Introductory Chapter: Defining the True Global Impact of Embolic Phenomena

*Samantha Wolfe, Stanislaw P. Stawicki, Mamta Swaroop, Jennifer C.B. Irick and Michael S. Firstenberg*

### **1. Introduction**

In the realm of medical practice, the word "embolism" has many implications to many people [1, 2], with most providers instinctively placing this word within a negative context [3–5]. Derived from the Greek word, ἐμβολισμός, this term most literally means "interposition" [6]. Yet regardless of how benign the etymology may be, the clinical context is quite the opposite—synonymous with much dreaded morbidity and mortality [1, 2, 7–10]. Whether the embolus consists of a blood clot [8], a fat globule [11], a bubble of gas [12], amniotic fluid [9, 10], or even an iatrogenic or traumatic foreign body [13, 14], the unfavorable connotations persist even if the patient has few or no associated symptoms and requires no intervention.

The primary goal of this book is to provide the reader with an overview of the most common types of embolic phenomena encountered in clinical practice, including some of the key related diagnostic and therapeutic areas. The current collection of chapters includes important contributions in the areas of pulmonary embolism (PE), fat embolism (FE), embolic complications of nonmalignant cardiac tumors, acute arterial embolism (AAE) of the lower extremity, thrombophilia in pregnancy, bullet and shrapnel embolization (BSE), and coronary artery embolization (CAE), as well as a comprehensive chapter on venous interventions utilized in the management of thromboembolic disorders.

Perhaps the best way to paint the picture of the tremendous impact of "embolism" globally is to present the human costs and the resources required to treat various types, manifestations, and complications of embolic diseases. Although challenging to gather, such information was compiled by our team for the purposes of this introductory chapter and summarized in **Table 1** [12, 14–37]. Although far from comprehensive, we hope to provide the reader with valuable insight into the gravity of the collective problem.

### **2. Embolism types: a synopsis**

No discussion of "embolism" can be complete without the discussion of risk factors, diagnostics including laboratory and imaging tests, and therapeutic considerations. Here, one must emphasize the importance of looking at the "totality of evidence," considering things like clinical suspicion, presence/absence of specific risk factors, positive/negative predictive values, diagnostic test sensitivity/specificity, and the pre−/posttest probabilities.


**3**

*Introductory Chapter: Defining the True Global Impact of Embolic Phenomena*

Initial clinical tests obtained when a patient exhibits symptoms of a PE are commonly electrocardiogram (EKG), arterial blood gas (ABG) analysis, and chest X-ray (CXR). However, none of these studies are sufficiently sensitive or specific for this diagnosis. Clinical scoring systems such as the Wells or PERC score have been established but in isolation are not able to diagnose PE [38]; rather, they provide clinically relevant risk stratification. Based on such risk stratification, it is recommended that a test of exclusion (e.g., one with a high negative predictive value) such as D-dimer be performed in the setting of low or intermediate clinical probability of a PE [39]. In the cases where a PE is highly suspected or likely, it is preferred to proceed directly to imaging such as a computed tomography pulmonary arteriography (CTPA). The ease of obtaining it, combined with the high predictive value (92–96%), has placed CTPA as the dominant imaging modality for suspected PE [40]. In patients unable to receive iodinated contrast, a ventilation-perfusion (V-Q ) scan or a contrast-enhanced magnetic resonance angiography (MRA) may represent a valid alternative. MRA has a sensitivity of 78% and specificity of 99%. This imaging study, however, relies on patient participation and compliance, and therefore a nontrivial proportion of studies will be inadequate to obtain sufficient level of diagnostic accuracy [40]. Once diagnosed, the treatment of PE involves systemic anticoagulation, with more invasive measures such as thrombolysis or embolectomy performed in patients with significant hemodynamic instability, respiratory decompensation, or acute right ventricular dysfunction [37].

Fat embolism syndrome (FES) differs in that there is no reliably accurate diagnostic or imaging test. Rather, the diagnosis is primarily clinical [11]. Multiple scoring systems exist which utilize the findings of petechiae, respiratory symptoms, fever, tachycardia, and radiographic changes with these either being identified as "major" or "minor" in magnitude or assigned a value on a pre-determined scale [11, 21, 41]. The lack of an imaging confirmatory test, however, makes it difficult to evaluate the true diagnostic accuracy or sensitivity of these indices. Ultrasound and echocardiography have been used to detect circulating fat globules; however, several studies suggest that a much higher percentage of patients with long bone fractures have circulating fat globules than previously thought, and only a fraction of these patients develop symptoms or FES [21, 42]. Computed tomography (CT) and magnetic resonance imaging (MRI) have been used, often with few abnormal findings reported. Treatment is mainly supportive and consists of intravenous fluids, respiratory support, and other forms of symptomatic management as appropriate. Medications such as steroids, heparin, alcohol, and dextran have not been proven beneficial [21].

Amniotic fluid embolism (AFE) is another condition that requires a high degree

of clinical suspicion, as the diagnosis is based on a heterogeneous constellation of symptoms [9, 10]. AFE should be suspected in any case of sudden maternal cardiovascular collapse with accompanying coagulopathy, hypotension, seizures, or distress, with no other clearly identifiable cause [43–45]. There are currently no truly reliable laboratory tests that are diagnostic of AFE [46]. Detection of formed amniotic fluid components (epidermal squamous cells, meconium, or lanugo hairs) in the maternal pulmonary blood flow is sufficient for histologic diagnosis of AFE [20]. Unfortunately, in many cases AFE goes unrecognized until these findings are

*DOI: http://dx.doi.org/10.5772/intechopen.90488*

**2.1 Pulmonary embolism**

**2.2 Fat emboli**

**2.3 Amniotic fluid embolism**

#### *Embolic Diseases - Evolving Diagnostic and Management Approaches*

*Introductory Chapter: Defining the True Global Impact of Embolic Phenomena DOI: http://dx.doi.org/10.5772/intechopen.90488*

### **2.1 Pulmonary embolism**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

ICU admission

**2**

**Embolism type** 

**Number affected**

**Mortality**

**Morbidity**

**Healthcare costs**

Legal: median payment \$325,000/

ICU admission

claim

Prolonged hospitalization

ICU admission

Massive blood transfusion

Long-term neurologic

effects

Average maternal LOS–2.92 days

Average infant LOS–3.78 days

**Other considerations**

**(alphabetical) [Reference]**

Air emboli [12, 15–18]

Amniotic fluid [19, 20]

0.2–1% (with central line)

14% 21.7%

Neurologic complications–

encephalopathy to focal cerebral

lesions (19–50%)

Seizures (2.22%)

Maternal neurologic damage (4.44%)

Fetal neurologic damage (25–50%)

0.003–0.007% (cardiac bypass)

Overall, 2.65 per 100,000 cases

1/22,000 pregnancies

10% of all maternal

deaths

13–44% case

maternal mortality

Shock (15%)

Coagulopathy (8.8%)

Cardiac arrest (22.2%)

Fetal NICU admission 8.8–20%

ARDS, pneumonia

CVA

Seizures, epilepsy (2.86%)

DIC, thrombocytopenia (37%)

Cardiac failure

Cerebral ischemia

Medicare: endovascular retrieval

Requirement for

endovascular or operative

removal

of foreign body—9.03 RVU which

equates to \$342.15 reimbursement

Potential legal costs if foreign body

not immediately recognized

Requirement for fasciotomy,

limb amputation, loss of

function

Infarction

Cardiac dysrhythmia, tamponade

5–32% symptomatic

7–38% fetal

mortality

Fat emboli [21–24]

Iatrogenic foreign body

Retained guidewire

<2% mortality

Approximately 1 in 3000 cases

[14, 25–27]

Peripheral emboli [28–30]

Pulmonary embolism (PE)

97.8 per 100,000 population/

0.1–4.2% in

Bleeding related to thrombolytics

Between \$5,500 and \$11,665

Need for long-term

anticoagulation

Venous stasis

Pulmonary hypertension

Recurrent PE

(depending on severity) with mean

cost of \$8800

\$99,286/PE death (Cox)

and/or anticoagulants (4–7.5%)

Right ventricular systolic dysfunction

hospitalized

patients

~25% at 7 days

(20–60%)

*ARDS = Acute respiratory distress syndrome; CVA = Cerebrovascular accident; DIC = Disseminated intravascular coagulation; ICU = Intensive care unit; LOS = Length of stay; NICU = Neonatal ICU; PE =* 

*Selected metrics demonstrating the global impact of embolic diseases, including considerations of both patient- and health system level considerations.*

*Pulmonary embolism; RVU = Relative value unit.*

**Table 1.**

Up to 16% at 1 year

year (hospitalization rate)

[31–37]

About 14 per 100,000 cases

17–18% death

Amputation (28.9%)

Reperfusion injury (6%)

Symptomatic: 1–20% patients

5–15%

with long bone fractures (true

incidence is likely much higher)

Overall, 2–8/100,000 cases

Initial clinical tests obtained when a patient exhibits symptoms of a PE are commonly electrocardiogram (EKG), arterial blood gas (ABG) analysis, and chest X-ray (CXR). However, none of these studies are sufficiently sensitive or specific for this diagnosis. Clinical scoring systems such as the Wells or PERC score have been established but in isolation are not able to diagnose PE [38]; rather, they provide clinically relevant risk stratification. Based on such risk stratification, it is recommended that a test of exclusion (e.g., one with a high negative predictive value) such as D-dimer be performed in the setting of low or intermediate clinical probability of a PE [39]. In the cases where a PE is highly suspected or likely, it is preferred to proceed directly to imaging such as a computed tomography pulmonary arteriography (CTPA). The ease of obtaining it, combined with the high predictive value (92–96%), has placed CTPA as the dominant imaging modality for suspected PE [40]. In patients unable to receive iodinated contrast, a ventilation-perfusion (V-Q ) scan or a contrast-enhanced magnetic resonance angiography (MRA) may represent a valid alternative. MRA has a sensitivity of 78% and specificity of 99%. This imaging study, however, relies on patient participation and compliance, and therefore a nontrivial proportion of studies will be inadequate to obtain sufficient level of diagnostic accuracy [40]. Once diagnosed, the treatment of PE involves systemic anticoagulation, with more invasive measures such as thrombolysis or embolectomy performed in patients with significant hemodynamic instability, respiratory decompensation, or acute right ventricular dysfunction [37].

### **2.2 Fat emboli**

Fat embolism syndrome (FES) differs in that there is no reliably accurate diagnostic or imaging test. Rather, the diagnosis is primarily clinical [11]. Multiple scoring systems exist which utilize the findings of petechiae, respiratory symptoms, fever, tachycardia, and radiographic changes with these either being identified as "major" or "minor" in magnitude or assigned a value on a pre-determined scale [11, 21, 41]. The lack of an imaging confirmatory test, however, makes it difficult to evaluate the true diagnostic accuracy or sensitivity of these indices. Ultrasound and echocardiography have been used to detect circulating fat globules; however, several studies suggest that a much higher percentage of patients with long bone fractures have circulating fat globules than previously thought, and only a fraction of these patients develop symptoms or FES [21, 42]. Computed tomography (CT) and magnetic resonance imaging (MRI) have been used, often with few abnormal findings reported. Treatment is mainly supportive and consists of intravenous fluids, respiratory support, and other forms of symptomatic management as appropriate. Medications such as steroids, heparin, alcohol, and dextran have not been proven beneficial [21].

#### **2.3 Amniotic fluid embolism**

Amniotic fluid embolism (AFE) is another condition that requires a high degree of clinical suspicion, as the diagnosis is based on a heterogeneous constellation of symptoms [9, 10]. AFE should be suspected in any case of sudden maternal cardiovascular collapse with accompanying coagulopathy, hypotension, seizures, or distress, with no other clearly identifiable cause [43–45]. There are currently no truly reliable laboratory tests that are diagnostic of AFE [46]. Detection of formed amniotic fluid components (epidermal squamous cells, meconium, or lanugo hairs) in the maternal pulmonary blood flow is sufficient for histologic diagnosis of AFE [20]. Unfortunately, in many cases AFE goes unrecognized until these findings are


*CABG = Coronary artery bypass grafting; CP = Cardiopulmonary; CPR = Cardiopulmonary resuscitation; PFO = Patent foramen ovale; VSD = Ventricular septal defect.*

**5**

**3. Conclusion**

based on diagnostic probabilities.

*Introductory Chapter: Defining the True Global Impact of Embolic Phenomena*

presenting in a scenario where an air embolus is possible (**Table 2**).

The method of detecting a foreign body embolus (FBE) is dependent on the resting intravascular location of the embolus, which may vary according to the etiology, object type, and route of introduction [13, 14, 52, 53]. For cardiac emboli, transesophageal echocardiography (TEE) is commonly used and is beneficial in that it can also assess for any structural damage associated with such FBEs [54]. This imaging modality may be limited, however, especially in instances when the emboli are small, minimally echogenic, located in difficult-to-access locations, or obscured by acoustic shadowing. In these cases, computed tomography (CT) imaging may represent a helpful adjunct to determine location and operative or endovascular plan for removal. CT angiography is also useful for more peripherally located FBEs [52, 53]. The decision on whether to remove the foreign body is also highly dependent on symptomatology and potential complications of the emboli, especially when considered in the context of any downstream anatomic structures as well as immediately surrounding tissues. In the current age, an endovascular approach is the most common, with open approaches often reserved for failure of endovascular retrieval. Rarely, an embolus may be left in place if it is unlikely to further migrate and the patient is asymptomatic, though this does leave the patient at potential risk for future complications that can occur remotely, even years later [13, 14, 55, 56].

Perhaps the most valuable take-away message of this book is that diagnostic relativity—rather than absolutism—continues to prevail in the realm of "embolic diseases." Such is the state of modern medical decision-making in this important area of active clinical investigation and management. **Table 2** summarizes the most common risk factors, organized by "embolism" type. Compiled from variety of sources, this information represents an good foundation for clinical discussions

seen on autopsy [9, 10]. Treatment is supportive, involving respiratory support, Cesarean section (if not already delivered), correction of coagulopathy, blood/ blood product transfusion, vasopressors/inotropes, and fluids [9, 10, 43–45].

The most sensitive test for diagnosing an air embolism is the transesophageal echo (TEE), detecting as little as 0.02 ml/kg of air administered by bolus injection [12, 37]. In fact, it has been deemed almost "too sensitive," in that it will detect air in circulation that is not associated with any symptoms. A precordial Doppler is also highly sensitive, detecting as little as 0.25 ml of air (0.05 ml/kg) [37]. It is highly operator dependent, however, as one must rely on the detection of a change in sound with air interrupting the blood flow within the cardiac chambers. Much less sensitive is the pulmonary artery catheter, with a detection threshold of 0.25 mL/ kg of air [47]. Additionally, it is of limited use therapeutically as its small caliber internal lumen is often insufficient to withdraw air from the chamber as a therapeutic maneuver (or at least quickly enough to be truly effective). In the operating room, the most practical diagnostic tool is a sudden fall in end-tidal CO2, albeit this is highly nonspecific. Other times, air emboli will go undiagnosed by any formal means and may well end up being "presumed" based on clinical symptomatology

*DOI: http://dx.doi.org/10.5772/intechopen.90488*

**2.4 Air embolism**

**2.5 Foreign body embolism**

#### **Table 2.**

*Listing of the most common risk factors by embolism type.*

seen on autopsy [9, 10]. Treatment is supportive, involving respiratory support, Cesarean section (if not already delivered), correction of coagulopathy, blood/ blood product transfusion, vasopressors/inotropes, and fluids [9, 10, 43–45].

### **2.4 Air embolism**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

**Risk factors**

disconnection • CABG on CP bypass

atriobronchial)

• Uterine rupture

ment delivery • Maternal age > 35 years

• Joint arthroplasty

Fat emboli [24, 49, 50] • Long bone fracture (pelvis, femur)

• CABG • CPR

• Severe burn

Peripheral emboli [28–30] • PFO in setting of venous thrombosis

• Trauma

• Malignancy

• Atrial fibrillation

• Cell saver blood transfusion

• Percutaneous vertebroplasty • Liposuction, fat grafting

• Organ transplant (lung, renal) • Bone marrow transplant or harvest

Iatrogenic foreign body [14] • Guidewire–placement of central line, improper technique, or failure to

angioplasty balloon for deployment

• Prolonged hospitalization/immobility

*CABG = Coronary artery bypass grafting; CP = Cardiopulmonary; CPR = Cardiopulmonary resuscitation; PFO =* 

• History of central or peripheral atherosclerosis

tions, inexperienced staff, inadequate supervision)

• Chronic corticosteroid use

Air emboli [12, 16, 17, 48] • Venous catheterization, removal, manipulation, unintended

• Craniotomy, especially in sitting position

• PFO, VSD (for paradoxical air emboli) • Hemodialysis, cell saver transfusion Amniotic fluid [19, 20] • Multi-fetal pregnancy, placenta previa, placental abruption, eclampsia

• Fistulization between air filled viscus and vessel (aortoesophageal,

• Induction, C-section, fetal distress, cervical laceration/trauma, instru-

control guidewire during procedure (more likely in emergency situa-

• Catheter–fracture of catheter secondary to repetitive mechanical stress, damage during removal, and improper connection during placement • Coils–improperly sized or placed coils; tortuous vessels; usage of

• Central venous catheterization, venous thrombosis, thrombophilia

• Traumatic or iatrogenic pulmonary alveoli-venous fistula

**Embolism type (alphabetical)**

**4**

**Table 2.**

Pulmonary embolism

*Patent foramen ovale; VSD = Ventricular septal defect.*

*Listing of the most common risk factors by embolism type.*

(PE) [51]

The most sensitive test for diagnosing an air embolism is the transesophageal echo (TEE), detecting as little as 0.02 ml/kg of air administered by bolus injection [12, 37]. In fact, it has been deemed almost "too sensitive," in that it will detect air in circulation that is not associated with any symptoms. A precordial Doppler is also highly sensitive, detecting as little as 0.25 ml of air (0.05 ml/kg) [37]. It is highly operator dependent, however, as one must rely on the detection of a change in sound with air interrupting the blood flow within the cardiac chambers. Much less sensitive is the pulmonary artery catheter, with a detection threshold of 0.25 mL/ kg of air [47]. Additionally, it is of limited use therapeutically as its small caliber internal lumen is often insufficient to withdraw air from the chamber as a therapeutic maneuver (or at least quickly enough to be truly effective). In the operating room, the most practical diagnostic tool is a sudden fall in end-tidal CO2, albeit this is highly nonspecific. Other times, air emboli will go undiagnosed by any formal means and may well end up being "presumed" based on clinical symptomatology presenting in a scenario where an air embolus is possible (**Table 2**).

### **2.5 Foreign body embolism**

The method of detecting a foreign body embolus (FBE) is dependent on the resting intravascular location of the embolus, which may vary according to the etiology, object type, and route of introduction [13, 14, 52, 53]. For cardiac emboli, transesophageal echocardiography (TEE) is commonly used and is beneficial in that it can also assess for any structural damage associated with such FBEs [54]. This imaging modality may be limited, however, especially in instances when the emboli are small, minimally echogenic, located in difficult-to-access locations, or obscured by acoustic shadowing. In these cases, computed tomography (CT) imaging may represent a helpful adjunct to determine location and operative or endovascular plan for removal. CT angiography is also useful for more peripherally located FBEs [52, 53]. The decision on whether to remove the foreign body is also highly dependent on symptomatology and potential complications of the emboli, especially when considered in the context of any downstream anatomic structures as well as immediately surrounding tissues. In the current age, an endovascular approach is the most common, with open approaches often reserved for failure of endovascular retrieval. Rarely, an embolus may be left in place if it is unlikely to further migrate and the patient is asymptomatic, though this does leave the patient at potential risk for future complications that can occur remotely, even years later [13, 14, 55, 56].

### **3. Conclusion**

Perhaps the most valuable take-away message of this book is that diagnostic relativity—rather than absolutism—continues to prevail in the realm of "embolic diseases." Such is the state of modern medical decision-making in this important area of active clinical investigation and management. **Table 2** summarizes the most common risk factors, organized by "embolism" type. Compiled from variety of sources, this information represents an good foundation for clinical discussions based on diagnostic probabilities.

### *Embolic Diseases - Evolving Diagnostic and Management Approaches*

In summary, this book represents a collection of contributions by a multidisciplinary team of clinicians and medical researchers. The editors' goal was to solicit the highest quality contributions from some of the top experts in their respective fields. We hope we were able to achieve this goal satisfactorily. Ultimately, the book's readers will be the best arbiters of its success, whether it is determined by the number of downloaded chapters or the cumulative number of citations attributable to this collection of chapters. To be able to contribute to the generation and dissemination of new knowledge in this important area of clinical investigation is a true privilege.

## **Author details**

Samantha Wolfe1 , Stanislaw P. Stawicki1,2\*, Mamta Swaroop3 , Jennifer C.B. Irick4 and Michael S. Firstenberg5

1 Department of Surgery, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA

2 Department of Research and Innovation, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA

3 Department of Surgery, Northwestern University School of Medicine, Chicago, Illinois, USA

4 Department of Emergency Medicine, Richard A. Anderson Campus, St. Luke's University Health Network, Easton, Pennsylvania, USA

5 Department of Cardiothoracic Surgery, The Medical Center of Aurora, Aurora, Colorado, USA

\*Address all correspondence to: stawicki.ace@gmail.com

© 2020 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.

**7**

*Introductory Chapter: Defining the True Global Impact of Embolic Phenomena*

remain. Current Opinion in Obstetrics and Gynecology. 2015;**27**(6):398-405

[11] Kwiatt ME, Seamon MJ. Fat embolism syndrome. International Journal of Critical Illness and Injury

[12] Gordy S, Rowell S. Vascular air embolism. International Journal of Critical Illness and Injury Science.

Research. 2012;**178**(1):519-523

[14] Wojda TR et al. Foreign intravascular object embolization and migration: Bullets, catheters, wires, stents, filters, and more. In: Embolic Diseases: Unusual Therapies and Challenges. London, England:

IntechOpen; 2017. 109p

2017;**42**:255-263

2016;**362**:160-164

[15] Bessereau J, Genotelle N,

Chabbaut C, et al. Long-term outcome of iatrogenic gas embolism. Intensive Care Medicine. 2010;**36**(7):1180-1187

[16] Brull SJ, Prielipp RC. Vascular air embolism: A silent hazard to patient safety. Journal of Critical Care.

[17] Pinho J, Amorim JM, Araujo JM, et al. Cerebral gas embolism associated

[18] Hammon JW, Hines MH. Cardiac surgery in the adult. In: Cohn LH, editor. Extracorporeal Circulation. 4th ed. New York: McGraw-Hill; 2012

[19] Spiliopoulos M, Puri I, Jain NJ, et al. Amniotic fluid embolism-risk factors, maternal and neonatal outcomes. The

with central venous catheter: Systematic review. Journal of the Neurological Sciences.

[13] Moffatt-Bruce SD et al. Intravascular retained surgical items: A multicenter study of risk factors. Journal of Surgical

Science. 2013;**3**(1):64

2013;**3**(1):73

*DOI: http://dx.doi.org/10.5772/intechopen.90488*

[1] Nielsen HK et al. 178 fatal cases of pulmonary embolism in a medical department. Acta Medica Scandinavica.

[2] Stawicki SP et al. Septic embolism in the intensive care unit. International Journal of Critical Illness and Injury

[3] Piqué-Angordans J, Posteguillo S. Peer positive and negative assessment in medical English written genres. Advances in medical discourse analysis: Oral and written. Contexts. 2006;**45**:383

complicating artificial pneumothorax: A case with autopsy. American Review of

[5] Gross AF, Smith FA, Stern TA. Dread complications of catatonia: A case discussion and review of the literature. Primary Care Companion to the Journal of Clinical Psychiatry. 2008;**10**(2):153

[4] McCurdy T. Air-embolism

Tuberculosis. 1934;**30**(1):88-91

[6] Wikipedia. Embolism. 2019. Available from: https://en.wikipedia. org/wiki/Embolism [Accessed: August

1964;**270**(25):1353-1354

2005;**71**(5):387-391

2013;**3**(1):51

[7] Ericsson JA, Gottlieb JD, Sweet RB. Closed-chest cardiac massage in the treatment of venous air embolism. New England Journal of Medicine.

[8] Stawicki SP et al. Deep venous thrombosis and pulmonary embolism in trauma patients: An overstatement of the problem? The American Surgeon.

[9] Thongrong C et al. Amniotic fluid embolism. International Journal of Critical Illness and Injury Science.

[10] Balinger KJ et al. Amniotic fluid embolism: Despite progress, challenges

19, 2019]

1981;**209**(1-6):351-355

**References**

Science. 2013;**3**(1):58

*Introductory Chapter: Defining the True Global Impact of Embolic Phenomena DOI: http://dx.doi.org/10.5772/intechopen.90488*

### **References**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

In summary, this book represents a collection of contributions by a multidisciplinary team of clinicians and medical researchers. The editors' goal was to solicit the highest quality contributions from some of the top experts in their respective fields. We hope we were able to achieve this goal satisfactorily. Ultimately, the book's readers will be the best arbiters of its success, whether it is determined by the number of downloaded chapters or the cumulative number of citations attributable to this collection of chapters. To be able to contribute to the generation and dissemination of new knowledge in this important area of clinical investigation is a true privilege.

, Stanislaw P. Stawicki1,2\*, Mamta Swaroop3

1 Department of Surgery, St. Luke's University Health Network, Bethlehem,

3 Department of Surgery, Northwestern University School of Medicine,

5 Department of Cardiothoracic Surgery, The Medical Center of Aurora,

University Health Network, Easton, Pennsylvania, USA

\*Address all correspondence to: stawicki.ace@gmail.com

provided the original work is properly cited.

2 Department of Research and Innovation, St. Luke's University Health Network,

4 Department of Emergency Medicine, Richard A. Anderson Campus, St. Luke's

© 2020 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,

, Jennifer C.B. Irick4

**6**

**Author details**

Samantha Wolfe1

Pennsylvania, USA

Chicago, Illinois, USA

Aurora, Colorado, USA

and Michael S. Firstenberg5

Bethlehem, Pennsylvania, USA

[1] Nielsen HK et al. 178 fatal cases of pulmonary embolism in a medical department. Acta Medica Scandinavica. 1981;**209**(1-6):351-355

[2] Stawicki SP et al. Septic embolism in the intensive care unit. International Journal of Critical Illness and Injury Science. 2013;**3**(1):58

[3] Piqué-Angordans J, Posteguillo S. Peer positive and negative assessment in medical English written genres. Advances in medical discourse analysis: Oral and written. Contexts. 2006;**45**:383

[4] McCurdy T. Air-embolism complicating artificial pneumothorax: A case with autopsy. American Review of Tuberculosis. 1934;**30**(1):88-91

[5] Gross AF, Smith FA, Stern TA. Dread complications of catatonia: A case discussion and review of the literature. Primary Care Companion to the Journal of Clinical Psychiatry. 2008;**10**(2):153

[6] Wikipedia. Embolism. 2019. Available from: https://en.wikipedia. org/wiki/Embolism [Accessed: August 19, 2019]

[7] Ericsson JA, Gottlieb JD, Sweet RB. Closed-chest cardiac massage in the treatment of venous air embolism. New England Journal of Medicine. 1964;**270**(25):1353-1354

[8] Stawicki SP et al. Deep venous thrombosis and pulmonary embolism in trauma patients: An overstatement of the problem? The American Surgeon. 2005;**71**(5):387-391

[9] Thongrong C et al. Amniotic fluid embolism. International Journal of Critical Illness and Injury Science. 2013;**3**(1):51

[10] Balinger KJ et al. Amniotic fluid embolism: Despite progress, challenges remain. Current Opinion in Obstetrics and Gynecology. 2015;**27**(6):398-405

[11] Kwiatt ME, Seamon MJ. Fat embolism syndrome. International Journal of Critical Illness and Injury Science. 2013;**3**(1):64

[12] Gordy S, Rowell S. Vascular air embolism. International Journal of Critical Illness and Injury Science. 2013;**3**(1):73

[13] Moffatt-Bruce SD et al. Intravascular retained surgical items: A multicenter study of risk factors. Journal of Surgical Research. 2012;**178**(1):519-523

[14] Wojda TR et al. Foreign intravascular object embolization and migration: Bullets, catheters, wires, stents, filters, and more. In: Embolic Diseases: Unusual Therapies and Challenges. London, England: IntechOpen; 2017. 109p

[15] Bessereau J, Genotelle N, Chabbaut C, et al. Long-term outcome of iatrogenic gas embolism. Intensive Care Medicine. 2010;**36**(7):1180-1187

[16] Brull SJ, Prielipp RC. Vascular air embolism: A silent hazard to patient safety. Journal of Critical Care. 2017;**42**:255-263

[17] Pinho J, Amorim JM, Araujo JM, et al. Cerebral gas embolism associated with central venous catheter: Systematic review. Journal of the Neurological Sciences. 2016;**362**:160-164

[18] Hammon JW, Hines MH. Cardiac surgery in the adult. In: Cohn LH, editor. Extracorporeal Circulation. 4th ed. New York: McGraw-Hill; 2012

[19] Spiliopoulos M, Puri I, Jain NJ, et al. Amniotic fluid embolism-risk factors, maternal and neonatal outcomes. The

Journal of Maternal-Fetal & Neonatal Medicine. 2009;**22**(5):439-444

[20] Rath WH, Hofer S, Sinicina I. Amniotic fluid embolism: An interdisciplinary challenge: Epidemiology, diagnosis and treatment. Deutsches Ärzteblatt International. 2014;**111**(8):126

[21] Talbot M, Schemitsch EH. Fat embolism syndrome: History, definition, epidemiology. Injury. 2006;**37**(Suppl 4):S3-S7

[22] Habashi NM, Andrews PL, Scalea TM. Therapeutic aspects of fat embolism syndrome. Injury. 2006;**37**(Suppl 4):S68-S73

[23] Kavi T, Teklemariam E, Gaughan J, et al. Incidence of seizures in fat embolism syndrome over a 10-year period: Analysis of the national inpatient sample database. The Neurologist. 2019;**24**(3):84-86

[24] Kosova E, Bergmark B, Piazza G. Fat embolism syndrome. Circulation. 2015;**131**(3):317-320

[25] Vannucci A, Jeffcoat A, Ifune C, et al. Special article: Retained guidewires after intraoperative placement of central venous catheters. Anesthesia and Analgesia. 2013;**117**:102-108

[26] Schechter MA, O'Brien PJ, Cox MW. Retrieval of iatrogenic intravascular foreign bodies. Journal of Vascular Surgery. 2013;**57**:276-281

[27] Roddy SP. Endovascular foreign body retrieval. Journal of Vascular Surgery. 2013;**57**(2):599

[28] Costantini V, Lenti M. Treatment of acute occlusion of peripheral arteries. Thrombosis Research. 2002;**106**(6):V285-V294

[29] Aune S, Trippestad A. Operative mortality and long-term survival of

patients operated on for acute lower limb ischaemia. European Journal of Vascular and Endovascular Surgery. 1998;**15**:143-146

[30] Fagundes C, Fuchs FD, Fagundes A, et al. Prognostic factors for amputation or death in patients submitted to vascular surgery for acute limb ischemia. Vascular Health and Risk Management. 2005;**1**(4):345

[31] Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: A population-based case-control study. Archives of Internal Medicine. 2010;**160**(6):809-815

[32] Cox CE, Carson SS, Biddle AK. Costeffectiveness of ultrasound in preventing femoral venous catheterassociated pulmonary embolism. American Journal of Respiratory and Critical Care Medicine. 2003;**168**(12):1481-1487

[33] Kempny A et al. Incidence, mortality, and bleeding rates associated with pulmonary embolism in England between 1997 and 2015. International Journal of Cardiology. 2019;**277**:229-234

[34] Brennan P et al. Real World Outcomes for "Intermediate-High" Mortality Risk Patients Presenting with Submassive Pulmonary Embolism in a Tertiary Cardiothoracic Centre. London, United Kingdom: BMJ Publishing Group Ltd and British Cardiovascular Society; 2019

[35] Fanikos J et al. Hospital costs of acute pulmonary embolism. The American Journal of Medicine. 2013;**126**(2):127-132

[36] Dismuke SE, Wagner EH. Pulmonary embolism as a cause of death: The changing mortality in hospitalized patients. JAMA. 1986;**255**(15):2039-2042

**9**

*Introductory Chapter: Defining the True Global Impact of Embolic Phenomena*

[46] Stawicki SP, Papadimos TJ.

[47] Mirski MA, Lele AV,

2007;**106**(1):164-177

2012;**43**(9):1556-1561

Challenges in managing amniotic fluid embolism: An up-to-date perspective on diagnostic testing with focus on novel biomarkers and avenues for future research. Current Pharmaceutical Biotechnology. 2013;**14**(**14**):1168-1178

Fitzsimmons L, et al. Diagnosis and treatment of vascular air embolism. Anesthesiology: The Journal of the American Society of Anesthesiologists.

[48] Brook OR, Hirshenbaum A, Talor E, et al. Arterial air emboli on computed tomography (CT) autopsy. Injury.

[49] Morales-Vidal SG. Neurologic complications of fat embolism syndrome. Current Neurology and Neuroscience Reports. 2019;**19**(3):14

[50] Molière S, Kremer S, Bierry G. Case 254: Posttraumatic migrating fat embolus causing fat emboli syndrome. Radiology. 2018;**287**(3):1073-1080

[51] Bĕlohlávek J, Dytrych V, Linhart A.

[52] Huebner S, Ali S. Bilateral shotgun pellet pulmonary emboli. Journal of Radiology Case Reports. 2012;**6**(4):1

nonthrombotic pulmonary embolism: Biological materials, nonbiological materials, and foreign bodies. European Journal of Radiology.

[53] Bach AG et al. Imaging of

2013;**82**(3):e120-e141

[54] Herbert JT, Kertai MD.

Transesophageal echocardiography use in diagnosis and management of

Pulmonary embolism, part I: Epidemiology, risk factors, and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism. Experimental and Clinical Cardiology.

2013;**18**(2):129

*DOI: http://dx.doi.org/10.5772/intechopen.90488*

[37] Jaff M, McMurty MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: A scientific statement from the American Heart Association. Circulation. 2011;**123**(16):1788-1830

[38] Stawicki SP et al. Transthoracic echocardiography for suspected pulmonary embolism in the intensive care unit: Unjustly underused or rightfully ignored? Journal of Clinical Ultrasound. 2008;**36**(5):291-302

[39] Stein PD, Woodard PK, Weg JG,

PIOPEDII investigators. Radiology.

[40] Sherk WM, Stojanovska J. Role of clinical decision tools in the diagnosis of pulmonary embolism. American Journal of Roentgenology.

[41] Shaikh N. Emergency management of fat embolism syndrome. Journal of Emergencies, Trauma, and Shock.

[42] Eriksson EA, Pellegrini DC, Vanderkolk WE, et al. Incidence of pulmonary fat embolism at autopsy: An undiagnosed epidemic. Journal of Trauma and Acute Care Surgery.

[43] Clark SL. Amniotic fluid

embolism. Obstetrics & Gynecology.

[44] Killam A. Amniotic fluid embolism. Clinical Obstetrics and Gynecology.

[45] Pacheco LD et al. Amniotic fluid embolism: Diagnosis and management. American Journal of Obstetrics and Gynecology. 2016;**215**(2):B16-B24

et al. Diagnostic pathways in acute pulmonary embolism: Recommendations of the

2007;**242**(1):15-21

2017;**208**(3):W60-W70

2009;**2**(1):29

2011;**71**(2):312-315

2014;**123**(2):337-348

1985;**28**(1):32-36

*Introductory Chapter: Defining the True Global Impact of Embolic Phenomena DOI: http://dx.doi.org/10.5772/intechopen.90488*

[37] Jaff M, McMurty MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: A scientific statement from the American Heart Association. Circulation. 2011;**123**(16):1788-1830

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

patients operated on for acute lower limb ischaemia. European Journal of Vascular and Endovascular Surgery.

[30] Fagundes C, Fuchs FD, Fagundes A, et al. Prognostic factors for amputation or death in patients submitted to vascular surgery for acute limb ischemia. Vascular Health and Risk Management. 2005;**1**(4):345

[31] Heit JA, Silverstein MD, Mohr DN,

thrombosis and pulmonary embolism: A population-based case-control study. Archives of Internal Medicine.

[32] Cox CE, Carson SS, Biddle AK. Cost-

et al. Risk factors for deep vein

effectiveness of ultrasound in preventing femoral venous catheterassociated pulmonary embolism. American Journal of Respiratory and Critical Care Medicine. 2003;**168**(12):1481-1487

[33] Kempny A et al. Incidence, mortality, and bleeding rates

[34] Brennan P et al. Real World Outcomes for "Intermediate-High" Mortality Risk Patients Presenting with Submassive Pulmonary Embolism in a Tertiary Cardiothoracic Centre. London, United Kingdom: BMJ Publishing Group Ltd and British Cardiovascular Society; 2019

[35] Fanikos J et al. Hospital costs of acute pulmonary embolism. The American Journal of Medicine.

[36] Dismuke SE, Wagner EH. Pulmonary embolism as a cause of death: The changing mortality in hospitalized patients. JAMA.

1986;**255**(15):2039-2042

2013;**126**(2):127-132

2019;**277**:229-234

associated with pulmonary embolism in England between 1997 and 2015. International Journal of Cardiology.

2010;**160**(6):809-815

1998;**15**:143-146

Journal of Maternal-Fetal & Neonatal Medicine. 2009;**22**(5):439-444

interdisciplinary challenge: Epidemiology, diagnosis and treatment. Deutsches Ärzteblatt International. 2014;**111**(8):126

[20] Rath WH, Hofer S, Sinicina I. Amniotic fluid embolism: An

[21] Talbot M, Schemitsch EH. Fat embolism syndrome: History, definition, epidemiology. Injury.

[22] Habashi NM, Andrews PL, Scalea TM. Therapeutic aspects of fat embolism syndrome. Injury. 2006;**37**(Suppl 4):S68-S73

[23] Kavi T, Teklemariam E, Gaughan J, et al. Incidence of seizures in fat embolism syndrome over a 10-year period: Analysis of the national inpatient sample database. The Neurologist. 2019;**24**(3):84-86

[24] Kosova E, Bergmark B, Piazza G. Fat embolism syndrome. Circulation.

[25] Vannucci A, Jeffcoat A, Ifune C, et al. Special article: Retained guidewires after intraoperative placement of central venous

catheters. Anesthesia and Analgesia.

[27] Roddy SP. Endovascular foreign body retrieval. Journal of Vascular

[28] Costantini V, Lenti M. Treatment of acute occlusion of peripheral arteries. Thrombosis Research. 2002;**106**(6):V285-V294

[29] Aune S, Trippestad A. Operative mortality and long-term survival of

Surgery. 2013;**57**(2):599

[26] Schechter MA, O'Brien PJ, Cox MW. Retrieval of iatrogenic intravascular foreign bodies. Journal of Vascular Surgery. 2013;**57**:276-281

2006;**37**(Suppl 4):S3-S7

2015;**131**(3):317-320

2013;**117**:102-108

**8**

[38] Stawicki SP et al. Transthoracic echocardiography for suspected pulmonary embolism in the intensive care unit: Unjustly underused or rightfully ignored? Journal of Clinical Ultrasound. 2008;**36**(5):291-302

[39] Stein PD, Woodard PK, Weg JG, et al. Diagnostic pathways in acute pulmonary embolism: Recommendations of the PIOPEDII investigators. Radiology. 2007;**242**(1):15-21

[40] Sherk WM, Stojanovska J. Role of clinical decision tools in the diagnosis of pulmonary embolism. American Journal of Roentgenology. 2017;**208**(3):W60-W70

[41] Shaikh N. Emergency management of fat embolism syndrome. Journal of Emergencies, Trauma, and Shock. 2009;**2**(1):29

[42] Eriksson EA, Pellegrini DC, Vanderkolk WE, et al. Incidence of pulmonary fat embolism at autopsy: An undiagnosed epidemic. Journal of Trauma and Acute Care Surgery. 2011;**71**(2):312-315

[43] Clark SL. Amniotic fluid embolism. Obstetrics & Gynecology. 2014;**123**(2):337-348

[44] Killam A. Amniotic fluid embolism. Clinical Obstetrics and Gynecology. 1985;**28**(1):32-36

[45] Pacheco LD et al. Amniotic fluid embolism: Diagnosis and management. American Journal of Obstetrics and Gynecology. 2016;**215**(2):B16-B24

[46] Stawicki SP, Papadimos TJ. Challenges in managing amniotic fluid embolism: An up-to-date perspective on diagnostic testing with focus on novel biomarkers and avenues for future research. Current Pharmaceutical Biotechnology. 2013;**14**(**14**):1168-1178

[47] Mirski MA, Lele AV, Fitzsimmons L, et al. Diagnosis and treatment of vascular air embolism. Anesthesiology: The Journal of the American Society of Anesthesiologists. 2007;**106**(1):164-177

[48] Brook OR, Hirshenbaum A, Talor E, et al. Arterial air emboli on computed tomography (CT) autopsy. Injury. 2012;**43**(9):1556-1561

[49] Morales-Vidal SG. Neurologic complications of fat embolism syndrome. Current Neurology and Neuroscience Reports. 2019;**19**(3):14

[50] Molière S, Kremer S, Bierry G. Case 254: Posttraumatic migrating fat embolus causing fat emboli syndrome. Radiology. 2018;**287**(3):1073-1080

[51] Bĕlohlávek J, Dytrych V, Linhart A. Pulmonary embolism, part I: Epidemiology, risk factors, and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism. Experimental and Clinical Cardiology. 2013;**18**(2):129

[52] Huebner S, Ali S. Bilateral shotgun pellet pulmonary emboli. Journal of Radiology Case Reports. 2012;**6**(4):1

[53] Bach AG et al. Imaging of nonthrombotic pulmonary embolism: Biological materials, nonbiological materials, and foreign bodies. European Journal of Radiology. 2013;**82**(3):e120-e141

[54] Herbert JT, Kertai MD. Transesophageal echocardiography use in diagnosis and management of embolized intravascular foreign bodies. In: Seminars in Cardiothoracic and Vascular Anesthesia. Los Angeles, CA: SAGE Publications Sage CA; 2018

[55] Elison RMA et al. Surgical management of late bullet embolization from the abdomen to the right ventricle: Case report. International Journal of Surgery Case Reports. 2017;**39**:317-320

[56] Adegboyega PA, Sustento-Reodica N, Adesokan A. Arterial bullet embolism resulting in delayed vascular insufficiency: A rationale for mandatory extraction. Journal of Trauma and Acute Care Surgery. 1996;**41**(3):539-541

**11**

**Chapter 2**

**Abstract**

**1. Introduction**

Fat Embolism: What We Have

Learned from Animal Models

Pulmonary fat embolism may not be diagnosed before unrelated autopsy and have little clinical impact or lead to acute lung injury with fulminant fat embolism syndrome (FES). The fat may come from various anatomic locations, bone marrow being the most common. There is no specific treatment. This review discusses animal models that can lead to a better understanding of pathophysiological mechanisms underlying this condition and indicates the importance of specific cellular constituents. A hypothesis is postulated that there is a vicious cycle involving oleic acid and angiotensin II (both of which are pulmonary toxicants): oleic acid is derived from lipid embolism by pulmonary lipases that are stimulated by angiotensin; oleic acid also promotes local generation of angiotensin. The potential role of fatty acid receptors and the resolution of this cycle are discussed. Studies show there is potential for long-term effects that might not be revealed in the immediate post-recovery period. Evidence is reviewed that animals are vulnerable to "second hit" effects at a time remote from the initial event. Some beneficial pharmacological treatments are described. These include different drugs acting on the reninangiotensin system (RAS) that could eventually serve alone or in combination for

treatment or prevention. Future therapeutic developments are discussed.

time course, second hit, animal model, histopathology, triolein

**Keywords:** fat embolism, lung, renin-angiotensin system, rat, drug treatment,

Fat embolism was described many years ago. As early as 1862 [1] as cited in a 1971 review by Herndon [2], there was a report of fat droplets in the lungs of a factory worker who died after a crushing injury to his chest and abdomen. The term "fat embolism" itself includes many types of conditions in which some type of fatty substance is embedded in a tissue remote from its source. The most common source is from bone marrow that escapes into the venous system after trauma and surgery, including bone marrow reaming [3], liposuction [4], fat injection [5], or necrosis, as in sickle cell disease resulting in acute chest syndrome [6]. There are also some forms that do not result from trauma or surgery [7]. What distinguishes fat embolism from other strictly physical forms is that in addition to the physical obstruction of the vasculature that can accompany the lodging in capillaries, there are also biochemical consequences in response to the ensuing lipid metabolism and also pathological processes that are triggered intracellularly after engulfing of the fat. The most common target for embolic fat is the lung, but other significant sites include the skin, the eyes, and the brain with subsequent clinical sequelae [8].

*Alan M. Poisner and Agostino Molteni*

### **Chapter 2**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

embolized intravascular foreign bodies. In: Seminars in Cardiothoracic and Vascular Anesthesia. Los Angeles, CA: SAGE Publications Sage CA; 2018

management of late bullet embolization from the abdomen to the right ventricle: Case report. International Journal of Surgery Case Reports. 2017;**39**:317-320

[56] Adegboyega PA, Sustento-Reodica N, Adesokan A. Arterial bullet embolism

insufficiency: A rationale for mandatory extraction. Journal of Trauma and Acute

[55] Elison RMA et al. Surgical

resulting in delayed vascular

Care Surgery. 1996;**41**(3):539-541

**10**

## Fat Embolism: What We Have Learned from Animal Models

*Alan M. Poisner and Agostino Molteni*

### **Abstract**

Pulmonary fat embolism may not be diagnosed before unrelated autopsy and have little clinical impact or lead to acute lung injury with fulminant fat embolism syndrome (FES). The fat may come from various anatomic locations, bone marrow being the most common. There is no specific treatment. This review discusses animal models that can lead to a better understanding of pathophysiological mechanisms underlying this condition and indicates the importance of specific cellular constituents. A hypothesis is postulated that there is a vicious cycle involving oleic acid and angiotensin II (both of which are pulmonary toxicants): oleic acid is derived from lipid embolism by pulmonary lipases that are stimulated by angiotensin; oleic acid also promotes local generation of angiotensin. The potential role of fatty acid receptors and the resolution of this cycle are discussed. Studies show there is potential for long-term effects that might not be revealed in the immediate post-recovery period. Evidence is reviewed that animals are vulnerable to "second hit" effects at a time remote from the initial event. Some beneficial pharmacological treatments are described. These include different drugs acting on the reninangiotensin system (RAS) that could eventually serve alone or in combination for treatment or prevention. Future therapeutic developments are discussed.

**Keywords:** fat embolism, lung, renin-angiotensin system, rat, drug treatment, time course, second hit, animal model, histopathology, triolein

### **1. Introduction**

Fat embolism was described many years ago. As early as 1862 [1] as cited in a 1971 review by Herndon [2], there was a report of fat droplets in the lungs of a factory worker who died after a crushing injury to his chest and abdomen. The term "fat embolism" itself includes many types of conditions in which some type of fatty substance is embedded in a tissue remote from its source. The most common source is from bone marrow that escapes into the venous system after trauma and surgery, including bone marrow reaming [3], liposuction [4], fat injection [5], or necrosis, as in sickle cell disease resulting in acute chest syndrome [6]. There are also some forms that do not result from trauma or surgery [7]. What distinguishes fat embolism from other strictly physical forms is that in addition to the physical obstruction of the vasculature that can accompany the lodging in capillaries, there are also biochemical consequences in response to the ensuing lipid metabolism and also pathological processes that are triggered intracellularly after engulfing of the fat. The most common target for embolic fat is the lung, but other significant sites include the skin, the eyes, and the brain with subsequent clinical sequelae [8].

The clinical consequences of fat embolism have been reviewed many times over the years, including this year [8]. The symptoms may be so minor that they can be missed [9] or appear after an interval as much as 48–96 h leading to acute respiratory distress syndrome [ARDS] with mortality ranging from 10 to 15% [8, 9]. This has been called fat embolism syndrome [FES], sometimes with accompanying CNS [10], ocular [11] or dermal pathology [12]. Treatment has been supportive: recent reviews indicate that there is no specific treatment available [8, 12]. Although a patent foramen ovale is sometimes a contributing factor in systemic consequences of fat embolism, for instance, in the eye and the brain, this is clearly not the case in most cases of FES.

Therefore, there have been many attempts to produce an animal model in hopes of delineating the underlying pathophysiology, so specific treatment could be obtained. Animal models have included rats [13], mice [14], rabbits [15], dogs [16], sheep [17], pigs [18], and even baboons [19]. While a majority of these studies have focused on orthopedic-related problems [20], it would help to examine a wide variety of initiating causes in order to find some common underlying pathophysiological processes. This might lead to more specific methods to treat or prevent this condition before the array of downstream mediators, such as peptides and cytokines, have been activated. The aim of this chapter is to review what has been learned from the diverse animal studies and provide one unifying concept based on the role of the renin-angiotensin system as a key player in fat embolism syndrome.

### **2. Studies on bone**

#### **2.1 Reaming and nailing**

In order to simulate in animals the surgical procedure used in humans that can lead to fat embolism syndrome, a number of different animals have been subjected to nailing, with or without reaming [3]. It was concluded that more experiments should be carried out in order to determine the optimal method to perform the surgical procedures. It was also made clear that other factors influence the development of systemic and pulmonary complications [3]. A comprehensive review of animal studies of intramedullary nailing concludes that events that may predispose to adverse postsurgical impact are important and that studies should take these into consideration [20].

#### **2.2 Bone marrow fat and non-bone marrow fat injection**

A number of studies have been carried out with infusions of bone marrow extracts or non-marrow fat. An excellent review on animal studies of acute lung injury, which includes oleic acid as a possible model for fat embolism, indicates that this model does not really mimic the clinical syndrome of FES [21]. In addition, a study on rats showed that the intravenous injection of oleic acid, unlike neutral fat, did not result in the deposition of fat droplets [22].

A study on liposuction in rats performed on the lateral flank and the abdomen showed that fat was delivered to the lungs and other organs [23]. Some animal studies on fat embolism have utilized subcutaneous fat [22]. This has clinical parallels in which subcutaneous injection in humans has caused fatal fat embolism [24].

### **3. Triolein: the prototype fat embolism model**

Since neutral fat seems to be the main culprit in fat embolism and is the major fat in bone marrow and subcutaneous tissues [25] and pulmonary emboli [26], the

**13**

*Fat Embolism: What We Have Learned from Animal Models*

neutral fat triolein has been the most studied in vivo and in vitro. Although a number species have been studied, the rat has been studied the most, particularly after the groundbreaking work of L.F. Peltier [27–29]. He studied fat embolism in cats and dogs but mostly in rats. This work included description of the fat content of bone marrow and body fat, distribution of labeled triolein after i.v. injection, changes in blood and lung lipase after embolism, kinetics of the phenomena, and other studies in animals and patients. Some advantages of triolein studies in the rat are described below.

Triolein [glyceryl trioleate] is available as a pure liquid that can be injected i.v. directly or after emulsification. We have used conscious animals since there are studies indicating that anesthesia alters pulmonary response to fat embolism [30]. Although oleic acid is a well-known pulmonary toxicant, as mentioned above, it is not a suitable model for fat embolism syndrome. The conversion of triolein to oleic acid by pulmonary tissue [31] provides support for the proposed sequence of events

Initial histopathological studies on the time course of triolein-induced lung injury revealed changes as early as 12–24 h which included thickening of the arterial and arteriolar media, mostly with myofibroblasts and inflammation in the septa with increased numbers of macrophages. Bronchial alveolar lavage (BAL) at 24 h revealed macrophages, some of which showed inflammatory response and fat droplets. Inflammation

Later studies at 3 and 6 weeks showed that after the first peak [48–72 h] and partial resolution, there were persistent and progressive inflammatory and fibrotic changes up to 6 weeks after injection of triolein [34]. This was associated with an increase in angiotensin peptides [34], implicating the renin-angiotensin system

In order to determine if the lungs of the animals at this late time would be especially sensitive to another pulmonary insult, the animals were exposed to the known pulmonary toxicant lipopolysaccharide (LPS) at 6 weeks. Forty-eight hours after this "second hit," there was an enhanced histopathological response in animals

These animals had apparently recovered completely at 6 weeks from the initial triolein treatment as judged by normal weight gain and no observable behavioral changes. It was concluded that the compromised lungs seen at 6 weeks exposed the vulnerability of animals long after they had seemingly recovered. The histopathology was also found at 10 weeks along with the persistence of some small fat droplets

Because the renin-angiotensin system (RAS) has been implicated in a wide variety of other pulmonary experimental models [37, 38], we examined whether this might hold true for the fat embolism model, and in fact it has since been proposed that most forms of pulmonary inflammatory disease involve the RAS, but that list did not include fat embolism [39]. We found that three different agents that interfere

**3.2 Findings in the conscious rat triolein model of fat embolism**

was still present at 11 days with damage to the bronchial epithelium [33].

extracellularly and also in some macrophages [36] [see below].

*3.2.1 Time course of changes in pulmonary histopathology*

(RAS) in the pathophysiology (see below).

**4. Role of the renin-angiotensin system**

previously exposed to triolein [35].

*DOI: http://dx.doi.org/10.5772/intechopen.85178*

**3.1 Advantages of triolein and our model**

postulated by Szabo [32].

*Fat Embolism: What We Have Learned from Animal Models DOI: http://dx.doi.org/10.5772/intechopen.85178*

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

The clinical consequences of fat embolism have been reviewed many times over the years, including this year [8]. The symptoms may be so minor that they can be missed [9] or appear after an interval as much as 48–96 h leading to acute respiratory distress syndrome [ARDS] with mortality ranging from 10 to 15% [8, 9]. This has been called fat embolism syndrome [FES], sometimes with accompanying CNS [10], ocular [11] or dermal pathology [12]. Treatment has been supportive: recent reviews indicate that there is no specific treatment available [8, 12]. Although a patent foramen ovale is sometimes a contributing factor in systemic consequences of fat embolism, for instance, in the eye and the brain, this is clearly not the case in most cases of FES. Therefore, there have been many attempts to produce an animal model in hopes of delineating the underlying pathophysiology, so specific treatment could be obtained. Animal models have included rats [13], mice [14], rabbits [15], dogs [16], sheep [17], pigs [18], and even baboons [19]. While a majority of these studies have focused on orthopedic-related problems [20], it would help to examine a wide variety of initiating causes in order to find some common underlying pathophysiological processes. This might lead to more specific methods to treat or prevent this condition before the array of downstream mediators, such as peptides and cytokines, have been activated. The aim of this chapter is to review what has been learned from the diverse animal studies and provide one unifying concept based on the role of the renin-angiotensin system as a key player in fat embolism syndrome.

In order to simulate in animals the surgical procedure used in humans that can lead to fat embolism syndrome, a number of different animals have been subjected to nailing, with or without reaming [3]. It was concluded that more experiments should be carried out in order to determine the optimal method to perform the surgical procedures. It was also made clear that other factors influence the development of systemic and pulmonary complications [3]. A comprehensive review of animal studies of intramedullary nailing concludes that events that may predispose to adverse postsurgical impact are important and that studies should take these into consideration [20].

A number of studies have been carried out with infusions of bone marrow extracts or non-marrow fat. An excellent review on animal studies of acute lung injury, which includes oleic acid as a possible model for fat embolism, indicates that this model does not really mimic the clinical syndrome of FES [21]. In addition, a study on rats showed that the intravenous injection of oleic acid, unlike neutral fat,

A study on liposuction in rats performed on the lateral flank and the abdomen showed that fat was delivered to the lungs and other organs [23]. Some animal studies on fat embolism have utilized subcutaneous fat [22]. This has clinical parallels in

Since neutral fat seems to be the main culprit in fat embolism and is the major fat in bone marrow and subcutaneous tissues [25] and pulmonary emboli [26], the

which subcutaneous injection in humans has caused fatal fat embolism [24].

**2.2 Bone marrow fat and non-bone marrow fat injection**

did not result in the deposition of fat droplets [22].

**3. Triolein: the prototype fat embolism model**

**12**

**2. Studies on bone**

**2.1 Reaming and nailing**

neutral fat triolein has been the most studied in vivo and in vitro. Although a number species have been studied, the rat has been studied the most, particularly after the groundbreaking work of L.F. Peltier [27–29]. He studied fat embolism in cats and dogs but mostly in rats. This work included description of the fat content of bone marrow and body fat, distribution of labeled triolein after i.v. injection, changes in blood and lung lipase after embolism, kinetics of the phenomena, and other studies in animals and patients. Some advantages of triolein studies in the rat are described below.

### **3.1 Advantages of triolein and our model**

Triolein [glyceryl trioleate] is available as a pure liquid that can be injected i.v. directly or after emulsification. We have used conscious animals since there are studies indicating that anesthesia alters pulmonary response to fat embolism [30]. Although oleic acid is a well-known pulmonary toxicant, as mentioned above, it is not a suitable model for fat embolism syndrome. The conversion of triolein to oleic acid by pulmonary tissue [31] provides support for the proposed sequence of events postulated by Szabo [32].

#### **3.2 Findings in the conscious rat triolein model of fat embolism**

#### *3.2.1 Time course of changes in pulmonary histopathology*

Initial histopathological studies on the time course of triolein-induced lung injury revealed changes as early as 12–24 h which included thickening of the arterial and arteriolar media, mostly with myofibroblasts and inflammation in the septa with increased numbers of macrophages. Bronchial alveolar lavage (BAL) at 24 h revealed macrophages, some of which showed inflammatory response and fat droplets. Inflammation was still present at 11 days with damage to the bronchial epithelium [33].

Later studies at 3 and 6 weeks showed that after the first peak [48–72 h] and partial resolution, there were persistent and progressive inflammatory and fibrotic changes up to 6 weeks after injection of triolein [34]. This was associated with an increase in angiotensin peptides [34], implicating the renin-angiotensin system (RAS) in the pathophysiology (see below).

In order to determine if the lungs of the animals at this late time would be especially sensitive to another pulmonary insult, the animals were exposed to the known pulmonary toxicant lipopolysaccharide (LPS) at 6 weeks. Forty-eight hours after this "second hit," there was an enhanced histopathological response in animals previously exposed to triolein [35].

These animals had apparently recovered completely at 6 weeks from the initial triolein treatment as judged by normal weight gain and no observable behavioral changes. It was concluded that the compromised lungs seen at 6 weeks exposed the vulnerability of animals long after they had seemingly recovered. The histopathology was also found at 10 weeks along with the persistence of some small fat droplets extracellularly and also in some macrophages [36] [see below].

#### **4. Role of the renin-angiotensin system**

Because the renin-angiotensin system (RAS) has been implicated in a wide variety of other pulmonary experimental models [37, 38], we examined whether this might hold true for the fat embolism model, and in fact it has since been proposed that most forms of pulmonary inflammatory disease involve the RAS, but that list did not include fat embolism [39]. We found that three different agents that interfere

**Figure 1.** *Triolein increases lung renin staining: enhanced by captopril and losartan [64].*

with the RAS were found to ameliorate the pulmonary damage found at 48 h after triolein: the angiotensin-converting enzyme (ACE) inhibitor captopril [40], the angiotensin II type 1 receptor blocker losartan [40], and the renin inhibitor aliskiren [41]. In addition, it was found that the remaining inflammation that was evident at 6 weeks was also reduced when losartan was given at this late time period and the animals were sacrificed 4 weeks later (10 weeks after the initial exposure to triolein) [36]. These results suggest that angiotensin II, produced by the angiotensinconverting enzyme (ACE) and acting on the type 1 receptor, is a critical pathological actor in the pathophysiology of fat embolism both acutely and after a substantial delay. However, it does not indicate precisely where this peptide comes from or how it is formed. All of the components of the RAS have been found or implicated in the lung [42]. Possible players in its formation prior to ACE activity could be renin or prorenin that is catalytically active when bound to its receptor [43]. Furthermore, other angiotensin peptides with anti-inflammatory and antifibrotic activity could be counterbalancing forces as well. Most of the extrarenal renin is in the form of prorenin which also has angiotensin-independent pro-fibrotic properties [44–46].

There are many possible cells that could provide components of the RAS to the pulmonary inflammatory process. These include mast cells [47], fibroblasts [48], myofibroblasts [49], vascular smooth muscle [50], and macrophages [51].

There are a number of studies suggesting a critical role of mast cells in RAS mediation of pulmonary pathology [52–54]. It has been suggested that activated macrophages stimulate pulmonary mast cells to release renin and the subsequent production of angiotensin peptides leads to adverse reactions [54]. Mast cells have also been shown to stimulate fibroblasts in the lung [55]. Triolein increases mast cell accumulation in a chronic model, and their appearance is reduced by losartan [56], and aliskiren reduces the triolein-induced increase of mast cell number found at 48 hours [57]. Another mast cell enzyme that has been implicated in angiotensin formation is chymase [58, 59]. It is known that there is mast cell heterogeneity in rodents and humans [60–62], and in humans this includes the presence of renin and its localization within the lungs [62].

In support of the importance of renin/prorenin in fat embolism, we have found an increase in renin staining at 48 hours (**Figure 1**) and 6 weeks after trioleininduced fat embolism [63, 64].

### **5. The nexus of fat metabolism and action and the RAS in the lungs**

It has long been speculated that angiotensin II, acting through the type 1 receptor, was a primary inflammatory molecule [65]. In recent years it has become apparent that angiotensin II acting through its type 2 receptor has anti-inflammatory

**15**

*Fat Embolism: What We Have Learned from Animal Models*

angiotensin as well on mitochondria and nuclei.

angiotensin receptor blocker losartan [80].

induces angiotensin generation [54].

with an increase in circulating angiotensin peptides [74].

actions [66] and the literature on similar anti-inflammatory actions through the Ang 1-7/Mas receptor have exploded [67]. It appears that the pathophysiological state of the lungs is a balance between the pro-inflammatory, pro-fibrotic arm of the RAS, and the counterbalancing peptide/receptor activity. It is not surprising that Ang 1-7 has been found to have beneficial effects in the lung [68, 69].

How is the renin-angiotensin system activated in fat embolism, and what is the connection to fat (neutral and fatty acids)? One suggestion based on the work of Gonzalez et al. [52, 54, 70] would have a sequence of fat engulfment by macrophages, and subsequently the activated cells would release monocyte chemoattractant-1 (MCP-1) that stimulates mast cells (nearby or remote) to release renin and angiotensin generation. However, activated macrophages themselves might act in an autocrine or paracrine manner to release renin, and there is evidence for intracrine generation of angiotensin as well [71, 72]. There may be intracrine actions of

If the RAS is involved in many aspects, including initiating a cascade of downstream malevolent molecules, where does the fat enter the picture? As a host of review articles have discussed, there is a strictly mechanical phase during which the fat emboli obstruct capillaries and cause a short-term hypoxia. It is known that hypoxia itself can lead to pulmonary dysfunction and this can be offset experimentally by angiotensin-converting enzyme inhibition (ACEI) [73] and is associated

It is clear from the vast literature on metabolism of fat after embolism that most of the lipolysis of neutral fat (mostly triolein) takes place near pulmonary endothelial cells that convert triolein to the toxic oleic acid by lipoprotein lipase. It is now known that oleic acid, although not thought to enter cells [21], can activate its own fatty acid receptor (FFAR/GPR120) which can evoke pulmonary edema [75, 76]. Interestingly, the toxic effects of oleic acid (including pulmonary edema) are antagonized by the non-specific angiotensin receptor blocker 1-sarcosine, 8-isoleucine angiotensin II [77]. This implicates angiotensin II in another way as a key mediatory in pulmonary pathology. It has also been reported that oleic acid and angiotensin II are synergistic in promoting a mitogenic effect in vascular smooth muscle [78]. Oleic acid emanating from triolein thus is a co-conspirator in evoking pulmonary (and probably other) pathological conditions, such as cerebral fat embolism [10, 79]. Pathways that oleic acid and angiotensin utilize in producing pathological responses are listed in **Figure 2**.

**5.1 A vicious cycle of oleic acid and angiotensin II in fat embolism syndrome**

To explain how the sudden appearance of fat in the pulmonary circulation can sometimes produce an acute respiratory distress syndrome and why the neutral fat (primarily triolein) has the potential to lead to longer-term pulmonary damage, the following hypothesis is presented (**Figure 3**). The initial mechanical phase of vascular obstruction which leads to hypoxia is known to be ameliorated by the

The delayed metabolic phase is related to breakdown of the most abundant fat in emboli which is hydrolyzed by several triglyceride lipases to yield oleic acid. These include endothelial lipase (EL) and lipoprotein lipase (LIPL) [81, 82] as well as macrophage LIPL [83]. This in turn leads to the evolution of free fatty acids, mainly oleic acid, which is toxic to the endothelium and is released in part in close proximity to endothelial cells. Macrophages become activated after phagocytosing lipid particles which leads to paracrine and endocrine activation of mast cells that

In addition, there is generation of angiotensin and oleic acid intracellularly in macrophages (both of which are toxic to mitochondria [84, 85]). Since oleic acid

*DOI: http://dx.doi.org/10.5772/intechopen.85178*

#### *Fat Embolism: What We Have Learned from Animal Models DOI: http://dx.doi.org/10.5772/intechopen.85178*

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

*Triolein increases lung renin staining: enhanced by captopril and losartan [64].*

with the RAS were found to ameliorate the pulmonary damage found at 48 h after triolein: the angiotensin-converting enzyme (ACE) inhibitor captopril [40], the angiotensin II type 1 receptor blocker losartan [40], and the renin inhibitor aliskiren [41]. In addition, it was found that the remaining inflammation that was evident at 6 weeks was also reduced when losartan was given at this late time period and the animals were sacrificed 4 weeks later (10 weeks after the initial exposure to triolein) [36]. These results suggest that angiotensin II, produced by the angiotensinconverting enzyme (ACE) and acting on the type 1 receptor, is a critical pathological actor in the pathophysiology of fat embolism both acutely and after a substantial delay. However, it does not indicate precisely where this peptide comes from or how it is formed. All of the components of the RAS have been found or implicated in the lung [42]. Possible players in its formation prior to ACE activity could be renin or prorenin that is catalytically active when bound to its receptor [43]. Furthermore, other angiotensin peptides with anti-inflammatory and antifibrotic activity could be counterbalancing forces as well. Most of the extrarenal renin is in the form of prorenin which also has angiotensin-independent pro-fibrotic properties [44–46]. There are many possible cells that could provide components of the RAS to the pulmonary inflammatory process. These include mast cells [47], fibroblasts [48],

myofibroblasts [49], vascular smooth muscle [50], and macrophages [51].

an increase in renin staining at 48 hours (**Figure 1**) and 6 weeks after triolein-

**5. The nexus of fat metabolism and action and the RAS in the lungs**

It has long been speculated that angiotensin II, acting through the type 1 receptor, was a primary inflammatory molecule [65]. In recent years it has become apparent that angiotensin II acting through its type 2 receptor has anti-inflammatory

There are a number of studies suggesting a critical role of mast cells in RAS mediation of pulmonary pathology [52–54]. It has been suggested that activated macrophages stimulate pulmonary mast cells to release renin and the subsequent production of angiotensin peptides leads to adverse reactions [54]. Mast cells have also been shown to stimulate fibroblasts in the lung [55]. Triolein increases mast cell accumulation in a chronic model, and their appearance is reduced by losartan [56], and aliskiren reduces the triolein-induced increase of mast cell number found at 48 hours [57]. Another mast cell enzyme that has been implicated in angiotensin formation is chymase [58, 59]. It is known that there is mast cell heterogeneity in rodents and humans [60–62], and in humans this includes the presence of renin and its localization within the lungs [62]. In support of the importance of renin/prorenin in fat embolism, we have found

**14**

**Figure 1.**

induced fat embolism [63, 64].

actions [66] and the literature on similar anti-inflammatory actions through the Ang 1-7/Mas receptor have exploded [67]. It appears that the pathophysiological state of the lungs is a balance between the pro-inflammatory, pro-fibrotic arm of the RAS, and the counterbalancing peptide/receptor activity. It is not surprising that Ang 1-7 has been found to have beneficial effects in the lung [68, 69].

How is the renin-angiotensin system activated in fat embolism, and what is the connection to fat (neutral and fatty acids)? One suggestion based on the work of Gonzalez et al. [52, 54, 70] would have a sequence of fat engulfment by macrophages, and subsequently the activated cells would release monocyte chemoattractant-1 (MCP-1) that stimulates mast cells (nearby or remote) to release renin and angiotensin generation. However, activated macrophages themselves might act in an autocrine or paracrine manner to release renin, and there is evidence for intracrine generation of angiotensin as well [71, 72]. There may be intracrine actions of angiotensin as well on mitochondria and nuclei.

If the RAS is involved in many aspects, including initiating a cascade of downstream malevolent molecules, where does the fat enter the picture? As a host of review articles have discussed, there is a strictly mechanical phase during which the fat emboli obstruct capillaries and cause a short-term hypoxia. It is known that hypoxia itself can lead to pulmonary dysfunction and this can be offset experimentally by angiotensin-converting enzyme inhibition (ACEI) [73] and is associated with an increase in circulating angiotensin peptides [74].

It is clear from the vast literature on metabolism of fat after embolism that most of the lipolysis of neutral fat (mostly triolein) takes place near pulmonary endothelial cells that convert triolein to the toxic oleic acid by lipoprotein lipase. It is now known that oleic acid, although not thought to enter cells [21], can activate its own fatty acid receptor (FFAR/GPR120) which can evoke pulmonary edema [75, 76]. Interestingly, the toxic effects of oleic acid (including pulmonary edema) are antagonized by the non-specific angiotensin receptor blocker 1-sarcosine, 8-isoleucine angiotensin II [77]. This implicates angiotensin II in another way as a key mediatory in pulmonary pathology. It has also been reported that oleic acid and angiotensin II are synergistic in promoting a mitogenic effect in vascular smooth muscle [78]. Oleic acid emanating from triolein thus is a co-conspirator in evoking pulmonary (and probably other) pathological conditions, such as cerebral fat embolism [10, 79]. Pathways that oleic acid and angiotensin utilize in producing pathological responses are listed in **Figure 2**.

#### **5.1 A vicious cycle of oleic acid and angiotensin II in fat embolism syndrome**

To explain how the sudden appearance of fat in the pulmonary circulation can sometimes produce an acute respiratory distress syndrome and why the neutral fat (primarily triolein) has the potential to lead to longer-term pulmonary damage, the following hypothesis is presented (**Figure 3**). The initial mechanical phase of vascular obstruction which leads to hypoxia is known to be ameliorated by the angiotensin receptor blocker losartan [80].

The delayed metabolic phase is related to breakdown of the most abundant fat in emboli which is hydrolyzed by several triglyceride lipases to yield oleic acid. These include endothelial lipase (EL) and lipoprotein lipase (LIPL) [81, 82] as well as macrophage LIPL [83]. This in turn leads to the evolution of free fatty acids, mainly oleic acid, which is toxic to the endothelium and is released in part in close proximity to endothelial cells. Macrophages become activated after phagocytosing lipid particles which leads to paracrine and endocrine activation of mast cells that induces angiotensin generation [54].

In addition, there is generation of angiotensin and oleic acid intracellularly in macrophages (both of which are toxic to mitochondria [84, 85]). Since oleic acid

**Figure 2.** *Fat embolism pathways.*

*Oleic acid-angiotensin cycle: OA* ↑ *Ang release; Ang* ↑ *triolein lipolysis.*

has been shown to increase angiotensin II release from several cell types [86] and angiotensin increases the expression of various lipases [87], the cycle continues until rescue mechanisms ensue (**Figure 4**). It should be noted that losartan and perindopril, ACE inhibitors, prevent fatty acid-induced endothelial dysfunction

**17**

*Fat Embolism: What We Have Learned from Animal Models*

in humans in response to elevated blood lipids [88]. Furthermore, oleic acid also increases serum renin and angiotensin, and its effects on pulmonary edema are

Most cases of fat embolism do not lead to fat embolism syndrome because the amount of the fat is not of sufficient volume or due to the countervailing mechanisms. These include actions of angiotensin II on AT2 receptors, metabolism of angiotensin II by angiotensinases, anti-inflammatory actions of its metabolite, angiotensin (1-7), metabolism of oleic acid, clearance of lipids via vascular or

It is proposed that elements of the renin-angiotensin system are central mediators of tissue injury after fat embolism. Although hypoxia due to capillary blockage is a contributing factor to lung injury, oleic acid liberated from triolein hydrolysis is a crucial step, and it also is associated with angiotensin biology. Angiotensin II through its type 1 receptor is the major offender. Our animal experiments have indicated that three US Food and Drug Administration (FDA)-approved drugs (captopril, losartan, and aliskiren) may have protective value as mentioned above. However, in a clinical setting where trauma or surgery may be involved, stability of blood pressure may be compromised by these agents. Therefore, it is suggested that some of these types of

*DOI: http://dx.doi.org/10.5772/intechopen.85178*

blocked by blocked by an ACE inhibitor [89].

**6. Conclusions and prospects**

*Repair mechanisms for fat embolism.*

**Figure 4.**

lymphatic channels, and ultimately renal excretion (**Figure 4**).

agents (or a combination) could be administered by inhalation.

to be an important mediating system in many ocular diseases [93].

Rather than antagonizing the angiotensin II generation with ACE or renin inhibitors or angiotensin type 1 activity with antagonists (ARBS), it may be possible to treat/prevent fat embolism injury by stimulating the angiotensin type 2 receptor (AT2) with peptide or non-peptide agonists such as C21 [90]. Another possible therapeutic approach would be to activate the ACE2/angiotensin [1-7]/MAS axis with a peptide or non-peptide agonist, such as AVE0091 [68]. A more promising avenue for preventing or treating fat embolism will more likely be satisfactory if multiple points of the early stages of the pathophysiology are attacked simultaneously. That would include not only the RAS drugs mentioned above but also possibly mast stabilizers that can be given by the inhalation route and some of the newly described drugs that act on the FFA receptors mentioned above. In addition it is possible that some of the newer triglyceride lipase inhibitors could be of value as preventive treatment. Although the emphasis in this review is on pulmonary fat embolism, there is ample evidence from clinical experience and animal experiments that the eyes, particularly the retina, are frequently targets of fat embolism. Both triolein and oleic acid have been implicated in ocular pathology [91, 92], and the RAS is thought *Fat Embolism: What We Have Learned from Animal Models DOI: http://dx.doi.org/10.5772/intechopen.85178*

#### **Figure 4.** *Repair mechanisms for fat embolism.*

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

has been shown to increase angiotensin II release from several cell types [86] and angiotensin increases the expression of various lipases [87], the cycle continues until rescue mechanisms ensue (**Figure 4**). It should be noted that losartan and perindopril, ACE inhibitors, prevent fatty acid-induced endothelial dysfunction

*Oleic acid-angiotensin cycle: OA* ↑ *Ang release; Ang* ↑ *triolein lipolysis.*

**16**

**Figure 3.**

**Figure 2.**

*Fat embolism pathways.*

in humans in response to elevated blood lipids [88]. Furthermore, oleic acid also increases serum renin and angiotensin, and its effects on pulmonary edema are blocked by blocked by an ACE inhibitor [89].

Most cases of fat embolism do not lead to fat embolism syndrome because the amount of the fat is not of sufficient volume or due to the countervailing mechanisms. These include actions of angiotensin II on AT2 receptors, metabolism of angiotensin II by angiotensinases, anti-inflammatory actions of its metabolite, angiotensin (1-7), metabolism of oleic acid, clearance of lipids via vascular or lymphatic channels, and ultimately renal excretion (**Figure 4**).

### **6. Conclusions and prospects**

It is proposed that elements of the renin-angiotensin system are central mediators of tissue injury after fat embolism. Although hypoxia due to capillary blockage is a contributing factor to lung injury, oleic acid liberated from triolein hydrolysis is a crucial step, and it also is associated with angiotensin biology. Angiotensin II through its type 1 receptor is the major offender. Our animal experiments have indicated that three US Food and Drug Administration (FDA)-approved drugs (captopril, losartan, and aliskiren) may have protective value as mentioned above. However, in a clinical setting where trauma or surgery may be involved, stability of blood pressure may be compromised by these agents. Therefore, it is suggested that some of these types of agents (or a combination) could be administered by inhalation.

Rather than antagonizing the angiotensin II generation with ACE or renin inhibitors or angiotensin type 1 activity with antagonists (ARBS), it may be possible to treat/prevent fat embolism injury by stimulating the angiotensin type 2 receptor (AT2) with peptide or non-peptide agonists such as C21 [90]. Another possible therapeutic approach would be to activate the ACE2/angiotensin [1-7]/MAS axis with a peptide or non-peptide agonist, such as AVE0091 [68]. A more promising avenue for preventing or treating fat embolism will more likely be satisfactory if multiple points of the early stages of the pathophysiology are attacked simultaneously. That would include not only the RAS drugs mentioned above but also possibly mast stabilizers that can be given by the inhalation route and some of the newly described drugs that act on the FFA receptors mentioned above. In addition it is possible that some of the newer triglyceride lipase inhibitors could be of value as preventive treatment.

Although the emphasis in this review is on pulmonary fat embolism, there is ample evidence from clinical experience and animal experiments that the eyes, particularly the retina, are frequently targets of fat embolism. Both triolein and oleic acid have been implicated in ocular pathology [91, 92], and the RAS is thought to be an important mediating system in many ocular diseases [93].

Another non-pulmonary target of fat embolism in clinical FES is the brain, and cerebral fat embolism can be fatal [94]. Although a patent foramen ovale is sometimes an important factor in cerebral fat embolism, this is clearly not the case in many instances, and animal models have not provided any new insights of cardiac defects being major players. In a rat model, there is some evidence that cerebral fat embolism may involve a serine protease [79] and maybe this could be related to a non-renin generation of angiotensin by a chymase-like enzyme. The RAS is now believed to be important for much CNS pathology [95].

There now is reason to be optimistic that the next comprehensive review of fat embolism syndrome will describe some new available therapeutic options based on animal experiments. This reinforces the goal of animal experiments to delineate the pathophysiological mechanisms underlying human disease, so specific treatment can be implemented.

### **Acknowledgements**

We acknowledge the support of Dr. Gary Salzman, M.D., and the Mary Catherine Geldmacher Foundation of St. Louis, MO, the graphical help from Dr. Doud Arif, and the inspiration to begin this research from the late Dr. Federico Adler.

### **Author details**

Alan M. Poisner1 \* and Agostino Molteni<sup>2</sup>

1 University of Kansas Medical Center, Kansas City, KS, USA

2 University of Missouri Kansas City School of Medicine, Kansas City, MO, USA

\*Address all correspondence to: apoisner@kumc.edu

© 2019 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.

**19**

*Fat Embolism: What We Have Learned from Animal Models*

Fakhry SM, Cohle SD. Incidence of pulmonary fat embolism at autopsy: An undiagnosed epidemic. Journal of

[10] Dines DE, Burgher LW, Okazaki H. The clinical and pathologic correlation of fat embolism

syndrome. Mayo Clinic Proceedings.

[11] Spirn MJ, Biousse V. Retinal fat emboli. The Journal of Emergency Medicine. 2005;**29**(3):339-340

[12] Shaikh N. Emergency management of fat embolism syndrome. Journal of Emergencies, Trauma, and Shock.

[13] Inoue H, Hanagama M, Kamiya M, Shinone K, Nata M. Experimental pulmonary fat embolism induced by injection of triolein in rats. Legal Medicine. 2008;**10**:26-30

[14] Zhang Y, Tian K, Wang Y, Zhang R, Shang J, Jiang W, et al. The effects of aquaporin-1 in pulmonary edema induced by fat embolism syndrome. International Journal of Molecular

[15] Woo OH, Yong HS, Oh YW, Shin BK, Kim HK, Kang EY. Experimental pulmonary fat embolism: Computed

[16] Byrick RJ, Mullen JB, Mazer CD, Guest CB. Transpulmonary systemic fat embolism. Studies in mongrel dogs after cemented arthroplasty. American Journal of Respiratory and Critical Care

[17] Aebli N, Krebs J, Davis G, Walton M, Williams MJ, Theis JC. Fat embolism

Medicine. 1994;**150**:1416-1422

and acute hypotension during

Sciences. 2016;**17**(7):1183

tomography and pathologic findings of the sequential changes. Journal of Korean Medical Science.

2008;**23**(4):691-699

Trauma. 2011;**71**(2):312-315

1975;**50**(7):407-411

2009;**2**(1):29-33

*DOI: http://dx.doi.org/10.5772/intechopen.85178*

[1] Zenker FA. Beiträge zur normalen und pathologischen Anatomie der Lungen. Braunsnsdorf: Dresden; 1862

[2] Herndon JH, Riseborough EJ, Fischer JE. Fat embolism: A review of current concepts. The Journal of Trauma.

[4] Cantu CA, Pavlisko EN. Liposuctioninduced fat embolism syndrome: A brief review and postmortem diagnostic approach. Archives of Pathology & Laboratory Medicine.

[5] Cardenas-Camarena L, Bayter JE, Aguirre-Serrano H, Cuenca-Pardo J. Deaths caused by gluteal

[6] Vichinsky E, Williams R, Das M, Earles AN, Lewis N, Adler A, et al. Pulmonary fat embolism: A distinct cause of severe acute chest syndrome in sickle cell anemia. Blood.

[7] Schulz F, Trubner K, Hildebrand E. Fatal fat embolism in acute hepatic necrosis with associated fatty liver. The American Journal of Forensic Medicine and Pathology. 1996;**17**(3):264-268

[8] Fukumoto LE, Fukumoto KD. Fat embolism syndrome. The Nursing Clinics of North America.

[9] Eriksson EA, Pellegrini DC, Vanderkolk WE, Minshall CT,

2018;**53**(3):335-347

lipoinjection: What are we doing wrong? Plastic and Reconstructive Surgery.

[3] Hildebrand F, Andruszkow H, Barkatali BM, Pfeifer R, Lichte P, Kobbe P, et al. Animal models to assess the local and systemic effects of nailing: Review of the literature and considerations for future studies. Journal of Trauma and Acute Care Surgery. 2014;**76**(6):1495-1506

**References**

1971;**11**(8):673-680

2018;**142**(7):871-875

2015;**136**(1):58-66

1994;**83**(11):3107-3112

*Fat Embolism: What We Have Learned from Animal Models DOI: http://dx.doi.org/10.5772/intechopen.85178*

### **References**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

believed to be important for much CNS pathology [95].

Another non-pulmonary target of fat embolism in clinical FES is the brain, and cerebral fat embolism can be fatal [94]. Although a patent foramen ovale is sometimes an important factor in cerebral fat embolism, this is clearly not the case in many instances, and animal models have not provided any new insights of cardiac defects being major players. In a rat model, there is some evidence that cerebral fat embolism may involve a serine protease [79] and maybe this could be related to a non-renin generation of angiotensin by a chymase-like enzyme. The RAS is now

There now is reason to be optimistic that the next comprehensive review of fat embolism syndrome will describe some new available therapeutic options based on animal experiments. This reinforces the goal of animal experiments to delineate the pathophysiological mechanisms underlying human disease, so specific treatment

We acknowledge the support of Dr. Gary Salzman, M.D., and the Mary Catherine Geldmacher Foundation of St. Louis, MO, the graphical help from Dr. Doud Arif,

and the inspiration to begin this research from the late Dr. Federico Adler.

© 2019 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,

2 University of Missouri Kansas City School of Medicine, Kansas City, MO, USA

**18**

**Author details**

can be implemented.

**Acknowledgements**

Alan M. Poisner1

provided the original work is properly cited.

\* and Agostino Molteni<sup>2</sup>

\*Address all correspondence to: apoisner@kumc.edu

1 University of Kansas Medical Center, Kansas City, KS, USA

[1] Zenker FA. Beiträge zur normalen und pathologischen Anatomie der Lungen. Braunsnsdorf: Dresden; 1862

[2] Herndon JH, Riseborough EJ, Fischer JE. Fat embolism: A review of current concepts. The Journal of Trauma. 1971;**11**(8):673-680

[3] Hildebrand F, Andruszkow H, Barkatali BM, Pfeifer R, Lichte P, Kobbe P, et al. Animal models to assess the local and systemic effects of nailing: Review of the literature and considerations for future studies. Journal of Trauma and Acute Care Surgery. 2014;**76**(6):1495-1506

[4] Cantu CA, Pavlisko EN. Liposuctioninduced fat embolism syndrome: A brief review and postmortem diagnostic approach. Archives of Pathology & Laboratory Medicine. 2018;**142**(7):871-875

[5] Cardenas-Camarena L, Bayter JE, Aguirre-Serrano H, Cuenca-Pardo J. Deaths caused by gluteal lipoinjection: What are we doing wrong? Plastic and Reconstructive Surgery. 2015;**136**(1):58-66

[6] Vichinsky E, Williams R, Das M, Earles AN, Lewis N, Adler A, et al. Pulmonary fat embolism: A distinct cause of severe acute chest syndrome in sickle cell anemia. Blood. 1994;**83**(11):3107-3112

[7] Schulz F, Trubner K, Hildebrand E. Fatal fat embolism in acute hepatic necrosis with associated fatty liver. The American Journal of Forensic Medicine and Pathology. 1996;**17**(3):264-268

[8] Fukumoto LE, Fukumoto KD. Fat embolism syndrome. The Nursing Clinics of North America. 2018;**53**(3):335-347

[9] Eriksson EA, Pellegrini DC, Vanderkolk WE, Minshall CT,

Fakhry SM, Cohle SD. Incidence of pulmonary fat embolism at autopsy: An undiagnosed epidemic. Journal of Trauma. 2011;**71**(2):312-315

[10] Dines DE, Burgher LW, Okazaki H. The clinical and pathologic correlation of fat embolism syndrome. Mayo Clinic Proceedings. 1975;**50**(7):407-411

[11] Spirn MJ, Biousse V. Retinal fat emboli. The Journal of Emergency Medicine. 2005;**29**(3):339-340

[12] Shaikh N. Emergency management of fat embolism syndrome. Journal of Emergencies, Trauma, and Shock. 2009;**2**(1):29-33

[13] Inoue H, Hanagama M, Kamiya M, Shinone K, Nata M. Experimental pulmonary fat embolism induced by injection of triolein in rats. Legal Medicine. 2008;**10**:26-30

[14] Zhang Y, Tian K, Wang Y, Zhang R, Shang J, Jiang W, et al. The effects of aquaporin-1 in pulmonary edema induced by fat embolism syndrome. International Journal of Molecular Sciences. 2016;**17**(7):1183

[15] Woo OH, Yong HS, Oh YW, Shin BK, Kim HK, Kang EY. Experimental pulmonary fat embolism: Computed tomography and pathologic findings of the sequential changes. Journal of Korean Medical Science. 2008;**23**(4):691-699

[16] Byrick RJ, Mullen JB, Mazer CD, Guest CB. Transpulmonary systemic fat embolism. Studies in mongrel dogs after cemented arthroplasty. American Journal of Respiratory and Critical Care Medicine. 1994;**150**:1416-1422

[17] Aebli N, Krebs J, Davis G, Walton M, Williams MJ, Theis JC. Fat embolism and acute hypotension during

vertebroplasty: An experimental study in sheep. Spine [Phila Pa 1976 ]. 2002;**27**(5):460-466

[18] Wang AZ, Zhou M, Jiang W, Zhang WX. The differences between venous air embolism and fat embolism in routine intraoperative monitoring methods, transesophageal echocardiography, and fatal volume in pigs. The Journal of Trauma. 2008;**65**(2):416-423

[19] Kropfl A, Davies J, Berger U, Hertz H, Schlag G. Intramedullary pressure and bone marrow fat extravasation in reamed and unreamed femoral nailing. Journal of Orthopaedic Research. 1999;**17**(2):261-268

[20] Pape HC, Hildebrand F, Krettek C, Green J, Giannoudis PV. Experimental background—Review of animal studies. Injury. 2006;**37**(Suppl 4):S25-S38

[21] Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2008;**295**(3):L379-L399

[22] Takada M, Chiba S, Nagai T, Takeshita H, Kanno S, Ikawa T, et al. Inflammatory responses to neutral fat and fatty acids in multiple organs in a rat model of fat embolism syndrome. Forensic Science International. 2015;**254**:126-132

[23] Lim KR, Cho JM, Yoon CM, Lee KC, Lee SY, Ju MH. Correlation between the time elapsed after liposuction and the risk of fat embolism: An animal model. Archives of Plastic Surgery. 2018;**45**(1):14-22

[24] Mofid MM, Teitelbaum S, Suissa D, Ramirez-Montanana A, Astarita DC, Mendieta C, et al. Report on mortality from gluteal fat grafting: Recommendations from the ASERF Task Force. Aesthetic Surgery Journal. 2017;**37**(7):796-806

[25] Peltier LF, Wheller DH, BOYD HM, Scott JR. Fat embolism. II. The chemical composition of fat obtained from human long bones and subcutaneous tissue. Surgery. 1956;**40**(4):661-664

[26] Sherr S, Montemurno R, Raffer P. Lipids of recovered pulmonary fat emboli following trauma. The Journal of Trauma. 1974;**14**(3):242-246

[27] Peltier LF. Fat embolism following intramedullary nailing; report of a fatality. Surgery. 1952;**32**(4):719-722

[28] Peltier LF. Fat embolism: A pulmonary disease. Surgery. 1967;**62**(4):756-758

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[30] Wang AZ, Ma QX, Zhao HJ, Zhou QH, Jiang W, Sun JZ. A comparative study of the mortality rate of rats receiving a half lethal dose of fat intravenously: Under general anaesthesia versus under spinal anaesthesia. Injury. 2012;**43**(3):311-314

[31] Compton SK, Hamosh M, Hamosh P. Hydrolysis of triglycerides in the isolated perfused rat lung. Lipids. 1982;**17**:696-702

[32] Szabo G, Magyar Z, Reffy A. The role of free fatty acids in pulmonary fat embolism. Injury. 1977;**8**(4):278-283

[33] McIff TE, Poisner AM, Herndon B, Lankachandra K, Schutt S, Haileselassie B, et al. Fat embolism: Evolution of histopathological changes in the rat lung. Journal of Orthopaedic Research. 2010;**28**(2):191-197

[34] Poisner AM, Adler F, Uhal B, McIff TE, Schroeppel JP, Mehrer A, et al. Persistent and progressive pulmonary fibrotic changes in a model of fat embolism. Journal of Trauma and Acute Care Surgery. 2012;**72**(4):992-998

**21**

*Fat Embolism: What We Have Learned from Animal Models*

the histopathological effects of fat embolism. Journal of Trauma and Acute

Care Surgery. 2017;**82**:338-344

2003;**9**(9):715-722

2011;**17**(33):3611-3621

2010;**78**(3):246-256

2018;**314**(2):H139-H145

1992;**263**:C851-C863

1997;**29**:1375-1386

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[42] Marshall RP. The pulmonary renin-angiotensin system. Current Pharmaceutical Design.

[43] Ahmed BA, Seda O, Lavoie JL. [Pro]renin receptor as a new drug target. Current Pharmaceutical Design.

[44] Sealey JE, Rubattu S. Prorenin and renin as separate mediators of tissue and circulating systems. American Journal of Hypertension. 1989;**2**:358-366

[45] Sihn G, Rousselle A, Vilianovitch L, Burckle C, Bader M. Physiology of the [pro]renin receptor: Wnt of change? Kidney International.

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[36] Poisner A, Herndon B, Bass D, Fletcher A, Jain A, England JP, et al. Evidence for angiotensin mediation of the late histopathological effects of fat embolism: Protection by losartan in a rat model. Experimental Lung Research.

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2019;**44**:363-367

2000;**76**(4):523-532

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M. Monocrotaline-induced pulmonary

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Trauma. 2011;**70**:1186-1191

[41] Fletcher A, Molteni A, Ponnapureddy R, Patel C, Pluym M, Poisner AM. The renin inhibitor aliskiren protects rat lungs from

*Fat Embolism: What We Have Learned from Animal Models DOI: http://dx.doi.org/10.5772/intechopen.85178*

[35] Poisner AM, Herndon B, Lankachandra K, Likhitsup A, Al Hariri A, Kesh S, et al. Fat embolism sensitizes rats to a "second hit" with lipopolysaccharide: An animal model of pulmonary fibrosis. Journal of Trauma and Acute Care Surgery. 2015;**78**:552-557

[36] Poisner A, Herndon B, Bass D, Fletcher A, Jain A, England JP, et al. Evidence for angiotensin mediation of the late histopathological effects of fat embolism: Protection by losartan in a rat model. Experimental Lung Research. 2019;**44**:363-367

[37] Molteni A, Moulder JE, Cohen EF, Ward WF, Fish BL, Taylor JM, et al. Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker. International Journal of Radiation Biology. 2000;**76**(4):523-532

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[39] Tan WSD, Liao W, Zhou S, Mei D, Wong WF. Targeting the reninangiotensin system as novel therapeutic strategy x for pulmonary diseases. Current Opinion in Pharmacology. 2018;**40**:9-17

[40] McIff TE, Poisner AM, Herndon B, Lankachandra K, Molteni A, Adler F. Mitigating effects of captopril and losartan on lung histopathology in a rat model of fat embolism. The Journal of Trauma. 2011;**70**:1186-1191

[41] Fletcher A, Molteni A, Ponnapureddy R, Patel C, Pluym M, Poisner AM. The renin inhibitor aliskiren protects rat lungs from

the histopathological effects of fat embolism. Journal of Trauma and Acute Care Surgery. 2017;**82**:338-344

[42] Marshall RP. The pulmonary renin-angiotensin system. Current Pharmaceutical Design. 2003;**9**(9):715-722

[43] Ahmed BA, Seda O, Lavoie JL. [Pro]renin receptor as a new drug target. Current Pharmaceutical Design. 2011;**17**(33):3611-3621

[44] Sealey JE, Rubattu S. Prorenin and renin as separate mediators of tissue and circulating systems. American Journal of Hypertension. 1989;**2**:358-366

[45] Sihn G, Rousselle A, Vilianovitch L, Burckle C, Bader M. Physiology of the [pro]renin receptor: Wnt of change? Kidney International. 2010;**78**(3):246-256

[46] Hennrikus M, Gonzalez AA, Prieto MC. The prorenin receptor in the cardiovascular system and beyond. American Journal of Physiology. Heart and Circulatory Physiology. 2018;**314**(2):H139-H145

[47] Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, et al. Mast cells: A unique source of renin. Proceedings of the National Academy of Sciences of the United States of America. 2004;**101**(37):13607-13612

[48] Dostal DE, Rothblum KN, Conrad KM, Cooper GR, Baker KM. Detection of angiotensin I and II in cultured rat cardiac myocytes and fibroblasts. The American Journal of Physiology. 1992;**263**:C851-C863

[49] Katwa LC, Campbell SE, Tyagi SC, Lee SJ, Cicila GT, Weber KT. Cultured myofibroblasts generate angiotensin peptides de novo. Journal of Molecular and Cellular Cardiology. 1997;**29**:1375-1386

**20**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

composition of fat obtained from human long bones and subcutaneous tissue. Surgery. 1956;**40**(4):661-664

[26] Sherr S, Montemurno R, Raffer P. Lipids of recovered pulmonary fat emboli following trauma. The Journal of

[27] Peltier LF. Fat embolism following intramedullary nailing; report of a fatality. Surgery. 1952;**32**(4):719-722

Trauma. 1974;**14**(3):242-246

[28] Peltier LF. Fat embolism: A pulmonary disease. Surgery.

[29] Peltier LF. Fat embolism. A perspective. Clinical

Orthopaedics and Related Research.

[30] Wang AZ, Ma QX, Zhao HJ, Zhou QH, Jiang W, Sun JZ. A comparative study of the mortality rate of rats receiving a half lethal dose of fat intravenously: Under general anaesthesia versus under spinal anaesthesia. Injury. 2012;**43**(3):311-314

[31] Compton SK, Hamosh M, Hamosh P. Hydrolysis of triglycerides in the isolated perfused rat lung. Lipids.

[32] Szabo G, Magyar Z, Reffy A. The role of free fatty acids in pulmonary fat embolism. Injury. 1977;**8**(4):278-283

[33] McIff TE, Poisner AM, Herndon B, Lankachandra K, Schutt S, Haileselassie B, et al. Fat embolism: Evolution of histopathological changes in the rat lung. Journal of Orthopaedic Research.

[34] Poisner AM, Adler F, Uhal B, McIff TE, Schroeppel JP, Mehrer A, et al. Persistent and progressive pulmonary fibrotic changes in a model of fat embolism. Journal of Trauma and Acute Care Surgery. 2012;**72**(4):992-998

1967;**62**(4):756-758

1988;**232**:263-270

1982;**17**:696-702

2010;**28**(2):191-197

vertebroplasty: An experimental study in sheep. Spine [Phila Pa 1976 ].

Trauma. 2008;**65**(2):416-423

1999;**17**(2):261-268

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[51] Iwai N, Inagami T, Ohmichi N, Kinoshita M. Renin is expressed in rat macrophage/monocyte cells. Hypertension. 1996;**27**:399-403

[52] Gonzalez NC, Allen J, Schmidt EJ, Casillan AJ, Orth T, Wood JG. Role of the renin-angiotensin system in the systemic microvascular inflammation of alveolar hypoxia. American Journal of Physiology. Heart and Circulatory Physiology. 2007;**292**:H2285-H2294

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[54] Chao J, Blanco G, Wood JG, Gonzalez NC. Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia. American Journal of Physiology. Heart and Circulatory Physiology. 2011;**301**(6):H2264-H2270

[55] Garbuzenko E, Berkman N, Puxeddu I, Kramer M, Nagler A, Levi-Schaffer F. Mast cells induce activation of human lung fibroblasts in vitro. Experimental Lung Research. 2004;**30**:705-721

[56] Poisner AM, Hamidpour S, Ho A, Skaria P, Fletcher A, Simon S, et al. Losartan blocks the recruitment of mast cells in the lungs of rats subjected to fat embolism with or without a second hit with LPS. The FASEB Journal. 2016;**30**:700.2

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[59] Hultsch T, Ennis MF, Heidtmann HH. The role of chymase in ionophoreinduced histamine release from human pulmonary mast cells. Advances in Experimental Medicine and Biology. 1988;**240**:133-136

[60] Tainsh KR, Pearce FL. Mast cell heterogeneity: Evidence that mast cells isolated from various connective tissue locations in the rat display markedly graded phenotypes. International Archives of Allergy and Immunology. 1992;**98**(1):26-34

[61] Irani AM, Schwartz LB. Mast cell heterogeneity. Clinical and Experimental Allergy. 1989;**19**(2):143-155

[62] Andersson CK, Mori M, Bjermer L, Lofdahl CG, Erjefalt JS. Novel site-specific mast cell subpopulations in the human lung. Thorax. 2009;**64**(4):297-305

[63] Poisner A, Herndon B, Al Hariri A, Qin C, Quinn T. Renin as a mediator of pulmonary damage caused by fat embolism and LPS. The FASEB Journal. 2013;**27**(1 Supplement):lb444

[64] Hamidpour S, Poisner A, Molteni A, Al-Husseinawi A, Colson J, Samir H, et al. Increased staining for renin/ prorenin in the lungs in a rat model of fat embolism is enhanced by captopril and losartan which ameliorate the pulmonary damage. American Journal of Respiratory and Critical Care Medicine. 2018;**197**:A1859

[65] Das UN. Is angiotensin-II an endogenous pro-inflammatory

**23**

1):155-159

2009;**10**:54

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chronic alveolar hypoxia by inhibition of angiotensin I-converting enzyme in the rat. Laboratory Investigation.

[74] Zakheim RM, Molteni A, Mattioli L, Park M. Plasma angiotensin II levels in hypoxic and hypovolemic stress in unanesthetized rabbits. Journal of Applied Physiology. 1976;**41**(4):462-465

[75] Mizuta K, Zhang Y, Mizuta F, Hoshijima H, Shiga T, Masaki E, et al. Novel identification of the free fatty acid receptor FFAR1 that promotes contraction in airway smooth muscle. American Journal of Physiology. Lung Cellular and Molecular Physiology.

[76] Rohwedder A, Zhang Q, Rudge SA, Wakelam MJ. Lipid droplet formation in response to oleic acid in Huh-7 cells is mediated by the fatty acid receptor FFAR4. Journal of Cell Science. 2014;**127**(Pt 14):3104-3115

[77] Yukioka T, Yukioka N, Aulick LH, Goodwin CW, Mason AD Jr, Sugimoto T, et al. Evaluation of [1-sarcosine, 8-isoleucine] angiotensin II as a therapeutic agent for oleic acidinduced pulmonary edema. Surgery.

[78] Lu G, Meier KE, Jaffa AA, Rosenzweig SA, Egan BM. Oleic acid and angiotensin II induce a synergistic

mitogenic response in vascular smooth muscle cells. Hypertension.

[79] Xiong L, Sun L, Liu S, Zhu X, Teng Z, Yan J. The protective roles of urinary trypsin inhibitor in brain injury following fat embolism syndrome in a rat model. Cell Transplantation.

[80] Kiely DG, Cargill RI, Lipworth BJ. Acute hypoxic pulmonary

vasoconstriction in man is attenuated by type I angiotensin II receptor

2018;**963689718814766**:1-9

2015;**309**(9):L970-L982

1986;**99**(2):235-244

1998;**31**(4):978-985

1975;**33**(1):57-61

*DOI: http://dx.doi.org/10.5772/intechopen.85178*

molecule? Medical Science Monitor.

[66] Karnik SS, Unal H, Kemp JR, Tirupula KC, Eguchi S, Vanderheyden PM, et al. Angiotensin receptors: Interpreters of pathophysiological

[67] Gironacci MM. Angiotensin-[1-7]: Beyond its central effects on blood pressure. Therapeutic Advances in Cardiovascular Disease.

[68] Klein N, Gembardt F, Supe S, Kaestle SM, Nickles H, Erfinanda L, et al. Angiotensin-[1-7] protects from experimental acute lung injury. Critical Care Medicine. 2013;**41**(11):e334-e343

[69] Uhal BD, Nguyen H, Dang M, Gopallawa I, Jiang J, Dang V, et al. Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1-7. American Journal of Physiology-Lung Cellular and Molecular

Physiology. 2013;**305**(1):L33-L41

hypoxia-induced systemic

[70] Gonzalez NC, Wood JG. Alveolar

[71] Dezso B, Nielsen AH, Poulsen K. Identification of renin in resident alveolar macrophages and monocytes: HPLC and immunohistochemical stu. Journal of Cell Science. 1988;**91**(Pt

[72] Chao J, Wood JG, Gonzalez NC. Alveolar hypoxia, alveolar macrophages, and systemic

inflammation. Respiratory Research.

[73] Zakheim RM, Mattioli L, Molteni A, Mullis KB, Bartley J. Prevention of pulmonary vascular changes of

inflammation: What low PO[2] does and does not do. Advances in Experimental Medicine and Biology. 2010;**662**:27-32

2005;**11**(5):RA155-RA162

angiotensinergic stimuli. Pharmacological Reviews. 2015;**67**(4):754-819

2015;**9**(4):209-216

*Fat Embolism: What We Have Learned from Animal Models DOI: http://dx.doi.org/10.5772/intechopen.85178*

molecule? Medical Science Monitor. 2005;**11**(5):RA155-RA162

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

An International Journal of Medicine.

[58] Reilly CF, Tewksbury DA, Schechter NM, Travis J. Rapid conversion of angiotensin I to angiotensin II by neutrophil and mast cell proteinases. The Journal of Biological Chemistry.

[59] Hultsch T, Ennis MF, Heidtmann HH. The role of chymase in ionophoreinduced histamine release from human pulmonary mast cells. Advances in Experimental Medicine and Biology.

[60] Tainsh KR, Pearce FL. Mast cell heterogeneity: Evidence that mast cells isolated from various connective tissue locations in the rat display markedly graded phenotypes. International Archives of Allergy and Immunology.

[61] Irani AM, Schwartz LB. Mast cell heterogeneity. Clinical and Experimental Allergy.

[62] Andersson CK, Mori M, Bjermer L, Lofdahl CG, Erjefalt JS. Novel site-specific mast cell subpopulations

[63] Poisner A, Herndon B, Al Hariri A, Qin C, Quinn T. Renin as a mediator of pulmonary damage caused by fat embolism and LPS. The FASEB Journal.

[64] Hamidpour S, Poisner A, Molteni A, Al-Husseinawi A, Colson J, Samir H, et al. Increased staining for renin/ prorenin in the lungs in a rat model of fat embolism is enhanced by captopril and losartan which ameliorate the pulmonary damage. American Journal of Respiratory and Critical Care Medicine. 2018;**197**:A1859

in the human lung. Thorax.

2013;**27**(1 Supplement):lb444

[65] Das UN. Is angiotensin-II an endogenous pro-inflammatory

2016;**109**(Suppl 1):S48

1982;**257**:8619-8622

1988;**240**:133-136

1992;**98**(1):26-34

1989;**19**(2):143-155

2009;**64**(4):297-305

[50] Iwai N, Matsunaga M, Kita T, Tei M, Kawai C. Regulation of renin-like enzyme in cultured human vascular smooth muscle cells. Japanese

Circulation Journal. 1988;**52**:1338-1345

[52] Gonzalez NC, Allen J, Schmidt EJ, Casillan AJ, Orth T, Wood JG. Role of the renin-angiotensin system in the systemic microvascular inflammation of alveolar hypoxia. American Journal of Physiology. Heart and Circulatory Physiology. 2007;**292**:H2285-H2294

[53] Veerappan A, O'Connor NJ, Brazin J, Reid AC, Jung A, McGee D, et al. Mast cells: A pivotal role in pulmonary fibrosis. DNA and Cell Biology.

[54] Chao J, Blanco G, Wood JG, Gonzalez NC. Renin released from mast cells activated by circulating MCP-1 initiates the microvascular phase of the systemic inflammation of alveolar hypoxia. American Journal of Physiology. Heart and Circulatory Physiology. 2011;**301**(6):H2264-H2270

[55] Garbuzenko E, Berkman N, Puxeddu I, Kramer M, Nagler A, Levi-Schaffer F. Mast cells induce activation of human lung fibroblasts in vitro. Experimental Lung Research.

[56] Poisner AM, Hamidpour S, Ho A, Skaria P, Fletcher A, Simon S, et al. Losartan blocks the recruitment of mast cells in the lungs of rats subjected to fat embolism with or without a second hit with LPS. The FASEB Journal.

[57] Kesh S, Fletcher A, Voelker P, Guidos P, Poisner A, Tylski E, et al. Aliskiren, a direct renin inhibitor, reduces mast cell accumulation in lungs of rats after fat embolism. Q JM:

2013;**32**(4):206-218

2004;**30**:705-721

2016;**30**:700.2

[51] Iwai N, Inagami T, Ohmichi N, Kinoshita M. Renin is expressed in rat macrophage/monocyte cells. Hypertension. 1996;**27**:399-403

**22**

[66] Karnik SS, Unal H, Kemp JR, Tirupula KC, Eguchi S, Vanderheyden PM, et al. Angiotensin receptors: Interpreters of pathophysiological angiotensinergic stimuli. Pharmacological Reviews. 2015;**67**(4):754-819

[67] Gironacci MM. Angiotensin-[1-7]: Beyond its central effects on blood pressure. Therapeutic Advances in Cardiovascular Disease. 2015;**9**(4):209-216

[68] Klein N, Gembardt F, Supe S, Kaestle SM, Nickles H, Erfinanda L, et al. Angiotensin-[1-7] protects from experimental acute lung injury. Critical Care Medicine. 2013;**41**(11):e334-e343

[69] Uhal BD, Nguyen H, Dang M, Gopallawa I, Jiang J, Dang V, et al. Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1-7. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2013;**305**(1):L33-L41

[70] Gonzalez NC, Wood JG. Alveolar hypoxia-induced systemic inflammation: What low PO[2] does and does not do. Advances in Experimental Medicine and Biology. 2010;**662**:27-32

[71] Dezso B, Nielsen AH, Poulsen K. Identification of renin in resident alveolar macrophages and monocytes: HPLC and immunohistochemical stu. Journal of Cell Science. 1988;**91**(Pt 1):155-159

[72] Chao J, Wood JG, Gonzalez NC. Alveolar hypoxia, alveolar macrophages, and systemic inflammation. Respiratory Research. 2009;**10**:54

[73] Zakheim RM, Mattioli L, Molteni A, Mullis KB, Bartley J. Prevention of pulmonary vascular changes of

chronic alveolar hypoxia by inhibition of angiotensin I-converting enzyme in the rat. Laboratory Investigation. 1975;**33**(1):57-61

[74] Zakheim RM, Molteni A, Mattioli L, Park M. Plasma angiotensin II levels in hypoxic and hypovolemic stress in unanesthetized rabbits. Journal of Applied Physiology. 1976;**41**(4):462-465

[75] Mizuta K, Zhang Y, Mizuta F, Hoshijima H, Shiga T, Masaki E, et al. Novel identification of the free fatty acid receptor FFAR1 that promotes contraction in airway smooth muscle. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2015;**309**(9):L970-L982

[76] Rohwedder A, Zhang Q, Rudge SA, Wakelam MJ. Lipid droplet formation in response to oleic acid in Huh-7 cells is mediated by the fatty acid receptor FFAR4. Journal of Cell Science. 2014;**127**(Pt 14):3104-3115

[77] Yukioka T, Yukioka N, Aulick LH, Goodwin CW, Mason AD Jr, Sugimoto T, et al. Evaluation of [1-sarcosine, 8-isoleucine] angiotensin II as a therapeutic agent for oleic acidinduced pulmonary edema. Surgery. 1986;**99**(2):235-244

[78] Lu G, Meier KE, Jaffa AA, Rosenzweig SA, Egan BM. Oleic acid and angiotensin II induce a synergistic mitogenic response in vascular smooth muscle cells. Hypertension. 1998;**31**(4):978-985

[79] Xiong L, Sun L, Liu S, Zhu X, Teng Z, Yan J. The protective roles of urinary trypsin inhibitor in brain injury following fat embolism syndrome in a rat model. Cell Transplantation. 2018;**963689718814766**:1-9

[80] Kiely DG, Cargill RI, Lipworth BJ. Acute hypoxic pulmonary vasoconstriction in man is attenuated by type I angiotensin II receptor

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**25**

**Chapter 3**

**Abstract**

Non-Malignant Cardiac Tumors

Cardiac tumors represent an unusual clinical problem in that they are often discovered as an incidental finding during a routine echocardiogram or in the course of a work-up for a source of embolism. Malignant tumors of the heart are either defined as primary or metastatic from an extra-cardiac primary source regardless, the prognosis is poor. However, there are several cardiac tumors that are characterized as being non-malignant with regard to their tumor biology, but their tendencies to cause embolic or obstructive complications can be just as catastrophic despite a lack of invasiveness or potential to metastasize. The purpose of this chapter is to review the common types of non-malignant cardiac tumors with regard to their incidence, presentation, potential for complications, and management—with

**Keywords:** cardiac tumor, myxoma, fibroelastoma, cardiac surgery, benign tumors,

Embolic strokes are one of the most devastating medical conditions with regard to the overall impact on quality and quantity of life. Once an embolic complication occurs, management options are sometimes limited, but a critical aspect of appropriate disease management is searching for a source of embolism. The same concepts hold true with peripheral embolisms. Part of the rationale for the search for a source is to help determine optimal therapies with the goal of reducing addition embolic events and further complications. Despite substantial resources devoted to

stroke (and embolic) prevention, it still remains a considerable problem.

The focus of this chapter is non-malignant and non-infectious cardiac masses—with an emphasis on diagnosis and management. Cardiac tumors are often

endocarditis—a topic that is the focus of other chapters [4].

A recent report by the American Heart Association illustrates the enormous burden that strokes represent to society. A cerebrovascular event (i.e., a stroke) occurs every 40 seconds in the United States with a related death occurring every 3.7 minutes [1]. While the causes of strokes are complex and often multi-factorial, cardiac sources represent a common etiology. Atrial fibrillation and associated left atrial appendage thrombi are one of the more frequently encountered sources [2]. Even though mechanical left atrial appendage closure or systemic anticoagulation remain the standard of care for treatment [3], it is important to consider that there are a variety of other cardiac-related causes of embolism and stroke. The most common non-thrombotic causes of cardiac embolism are infectious and non-infectious

*Sarah Eapen, Bethany Malone, Jennifer Hanna*

*and Michael S. Firstenberg*

emphasis on surgical indications and techniques.

cardiac lipomas, heart disease

**1. Introduction**

### **Chapter 3**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

of the renin-angiotensin system prevents free fatty acid-induced acute endothelial dysfunction in humans. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;**25**(11):2376-2380

[89] Leeman M, Lejeune P, Naeije R. Inhibition of angiotensin-converting enzyme by perindopril diacid in canine oleic acid pulmonary edema. Critical Care Medicine. 1987;**15**(6):567-573

[90] Bruce E, Shenoy V,

2015;**172**(9):2219-2231

1985;**92**(3):370-374

2009;**41**(1):14-20

Care. 2018;**7813175**

2018;**19**(3):876-879

Rathinasabapathy A, Espejo A, Horowitz A, Oswalt A, et al. Selective

activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis. British Journal of Pharmacology.

[91] Chuang EL, Miller FS, Kalina RE. Retinal lesions following long bone fractures. Ophthalmology.

[92] Lee JE, Jea SY, Oum BS, Kim HJ, Ohn YH. Effect of fat embolism with triolein emulsion on bloodretinal barrier. Ophthalmic Research.

[93] Choudhary R, Kapoor MS, Singh A, Bodakhe SH. Therapeutic targets of renin-angiotensin system in ocular disorders. Journal of Current Ophthalmology. 2017;**29**(1):7-16

[94] Berlot G, Bussani R, Shafiei V, Zarrillo N. Fulminant cerebral fat embolism: Case description and review of the literature. Case Reports in Critical

[95] Jackson L, Eldahshan W, Fagan SC, Ergul A. Within the brain: The renin angiotensin system. International

Journal of Molecular Sciences.

blockade. Cardiovascular Research.

[81] Coonrod JD, Karathanasis P, Lin R. Lipoprotein lipase: A source of free fatty acids in bronchoalveolar lining fluid. Journal of Laboratory and Clinical

Medicine. 1989;**113**(4):449-457

[82] Gal S, Bassett DJ, Hamosh M, Hamosh P. Triacylglycerol hyrolysis in the isolated, perfused rat lung. Biochimica et Biophysica Acta.

[83] Okabe TF, Yorifuji HF, Murase TF, Takaku F. Pulmonary macrophage: A major source of lipoprotein lipase in the lung. Biochemical and Biophysical Research Communications.

[84] Re RN, Cook JL. The mitochondrial

[85] Hirabara SM, Silveira LR, Alberici LC, Leandro CV, Lambertucci RH, Polimeno GC, et al. Acute effect of fatty acids on metabolism and mitochondrial coupling in skeletal muscle. Biochimica et Biophysica Acta. 2006;**1757**(1):57-66

[86] Azekoshi Y, Yasu T, Watanabe S, Tagawa T, Abe S, Yamakawa K, et al. Free fatty acid causes leukocyte activation and resultant endothelial dysfunction through enhanced angiotensin II production in mononuclear and polymorphonuclear cells. Hypertension. 2010;**56**(1):136-142

[87] Shimokawa Y, Hirata K, Ishida T, Kojima Y, Inoue N, Quertermous T, et al. Increased expression of endothelial lipase in rat models of hypertension. Cardiovascular Research.

[88] Watanabe S, Tagawa T, Yamakawa K, Shimabukuro M, Ueda S. Inhibition

2005;**66**(3):594-600

component of intracrine action. American Journal of Physiology. Heart and Circulatory Physiology.

2010;**299**(3):H577-H583

1995;**30**:875-880

1982;**713**:222-229

1984;**125**:273-278

**24**

## Non-Malignant Cardiac Tumors

*Sarah Eapen, Bethany Malone, Jennifer Hanna and Michael S. Firstenberg*

### **Abstract**

Cardiac tumors represent an unusual clinical problem in that they are often discovered as an incidental finding during a routine echocardiogram or in the course of a work-up for a source of embolism. Malignant tumors of the heart are either defined as primary or metastatic from an extra-cardiac primary source regardless, the prognosis is poor. However, there are several cardiac tumors that are characterized as being non-malignant with regard to their tumor biology, but their tendencies to cause embolic or obstructive complications can be just as catastrophic despite a lack of invasiveness or potential to metastasize. The purpose of this chapter is to review the common types of non-malignant cardiac tumors with regard to their incidence, presentation, potential for complications, and management—with emphasis on surgical indications and techniques.

**Keywords:** cardiac tumor, myxoma, fibroelastoma, cardiac surgery, benign tumors, cardiac lipomas, heart disease

### **1. Introduction**

Embolic strokes are one of the most devastating medical conditions with regard to the overall impact on quality and quantity of life. Once an embolic complication occurs, management options are sometimes limited, but a critical aspect of appropriate disease management is searching for a source of embolism. The same concepts hold true with peripheral embolisms. Part of the rationale for the search for a source is to help determine optimal therapies with the goal of reducing addition embolic events and further complications. Despite substantial resources devoted to stroke (and embolic) prevention, it still remains a considerable problem.

A recent report by the American Heart Association illustrates the enormous burden that strokes represent to society. A cerebrovascular event (i.e., a stroke) occurs every 40 seconds in the United States with a related death occurring every 3.7 minutes [1]. While the causes of strokes are complex and often multi-factorial, cardiac sources represent a common etiology. Atrial fibrillation and associated left atrial appendage thrombi are one of the more frequently encountered sources [2]. Even though mechanical left atrial appendage closure or systemic anticoagulation remain the standard of care for treatment [3], it is important to consider that there are a variety of other cardiac-related causes of embolism and stroke. The most common non-thrombotic causes of cardiac embolism are infectious and non-infectious endocarditis—a topic that is the focus of other chapters [4].

The focus of this chapter is non-malignant and non-infectious cardiac masses—with an emphasis on diagnosis and management. Cardiac tumors are often delineated as malignant and non-malignant with malignant tumors being either primary (i.e., cardiac sarcomas) or metastatic (i.e., breast carcinoma). They are distinguished from non-malignant tumors, such as myxomas and fibroelastomas, in that the latter, despite the pathologic implications of growth (i.e., valvular obstruction) and systemic embolism, lack true metastatic potential. Nevertheless, non-malignant cardiac tumors can be clinically devastating (i.e., malignant) by their tendency to cause potentially devastating, and occasionally fatal, embolic complications [5].

### **2. Methods**

The focus of this review is on non-malignant tumors. The review methods consisted of Google Scholar (https://scholar.google.com) and PubMed (https:// www.ncbi.nlm.nih.gov/pmc/) searches with emphasis on the following key words: cardiac tumors, benign cardiac masses, myxomas, fibroelastomas, and fibromas. Additional associated search terms included: surgery, diagnosis, imaging, and management. Selected references, including manuscript abstracts and full texts, were reviewed for relevance in the context of this review.

### **3. Myxomas**

Cardiac tumors are rare, occurring at a frequency of 0.0017–0.33% [6]. Cardiac myxomas are one of the most common, comprising 77% of surgically excised tumors in autopsy series [7]. Myxomas affect females predominantly with an incidence 1.5–2 times that of males [8]. The average age at presentation is 53 [8]. The majority of myxomas are sporadic. Inherited forms are less common, seen in 7% of myxomas [9]. Initially reported by Carney in 1985, cardiac myxomas seen in association with pigmented skin lesions and endocrine tumors are collectively known as Carney complex, an autosomal dominant genetic disorder. Familial myxomas tend to affect younger patients and have a higher prevalence among females. In addition, they are more often multicentric with higher rates of embolism and recurrence following resection [9].

Myxomas tend to be rare tumors of mesenchymal origin. They are comprised of stromal cells and are characterized as being benign (**Figure 1**). Biochemically, they

#### **Figure 1.**

*Histology of cardiac myxoma. Representative histology of cardiac myxoma tissue in a 26-year-old woman with multiple recurrences of cardiac myxoma (HE, 100×). A: Tumor in 2005. B: Tumor in 2010. Similar histologic appearance of A and B with irregular and papillary proliferations in the myxoid stroma. Bar = 30 μm [10].*

**27**

**Figure 2.**

*Non-Malignant Cardiac Tumors*

*DOI: http://dx.doi.org/10.5772/intechopen.86944*

have been correlated with increased production of interleukin 6 (IL-6), however, the significance of this is unclear [11]. While ocular, cutaneous, intramuscular, and juxta-articular involvement has been described, the most common presentation is

Cardiac myxomas are typically solitary lesions and most commonly arise from the septal endocardium near the fossa ovalis [8]. 85% arise from the left atrial septum and 11% arise from the right atrial septum [7]. The clinical presentation of myxomas is dependent on tumor location. When confined to the left atrium, myxomas present with symptoms of mitral valve stenosis [13]. Dyspnea and orthopnea result from pulmonary edema and left-sided heart failure. Conversely, right atrial myxomas cause tricuspid valve stenosis, leading to symptoms of right-sided heart failure [13]. In 22% of patients, embolism may occur, leading to symptoms of peripheral ischemia or stroke [8]. 20% of patients develop systemic symptoms, which are attributed to production of IL-6 by tumor cells [14]. Rarely, myxomas may become infected with symptoms similar to those of infective endocarditis [13]. Echocardiography is the primary diagnostic modality for cardiac myxomas [15]. Typical echocardiographic findings are of a mobile mass arising from the septal endocardium, attached by a narrow stalk. Echocardiography is preferred to MRI and CT imaging due to enhanced spatial and temporal resolution. If echocardiography is non-diagnostic, MRI findings of a heterogeneous mass bright on T2-weighted imaging and CT findings of a heterogeneous mass with low attenuation are consistent with myxoma (**Figures 2** and **3**) [15]. Advanced imaging is often performed to help differentiate "benign" myxomas from more aggressive or potentially malignant cardiac tumors that might require a more comprehensive oncologic management strategy (i.e., aggressive debulking, adjuvant chemotherapy, or even palliative care for advanced tumors). While the imaging characteristics, as described above, of myxomas are often diagnostic, unusual appearing masses might prompt further imaging to rule-out other tissue types. The differential diagnosis for such masses includes teratomas (rare), lipomas, angiosarcomas, rhabdomyomas, and rhabdomyosarcomas [18]. Distinguishing characteristics often consist of intramyocardial tumor invasion on imaging. Tissue biopsy is rarely indicated as the risk of embolism from endomyocardial biopsies will typically prompt definitive surgical resection for primary diagnosis and therapeutic intervention. Tumor location and imaging characteristics, along with a detailed history and physical, can also help distinguish cardiac tumors from other types of intra-cardiac pathology, such as endocarditis or thrombus. A recent history of acute myocardial infarction or known left ventricular

*Representative echocardiographic images of a large left atrial myxoma. From: Surgical resection of cardiac myxoma. Images of a rapidly growing myxoma. (a): A small myxoma is attached to the left atrial side of the fossa ovalis. (b): An enlarged myxoma passes in and out of the mitral valve according to the cardiac cycle [16].*

intra-cardiac with most (85%) involving the left atrium [12].

#### *Non-Malignant Cardiac Tumors DOI: http://dx.doi.org/10.5772/intechopen.86944*

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

were reviewed for relevance in the context of this review.

complications [5].

**2. Methods**

**3. Myxomas**

following resection [9].

delineated as malignant and non-malignant with malignant tumors being either primary (i.e., cardiac sarcomas) or metastatic (i.e., breast carcinoma). They are distinguished from non-malignant tumors, such as myxomas and fibroelastomas, in that the latter, despite the pathologic implications of growth (i.e., valvular obstruction) and systemic embolism, lack true metastatic potential. Nevertheless, non-malignant cardiac tumors can be clinically devastating (i.e., malignant) by their tendency to cause potentially devastating, and occasionally fatal, embolic

The focus of this review is on non-malignant tumors. The review methods consisted of Google Scholar (https://scholar.google.com) and PubMed (https:// www.ncbi.nlm.nih.gov/pmc/) searches with emphasis on the following key words: cardiac tumors, benign cardiac masses, myxomas, fibroelastomas, and fibromas. Additional associated search terms included: surgery, diagnosis, imaging, and management. Selected references, including manuscript abstracts and full texts,

Cardiac tumors are rare, occurring at a frequency of 0.0017–0.33% [6]. Cardiac

Myxomas tend to be rare tumors of mesenchymal origin. They are comprised of stromal cells and are characterized as being benign (**Figure 1**). Biochemically, they

*Histology of cardiac myxoma. Representative histology of cardiac myxoma tissue in a 26-year-old woman with multiple recurrences of cardiac myxoma (HE, 100×). A: Tumor in 2005. B: Tumor in 2010. Similar histologic appearance of A and B with irregular and papillary proliferations in the myxoid stroma. Bar = 30 μm [10].*

myxomas are one of the most common, comprising 77% of surgically excised tumors in autopsy series [7]. Myxomas affect females predominantly with an incidence 1.5–2 times that of males [8]. The average age at presentation is 53 [8]. The majority of myxomas are sporadic. Inherited forms are less common, seen in 7% of myxomas [9]. Initially reported by Carney in 1985, cardiac myxomas seen in association with pigmented skin lesions and endocrine tumors are collectively known as Carney complex, an autosomal dominant genetic disorder. Familial myxomas tend to affect younger patients and have a higher prevalence among females. In addition, they are more often multicentric with higher rates of embolism and recurrence

**26**

**Figure 1.**

have been correlated with increased production of interleukin 6 (IL-6), however, the significance of this is unclear [11]. While ocular, cutaneous, intramuscular, and juxta-articular involvement has been described, the most common presentation is intra-cardiac with most (85%) involving the left atrium [12].

Cardiac myxomas are typically solitary lesions and most commonly arise from the septal endocardium near the fossa ovalis [8]. 85% arise from the left atrial septum and 11% arise from the right atrial septum [7]. The clinical presentation of myxomas is dependent on tumor location. When confined to the left atrium, myxomas present with symptoms of mitral valve stenosis [13]. Dyspnea and orthopnea result from pulmonary edema and left-sided heart failure. Conversely, right atrial myxomas cause tricuspid valve stenosis, leading to symptoms of right-sided heart failure [13]. In 22% of patients, embolism may occur, leading to symptoms of peripheral ischemia or stroke [8]. 20% of patients develop systemic symptoms, which are attributed to production of IL-6 by tumor cells [14]. Rarely, myxomas may become infected with symptoms similar to those of infective endocarditis [13].

Echocardiography is the primary diagnostic modality for cardiac myxomas [15]. Typical echocardiographic findings are of a mobile mass arising from the septal endocardium, attached by a narrow stalk. Echocardiography is preferred to MRI and CT imaging due to enhanced spatial and temporal resolution. If echocardiography is non-diagnostic, MRI findings of a heterogeneous mass bright on T2-weighted imaging and CT findings of a heterogeneous mass with low attenuation are consistent with myxoma (**Figures 2** and **3**) [15]. Advanced imaging is often performed to help differentiate "benign" myxomas from more aggressive or potentially malignant cardiac tumors that might require a more comprehensive oncologic management strategy (i.e., aggressive debulking, adjuvant chemotherapy, or even palliative care for advanced tumors). While the imaging characteristics, as described above, of myxomas are often diagnostic, unusual appearing masses might prompt further imaging to rule-out other tissue types. The differential diagnosis for such masses includes teratomas (rare), lipomas, angiosarcomas, rhabdomyomas, and rhabdomyosarcomas [18]. Distinguishing characteristics often consist of intramyocardial tumor invasion on imaging. Tissue biopsy is rarely indicated as the risk of embolism from endomyocardial biopsies will typically prompt definitive surgical resection for primary diagnosis and therapeutic intervention. Tumor location and imaging characteristics, along with a detailed history and physical, can also help distinguish cardiac tumors from other types of intra-cardiac pathology, such as endocarditis or thrombus. A recent history of acute myocardial infarction or known left ventricular

#### **Figure 2.**

*Representative echocardiographic images of a large left atrial myxoma. From: Surgical resection of cardiac myxoma. Images of a rapidly growing myxoma. (a): A small myxoma is attached to the left atrial side of the fossa ovalis. (b): An enlarged myxoma passes in and out of the mitral valve according to the cardiac cycle [16].*

#### **Figure 3.**

*Representative cardiac MRI demonstrating a right atrial myxoma. Right atrial myxoma causing syncope. A: Cardiac MRI showing atrial myxoma during systole. B: Cardiac MRI showing atrial myxoma during diastole. RA, Right atrium; RV, Right ventricle; LA, Left atrium; LV, Left ventricle; arrow—Myxoma [17].*

dysfunction might predispose to apical thrombus just as a history of atrial fibrillation is known to predispose to left atrial or left atrial appendage thrombus [19, 20].

Histologically, myxomas are composed of stellate mesenchymal cells in a background of myxoid stroma. Myxoma cells are variably positive for S-100, CD31, and CD34 [13]. In addition, 73.9% of cardiac myxomas express calretinin [21]. Inactivating mutations in the PRKAR1A gene are observed in both sporadic and non-sporadic myxomas. For this reason, routine immunohistochemical staining for PRKAR1A is recommended [22].

Recommended treatment for suspected cardiac myxomas, regardless of size, is immediate surgical resection due to embolic risk [23]. Tumor size ≥ 4.5 cm and soft tumors have been identified as independent risk factors for embolism. Prognosis is favorable with a 92.7% 10-year survival rate following surgical resection. Tumor recurrence is extremely rare. Multicentricity, observed with Carney complex, is an independent risk factor for recurrence following surgical resection [23]. Recurrence has been associated with incomplete resection and family history of complex or multiple myxomas [24]. In general, recurrence rates are typically less than 3%, often in complex or unusual cases [25].

### **4. Papillary fibroelastomas**

Papillary fibroelastomas comprise less than 10% of primary cardiac tumors and are the most common primary tumor of cardiac valves (**Figure 4**) [14]. Men and women are affected equally at an average age of 60. Fibroelastomas are now thought to be more prevalent than myxomas, contradicting previous autopsy series in which myxomas were the most common primary intracardiac tumor [26]. Their etiology is unclear with development related to organizing thrombi, hamartoma proliferation, chronic viral endocarditis, and repeated hemodynamic trauma [27]. Iatrogenic cases of fibroelastomas following thoracic radiation and cardiac surgery have also been described, though these are typically non-valvular [28]. Fibroelastomas are valvular in 90% of cases, most commonly involving the aortic and mitral valves [29]. Less commonly, the left ventricular endocardium and tricuspid valves are affected [15]. Diseased valves are affected in 69.5% of cases, specifically post-rheumatic valves in 37.8% and fibrotic calcified valves in 62.2%. This finding has led some to speculate that a contributing factor to their development is repeated trauma to the cardiac valve surface from abnormal intra-cardiac blood flow and turbulence [13].

**29**

*Non-Malignant Cardiac Tumors*

**Figure 4.**

**Figure 5.**

*bypass surgery.*

*DOI: http://dx.doi.org/10.5772/intechopen.86944*

Clinically, fibroelastomas may present with acute embolism following platelet and fibrin aggregation [8]. Alternatively, prolapse of fibroelastomas adjacent to coronary ostia may lead to angina, syncope, and sudden death. The diagnosis is made by echocardiography, which demonstrates a small, homogenous mobile mass attached to a valve by a short pedicle [15]. They have characteristic papillary fronds and resemble sea anemones (**Figure 5**) [31]. These papillary projections give fibroelastomas characteristic stippled edges on echocardiographic imaging [32]. Fibroelastomas may be mistaken for Lambl's excrescences, which are mobile frondlike lesions that occur along lines of valve closure [33]. Interestingly, there have been some anecdotal reports of spontaneous regression. For this reason, intraoperative transesophageal echocardiography is clearly indicated prior to surgical intervention [34]. However, these reports should not be used to advocate non-operative management except in very high-risk patients. In addition, there is no evidence to suggest a role for anti-platelet or anti-coagulation therapy as a means of treatment or secondary prevention once an embolic complication occurs. Nevertheless, in

*Photomicrograph of a fibroelastoma. Photomicrograph of papillary fibroelastoma. From: Robotic excision of* 

*aortic valve papillary fibroelastoma and concomitant maze procedure [30].*

*Surgical specimen of a fibroelastoma. Surgical specimen of an incidental 5 mm fibroelastoma found during routine intra-operative transesophageal echocardiography in a patient undergoing routine coronary artery* 

#### **Figure 4.**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

PRKAR1A is recommended [22].

**Figure 3.**

often in complex or unusual cases [25].

**4. Papillary fibroelastomas**

blood flow and turbulence [13].

dysfunction might predispose to apical thrombus just as a history of atrial fibrillation is known to predispose to left atrial or left atrial appendage thrombus [19, 20]. Histologically, myxomas are composed of stellate mesenchymal cells in a background of myxoid stroma. Myxoma cells are variably positive for S-100, CD31, and CD34 [13]. In addition, 73.9% of cardiac myxomas express calretinin [21]. Inactivating mutations in the PRKAR1A gene are observed in both sporadic and non-sporadic myxomas. For this reason, routine immunohistochemical staining for

*Representative cardiac MRI demonstrating a right atrial myxoma. Right atrial myxoma causing syncope. A: Cardiac MRI showing atrial myxoma during systole. B: Cardiac MRI showing atrial myxoma during diastole. RA, Right atrium; RV, Right ventricle; LA, Left atrium; LV, Left ventricle; arrow—Myxoma [17].*

Recommended treatment for suspected cardiac myxomas, regardless of size, is immediate surgical resection due to embolic risk [23]. Tumor size ≥ 4.5 cm and soft tumors have been identified as independent risk factors for embolism. Prognosis is favorable with a 92.7% 10-year survival rate following surgical resection. Tumor recurrence is extremely rare. Multicentricity, observed with Carney complex, is an independent risk factor for recurrence following surgical resection [23]. Recurrence has been associated with incomplete resection and family history of complex or multiple myxomas [24]. In general, recurrence rates are typically less than 3%,

Papillary fibroelastomas comprise less than 10% of primary cardiac tumors and are the most common primary tumor of cardiac valves (**Figure 4**) [14]. Men and women are affected equally at an average age of 60. Fibroelastomas are now thought to be more prevalent than myxomas, contradicting previous autopsy series in which myxomas were the most common primary intracardiac tumor [26]. Their etiology is unclear with development related to organizing thrombi, hamartoma proliferation, chronic viral endocarditis, and repeated hemodynamic trauma [27]. Iatrogenic cases of fibroelastomas following thoracic radiation and cardiac surgery have also been described, though these are typically non-valvular [28]. Fibroelastomas are valvular in 90% of cases, most commonly involving the aortic and mitral valves [29]. Less commonly, the left ventricular endocardium and tricuspid valves are affected [15]. Diseased valves are affected in 69.5% of cases, specifically post-rheumatic valves in 37.8% and fibrotic calcified valves in 62.2%. This finding has led some to speculate that a contributing factor to their development is repeated trauma to the cardiac valve surface from abnormal intra-cardiac

**28**

*Surgical specimen of a fibroelastoma. Surgical specimen of an incidental 5 mm fibroelastoma found during routine intra-operative transesophageal echocardiography in a patient undergoing routine coronary artery bypass surgery.*

#### **Figure 5.**

*Photomicrograph of a fibroelastoma. Photomicrograph of papillary fibroelastoma. From: Robotic excision of aortic valve papillary fibroelastoma and concomitant maze procedure [30].*

Clinically, fibroelastomas may present with acute embolism following platelet and fibrin aggregation [8]. Alternatively, prolapse of fibroelastomas adjacent to coronary ostia may lead to angina, syncope, and sudden death. The diagnosis is made by echocardiography, which demonstrates a small, homogenous mobile mass attached to a valve by a short pedicle [15]. They have characteristic papillary fronds and resemble sea anemones (**Figure 5**) [31]. These papillary projections give fibroelastomas characteristic stippled edges on echocardiographic imaging [32]. Fibroelastomas may be mistaken for Lambl's excrescences, which are mobile frondlike lesions that occur along lines of valve closure [33]. Interestingly, there have been some anecdotal reports of spontaneous regression. For this reason, intraoperative transesophageal echocardiography is clearly indicated prior to surgical intervention [34]. However, these reports should not be used to advocate non-operative management except in very high-risk patients. In addition, there is no evidence to suggest a role for anti-platelet or anti-coagulation therapy as a means of treatment or secondary prevention once an embolic complication occurs. Nevertheless, in

patients who are not surgical candidates, such medical therapy might be reasonable. In theory, very small tumors could be drawn into the cardiopulmonary bypass circuit or surgical suction prior to excision precluding pathologic evaluation. In such cases, pre- and post-bypass imaging is critical to not only confirm the diagnosis, but also to demonstrate resection.

Although transthoracic echocardiography can be used to screen for papillary fibroelastomas, transesophageal echocardiography is preferred due to higher resolution and enhanced imaging capability (**Figure 6**) [36]. Multiplanar transesophageal echocardiography identifies the exact point of endocardial attachment, which facilitates operative planning. One of the limitations of echocardiography is its inability to stratify risk of embolization based on lesion characteristics [37]. Fibroelastomas are usually not visualized on MRI and CT imaging [15]. Histologically, fibroelastomas have a central core of dense connective tissue, which is surrounded by loose connective tissue and lined with hyperplastic endothelial cells [31]. These surface endothelial cells express vimentin and CD34. These findings have unclear clinical significance, but are helpful in establishing a pathologic diagnosis [13].

Surgical resection sparing underlying valve tissue is recommended in cases of papillary fibroelastoma. In a study of 511 cases over a 15-year period at the Mayo Clinic, 185 patients (36.2%) underwent surgical resection [37]. Primary excision was performed in 51% while excision as an adjunct to other cardiac surgery was performed in 49%. The aortic valve was most commonly affected and in 98% of cases, the native valve was preserved. Three hundred and twenty-six patients (63.8%) with echocardiographic findings of papillary fibroelastoma were managed non-operatively. Patients with papillary fibroelastoma suspected on echocardiography who did not undergo surgical resection had higher rates of stroke and mortality [37].

In the above described Mayo Clinic operative series, there was a 98% native valve preservation rate and 1.6% recurrence rate. Most importantly were their neurologic embolic outcomes. For the surgical population, the stroke risk was 2% at 1 year and 8% at 5 years. This rate was approximately 2.5x age-matched controlled. For the medically managed patients, the 1- and 5-year stroke risk was significantly higher than the operative group at 6 and 13%, respectively. There were 29 observed strokes versus 8.4 expected. Obviously, it was difficult to determine the impact of confounding risk factors that might have increased the stroke risk in patients who were otherwise poor surgical candidates. Regardless, the incidence was still nearly 3.5× that of matched controls. Furthermore, in the non-operative group, medical management with anti-thrombotic therapy (i.e., anti-platelet and anti-coagulant therapy, including dual therapy) had no impact on the stroke risk at 5 years when compared

#### **Figure 6.**

*Echocardiographic imaging of a fibroelastoma. Fibroelastoma of the aortic valve. Short and long axis view transesophageal echocardiography. From: Surgery for cardiac papillary fibroelastoma: A 12-year single institution experience [35].*

**31**

**Figure 7.**

*FE: Fibroelastoma. \**

*anti-coagulant therapy in this population.*

*Non-Malignant Cardiac Tumors*

embolic complications.

*DOI: http://dx.doi.org/10.5772/intechopen.86944*

survival at a mean follow-up of 4.2 years [40].

to those without anti-thrombotic therapy [37]. Overall, the authors did not find any echocardiographic or clinical variables that helped stratify patients into high- or low-risk groups for embolic complications. The significant increased stroke risk in the non-operative group (even when matched for age-adjusted controls) and the lack of benefit of medical therapies serve as contemporary evidence to justify surgical management as first-line therapy in appropriate risk-stratified patients (**Figure 7**). Surgical intervention for papillary fibroelastoma should be considered in patients who are symptomatic, undergoing cardiac surgery for other reasons, or have large, highly mobile lesions [38]. Further study through randomized controlled, multicenter trials is needed to determine if the potential benefit of surgical resection outweighs risk in asymptomatic patients. In asymptomatic patients who are otherwise good surgical candidates, the decision for non-operative management should be well-documented as part of shared decision-making with the patients with emphasis on the theoretical risks and benefits of surgery versus the risks of

In another single-center review, there was a tendency for occurrence in elderly males (71% males and 57% older than 61 years of age). Most (72%) occurred on a cardiac valve. Rarely was more than 1 lesion encountered and rarely were they >1.5 cm in size (27.8%). Surgical management was uncomplicated in all cases, even though some patients required concomitant surgery (i.e., coronary artery bypass grafting), and 30-day survival was 100%. No recurrences were reported at 1-year follow-up [39]. Similar outcomes were reported from another large-volume program in which Mkalaluh and colleagues reported 0 peri-operative mortalities in 11 patients (7 of whom had valvular involvement) with 100% 1-year survival and 91%

The indications for surgical resection are often a function of presentation and whether the patient is an appropriate surgical candidate. Since many fibroelastomas are incidental findings and hence asymptomatic, the natural history is unclear even though their tendency to embolize as pedunculated masses is unpredictable. For this reason, in appropriate surgical candidates, the presence of a presumed fibroelastoma is often an indication for surgical management, especially with left-sided

*Proposed algorithm for left-sided possible fibroelastoma. Legend: Adopted from Tamin et al. [37].* 

*Note: there is little evidence to support the overall recommendation for anti-platelet or* 

#### *Non-Malignant Cardiac Tumors DOI: http://dx.doi.org/10.5772/intechopen.86944*

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

also to demonstrate resection.

patients who are not surgical candidates, such medical therapy might be reasonable. In theory, very small tumors could be drawn into the cardiopulmonary bypass circuit or surgical suction prior to excision precluding pathologic evaluation. In such cases, pre- and post-bypass imaging is critical to not only confirm the diagnosis, but

Although transthoracic echocardiography can be used to screen for papillary fibroelastomas, transesophageal echocardiography is preferred due to higher resolution and enhanced imaging capability (**Figure 6**) [36]. Multiplanar transesophageal echocardiography identifies the exact point of endocardial attachment, which facilitates operative planning. One of the limitations of echocardiography is its inability to stratify risk of embolization based on lesion characteristics [37]. Fibroelastomas are usually not visualized on MRI and CT imaging [15]. Histologically, fibroelastomas have a central core of dense connective tissue, which is surrounded by loose connective tissue and lined with hyperplastic endothelial cells [31]. These surface endothelial cells express vimentin and CD34. These findings have unclear clinical

Surgical resection sparing underlying valve tissue is recommended in cases of papillary fibroelastoma. In a study of 511 cases over a 15-year period at the Mayo Clinic, 185 patients (36.2%) underwent surgical resection [37]. Primary excision was performed in 51% while excision as an adjunct to other cardiac surgery was performed in 49%. The aortic valve was most commonly affected and in 98% of cases, the native valve was preserved. Three hundred and twenty-six patients (63.8%) with echocardiographic findings of papillary fibroelastoma were managed non-operatively. Patients with papillary fibroelastoma suspected on echocardiography who did not

In the above described Mayo Clinic operative series, there was a 98% native valve preservation rate and 1.6% recurrence rate. Most importantly were their neurologic embolic outcomes. For the surgical population, the stroke risk was 2% at 1 year and 8% at 5 years. This rate was approximately 2.5x age-matched controlled. For the medically managed patients, the 1- and 5-year stroke risk was significantly higher than the operative group at 6 and 13%, respectively. There were 29 observed strokes versus 8.4 expected. Obviously, it was difficult to determine the impact of confounding risk factors that might have increased the stroke risk in patients who were otherwise poor surgical candidates. Regardless, the incidence was still nearly 3.5× that of matched controls. Furthermore, in the non-operative group, medical management with anti-thrombotic therapy (i.e., anti-platelet and anti-coagulant therapy, including dual therapy) had no impact on the stroke risk at 5 years when compared

*Echocardiographic imaging of a fibroelastoma. Fibroelastoma of the aortic valve. Short and long axis view transesophageal echocardiography. From: Surgery for cardiac papillary fibroelastoma: A 12-year single* 

significance, but are helpful in establishing a pathologic diagnosis [13].

undergo surgical resection had higher rates of stroke and mortality [37].

**30**

**Figure 6.**

*institution experience [35].*

to those without anti-thrombotic therapy [37]. Overall, the authors did not find any echocardiographic or clinical variables that helped stratify patients into high- or low-risk groups for embolic complications. The significant increased stroke risk in the non-operative group (even when matched for age-adjusted controls) and the lack of benefit of medical therapies serve as contemporary evidence to justify surgical management as first-line therapy in appropriate risk-stratified patients (**Figure 7**).

Surgical intervention for papillary fibroelastoma should be considered in patients who are symptomatic, undergoing cardiac surgery for other reasons, or have large, highly mobile lesions [38]. Further study through randomized controlled, multicenter trials is needed to determine if the potential benefit of surgical resection outweighs risk in asymptomatic patients. In asymptomatic patients who are otherwise good surgical candidates, the decision for non-operative management should be well-documented as part of shared decision-making with the patients with emphasis on the theoretical risks and benefits of surgery versus the risks of embolic complications.

In another single-center review, there was a tendency for occurrence in elderly males (71% males and 57% older than 61 years of age). Most (72%) occurred on a cardiac valve. Rarely was more than 1 lesion encountered and rarely were they >1.5 cm in size (27.8%). Surgical management was uncomplicated in all cases, even though some patients required concomitant surgery (i.e., coronary artery bypass grafting), and 30-day survival was 100%. No recurrences were reported at 1-year follow-up [39]. Similar outcomes were reported from another large-volume program in which Mkalaluh and colleagues reported 0 peri-operative mortalities in 11 patients (7 of whom had valvular involvement) with 100% 1-year survival and 91% survival at a mean follow-up of 4.2 years [40].

The indications for surgical resection are often a function of presentation and whether the patient is an appropriate surgical candidate. Since many fibroelastomas are incidental findings and hence asymptomatic, the natural history is unclear even though their tendency to embolize as pedunculated masses is unpredictable. For this reason, in appropriate surgical candidates, the presence of a presumed fibroelastoma is often an indication for surgical management, especially with left-sided

#### **Figure 7.**

*Proposed algorithm for left-sided possible fibroelastoma. Legend: Adopted from Tamin et al. [37]. FE: Fibroelastoma. \* Note: there is little evidence to support the overall recommendation for anti-platelet or anti-coagulant therapy in this population.*

lesions. While tumor size has not been correlated with embolic risk [41], there is some evidence to suggest that in medically managed patients, the risk of neurologic events was as high as 22% [42]. Nevertheless, the risks of non-operative management are poorly understood. Advocating for surgical intervention must be individualized as part of shared decision-making [43].

### **5. Cardiac lipomas**

Cardiac lipomas, much like lipomas encountered elsewhere in the body, are typically composed of mature adipose (fat) cells and are well-encapsulated. The majority of cardiac lipomas are subendocardial (50%), while the remainder are myocardial (25%) or subpericardial (25%) (**Figure 8**). They are typically found in the left ventricle or right atrium. Embolic complications are extremely rare unless the tumor is coated with thrombus from abnormal flow patterns. Typically, the presentation is characterized by obstructive symptoms [46, 47]. Surgical resection is typically reserved for symptomatic patients and consistent of removal of the entire capsule with pericardial reconstruction of the residual defect if necessary [48]. Asymptomatic patients can be managed expectantly. It is important to note that lipomas must be distinguished from lipomatous hypertrophy of the intra-atrial septum. Lipomatous hypertrophy is considered a benign infiltrative process of the adipose septal tissue. However, obstructive symptoms and even complex atrial arrhythmias can develop from cellular proliferation. In such symptomatic cases, surgical debulking and reconstruction may be considered [49].

#### **Figure 8.**

*MRI and surgical specimen of a cardiac lipoma. Left figure: Cardiac lipoma in the interventricular septum. Cardiac MRI showed a round-like signal, measuring 36 × 20 mm, in the upper portion of IVS, anterior to the right coronary sinus of aorta [44]. Right figure: Cardiac lipoma. The surface of the specimen is lined by smooth endocardial and epicardial tissue. The cut surface displays a yellow, lobulated appearance without hemorrhage, necrosis, fleshy change, or calcification [45]. Note: The surgical specimen is from the same patient as the MRI (both cc\*: Figures with this marker are used under the terms of Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work noncommercially, as long as the author is credited and the new creations are licensed under the identical terms).*

### **6. Unusual/rare non-malignant cardiac tumors**

While myxomas and fibroelastomas are the most common forms of nonmalignant cardiac tumors, other cellular types have been encountered as intra-cardiac masses. Most are considered extremely rare and limited to cases

**33**

*Non-Malignant Cardiac Tumors*

expectantly with serial imaging.

or valve replacement.

**7. Surgical management of benign cardiac tumors**

*DOI: http://dx.doi.org/10.5772/intechopen.86944*

reports or small series from large institutions. These masses include teratomas, hamartomas, fibromas, hemangiomas, paragangliomas, and mesotheliomas of the atrioventricular node [50, 51]. Management is often similar to other cardiac masses and based on presenting symptoms, concern for embolic risk or obstructive physiology, and clinical risk of surgical intervention [52]. Because of the rarity of these types of tumors, little is known about pre-operative incidence. A definitive tissue diagnosis is often made at the time of surgical resection [53]. Unlike myxomas and fibroelastomas, embolic complications of these unusual tumors are rare. Patients typically present with obstructive heart failure symptoms. As most are asymptomatic, they are often only encountered at autopsy and are rarely considered the cause of death [54]. Resection or debulking is typically indicated based on presentation, tumor location (especially with regard to surrounding cardiac structures), and size. However, some patients with large tumors, presumed to be benign or potentially curative with resection, might need cardiac transplantation if safe resection is not possible [55]. Most ventricular fibromas can undergo safe resection, even if the tumor involvement is extensive, with good short- and long-term results and trivial risk of recurrence [56]. In general, symptoms of heart failure and arrhythmias resolve with resection. Asymptomatic tumors that fit into this category can be managed

The surgical management of non-malignant cardiac tumors varies depending on the location of the tumor and the potential involvement of intra-cardiac structures [57]. Not only is the oncologic principle of wide excisional margins is not always possible due to the critical nature of certain cardiac structures, it is not necessary. The key principle is complex tumor excision if possible. Unless the diagnosis is obvious based on presentation, location, and clinical appearance, non-malignant tumors can often be confused with subacute endocarditis or intra-cardiac thrombus. Nevertheless, complex excision is necessary. Fibroelastomas can often be the easiest to remove, typically by sharp excision from their adherent structures. Even with valvular involvement, it would be uncommon to require leaflet reconstruction

Intra-cardiac excisions, almost by definition, require cardiopulmonary bypass, aortic cross-clamping, and cardiac arrest. The specific techniques are beyond the scope of this chapter, as are the advantages and disadvantages of choice of incision (i.e., conventional full sternotomy, minimally-invasive sternal or right thoracotomy, or robotic-assisted techniques) and myocardial protection. The approach is probably best left to the individual comfort level and skill of the surgeon [58]. Nevertheless, because focused resection compared to wide debridement is typically the surgical goal, minimally-invasive approaches may be reasonable in appropriately selected patients. Cannulation techniques will vary depending on the tumor location. However, there should be a low threshold for bi-caval cannulation to assist in access to the atrial chambers and possible resection and reconstruction of the intra-atrial septum. In addition, root venting should always be considered, even with primary right-sided structures, as communication or left-sided involvement might introduce intra-cardiac air that would require appropriate de-airing upon weaning from cardiopulmonary bypass. In patients with concomitant cardiovascular pathology (i.e., coronary artery disease, aortic aneurysms, or separate valvular pathology), appropriate surgical intervention should be performed. The decision to perform a preoperative cardiac

#### *Non-Malignant Cardiac Tumors DOI: http://dx.doi.org/10.5772/intechopen.86944*

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

surgical debulking and reconstruction may be considered [49].

**6. Unusual/rare non-malignant cardiac tumors**

While myxomas and fibroelastomas are the most common forms of nonmalignant cardiac tumors, other cellular types have been encountered as intra-cardiac masses. Most are considered extremely rare and limited to cases

*MRI and surgical specimen of a cardiac lipoma. Left figure: Cardiac lipoma in the interventricular septum. Cardiac MRI showed a round-like signal, measuring 36 × 20 mm, in the upper portion of IVS, anterior to the right coronary sinus of aorta [44]. Right figure: Cardiac lipoma. The surface of the specimen is lined by smooth endocardial and epicardial tissue. The cut surface displays a yellow, lobulated appearance without hemorrhage, necrosis, fleshy change, or calcification [45]. Note: The surgical specimen is from the same patient as the MRI (both cc\*: Figures with this marker are used under the terms of Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work noncommercially, as long as the author is credited and the new creations are licensed under the identical terms).*

alized as part of shared decision-making [43].

**5. Cardiac lipomas**

lesions. While tumor size has not been correlated with embolic risk [41], there is some evidence to suggest that in medically managed patients, the risk of neurologic events was as high as 22% [42]. Nevertheless, the risks of non-operative management are poorly understood. Advocating for surgical intervention must be individu-

Cardiac lipomas, much like lipomas encountered elsewhere in the body, are typically composed of mature adipose (fat) cells and are well-encapsulated. The majority of cardiac lipomas are subendocardial (50%), while the remainder are myocardial (25%) or subpericardial (25%) (**Figure 8**). They are typically found in the left ventricle or right atrium. Embolic complications are extremely rare unless the tumor is coated with thrombus from abnormal flow patterns. Typically, the presentation is characterized by obstructive symptoms [46, 47]. Surgical resection is typically reserved for symptomatic patients and consistent of removal of the entire capsule with pericardial reconstruction of the residual defect if necessary [48]. Asymptomatic patients can be managed expectantly. It is important to note that lipomas must be distinguished from lipomatous hypertrophy of the intra-atrial septum. Lipomatous hypertrophy is considered a benign infiltrative process of the adipose septal tissue. However, obstructive symptoms and even complex atrial arrhythmias can develop from cellular proliferation. In such symptomatic cases,

**32**

**Figure 8.**

reports or small series from large institutions. These masses include teratomas, hamartomas, fibromas, hemangiomas, paragangliomas, and mesotheliomas of the atrioventricular node [50, 51]. Management is often similar to other cardiac masses and based on presenting symptoms, concern for embolic risk or obstructive physiology, and clinical risk of surgical intervention [52]. Because of the rarity of these types of tumors, little is known about pre-operative incidence. A definitive tissue diagnosis is often made at the time of surgical resection [53]. Unlike myxomas and fibroelastomas, embolic complications of these unusual tumors are rare. Patients typically present with obstructive heart failure symptoms. As most are asymptomatic, they are often only encountered at autopsy and are rarely considered the cause of death [54]. Resection or debulking is typically indicated based on presentation, tumor location (especially with regard to surrounding cardiac structures), and size. However, some patients with large tumors, presumed to be benign or potentially curative with resection, might need cardiac transplantation if safe resection is not possible [55]. Most ventricular fibromas can undergo safe resection, even if the tumor involvement is extensive, with good short- and long-term results and trivial risk of recurrence [56]. In general, symptoms of heart failure and arrhythmias resolve with resection. Asymptomatic tumors that fit into this category can be managed expectantly with serial imaging.

### **7. Surgical management of benign cardiac tumors**

The surgical management of non-malignant cardiac tumors varies depending on the location of the tumor and the potential involvement of intra-cardiac structures [57]. Not only is the oncologic principle of wide excisional margins is not always possible due to the critical nature of certain cardiac structures, it is not necessary. The key principle is complex tumor excision if possible. Unless the diagnosis is obvious based on presentation, location, and clinical appearance, non-malignant tumors can often be confused with subacute endocarditis or intra-cardiac thrombus. Nevertheless, complex excision is necessary. Fibroelastomas can often be the easiest to remove, typically by sharp excision from their adherent structures. Even with valvular involvement, it would be uncommon to require leaflet reconstruction or valve replacement.

Intra-cardiac excisions, almost by definition, require cardiopulmonary bypass, aortic cross-clamping, and cardiac arrest. The specific techniques are beyond the scope of this chapter, as are the advantages and disadvantages of choice of incision (i.e., conventional full sternotomy, minimally-invasive sternal or right thoracotomy, or robotic-assisted techniques) and myocardial protection. The approach is probably best left to the individual comfort level and skill of the surgeon [58]. Nevertheless, because focused resection compared to wide debridement is typically the surgical goal, minimally-invasive approaches may be reasonable in appropriately selected patients. Cannulation techniques will vary depending on the tumor location. However, there should be a low threshold for bi-caval cannulation to assist in access to the atrial chambers and possible resection and reconstruction of the intra-atrial septum. In addition, root venting should always be considered, even with primary right-sided structures, as communication or left-sided involvement might introduce intra-cardiac air that would require appropriate de-airing upon weaning from cardiopulmonary bypass. In patients with concomitant cardiovascular pathology (i.e., coronary artery disease, aortic aneurysms, or separate valvular pathology), appropriate surgical intervention should be performed. The decision to perform a preoperative cardiac

catheterization should be based on an appropriate multi-disciplinary assessment of the risks of underlying coronary artery disease, risks of the procedures (i.e., catheter-induced dislodgement of the tumor), and the age and co-morbidities of the patient as suggested by clinical guidelines [59]. In situations in which cardiac catheterization is either relatively contraindicated (i.e., presence of an aortic valve mass) or perceived to be of low clinical benefit, coronary computed tomography might be considered and potentially helpful in guiding therapy [60]. Intraoperative transesophageal echocardiography should be used routinely to ensure an accurate diagnosis, clear identification of involved structures, and complete resection prior to surgical closure [61].

For tumors that involve either the aortic valve or left ventricular outflow track, the surgical approach should be trans-aortic—essentially a similar approach as is used for traditional aortic valve replacement surgery. Aortic valve replacement is rarely necessary. Careful trans-aortic exposure to the left ventricular outflow track can provide access to tumors in the LVOT or on the left ventricular side of the anterior leaflet of the mitral valve. Even residual aortic or mitral insufficiency, either primary insufficiency or as a consequence of resection, can be well tolerated for many years. The indications for valve replacement in such cases should be limited to those patients in whom residual regurgitation would otherwise require repair or replacement based upon current guidelines for valvular dysfunction management [62].

For tumors that involve an isolated valve, a standard surgical approach to the specific valve is typically employed based on surgeon preference, i.e., trans-right atrial for tricuspid pathology and right ventricular masses. For masses such as myxomas that involve the intra-atrial septum, a variety of approaches can be used. The most common approach is through the right atrium (even if the tumor is on the left atrial side of the septum) with excision of the fossa ovalis or the involved intra-atrial septum to remove not only the tumor, but the stalk and the potential "tumor roots" in the septal tissue (**Figure 9**). Even with large tumors, primary reconstruction of the intra-atrial septum can be often performed as the size (width and length) of the associated stalk rarely correlates with the actual extent of septal tissue involvement. For large septal defects, reconstruction with bovine pericardium can easily be performed [16]. Depending on surgeon experience, preference, and tumor location, a right thoracotomy approach to either the left or right atrium can be considered [63]. While a left atrial approach has been described for tumors on the left atrial side of the intra-atrial septum, if such an approach is chosen, it is critical that the principles of complex tumor excision, including the stalk and septal roots (with reconstruction of the intra-atrial septum if necessary), be maintained [64]. Merely shaving the tumor off the intra-atrial septum without resecting the septal tissue is inappropriate as it might leave residual tumor behind and predispose to tumor recurrence.

All surgical excisions should be sent for pathology and microbiology. A comprehensive pathological evaluation is critical as many tumors have extensive thrombotic material covering them that might confound a true diagnosis. Occasionally, tumors can become infected with presentations similar to endocarditis. When encountered, a prolonged course of targeted antibiotic therapy is recommended, as with any form of endocarditis. Likewise, microbiologic assessment of the mass is necessary to rule out a potentially infectious etiology, especially in the absence of a clear preoperative diagnosis. Concomitant infected tumors, while part of any differential diagnosis, are rare [65].

Post-operative management should be consistent with that of any other post-cardiotomy patient. Anti-coagulation should only be considered if indicated for other reasons, such as if recommended by neurologic consultants for the

**35**

to a tertiary care center should be considered.

*Non-Malignant Cardiac Tumors*

resection or recurrence.

*Note the resected intra-atrial septal tissue.*

**8. Summary**

**Figure 9.**

*DOI: http://dx.doi.org/10.5772/intechopen.86944*

treatment of embolic strokes. For patients whose tumors appear to have a large thrombus burden, a hypercoagulable state work-up and appropriate treatment should be considered. Guidelines for post-resection imaging surveillance are lacking and should be symptom-based unless there is concern for incomplete

*Surgical specimen of a left atrial myxoma. Approximately 3 cm left atrial cardiac myxoma surgical specimen.* 

Intra-cardiac masses represent a challenging clinical problem. Patients often present with embolic complications or obstructive heart failure symptoms. Alternatively, they may be asymptomatic with the mass discovered as an incidental finding in work-up of an alternative diagnosis or in preparation for other therapies (i.e., coronary artery bypass surgery). As discussed, such tumors are rare and must be distinguished from other cardiac masses, specifically endocarditis and intra-cardiac thrombus for which the management strategies are well-established. The overriding principle of management is prevention of potentially catastrophic embolic complications, specifically neurologic events. However, the data to support this approach is either limited or not based on high-quality randomized or controlled trials [3, 29]. As such, when encountered in appropriately risk-stratified patients, surgical removal is often curative and should be considered first-line therapy. While STS risk scoring is often used to evaluate these patients, a specific risk-model for treatment is not part of the STS calculator. However, it most closely matches the risks for patients undergoing valve repair or replacement (http://riskcalc.sts.org/stswebriskcalc/calculate), Risk for recurrence is low and post-operative survival is excellent. While medical management of these masses is considered in high-risk patients and those who refuse surgery, it is important to consider there is little data to support this approach and some evidence to suggest an increased stroke risk. Medical management, specifically anti-thrombotic therapies, have little role and can potentially delay a diagnosis until a catastrophic neurologic event occurs. It should only be considered in unusual cases. Furthermore, while the mere presence of an intra-cardiac mass is considered an indication for surgical resection, if there are concerns about the diagnosis based on echocardiographic characteristics or if there is concern for an invasive primary or metastatic malignant tumor, CT or MRI imaging can be useful. Given the rarity of these tumors, if there are any concerns about the diagnosis or management, referral

#### **Figure 9.**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

resection prior to surgical closure [61].

catheterization should be based on an appropriate multi-disciplinary assessment of the risks of underlying coronary artery disease, risks of the procedures (i.e., catheter-induced dislodgement of the tumor), and the age and co-morbidities of the patient as suggested by clinical guidelines [59]. In situations in which cardiac catheterization is either relatively contraindicated (i.e., presence of an aortic valve mass) or perceived to be of low clinical benefit, coronary computed tomography might be considered and potentially helpful in guiding therapy [60]. Intraoperative transesophageal echocardiography should be used routinely to ensure an accurate diagnosis, clear identification of involved structures, and complete

For tumors that involve either the aortic valve or left ventricular outflow track, the surgical approach should be trans-aortic—essentially a similar approach as is used for traditional aortic valve replacement surgery. Aortic valve replacement is rarely necessary. Careful trans-aortic exposure to the left ventricular outflow track can provide access to tumors in the LVOT or on the left ventricular side of the anterior leaflet of the mitral valve. Even residual aortic or mitral insufficiency, either primary insufficiency or as a consequence of resection, can be well tolerated for many years. The indications for valve replacement in such cases should be limited to those patients in whom residual regurgitation would otherwise require repair or replacement based

For tumors that involve an isolated valve, a standard surgical approach to the specific valve is typically employed based on surgeon preference, i.e., trans-right atrial for tricuspid pathology and right ventricular masses. For masses such as myxomas that involve the intra-atrial septum, a variety of approaches can be used. The most common approach is through the right atrium (even if the tumor is on the left atrial side of the septum) with excision of the fossa ovalis or the involved intra-atrial septum to remove not only the tumor, but the stalk and the potential "tumor roots" in the septal tissue (**Figure 9**). Even with large tumors, primary reconstruction of the intra-atrial septum can be often performed as the size (width and length) of the associated stalk rarely correlates with the actual extent of septal tissue involvement. For large septal defects, reconstruction with bovine pericardium can easily be performed [16]. Depending on surgeon experience, preference, and tumor location, a right thoracotomy approach to either the left or right atrium can be considered [63]. While a left atrial approach has been described for tumors on the left atrial side of the intra-atrial septum, if such an approach is chosen, it is critical that the principles of complex tumor excision, including the stalk and septal roots (with reconstruction of the intra-atrial septum if necessary), be maintained [64]. Merely shaving the tumor off the intra-atrial septum without resecting the septal tissue is inappropriate as it might leave residual tumor behind and pre-

All surgical excisions should be sent for pathology and microbiology. A comprehensive pathological evaluation is critical as many tumors have extensive thrombotic material covering them that might confound a true diagnosis. Occasionally, tumors can become infected with presentations similar to endocarditis. When encountered, a prolonged course of targeted antibiotic therapy is recommended, as with any form of endocarditis. Likewise, microbiologic assessment of the mass is necessary to rule out a potentially infectious etiology, especially in the absence of a clear preoperative diagnosis. Concomitant infected tumors, while part of any

Post-operative management should be consistent with that of any other post-cardiotomy patient. Anti-coagulation should only be considered if indicated for other reasons, such as if recommended by neurologic consultants for the

upon current guidelines for valvular dysfunction management [62].

**34**

dispose to tumor recurrence.

differential diagnosis, are rare [65].

*Surgical specimen of a left atrial myxoma. Approximately 3 cm left atrial cardiac myxoma surgical specimen. Note the resected intra-atrial septal tissue.*

treatment of embolic strokes. For patients whose tumors appear to have a large thrombus burden, a hypercoagulable state work-up and appropriate treatment should be considered. Guidelines for post-resection imaging surveillance are lacking and should be symptom-based unless there is concern for incomplete resection or recurrence.

### **8. Summary**

Intra-cardiac masses represent a challenging clinical problem. Patients often present with embolic complications or obstructive heart failure symptoms. Alternatively, they may be asymptomatic with the mass discovered as an incidental finding in work-up of an alternative diagnosis or in preparation for other therapies (i.e., coronary artery bypass surgery). As discussed, such tumors are rare and must be distinguished from other cardiac masses, specifically endocarditis and intra-cardiac thrombus for which the management strategies are well-established. The overriding principle of management is prevention of potentially catastrophic embolic complications, specifically neurologic events. However, the data to support this approach is either limited or not based on high-quality randomized or controlled trials [3, 29]. As such, when encountered in appropriately risk-stratified patients, surgical removal is often curative and should be considered first-line therapy. While STS risk scoring is often used to evaluate these patients, a specific risk-model for treatment is not part of the STS calculator. However, it most closely matches the risks for patients undergoing valve repair or replacement (http://riskcalc.sts.org/stswebriskcalc/calculate), Risk for recurrence is low and post-operative survival is excellent. While medical management of these masses is considered in high-risk patients and those who refuse surgery, it is important to consider there is little data to support this approach and some evidence to suggest an increased stroke risk. Medical management, specifically anti-thrombotic therapies, have little role and can potentially delay a diagnosis until a catastrophic neurologic event occurs. It should only be considered in unusual cases. Furthermore, while the mere presence of an intra-cardiac mass is considered an indication for surgical resection, if there are concerns about the diagnosis based on echocardiographic characteristics or if there is concern for an invasive primary or metastatic malignant tumor, CT or MRI imaging can be useful. Given the rarity of these tumors, if there are any concerns about the diagnosis or management, referral to a tertiary care center should be considered.

## **9. Conclusions**

Intra-cardiac masses are rare, but are occasionally found during work-up for a source of embolism or encountered as an incidental finding. Tumor location and echocardiographic characteristics often suggest a diagnosis. However, definitive surgical resection for both diagnostic and therapeutic reasons should be considered first-line therapy. Patients managed non-operatively have increased risk for embolic complications. Medical therapies have not been shown to be effective although definitive data is lacking and controlled trials may be difficult to perform.

## **Author details**

Sarah Eapen1 , Bethany Malone1 , Jennifer Hanna2 and Michael S. Firstenberg2 \*

1 Department of Surgery, Summa Akron City Hospital, Akron, OH, USA

2 Department of Cardiothoracic and Vascular Surgery, The Medical Center of Aurora, Aurora, CO, USA

\*Address all correspondence to: msfirst@gmail.com

© 2019 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.

**37**

pp. 1-11

*Non-Malignant Cardiac Tumors*

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### **References**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

Intra-cardiac masses are rare, but are occasionally found during work-up for a source of embolism or encountered as an incidental finding. Tumor location and echocardiographic characteristics often suggest a diagnosis. However, definitive surgical resection for both diagnostic and therapeutic reasons should be considered first-line therapy. Patients managed non-operatively have increased risk for embolic complications. Medical therapies have not been shown to be effective although definitive data is lacking and controlled trials may be difficult to perform.

**9. Conclusions**

**36**

**Author details**

Aurora, Aurora, CO, USA

, Bethany Malone1

\*Address all correspondence to: msfirst@gmail.com

provided the original work is properly cited.

, Jennifer Hanna2

2 Department of Cardiothoracic and Vascular Surgery, The Medical Center of

© 2019 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,

1 Department of Surgery, Summa Akron City Hospital, Akron, OH, USA

and Michael S. Firstenberg2

\*

Sarah Eapen1

[1] Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke statistics—2018 update: A report from the American Heart Association. Circulation 2018;137(12):e67-492

[2] Khurram IM, Dewire J, Mager M, Maqbool F, Zimmerman SL, Zipunnikov V, et al. Relationship between left atrial appendage morphology and stroke in patients with atrial fibrillation. Heart Rhythm. 2013;**10**(12):1843-1849

[3] Holmes DR, Doshi SK, Kar S, Price MJ, Sanchez JM, Sievert H, et al. Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: A patient-level meta-analysis. Journal of the American College of Cardiology. 2015;**65**(24):2614-2623

[4] Firstenberg MS. Introductory chapter: Introduction to advanced concepts in endocarditis. In: Firstenberg MS, editor. Advanced Concepts in Endocarditis. London: IntechOpen; 2018. p. 79883. DOI: 10.5772/intechopen. Available from: https://www.intechopen.com/books/ advanced-concepts-in-endocarditis/ introductory-chapter-introduction-toadvanced-concepts-in-endocarditis

[5] Butany J, Nair V, Naseemuddin A, Nair GM, Catton C, Yau T. Cardiac tumours: Diagnosis and management. The Lancet Oncology. 2005;**6**(4):219-228

[6] Wold LE, Lie JT. Cardiac myxomas: A clinicopathologic profile. The American Journal of Pathology. 1980;**101**:219-240

[7] Burke AP, Virmani R. Tumors of the Heart and Great Vessels. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 1996. pp. 1-11

[8] Burke A, Tavora F. The 2015 WHO classification of tumors of the heart

and pericardium. Journal of Thoracic Oncology. 2016;**11**(4):441-452

[9] Wei K, Guo HW, Fan SY, Sun XG, Hu SS. Clinical features and surgical results of cardiac myxoma in carney complex. Journal of Cardiac Surgery. 2019;**34**:14-19

[10] Cao H et al. Journal of Biomedical Research. 2011;**25**(5):368-372

[11] Seino Y, Ikeda U, Shimada K. Increased expression of interleukin 6 mRNA in cardiac myxomas. British Heart Journal. 1993;**69**(6):565-567. DOI: 10.1136/hrt.69.6.565. PMC 1025174. PMID 8343326

[12] Knepper LE, Biller J, Adams HP, Bruno A. Neurologic manifestations of atrial myxoma. A 12-year experience and review. Stroke. 1988;**19**(11):1435-1440. DOI: 10.1161/01.str.19.11.1435. PMID 3188128

[13] Burke AP, Tazellar H, Gomez-Roman J, et al. WHO Classification of Tumours. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004. pp. 260-265

[14] Wang JG, Li YJ, Liu H, et al. Clinicopathologic analysis of cardiac myxomas: Seven years' experience with 61 patients. Journal of Thoracic Disease. 2012;**4**(3):272-283

[15] Araoz PA, Mulvagh SL, Tazelaar HD, Julsrud PR, Breen JF. CT and MR imaging of benign primary cardiac neoplasms with echocardiographic correlation. Radiographics. 2000;**20**(5):1303-1319

[16] Lee KS, Kim GS, Jung Y, Jeong IS, Na KJ, Oh BS, et al. Surgical resection of cardiac myxoma—A 30-year single institutional experience. Journal of Cardiothoracic Surgery. 2017;**12**(1):18

[17] Animashaun IB, Akinseye OA, Akinseye LI, Akinboboye OO. Right atrial myxoma and syncope. The American Journal of Case Reports. 2015;**16**:645-647

[18] Kassi M, Polsani V, Schutt RC, Wong S, Nabi F, Reardon MJ, et al. Differentiating benign from malignant cardiac tumors with cardiac magnetic resonance imaging. The Journal of Thoracic and Cardiovascular Surgery. 2019;**157**(5):1912-1922

[19] McCarthy CP, Vaduganathan M, McCarthy KJ, Januzzi JL, Bhatt DL, McEvoy JW. Left ventricular thrombus after acute myocardial infarction: Screening, prevention, and treatment. JAMA Cardiology. 2018;**3**(7):642-649

[20] Di Minno MN, Ambrosino P, Russo AD, Casella M, Tremoli E, Tondo C. Prevalence of left atrial thrombus in patients with non-valvular atrial fibrillation. Thrombosis and Haemostasis. 2016;**115**(03):663-677

[21] Acebo E, Val-Bernal JF, Gomez-Roman JJ. Thrombomodulin, calretinin and c-kit (CD117) expression in cardiac myxoma. Histology and Histopathology. 2001;**16**(4):1031-1036

[22] Maleszewski JJ, Larsen BT, Kip NS, et al. PRKAR1A in the development of cardiac myxoma: A study of 110 cases including isolated and syndromic tumors. The American Journal of Surgical Pathology. 2014;**38**(8):1079-1087

[23] Wang Z, Chen S, Zhu M, et al. Risk prediction for emboli and recurrence of primary cardiac myxomas after resection. Journal of Cardiothoracic Surgery. 2016;**11**(22):1-8

[24] Reynen K. Cardiac myxomas. The New England Journal of Medicine. 1995;**333**(24):1610-1617

[25] Shinfeld A, Katsumata T, Westaby S. Recurrent cardiac myxoma: Seeding or multifocal disease? The Annals of Thoracic Surgery. 1998;**66**(1):285-288

[26] Fleischmann KE, Schiller NB. Papillary fibroelastoma: Move over myxoma. Journal of the American College of Cardiology. 2015;**65**(22):2430-2432

[27] Bicer M, Cikirikcioglu M, Pektok E, et al. Papillary fibroelastoma of the left atrial wall: A case report. Journal of Cardiothoracic Surgery. 2009;**4**(28):1-4

[28] Kurup AN, Tazelaar HD, Edwards WD, et al. Iatrogenic cardiac papillary fibroelastoma: A study of 12 cases (1990 to 2000). Human Pathology. 2002;**33**(12):1165-1169

[29] Remadi JP, Degandt A, Rakotoarivello Z. Cardiac papillary fibroelastoma of the mitral valve chordae. Heart. 2004;**90**:12

[30] Murphy ET. Robotic excision of aortic valve papillary fibroelastoma and concomitant maze procedure. Global Cardiology Science and Practice. 1 Nov 2013;**2012**(2):93-100. DOI: 10.5339/gcsp.2012.27. PubMed PMID: 24688994; PubMed Central PMCID: PMC3963717

[31] Grinda JM, Couetil JP, Chauvaud S, et al. Cardiac valve papillary fibroelastoma: Surgical excision for revealed or potential embolization. The Journal of Thoracic and Cardiovascular Surgery. 1999;**117**:106-110

[32] Klarich KW, Enriquez-Sarano M, Gura GM, et al. Papillary fibroelastoma: Echocardiographic characteristics for diagnosis and pathologic correlation. Journal of the American College of Cardiology. 1997;**30**(3):784-790

[33] Kamran H, Patel N, Singh G. Lambl's excrescences: A case report and review of the literature. Clinical Case Reports and Reviews. 2016;**2**(7):476-478

**39**

*Non-Malignant Cardiac Tumors*

*DOI: http://dx.doi.org/10.5772/intechopen.86944*

[34] Marstrand P, Jensen MB, Ihlemann N. Valvular excrescences: A possible transient phenomenon. Case Reports in Cardiology. 2015;**2015**:380765. DOI: 10.1155/2015/380765. Epub 2015 Nov 16 [42] Klarich KW, Enriquez-Sarano M, Gura GM, Edwards WD, Tajik AJ, Seward JB. Papillary fibroelastoma: Echocardio-graphic characteristics for diagnosis and pathologic correlation. Journal of the American College of Cardiology.

[43] Sabet A, Haghighiabyaneh M, Tazelaar H, Raisinghani A, DeMaria A. The clinical dilemma of cardiac fibroelastic papilloma. Structural Heart. 2018;**2**(4):274-280

[44] Li D, Wang W, Zhu Z, Wang Y, Xu R, Liu K. Cardiac lipoma in the interventricular septum: A case report. Journal of Cardiothoracic Surgery. Dec

[45] Naseerullah FS, Javaiya H, Murthy A. Cardiac lipoma: An uncharacteristically large intra-atrial mass causing symptoms. Case Reports in Cardiology. 2018;**2018**:3531982

[46] Laeeq R, Merchant O, Khalid UM, Lakkis NM. Large cardiac lipoma in a patient presenting with atrial tachycardia and systolic heart failure. Journal of Cardiac Failure. 2017;**23**(8):S94

[47] Wijesurendra RS, Sheppard KA, Westaby S, Ormerod O, Myerson SG. The many faces of cardiac lipoma—An egg in the heart! European Heart Journal Cardiovascular Imaging. 2017;**18**(7):821

[48] Kim YS, Lee KH, Choi SJ, Baek WK.

[49] Dickerson JA, Smith M, Kalbfleisch

Cardiac lipoma arising from left ventricular papillary muscle: Resect or not? The Journal of Thoracic and Cardiovascular Surgery.

S, Firstenberg MS. Lipomatous hypertrophy of the intraatrial septum

resulting in right atrial inflow obstruction and atrial flutter. The Annals of Thoracic Surgery. 2010;**89**(5):1647-1649

2018;**156**(1):244-246

1997;**30**(3):784-790

2015;**10**(1):69

[35] Mkalaluh S, Szczechowicz M, Torabi S, Dib B, Sabashnikov A, Mashhour A, et al. Surgery for cardiac papillary fibroelastoma: A 12-year single institution experience. Medical Science Monitor Basic Research.

transesophageal echocardiography detection of papillary fibroelastomas

[37] Tamin SS, Maleszewski JJ, Scot CG, et al. Prognostic and bioepidemiologic implications of papillary fibroelastoma. Journal of the American College of Cardiology. 2015;**65**(22):2420-2429

[38] Sun JP, Asher CR, Yang S, et al. Clinical and echocardiographic characteristics of papillary

fibroelastomas. A retrospective and prospective study in 162 patients. Circulation. 2001;**103**:2687-2693

[39] Abu Saleh WK, Al Jabbari O, Ramlawi B, Reardon MJ. Cardiac papillary fibroelastoma: Single-

[40] Mkalaluh S, Szczechowicz M, Torabi S, Dib B, Sabashnikov A, Mashhour A, et al. Surgery for cardiac papillary fibroelastoma: A 12-year single institution experience. Medical Science Monitor Basic Research. 2017;**23**:258

[41] Gowda RM, Khan IA, Nair CK, Mehta NJ, Vasavada BC, Sacchi TJ. Cardiac papillary fibroelastoma: A comprehensive analysis of 725 cases. American Heart Journal.

2016;**43**(2):148-151

2003;**146**(3):404-410

institution experience with 14 surgical patients. Texas Heart Institute Journal.

2017;**23**:258-263

1997;**18**(4):702-703

[36] Shelh M. Multiplane

of the aortic valve causing a stroke. European Heart Journal. *Non-Malignant Cardiac Tumors DOI: http://dx.doi.org/10.5772/intechopen.86944*

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

or multifocal disease? The Annals of Thoracic Surgery. 1998;**66**(1):285-288

[26] Fleischmann KE, Schiller NB. Papillary fibroelastoma: Move over myxoma. Journal of the American College of Cardiology.

[27] Bicer M, Cikirikcioglu M, Pektok E, et al. Papillary fibroelastoma of the left atrial wall: A case report. Journal of Cardiothoracic Surgery.

[28] Kurup AN, Tazelaar HD, Edwards WD, et al. Iatrogenic cardiac papillary fibroelastoma: A study of 12 cases (1990 to 2000). Human Pathology.

2015;**65**(22):2430-2432

2002;**33**(12):1165-1169

[29] Remadi JP, Degandt A,

Rakotoarivello Z. Cardiac papillary fibroelastoma of the mitral valve chordae. Heart. 2004;**90**:12

[30] Murphy ET. Robotic excision of aortic valve papillary fibroelastoma and concomitant maze procedure. Global Cardiology Science and Practice. 1 Nov 2013;**2012**(2):93-100. DOI: 10.5339/gcsp.2012.27. PubMed PMID: 24688994; PubMed Central PMCID:

[31] Grinda JM, Couetil JP, Chauvaud S, et al. Cardiac valve papillary fibroelastoma: Surgical excision for revealed or potential embolization. The Journal of Thoracic and Cardiovascular

[32] Klarich KW, Enriquez-Sarano M,

fibroelastoma: Echocardiographic characteristics for diagnosis and pathologic correlation. Journal of the American College of Cardiology.

[33] Kamran H, Patel N, Singh G. Lambl's excrescences: A case report and review of the literature. Clinical Case Reports and Reviews. 2016;**2**(7):476-478

Surgery. 1999;**117**:106-110

Gura GM, et al. Papillary

1997;**30**(3):784-790

2009;**4**(28):1-4

PMC3963717

[17] Animashaun IB, Akinseye OA, Akinseye LI, Akinboboye OO. Right atrial myxoma and syncope. The American Journal of Case Reports.

[18] Kassi M, Polsani V, Schutt RC, Wong S, Nabi F, Reardon MJ, et al. Differentiating benign from malignant cardiac tumors with cardiac magnetic resonance imaging. The Journal of Thoracic and Cardiovascular Surgery.

[19] McCarthy CP, Vaduganathan M, McCarthy KJ, Januzzi JL, Bhatt DL, McEvoy JW. Left ventricular thrombus after acute myocardial infarction: Screening, prevention, and treatment. JAMA Cardiology.

[20] Di Minno MN, Ambrosino P, Russo AD, Casella M, Tremoli E, Tondo C. Prevalence of left atrial thrombus in patients with non-valvular atrial fibrillation. Thrombosis and Haemostasis. 2016;**115**(03):663-677

[21] Acebo E, Val-Bernal JF, Gomez-Roman JJ. Thrombomodulin, calretinin and c-kit (CD117) expression in cardiac myxoma. Histology and Histopathology. 2001;**16**(4):1031-1036

[22] Maleszewski JJ, Larsen BT, Kip NS, et al. PRKAR1A in the development of cardiac myxoma: A study of 110 cases including isolated and syndromic tumors. The American Journal of

Surgical Pathology. 2014;**38**(8):1079-1087

[23] Wang Z, Chen S, Zhu M, et al. Risk prediction for emboli and recurrence of primary cardiac myxomas after resection. Journal of Cardiothoracic

[24] Reynen K. Cardiac myxomas. The New England Journal of Medicine.

[25] Shinfeld A, Katsumata T, Westaby S. Recurrent cardiac myxoma: Seeding

Surgery. 2016;**11**(22):1-8

1995;**333**(24):1610-1617

2015;**16**:645-647

2019;**157**(5):1912-1922

2018;**3**(7):642-649

**38**

[34] Marstrand P, Jensen MB, Ihlemann N. Valvular excrescences: A possible transient phenomenon. Case Reports in Cardiology. 2015;**2015**:380765. DOI: 10.1155/2015/380765. Epub 2015 Nov 16

[35] Mkalaluh S, Szczechowicz M, Torabi S, Dib B, Sabashnikov A, Mashhour A, et al. Surgery for cardiac papillary fibroelastoma: A 12-year single institution experience. Medical Science Monitor Basic Research. 2017;**23**:258-263

[36] Shelh M. Multiplane transesophageal echocardiography detection of papillary fibroelastomas of the aortic valve causing a stroke. European Heart Journal. 1997;**18**(4):702-703

[37] Tamin SS, Maleszewski JJ, Scot CG, et al. Prognostic and bioepidemiologic implications of papillary fibroelastoma. Journal of the American College of Cardiology. 2015;**65**(22):2420-2429

[38] Sun JP, Asher CR, Yang S, et al. Clinical and echocardiographic characteristics of papillary fibroelastomas. A retrospective and prospective study in 162 patients. Circulation. 2001;**103**:2687-2693

[39] Abu Saleh WK, Al Jabbari O, Ramlawi B, Reardon MJ. Cardiac papillary fibroelastoma: Singleinstitution experience with 14 surgical patients. Texas Heart Institute Journal. 2016;**43**(2):148-151

[40] Mkalaluh S, Szczechowicz M, Torabi S, Dib B, Sabashnikov A, Mashhour A, et al. Surgery for cardiac papillary fibroelastoma: A 12-year single institution experience. Medical Science Monitor Basic Research. 2017;**23**:258

[41] Gowda RM, Khan IA, Nair CK, Mehta NJ, Vasavada BC, Sacchi TJ. Cardiac papillary fibroelastoma: A comprehensive analysis of 725 cases. American Heart Journal. 2003;**146**(3):404-410

[42] Klarich KW, Enriquez-Sarano M, Gura GM, Edwards WD, Tajik AJ, Seward JB. Papillary fibroelastoma: Echocardio-graphic characteristics for diagnosis and pathologic correlation. Journal of the American College of Cardiology. 1997;**30**(3):784-790

[43] Sabet A, Haghighiabyaneh M, Tazelaar H, Raisinghani A, DeMaria A. The clinical dilemma of cardiac fibroelastic papilloma. Structural Heart. 2018;**2**(4):274-280

[44] Li D, Wang W, Zhu Z, Wang Y, Xu R, Liu K. Cardiac lipoma in the interventricular septum: A case report. Journal of Cardiothoracic Surgery. Dec 2015;**10**(1):69

[45] Naseerullah FS, Javaiya H, Murthy A. Cardiac lipoma: An uncharacteristically large intra-atrial mass causing symptoms. Case Reports in Cardiology. 2018;**2018**:3531982

[46] Laeeq R, Merchant O, Khalid UM, Lakkis NM. Large cardiac lipoma in a patient presenting with atrial tachycardia and systolic heart failure. Journal of Cardiac Failure. 2017;**23**(8):S94

[47] Wijesurendra RS, Sheppard KA, Westaby S, Ormerod O, Myerson SG. The many faces of cardiac lipoma—An egg in the heart! European Heart Journal Cardiovascular Imaging. 2017;**18**(7):821

[48] Kim YS, Lee KH, Choi SJ, Baek WK. Cardiac lipoma arising from left ventricular papillary muscle: Resect or not? The Journal of Thoracic and Cardiovascular Surgery. 2018;**156**(1):244-246

[49] Dickerson JA, Smith M, Kalbfleisch S, Firstenberg MS. Lipomatous hypertrophy of the intraatrial septum resulting in right atrial inflow obstruction and atrial flutter. The Annals of Thoracic Surgery. 2010;**89**(5):1647-1649

[50] Shah DJ, Reardon MJ. Case of a hamartoma or hamartoma of a case? The Journal of Thoracic and Cardiovascular Surgery. 2018;**155**(1):351-352

[51] El-Ashry AA, Cerfolio RJ, Singh SP, McGiffin D. Cardiac paraganglioma. Journal of Cardiac Surgery. 2015;**30**(2):135-139

[52] Tudor AA, Tschui J, Schmidli J, Schmid RA, Dorn P. Cardiac paraganglioma—A rare subset of a rare tumor. World Journal of Cardiovascular Diseases. 2017;**7**:1-9

[53] Thompson KA. Managing benign cardiac tumors. MD Anderson Practices. Onco-Cardiology. 2016;**30**:30-35

[54] Sarjeant JM, Butany J, Cusimano RJ. Cancer of the heart: Epidemiology and management of primary neoplasms and metastases. American Journal of Cardiovascular Drugs. 2003;**3**:407-421

[55] Valente M, Cocco P, Thiene G, Casula R, Poletti A, Milanesi O, et al. Cardiac fibroma and heart transplantation. The Journal of Thoracic and Cardiovascular Surgery. 1993;**106**(6):1208-1212

[56] Cho JM, Danielson GK, Puga FJ, Dearani JA, McGregor CG, Tazelaar HD, et al. Surgical resection of ventricular cardiac fibromas: Early and late results. The Annals of Thoracic Surgery. 2003;**76**(6):1929-1934

[57] Yanagawa B, Mazine A, Chan EY, Barker CM, Gritti M, Reul RM, et al. Surgery for tumors of the heart. Seminars in Thoracic and Cardiovascular Surgery. 2018;**30**(4):385-397

[58] Luo C, Zhu J, Bao C, Ding F, Mei J. Minimally invasive and conventional surgical treatment of primary benign cardiac tumors. Journal of Cardiothoracic Surgery. 2019;**14**(1):76

[59] Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, et al. ESC/ EACTS guidelines for the management of valvular heart disease. European Heart Journal. 2017;**38**(36):2739-2791

[60] Opolski MP, Staruch AD, Jakubczyk M, Min JK, Gransar H, Staruch M, et al. CT angiography for the detection of coronary artery stenoses in patients referred for cardiac valve surgery: Systematic review and meta-analysis. JACC: Cardiovascular Imaging. 2016;**9**(9):1059-1070

[61] Couture P, Denault AY, McKenty S, Boudreault D, Plante F, Perron R, et al. Impact of routine use of intraoperative transesophageal echocardiography during cardiac surgery. Canadian Journal of Anesthesia. 2000;**47**(1):20-26

[62] Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Fleisher LA, et al. AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/ American Heart Association task force on clinical practice guidelines. Journal of the American College of Cardiology. 2017;**70**(2):252-289

[63] Ellouze M, Pellerin M, Jeanmart H, Lebon JS, Bouchard D. Mini right anterior thoracotomy approach versus sternotomy for resection of intracardiac myxoma. Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery. 2018;**13**(4):292-295

[64] Jain S, Maleszewski JJ, Stephenson CR, Klarich KW. Current diagnosis and management of cardiac myxomas. Expert Review of Cardiovascular Therapy. 2015;**13**(4):369-375

[65] Yuan SM. Infected cardiac myxoma: An updated review. Brazilian Journal of Cardiovascular Surgery. 2015;**30**(5):571-578

**41**

**Chapter 4**

Events

*and Peter Puleo*

management guidelines.

management, risk factors

**1. Introduction**

**Abstract**

Coronary Embolic Phenomena:

High-Impact, Low-Frequency

*Qasim Malik, Ambreen Ahmad, Stanislaw P. Stawicki* 

Coronary embolic phenomena (CEP) are difficult to diagnose yet carry potentially devastating clinical consequences. The goal of this chapter is to outline key processes and pathophysiologic mechanisms underlying CEP, primarily in the context of acute coronary syndrome (ACS). Not surprisingly, most reported cases of CEP occur in the left coronary circulation, but some right-sided events have been reported. Overall, causes include thrombotic, septic/infectious, neoplastic, valverelated, and iatrogenic mechanisms such as air embolization. Coronary angiography remains the definitive diagnostic and therapeutic approach, with computed tomography being increasingly utilized. Transthoracic echocardiography (TTE) should be part of a routine work up for patients with suspected CEP. Holter/event monitoring for atrial fibrillation may also be indicated in patients with embolic phenomena. Clinical management includes procedural restoration of coronary blood flow, followed by appropriate anticoagulation or antiplatelet therapy, in conjunction with appropriate treatment of any arrhythmias or other associated cardiac manifestations or conditions. Timely diagnosis, based on a high index of suspicion (especially in high-risk population) may be important in improving morbidity and mortality in affected patients. Since CEPs are often underdiagnosed and may be due to a number of heterogeneous causes, the need arises for increasing provider awareness of these important phenomena, as well as for the implementation of appropriate clinical

**Keywords:** coronary artery embolism, coronary embolic phenomena, diagnosis,

Coronary embolic phenomena (CEP) constitute an under-reported and underdiagnosed set of clinical phenomena, with potentially devastating consequences if not recognized and treated promptly [1–3]. From coronary air embolism to paradoxical venous thromboembolism, CEPs represent an etiologically heterogeneous group of events [4–7]. It has been postulated that CEPs are the underlying cause of up to 3% of acute coronary syndromes (ACS) [6]. Given their rarity, CEPs require a high index of suspicion by the treating clinician [8–10]. In this chapter, we will aim to cover the various processes and pathophysiology underlying this cause of acute coronary

### **Chapter 4**

*Embolic Diseases - Evolving Diagnostic and Management Approaches*

[59] Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, et al. ESC/ EACTS guidelines for the management of valvular heart disease. European Heart Journal. 2017;**38**(36):2739-2791

[60] Opolski MP, Staruch AD, Jakubczyk M, Min JK, Gransar H, Staruch M, et al. CT angiography for the detection of coronary artery stenoses in patients referred for cardiac valve surgery: Systematic review and meta-analysis. JACC: Cardiovascular Imaging.

[61] Couture P, Denault AY, McKenty S, Boudreault D, Plante F, Perron R, et al. Impact of routine use of intraoperative transesophageal echocardiography

2016;**9**(9):1059-1070

during cardiac surgery.

2000;**47**(1):20-26

2017;**70**(2):252-289

Canadian Journal of Anesthesia.

[62] Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Fleisher LA, et al. AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/ American Heart Association task force on clinical practice guidelines. Journal of the American College of Cardiology.

[63] Ellouze M, Pellerin M, Jeanmart H, Lebon JS, Bouchard D. Mini right anterior thoracotomy approach versus sternotomy for resection of intracardiac myxoma. Innovations: Technology and Techniques in Cardiothoracic and Vascular Surgery. 2018;**13**(4):292-295

[64] Jain S, Maleszewski JJ, Stephenson CR, Klarich KW. Current diagnosis and management of cardiac myxomas. Expert Review of Cardiovascular Therapy. 2015;**13**(4):369-375

myxoma: An updated review. Brazilian Journal of Cardiovascular Surgery.

[65] Yuan SM. Infected cardiac

2015;**30**(5):571-578

[50] Shah DJ, Reardon MJ. Case of a hamartoma or hamartoma of a case? The Journal of Thoracic and Cardiovascular Surgery.

Journal of Cardiac Surgery.

[52] Tudor AA, Tschui J, Schmidli J, Schmid RA, Dorn P. Cardiac

paraganglioma—A rare subset of a rare tumor. World Journal of Cardiovascular

[53] Thompson KA. Managing benign cardiac tumors. MD Anderson Practices.

[54] Sarjeant JM, Butany J, Cusimano RJ. Cancer of the heart: Epidemiology and management of primary neoplasms and metastases. American Journal of Cardiovascular Drugs. 2003;**3**:407-421

[55] Valente M, Cocco P, Thiene G, Casula R, Poletti A, Milanesi O, et al. Cardiac fibroma and heart transplantation. The Journal of Thoracic and Cardiovascular Surgery.

[56] Cho JM, Danielson GK, Puga FJ, Dearani JA, McGregor CG, Tazelaar HD, et al. Surgical resection of ventricular cardiac fibromas: Early and late results. The Annals of Thoracic Surgery.

[57] Yanagawa B, Mazine A, Chan EY, Barker CM, Gritti M, Reul RM, et al. Surgery for tumors of the heart. Seminars in Thoracic and Cardiovascular Surgery.

[58] Luo C, Zhu J, Bao C, Ding F, Mei J. Minimally invasive and conventional

surgical treatment of primary benign cardiac tumors. Journal of Cardiothoracic Surgery. 2019;**14**(1):76

1993;**106**(6):1208-1212

2003;**76**(6):1929-1934

2018;**30**(4):385-397

Onco-Cardiology. 2016;**30**:30-35

[51] El-Ashry AA, Cerfolio RJ, Singh SP, McGiffin D. Cardiac paraganglioma.

2018;**155**(1):351-352

2015;**30**(2):135-139

Diseases. 2017;**7**:1-9

**40**
