NIST is not necessary in all patients undergoing revascularization for CLI, especially for patients in the low-risk group and for those undergoing endovascular

in predicting postoperative cardiac events [24, 39].

**Figure 1.** Suggested algorithm for preoperative optimization in vascular surgical patients. AP—Antiplatelet therapy; HTN—Hypertension. Adapted from [13].

nonvascular surgical patients, vascular patients being relatively protected by cardiovascular medication previously administered, and that postoperative events such as anemia play a major role in postoperative MI [41].

however, that NIST does not provide additional predictive perioperative risk elements. Also, these tests do not provide information about cerebrovascular ischemic risk, derived from cervical arterial lesions, almost equally founded as coronary involvement in vascular surgery patients [7, 29]. Clinical judgment is important in assessing the balance between the relative urgency of identified cardiac and noncardiac surgery problems. A relatively small proportion of surgical patients require urgent preoperative treatment of cardiac conditions: congestive HF, life-threatening arrhythmias or acute coronary syndrome (ACS) (recent MI with significant evidence of ischemic risk or unstable, severe AP). However, there are situations in which the surgical situation with an important vital risk imposes the operative decision, even under

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Patients in noncardiac surgery are at risk of major perioperative cardiac events (sudden cardiac death, cardiorespiratory arrest, MI). In these patients, the in hospital mortality rate is among 15–25%. Patients who underwent a postsurgery intervention cardiac arrest have a mortality rate in the hospital up to 65% and represent a risk factor for cardiac death within the next 5 years postoperatively. Perioperative MI is an independent risk factor for the risk of CVD and the increase incidence of a new MI over the next 6 months postoperatively [7]. This is why the concern is both for the most discriminatory assessment of noncardiac surgery patients in different risk groups, as well as for finding the best prevention strategies (interventional, medical, etc.) for perioperative CV events. By preoperative coronary angiography, the prevalence of CAD ranged between 50 and 80% and is dependent on the specific distribution of the PAD. It is also clear that periprocedural myocardial ischemia, even non-ST segment MI and Tn leaks, confer a significant 26–55% decreased survival through 5 years, supporting the

In retrospective studies, for both vascular and nonvascular surgery patients, the "protective" effects of coronary revascularization in reducing perioperative MACE were controversial [7]. "Prophylactic" preoperative myocardial revascularization of significant lesions could reduce perioperative coronary complications in patients with unstable CAD (ACS) and high CVR.There is a significant difference in mortality among high CVR patients who underwent coronary revascularization prior to noncardiac surgery (0.9%) compared to high CVR patients who did not undergo coronary revascularization procedures (2.4%) [7]. Coronary revascularization performed prior to noncardiac surgery has as a primary objective the reduction of CV mortality in the long-term outcome and as a secondary objective, the reduction of CVR in patients with high coronary risk: unstable refractory AP, left main coronary artery stenosis, coronary multivessel significant lesions, including anterior descendent artery (ADA) and altered LV systolic function. Patients who underwent myocardial revascularization before noncardiac surgery had a lower rate of long-term postoperative cardiac events (up to 5 years after noncardiac surgery). The lowest incidence of CV events in long-term outcome after noncardiac vascular surgery was observed in the group of patients with PCI versus revascularized patients by CABG [50, 51].

The Coronary Artery Revascularization Prophylaxis (CARP) trial showed no difference in the rate of postoperative MI (defined by elevated Tn level) (12 vs. 14%) in 30-day mortality, and MACE and mortality at 2.7 years (22 vs. 23%) in patients scheduled for vascular surgery

*2.6.2. Impact of coronary revascularization decision on noncardiac surgery patients*

an incomplete cardiac evaluation [7, 29].

impetus for careful patient preparation [13].

#### *2.5.3. Cardiac ultrasound evaluation in perioperative assessment of PAD patients*

With cardiac ultrasound (US) (or echocardiography), we can evaluate both the function and the morphology of the heart. The presence of LVH is associated with an increased risk of CV morbidity and all-cause mortality, which emphasizes the importance of diagnosis. The quantitative evaluation of the LV systolic function by LV ejection fraction (LVEF) is a simple and specific predictive index in relation to clinical utility [42]. End-systolic LV volume is an independent predictor of survival in CAD and LVEF has prognostic value for survival in post-MI patients. The presence of diastolic dysfunction represents an early indicator of LV function impairment. Although that high mortality of PAD patients was mainly attributable to coexisting coronary or cervical arteries disease, the prevalence of US abnormalities in patients with peripheral arterial ischemia was not systematically studied. Asymptomatic LV dysfunction is predictive for short- and long-term perioperative CV events in vascular surgery patients; therefore, the echocardiogram should be routinely performed in surgical patients for stratification of CV risk, even in the absence of HF symptoms [43].

The prevalence of CVRF (smoking, DM, dyslipidemia, HT) in PAD patients causes, in addition to peripheral arterial lesions, coronary arteries and myocardial involvement with ischemic, hypertensive and/or diabetic heart disease, aortic and mitral valve calcifications and sometimes myophatic evolution through dilated cardiac disease [44–46]. In PAD patients were found high prevalence of clinically significant cardiac US changes (61.6% vs. 35.3%), especially related to the LV dysfunction and the presence of aortic stenosis (AS) compared to patients without PAD. The presence of PAD is shown to be an independent predictor of LVEF <50%. In PAD patients, MI and HF are the main causes of mortality [47]. PAD patients develop a significantly higher degree of LVH compared with patients with the same means BP but with no PAD. By cardiac US examination, LVH was found in 75% of patients with HT, CAD and PAD and in 46% of patients with HT and CAD but without PAD, respectively. LVH was found in 93% of PAD patients, with ABI <0.6, and 62% of patients with ABI between 0.6 and 0.9 [43, 47–49]. PAD patients with CLI have higher CV morbidity than stable PAD patients. US evaluation is useful in defining the group of patients with low CV risk, in which can be performed with relative safety the revascularization of the limb by interventional/surgery procedures. In the case of the intermediate risk group, additional CV risk assessment tests are required [44–50].

#### **2.6. Perioperative cardiac management strategies**

#### *2.6.1. The impact of perioperative risk stratification in the management of PAD patients*

Approximately 10% of general surgery patients are included in the high-risk surgical perioperative group after the standard clinical and noninvasive assessment. But for vascular surgery patients, the percentage of high-risk patients may increase by 10–20%. From these, 5–10% may be eligible for myocardial revascularization (PCI or CABG) [7]. In vascular surgery patients in intermediate or low perioperative risk groups, it is advisable to perform NIST. It is possible, however, that NIST does not provide additional predictive perioperative risk elements. Also, these tests do not provide information about cerebrovascular ischemic risk, derived from cervical arterial lesions, almost equally founded as coronary involvement in vascular surgery patients [7, 29]. Clinical judgment is important in assessing the balance between the relative urgency of identified cardiac and noncardiac surgery problems. A relatively small proportion of surgical patients require urgent preoperative treatment of cardiac conditions: congestive HF, life-threatening arrhythmias or acute coronary syndrome (ACS) (recent MI with significant evidence of ischemic risk or unstable, severe AP). However, there are situations in which the surgical situation with an important vital risk imposes the operative decision, even under an incomplete cardiac evaluation [7, 29].

#### *2.6.2. Impact of coronary revascularization decision on noncardiac surgery patients*

nonvascular surgical patients, vascular patients being relatively protected by cardiovascular medication previously administered, and that postoperative events such as anemia play a

With cardiac ultrasound (US) (or echocardiography), we can evaluate both the function and the morphology of the heart. The presence of LVH is associated with an increased risk of CV morbidity and all-cause mortality, which emphasizes the importance of diagnosis. The quantitative evaluation of the LV systolic function by LV ejection fraction (LVEF) is a simple and specific predictive index in relation to clinical utility [42]. End-systolic LV volume is an independent predictor of survival in CAD and LVEF has prognostic value for survival in post-MI patients. The presence of diastolic dysfunction represents an early indicator of LV function impairment. Although that high mortality of PAD patients was mainly attributable to coexisting coronary or cervical arteries disease, the prevalence of US abnormalities in patients with peripheral arterial ischemia was not systematically studied. Asymptomatic LV dysfunction is predictive for short- and long-term perioperative CV events in vascular surgery patients; therefore, the echocardiogram should be routinely performed in surgical patients for stratifi-

The prevalence of CVRF (smoking, DM, dyslipidemia, HT) in PAD patients causes, in addition to peripheral arterial lesions, coronary arteries and myocardial involvement with ischemic, hypertensive and/or diabetic heart disease, aortic and mitral valve calcifications and sometimes myophatic evolution through dilated cardiac disease [44–46]. In PAD patients were found high prevalence of clinically significant cardiac US changes (61.6% vs. 35.3%), especially related to the LV dysfunction and the presence of aortic stenosis (AS) compared to patients without PAD. The presence of PAD is shown to be an independent predictor of LVEF <50%. In PAD patients, MI and HF are the main causes of mortality [47]. PAD patients develop a significantly higher degree of LVH compared with patients with the same means BP but with no PAD. By cardiac US examination, LVH was found in 75% of patients with HT, CAD and PAD and in 46% of patients with HT and CAD but without PAD, respectively. LVH was found in 93% of PAD patients, with ABI <0.6, and 62% of patients with ABI between 0.6 and 0.9 [43, 47–49]. PAD patients with CLI have higher CV morbidity than stable PAD patients. US evaluation is useful in defining the group of patients with low CV risk, in which can be performed with relative safety the revascularization of the limb by interventional/surgery procedures. In the case of the

intermediate risk group, additional CV risk assessment tests are required [44–50].

*2.6.1. The impact of perioperative risk stratification in the management of PAD patients*

Approximately 10% of general surgery patients are included in the high-risk surgical perioperative group after the standard clinical and noninvasive assessment. But for vascular surgery patients, the percentage of high-risk patients may increase by 10–20%. From these, 5–10% may be eligible for myocardial revascularization (PCI or CABG) [7]. In vascular surgery patients in intermediate or low perioperative risk groups, it is advisable to perform NIST. It is possible,

*2.5.3. Cardiac ultrasound evaluation in perioperative assessment of PAD patients*

cation of CV risk, even in the absence of HF symptoms [43].

**2.6. Perioperative cardiac management strategies**

major role in postoperative MI [41].

60 Peripheral Arterial Disease - A Practical Approach

Patients in noncardiac surgery are at risk of major perioperative cardiac events (sudden cardiac death, cardiorespiratory arrest, MI). In these patients, the in hospital mortality rate is among 15–25%. Patients who underwent a postsurgery intervention cardiac arrest have a mortality rate in the hospital up to 65% and represent a risk factor for cardiac death within the next 5 years postoperatively. Perioperative MI is an independent risk factor for the risk of CVD and the increase incidence of a new MI over the next 6 months postoperatively [7]. This is why the concern is both for the most discriminatory assessment of noncardiac surgery patients in different risk groups, as well as for finding the best prevention strategies (interventional, medical, etc.) for perioperative CV events. By preoperative coronary angiography, the prevalence of CAD ranged between 50 and 80% and is dependent on the specific distribution of the PAD. It is also clear that periprocedural myocardial ischemia, even non-ST segment MI and Tn leaks, confer a significant 26–55% decreased survival through 5 years, supporting the impetus for careful patient preparation [13].

In retrospective studies, for both vascular and nonvascular surgery patients, the "protective" effects of coronary revascularization in reducing perioperative MACE were controversial [7]. "Prophylactic" preoperative myocardial revascularization of significant lesions could reduce perioperative coronary complications in patients with unstable CAD (ACS) and high CVR.There is a significant difference in mortality among high CVR patients who underwent coronary revascularization prior to noncardiac surgery (0.9%) compared to high CVR patients who did not undergo coronary revascularization procedures (2.4%) [7]. Coronary revascularization performed prior to noncardiac surgery has as a primary objective the reduction of CV mortality in the long-term outcome and as a secondary objective, the reduction of CVR in patients with high coronary risk: unstable refractory AP, left main coronary artery stenosis, coronary multivessel significant lesions, including anterior descendent artery (ADA) and altered LV systolic function. Patients who underwent myocardial revascularization before noncardiac surgery had a lower rate of long-term postoperative cardiac events (up to 5 years after noncardiac surgery). The lowest incidence of CV events in long-term outcome after noncardiac vascular surgery was observed in the group of patients with PCI versus revascularized patients by CABG [50, 51].

The Coronary Artery Revascularization Prophylaxis (CARP) trial showed no difference in the rate of postoperative MI (defined by elevated Tn level) (12 vs. 14%) in 30-day mortality, and MACE and mortality at 2.7 years (22 vs. 23%) in patients scheduled for vascular surgery with coronary artery revascularization before surgery compared with patients with no revascularization before surgery, but there was a statistically significant survival benefit at 4 years (87% vs. 70%) that persisted up to 8 years. The CARP trial focused on patients who had stable CAD and those without left main coronary disease or significant valvular heart disease. Time to vascular surgery was significantly longer in the revascularization group [52, 53]. Although this evidence is encouraging, caution is warranted. Of note, excellent adherence with cardioprotective drugs was documented. At least one large database review of nonvascular surgical patients concluded opposite findings, suggesting a benefit of revascularization, so the controversy remains open [54].

noncardiac surgery after stenting, consideration should be given to the risk of interrupting thienopyridine antiplatelet therapy compared with the risk of bleeding from surgical procedures, to continuation of aspirin in the perioperative period and to restarting thienopyridine

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Coronary revascularization is not recommended before surgery for patients with stable CAD in both ACC/AHA and ESC guidelines for the management in patients undergoing noncardiac surgery and it is recommended only in circumstances where it would be indicated even in the nonoperative setting. In general, CABG is recommended for left main disease, triple-vessel disease, complex anatomy or high-risk comorbidities (e.g. diabetes). Given the uncertain benefits of preoperative PCI for improving outcome after noncardiac surgery, current guidelines suggest consideration of PCI only for patients with left main disease whose comorbidities preclude CABG and for patients with unstable CAD (e.g. ST-elevation MI, non-ST-elevation ACS) who are appropriate candidates for emergency or urgent revascularization. If revascularization by PCI is considered, BMS is preferred over DES for vascular surgery patients given

The additional risk of anesthesia and intervention stress in noncardiac surgery patients who also have simultaneous cardiac problems should be noted. Even under these conditions, the idea of "prophylactic" coronary revascularization, in all cases, could not be accredited to patients who undergo vascular surgery, on the premises that they have multisite arterial lesions and therefore they also have coronary ATS [36]. Probably only prophylactic coronary revascularization of significant lesions in confirmed CAD could prevent perioperative com-

In the Reduction of Atherothrombosis for Continued Health (REACH) Registry, more than 50% of PAD patients had a concomitant CAD [2]. This means that modification of ATS risk factors is important in the long term and perioperative CVR is high in the short term [55]. Patients with high CVR should benefit from a sustained medical treatment and control of CVRF, considering the context of a possible myocardial revascularization intervention by PCI or by CABG, as well as the perspective of a future vascular surgery. Patients at risk of having CAD (regardless of the risk group) should be given control of blood pressure, serum cholesterol (via statins), cardiac compensation (angiotensin converting enzyme inhibitors (ACEI), diuretics) and arrhythmia (β-blockers, amiodarone). Numerous scientific studies have demonstrated the beneficial role of β-blockers, antiplatelets, ACEI and statins in reducing perioperative CV mortality in patients undergoing noncardiac vascular surgery. Statins and antiplatelet therapies are also involved in ATS plaque stabilization and improvement of

**2.7. Cervical arterial ultrasound evaluation in perioperative assessment of PAD** 

With the increase in the use of cardiac and arterial ultrasound (US) in assessing the patient with suspected or known PAD, the diagnostic and prognostic accuracy of these explorations has increased, the sensitivity and specificity of US detection cervical arterial lesions may reach 95%. Noninvasive US methods can also be applied to a wide range of patients including those

the time pressure to proceed with vascular surgery [15, 19].

plications in noncardiac surgery patients [8].

endothelial dysfunction [56–58].

**patients**

as soon as possible [4].

A prospective study included patients evaluated before vascular surgery by MPI to complete the coronary angiography indication followed by myocardial revascularization by PCI and/ or CABG. The results of MPI have increased the rate of coronary revascularization from 4.1% to 14.7%, without significantly improving postoperative MACE (MI, sudden cardiac death in the first 30 days after surgery intervention). However, it should be noted that the patients included in the study had one or two coronary vessels significant lesions with preserved LV systolic function and with optimal medical therapy. Patients with CAD and with severe impairment of LV systolic function, unstable AP and AS were not included. In vascular surgery patients having three coronary vessels significant lesions, there was a slight decrease in the incidence of perioperative cardiac events in myocardial revascularized patients before vascular surgery (43%) versus those treated by standard medical therapy (33%) [7]. Therefore in the coronary revascularization decision made prior to noncardiac surgery, three elements should be considered: the coronary risk of the patient, the risk of bypass surgery and the risk of noncardiac surgery. These results do not suggest that there are benefits in prophylactic coronary revascularization in patients with stable CAD regarding the short-term evolution after vascular surgery intervention [50, 51].

One of the main objectives of preoperative cardiac evaluation should be the identification of patients with high-risk coronary anatomy, amenable to revascularization, by an appropriate and discriminatory noninvasive/invasive cardiac evaluation. Once identified, the next question that needs to be answered is what the best revascularization strategy would be, CABG or PCI? The indication and the accomplishment of PCI before noncardiac vascular surgery are directed toward patients with high coronary risk prior to noncardiac surgery. PCI has the advantage of a low periprocedural risk (0.01%) and avoids the stress of CABG. The disadvantage of the PCI is that some lesions could not be accessed by angioplasty and should be resolved later by CABG [7, 50, 51]. Long-term outcomes appear to be better in patients undergoing CABG when compared to PCI, but incomplete revascularization after PCI, impact of stent-related complications and progressive occlusive CAD should be considered while evaluating the disadvantages of PCI over CABG. The heightened thrombogenic potential of newly implanted stents and prothrombotic state induced by the surgical stress increase the risk of in stent thrombosis. Premature discontinuation of antiplatelet therapy in patients with bare metal stents (BMS) or drug eluting stent (DES) is associated with a high rate of stent thrombosis and perioperative mortality. Elective surgical procedures that carry a potential for increased perioperative bleeding should be postponed until a minimum course of dual antiplatelet therapy (DAPT) has been completed. In patients presenting for emergency noncardiac surgery after stenting, consideration should be given to the risk of interrupting thienopyridine antiplatelet therapy compared with the risk of bleeding from surgical procedures, to continuation of aspirin in the perioperative period and to restarting thienopyridine as soon as possible [4].

with coronary artery revascularization before surgery compared with patients with no revascularization before surgery, but there was a statistically significant survival benefit at 4 years (87% vs. 70%) that persisted up to 8 years. The CARP trial focused on patients who had stable CAD and those without left main coronary disease or significant valvular heart disease. Time to vascular surgery was significantly longer in the revascularization group [52, 53]. Although this evidence is encouraging, caution is warranted. Of note, excellent adherence with cardioprotective drugs was documented. At least one large database review of nonvascular surgical patients concluded opposite findings, suggesting a benefit of revascularization, so the contro-

A prospective study included patients evaluated before vascular surgery by MPI to complete the coronary angiography indication followed by myocardial revascularization by PCI and/ or CABG. The results of MPI have increased the rate of coronary revascularization from 4.1% to 14.7%, without significantly improving postoperative MACE (MI, sudden cardiac death in the first 30 days after surgery intervention). However, it should be noted that the patients included in the study had one or two coronary vessels significant lesions with preserved LV systolic function and with optimal medical therapy. Patients with CAD and with severe impairment of LV systolic function, unstable AP and AS were not included. In vascular surgery patients having three coronary vessels significant lesions, there was a slight decrease in the incidence of perioperative cardiac events in myocardial revascularized patients before vascular surgery (43%) versus those treated by standard medical therapy (33%) [7]. Therefore in the coronary revascularization decision made prior to noncardiac surgery, three elements should be considered: the coronary risk of the patient, the risk of bypass surgery and the risk of noncardiac surgery. These results do not suggest that there are benefits in prophylactic coronary revascularization in patients with stable CAD regarding the short-term evolution

One of the main objectives of preoperative cardiac evaluation should be the identification of patients with high-risk coronary anatomy, amenable to revascularization, by an appropriate and discriminatory noninvasive/invasive cardiac evaluation. Once identified, the next question that needs to be answered is what the best revascularization strategy would be, CABG or PCI? The indication and the accomplishment of PCI before noncardiac vascular surgery are directed toward patients with high coronary risk prior to noncardiac surgery. PCI has the advantage of a low periprocedural risk (0.01%) and avoids the stress of CABG. The disadvantage of the PCI is that some lesions could not be accessed by angioplasty and should be resolved later by CABG [7, 50, 51]. Long-term outcomes appear to be better in patients undergoing CABG when compared to PCI, but incomplete revascularization after PCI, impact of stent-related complications and progressive occlusive CAD should be considered while evaluating the disadvantages of PCI over CABG. The heightened thrombogenic potential of newly implanted stents and prothrombotic state induced by the surgical stress increase the risk of in stent thrombosis. Premature discontinuation of antiplatelet therapy in patients with bare metal stents (BMS) or drug eluting stent (DES) is associated with a high rate of stent thrombosis and perioperative mortality. Elective surgical procedures that carry a potential for increased perioperative bleeding should be postponed until a minimum course of dual antiplatelet therapy (DAPT) has been completed. In patients presenting for emergency

versy remains open [54].

62 Peripheral Arterial Disease - A Practical Approach

after vascular surgery intervention [50, 51].

Coronary revascularization is not recommended before surgery for patients with stable CAD in both ACC/AHA and ESC guidelines for the management in patients undergoing noncardiac surgery and it is recommended only in circumstances where it would be indicated even in the nonoperative setting. In general, CABG is recommended for left main disease, triple-vessel disease, complex anatomy or high-risk comorbidities (e.g. diabetes). Given the uncertain benefits of preoperative PCI for improving outcome after noncardiac surgery, current guidelines suggest consideration of PCI only for patients with left main disease whose comorbidities preclude CABG and for patients with unstable CAD (e.g. ST-elevation MI, non-ST-elevation ACS) who are appropriate candidates for emergency or urgent revascularization. If revascularization by PCI is considered, BMS is preferred over DES for vascular surgery patients given the time pressure to proceed with vascular surgery [15, 19].

The additional risk of anesthesia and intervention stress in noncardiac surgery patients who also have simultaneous cardiac problems should be noted. Even under these conditions, the idea of "prophylactic" coronary revascularization, in all cases, could not be accredited to patients who undergo vascular surgery, on the premises that they have multisite arterial lesions and therefore they also have coronary ATS [36]. Probably only prophylactic coronary revascularization of significant lesions in confirmed CAD could prevent perioperative complications in noncardiac surgery patients [8].

In the Reduction of Atherothrombosis for Continued Health (REACH) Registry, more than 50% of PAD patients had a concomitant CAD [2]. This means that modification of ATS risk factors is important in the long term and perioperative CVR is high in the short term [55]. Patients with high CVR should benefit from a sustained medical treatment and control of CVRF, considering the context of a possible myocardial revascularization intervention by PCI or by CABG, as well as the perspective of a future vascular surgery. Patients at risk of having CAD (regardless of the risk group) should be given control of blood pressure, serum cholesterol (via statins), cardiac compensation (angiotensin converting enzyme inhibitors (ACEI), diuretics) and arrhythmia (β-blockers, amiodarone). Numerous scientific studies have demonstrated the beneficial role of β-blockers, antiplatelets, ACEI and statins in reducing perioperative CV mortality in patients undergoing noncardiac vascular surgery. Statins and antiplatelet therapies are also involved in ATS plaque stabilization and improvement of endothelial dysfunction [56–58].

#### **2.7. Cervical arterial ultrasound evaluation in perioperative assessment of PAD patients**

With the increase in the use of cardiac and arterial ultrasound (US) in assessing the patient with suspected or known PAD, the diagnostic and prognostic accuracy of these explorations has increased, the sensitivity and specificity of US detection cervical arterial lesions may reach 95%. Noninvasive US methods can also be applied to a wide range of patients including those at high risk for myocardial stress testing. With respect to CVD, a history should ascertain any previous stroke or transient ischemic attack, as well as detail the associated presentation and deficits. It is important to document the etiology to distinguish ATS carotid stenosis from cardio-embolic disease [44].

arteries), often symptomatic in one of the arterial areas and asymptomatic in other affected arterial areas [44–46]. There are fewer studies that investigated the lesions in the cervical arterial system in patients with PAD, compared to the large number of studies investigating the coronary-carotid relationship [65]. Noninvasive vascular imaging, especially CV ultrasound, plays a particularly important role in the carotid evaluation system, and in some aspects (the morphological characterization of the ATS lesion and the possibility of analysis in multiple "nonstandardized" incidences) is superior to conventional angiography allowing accurate measurement of the functional diameter and the lumen area of the vessel, precise localization and dimension (thickness/length/extension and volume) of the ATS plaque, the ecostructure and the surface characterization of the ATS plaque and defining the type of vascular remodeling. Thickness, ecogenicity and endoluminal surface of the ATS plaque are the first features related to a possible instability characterized by the US assessment of vascular lesions [67, 68]. There are studies that argue that US technique overestimates the severity of carotid stenosis compared to angiographic assessment, but these results depend on the US way of quantifying stenosis. The two-dimensional US combined with color and pulse doppler modules generally leads to superimposable results with angiographic quantification [68–71]. Carotid angiography is indicated in selected cases and, particularly in cases where US is difficult to perform and poses diagnosis problems, shows particular aspects or atypical pathological pathways. Angiography visualizes intracranial circulation, not quite accessible to extracranial US (even transcranial doppler), which delivers indirect and segmental information related to cerebral circulation, which may present morphological and trajectory abnormalities. Information on the patency of intracranial collateral supply is important in the prognosis of carotid occlusion. Carotid angiography, in this case, helps to diagnose a possible subocclusive carotid stenosis, which would make the patient a candidate for a probably invasive solution [44–46, 66–71].

Cardiovascular Risk Evaluation in Patients with Critical Leg Ischemia before Vascular Surgery

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65

Patients with PAD undergoing elective vascular surgery have a high prevalence of coronary and cerebrovascular ATS with associated comorbidities (DM, renal failure, anemia) and are at an increased risk of perioperative death and MACE (MI or stroke). The management of patients with PAD refered to high-risk vascular surgical procedure for intermittent claudication, CLI or expanding abdominal aortic aneurysm requires risk stratification, optimization of medical therapies and limited use of cardiac imaging prior to surgery. Preventive coronary revascularization in patients with stable CAD, prior to the vascular operation, with the sole intention of mitigating the risk of CV complications in the perioperative period, is not effective and may be associated with significant bleeding and thrombotic risks, in particular, if stents are used. The patient, surgeon and anesthesiologist can be initially informed about the risk of surgery using modern preoperative risk indices (RCRI, NSQIP, VSG-CRI calculator). Modern biomarkers, such as BNP and high-sensitivity Tn assays, are likely to play a more substantial role in preoperative assessment in the future, but for now they are indicated for high-risk patients. A strategy of universal use of cardiac Tn in the perioperative period for active surveillance of myocardial ischemia may be more reasonable and cost-effective than the current standard of care and widespread use of cardiac imaging prior to high-risk

**3. Conclusions**

Carotid intima media thickness (IMT) measured by US is a noninvasive predictive marker independent of the onset, progression and extension of ATS disease, demonstrated in numerous studies. The increase in carotid IMT is associated with a higher incidence of coronary events and multisite ATS lesions [59]. Increased IMT has common risk factors with the onset and progression of coronary and cerebrovascular ATS lesions (HT, DM, dyslipidemia, smoking) [60, 61]. Furthermore, increased IMT demonstrates good reproducibility for both the progression and regression of ATS disease and has been validated as a vascular marker of ATS evolution in numerous clinical trials. At the same time, invasive studies have shown that treating CVRF for CAD can also significantly reduce progression of IMT [62, 63]. Carotid and femoral IMT thickening are associated with the presence of CVRF; the occurrence of CV events is an indicator of the presence of PAD. It has been shown that these risk factors and CV events are significantly linked to increased carotid and femoral IMT. The treatment of CVRF is associated with a decrease in the progression of IMT thickening, parallel to the reduction of CV events and an improvement in the symptoms associated with PAD. This finding is particularly evident in the context of hypolipemiant therapy. IMT, as an additional predictor of CVR, may influence the decision of therapeutic intervention by medication [59–63].

Significantly elevated IMT values were seen in PAD patients at femoral artery, simultaneous with carotid artery, which allowed the conclusion that the presence of PAD is associated with morphological alterations and dynamic variations of both the femoral and the carotid artery walls. DM patients with PAD had a significantly higher IMT at the carotid bifurcation and at the distal common carotid artery, relative to those without PAD. Thus, carotid IMT may be a marker of ATS with different localizations in patients with type 2 DM and reflects morphological and hemodynamic similarities between arterial beds [64]. Today, IMT is one of the most commonly used parameters of noninvasive assessment of CV-ATS risk. In the initial stages, clinical latency of ATS, the increase of carotid IMT over normal value, often is an indicator of the asymptomatic arterial ATS lesions as well as an accompanied predictor for the increased risk of future CV events in already symptomatic arterial ATS territories [1, 65]. The amount of carotid IMT in PAD patients is correlated with body mass index (BMI), ABI, serum LDLcholesterol and the number of arterial cervical ATS plaques. These results support the hypothesis that ATS is a systemic, generalized disease, leading to functional and structural changes in each of the segments of the arterial system, as confirmed by many other studies that described the concomitant occurrence of carotid, coronary and peripheral arterial ATS disease. Up to 81% of PAD patients with increased IMT had angiographic coronary artery lesions, while 57% had carotid ATS plaques. Therefore, there is a statistically significant correlation between increased carotid IMT and the severity of CAD and also the presence of carotid ATS plaques and PAD clinically manifested which are positive predictive factors for the presence of CAD [1, 65].

PAD patients had advanced cervical arterial ATS lesions expressed both by a higher IMT and an increased prevalence of ATS plaques. Stenotic and occlusive ATS is a systemic phenomenon commonly coexisting in several arterial territories (coronary, carotid, peripheral arteries), often symptomatic in one of the arterial areas and asymptomatic in other affected arterial areas [44–46]. There are fewer studies that investigated the lesions in the cervical arterial system in patients with PAD, compared to the large number of studies investigating the coronary-carotid relationship [65]. Noninvasive vascular imaging, especially CV ultrasound, plays a particularly important role in the carotid evaluation system, and in some aspects (the morphological characterization of the ATS lesion and the possibility of analysis in multiple "nonstandardized" incidences) is superior to conventional angiography allowing accurate measurement of the functional diameter and the lumen area of the vessel, precise localization and dimension (thickness/length/extension and volume) of the ATS plaque, the ecostructure and the surface characterization of the ATS plaque and defining the type of vascular remodeling. Thickness, ecogenicity and endoluminal surface of the ATS plaque are the first features related to a possible instability characterized by the US assessment of vascular lesions [67, 68].

There are studies that argue that US technique overestimates the severity of carotid stenosis compared to angiographic assessment, but these results depend on the US way of quantifying stenosis. The two-dimensional US combined with color and pulse doppler modules generally leads to superimposable results with angiographic quantification [68–71]. Carotid angiography is indicated in selected cases and, particularly in cases where US is difficult to perform and poses diagnosis problems, shows particular aspects or atypical pathological pathways. Angiography visualizes intracranial circulation, not quite accessible to extracranial US (even transcranial doppler), which delivers indirect and segmental information related to cerebral circulation, which may present morphological and trajectory abnormalities. Information on the patency of intracranial collateral supply is important in the prognosis of carotid occlusion. Carotid angiography, in this case, helps to diagnose a possible subocclusive carotid stenosis, which would make the patient a candidate for a probably invasive solution [44–46, 66–71].

#### **3. Conclusions**

at high risk for myocardial stress testing. With respect to CVD, a history should ascertain any previous stroke or transient ischemic attack, as well as detail the associated presentation and deficits. It is important to document the etiology to distinguish ATS carotid stenosis from

Carotid intima media thickness (IMT) measured by US is a noninvasive predictive marker independent of the onset, progression and extension of ATS disease, demonstrated in numerous studies. The increase in carotid IMT is associated with a higher incidence of coronary events and multisite ATS lesions [59]. Increased IMT has common risk factors with the onset and progression of coronary and cerebrovascular ATS lesions (HT, DM, dyslipidemia, smoking) [60, 61]. Furthermore, increased IMT demonstrates good reproducibility for both the progression and regression of ATS disease and has been validated as a vascular marker of ATS evolution in numerous clinical trials. At the same time, invasive studies have shown that treating CVRF for CAD can also significantly reduce progression of IMT [62, 63]. Carotid and femoral IMT thickening are associated with the presence of CVRF; the occurrence of CV events is an indicator of the presence of PAD. It has been shown that these risk factors and CV events are significantly linked to increased carotid and femoral IMT. The treatment of CVRF is associated with a decrease in the progression of IMT thickening, parallel to the reduction of CV events and an improvement in the symptoms associated with PAD. This finding is particularly evident in the context of hypolipemiant therapy. IMT, as an additional predictor

of CVR, may influence the decision of therapeutic intervention by medication [59–63].

Significantly elevated IMT values were seen in PAD patients at femoral artery, simultaneous with carotid artery, which allowed the conclusion that the presence of PAD is associated with morphological alterations and dynamic variations of both the femoral and the carotid artery walls. DM patients with PAD had a significantly higher IMT at the carotid bifurcation and at the distal common carotid artery, relative to those without PAD. Thus, carotid IMT may be a marker of ATS with different localizations in patients with type 2 DM and reflects morphological and hemodynamic similarities between arterial beds [64]. Today, IMT is one of the most commonly used parameters of noninvasive assessment of CV-ATS risk. In the initial stages, clinical latency of ATS, the increase of carotid IMT over normal value, often is an indicator of the asymptomatic arterial ATS lesions as well as an accompanied predictor for the increased risk of future CV events in already symptomatic arterial ATS territories [1, 65]. The amount of carotid IMT in PAD patients is correlated with body mass index (BMI), ABI, serum LDLcholesterol and the number of arterial cervical ATS plaques. These results support the hypothesis that ATS is a systemic, generalized disease, leading to functional and structural changes in each of the segments of the arterial system, as confirmed by many other studies that described the concomitant occurrence of carotid, coronary and peripheral arterial ATS disease. Up to 81% of PAD patients with increased IMT had angiographic coronary artery lesions, while 57% had carotid ATS plaques. Therefore, there is a statistically significant correlation between increased carotid IMT and the severity of CAD and also the presence of carotid ATS plaques and PAD clinically manifested which are positive predictive factors for the presence of CAD [1, 65].

PAD patients had advanced cervical arterial ATS lesions expressed both by a higher IMT and an increased prevalence of ATS plaques. Stenotic and occlusive ATS is a systemic phenomenon commonly coexisting in several arterial territories (coronary, carotid, peripheral

cardio-embolic disease [44].

64 Peripheral Arterial Disease - A Practical Approach

Patients with PAD undergoing elective vascular surgery have a high prevalence of coronary and cerebrovascular ATS with associated comorbidities (DM, renal failure, anemia) and are at an increased risk of perioperative death and MACE (MI or stroke). The management of patients with PAD refered to high-risk vascular surgical procedure for intermittent claudication, CLI or expanding abdominal aortic aneurysm requires risk stratification, optimization of medical therapies and limited use of cardiac imaging prior to surgery. Preventive coronary revascularization in patients with stable CAD, prior to the vascular operation, with the sole intention of mitigating the risk of CV complications in the perioperative period, is not effective and may be associated with significant bleeding and thrombotic risks, in particular, if stents are used. The patient, surgeon and anesthesiologist can be initially informed about the risk of surgery using modern preoperative risk indices (RCRI, NSQIP, VSG-CRI calculator). Modern biomarkers, such as BNP and high-sensitivity Tn assays, are likely to play a more substantial role in preoperative assessment in the future, but for now they are indicated for high-risk patients. A strategy of universal use of cardiac Tn in the perioperative period for active surveillance of myocardial ischemia may be more reasonable and cost-effective than the current standard of care and widespread use of cardiac imaging prior to high-risk surgery. An elevated cardiac Tn after vascular surgery is recommended and predictive to detect perioperative ischemic events associated with a long-term mortality risk. If the cardiac biomarkers are negative and medical therapy is thought optimized, proceeding with the surgery seems safe. If the cardiac biomarkers are positive, NIST with either DSE or MPI is recommend (particular attention to whether it has potential to change management), taking into account specific patient characteristics that would afford benefit from one modality when compared to another. If the NIST is positive, then a cardiology consultation should be obtained with the appropriate preoperative steps and interventions taken to optimize the patient for their procedure. In general, preoperative coronary revascularization has a limited role, being reserved for the same indications as in routine circumstances. For the most part, chronic CV medications, such as aspirin, ACEI, ARBs and β-blockers, should be continued, but the decision should be individualized to each patient's circumstances. Ideally, thienopyridine antiplatelets therapy should be held before surgery, aside from cases of recent coronary stenting, where expert opinion should be sought. Using clinical risk assessment with biomarkers may decrease further expensive testing and might clarify, optimize risk stratification and indicate whether abnormal cardiac biomarker therapies will change outcomes [71, 72].

[5] Stoia M. Arterial Pathology in Vida-Simiti LA. Cluj-Napoca: Cardiologia, Ed. Medicala

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[6] Olinic D, Stoia M, et al. Doppler ultrasound evaluation of the topographic features of arterial lesions associated with chronic lower limb ischemia. Clujul Medical, 1999;

[7] Poldermans D, Hoeks SE, Feringa HH. Preoperative risk assessement and risk reduction before surgery. Journal of the American College of Cardiology. 2008;**51**(20):1913-1924.

[8] Eagle KA, Vaishnava P, Froehlich JB. Perioperative cardiovasculare care for patients undergoing noncardial surgical intervention. JAMA Internal Medicine. 2015;**175**(5):835-

[9] Di Minno G, Spadarella G, Cafaro G, et al. Systematic reviews and meta-analyses for more profitable strategies in peripheral arteries disease. Clinical perspectives and PAD research. Annals of Medicine. 2014;**46**(7):475-489. DOI: 10.3109/07853890.2014.932618 [10] Ford MK, Beattie S, Wijeysundera DN. Systematic review: Prediction of perioperative cardiac complications and mortality by the revised cardiac risk index. Annals of Internal

Medicine. 2010;**152**(1):26-35. DOI: 10.7326/0003-4819-152-1-201001050-00007

[11] Tsialtas D, Bolognesi MG, Tecchio T, Azzarone M, Quaini F, Bolognesi R. Clinical, electrocardiografic and echografic features in patients with major arterial vascular disease assigned to surgical revascularization. VASA. 2014;**43**(6):443-449. DOI: 10.1024/0301-1526/

[12] Moran PJ, Ghidella T, Power G, et al. The use of lee and co-workers index to assist a risk adjusted of perioperativecardiac outcome. Anaesthesia and Intensive Care. 2008;

[13] Zarinsefat A, Henke P. Update in preoperative risk assessment in vascular surgery patients. Journal of Vascular Surgery. 2015;**62**:499-509. DOI: 10.1016/j.jvs.2015.05.031 [14] Ford MK, Beattie WS, Wijeysundera DN. Systematic review: Prediction of perioperative cardiac complications and mortality by the revised cardiac risk index. Annals of Internal

[15] Fleischer LA et al. ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Journal of the American

[16] Moodley Y, Naidoo P, Biccard BM. The South African Vascular Surgical Cardiac Risk Index (SAVS-CRI): A prospective observational study. South African Medical Journal.

[17] de Hert SP, de Rango P. The concept of risk assessment and being unfit for surgery. European Journal of Vascular and Endovascular Surgery. 2016;**51**:857-866. DOI: 10.1016/j.

Medicine. 2010;**152**:26-35. DOI: 10.7326/0003-4819-152-1-201001050-00007

College of Cardiology. 2014;**64**(22):e77-e137. DOI: 10.1016 /j.jacc.201 4.07.944

Universitara "Iuliu Hatieganu; 2013. pp. 448-463

**LXXII**(4):476-483

a000391

ejvs.2016.02.00

DOI: 10.1016/j.jacc.2008.03.005

**36**(2):167-173. (PMID:18361006)

2013;**103**(10):746-750. DOI: 10.7196/SAMJ.6967

839. DOI: 10.1001/jamainternmed.2015.0150

#### **Author details**

Mirela-Anca Stoia\*, Mihaela Mocan, Cerasela Mihaela Goidescu, Diana Larisa Hognogi Mocan and Roxana Chiorescu

\*Address all correspondence to: mirelastoia@yahoo.com

Department of Cardiology, County Clinical Emergency Hospital, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania

#### **References**


[5] Stoia M. Arterial Pathology in Vida-Simiti LA. Cluj-Napoca: Cardiologia, Ed. Medicala Universitara "Iuliu Hatieganu; 2013. pp. 448-463

surgery. An elevated cardiac Tn after vascular surgery is recommended and predictive to detect perioperative ischemic events associated with a long-term mortality risk. If the cardiac biomarkers are negative and medical therapy is thought optimized, proceeding with the surgery seems safe. If the cardiac biomarkers are positive, NIST with either DSE or MPI is recommend (particular attention to whether it has potential to change management), taking into account specific patient characteristics that would afford benefit from one modality when compared to another. If the NIST is positive, then a cardiology consultation should be obtained with the appropriate preoperative steps and interventions taken to optimize the patient for their procedure. In general, preoperative coronary revascularization has a limited role, being reserved for the same indications as in routine circumstances. For the most part, chronic CV medications, such as aspirin, ACEI, ARBs and β-blockers, should be continued, but the decision should be individualized to each patient's circumstances. Ideally, thienopyridine antiplatelets therapy should be held before surgery, aside from cases of recent coronary stenting, where expert opinion should be sought. Using clinical risk assessment with biomarkers may decrease further expensive testing and might clarify, optimize risk stratification and indicate whether abnormal cardiac biomarker therapies will change outcomes [71, 72].

**Author details**

66 Peripheral Arterial Disease - A Practical Approach

**References**

10373299

1358863X10373299

Mirela-Anca Stoia\*, Mihaela Mocan, Cerasela Mihaela Goidescu,

Department of Cardiology, County Clinical Emergency Hospital, University of Medicine

[1] Stoia M, Farcas A, et al. The complete arterial screening of patients with peripheral artery disease frequently reveals the polyarterial status with particular implications in

[2] Suarez C et al. Influence of polyvascular disease on cardiovascular event rates. Insights from REACH registry. Vascular Medicine. 2015;**15**(4):259-265. DOI: 10.1177/1358863X

[3] Jeffrey WO, Brett AS. Peripheral artery disease: Current insight into the disease and its diagnosis and management. Mayo Clinic Proceedings. 2010;**85**(7):678-692. DOI: 10.1177/

[4] Arora V, Velanovich V, Alarcom W, et al. Preoperative assessement of cardiac risk and perioperative cardiac management in noncardiac surgery. International Journal of Sur-

the therapeutic strategy. Clujul Medical. 2005;**LXXVIII**(3):583-591

Diana Larisa Hognogi Mocan and Roxana Chiorescu

\*Address all correspondence to: mirelastoia@yahoo.com

and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania

gery. 2011;**9**:23-28. DOI: 10.1016/j.ijsu.2010.09.010


[18] Bertges DJ, Goodney PP, et al. The Vascular Study Group of New England Cardiac Risk Index (VSG-CRI) predicts cardiac complications more accurately than the revised cardiac index in vascular surgery patients. Journal of Vascular Surgery. 2010;**52**:674-683. DOI: 10.1016/j.jvs.2010.03.031

[30] Devereaux PJ, Chan MT, Alonso-Coello P, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery.

Cardiovascular Risk Evaluation in Patients with Critical Leg Ischemia before Vascular Surgery

http://dx.doi.org/10.5772/intechopen.78046

69

[31] Moodley Y, Naidoo P, Biccard BM. The south African vascular surgical cardiac risk index (SAVS-CRI): A prospective observational study. South African Medical Journal.

[32] Koizumi M, Sata N, Yasuda Y, et al. Preoperative cardiac evaluation: When should the surgeon consult the cardiologist? Surgery Today. 2006;**36**(5):425-435. DOI: 10.1007/

[33] Wright DE, Hunt DP. Perioperative surveillance for adverse myocardial events. Southern

[34] Flu WJ, Schouten O, Kuijk JP, Poldermans D. Perioperative cardiac damage in vascular surgery. European Journal of Vascular and Endovascular Surgery. 2010;**40**:1-8. DOI:

[35] Subherval S et al. Polyvascular disease and long term cardiovascular outcomes in older patients with non-ST segment elevation myocardial infarction. Circulation. Cardiovascular Quality and Outcomes. 2012;**5**(4):541-549. DOI: 10.1161/CIRCOUTCOMES.111.964379 [36] Cove C, Hamburg N, et al. The association of diagnostic criteria for myocardial infarction and perioperative cardiac risk factors in vascular surgery patients. Epidemiology and Prevention of CV Disease: Physiology, Pharmacology and Lifestyle; session title:

[37] Karagiannis SE, Feringa HH, et al. Value of myocardial viability estimation using dobutamine stress echocardiography in assessing risk ppreoperative before noncardiac vascular surgery in patients with left ventricular ejection fraction<35%. The American

Journal of Cardiology. 2007;**99**(11):1555-1559. DOI: 10.1016/j.amjcard.2007.01.033 [38] Poldermans D, Bax JJ, Schouten O, et al. Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving betablocker therapy with tight heart rate control? Journal of the American College of

[39] Weinstein H, Steingart R. Myocardial perfusion imaging for preoperative risk stratification. Journal of Nuclear Medicine. 2011;**52**:750-760. DOI: 10.2967/jnumed.110.076158 [40] Kim TY, Yun WS, Park K. Cardiac risk factors of revascularization in chronic atherosclerotic lower extremity ischemia. Journal of the Korean Surgical Society. 2013;**84**:178-184.

[41] Henke PK, Zamora-Berridi G, Englesbe MJ, et al. A case-cohort study of postoperative myocardial infarction. Surgery. 2014;**156**(4):pp.1018-1026, 1029. DOI: 10.1016/j.

[42] Tsao C et al. Subclinical and clinical correlate of left ventricular wall motion abnormalities in the community. The American Journal of Cardiology. 2011;**107**(6):949-955. DOI:

Medical Journal. 2008;**101**(1):52-58. DOI: 10.1097/SMJ.0b013e31815d3d19

JAMA. 2012;**307**:2295-2304. DOI: 10.1001/jama.2012.5502

2013;**103**(10):746-750. DOI: 10.7196/SAMJ.6967

Markers for prognosis in CVD. 2013;**2**:e000136

DOI: 10.4174/jkss.2013.84.3.178

10.1016/j.amjcard.2010.11.014

surg.2014.06.055

Cardiology. 2006;**48**:964-969. DOI: 10.1016/j.jacc.2006.03.059

s00595-005-3169-2

10.1016/j.ejvs.2010.03.014


[30] Devereaux PJ, Chan MT, Alonso-Coello P, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012;**307**:2295-2304. DOI: 10.1001/jama.2012.5502

[18] Bertges DJ, Goodney PP, et al. The Vascular Study Group of New England Cardiac Risk Index (VSG-CRI) predicts cardiac complications more accurately than the revised cardiac index in vascular surgery patients. Journal of Vascular Surgery. 2010;**52**:674-683.

[19] Kristensen SD, Knuuti J, et al. 2014 ESC/ESA guidelines on non-cardiac surgery: Cardiovascular assessment and management. European Heart Journal. 2014;**35**:2383-2431.

[20] Zethelius B, Berglund L, Sundstrom J, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. The New England Journal of Medicine.

[21] Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA.

[22] Kavousi M, Elias-Smale S, Rutten JH, et al. Evaluation of newer risk markers for coronary heart disease risk classification: A cohort study. Annals of Internal Medicine.

[23] Ahn JH, Park JR, Min JH, et al. Risk stratification using computed tomography coronary angiography in patients undergoing intermediate-risk noncardiac surgery. Journal of the American College of Cardiology. 2013;**61**:661-668. DOI: 10.1016/j.jacc.2012.09.060

[24] Sheth T, Chan M, Butler C, et al. Prognostic capabilities of coronary computed tomographic angiography before non-cardiac surgery: Prospective cohort study. BMJ. 2015;

[25] Owens CD, Ridker PM, Belkin M, et al. Elevated C-reactive protein levels are associated with postoperative events in patients undergoing lower extremity vein bypass surgery.

[26] Biccard BM, Devereaux PJ, Rodseth RN. Cardiac biomarkers in the prediction of risk in the non-cardiac surgery setting. Anaesthesia. 2014;**69**:484-493. DOI: 10.1111/anae.12635

[27] Rodseth RN, Biccard BM, Le Manach Y, et al. The prognostic value of pre - operative and postoperative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: A systematic review and individual patient data meta-analysis. Journal of the American

[28] Devereaux PJ, Xavier D, Pogue J, et al. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: A cohort study. Annals of Internal Medicine. 2011;**154**:523-528. DOI: 10.7326/

[29] Garcia S, McFalls E. Perioperative clinical variables and long-term survival following vascular surgery. World Journal of Cardiology. 2014;**6**(10):1100-1107. DOI: 10.4330/wjc.

Journal of Vascular Surgery. 2007;**45**:2-9. DOI: 10.1016/j.jvs.2006.08.048

College of Cardiology. 2014;**63**:170-180. DOI: 10.1016/j.jacc.2013.08.1630

2012;**156**:438-444. DOI: 10.7326/0003-4819-156-6-201203200-00006

DOI: 10.1016/j.jvs.2010.03.031

68 Peripheral Arterial Disease - A Practical Approach

DOI: 10.1093/eurheartj/ehu282

2008;**358**:2107-2116. DOI: 10.1056/NEJMoa0707064

2012;**308**:788-795. DOI: 10.1001/jama.2012.9624

**350**:h1907. DOI: 10.1136/bmj.h1907

0003-4819-154-8-201104190-00003

v6.i10.1100. ISSN 1949-8462 (online)


[43] Flu WJ, van Kujik JP, Hoeks SE, Poldermans D. Prognostic implications of asymptomatic left ventricular dysfunction in patients undergoing vascular surgery. Anesthesiology. 2010;**112**:1316-1324. DOI: 10.1097/ALN.0b013e3181da89ca

[54] Livhits M, Gibbons MM, de Virgilio C, et al. Coronary revascularization after myocardial infarction can reduce risks of noncardiac surgery. Journal of the American College

Cardiovascular Risk Evaluation in Patients with Critical Leg Ischemia before Vascular Surgery

http://dx.doi.org/10.5772/intechopen.78046

71

[55] Bhatt LD, (REACH Registry Investigators). Comparative determinants of 4-year cardiovascular events rates in stable outpatients at risk of or with atherotrombosis. JAMA,

[56] Poredos P, Jezovnik M, Kalodiki E, et al. Medical management of patients with peripheral arterial disease. International Angiology. 2015;**34**(1):75-93 PMID:24916346

[57] Hammill BG, Curtis LH, Bennett-Guerrero E, et al. Impact of heart failure on patients undergoing major noncardiac surgery. Anesthesiology. 2008;**108**(4):559-567. DOI: 10.1097/

[58] Stoia M, Lupu A, Farcaș A, Catalano M. Diffuse and extensive changes of the carotid and abdominal arteries distensibility and arterial resistivity in patient with diabetic mellitus.

[59] Bots ML, Sutton-Tyrrell K. Lessons from the past and promises for the future for carotid intima-media thickness. JAMA. 2012;**60**(17):1599-1604. DOI: 10.1016/j.jacc.2011.12.061 [60] Baldassarre D, Hamsten A, et al. Measurement of carotid-media thickness and of interadventitia common carotid diameter improve prediction of cardiovascular events (results of the IMPROVE-carotid intima media thickness[IMT] and IMTprogression as predictors of vascular events in high risk European population) study. Journal of the American College of Cardiology. 2012;**60**(16):1489-1499. DOI: 10.1016/j.

[61] Ruijter HM, Peters SAE, et al. Common carotid intima-media thickness measurements in cardiovascular risk prediction-a meta-analysis. JAMA. 2012;**308**(8):796-803. DOI:

[62] Chironi G, Simon A. The prognostic of intima-media thickness revisited. Archives of

[63] Bots ML, den Ruijter HM. Variability in the intima-media thickness measurement as marker for cardiovascular risk? Not quite settled yet. Cardiovascular Diagnosis and

[64] Peters SAE, den Ruijter M, Bots L, Moons KGM. Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: A sys-

[65] Nicolaides A, Kakkos S, et al. Asymptomatic internal carotid stenosis and cerebrovascular risk stratification. Journal of Vascular Surgery. 2010;**52**(1):1486-1496. DOI: 10.1016/j.

[66] Olinic D, Stoia M, et al. Doppler ultrasound examination in the quantification and characterization of the carotid stenosis ecostructure. International Angiology. 1997;**16**(1-3):

tematic review. Heart. 2012;**98**:177-184. DOI: 10.1136/heartjnl-2011-300747

Cardiovascular Diseases. 2013;**106**:1-3. DOI: 10.1016/j.acvd.2013.01.001

Therapy. 2012;**2**(1):3-5. DOI: 10.3978/ j.issn.2223-3652.2012.01.06

Romanian Journal of Angiology and Vascular Surgery. 2006;**3-4**:86-91

of Surgeons. 2011;**212**:1018-1026. DOI: 10.1016/j.jamcollsurg.2011.02.018

2010;**304**(12):1350-1357. DOI: 10.1001/ jama.2010.1322

ALN.0b013e31816725ef

jacc.2012.06.034

jvs.2010.07.021

1615-5939. ISSN: 1061-1711 (Print)

10.1001/jama.2012.9630


[54] Livhits M, Gibbons MM, de Virgilio C, et al. Coronary revascularization after myocardial infarction can reduce risks of noncardiac surgery. Journal of the American College of Surgeons. 2011;**212**:1018-1026. DOI: 10.1016/j.jamcollsurg.2011.02.018

[43] Flu WJ, van Kujik JP, Hoeks SE, Poldermans D. Prognostic implications of asymptomatic left ventricular dysfunction in patients undergoing vascular surgery. Anesthesiology.

[44] Stoia MA.Arterial and cardiac ultrasonography contribution in evaluation and establishing therapeutic strategy in patients with peripheral artery disease [thesis]. Cluj-Napoca:

[45] Stoia MA, Farcas AD, et al. Comparative analysis of cardiovascular risk profile, cardiac and cervical arterial ultrasound in patients with chronic coronary and peripheral arterial ischemia. In: Vlad S., Roman N editors. International Conference on Advancements of Medicine and Health Care through Technology, 2016. Cluj-Napoca, Romania: IFMBE

[46] Farcas AD, Stoia MA, et al. Cardiovascular risk profile, cardiac and cervical artery ultrasound in patients with peripheral artery disease. In: Vlad S, Roman N, editors. International Conference on Advancements of Medicine and Health Care through Technology; 2016. Cluj-Napoca, Romania: IFMBE Proceedings, Springer; 2017;**59**:

[47] Ward RP, Min JK, McDonough KM, Lang RM. High prevalence of important cardiac findings in patients with peripheral arterial disease referred for echocardiography. Journal of the American Society of Echocardiography. 2005;**18**(8):844-849. DOI: 10.1016/j.echo.2005.01.004

[48] Shigematsu H, Nishibe T, et al. Three year cardiovascular events and disease progression in patients with peripheral arterial disease: Results from the Japan medication therapy for peripheral arterial disease (J-METHOD). International Angiology. 2010;(2

[49] Van Kujik JP, Flu WJ, Valentijn TM, et al. Influence of left ventricular dysfunction (diastolic versus systolic) on long term prognosis in patients with or without diabetes mellitus having elective peripheral arterial surgery. The American Journal of Cardiology.

[50] Cassar A, Poldermans D, Rihal CS, Gersh B. The management of combined coronary artery disease and peripheral vascular disease. European Heart Journal. 2010;**31**:

[51] Freeman WK, Gibbons RJ. Perioperative cardiovascular assessment of patients undergoing noncardiac surgery. Mayo Clinic Proceedings. 2009;**84**(1):79-90. PMCID:

[52] McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major vascular surgery. The New England Journal of Medicine. 2004;**351**:2795-2804.

[53] Duncan D, Wijeysundera DM. Preoperative cardiac evaluation and management of the patient undergoing major vascular surgery. International Anesthesiology Clinics.

Proceedings, Springer; 2017;**59**:p.53-56. DOI: 10.1007/978-3-319-52875-5\_13

2010;**112**:1316-1324. DOI: 10.1097/ALN.0b013e3181da89ca

Editura Medicală Universitară "Iuliu Haţieganu"; 2015

pp. 57-60. DOI: 10.1007/978-3-319-52875-5\_13

2010;**106**(6):860-864. DOI: 10.1016/j.amjcard.2010.05.010

2016;**54**(2):1-32. DOI: 10.1097/AIA.0000000000000091

1565-1572. DOI: 10.1093/eurheartj/ehq186

PMC2664575, PMID: 19121258

DOI: 10.1056/NEJMoa041905

suppl):2-13 PMID:20357743

70 Peripheral Arterial Disease - A Practical Approach


[67] Olinic D, Stoia M, et al. Carotid plaque echostructure: Relation to carotid stenosis severity and symptomatology. Romanian Journal of Angiology and Vascular Surgery. 2000;**2**(2):77-81

**Chapter 5**

**Provisional chapter**

**Risk Factors in the Patients with Extracranial Carotid**

**Risk Factors in the Patients with Extracranial Carotid** 

There are vascular risk factors known to be associated with stroke. These risk factors have been shown to either directly or indirectly lead to stroke. The risk factors include hypertension (HT), diabetes mellitus (DM), smoking, hyperlipidaemia, ischemic heart disease (IHD) and atrial fibrillation (AF). Studies have shown that carotid atherosclerosis is a cause of stroke. Extracranial carotid atherosclerosis accounts for up to 40% of the ischemic strokes in the Western countries. The latest stroke guidelines recommend the routine use of Ultrasound Carotid Doppler to assess for extracranial carotid artery atherosclerotic diseases (carotid intima media thickness, plaques, carotid stenosis) in these patients. A previous study emphasized the value of carotid ultrasonography in the detec-

Stroke is one of the most common diseases in the world and results in up to 10% of mortality globally [1]. Stroke is the third leading cause of mortality and long-term disability in the

There are vascular risk factors known to be associated with ischemic strokes [3]. These risk factors have been shown to either directly or indirectly lead to stroke [3]. The risk factors include hypertension (HT), diabetes mellitus (DM), smoking, hyperlipidaemia, ischemic

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.75808

**Atherosclerosis**

**Abstract**

**1. Introduction**

United States of America [2].

**Atherosclerosis**

Mei-Ling Sharon Tai, Julia Sien Yuin Liew,

Mei-Ling Sharon Tai, Julia Sien Yuin Liew,

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

tion of early extracranial carotid atherosclerosis.

heart disease (IHD) and atrial fibrillation (AF) [3].

**Keywords:** extracranial, carotid, atherosclerosis, risk, factors

http://dx.doi.org/10.5772/intechopen.75808

Sheun Yu Mo and Mohamed Abdusalam Elwaifa

Sheun Yu Mo and Mohamed Abdusalam Elwaifa


#### **Risk Factors in the Patients with Extracranial Carotid Atherosclerosis Risk Factors in the Patients with Extracranial Carotid Atherosclerosis**

DOI: 10.5772/intechopen.75808

Mei-Ling Sharon Tai, Julia Sien Yuin Liew, Sheun Yu Mo and Mohamed Abdusalam Elwaifa Mei-Ling Sharon Tai, Julia Sien Yuin Liew, Sheun Yu Mo and Mohamed Abdusalam Elwaifa

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.75808

#### **Abstract**

[67] Olinic D, Stoia M, et al. Carotid plaque echostructure: Relation to carotid stenosis severity and symptomatology. Romanian Journal of Angiology and Vascular Surgery.

[68] Bekelis K, Labropoulos N, Pappas P, Gasparis A. B-mode estimate of carotid stenosis: Planimetric measurements complement the velocity estimate of internal carotid stenosis.

[69] Beach KW, Bergelin RO, Leotta DF, Primozich JF, Sevareid PM, Stutzman ET, Zierler RE. Standardized ultrasound evaluation of carotid stenosis for clinical trials: University of Washington Ultrasound reading center. Cardiovascular Ultrasound. 2010;**8**(44):1-15.

[70] Byrnes KR, Ross CB. The current role of duplex ultrasonography in the management of carotid atherosclerosis: Foundations and advances. International Journal of Vascular

[71] AbuRahma AF, Srivastava M, et al. Critical appraisal of the carotid duplex consensus criteria in the diagnosis of carotid artery stenosis. Journal of Vascular Surgery. 2011;**53**:

[72] Norgren L, Hiatt WR, Dormandy JA, Hirsch AT, Jaff MR, Diehm C, Baumgartner I, Belch JJF. The next 10 years in the management of peripheral artery disease: Perspectives from the 'PAD 2009' conference. European Journal of Vascular and Endovascular Surgery.

International Angiology. 2013;**32**(5):506-511 PMID:23903310

Medicine. 2012:1-10. DOI: 10.1155/2012/187872

2010;**40**:375-380. DOI: 10.1016/j.ejvs.2010.05.005

53-56. DOI: 10.1016/j.jvs.2010.07.045

2000;**2**(2):77-81

72 Peripheral Arterial Disease - A Practical Approach

DOI: 10.1002/ajum.12080

There are vascular risk factors known to be associated with stroke. These risk factors have been shown to either directly or indirectly lead to stroke. The risk factors include hypertension (HT), diabetes mellitus (DM), smoking, hyperlipidaemia, ischemic heart disease (IHD) and atrial fibrillation (AF). Studies have shown that carotid atherosclerosis is a cause of stroke. Extracranial carotid atherosclerosis accounts for up to 40% of the ischemic strokes in the Western countries. The latest stroke guidelines recommend the routine use of Ultrasound Carotid Doppler to assess for extracranial carotid artery atherosclerotic diseases (carotid intima media thickness, plaques, carotid stenosis) in these patients. A previous study emphasized the value of carotid ultrasonography in the detection of early extracranial carotid atherosclerosis.

**Keywords:** extracranial, carotid, atherosclerosis, risk, factors

#### **1. Introduction**

Stroke is one of the most common diseases in the world and results in up to 10% of mortality globally [1]. Stroke is the third leading cause of mortality and long-term disability in the United States of America [2].

There are vascular risk factors known to be associated with ischemic strokes [3]. These risk factors have been shown to either directly or indirectly lead to stroke [3]. The risk factors include hypertension (HT), diabetes mellitus (DM), smoking, hyperlipidaemia, ischemic heart disease (IHD) and atrial fibrillation (AF) [3].

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Studies have shown that carotid atherosclerosis is a cause of stroke [4]. Annually, about 20–30% of new strokes are due to atherosclerotic carotid artery disease [5]. The latest stroke guidelines recommend the routine use of ultrasound carotid Doppler to assess for extracranial carotid artery atherosclerotic diseases (carotid intima media thickness, plaques, carotid stenosis) in these patients [6].

which is a major anti-atherosclerotic agent [20–22]. Hyperglycemia inhibits the production of NO by restraining the activation of endothelial NO synthase [23]. In addition, the prevalence of extracranial carotid atherosclerosis is significantly higher in the ketosis-onset DM patients than in the control subjects [24]. The frequency of extracranial carotid atherosclerosis in the

Risk Factors in the Patients with Extracranial Carotid Atherosclerosis

http://dx.doi.org/10.5772/intechopen.75808

75

Smoking is also known to be associated with atherosclerosis of the extracranial carotid vessels [14]. The percentage of the patients with smoking history was 25% in Wasay et al.'s study [16]. Smoking leads to damage of cells that line the arteries. In addition, smoking increases the build-up of plaque constituents in the arteries. Moreover, smoking results in thickening and

Smoking history is a determinant of the occurrence of a new carotid plaque in the subjects with no previous carotid atherosclerosis and also free of previous vascular events [8]. In addition, there is a significant association between severe extracranial carotid atherosclerosis and smoking [4]. Furthermore, smoking was found to be associated with carotid plaque and extracranial carotid stenosis in several studies [9, 26, 27]. Cessation of smoking will be helpful in

IHD and ischemic stroke are vascular diseases [28]. IHD was present in 11.8–20% of the Singapore stroke patients [3]. Moreover, IHD was associated with carotid stenosis in a study [27]. In another study conducted in Japan on consecutive patients who had coronary angiog-

AF is known cardiovascular risk factor of stroke [30]. AF can predispose to embolism and stroke [31]. AF is commonly associated with stroke in South Asia, Western Europe, North America and Australia [32]. Increased CIMT and presence of carotid plaque are associated with increased risk of ischemic stroke in the patients with AF [33]. Higher CIMT and the pres-

Age is an important risk factor for extracranial carotid atherosclerosis, especially in the Chinese and South Koreans [9, 11, 14, 19, 35]. These patients tend to be older in age [9, 11, 19, 35]. Age is a significant predictor of the occurrence of a new carotid plaque in the general population [8]. The incremental probability of the occurrence of plaque is higher in the subject's midlife [8]. In the subjects aged ≥40 years old, the severity of carotid atherosclerosis (plaques, stenosis) was significantly associated with age [4]. Moreover, the frequency of extracranial carotid atherosclerosis significantly increases with age in the DM patients (ketosis-onset and non-ketotic

Male gender is also risk factor for extracranial atherosclerosis [9, 19]. 14.8% of the patients with extracranial atherosclerosis, had family history of stroke [9]. In a Chinese study, 48.4% of

Elevated CIMT is associated with an increased risk of stroke [20]. Plaque rupture with subsequent embolism can lead to stroke [20]. The presence of plaque is associated with an increased

One population study showed the relationship between extracranial carotid atherosclerotic lesions with the classic risk factors such hypertension, hyperlipidaemia and smoking [28].

ence of carotid plaque are associated with higher incidence of AF incidence [34].

the healthy population with extracranial carotid atherosclerosis had obesity [19].

ketosis-onset DM patients is similar to the non-ketotic type 2 DM patients [24].

narrowing of the arteries [25].

DM) [24].

the management of these stroke patients.

raphy, 6% of them had extracranial carotid stenosis [29].

risk morbidity and mortality secondary to stroke [28].

Ultrasound carotid Doppler is a non-invasive and cost-effective test [7]. Carotid intima media thickness (CIMT) measurements and plaque location are evaluated on gray scale imaging (B-mode) [7]. Flow disturbance and stenosis is assessed on color Doppler [7]. The blood flow velocities are examined on spectral Doppler [7].

A previous study emphasized the value of ultrasound carotid Doppler in the detection of early extracranial carotid atherosclerosis [4]. In the world, an increased CIMT is found in 9.4% of the men and 11.7% of the women [4]. Assessment of CIMT increases with ultrasound carotid Doppler in the subjects without carotid atherosclerosis and free of previous vascular events predicts the occurrence of carotid plaque [8].

The prevalence of carotid plaque is 13.3% in the men and 13.4% in the women in the world [8]. The prevalence of extracranial carotid stenosis is 2.7% in the men and 1.5% in the women globally [8]. Stroke is associated with the plaques containing softer tissue, especially with thin fibrous cap [2].

Hyperlipidaemia is a common risk factor for extracranial atherosclerosis [9]. The risk factor of hyperlipidaemia was one of the two most common risk factors for stroke in Singapore (76.5–86.4%) [3]. Hyperlipidaemia results in an atheroma or a fibrofatty plaque leading to gradual occlusion of the arteries. As the plaques increase in size, they progressively occlude the lumen and compromise the blood flow causing stroke [10]. In the South Korean studies, extracranial atherosclerosis was associated with higher LDL levels [9, 11].

Furthermore, low levels of HDL cholesterol are associated with an increased risk of having echolucent, rupture-prone atherosclerotic plaques [12]. In addition, an increased risk of having an echolucent plaque is independently associated with increasing degree of stenosis [12]. The subjects with echolucent plaques have increased risk of ischemic cerebrovascular events and stroke independent of the degree of stenosis and cardiovascular risk factors [13].

A community-based study in Taiwan showed that hypertension strongly influenced extracranial carotid atherosclerosis and hypertension was the predictor of carotid stenosis ≥50% [14, 15]. The frequencies of hypertension among the stroke patients in the other Asian countries were: 59% in Pakistan [16], 38.3% in Japan [17], and 19–28% in China, Korea and Taiwan [17].

There are several mechanisms of stroke due to hypertension. High blood pressure results in endothelial damage, which leads to thrombi formation [18]. Hypertension is also known to accelerate the atherosclerotic process [18]. Moreover, in the general population, hypertension is a predictor of the occurrence of plaques [8]. Systolic blood pressure is significantly associated with severe extracranial carotid atherosclerosis (plaque, stenosis) [4].

The percentages of ischemic stroke patients with DM were 37% in Pakistan [16] and 30% in South Korea [11]. DM is an important risk factor for extracranial carotid atherosclerosis [14, 19]. DM affects the vascular endothelium and reduces the bioavailability of nitric oxide (NO), which is a major anti-atherosclerotic agent [20–22]. Hyperglycemia inhibits the production of NO by restraining the activation of endothelial NO synthase [23]. In addition, the prevalence of extracranial carotid atherosclerosis is significantly higher in the ketosis-onset DM patients than in the control subjects [24]. The frequency of extracranial carotid atherosclerosis in the ketosis-onset DM patients is similar to the non-ketotic type 2 DM patients [24].

Studies have shown that carotid atherosclerosis is a cause of stroke [4]. Annually, about 20–30% of new strokes are due to atherosclerotic carotid artery disease [5]. The latest stroke guidelines recommend the routine use of ultrasound carotid Doppler to assess for extracranial carotid artery atherosclerotic diseases (carotid intima media thickness, plaques, carotid

Ultrasound carotid Doppler is a non-invasive and cost-effective test [7]. Carotid intima media thickness (CIMT) measurements and plaque location are evaluated on gray scale imaging (B-mode) [7]. Flow disturbance and stenosis is assessed on color Doppler [7]. The blood flow

A previous study emphasized the value of ultrasound carotid Doppler in the detection of early extracranial carotid atherosclerosis [4]. In the world, an increased CIMT is found in 9.4% of the men and 11.7% of the women [4]. Assessment of CIMT increases with ultrasound carotid Doppler in the subjects without carotid atherosclerosis and free of previous vascular

The prevalence of carotid plaque is 13.3% in the men and 13.4% in the women in the world [8]. The prevalence of extracranial carotid stenosis is 2.7% in the men and 1.5% in the women globally [8]. Stroke is associated with the plaques containing softer tissue, especially with thin

Hyperlipidaemia is a common risk factor for extracranial atherosclerosis [9]. The risk factor of hyperlipidaemia was one of the two most common risk factors for stroke in Singapore (76.5–86.4%) [3]. Hyperlipidaemia results in an atheroma or a fibrofatty plaque leading to gradual occlusion of the arteries. As the plaques increase in size, they progressively occlude the lumen and compromise the blood flow causing stroke [10]. In the South Korean studies,

Furthermore, low levels of HDL cholesterol are associated with an increased risk of having echolucent, rupture-prone atherosclerotic plaques [12]. In addition, an increased risk of having an echolucent plaque is independently associated with increasing degree of stenosis [12]. The subjects with echolucent plaques have increased risk of ischemic cerebrovascular events

A community-based study in Taiwan showed that hypertension strongly influenced extracranial carotid atherosclerosis and hypertension was the predictor of carotid stenosis ≥50% [14, 15]. The frequencies of hypertension among the stroke patients in the other Asian countries were:

There are several mechanisms of stroke due to hypertension. High blood pressure results in endothelial damage, which leads to thrombi formation [18]. Hypertension is also known to accelerate the atherosclerotic process [18]. Moreover, in the general population, hypertension is a predictor of the occurrence of plaques [8]. Systolic blood pressure is significantly associ-

The percentages of ischemic stroke patients with DM were 37% in Pakistan [16] and 30% in South Korea [11]. DM is an important risk factor for extracranial carotid atherosclerosis [14, 19]. DM affects the vascular endothelium and reduces the bioavailability of nitric oxide (NO),

and stroke independent of the degree of stenosis and cardiovascular risk factors [13].

59% in Pakistan [16], 38.3% in Japan [17], and 19–28% in China, Korea and Taiwan [17].

ated with severe extracranial carotid atherosclerosis (plaque, stenosis) [4].

extracranial atherosclerosis was associated with higher LDL levels [9, 11].

stenosis) in these patients [6].

74 Peripheral Arterial Disease - A Practical Approach

fibrous cap [2].

velocities are examined on spectral Doppler [7].

events predicts the occurrence of carotid plaque [8].

Smoking is also known to be associated with atherosclerosis of the extracranial carotid vessels [14]. The percentage of the patients with smoking history was 25% in Wasay et al.'s study [16]. Smoking leads to damage of cells that line the arteries. In addition, smoking increases the build-up of plaque constituents in the arteries. Moreover, smoking results in thickening and narrowing of the arteries [25].

Smoking history is a determinant of the occurrence of a new carotid plaque in the subjects with no previous carotid atherosclerosis and also free of previous vascular events [8]. In addition, there is a significant association between severe extracranial carotid atherosclerosis and smoking [4]. Furthermore, smoking was found to be associated with carotid plaque and extracranial carotid stenosis in several studies [9, 26, 27]. Cessation of smoking will be helpful in the management of these stroke patients.

IHD and ischemic stroke are vascular diseases [28]. IHD was present in 11.8–20% of the Singapore stroke patients [3]. Moreover, IHD was associated with carotid stenosis in a study [27]. In another study conducted in Japan on consecutive patients who had coronary angiography, 6% of them had extracranial carotid stenosis [29].

AF is known cardiovascular risk factor of stroke [30]. AF can predispose to embolism and stroke [31]. AF is commonly associated with stroke in South Asia, Western Europe, North America and Australia [32]. Increased CIMT and presence of carotid plaque are associated with increased risk of ischemic stroke in the patients with AF [33]. Higher CIMT and the presence of carotid plaque are associated with higher incidence of AF incidence [34].

Age is an important risk factor for extracranial carotid atherosclerosis, especially in the Chinese and South Koreans [9, 11, 14, 19, 35]. These patients tend to be older in age [9, 11, 19, 35]. Age is a significant predictor of the occurrence of a new carotid plaque in the general population [8]. The incremental probability of the occurrence of plaque is higher in the subject's midlife [8]. In the subjects aged ≥40 years old, the severity of carotid atherosclerosis (plaques, stenosis) was significantly associated with age [4]. Moreover, the frequency of extracranial carotid atherosclerosis significantly increases with age in the DM patients (ketosis-onset and non-ketotic DM) [24].

Male gender is also risk factor for extracranial atherosclerosis [9, 19]. 14.8% of the patients with extracranial atherosclerosis, had family history of stroke [9]. In a Chinese study, 48.4% of the healthy population with extracranial carotid atherosclerosis had obesity [19].

Elevated CIMT is associated with an increased risk of stroke [20]. Plaque rupture with subsequent embolism can lead to stroke [20]. The presence of plaque is associated with an increased risk morbidity and mortality secondary to stroke [28].

One population study showed the relationship between extracranial carotid atherosclerotic lesions with the classic risk factors such hypertension, hyperlipidaemia and smoking [28]. An European Rotterdam Elderly Study showed that hypertension, smoking and reduced serum HDL were associated with carotid artery stenosis [36]. In that study, factor VIIc and factor VIIIc (hemostatic factor) activity was higher in the patients with extracranial carotid disease [36].

Altogether, the number of classic risk factors among the patients with extracranial atherosclerosis was 1.67 in a South Korean study [11]. The number of traditional risk factors in the patients with severe extracranial atherosclerosis was almost similar (1.68) [11].

CIMT is a marker of subclinical atherosclerosis and hypertension has been known to be risk factor of atherosclerosis [28]. Therefore, proper monitoring of CIMT and treatment can potentially be helpful to these patients to prevent further progression to plaques and stenosis. In a previous study, 18.2% of the patients with extracranial atherosclerosis had history of previous stroke [11]. Among the patients with severe extracranial atherosclerosis, 21.6% of them had history of previous stroke [11].

Furthermore, a study by Amarenco et al. showed that there was a higher prevalence of coronary plaques, with concomitant carotid plaques, in patients with non-fatal ischemic stroke with no known IHD [37]. In a study done among Chinese patients, 7.8% of the patients with paroxysmal AF had a combination of extracranial carotid stenosis and IHD [30].

The miR-146a rs2910164 polymorphism may be associated with carotid vulnerable plaque risk in the Chinese patients with type 2 DM, particularly in older patients and women [38]. This polymorphism may be associated with carotid vulnerable plaque risk in the patients with DM duration of >10 years and the patients with hypertension [38].

In addition, the metabolically abnormal but normal weight subjects have increased CIMT compared to the metabolically healthy but obese subjects and metabolically healthy normal weight subjects [39]. The patients with extracranial carotid atherosclerosis are more likely to have contralateral extracranial carotid atherosclerosis [26].

In terms of ethnic variation, the South Asians have the higher prevalence of extracranial carotid atherosclerosis compared to the Europeans and Chinese [20]. The South Asians have an increased frequency of impaired glucose tolerance, hypercholesterolemia (higher total and LDL cholesterol), hypertriglyceridemia and lower HDL cholesterol [20]. In addition, the South Asians have higher concentrations of fibrinogen, homocysteine, lipoprotein (a), and plasminogen activator inhibitor-1 [20].

**Author details**

1. Hypertension 2. Diabetes mellitus 3. Hyperlipidaemia

4. Smoking

5. Ischemic heart disease 6. Atrial fibrillation 7. Advancing age 8. Male gender

Malaysia

**References**

Mohamed Abdusalam Elwaifa

9. miR-146a rs2910164 polymorphism

10. Metabolically abnormal but normal weight

Mei-Ling Sharon Tai\*, Julia Sien Yuin Liew, Sheun Yu Mo and

**Table 1.** Risk factors of extracranial carotid atherosclerosis [9, 14, 18, 19, 28, 30, 38, 39].

**Figure 1.** Diagram showing plaques at the carotid bulb extending to the internal carotid artery [2].

Risk Factors in the Patients with Extracranial Carotid Atherosclerosis

http://dx.doi.org/10.5772/intechopen.75808

77

Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya,

[1] Santulli G. Epidemiology of cardiovascular disease in the 21st century: Updated num-

bers and updated facts. Journal of Cardiovascular Disease. 2013;**1**:1-2

\*Address all correspondence to: sharont1990@gmail.com

The Chinese have lower rates of cardiovascular disease than the Europeans [40]. Furthermore, the Chinese have a more favorable risk factor profile except for impaired glucose tolerance [40]. The Europeans are more likely to be current or former smokers [20]. The Caucasians with severe extracranial carotid stenosis are more obese than those without such stenosis, unlike the Japanese [41].

In conclusion, proper identification and optimization of the risk factors in the patients with extracranial carotid atherosclerosis in important. This will help to prevent or slow down the progression of the extracranial carotid atherosclerosis. By preventing the development of carotid stenosis, the occurrence of ischemic stroke can be minimized (**Figure 1** and **Table 1**).

Risk Factors in the Patients with Extracranial Carotid Atherosclerosis http://dx.doi.org/10.5772/intechopen.75808 77

**Figure 1.** Diagram showing plaques at the carotid bulb extending to the internal carotid artery [2].

1. Hypertension 2. Diabetes mellitus 3. Hyperlipidaemia 4. Smoking 5. Ischemic heart disease 6. Atrial fibrillation 7. Advancing age 8. Male gender 9. miR-146a rs2910164 polymorphism 10. Metabolically abnormal but normal weight

**Table 1.** Risk factors of extracranial carotid atherosclerosis [9, 14, 18, 19, 28, 30, 38, 39].

#### **Author details**

An European Rotterdam Elderly Study showed that hypertension, smoking and reduced serum HDL were associated with carotid artery stenosis [36]. In that study, factor VIIc and factor VIIIc (hemostatic factor) activity was higher in the patients with extracranial carotid disease [36].

Altogether, the number of classic risk factors among the patients with extracranial atherosclerosis was 1.67 in a South Korean study [11]. The number of traditional risk factors in the

CIMT is a marker of subclinical atherosclerosis and hypertension has been known to be risk factor of atherosclerosis [28]. Therefore, proper monitoring of CIMT and treatment can potentially be helpful to these patients to prevent further progression to plaques and stenosis. In a previous study, 18.2% of the patients with extracranial atherosclerosis had history of previous stroke [11]. Among the patients with severe extracranial atherosclerosis, 21.6% of them had

Furthermore, a study by Amarenco et al. showed that there was a higher prevalence of coronary plaques, with concomitant carotid plaques, in patients with non-fatal ischemic stroke with no known IHD [37]. In a study done among Chinese patients, 7.8% of the patients with

The miR-146a rs2910164 polymorphism may be associated with carotid vulnerable plaque risk in the Chinese patients with type 2 DM, particularly in older patients and women [38]. This polymorphism may be associated with carotid vulnerable plaque risk in the patients

In addition, the metabolically abnormal but normal weight subjects have increased CIMT compared to the metabolically healthy but obese subjects and metabolically healthy normal weight subjects [39]. The patients with extracranial carotid atherosclerosis are more likely to

In terms of ethnic variation, the South Asians have the higher prevalence of extracranial carotid atherosclerosis compared to the Europeans and Chinese [20]. The South Asians have an increased frequency of impaired glucose tolerance, hypercholesterolemia (higher total and LDL cholesterol), hypertriglyceridemia and lower HDL cholesterol [20]. In addition, the South Asians have higher concentrations of fibrinogen, homocysteine, lipoprotein (a), and

The Chinese have lower rates of cardiovascular disease than the Europeans [40]. Furthermore, the Chinese have a more favorable risk factor profile except for impaired glucose tolerance [40]. The Europeans are more likely to be current or former smokers [20]. The Caucasians with severe extracranial carotid stenosis are more obese than those without such stenosis, unlike

In conclusion, proper identification and optimization of the risk factors in the patients with extracranial carotid atherosclerosis in important. This will help to prevent or slow down the progression of the extracranial carotid atherosclerosis. By preventing the development of carotid stenosis, the occurrence of ischemic stroke can be minimized (**Figure 1**

patients with severe extracranial atherosclerosis was almost similar (1.68) [11].

paroxysmal AF had a combination of extracranial carotid stenosis and IHD [30].

with DM duration of >10 years and the patients with hypertension [38].

have contralateral extracranial carotid atherosclerosis [26].

plasminogen activator inhibitor-1 [20].

the Japanese [41].

and **Table 1**).

history of previous stroke [11].

76 Peripheral Arterial Disease - A Practical Approach

Mei-Ling Sharon Tai\*, Julia Sien Yuin Liew, Sheun Yu Mo and Mohamed Abdusalam Elwaifa

\*Address all correspondence to: sharont1990@gmail.com

Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Malaysia

#### **References**

[1] Santulli G. Epidemiology of cardiovascular disease in the 21st century: Updated numbers and updated facts. Journal of Cardiovascular Disease. 2013;**1**:1-2

[2] Allen JD, Ham KL, Dumont DM, Sileshi B, Trahey GE, Dahl JJ. The development and potential of acoustic radiation force impulse (ARFI) imaging for carotid artery plaque characterization. Vascular Medicine. 2011 Aug;**16**(4):302-311

[12] Mathiesen EB, Bønaa KH, Joakimsen O. Low levels of high-density lipoprotein cholesterol are associated with echolucent carotid artery plaques: The tromsø study. Stroke.

Risk Factors in the Patients with Extracranial Carotid Atherosclerosis

http://dx.doi.org/10.5772/intechopen.75808

79

[13] Mathiesen EB, Bønaa KH, Joakimsen O. Echolucent plaques are associated with high risk of ischemic cerebrovascular events in carotid stenosis: The tromsø study. Circulation.

[14] Liu CY, Chen CQ.Intra- and extracranial atherosclerotic stenosis in China: Epidemiology, diagnosis, treatment and risk factors. European Review for Medical and Pharmacological

[15] Su TC, Jeng JS, Chien KL, Sung FC, Hsu HC, Lee YT. Hypertension status is the major determinant of carotid atherosclerosis: A community-based study in Taiwan. Stroke.

[16] Wasay M, Azeemuddin M, Masroor I, Sajjad Z, Ahmed R, Khealani BA, Malik MA, Afridi MB, Kamal A. Frequency and outcome of carotid atheromatous disease in patients with

[17] Kim YD, Jung YH, Saposnik G. Traditional risk factors for stroke in East Asia. Journal of

[18] Johansson BB. Hypertension mechanisms causing stroke. Clinical and Experimental

[19] Pan XF, Lai YX, Gu JQ, Wang HY, Liu AH, Shan ZY. Factors significantly associated with the increased prevalence of carotid atherosclerosis in a northeast Chinese middle-aged and elderly population: A cross-sectional study. Medicine (Baltimore). 2016

[20] Anand SS, Yusuf S, Vuksan V, Devanesen S, Teo KK, Montague PA, Kelemen L, Yi C, Lonn E, Gerstein H, Hegele RA, McQueen M. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: The study of health assessment and risk in ethnic groups (SHARE). Lancet. 2000 Jul 22;**356**(9226):279-284 [21] Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: Epidemiology, pathophysiology, and management. Journal of the American Medical Association.

[22] Lloyd-Jones DM, Bloch KD. The vascular biology of nitric oxide and its role in athero-

[23] De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial

[24] Li LX, Zhao CC, Ren Y, Tu YF, Lu JX, Wu X, Zhang WX, Zhu JA, Li MF, Yu LB, Bao YQ, Jia WP. Prevalence and clinical characteristics of carotid atherosclerosis in newly diagnosed patients with ketosis-onset diabetes: A cross-sectional study. Cardiovascular

dysfunction in diabetes. British Journal of Pharmacology 2000;**130**:963-974

2001 Sep;**32**(9):1960-1965

2001;**32**:2265-2271

Apr;**95**(14):e3253

2002;**287**:2570-2581

Diabetology. 2013 Jan 16;**12**:18

2001 May 1;**103**(17):2171-2175

Stroke. 2016 Sep;**18**(3):273-285

Sciences. 2014 Nov;**18**(22):3368-3379

stroke in Pakistan. Stroke. 2009 Mar;**40**(3):708-712

Pharmacology & Physiology. 1999 Jul;**26**(7):563-565

genesis. Annual Review of Medicine. 1996;**47**:365-375


[12] Mathiesen EB, Bønaa KH, Joakimsen O. Low levels of high-density lipoprotein cholesterol are associated with echolucent carotid artery plaques: The tromsø study. Stroke. 2001 Sep;**32**(9):1960-1965

[2] Allen JD, Ham KL, Dumont DM, Sileshi B, Trahey GE, Dahl JJ. The development and potential of acoustic radiation force impulse (ARFI) imaging for carotid artery plaque

[3] Sharma VK, Tsivgoulis G, Teoh HL, Ong BK, Chan BP. Stroke risk factors and outcomes among various Asian ethnic groups in Singapore. Journal of Stroke and Cerebrovascular

[4] Prati P, Vanuzzo D, Casaroli M, Di Chiara A, De Biasi F, Feruglio GA, Touboul PJ. Prevalence and determinants of carotid atherosclerosis in a general population. Stroke.

[5] Timsit S, Sacco R, Mohr J, Foulkes M, Tatemichi T, Wolf P, Price T, Hier D. Early clinical differentiation of cerebral infarction from severe atherosclerotic stenosis and cardioem-

[6] Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, Cates CU, Creager MA, Fowler SB, Friday G, Hertzberg VS, McIff EB, Moore WS, Panagos PD, Riles TS, Rosenwasser RH, Taylor AJ. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/ CNS/SAIP/SC'AI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, society of NeuroInterventional surgery, Society for Vascular Medicine, and society for vascular

[7] Gaitini D, Soudack M. Diagnosing carotid stenosis by Doppler sonography: State of the

[8] Prati P, Vanuzzo D, Casaroli M, Bader G, Mos L, Pilotto L, Canciani L, Ruscio M, Touboul PJ. Determinants of carotid plaque occurrence. A long-term prospective population

[9] Kim JS, Nah HW, Park SM, Kim SK, Cho KH, Lee J, Lee YS, Kim J, Ha SW, Kim EG, Kim DE, Kang DW, Kwon SU, Yu KH, Lee BC. Risk factors and stroke mechanisms in atherosclerotic stroke: Intracranial compared with extracranial and anterior compared with

[10] Khan MRK. Hyperlipidemia as a Risk Factor for Ischaemic Stroke. www.orion-group.

[11] Kim YD, Choi HY, Jung YH, Nam CM, Yang JH, Cho HJ, Nam HS, Lee KY, Heo JH. Classic risk factors for atherosclerosis are not major determinants for location of extracranial or

intracranial cerebral atherosclerosis. Neuroepidemiology. 2009;**32**(3):201-207

study: The san Daniele project. Cerebrovascular Diseases. 2006;**22**(5-6):416-422

art. Journal of Ultrasound in Medicine. 2005 Aug;**24**(8):1127-1136

posterior circulation disease. Stroke. 2012 Dec;**43**(12):3313-3318

net/journals/Journals/vol19\_Sept2004/199.htm

characterization. Vascular Medicine. 2011 Aug;**16**(4):302-311

Diseases. 2012 May;**21**(4):299-304

1992 Dec;**23**(12):1705-1711

78 Peripheral Arterial Disease - A Practical Approach

bolism. Stroke. 2007;**23**:486-491

surgery. Stroke. 2011;**42**:e420-e463


[25] Centre for Disease Control and Prevention (CDC)-Health Effects-Heart Disease-Smoking &TobaccoUse. http://www.cdc.gov/tobacco/basic\_information/health\_effects/ heart\_disease/

[36] Bots ML, Breslau PJ, Briët E, de Bruyn AM, van Vliet HH, van den Ouweland FA, de Jong PT, Hofman A, Grobbee DE. Cardiovascular determinants of carotid artery disease. The

Risk Factors in the Patients with Extracranial Carotid Atherosclerosis

http://dx.doi.org/10.5772/intechopen.75808

81

[37] Amarenco P, Lavallée PC, Labreuche J, Ducrocq G, Juliard JM, Feldman L, Cabrejo L, Meseguer E, Guidoux C, Adraï V, Ratani S, Kusmierek J, Lapergue B, Klein IF, Gongora-Rivera F, Jaramillo A, Mazighi M, Touboul PJ, Steg PG. Prevalence of coronary athero-

[38] Shen J, Zhang M, Sun M, Tang K, Zhou B. The relationship of miR-146a gene polymorphism with carotid atherosclerosis in Chinese patients with type 2 diabetes mellitus.

[39] Yoo HJ, Hwang SY, Hong HC, Choi HY, Seo JA, Kim SG, Kim NH, Choi DS, Baik SH, Choi KM. Association of metabolically abnormal but normal weight (MANW) and metabolically healthy but obese (MHO) individuals with arterial stiffness and carotid ath-

[40] Harland J, Unwin N, Bhopal R, White M, Watson B, Laker M, Alberti KG. Low levels of cardiovascular risk factors and coronary heart disease in a UK Chinese population.

[41] Nishimaru K, McHenry LC Jr, Toole JF. Cerebral angiographic and clinical differences in carotid system transient ischemic attacks between American Caucasian and Japanese

Rotterdam Elderly Study. Hypertension. 1992 Jun; **19**(6 Pt 2):717-720

sclerosis in patients with cerebral infarction. Stroke. 2011 Jan;**42**(1):22-29

Thrombosis Research. 2015 Dec;**136**(6):1149-1155

erosclerosis. Atherosclerosis. 2014 May;**234**(1):218-223

patients. Stroke. 1984 Jan-Feb;**15**(1):56-59

Journal of Epidemiology and Community Health. 1997;**51**:636-642


[36] Bots ML, Breslau PJ, Briët E, de Bruyn AM, van Vliet HH, van den Ouweland FA, de Jong PT, Hofman A, Grobbee DE. Cardiovascular determinants of carotid artery disease. The Rotterdam Elderly Study. Hypertension. 1992 Jun; **19**(6 Pt 2):717-720

[25] Centre for Disease Control and Prevention (CDC)-Health Effects-Heart Disease-Smoking &TobaccoUse. http://www.cdc.gov/tobacco/basic\_information/health\_effects/

[26] Chen H, Hong H, Xing S, Liu G, Zhang A, Tan S, Zhang J, Zeng J. Intracranial versus Extracranial symptomatic carotid atherosclerosis in Chinese patients: Risk factors, stroke mechanisms, and long-term prognosis. Journal of Stroke and Cerebrovascular

[27] Leung SY, Ng TH, Yuen ST, Lauder IJ, Ho FC. Pattern of cerebral atherosclerosis in Hong Kong Chinese. Severity in intracranial and extracranial vessels. Stroke. 1993

[28] Keo HH, Baumgartner, Hirsch AT, Duval S, Steg PG, Pasquet B, Bhatt DL, Roether J, REACH Registry Investigators. Carotid plaque and intima-media thickness and the incidence of ischemic events in patients with atherosclerotic vascular disease. Vascular

[29] Tanimoto S, Ikari Y, Tanabe K, Yachi S, Nakajima H, Nakayama T, Hatori M, Nakazawa G, Onuma Y, Higashikuni Y, Yamamoto H, Tooda E, Hara K. Prevalence of carotid artery stenosis in patients with coronary artery disease in Japanese population. Stroke. 2005 Oct;**36**(10):

[30] Gu Y, Feng L, Xu Y, Zhao Y. Co-prevalence of carotid stenosis and coronary artery disease in Chinese patients with paroxysmal atrial fibrillation. The Journal of International

[31] Chee KH, Tan KS. Impact of atrial fibrillation among stroke patients in a Malaysian

[32] O' Donnell MJ, Chin SL, Rangarajan S, Xavier D, Liu L, Zhang H, et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries

[33] Bekwelem W, Jensen PN, Norby FL, Soliman EZ, Agarwal SK, Lip GY, Pan W, Folsom AR, Longstreth WT Jr, Alonso A, Heckbert SR, Chen LY. Carotid atherosclerosis and stroke in Atrial fibrillation: The atherosclerosis risk in communities study. Stroke. 2016

[34] Chen LY, Leening MJ, Norby FL, Roetker NS, Hofman A, Franco OH, Pan W, Polak JF, Witteman JC, Kronmal RA, Folsom AR, Nazarian S, Stricker BH, Heckbert SR, Alonso A. Carotid Intima-media thickness and arterial stiffness and the risk of Atrial fibrillation: The atherosclerosis risk in communities (ARIC) study, multi-ethnic study of atherosclerosis (MESA), and the Rotterdam study. Journal of the American Heart Association. 2016

[35] Li D, Wang ML, Li SM, Ling F. Distribution and risk factors of steno-occlusive lesions in patients with ischemic cerebrovascular disease. Zhonghua Yi Xue Za Zhi.

(INTERSTROKE): A case-control study. Lancet. 2016 Aug 20;**388**(10046):761-775

teaching hospital. The Medical Journal of Malaysia. 2014 Jun;**69**(3):119-123

heart\_disease/

80 Peripheral Arterial Disease - A Practical Approach

Jun;**24**(6):779-786

2094-2098

Jun;**47**(6):1643-1646

May;**20**:5(5)

2008;**88**:1158-1162

Diseases. 2015 Nov;**24**(11):2632-2639

Medicine. 2011 Oct;**16**(5):323-330

Medical Research. 2014 Dec;**42**(6):1294-1300


**Section 3**

**Diagnosis of Peripheral Arterial Disease**

**Diagnosis of Peripheral Arterial Disease**

**Chapter 6**

Provisional chapter

**The Role of Imaging in Peripheral Arterial Disease**

DOI: 10.5772/intechopen.75675

Peripheral arterial disease, specifically lower limb peripheral arterial disease, can be defined as atheromatous narrowing or occlusion of an artery or arteries in the lower limb. This is becoming an ever more present disease affecting more and more people each year. Diagnosis and prompt treatment are key as the effects of untreated peripheral arterial disease can be dire. Symptoms can range from largely asymptomatic to severe pain, ulcerations, claudication, and rest pain. Treatment is dependent upon the degree of stenosis; this makes diagnosis and visualization of the affected area key. In the past, the cornerstones for diagnosis consisted of contrast, or conventional, angiography and duplex ultrasonography. Newer imaging modalities for diagnosis have since emerged, which consist of magnetic resonance angiography and, more recently, computed tomography angiography. No modality is without fault; therefore, it will be essential to consider side effects, potential risk, and specificity and sensitivity of results, all of which will be covered

Keywords: peripheral arterial disease (PAD), computed tomography angiography (CTA),

There are several instances in which non-invasive imaging can be used in patients with, or suspected of having, peripheral arterial disease (PAD). It is reasonable to consider ordering imaging for patients who are suspected to have PAD, based on risk factors, to aid in future management. Imaging can be done on a patient to confirm a diagnosis of PAD or in patients who have signs or symptoms of PAD. Most importantly, imaging will be useful in evaluating patients prior to a planned vascular intervention or to provide surveillance after a vascular intervention has been performed. This chapter will discuss the pertinent imaging modalities:

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

magnetic resonance angiography (MRA), duplex ultrasonography, conventional

The Role of Imaging in Peripheral Arterial Disease

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.75675

Stacy Willner

Stacy Willner

Abstract

in this chapter.

angiography

1. Introduction

#### **The Role of Imaging in Peripheral Arterial Disease** The Role of Imaging in Peripheral Arterial Disease

DOI: 10.5772/intechopen.75675

#### Stacy Willner Stacy Willner

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.75675

#### Abstract

Peripheral arterial disease, specifically lower limb peripheral arterial disease, can be defined as atheromatous narrowing or occlusion of an artery or arteries in the lower limb. This is becoming an ever more present disease affecting more and more people each year. Diagnosis and prompt treatment are key as the effects of untreated peripheral arterial disease can be dire. Symptoms can range from largely asymptomatic to severe pain, ulcerations, claudication, and rest pain. Treatment is dependent upon the degree of stenosis; this makes diagnosis and visualization of the affected area key. In the past, the cornerstones for diagnosis consisted of contrast, or conventional, angiography and duplex ultrasonography. Newer imaging modalities for diagnosis have since emerged, which consist of magnetic resonance angiography and, more recently, computed tomography angiography. No modality is without fault; therefore, it will be essential to consider side effects, potential risk, and specificity and sensitivity of results, all of which will be covered in this chapter.

Keywords: peripheral arterial disease (PAD), computed tomography angiography (CTA), magnetic resonance angiography (MRA), duplex ultrasonography, conventional angiography

#### 1. Introduction

There are several instances in which non-invasive imaging can be used in patients with, or suspected of having, peripheral arterial disease (PAD). It is reasonable to consider ordering imaging for patients who are suspected to have PAD, based on risk factors, to aid in future management. Imaging can be done on a patient to confirm a diagnosis of PAD or in patients who have signs or symptoms of PAD. Most importantly, imaging will be useful in evaluating patients prior to a planned vascular intervention or to provide surveillance after a vascular intervention has been performed. This chapter will discuss the pertinent imaging modalities:

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

duplex ultrasonography, computed tomography angiography (CTA), magnetic resonance angiography (MRA), and the gold standard, conventional angiography. These imaging modalities will then be compared according to the latest studies.

As was stated in the introduction, no modality is without fault, and duplex ultrasonography is no exception. First off, duplex ultrasonography requires contact with the skin. Some of the patients that need this testing done suffer from chronic leg wounds that can be severe. These wounds can preclude appropriate placement of the probe; therefore, a high-quality exam cannot be performed. Other factors that could make a high-quality exam difficult include contractures, largely edematous legs, and morbid obesity. Another thing to remember with duplex ultrasonography is that it is entirely operator dependent; it is important to have someone educated on proper technique when ordering this test. Lastly, duplex ultrasonography fails to categorize stenosis in the presence of calcified walls and/or plaques [3]. Whenever picking an imaging modality it is important to weigh the pros and cons and adjust accordingly

Another commonly utilized imaging modality is CTA. It is an attractive option for a few reasons, those being: it is non-invasive, there are shorter acquisition times, thinner slices, higher spatial resolution, and improvement of multidetector computed tomography (CT) scanners that enable scanning of the whole vascular tree in a limited period of time with a smaller (but still significant) amount of contrast medium. Some further benefits include CTA being more cost-effective than MRA, and there being less patient contraindications. Recent studies have reported a sensitivity and specificity of 98% for the diagnosis of PAD [4] (Table 1).

Sensitivity Specificity Advantages Disadvantages

• Non-invasive • Helpful for monitoring after intervention has taken place

• Contraindications: edematous legs, morbid obesity, open sores, contractures

The Role of Imaging in Peripheral Arterial Disease http://dx.doi.org/10.5772/intechopen.75675 87

• Unable to classify calcified vessels or

• Unable to classify calcified vessels [4]

• Contraindications: pacemakers, other metallic implants; if patient is claustro-

phobic, may need sedation • Gadolinium administration and risk of nephrogenic systemic fibrosis [5]

• Operator dependent

plaques [3]

• Radiation • Iodinated contrast

• Low cost [3]

[4]

64–99% [5] • Non-invasive

• Short acquisition time • Techniques are being developed to utilize less contrast

• Iodinated contrast not needed • No radiation [5]

Table 1. Summarized overview of the sensitivity, specificity, advantages, and disadvantages of the imaging modalities.

for the specific patient.

Imaging modality

Duplex ultrasonography

Computed tomography angiography (CTA)

Magnetic resonance angiography (MRA)

3. Computed tomography angiography (CTA)

89–99% [2, 5]

89–99% [5] 83–97% [5] • Non-invasive

80–98% [2, 5]

93–99.5% [5]

#### 2. Duplex ultrasonography

Duplex ultrasonography is a method that uses sound waves with frequencies above those heard by the human ear. When this ultrasound beam travels, it runs into various "targets," such as soft tissue, bone, blood, fluid, etc., and is reflected back creating an image. The term duplex ultrasonography refers to the utilization of both B-mode and pulsed Doppler analysis of the velocity of blood flowing in the various arteries and veins. B-mode, "brightness-mode," is a technology that provides real-time, gray scale images. For analyzing the presence or severity of PAD in the lower extremity, high frequency transducers are best, in that they provide excellent image resolution in superficial structures. The "Doppler shift" has been studied and described by Christian Doppler, who found that as an artery is narrowed, the blood velocity will be increased. This has served as the foundation for all vascular ultrasonography [1].

Arterial duplex ultrasonography allows direct visualization of the arteries of the lower extremities. Vessels are classified into 1 of 4 groups. The first being "normal," which is considered 1– 19% stenosis, followed by 20–49%, 50–99% stenosis, and full occlusion. Knowing where and how severe various lesions are allows for the clinician to determine the best therapy, whether that be nothing at all, medical therapy, or invasive therapy, such as percutaneous transluminal angioplasty, stent, or even surgery for bypass [1]. According to Whelan et al., Doppler ultrasonography demonstrated a sensitivity and specificity of 95 and 99%, respectively, for patency versus occlusive disease, and 92 and 97%, respectively, for hemodynamically significant lesions [2].

The following are a few of the accepted clinical applications for the use of duplex ultrasonography imaging: (1) the evaluation of symptomatic patients with abnormal ABIs (<0.9) to identify lesions amenable to endovascular intervention; (2) the occlusion of occult inflow aorto-iliac disease in patients that require a lower limb femoral-distal bypass graft; (3) the evaluation of hemodynamics in distal arterial segments in patients who have an ambiguous history and/or physical exam [3].

Besides being useful for diagnosis and planning interventions, duplex ultrasonography is also useful for after an intervention has taken place [1, 3]. If a patient has received a stent or bypass, he or she will likely be closely monitored by serial ultrasonography's to make sure that the stent or bypass stays patent. Some further benefits of duplex ultrasonography are that it is noninvasive, which means that there are usually no contraindications. As far as diagnostic accuracy, studies have shown duplex ultrasonography to be similar to contrast angiography, and superior to standard MRA [3].

As was stated in the introduction, no modality is without fault, and duplex ultrasonography is no exception. First off, duplex ultrasonography requires contact with the skin. Some of the patients that need this testing done suffer from chronic leg wounds that can be severe. These wounds can preclude appropriate placement of the probe; therefore, a high-quality exam cannot be performed. Other factors that could make a high-quality exam difficult include contractures, largely edematous legs, and morbid obesity. Another thing to remember with duplex ultrasonography is that it is entirely operator dependent; it is important to have someone educated on proper technique when ordering this test. Lastly, duplex ultrasonography fails to categorize stenosis in the presence of calcified walls and/or plaques [3]. Whenever picking an imaging modality it is important to weigh the pros and cons and adjust accordingly for the specific patient.

#### 3. Computed tomography angiography (CTA)

duplex ultrasonography, computed tomography angiography (CTA), magnetic resonance angiography (MRA), and the gold standard, conventional angiography. These imaging modal-

Duplex ultrasonography is a method that uses sound waves with frequencies above those heard by the human ear. When this ultrasound beam travels, it runs into various "targets," such as soft tissue, bone, blood, fluid, etc., and is reflected back creating an image. The term duplex ultrasonography refers to the utilization of both B-mode and pulsed Doppler analysis of the velocity of blood flowing in the various arteries and veins. B-mode, "brightness-mode," is a technology that provides real-time, gray scale images. For analyzing the presence or severity of PAD in the lower extremity, high frequency transducers are best, in that they provide excellent image resolution in superficial structures. The "Doppler shift" has been studied and described by Christian Doppler, who found that as an artery is narrowed, the blood velocity will be increased. This has served as the foundation for all vascular ultrasonog-

Arterial duplex ultrasonography allows direct visualization of the arteries of the lower extremities. Vessels are classified into 1 of 4 groups. The first being "normal," which is considered 1– 19% stenosis, followed by 20–49%, 50–99% stenosis, and full occlusion. Knowing where and how severe various lesions are allows for the clinician to determine the best therapy, whether that be nothing at all, medical therapy, or invasive therapy, such as percutaneous transluminal angioplasty, stent, or even surgery for bypass [1]. According to Whelan et al., Doppler ultrasonography demonstrated a sensitivity and specificity of 95 and 99%, respectively, for patency versus occlusive disease, and 92 and 97%, respectively, for hemodynamically significant

The following are a few of the accepted clinical applications for the use of duplex ultrasonography imaging: (1) the evaluation of symptomatic patients with abnormal ABIs (<0.9) to identify lesions amenable to endovascular intervention; (2) the occlusion of occult inflow aorto-iliac disease in patients that require a lower limb femoral-distal bypass graft; (3) the evaluation of hemodynamics in distal arterial segments in patients who have an ambiguous

Besides being useful for diagnosis and planning interventions, duplex ultrasonography is also useful for after an intervention has taken place [1, 3]. If a patient has received a stent or bypass, he or she will likely be closely monitored by serial ultrasonography's to make sure that the stent or bypass stays patent. Some further benefits of duplex ultrasonography are that it is noninvasive, which means that there are usually no contraindications. As far as diagnostic accuracy, studies have shown duplex ultrasonography to be similar to contrast angiography, and

ities will then be compared according to the latest studies.

2. Duplex ultrasonography

86 Peripheral Arterial Disease - A Practical Approach

raphy [1].

lesions [2].

history and/or physical exam [3].

superior to standard MRA [3].

Another commonly utilized imaging modality is CTA. It is an attractive option for a few reasons, those being: it is non-invasive, there are shorter acquisition times, thinner slices, higher spatial resolution, and improvement of multidetector computed tomography (CT) scanners that enable scanning of the whole vascular tree in a limited period of time with a smaller (but still significant) amount of contrast medium. Some further benefits include CTA being more cost-effective than MRA, and there being less patient contraindications. Recent studies have reported a sensitivity and specificity of 98% for the diagnosis of PAD [4] (Table 1).


Table 1. Summarized overview of the sensitivity, specificity, advantages, and disadvantages of the imaging modalities.

Disadvantages of CTA include exposure to radiation, which can accumulate with repeated studies and be potentially carcinogenic, along with the necessity of giving iodinated contrast, which can be problematic for those patients with kidney disease. Some patients also have allergies to iodine; a CTA can still be done, but the patient will need pre-medication with a combination of Benadryl, steroids, hydration, and possibly N-acetylcysteine, which is still under investigation. Another disadvantage includes the inability to accurately assess vessels that have been calcified [4].

6. Comparing the different imaging modalities

As reported above, duplex ultrasonography has a high sensitivity and specificity; however this goes down when multivessel disease is present. Normally, when compared to the "gold standard" of conventional angiography the diagnostic accuracy of duplex ultrasonography is >80% for the detection of a >50% diameter stenosis or occlusion. This diagnostic accuracy can reach up to >90% without the presence of multivessel disease. But overall, in 50% of patients with symptomatic PAD, duplex ultrasonography can detect disease amenable to endovascular therapy. Two prospective studies were done in 1990 and 2003, comparing duplex ultrasonography and conventional angiography in planning for infrainguinal bypass procedures; patient outcomes, which included limb salvage and graft patency, were similar. This indicates that, "the clinical accuracy of duplex ultrasonography to select appropriate inflow-outflow anasto-

The Role of Imaging in Peripheral Arterial Disease http://dx.doi.org/10.5772/intechopen.75675 89

According to a systemic review that included over 100 studies that compared MRA, CTA, and duplex ultrasonography for the evaluation of lower extremity PAD, the following findings were found: contrast enhanced MRA had the highest diagnostic accuracy, with sensitivities ranging from 93 to 99.5% and specificities from 64 to 99% for the detection of whole leg arterial stenosis >50%. Two dimensional TOF MRA had sensitivities ranging from 79 to 94% and specificities from 74 to 92%. CTA appeared to be slightly inferior when compared to contrast enhanced MRA, but better than duplex ultrasonography, with sensitivities of 89–99% and specificities of 83–97%. Similar to what was stated earlier, duplex ultrasonography has sensitivities of 80–98% and specificities of 89–99%. Contrast enhanced MRA and duplex ultrasonography appeared to be more accurate for detecting proximal lesions and occlusions above the knee when compared to lesions below the knee or in the pedal artery. When comparing adverse events, MRA had the highest overall incidence of adverse events, however contrast angiography was associated with more severe adverse events. For evaluation of the whole extremity, duplex ultrasonography was the most cost-effective option when compared to CTA and MRA; however when the assessment was limited to a specific section, above or below the knee, two dimensional TOF MRA was more cost effective. Finally, when evaluating patient's attitudes and comfort levels associated with MRA, CTA, and conventional angiography it was found that, not surprisingly, conventional angiography was the most uncomfortable, followed

When it comes to choosing an appropriate imaging modality for a patient, it is important to consider the symptoms the patient is dealing with, whether an intervention is anticipated, and what their current situation is. PAD is a very complex disease with many available tools, imaging being one of them. Armed with the right information, a thorough history and physical exam, and an appropriate imaging modality, the patient will be on the right track to getting the

motic sites for lower limb arterial bypass was equivalent to angiography" [3].

by contrast enhanced MRA, with CTA being the most comfortable [5].

7. Conclusion

help and care he or she needs.

#### 4. Magnetic resonance angiography (MRA)

Gaining more popularity is the imaging modality called MRA. The most obvious benefit in using this modality to diagnose PAD is that intravenous contrast is not standardly needed, and it does not utilize ionizing radiation. Both phase-contrast (PC) and time-of-flight (TOF) MRA's are non-contrast techniques that detect blood by its movement compared with static surrounding tissue. MRA is also non-invasive, which gives it an edge over the gold standard, contrast angiography. For completeness sake, there is a form of contrast MRA that is called contrast enhanced MRA; this modality uses an intravenous contrast and relies on the T1 shortening effect of the contrast medium within the arterial system [5].

Although MRA is considered a non-invasive, cost effective, time efficient way to assess and diagnose lower extremity PAD, there are some downfalls. For example, if a patient has a pacemaker that is not compatible with magnetic resonance imaging (MRI), if he or she is claustrophobic, or have other metallic implants, MRI might be contraindicated. There is also the risk of nephrogenic systemic fibrosis with the administration of gadolinium [5].

#### 5. Conventional angiography

Conventional angiography is the gold standard for diagnosis in PAD. This modality involves the intravascular injection of a contrast agent during planar radiographic imaging. The base images are then enhanced by background subtraction of a precontrast frame using a digital technique, such as digital subtraction angiography (DSA), which allows only the opacified arterial system to be seen on the final image. DSA is able to provide superior contrast resolution with lower doses of intravenous contrast, while also having the ability to magnify images and image vessels in real-time, which provides the option for simultaneous intervention [5].

Like the other modalities that have been discussed, conventional angiography has some downsides. In contrast to the other modalities discussed in this chapter, conventional angiography is invasive, and there can be issues with arterial punctures, such as uncontrollable bleeding or hematoma formation. It also involves higher levels of radiation, along with a strong potential for nephrotoxicity and allergic reactions to the contrast agent [5].

#### 6. Comparing the different imaging modalities

Disadvantages of CTA include exposure to radiation, which can accumulate with repeated studies and be potentially carcinogenic, along with the necessity of giving iodinated contrast, which can be problematic for those patients with kidney disease. Some patients also have allergies to iodine; a CTA can still be done, but the patient will need pre-medication with a combination of Benadryl, steroids, hydration, and possibly N-acetylcysteine, which is still under investigation. Another disadvantage includes the inability to accurately assess vessels

Gaining more popularity is the imaging modality called MRA. The most obvious benefit in using this modality to diagnose PAD is that intravenous contrast is not standardly needed, and it does not utilize ionizing radiation. Both phase-contrast (PC) and time-of-flight (TOF) MRA's are non-contrast techniques that detect blood by its movement compared with static surrounding tissue. MRA is also non-invasive, which gives it an edge over the gold standard, contrast angiography. For completeness sake, there is a form of contrast MRA that is called contrast enhanced MRA; this modality uses an intravenous contrast and relies on the T1

Although MRA is considered a non-invasive, cost effective, time efficient way to assess and diagnose lower extremity PAD, there are some downfalls. For example, if a patient has a pacemaker that is not compatible with magnetic resonance imaging (MRI), if he or she is claustrophobic, or have other metallic implants, MRI might be contraindicated. There is also

Conventional angiography is the gold standard for diagnosis in PAD. This modality involves the intravascular injection of a contrast agent during planar radiographic imaging. The base images are then enhanced by background subtraction of a precontrast frame using a digital technique, such as digital subtraction angiography (DSA), which allows only the opacified arterial system to be seen on the final image. DSA is able to provide superior contrast resolution with lower doses of intravenous contrast, while also having the ability to magnify images and image vessels in real-time, which provides the option for simultaneous intervention [5]. Like the other modalities that have been discussed, conventional angiography has some downsides. In contrast to the other modalities discussed in this chapter, conventional angiography is invasive, and there can be issues with arterial punctures, such as uncontrollable bleeding or hematoma formation. It also involves higher levels of radiation, along with a

the risk of nephrogenic systemic fibrosis with the administration of gadolinium [5].

strong potential for nephrotoxicity and allergic reactions to the contrast agent [5].

that have been calcified [4].

88 Peripheral Arterial Disease - A Practical Approach

5. Conventional angiography

4. Magnetic resonance angiography (MRA)

shortening effect of the contrast medium within the arterial system [5].

As reported above, duplex ultrasonography has a high sensitivity and specificity; however this goes down when multivessel disease is present. Normally, when compared to the "gold standard" of conventional angiography the diagnostic accuracy of duplex ultrasonography is >80% for the detection of a >50% diameter stenosis or occlusion. This diagnostic accuracy can reach up to >90% without the presence of multivessel disease. But overall, in 50% of patients with symptomatic PAD, duplex ultrasonography can detect disease amenable to endovascular therapy. Two prospective studies were done in 1990 and 2003, comparing duplex ultrasonography and conventional angiography in planning for infrainguinal bypass procedures; patient outcomes, which included limb salvage and graft patency, were similar. This indicates that, "the clinical accuracy of duplex ultrasonography to select appropriate inflow-outflow anastomotic sites for lower limb arterial bypass was equivalent to angiography" [3].

According to a systemic review that included over 100 studies that compared MRA, CTA, and duplex ultrasonography for the evaluation of lower extremity PAD, the following findings were found: contrast enhanced MRA had the highest diagnostic accuracy, with sensitivities ranging from 93 to 99.5% and specificities from 64 to 99% for the detection of whole leg arterial stenosis >50%. Two dimensional TOF MRA had sensitivities ranging from 79 to 94% and specificities from 74 to 92%. CTA appeared to be slightly inferior when compared to contrast enhanced MRA, but better than duplex ultrasonography, with sensitivities of 89–99% and specificities of 83–97%. Similar to what was stated earlier, duplex ultrasonography has sensitivities of 80–98% and specificities of 89–99%. Contrast enhanced MRA and duplex ultrasonography appeared to be more accurate for detecting proximal lesions and occlusions above the knee when compared to lesions below the knee or in the pedal artery. When comparing adverse events, MRA had the highest overall incidence of adverse events, however contrast angiography was associated with more severe adverse events. For evaluation of the whole extremity, duplex ultrasonography was the most cost-effective option when compared to CTA and MRA; however when the assessment was limited to a specific section, above or below the knee, two dimensional TOF MRA was more cost effective. Finally, when evaluating patient's attitudes and comfort levels associated with MRA, CTA, and conventional angiography it was found that, not surprisingly, conventional angiography was the most uncomfortable, followed by contrast enhanced MRA, with CTA being the most comfortable [5].

#### 7. Conclusion

When it comes to choosing an appropriate imaging modality for a patient, it is important to consider the symptoms the patient is dealing with, whether an intervention is anticipated, and what their current situation is. PAD is a very complex disease with many available tools, imaging being one of them. Armed with the right information, a thorough history and physical exam, and an appropriate imaging modality, the patient will be on the right track to getting the help and care he or she needs.

#### Conflict of interest

There are no conflicts of interest.

#### Author details

Stacy Willner

Address all correspondence to: stacy.willner@beaumont.org

Beaumont Hospital Royal Oak, United States

#### References

[1] Olin JW, Kaufman JA, Bluemke DA, et al. Atherosclerotic vascular disease conference writing group IV: Imaging. American Heart Association. June 2004;109:2626-2633. DOI: 10.1161/01.CIR.0000128521.02390.72

**Section 4**

**Extracranial Carotid Disease**


## **Extracranial Carotid Disease**

Conflict of interest

Author details

Stacy Willner

References

Springer; 2010

February 5, 2018]

There are no conflicts of interest.

90 Peripheral Arterial Disease - A Practical Approach

Address all correspondence to: stacy.willner@beaumont.org

access\_num=1328307&link\_type=MED&dopt=Abstract

[1] Olin JW, Kaufman JA, Bluemke DA, et al. Atherosclerotic vascular disease conference writing group IV: Imaging. American Heart Association. June 2004;109:2626-2633. DOI:

[2] Whelan JF, Barry MH, Moir JD. Color flow Doppler ultrasonography: Comparison with peripheral arteriography for the investigation of peripheral vascular disease. Journal of Clinical Ultrasound. 1992;20(6):369-374. https://www.ncbi.nlm.nih.gov/pubmed/1328307?

[3] Aburahma AF, Bergan JJ. Noninvasive Peripheral Arterial Diagnosis. 2nd ed. London:

[4] Met R, Bipat S, Legemate DA, Reekers JA, Koelemay MJW. Diagnostic performance of computed tomography angiography in peripheral arterial disease. JAMA. 2009;301(4):415-424 [5] Mitchell E. Noninvasive diagnosis of arterial disease. UpToDate. 2018. https://www. uptodate.com/contents/noninvasive-diagnosis-of-arterial-disease?search=CTA%20PAD& source=search\_result&selectedTitle=3~150&usage\_type=default&display\_rank=3 [Accessed:

Beaumont Hospital Royal Oak, United States

10.1161/01.CIR.0000128521.02390.72

**Chapter 7**

**Provisional chapter**

**Extracranial Carotid Atherosclerosis in the Patients**

**Extracranial Carotid Atherosclerosis in the Patients** 

Management of transient ischemic attack (TIA) is important because potentially fatal ischemic strokes can be prevented. Detection of extracranial carotid atherosclerosis in these patients is beneficial because medical therapy can be given, and in certain cases, surgery can be performed. In a Chinese study conducted on the patients with TIA, only 19% of them had extracranial carotid atherosclerosis. Another study was conducted to compare the location and the severity of atherosclerotic lesions between Americans and the Japanese who presented with carotid system TIA. This study showed that 85% of the American patients had extracranial carotid stenosis (stenosis ≥50%). However, only

**Keywords:** transient ischemic attack, extracranial, carotid, atherosclerosis, stroke

In the patients with transient ischemic attack (TIA), ischemic strokes often occur early after the first presenting clinical features especially in the first 7 days [1–4]. Management of TIA is important because potentially fatal ischemic strokes can be prevented [5]. It is important to identify the highest risk patients urgently so that the necessary management can be instituted

Neuroimaging is beneficial to stratify the risk of recurrent stroke [8]. The modalities useful for imaging of the extracranial carotid vessels are ultrasound carotid Doppler with/without

DOI: 10.5772/intechopen.75792

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**with Transient Ischemic Attack**

**with Transient Ischemic Attack**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

16.7% of the Japanese patients had similar lesions.

Mei-Ling Sharon Tai, Jun Kit Khoo and

Mei-Ling Sharon Tai, Jun Kit Khoo and

Mohamed Abdusalam Elwaifa

Mohamed Abdusalam Elwaifa

http://dx.doi.org/10.5772/intechopen.75792

**Abstract**

**1. Introduction**

for appropriate early treatments [6, 7].

#### **Extracranial Carotid Atherosclerosis in the Patients with Transient Ischemic Attack Extracranial Carotid Atherosclerosis in the Patients with Transient Ischemic Attack**

DOI: 10.5772/intechopen.75792

Mei-Ling Sharon Tai, Jun Kit Khoo and Mohamed Abdusalam Elwaifa Mei-Ling Sharon Tai, Jun Kit Khoo and Mohamed Abdusalam Elwaifa

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.75792

#### **Abstract**

Management of transient ischemic attack (TIA) is important because potentially fatal ischemic strokes can be prevented. Detection of extracranial carotid atherosclerosis in these patients is beneficial because medical therapy can be given, and in certain cases, surgery can be performed. In a Chinese study conducted on the patients with TIA, only 19% of them had extracranial carotid atherosclerosis. Another study was conducted to compare the location and the severity of atherosclerotic lesions between Americans and the Japanese who presented with carotid system TIA. This study showed that 85% of the American patients had extracranial carotid stenosis (stenosis ≥50%). However, only 16.7% of the Japanese patients had similar lesions.

**Keywords:** transient ischemic attack, extracranial, carotid, atherosclerosis, stroke

#### **1. Introduction**

In the patients with transient ischemic attack (TIA), ischemic strokes often occur early after the first presenting clinical features especially in the first 7 days [1–4]. Management of TIA is important because potentially fatal ischemic strokes can be prevented [5]. It is important to identify the highest risk patients urgently so that the necessary management can be instituted for appropriate early treatments [6, 7].

Neuroimaging is beneficial to stratify the risk of recurrent stroke [8]. The modalities useful for imaging of the extracranial carotid vessels are ultrasound carotid Doppler with/without

enhancement, computed tomography angiography (CTA), magnetic resonance angiography (MRA), and positron emission tomography (PET)/CT [8–14].

A TIA event within 7 days before TIA (dual TIA) is a useful predictive factor for short- and long-term stroke [1]. In addition, ischemic stroke risk is elevated with increasing severity of carotid stenosis [19]. The risk of stroke is 5.4% with <50% carotid stenosis and 17.2% with

Extracranial Carotid Atherosclerosis in the Patients with Transient Ischemic Attack

http://dx.doi.org/10.5772/intechopen.75792

95

The advantages and disadvantages of the various imaging modalities are illustrated in **Table 1**. Ultrasound carotid Doppler is easily available, cheap, and noninvasive [19]. The sensitivity in carotid stenosis >70% is 91–95% [11, 24]. The specificity in severe stenosis of more than 70% is 86–97% [11, 24]. Being operator dependent is one of the limitations of ultrasound carotid Doppler [11]. The peak systolic velocity (PSV) analysis on the insonated tortuous vessel is difficult, and the stenosis in internal carotid artery (ICA) at the distal end also is difficult to be examined [11].

The diagnostic criteria for stenosis according to The Society of Radiologists in Ultrasound Consensus Criteria for Carotid Stenosis are used to classify the degrees of stenosis [25]. Carotid stenosis of at least 50% is defined as peak systolic velocity (PSV) ≥ 125 and end-diastolic velocity (EDV) ≥ 40. Carotid stenosis of at least ≥70% is defined as peak systolic velocity

Contrast-enhanced ultrasound is a novel, noninvasive, and cost-effective technique to assess plaque morphology and characteristics [13, 14]. Contrast-enhanced ultrasound assists with the identification of several surrogate markers of vulnerable carotid plaques [14]. The use of ultrasound microbubbles allows a reliable detection of microulcerations [14]. As microbubbles are intravascular tracers, the detection of individual microbubbles inside the plaque signifies intraplaque neovessels [14]. The limitation is the poor sensitivity and specificity for

detection of lipid-rich necrotic core and plaque hemorrhage compared with MRI [13].

modality which is more easily and rapidly available in the hospitals [8].

An early evaluation of the extracranial vessels with computed tomography (CT) and CT angiography (CTA) predicts recurrent stroke and functional outcome in the patients with TIA [8]. In many hospitals especially in the developing countries, CTA is more readily available than magnetic resonance imaging (MRI) due to the cost factor [8]. The doctors will utilize the

Multislice helical CT scan machines with CTA are widely available in many hospitals [8]. CTA involves the administration of intravenous contrast media to evaluate the extracranial and

Multirow spiral CTA helps with the evaluation of plaques and stenosis [11, 27, 28]. CTA helps to identify large artery atherosclerosis [10, 29]. CT also enables high-resolution imaging and accurately detects ulceration and calcification [13]. The limitation of CTA is the inadequate detection of the morphology of the plaque and its content [11, 27, 28]. In addition, CT is unable to distinguish between lipid-rich necrotic core and intraplaque hemorrhage accurately [13].

There is a technological advancement in the imaging of extracranial carotid atherosclerotic lesions with high-resolution MRI and MRA [11]. Presently, MRI is the gold standard in the

severe carotid stenosis and occlusion at 90 days after TIA [19].

(PSV) ≥ 230 and end-diastolic velocity (EDV) ≥ 100 [25].

intracranial vessels with high spatial resolution [8, 26].

**2. Diagnostic modalities**

With improvements in vascular imaging techniques, it is now possible to risk stratify the patients on the degree of carotid artery stenosis and also on the vulnerability of the plaque to rupture [13]. The risk stratifications are based on the presence of imaging features such as intraplaque hemorrhage (IPH), plaque ulceration, plaque neovascularity, fibrous cap thickness, and presence of a lipid-rich necrotic core (LRNC) [13].

The risk of early recurrent stroke in the patients with TIA is 9.5–20% at 90 days [2, 15, 16].

The risk of early recurrent stroke is highest in patients with large artery atherosclerosis, which consists of extracranial carotid atherosclerosis and intracranial stenosis [9]. Therefore, it is important for urgent ultrasound carotid Doppler and transcranial Doppler (TCD) to be performed in these high-risk patients [9].

The carotid arteries are elastic and are predilection sites for atherosclerosis [17, 18]. Carotid intima media thickening is an indicator for subclinical atherosclerosis, and this frequently occurs earlier than atherosclerosis in coronary arteries and intracranial arteries [17, 18].

The patients who developed a hemispheric TIA due to internal carotid artery (ICA) disease had the greatest risk of ischemic stroke in the first few days after the TIA [9]. Carotid stenosis is associated with recurrent strokes [9, 19]. In the TIA patients, carotid stenosis predicted 90-day stroke [19]. Carotid stenosis is significantly associated with stroke in the short term, and also in the long term for up to 3 years [1].

In a Chinese study conducted on the patients with TIA, only 19% of them had extracranial carotid atherosclerosis [20]. Another study was conducted to compare the location and the severity of atherosclerotic lesions between Americans and the Japanese who presented with carotid system TIA [21]. This study showed that 85% of the American patients had extracranial carotid stenosis (stenosis ≥50%) [21]. However, only 16.7% of the Japanese patients had similar lesions [21]. In another study, the African-Americans had slightly more extracranial carotid atherosclerosis compared to the Caucasians [22].

In a multicenter study on the patients with TIA or minor stroke, 15.5% of the patients (28 out of 85) had at least one stenosis of ≥50% or occlusion [23]. In a recent study, 6.3% of the TIA patients had extracranial carotid artery disease [5]. In that study, 10 (35.7%) patients had moderate stenosis (50–69% stenosis), 8 (28.6%) patients had severe stenosis (70–99% stenosis), and 10 (35.7%) had total occlusion [4]. Five (17.9%) patients had recurrent TIAs before admission [5]. No patient had ischemic stroke within 90 days of TIA onset [5].

In another prospective study on the patients with TIA and minor stroke, extracranial carotid artery occlusion or stenosis ≥50% was found in 9.4% of the patients [8]. In a Japanese study, 21.8% of patients had carotid stenosis [1]. In a study conducted in Ireland, 23.8% of the TIA patients had unilateral carotid stenosis (40.4%, with 50–69% stenosis, 59.6% with ≥70% stenosis or occlusion) [19].

In the study by Coutts et al., 19% of the patients with TIA and minor stroke who developed recurrent stroke had extracranial carotid stenosis ≥50% or occlusion [8]. In comparison, only 9% of the patients with TIA and minor stroke who developed recurrent stroke had similar lesions [8].

A TIA event within 7 days before TIA (dual TIA) is a useful predictive factor for short- and long-term stroke [1]. In addition, ischemic stroke risk is elevated with increasing severity of carotid stenosis [19]. The risk of stroke is 5.4% with <50% carotid stenosis and 17.2% with severe carotid stenosis and occlusion at 90 days after TIA [19].

#### **2. Diagnostic modalities**

enhancement, computed tomography angiography (CTA), magnetic resonance angiography

With improvements in vascular imaging techniques, it is now possible to risk stratify the patients on the degree of carotid artery stenosis and also on the vulnerability of the plaque to rupture [13]. The risk stratifications are based on the presence of imaging features such as intraplaque hemorrhage (IPH), plaque ulceration, plaque neovascularity, fibrous cap thick-

The risk of early recurrent stroke in the patients with TIA is 9.5–20% at 90 days [2, 15, 16].

The risk of early recurrent stroke is highest in patients with large artery atherosclerosis, which consists of extracranial carotid atherosclerosis and intracranial stenosis [9]. Therefore, it is important for urgent ultrasound carotid Doppler and transcranial Doppler (TCD) to be per-

The carotid arteries are elastic and are predilection sites for atherosclerosis [17, 18]. Carotid intima media thickening is an indicator for subclinical atherosclerosis, and this frequently occurs earlier than atherosclerosis in coronary arteries and intracranial arteries [17, 18].

The patients who developed a hemispheric TIA due to internal carotid artery (ICA) disease had the greatest risk of ischemic stroke in the first few days after the TIA [9]. Carotid stenosis is associated with recurrent strokes [9, 19]. In the TIA patients, carotid stenosis predicted 90-day stroke [19]. Carotid stenosis is significantly associated with stroke in the short term,

In a Chinese study conducted on the patients with TIA, only 19% of them had extracranial carotid atherosclerosis [20]. Another study was conducted to compare the location and the severity of atherosclerotic lesions between Americans and the Japanese who presented with carotid system TIA [21]. This study showed that 85% of the American patients had extracranial carotid stenosis (stenosis ≥50%) [21]. However, only 16.7% of the Japanese patients had similar lesions [21]. In another study, the African-Americans had slightly more extracranial

In a multicenter study on the patients with TIA or minor stroke, 15.5% of the patients (28 out of 85) had at least one stenosis of ≥50% or occlusion [23]. In a recent study, 6.3% of the TIA patients had extracranial carotid artery disease [5]. In that study, 10 (35.7%) patients had moderate stenosis (50–69% stenosis), 8 (28.6%) patients had severe stenosis (70–99% stenosis), and 10 (35.7%) had total occlusion [4]. Five (17.9%) patients had recurrent TIAs before admission

In another prospective study on the patients with TIA and minor stroke, extracranial carotid artery occlusion or stenosis ≥50% was found in 9.4% of the patients [8]. In a Japanese study, 21.8% of patients had carotid stenosis [1]. In a study conducted in Ireland, 23.8% of the TIA patients had unilateral carotid stenosis (40.4%, with 50–69% stenosis, 59.6% with ≥70% steno-

In the study by Coutts et al., 19% of the patients with TIA and minor stroke who developed recurrent stroke had extracranial carotid stenosis ≥50% or occlusion [8]. In comparison, only 9% of the patients with TIA and minor stroke who developed recurrent stroke had similar lesions [8].

(MRA), and positron emission tomography (PET)/CT [8–14].

ness, and presence of a lipid-rich necrotic core (LRNC) [13].

formed in these high-risk patients [9].

94 Peripheral Arterial Disease - A Practical Approach

and also in the long term for up to 3 years [1].

sis or occlusion) [19].

carotid atherosclerosis compared to the Caucasians [22].

[5]. No patient had ischemic stroke within 90 days of TIA onset [5].

The advantages and disadvantages of the various imaging modalities are illustrated in **Table 1**. Ultrasound carotid Doppler is easily available, cheap, and noninvasive [19]. The sensitivity in carotid stenosis >70% is 91–95% [11, 24]. The specificity in severe stenosis of more than 70% is 86–97% [11, 24]. Being operator dependent is one of the limitations of ultrasound carotid Doppler [11]. The peak systolic velocity (PSV) analysis on the insonated tortuous vessel is difficult, and the stenosis in internal carotid artery (ICA) at the distal end also is difficult to be examined [11].

The diagnostic criteria for stenosis according to The Society of Radiologists in Ultrasound Consensus Criteria for Carotid Stenosis are used to classify the degrees of stenosis [25]. Carotid stenosis of at least 50% is defined as peak systolic velocity (PSV) ≥ 125 and end-diastolic velocity (EDV) ≥ 40. Carotid stenosis of at least ≥70% is defined as peak systolic velocity (PSV) ≥ 230 and end-diastolic velocity (EDV) ≥ 100 [25].

Contrast-enhanced ultrasound is a novel, noninvasive, and cost-effective technique to assess plaque morphology and characteristics [13, 14]. Contrast-enhanced ultrasound assists with the identification of several surrogate markers of vulnerable carotid plaques [14]. The use of ultrasound microbubbles allows a reliable detection of microulcerations [14]. As microbubbles are intravascular tracers, the detection of individual microbubbles inside the plaque signifies intraplaque neovessels [14]. The limitation is the poor sensitivity and specificity for detection of lipid-rich necrotic core and plaque hemorrhage compared with MRI [13].

An early evaluation of the extracranial vessels with computed tomography (CT) and CT angiography (CTA) predicts recurrent stroke and functional outcome in the patients with TIA [8]. In many hospitals especially in the developing countries, CTA is more readily available than magnetic resonance imaging (MRI) due to the cost factor [8]. The doctors will utilize the modality which is more easily and rapidly available in the hospitals [8].

Multislice helical CT scan machines with CTA are widely available in many hospitals [8]. CTA involves the administration of intravenous contrast media to evaluate the extracranial and intracranial vessels with high spatial resolution [8, 26].

Multirow spiral CTA helps with the evaluation of plaques and stenosis [11, 27, 28]. CTA helps to identify large artery atherosclerosis [10, 29]. CT also enables high-resolution imaging and accurately detects ulceration and calcification [13]. The limitation of CTA is the inadequate detection of the morphology of the plaque and its content [11, 27, 28]. In addition, CT is unable to distinguish between lipid-rich necrotic core and intraplaque hemorrhage accurately [13].

There is a technological advancement in the imaging of extracranial carotid atherosclerotic lesions with high-resolution MRI and MRA [11]. Presently, MRI is the gold standard in the imaging of carotid plaque [13]. MRI has high resolution and high sensitivity for assessment of intraplaque hemorrhage, ulcerated plaque, and lipid-rich necrotic core [30]. The limitation of MRI is time factor [13].

has numerous limitations [11, 36]. Firstly, DSA is invasive [11, 36]. Secondly, the sensitivity is

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Higher levels of cystatin C are independently associated with symptomatic extracranial internal carotid artery (ICA) stenosis, in patients with noncardioembolic stroke [37]. Cystatin C is a biomarker and it is a protein with low molecular weight of 13 kDa [38]. Cystatin C is a

Cystatin C is an independent risk factor for cardiovascular events and all-cause death in the elderly patients with a normal estimated glomerular filtration rate (eGFR) [39, 40]. It has been suggested that cystatin C levels are associated with inflammation and atherosclerosis [41].

The association between cystatin C and the risk of cardiovascular events is observed in the patients with asymptomatic carotid atherosclerosis, thus ultrasound carotid Doppler can be

**Advantages Disadvantages**

• Operator dependent

hemorrhage

fore can cause allergy

rhage accurately

• Time factor • Cost factor

• Poor sensitivity and specificity for detection of lipid-rich necrotic core and plaque

• Administration of contrast media, there-

• Inadequate detection of the morphology of the plaque and the content • Cannot distinguish between lipid-rich necrotic core and intraplaque hemor-

• Not good in the assessment of anatomy, ulceration, intraplaque hemorrhage, and

lipid-rich necrotic core

• Poor sensitivity • Poor specificity

ordered to detect the carotid abnormalities early [38] (**Table 1**).

• Detection of microulcerations

• More easily and rapidly available in the hospitals due to lower cost • High spatial resolution

• Gold standard in the imaging of carotid

• High resolution and high sensitivity to assess intraplaque hemorrhage, ulcerated plaque, and lipid-rich necrotic core

• Very accurate • Invasive

• Easily available

• Noninvasive • Cost-effective

plaque

PET/CT [13, 18, 35] • Evaluates active inflammation in the plaque

**Table 1.** Advantages and disadvantages of the various imaging modalities.

• Cheap • Noninvasive

only 46% and the specificity is 74% [11, 36].

cysteine proteinase inhibitor [38].

Conventional ultrasound carotid Doppler [11, 24]

Contrast-enhanced ultrasound [13, 14]

CT/CTA brain and carotid [8, 13, 26–28]

MRI/MRA brain and carotid [11, 13, 30]

Digital subtraction angiography [11, 36]

Careful examination of these lesions with high-resolution bright-blood and black-blood MRI analysis of the extracranial carotid vessels accurately evaluates the contents in the plaques [11]. This is performed using the 3.0-Tesla MRI machine [11, 31, 32]. The advantage is the high spatial resolution [11, 31, 32].

The time-of-flight sequence bright-blood technique demonstrates calcified plaques [11, 33]. Black-blood technique is the MRI technique in which the imaging of vessel wall adjacent to the intravascular space is clearer [11, 33]. The bright-blood and black-blood techniques are highly correlated with the diagnosis of contrast-enhanced MRA in the degree of stenosis [11]. The sensitivity and specificity of using MRI technique to detect stenosis of ≥50% are 88.9 and 100%, respectively [11]. The accuracy of MRI diagnosis of similar degree of stenosis is 97.9% [11].

The fibrous cap is isointense in T1-weighted image (T1WI) and hyperintense in proton density weighted image (PDWI) and T2-weighted image (T2WI) [11]. The lipid core is isointense or hyperintense (mild) in T1WI [11]. It is isointense, hyperintense, or hypointense in PDWI and hypointense in T2WI [11].

Ulcerative plaques are characterized by irregular intravascular space surface in the blackblood sequences [11]. In addition, the black hypointensity band is not observed in threedimensional time-of-flight MRA [11]. The hypointensity band is not continuous, and the intrusion of hyperintensities into the plaques can be picked up [11].

In a recent study on extracranial carotid atherosclerosis with MRI, visual and quantitative analyses demonstrated that the border between the plaque and vessel lumen was better delineated on three-dimensional (3-D) T1-weighted turbo-spin echo black-blood (TSEBB) MRI than on 3-D T1-turbo field-echo black-blood (TFEBB) MRI [12]. Three-dimensional T1-TSEBB MRI was superior to 3-D T1-TFEBB MRI for delineating carotid plaques [12]. But the high signal plaques were underestimated on 3-D T1-TSEBB MRI [12]. In another recently conducted study, 7.0-Tesla MRI enables adequate evaluation to determine luminal and vessel wall areas [34]. Signal hyperintensity in 7.0-Tesla MRI images was inversely proportional to calcification [34].

Positron emission tomography (PET)/CT is an effective modality to evaluate active inflammation in the plaque [13]. However, PET/CT does not allow for assessment of anatomy, ulceration, intraplaque hemorrhage, and lipid-rich necrotic core [13]. In addition, a combination of [18] F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and MRI are complementary to predict high-risk carotid plaque, such as lipid-rich or hemorrhagic plaque [35]. FDG-PET accurately evaluates the lipid-rich and inflamed plaque [35]. MRI is valuable to identify unstable plaque with a large intraplaque hemorrhage [35].

Digital subtraction angiography (DSA) was the gold standard for the assessment of intracranial and extracranial vasculature before the era for MRI [11, 36]. This investigation method has numerous limitations [11, 36]. Firstly, DSA is invasive [11, 36]. Secondly, the sensitivity is only 46% and the specificity is 74% [11, 36].

imaging of carotid plaque [13]. MRI has high resolution and high sensitivity for assessment of intraplaque hemorrhage, ulcerated plaque, and lipid-rich necrotic core [30]. The limitation

Careful examination of these lesions with high-resolution bright-blood and black-blood MRI analysis of the extracranial carotid vessels accurately evaluates the contents in the plaques [11]. This is performed using the 3.0-Tesla MRI machine [11, 31, 32]. The advantage is the high

The time-of-flight sequence bright-blood technique demonstrates calcified plaques [11, 33]. Black-blood technique is the MRI technique in which the imaging of vessel wall adjacent to the intravascular space is clearer [11, 33]. The bright-blood and black-blood techniques are highly correlated with the diagnosis of contrast-enhanced MRA in the degree of stenosis [11]. The sensitivity and specificity of using MRI technique to detect stenosis of ≥50% are 88.9 and 100%, respectively [11]. The accuracy of MRI diagnosis of similar degree of stenosis

The fibrous cap is isointense in T1-weighted image (T1WI) and hyperintense in proton density weighted image (PDWI) and T2-weighted image (T2WI) [11]. The lipid core is isointense or hyperintense (mild) in T1WI [11]. It is isointense, hyperintense, or hypointense in PDWI

Ulcerative plaques are characterized by irregular intravascular space surface in the blackblood sequences [11]. In addition, the black hypointensity band is not observed in threedimensional time-of-flight MRA [11]. The hypointensity band is not continuous, and the

In a recent study on extracranial carotid atherosclerosis with MRI, visual and quantitative analyses demonstrated that the border between the plaque and vessel lumen was better delineated on three-dimensional (3-D) T1-weighted turbo-spin echo black-blood (TSEBB) MRI than on 3-D T1-turbo field-echo black-blood (TFEBB) MRI [12]. Three-dimensional T1-TSEBB MRI was superior to 3-D T1-TFEBB MRI for delineating carotid plaques [12]. But the high signal plaques were underestimated on 3-D T1-TSEBB MRI [12]. In another recently conducted study, 7.0-Tesla MRI enables adequate evaluation to determine luminal and vessel wall areas [34]. Signal hyperintensity in 7.0-Tesla MRI images was inversely proportional to

Positron emission tomography (PET)/CT is an effective modality to evaluate active inflammation in the plaque [13]. However, PET/CT does not allow for assessment of anatomy, ulceration, intraplaque hemorrhage, and lipid-rich necrotic core [13]. In addition, a combination of [18] F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and MRI are complementary to predict high-risk carotid plaque, such as lipid-rich or hemorrhagic plaque [35]. FDG-PET accurately evaluates the lipid-rich and inflamed plaque [35]. MRI is valuable to

Digital subtraction angiography (DSA) was the gold standard for the assessment of intracranial and extracranial vasculature before the era for MRI [11, 36]. This investigation method

intrusion of hyperintensities into the plaques can be picked up [11].

identify unstable plaque with a large intraplaque hemorrhage [35].

of MRI is time factor [13].

96 Peripheral Arterial Disease - A Practical Approach

spatial resolution [11, 31, 32].

and hypointense in T2WI [11].

is 97.9% [11].

calcification [34].

Higher levels of cystatin C are independently associated with symptomatic extracranial internal carotid artery (ICA) stenosis, in patients with noncardioembolic stroke [37]. Cystatin C is a biomarker and it is a protein with low molecular weight of 13 kDa [38]. Cystatin C is a cysteine proteinase inhibitor [38].

Cystatin C is an independent risk factor for cardiovascular events and all-cause death in the elderly patients with a normal estimated glomerular filtration rate (eGFR) [39, 40]. It has been suggested that cystatin C levels are associated with inflammation and atherosclerosis [41].

The association between cystatin C and the risk of cardiovascular events is observed in the patients with asymptomatic carotid atherosclerosis, thus ultrasound carotid Doppler can be ordered to detect the carotid abnormalities early [38] (**Table 1**).


**Table 1.** Advantages and disadvantages of the various imaging modalities.

#### **3. Therapeutic options**

Detection of extracranial carotid atherosclerosis in these patients is beneficial because proper management can be given [32, 42]. The patients with TIA due to extracranial carotid stenosis should be given intensive medical therapy [42]. Intensive medical therapy consists of pharmacological management and lifestyle interventions [42].

intraplaque signal on time-of-flight imaging is associated with vulnerable plaque and in-creased rates of adverse events in patients undergoing stenting but not carotid endarterectomy [13]. In the recent guidelines, carotid endarterectomy is likely the preferred option for the management of asymptomatic carotid stenosis [44, 45]. Carotid artery stenting has higher risk of periprocedural stroke and mortality [44–46]. Carotid endarterectomy is safer in comparison to carotid artery stenting [44, 45]. The risk of periprocedural stroke and mortality after carotid

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However, carotid endarterectomy is associated with an increased risk of periprocedural myocardial infarction [44, 45, 48]. To date, the long-term outcomes of these two modalities remain uncertain [44]. In patients with high risk of periprocedural complications, best medical treatment is recommended by the American Heart Association and the Society for Vascular

In conclusion, evaluation of extracranial carotid atherosclerosis in the patients with TIA is very important. There are several modalities which can be employed to investigate for extracranial carotid stenosis. Pharmacological and nonpharmacological management can be given

Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya,

[1] Kiyohara T, Kamouchi M, Kunai Y, Ninomiya T, Hata J, Yoshimura S, et al. ABCD3 and ABCD3-I scores are superior to ABCD2 score in the prediction of short- and long-term

[2] Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. Journal of the American Medical Association.

[3] Lisabeth LD, Ireland JK, Risser JM, Brown DL, Smith MA, Garcia NM, et al. Stroke risk after transient ischemic attack in a population-based setting. Stroke. 2004;**35**:1842-1846

risks of stroke after transient ischemic attack. Stroke. 2014;**45**:418-425

endarterectomy has declined tremendously throughout the years [47].

to the patients with extracranial carotid atherosclerosis.

\*Address all correspondence to: sharont1990@gmail.com

Mei-Ling Sharon Tai\*, Jun Kit Khoo and Mohamed Abdusalam Elwaifa

Surgery [32, 44, 49].

**6. Conclusion**

**Author details**

Malaysia

**References**

2000;**284**:2901-2906

The pharmacological management involves antiplatelet therapy and statin use [5, 42]. The antiplatelet therapy which routinely administered is aspirin or clopidogrel [43]. Adequate blood pressure control is necessary with a target blood pressure of less than 140/90 [42]. A reduction in blood pressure to the ideal level slows down the progression of carotid artery stenosis and also reduces the carotid intima media thickness (CIMT) [43]. Identification and treatment of vascular risk factors are important [43].

Lifestyle changes involve Mediterranean-style diet, exercise, and smoking cessation [42, 43]. In addition, lifestyle choices such as unhealthy diet and excessive alcohol intake are modifiable risk factors [43]. The combination of dietary modification, physical exercise, and use of aspirin, statin, and an antihypertensive agent can give a cumulative relative stroke risk reduction of 80% [43]. The antiplatelet therapy and statin use reduce the risk of recurrent stroke in patients with symptomatic extracranial carotid stenosis [5].

#### **4. Carotid endarterectomy and carotid artery stenting**

In the patients with carotid stenosis of 70–99%, the revascularization procedures such as carotid endarterectomy (CEA) and carotid artery stenting (CAS) may be considered [5, 42]. The patient with a low-grade stenosis but an ulcerated plaque or intraplaque hemorrhage may benefit more from a revascularization procedure than a patient with a stable 70% asymptomatic stenosis with a thick fibrous cap [13].

#### **5. Carotid endarterectomy and carotid artery stenting in symptomatic extracranial carotid stenosis**

Carotid endarterectomy and carotid artery stenting reduce the risk of recurrent stroke in patients with symptomatic extracranial carotid stenosis [5]. The revascularization procedures reduce the 90-day risk of subsequent ischemic stroke in the patients with severe extracranial carotid artery stenosis [5]. While awaiting the revascularization procedures, a combination of aspirin and clopidogrel in recently symptomatic patients with carotid stenosis can be given [43].

MR plaque imaging is useful in identifying revascularization candidates who are better candidates for carotid endarterectomy than carotid artery stenting [13]. This is because high intraplaque signal on time-of-flight imaging is associated with vulnerable plaque and in-creased rates of adverse events in patients undergoing stenting but not carotid endarterectomy [13].

In the recent guidelines, carotid endarterectomy is likely the preferred option for the management of asymptomatic carotid stenosis [44, 45]. Carotid artery stenting has higher risk of periprocedural stroke and mortality [44–46]. Carotid endarterectomy is safer in comparison to carotid artery stenting [44, 45]. The risk of periprocedural stroke and mortality after carotid endarterectomy has declined tremendously throughout the years [47].

However, carotid endarterectomy is associated with an increased risk of periprocedural myocardial infarction [44, 45, 48]. To date, the long-term outcomes of these two modalities remain uncertain [44]. In patients with high risk of periprocedural complications, best medical treatment is recommended by the American Heart Association and the Society for Vascular Surgery [32, 44, 49].

#### **6. Conclusion**

**3. Therapeutic options**

98 Peripheral Arterial Disease - A Practical Approach

cological management and lifestyle interventions [42].

treatment of vascular risk factors are important [43].

patients with symptomatic extracranial carotid stenosis [5].

tomatic stenosis with a thick fibrous cap [13].

sis can be given [43].

**symptomatic extracranial carotid stenosis**

**4. Carotid endarterectomy and carotid artery stenting**

**5. Carotid endarterectomy and carotid artery stenting in** 

Detection of extracranial carotid atherosclerosis in these patients is beneficial because proper management can be given [32, 42]. The patients with TIA due to extracranial carotid stenosis should be given intensive medical therapy [42]. Intensive medical therapy consists of pharma-

The pharmacological management involves antiplatelet therapy and statin use [5, 42]. The antiplatelet therapy which routinely administered is aspirin or clopidogrel [43]. Adequate blood pressure control is necessary with a target blood pressure of less than 140/90 [42]. A reduction in blood pressure to the ideal level slows down the progression of carotid artery stenosis and also reduces the carotid intima media thickness (CIMT) [43]. Identification and

Lifestyle changes involve Mediterranean-style diet, exercise, and smoking cessation [42, 43]. In addition, lifestyle choices such as unhealthy diet and excessive alcohol intake are modifiable risk factors [43]. The combination of dietary modification, physical exercise, and use of aspirin, statin, and an antihypertensive agent can give a cumulative relative stroke risk reduction of 80% [43]. The antiplatelet therapy and statin use reduce the risk of recurrent stroke in

In the patients with carotid stenosis of 70–99%, the revascularization procedures such as carotid endarterectomy (CEA) and carotid artery stenting (CAS) may be considered [5, 42]. The patient with a low-grade stenosis but an ulcerated plaque or intraplaque hemorrhage may benefit more from a revascularization procedure than a patient with a stable 70% asymp-

Carotid endarterectomy and carotid artery stenting reduce the risk of recurrent stroke in patients with symptomatic extracranial carotid stenosis [5]. The revascularization procedures reduce the 90-day risk of subsequent ischemic stroke in the patients with severe extracranial carotid artery stenosis [5]. While awaiting the revascularization procedures, a combination of aspirin and clopidogrel in recently symptomatic patients with carotid steno-

MR plaque imaging is useful in identifying revascularization candidates who are better candidates for carotid endarterectomy than carotid artery stenting [13]. This is because high In conclusion, evaluation of extracranial carotid atherosclerosis in the patients with TIA is very important. There are several modalities which can be employed to investigate for extracranial carotid stenosis. Pharmacological and nonpharmacological management can be given to the patients with extracranial carotid atherosclerosis.

### **Author details**

Mei-Ling Sharon Tai\*, Jun Kit Khoo and Mohamed Abdusalam Elwaifa

\*Address all correspondence to: sharont1990@gmail.com

Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Malaysia

#### **References**


[4] Rothwell PM, Warlow CP. Timing of TIAs preceding stroke: Time window for prevention is very short. Neurology. 2005;**64**:817-820

[17] Nomura M, Kasami R, Ohashi M, Yamada Y, Abe H. Significantly higher incidence of carotid atherosclerosis found in Japanese type 2 diabetic patients with early nephropa-

Extracranial Carotid Atherosclerosis in the Patients with Transient Ischemic Attack

http://dx.doi.org/10.5772/intechopen.75792

101

[18] Frauchiger B, Schmid HP, Roedel C, Moosmann P, Staub D. Comparison of carotid arterial resistive indices with intima-media thickness as sonographic markers of atheroscle-

[19] Sheehan OC, Kyne L, Kelly LA, Hannon N, Marnane M, Merwick A, et al. Populationbased study of ABCD2 score, carotid stenosis, and atrial fibrillation for early stroke prediction after transient ischemic attack: The North Dublin TIA study. Stroke. 2010;**41**:844-850

[20] Huang YN, Gao S, Li SW, Huang Y, Li JF, Wong KS, Kay R. Vascular lesions in Chinese

[21] Nishimaru K, McHenry Jr LC, Toole JF. Cerebral angiographic and clinical differences in carotid system transient ischemic attacks between American Caucasian and Japanese

[22] Ryu JE, Murros K, Espeland MA, Rubens J, McKinney WM, Toole JF, Crouse JR. Extracranial carotid atherosclerosis in black and white patients with transient isch-

[23] Amarenco P, Lavallée PC, Labreuche J, Albers GW, Bornstein NM, Canhão P, et al. Oneyear risk of stroke after transient ischemic attack or minor stroke. The New England

[24] Landwehr P, Schulte O, Voshage G. Ultrasound examination of carotid and vertebral

[25] Grant EG, Benson CB, Moneta GL, Alexandrov AV, Baker JD, Bluth EI, et al. Carotid artery stenosis: Gray-scale and Doppler US diagnosis. Radiology. Nov 2003;**229**:340-346

[26] Lima FO, Lev MH, Levy RA, Silva GS, Ebril M, de Camargo EC, et al. Functional contrast-enhanced CT for evaluation of acute ischemic stroke does not increase the risk of contrast-induced nephropathy. AJNR. American Journal of Neuroradiology.

[27] Nandalur KR, Baskurt E, Hagspiel KD, Phillips CD, Kramer CM. Calcified carotid atherosclerotic plaque is associated less with ischemic symptoms than is noncalcified

[28] Wintermark M, Jawadi SS, Rapp JH, Tihan T, Tong E, Glidden DV, et al. Highresolution CT imaging of carotid artery atherosclerotic plaques. American Journal of

[29] Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. The

[30] Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic

plaque on MDCT. American Journal of Roentgenology. 2005;**184**:295-298

patients with transient ischemic attacks. Neurology. Feb 1997;**48**(2):524-525

thy. Diabetes Research and Clinical Practice. 2004;**66**(Suppl 1):S161-S163

rosis. Stroke. 2001;**32**:836-841

patients. Stroke. Jan–Feb 1984;**15**(1):56-59

emic attacks. Stroke. Sep 1989;**20**(9):1133-1137

Journal of Medicine. Apr 21, 2016;**374**(16):1533-1542

arteries. European Radiology. 2001;**11**:1521-1534

2010;**31**:817-821

Neuroradiology. 2008;**29**:875-882

New England Journal of Medicine. 2005;**352**:1305-1316


[17] Nomura M, Kasami R, Ohashi M, Yamada Y, Abe H. Significantly higher incidence of carotid atherosclerosis found in Japanese type 2 diabetic patients with early nephropathy. Diabetes Research and Clinical Practice. 2004;**66**(Suppl 1):S161-S163

[4] Rothwell PM, Warlow CP. Timing of TIAs preceding stroke: Time window for preven-

[5] Uehara T, Ohara T, Toyoda K, Nagatsuka K, Minematsu K. Clinical, laboratory, and imaging characteristics of transient ischemic attack caused by large artery lesions: A comparison between carotid and intracranial arteries. Cerebrovascular Diseases Extra.

[6] Rothwell PM, Giles MF, Chandratheva A, Marquardt L, Geraghty O, Redgrave JN, et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): A prospective population-based sequential comparison.

[7] Lavallee PC, Meseguer E, Abboud H, Cabrejo L, Olivot JM, Simon O, et al. A transient ischaemic attack clinic with round-the-clock access (SOS-TIA): Feasibility and effects.

[8] Coutts SB, Modi J, Patel SK, Demchuk AM, Goyal M, Hill MD, Calgary Stroke Program. CT/CT angiography and MRI findings predict recurrent stroke after transient ischemic attack and minor stroke: Results of the prospective CATCH study. Stroke.

[9] Purroy F, Montaner J, Molina CA, Delgado P, Ribo M, Alvarez-Sabín J. Patterns and predictors of early risk of recurrence after transient ischemic attack with respect to etiologic

[10] Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke

[11] Li M, Le WJ, Tao XF, Li MH, Li YH, Qu N. Advantage in bright-blood and black-blood magnetic resonance imaging with high-resolution for analysis of carotid atherosclerotic

[12] Inoue K, Maeda M, Umino M, Takase S, Yamahata T, Sakuma H. Cervical carotid plaque evaluation using 3D T1-weighted black-blood magnetic resonance imaging: Comparison of turbo field-echo and turbo spin-echo sequences. European Journal of Radiology. May

[13] Brinjikji W, Huston 3rd J, Rabinstein AA, Kim GM, Lerman A, Lanzino G. Contemporary carotid imaging: From degree of stenosis to plaque vulnerability. Journal of Neurosurgery.

[14] Alonso A, Artemis D, Hennerici MG. Molecular imaging of carotid plaque vulnerability.

[15] Hill MD, Yiannakoulias N, Jeerakathil T, Tu JV, Svenson LW, Schopflocher DP. The high risk of stroke immediately after transient ischemic attack: A population-based study.

[16] Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: Implications for public education and organ-

in population-based incidence studies. Neurology. 2004;**62**:569-573

plaques. Chinese Medical Journal. Sep 20, 2015;**128**(18):2478-2484

tion is very short. Neurology. 2005;**64**:817-820

Oct 16, 2015;**5**(3):115-123

100 Peripheral Arterial Disease - A Practical Approach

Lancet. 2007;**370**:1432-1442

2012;**43**:1013-1017

2016;**85**(5):1035-1039

Jan 2016;**124**(1):27-42

Cerebrovascular Diseases. 2015;**39**(1):5-12

isation of services. British Medical Journal. 2004;**328**:326

Neurology. 2004;**62**:2015-2020

Lancet Neurology. 2007;**6**:953-960

subtypes. Stroke. 2007;**38**:3225-3229


attack: A guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2014;**45**:2160-2236

[43] Cheng SF, Brown MM. Contemporary medical therapies of atherosclerotic carotid artery

Extracranial Carotid Atherosclerosis in the Patients with Transient Ischemic Attack

http://dx.doi.org/10.5772/intechopen.75792

103

[44] Moresoli P, Habib B, Reynier P, Secrest MH, Eisenberg MJ, Filion KB. Carotid stenting versus endarterectomy for asymptomatic carotid artery stenosis: A systematic review

[45] Kakkos SK, Kakisis I, Tsolakis IA, Geroulakos G. Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.

[46] Liu ZJ, Fu WG, Guo ZY, Shen LG, Shi ZY, Li JH. Updated systematic review and metaanalysis of randomized clinical trials comparing carotid artery stenting and carotid endarterectomy in the treatment of carotid stenosis. Annals of Vascular Surgery.

[47] Lokuge K, de Waard DD, Halliday A, Gray A, Bulbulia R, Mihaylova B. Meta-analysis of the procedural risks of carotid endarterectomy and carotid artery stenting over time.

[48] Sardar P, Chatterjee S, Aronow HD, Kundu A, Ramchand P, Mukherjee D, et al. Carotid artery stenting versus endarterectomy for stroke prevention: A meta-analysis of clinical

[49] Ricotta JJ, Aburahma A, Ascher E, Eskandari M, Faries P, Lal BK, Society for Vascular Surgery. Updated Society for Vascular Surgery guidelines for management of extracranial carotid disease: Executive summary. Journal of Vascular Surgery. 2011;**54**:832-836

trials. Journal of the American College of Cardiology. 2017;**69**:2266-2275

disease. Seminars in Vascular Surgery. Mar 2017;**30**(1):8-16

and meta-analysis. Stroke. Aug 2017;**48**(8):2150-2157

Journal of Vascular Surgery. Aug 2017;**66**(2):607-617

The British Journal of Surgery. Jan 2018;**105**(1):26-36

2012;**26**:576-590


[43] Cheng SF, Brown MM. Contemporary medical therapies of atherosclerotic carotid artery disease. Seminars in Vascular Surgery. Mar 2017;**30**(1):8-16

attack: A guideline for healthcare professionals from the American Heart Association/

[31] Hinton DP, Cury RC, Chan RC, Wald LL, Sherwood JB, Furie KL, et al. Bright and black blood imaging of the carotid bifurcation at 3.0T. European Journal of Radiology.

[32] Anumula S, Song HK, Wright AC, Wehrli FW. High-resolution black-blood MRI of the carotid vessel wall using phased-array coils at 1.5 and 3 Tesla. Academic Radiology.

[33] Hatsukami TS, Ross R, Polissar NL, Yuan C. Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high-resolution magnetic

[34] de Rotte AA, Koning W, Truijman MT, den Hartog AG, Bovens SM, Vink A, et al. Seventesla magnetic resonance imaging of atherosclerotic plaque in the significantly stenosed carotid artery: A feasibility study. Investigative Radiology. Nov 2014;**49**(11):749-757 [35] Saito H, Kuroda S, Hirata K, Magota K, Shiga T, Tamaki N, et al. Validity of dual MRI and F-FDG PET imaging in predicting vulnerable and inflamed carotid plaque.

[36] Streifler JY, Eliasziw M, Fox AJ, Benavente OR, Hachinski VC, Ferguson GG, et al. Angiographic detection of carotid plaque ulceration. Comparison with surgical observations in a multicenter study. North American Symptomatic Carotid Endarterectomy

[37] Umemura T, Kawamura T, Mashita S, Kameyama T, Sobue G. Higher levels of cystatin C are associated with extracranial carotid artery steno-occlusive disease in patients with noncardioembolic ischemic stroke. Cerebrovascular Diseases Extra. Jan 20, 2016;**6**(1):1-11

[38] Hoke M, Amighi J, Mlekusch W, Schlager O, Exner M, Sabeti S, et al. Cystatin C and the risk for cardiovascular events in patients with asymptomatic carotid atherosclerosis.

[39] Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. The New England

[40] Ix JH, Shlipak MG, Chertow GM, Whooley MA. Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart

[41] Salgado JV, Souza FL, Salgado BJ. How to understand the association between cystatin C levels and cardiovascular disease: Imbalance, counterbalance, or consequence? Journal

[42] Wabnitz AM, Turan TN. Symptomatic carotid artery stenosis: Surgery, stenting, or medical therapy? Current Treatment Options in Cardiovascular Medicine. Aug 2017;**19**(8):62

disease: Data from the Heart and Soul Study. Circulation. 2007;**115**:173-179

American Stroke Association. Stroke. 2014;**45**:2160-2236

resonance imaging. Circulation. 2000;**102**:959-964

Cerebrovascular Diseases. 2013;**35**(4):370-377

Trial. Stroke. 1994;**25**:1130-1132

Stroke. 2010;**41**:674-679

Journal of Medicine. 2005;**352**:2049-2060

of Cardiology. 2013;**62**:331-335

2006;**57**:403-411

102 Peripheral Arterial Disease - A Practical Approach

2005;**12**:1521-1526


**Section 5**

**Genetics in Peripheral Arterial Disease**

**Genetics in Peripheral Arterial Disease**

**Chapter 8**

**Provisional chapter**

**Genetics in Peripheral Artery Disease**

**Genetics in Peripheral Artery Disease**

DOI: 10.5772/intechopen.77209

Besides traditional risk factor, it has been proved that genetics and gene–environment interaction have a possible independent role in the development and progression of peripheral arterial disease (PAD). Knowledge about such genetic factors will increases our understanding about pathophysiologic mechanisms of PAD and could facilitate the therapeutic approaches. Human genetics has gone through an advanced improvement and it increases our chance to acquire better diagnostic and therapeutic approaches. In this chapter, we try to provide an update on the genetics of PAD, which is mostly about genome-wide association studies, linkage analyses, heritability, candidate gene studies, and epigenetics. Finally, we discuss challenges and future developments of researches in

**Keywords:** peripheral arterial disease, genetics, genome-wide association study, linkage

Common cause of PAD is atherosclerosis. Besides environmental risk factors (e.g., smoking, gender, age), some heritable risk factors are described for atherosclerosis. These are included hyperlipidemia, hypertension and diabetes mellitus. A reliable genetic marker could identify those individuals with PAD and accelerate their treatment. Besides, finding new genetic targets uncover new insights to the pathophysiology of PAD, and consequently new target for the cure. Earlier studies suggested heritability of PAD [1–4]. One study on monozygotic and dizygotic pairs revealed that with the similar environmental risk factors 48% variability of Ankle brachial Index (ABI) could be explained by additive genetic effects [2]. GENOA study

analyses, heritability, candidate gene studies, epigenetics

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Amir-Houshang Shemirani, Katalin Szilvia Zsóri,

Amir-Houshang Shemirani, Katalin Szilvia Zsóri,

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

András Jávor and Zoltán Csiki

András Jávor and Zoltán Csiki

**Abstract**

PAD genetics.

**1. Introduction**

http://dx.doi.org/10.5772/intechopen.77209

#### **Genetics in Peripheral Artery Disease Genetics in Peripheral Artery Disease**

Amir-Houshang Shemirani, Katalin Szilvia Zsóri, András Jávor and Zoltán Csiki Amir-Houshang Shemirani, Katalin Szilvia Zsóri, András Jávor and Zoltán Csiki

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77209

#### **Abstract**

Besides traditional risk factor, it has been proved that genetics and gene–environment interaction have a possible independent role in the development and progression of peripheral arterial disease (PAD). Knowledge about such genetic factors will increases our understanding about pathophysiologic mechanisms of PAD and could facilitate the therapeutic approaches. Human genetics has gone through an advanced improvement and it increases our chance to acquire better diagnostic and therapeutic approaches. In this chapter, we try to provide an update on the genetics of PAD, which is mostly about genome-wide association studies, linkage analyses, heritability, candidate gene studies, and epigenetics. Finally, we discuss challenges and future developments of researches in PAD genetics.

DOI: 10.5772/intechopen.77209

**Keywords:** peripheral arterial disease, genetics, genome-wide association study, linkage analyses, heritability, candidate gene studies, epigenetics

#### **1. Introduction**

Common cause of PAD is atherosclerosis. Besides environmental risk factors (e.g., smoking, gender, age), some heritable risk factors are described for atherosclerosis. These are included hyperlipidemia, hypertension and diabetes mellitus. A reliable genetic marker could identify those individuals with PAD and accelerate their treatment. Besides, finding new genetic targets uncover new insights to the pathophysiology of PAD, and consequently new target for the cure. Earlier studies suggested heritability of PAD [1–4]. One study on monozygotic and dizygotic pairs revealed that with the similar environmental risk factors 48% variability of Ankle brachial Index (ABI) could be explained by additive genetic effects [2]. GENOA study

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

(Genetic Epidemiology Network of Arteriopathy) and the Framingham Offspring cohort study also found heritability in ABI variations [3, 4]. The degree of genetic variations on the PAD, regardless of the influences of other risk factors, remains to be revealed.

Although, linkage analysis does not require specific candidate gene and scans full genome, it did not show promising results. That could be related to lack of large family pedigrees and polygenic nature of PAD. Linkage analysis cannot identify the genetic contributions arise

Genetics in Peripheral Artery Disease http://dx.doi.org/10.5772/intechopen.77209 109

In this observational study, a genome-wide set of genetic variants (SNPs) can be screened in a large cohorts of patients. This approach determines the associations between SNPs and specific phenotype compared to control individuals. Unlike linkage analysis, GWAS has the

In one study rs10757278 SNP at 9p21 was found to be associated with PAD (OR = 1.14, p = 6.1 × 10−5), but exclusion of known CAD cases from sample sets reduced the effect of this variant significantly (OR = 1.09, p = 0.075) [7]. Another similar study showed an association between 9p21 SNP (rs 1,333,049) with severity and prevalence of PAD [8]. A Japanese study on 785 PAD and 20,134 control individuals found rs9584669 in IPO5/ RAP2A related protein 2A (OR = 0.58, p = 6.78 × 10−14), rs6842241 in endothelin receptor type A (ENDRA gene; p = 5.32 × 10−9), and rs2074633 in histone deacylase 9 (HDAC9 gene; p = 8.43 × 10−8) loci with susceptibility to PAD [9]. Thorgeirsson et al. identified a common variant (rs1051730) in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with higher risk for PAD (OR = 1.19, P = 1.4 × 10−7) [10]. A GWAS study found rs7025486 at 9q33 associated with PAD (OR = 1.14, p = 3.9 × 10−5) [11]. An investigation performed on 699 PAD and 1540 Japanese controls identified rs1902341-A to have a strong association with PAD (OR = 1.31, p = 4.7 × 10−7) [12]. A recent meta-analysis with a total of 41,692 participants of European ancestry demonstrated that rs10757269 at 9p21 had the strongest association with ABI and achieved genome-wide

After above mentioned meta-analysis, one study investigated 537,872 SNPs in 1641 PAD and 1604 control individuals in The Electronic Medical Records and Genomics consortium (eMERGE)-based GWAS of PAD [14]. They revealed that rs653178 in the ATXN2-SH2B3 locus was significantly associated with PAD (OR = 1.22, p = 6.46 × 10−7). Another outcome of this study was that neither loci was linked to PAD after investigation of prior known SNPs related to PAD. eMERGE analyses of PAD GEWAS results could not reveal any strong associations between SNPs and PAD by investigating of mitochondrial SNPs and haplogroups in 1652

This kind of study focuses on differences in allele frequency of a known specific variant between cases and controls among unrelated individuals. With ability for finer mapping of the causal variant, association studies demonstrate greater power to detect modest genetic effects. Generally, search of insertions, deletions, and individual SNPs among cases and controls points out to genes to be associated with the development of atherosclerosis and changes

from many genes each with small effect sizes.

**2.2. Genome-wide association study**

ability to detect modest genotypic effects.

significance (p = 2.46 × 10−8) [13].

PAD and 1629 control individuals [15].

**2.3. Candidate gene studies**

#### **2. Genetic studies**

**Table 1** demonstrates comparisons between different genetic tests.

#### **2.1. Linkage analysis**

Genetic linkage analysis has the power to identify parts of genome that contain genes that could be inherited together. In this kind of genetic study, low resolution genome scanning investigates for genetic markers (microsatellites and Single nucleotide polymorphisms-SNPs) and that are pass to the next generation with the phenotype of interest. The results express in logarithm of the odds (LOD). Positive LOD indicates that co-segregation of two genetic markers is more likely, and negative LOD favors that likelihood less likely. It is advisable to consider LOD more than three statistically significant [5]. Next step is then to map neighboring region of the genome with tied association between genetic marker and phenotype.

Three studies demonstrated relation between different loci and PAD [3, 6]. First Gudmundsson and colleagues [6], identified a locus as "PAOD1" on chromosome 1p31 (LOD = 3.93; p = 1.04 × 10−5) conferring susceptibility to PAD even after nullifying the effects of diabetes mellitus, hypertension and hyperlipidemia. Interestingly, the genes responsible for PAOD1 did not identified which is not surprising based on the difficulties for analyzing genetic background of a complex disease such as PAD. Another study demonstrated the association of ankle-brachial index (ABI) with 250 microsatellite markers on chromosomes 1p, 6q, 7q, and 10p in 1310 African Americans and on chromosomes 3p and 3q in 796 non-Hispanic whites [3]. This study was also unable to demonstrate any evidence of linkage to the PAD trait.


**Table 1.** Comparison of different genetic tests for PAD genetics analysis.

Although, linkage analysis does not require specific candidate gene and scans full genome, it did not show promising results. That could be related to lack of large family pedigrees and polygenic nature of PAD. Linkage analysis cannot identify the genetic contributions arise from many genes each with small effect sizes.

#### **2.2. Genome-wide association study**

(Genetic Epidemiology Network of Arteriopathy) and the Framingham Offspring cohort study also found heritability in ABI variations [3, 4]. The degree of genetic variations on the

Genetic linkage analysis has the power to identify parts of genome that contain genes that could be inherited together. In this kind of genetic study, low resolution genome scanning investigates for genetic markers (microsatellites and Single nucleotide polymorphisms-SNPs) and that are pass to the next generation with the phenotype of interest. The results express in logarithm of the odds (LOD). Positive LOD indicates that co-segregation of two genetic markers is more likely, and negative LOD favors that likelihood less likely. It is advisable to consider LOD more than three statistically significant [5]. Next step is then to map neighboring region of the genome with tied association between genetic marker and phenotype.

Three studies demonstrated relation between different loci and PAD [3, 6]. First Gudmundsson and colleagues [6], identified a locus as "PAOD1" on chromosome 1p31 (LOD = 3.93; p = 1.04 × 10−5) conferring susceptibility to PAD even after nullifying the effects of diabetes mellitus, hypertension and hyperlipidemia. Interestingly, the genes responsible for PAOD1 did not identified which is not surprising based on the difficulties for analyzing genetic background of a complex disease such as PAD. Another study demonstrated the association of ankle-brachial index (ABI) with 250 microsatellite markers on chromosomes 1p, 6q, 7q, and 10p in 1310 African Americans and on chromosomes 3p and 3q in 796 non-Hispanic whites [3].

This study was also unable to demonstrate any evidence of linkage to the PAD trait.

Cost; no off-target incidental findings Low sensitivity

Genome sequencing Full coverage of DNA sequence Cost, turnaround time, analytical challenges,

No detection of balanced rearrangements

inaccurate for SNPs with lower frequency

disorders

It needs a high participants number with several affected generations, less helpful for complex

**Genetic test type Advantages Disadvantages**

detection

Linkage studying different areas across the

High resolution, good copy number

GWAS novel marker finding high participants number

genome, analyzing multiple genetic

markers at the same time

**Table 1.** Comparison of different genetic tests for PAD genetics analysis.

PAD, regardless of the influences of other risk factors, remains to be revealed.

**Table 1** demonstrates comparisons between different genetic tests.

**2. Genetic studies**

108 Peripheral Arterial Disease - A Practical Approach

**2.1. Linkage analysis**

Single gene/panel gene

sequencing

Oligonucleotide microarray

In this observational study, a genome-wide set of genetic variants (SNPs) can be screened in a large cohorts of patients. This approach determines the associations between SNPs and specific phenotype compared to control individuals. Unlike linkage analysis, GWAS has the ability to detect modest genotypic effects.

In one study rs10757278 SNP at 9p21 was found to be associated with PAD (OR = 1.14, p = 6.1 × 10−5), but exclusion of known CAD cases from sample sets reduced the effect of this variant significantly (OR = 1.09, p = 0.075) [7]. Another similar study showed an association between 9p21 SNP (rs 1,333,049) with severity and prevalence of PAD [8]. A Japanese study on 785 PAD and 20,134 control individuals found rs9584669 in IPO5/ RAP2A related protein 2A (OR = 0.58, p = 6.78 × 10−14), rs6842241 in endothelin receptor type A (ENDRA gene; p = 5.32 × 10−9), and rs2074633 in histone deacylase 9 (HDAC9 gene; p = 8.43 × 10−8) loci with susceptibility to PAD [9]. Thorgeirsson et al. identified a common variant (rs1051730) in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with higher risk for PAD (OR = 1.19, P = 1.4 × 10−7) [10]. A GWAS study found rs7025486 at 9q33 associated with PAD (OR = 1.14, p = 3.9 × 10−5) [11]. An investigation performed on 699 PAD and 1540 Japanese controls identified rs1902341-A to have a strong association with PAD (OR = 1.31, p = 4.7 × 10−7) [12]. A recent meta-analysis with a total of 41,692 participants of European ancestry demonstrated that rs10757269 at 9p21 had the strongest association with ABI and achieved genome-wide significance (p = 2.46 × 10−8) [13].

After above mentioned meta-analysis, one study investigated 537,872 SNPs in 1641 PAD and 1604 control individuals in The Electronic Medical Records and Genomics consortium (eMERGE)-based GWAS of PAD [14]. They revealed that rs653178 in the ATXN2-SH2B3 locus was significantly associated with PAD (OR = 1.22, p = 6.46 × 10−7). Another outcome of this study was that neither loci was linked to PAD after investigation of prior known SNPs related to PAD. eMERGE analyses of PAD GEWAS results could not reveal any strong associations between SNPs and PAD by investigating of mitochondrial SNPs and haplogroups in 1652 PAD and 1629 control individuals [15].

#### **2.3. Candidate gene studies**

This kind of study focuses on differences in allele frequency of a known specific variant between cases and controls among unrelated individuals. With ability for finer mapping of the causal variant, association studies demonstrate greater power to detect modest genetic effects. Generally, search of insertions, deletions, and individual SNPs among cases and controls points out to genes to be associated with the development of atherosclerosis and changes in various vascular biology pathways such as lipid metabolism [16], hemostasis [17–21], homocysteine [22–24], inflammation [25, 26], angiotensin converting enzyme [27], leukocyte adhesion [28], platelet activation and aggregation [29, 30], endothelial function [31, 32], and smooth muscle cell migration. A recent meta-analysis of around 50,000 SNPs and across about 2100 genes found only three SNPs associated with ABI or PAD [33]. They demonstrated that rs2171209 in SYTL3 (p = 6.02 × 10−7) (originally linked to lipoprotein (a)) and rs290481 in TCF7L2 (p = 7.01 × 10−7) (linked to diabetes mellitus type 2) were significantly associated with ABI and CYP2B6 (p = 4.99 × 10−5) (linked to smoking behavior) was associated to PAD.

INO80D, a subunit of the human INO80 chromatin remodeling complex [42]. INO80 complex is involved in cardiovascular physiology and development [43]. Another study repeated this

Genetics in Peripheral Artery Disease http://dx.doi.org/10.5772/intechopen.77209 111

This epidemiologic study design incorporates genetic results into epidemiologic methods. Mendelian randomization studies offer evidence for causal relations between risk factors and

Mendelian randomization has been used to examine the relations between polymorphisms of specific genes and the prevalence of coronary heart disease or myocardial infarction [44]. Recently, it is demonstrated that each standard deviation (SD, 2.76 points) increase in body mass index (BMI)-composite genetic risk score was associated with 0.43 in BMI and an odds

As multiple atherogenic pathways are involved in the pathophysiology of PAD, a profound monogenic effect is unlikely [46]. Environmental influences such as age, smoking, sport, ethnicity, and diabetes mellitus status besides genetic effects could vary the outcome for this disease. GWAS results are not comprehensive. It could be due to modest effect of susceptible variants. To power GWAS analysis, large sample sizes are needed. GWAS results so far revealed limited results. Two linkage studies did not demonstrate breakthrough to identify significant mechanisms behind inheritance of PAD. SNPs association studies have provided weak and/or conflicting findings results. Next generation sequencing and epigenetics seem to provide some promising future. Whole-genome or exome sequencing or NGS-based RNAsequencing has identified new causative links between new genes and PAD. It is imperative to merge deep sequencing data of the DNA findings with epigenetic data to find more interesting results. This is challenging as these methods produce huge amount of data to analyze. Environmental-Wide Association Study demonstrates gene-by-environment interactions. This new method to study inter-relation between environment and genomics was a topic in ascertaining causality in type II diabetes mellitus [47]. They showed that the pesticide heptachlor epoxide was associated with type II diabetes mellitus. This new method has some

In the future, we may apply personalized medicine on the basis of genetic analysis and treat

result in two patients with aortic hypoplasia, diffuse atherosclerosis, and PAD.

**2.6. Mendelian randomization**

disease outcome.

**3. Discussion**

ratio for PAD of 1.17 [45].

places in gene-environment studies in PAD.

the patient by specific therapeutic agents.

All authors declare no conflict of interest.

**Conflict of interest**

#### **2.4. Epigenetics**

By definition, epigenetics is a science of long-lived or even hereditary modification of gene function without alteration of DNA sequence. In epigenetics, DNA could go through methylation, histone post-translational modifications, or microRNAs (miRNA), long noncoding RNA (lncRNA) mechanisms [34, 35]. miRNAs are small (≈22 nucleotides) singlestranded RNAs that inhibit translation of mRNA after binding to a target gene. Each miRNA can regulate several genes, because they do not require 100% base pair match. lncRNAs defined as more than 200 nucleotide long transcripts with function other than translation to protein.

Epigenetic changes have been described in association with some PAD risk factors [36, 37]. Hyperhomocysteinemia induces DNA methylation and could contribute to development and progression of PAD [36]. DNA hypomethylation caused by smoking has been reported [37].

Most of the epigenetic studies relevant to PAD are currently about miRNAs. There are two approaches to explore the role of miRNA in PAD. They have involved either a small number of candidate intracellular miRNA which are known for their role in vascular diseases or the measure of a large cluster of miRNAs by microarrays. A miRNA SYBR Green Real-Time PCR assessed the alteration of miR-130a, miR-27b and miR-210 expression in PAD [38]. A whole-genome miRNA transcriptome profiling revealed downregulation of 12 miRNAs in PAD compared to controls [39]. Later, the same research group detected significant downregulation of miR-15a, miR-196b, and let-7e and upregulation of miR-411 in 40 PAD and 40 control individuals [40].

Alterations in mitochondrial DNA (mtDNA) were proposed as a pathway for myopathy in PAD [41]. Mitochondrial dysfunction could be as a result of bouts of ischemia in these patients which causes damage to mitochondrion (mitochodriopathy).

#### **2.5. Whole genome/exome sequencing**

While massively parallel sequencing has not been performed on PAD patients specifically, some results from researches on atherosclerosis could be attributed to PAD. In one study, exonic regions of two persons with the early atherosclerosis were sequenced with next generation sequencing platform, and they revealed a rare missense mutation (Ser818Cys) in INO80D, a subunit of the human INO80 chromatin remodeling complex [42]. INO80 complex is involved in cardiovascular physiology and development [43]. Another study repeated this result in two patients with aortic hypoplasia, diffuse atherosclerosis, and PAD.

#### **2.6. Mendelian randomization**

in various vascular biology pathways such as lipid metabolism [16], hemostasis [17–21], homocysteine [22–24], inflammation [25, 26], angiotensin converting enzyme [27], leukocyte adhesion [28], platelet activation and aggregation [29, 30], endothelial function [31, 32], and smooth muscle cell migration. A recent meta-analysis of around 50,000 SNPs and across about 2100 genes found only three SNPs associated with ABI or PAD [33]. They demonstrated that rs2171209 in SYTL3 (p = 6.02 × 10−7) (originally linked to lipoprotein (a)) and rs290481 in TCF7L2 (p = 7.01 × 10−7) (linked to diabetes mellitus type 2) were significantly associated with ABI and CYP2B6 (p = 4.99 × 10−5) (linked to smoking behavior) was associated to PAD.

By definition, epigenetics is a science of long-lived or even hereditary modification of gene function without alteration of DNA sequence. In epigenetics, DNA could go through methylation, histone post-translational modifications, or microRNAs (miRNA), long noncoding RNA (lncRNA) mechanisms [34, 35]. miRNAs are small (≈22 nucleotides) singlestranded RNAs that inhibit translation of mRNA after binding to a target gene. Each miRNA can regulate several genes, because they do not require 100% base pair match. lncRNAs defined as more than 200 nucleotide long transcripts with function other than

Epigenetic changes have been described in association with some PAD risk factors [36, 37]. Hyperhomocysteinemia induces DNA methylation and could contribute to development and progression of PAD [36]. DNA hypomethylation caused by smoking has been

Most of the epigenetic studies relevant to PAD are currently about miRNAs. There are two approaches to explore the role of miRNA in PAD. They have involved either a small number of candidate intracellular miRNA which are known for their role in vascular diseases or the measure of a large cluster of miRNAs by microarrays. A miRNA SYBR Green Real-Time PCR assessed the alteration of miR-130a, miR-27b and miR-210 expression in PAD [38]. A whole-genome miRNA transcriptome profiling revealed downregulation of 12 miRNAs in PAD compared to controls [39]. Later, the same research group detected significant downregulation of miR-15a, miR-196b, and let-7e and upregulation of miR-411 in 40 PAD and 40

Alterations in mitochondrial DNA (mtDNA) were proposed as a pathway for myopathy in PAD [41]. Mitochondrial dysfunction could be as a result of bouts of ischemia in these patients

While massively parallel sequencing has not been performed on PAD patients specifically, some results from researches on atherosclerosis could be attributed to PAD. In one study, exonic regions of two persons with the early atherosclerosis were sequenced with next generation sequencing platform, and they revealed a rare missense mutation (Ser818Cys) in

which causes damage to mitochondrion (mitochodriopathy).

**2.4. Epigenetics**

110 Peripheral Arterial Disease - A Practical Approach

translation to protein.

control individuals [40].

**2.5. Whole genome/exome sequencing**

reported [37].

This epidemiologic study design incorporates genetic results into epidemiologic methods. Mendelian randomization studies offer evidence for causal relations between risk factors and disease outcome.

Mendelian randomization has been used to examine the relations between polymorphisms of specific genes and the prevalence of coronary heart disease or myocardial infarction [44]. Recently, it is demonstrated that each standard deviation (SD, 2.76 points) increase in body mass index (BMI)-composite genetic risk score was associated with 0.43 in BMI and an odds ratio for PAD of 1.17 [45].

#### **3. Discussion**

As multiple atherogenic pathways are involved in the pathophysiology of PAD, a profound monogenic effect is unlikely [46]. Environmental influences such as age, smoking, sport, ethnicity, and diabetes mellitus status besides genetic effects could vary the outcome for this disease. GWAS results are not comprehensive. It could be due to modest effect of susceptible variants. To power GWAS analysis, large sample sizes are needed. GWAS results so far revealed limited results. Two linkage studies did not demonstrate breakthrough to identify significant mechanisms behind inheritance of PAD. SNPs association studies have provided weak and/or conflicting findings results. Next generation sequencing and epigenetics seem to provide some promising future. Whole-genome or exome sequencing or NGS-based RNAsequencing has identified new causative links between new genes and PAD. It is imperative to merge deep sequencing data of the DNA findings with epigenetic data to find more interesting results. This is challenging as these methods produce huge amount of data to analyze. Environmental-Wide Association Study demonstrates gene-by-environment interactions. This new method to study inter-relation between environment and genomics was a topic in ascertaining causality in type II diabetes mellitus [47]. They showed that the pesticide heptachlor epoxide was associated with type II diabetes mellitus. This new method has some places in gene-environment studies in PAD.

In the future, we may apply personalized medicine on the basis of genetic analysis and treat the patient by specific therapeutic agents.

#### **Conflict of interest**

All authors declare no conflict of interest.

### **Author details**

Amir-Houshang Shemirani1 \*, Katalin Szilvia Zsóri1 , András Jávor2 and Zoltán Csiki3 Circulation. Cardiovascular Genetics. 2009;**2**:347-353. DOI: 10.1161/CIRCGENETICS.

Genetics in Peripheral Artery Disease http://dx.doi.org/10.5772/intechopen.77209 113

[9] Matsukura M, Ozaki K, Takahashi A, Onouchi Y, Morizono T, Komai H, et al. Genomewide association study of peripheral arterial disease in a Japanese population. PLoS

[10] Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP, et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.

[11] Gretarsdottir S, Baas AF, Thorleifsson G, Holm H, den Heijer M, de Vries JP, et al. Genomewide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm. Nature Genetics. 2010;**42**:692-697.

[12] Koriyama H, Nakagami H, Katsuya T, Sugimoto K, Yamashita H, Takami Y, et al. Identification of evidence suggestive of an association with peripheral arterial disease at the OSBPL10 locus by genome-wide investigation in the Japanese population. Journal of

[13] Murabito JM, White CC, Kavousi M, Sun YV, Feitosa MF, Nambi V, et al. Association between chromosome 9p21 variants and the ankle-brachial index identified by a metaanalysis of 21 genome-wide association studies. Circulation. Cardiovascular Genetics.

[14] Kullo IJ, Shameer K, Jouni H, Lesnick TG, Pathak J, Chute CG, et al. The ATXN2-SH2B3 locus is associated with peripheral arterial disease: An electronic medical record-based genome-wide association study. Frontiers in Genetics. 2014;**5**(166). DOI: 10.3389/fgene.

[15] Abrantes P, Rosa A, Francisco V, Sousa I, Xavier JM, Oliveira SA. Mitochondrial genome association study with peripheral arterial disease and venous thromboembolism.

[16] Resnick HE, Rodriguez B, Havlik R, Ferrucci L, Foley D, Curb JD, et al. Apo E genotype, diabetes, and peripheral arterial disease in older men: The Honolulu Asia-aging study. Genetic Epidemiology. 2000;**19**:52-63. DOI: 10.1002/1098-2272(200007)19:1<52::

[17] Vazquez F, Rodger M, Carrier M, Le Gal G, Reny JL, Sofi F, et al. Prothrombin G20210A mutation and lower extremity peripheral arterial disease: A systematic review and metaanalysis. European Journal of Vascular and Endovascular Surgery. 2015;**50**:232-240. DOI:

[18] Bayoglu B, Arslan C, Tel C, Ulutin T, Dirican A, Deser SB, et al. Genetic variants rs1994016 and rs3825807 in ADAMTS7 affect its mRNA expression in atherosclerotic occlusive peripheral arterial disease. Journal of Clinical Laboratory Analysis. 2017. DOI: 10.1002/

Atherosclerosis. 2016;**252**:97-105. DOI: 10.1016/j.atherosclerosis.2016.07.920

One. 2015;**10**:e0139262. DOI: 10.1371/journal.pone.0139262

Nature. 2008;**452**:638-642. DOI: 10.1038/nature06846

Atherosclerosis and Thrombosis. 2010;**17**:1054-1062

2012;**5**:100-112. DOI: 10.1161/CIRCGENETICS.111.961292

108.825935

DOI: 10.1038/ng.622

2014.00166

AID-GEPI4>3.0.CO;2-M

10.1016/j.ejvs.2015.04.033

jcla.22174

\*Address all correspondence to: shemirani1@gmail.com

1 Faculty of Medicine, Clinical Laboratory Research Division, Laboratory Medicine, University of Debrecen, Debrecen, Hungary

2 Debrecen University, Debrecen, Hungary

3 Faculty of Medicine, Institute of Internal Medicine, University of Debrecen, Debrecen, Hungary

### **References**


Circulation. Cardiovascular Genetics. 2009;**2**:347-353. DOI: 10.1161/CIRCGENETICS. 108.825935

**Author details**

Hungary

**References**

als.aje.a010230

atherosclerosis.2005.10.003

DOI: 10.1093/aje/kwj295

2008;**40**:217-224. DOI: 10.1038/ng.72

Amir-Houshang Shemirani1

112 Peripheral Arterial Disease - A Practical Approach

\*, Katalin Szilvia Zsóri1

1 Faculty of Medicine, Clinical Laboratory Research Division, Laboratory Medicine,

3 Faculty of Medicine, Institute of Internal Medicine, University of Debrecen, Debrecen,

[1] Allison MA, Criqui MH, McClelland RL, Scott JM, McDermott MM, Liu K, et al. The effect of novel cardiovascular risk factors on the ethnic-specific odds for peripheral arterial disease in the multi-ethnic study of atherosclerosis (MESA). Journal of the American

[2] Carmelli D, Fabsitz RR, Swan GE, Reed T, Miller B, Wolf PA. Contribution of genetic and environmental influences to ankle-brachial blood pressure index in the NHLBI twin study. American Journal of Epidemiology. 2000;**151**:452-458. DOI: 10.1093/oxfordjourn-

[3] Kullo IJ, Turner ST, Kardia SL, Mosley Jr TH, Boerwinkle E, de Andrade M.A genome-wide linkage scan for ankle-brachial index in African American and non-Hispanic white subjects participating in the GENOA study. Atherosclerosis. 2006;**187**:433-438. DOI: 10.1016/j.

[4] Murabito JM, Guo CY, Fox CS, D'Agostino RB. Heritability of the ankle-brachial index: The Framingham offspring study. American Journal of Epidemiology. 2006;**164**:963-968.

[5] Lander E, Kruglyak L. Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nature Genetics. 1995;**11**:241-247. DOI: 10.1038/ng1195-241 [6] Gudmundsson G, Matthiasson SE, Arason H, Johannsson H, Runarsson F, Bjarnason H, et al. Localization of a gene for peripheral arterial occlusive disease to chromosome 1p31. American Journal of Human Genetics. 2002;**70**:586-592. DOI: 10.1086/339251 [7] Helgadottir A, Thorleifsson G, Magnusson KP, Gretarsdottir S, Steinthorsdottir V, Manolescu A, et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nature Genetics.

[8] Cluett C, McDermott MM, Guralnik J, Ferrucci L, Bandinelli S, Miljkovic I, et al. The 9p21 myocardial infarction risk allele increases risk of peripheral artery disease in older people.

College of Cardiology. 2006;**48**:1190-1197. DOI: 10.1016/j.jacc.2006.05.049

\*Address all correspondence to: shemirani1@gmail.com

University of Debrecen, Debrecen, Hungary 2 Debrecen University, Debrecen, Hungary

, András Jávor2

and Zoltán Csiki3


[19] Renner W, Koppel H, Brodmann M, Pabst E, Schallmoser K, Toplak H, et al. Factor II G20210A and factor V G1691A gene mutations and peripheral arterial occlusive disease. Thrombosis and Haemostasis. 2000;**83**:20-22

[31] Flex A, Gaetani E, Angelini F, Sabusco A, Chilla C, Straface G, et al. Pro-inflammatory genetic profiles in subjects with peripheral arterial occlusive disease and critical limb ischemia. Journal of Internal Medicine. 2007;**262**:124-130. DOI: 10.1111/j.

Genetics in Peripheral Artery Disease http://dx.doi.org/10.5772/intechopen.77209 115

[32] Fatini C, Sticchi E, Sofi F, Said AA, Pratesi G, Pulli R, et al. Multilocus analysis in candidate genes ACE, AGT, and AGTR1 and predisposition to peripheral arterial disease: Role of ACE D/−240T haplotype. Journal of Vascular Surgery. 2009;**50**:1399-1404. DOI:

[33] Wassel CL, Lamina C, Nambi V, Coassin S, Mukamal KJ, Ganesh SK, et al. Genetic determinants of the ankle-brachial index: A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium.

[34] Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nature Reviews

[35] Man HS, Yan MS, Lee JJ, Marsden PA. Epigenetic determinants of cardiovascular gene expression: Vascular endothelium. Epigenomics. 2016;**8**:959-979. DOI: 10.2217/epi-

[36] Krishna SM, Dear A, Craig JM, Norman PE, Golledge J. The potential role of homocysteine mediated DNA methylation and associated epigenetic changes in abdominal aortic aneurysm formation. Atherosclerosis. 2013;**228**:295-305. DOI: 10.1016/j.atherosclerosis.2013.02.019

[37] Tsaprouni LG, Yang TP, Bell J, Dick KJ, Kanoni S, Nisbet J, et al. Cigarette smoking reduces DNA methylation levels at multiple genomic loci but the effect is partially reversible upon cessation. Epigenetics. 2014;**9**:1382-1396. DOI: 10.4161/15592294.2014.969637

[38] Li T, Cao H, Zhuang J, Wan J, Guan M, Yu B, et al. Identification of miR-130a, miR-27b and miR-210 as serum biomarkers for atherosclerosis obliterans. Clinica Chimica Acta.

[39] Stather PW, Sylvius N, Wild JB, Choke E, Sayers RD, Bown MJ. Differential microRNA expression profiles in peripheral arterial disease. Circulation. Cardiovascular Genetics.

[40] Stather PW, Sylvius N, Sidloff DA, Dattani N, Verissimo A, Wild JB, et al. Identification of microRNAs associated with abdominal aortic aneurysms and peripheral arterial dis-

[41] Pipinos II, Swanson SA, Zhu Z, Nella AA, Weiss DJ, Gutti TL, et al. Chronically ischemic mouse skeletal muscle exhibits myopathy in association with mitochondrial dysfunction and oxidative damage. American Journal of Physiology. Regulatory, Integrative and

Comparative Physiology. 2008;**295**:R290-R296. DOI: 10.1152/ajpregu.90374.2008

ease. The British Journal of Surgery. 2015;**102**:755-766. DOI: 10.1002/bjs.9802

Atherosclerosis. 2012;**222**:138-147. DOI: 10.1016/j.atherosclerosis.2012.01.039

Genetics. 2016;**17**:487-500. DOI: 10.1038/nrg.2016.59

2011;**412**:66-70. DOI: 10.1016/j.cca.2010.09.029

2013;**6**:490-497. DOI: 10.1161/CIRCGENETICS.111.000053

1365-2796.2007.01791.x

10.1016/j.jvs.2009.07.075


[31] Flex A, Gaetani E, Angelini F, Sabusco A, Chilla C, Straface G, et al. Pro-inflammatory genetic profiles in subjects with peripheral arterial occlusive disease and critical limb ischemia. Journal of Internal Medicine. 2007;**262**:124-130. DOI: 10.1111/j. 1365-2796.2007.01791.x

[19] Renner W, Koppel H, Brodmann M, Pabst E, Schallmoser K, Toplak H, et al. Factor II G20210A and factor V G1691A gene mutations and peripheral arterial occlusive disease.

[20] Lee AJ, Fowkes FG, Lowe GD, Connor JM, Rumley A. Fibrinogen, factor VII and PAI-1 genotypes and the risk of coronary and peripheral atherosclerosis: Edinburgh artery

[21] Fowkes FG, Connor JM, Smith FB, Wood J, Donnan PT, Lowe GD. Fibrinogen genotype

[22] Sabino A, Fernandes AP, Lima LM, Ribeiro DD, Sousa MO, de Castro Santos ME, et al. Polymorphism in the methylenetetrahydrofolate reductase (C677T) gene and homocysteine levels: A comparison in Brazilian patients with coronary arterial disease, ischemic stroke and peripheral arterial obstructive disease. Journal of Thrombosis and

[23] Sofi F, Lari B, Rogolino A, Marcucci R, Pratesi G, Dorigo W, et al. Thrombophilic risk factors for symptomatic peripheral arterial disease. Journal of Vascular Surgery.

[24] Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE. Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age. European Journal

[25] Pola R, Flex A, Gaetani E, Flore R, Serricchio M, Pola P. Synergistic effect of −174 G/C polymorphism of the interleukin-6 gene promoter and 469 E/K polymorphism of the intercellular adhesion molecule-1 gene in Italian patients with history of ischemic stroke.

[26] Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, et al. Inflammatory markers and onset of cardiovascular events: Results from the health ABC study. Circulation. 2003;**108**:2317-2322. DOI: 10.1161/01.CIR.0000097109.90783.FC [27] Renner W, Pabst E, Paulweber B, Malaimare L, Iglseder B, Wascher TC, et al. The angiotensin-converting-enzyme insertion/deletion polymorphism is not a risk factor for

[28] Brevetti G, Schiano V, Chiariello M. Cellular adhesion molecules and peripheral arterial disease. Vascular Medicine. 2006;**11**:39-47. DOI: 10.1191/1358863x06vm645ra

[29] Cassar K, Bachoo P, Ford I, Greaves M, Brittenden J. Platelet activation is increased in

[30] Fontana P, Gaussem P, Aiach M, Fiessinger JN, Emmerich J, Reny JL. P2Y12 H2 haplotype is associated with peripheral arterial disease: A case-control study. Circulation.

peripheral arterial disease. Journal of Vascular Surgery. 2003;**38**:99-103

Thrombosis and Haemostasis. 2000;**83**:20-22

114 Peripheral Arterial Disease - A Practical Approach

study. Thrombosis and Haemostasis. 1999;**81**:553-560

and risk of peripheral atherosclerosis. Lancet. 1992;**339**:693-696

Thrombolysis. 2009;**27**:82-87. DOI: 10.1007/s11239-007-0172-z

Stroke. 2003;**34**:881-885. DOI: 10.1161/01.STR.0000062346.70983.DF

peripheral arterial disease. Atherosclerosis. 2002;**165**:175-178

2003;**108**:2971-2973. DOI: 10.1161/01.CIR.0000106904.80795.35

2005;**41**:255-260. DOI: 10.1016/j.jvs.2004.11.015

of Clinical Investigation. 1999;**29**:1003-1009


[42] Shameer K, Klee EW, Dalenberg AK, Kullo IJ. Whole exome sequencing implicates an INO80D mutation in a syndrome of aortic hypoplasia, premature atherosclerosis, and arterial stiffness. Circulation. Cardiovascular Genetics. 2014;**7**:607-614. DOI: 10.1161/

[43] Han P, Hang CT, Yang J, Chang CP. Chromatin remodeling in cardiovascular develop ment and physiology. Circulation Research. 2011;**108**:378-396. DOI: 10.1161/CIRCRE-

[44] Yamada Y, Ichihara S, Nishida T. Molecular genetics of myocardial infarction. Genomic

[45] Huang Y, Xu M, Xie L, Wang T, Huang X, Lv X, et al. Obesity and peripheral arterial disease: A Mendelian randomization analysis. Atherosclerosis. 2016;**247**:218-224. DOI:

[46] Lusis AJ, Mar R, Pajukanta P. Genetics of atherosclerosis. Annual Review of Genomics and Human Genetics. 2004;**5**:189-218. DOI: 10.1146/annurev.genom.5.061903.175930 [47] Patel CJ, Bhattacharya J, Butte AJ. An environment-wide association study (EWAS) on type 2 diabetes mellitus. PLoS One. 2010;**5**:e10746. DOI: 10.1371/journal.pone.0010746

Medicine. 2008;**2**:7-22. DOI: 10.1007/s11568-008-9025-x

CIRCGENETICS.113.000233

116 Peripheral Arterial Disease - A Practical Approach

10.1016/j.atherosclerosis.2015.12.034

SAHA.110.224287

## *Edited by Nishtha Sareen and Abhishek Ojha*

"Peripheral Arterial Disease - A Practical Approach" is an honest effort to provide a clinically relevant approach to the management plan in patients presenting with peripheral vascular symptoms. We have summarized the most pertinent practical aspects of peripheral vascular disease, their clinical implications, diagnostic testing, therapeutic interventions and innovations. We hope this book serves as a reference for basic and advanced peripheral vascular care.

Published in London, UK © 2018 IntechOpen © Fredex8 / iStock

Peripheral Arterial Disease - A Practical Approach

Peripheral Arterial Disease

A Practical Approach

*Edited by Nishtha Sareen and Abhishek Ojha*