**Significance of Arterial Endothelial Dysfunction and Possibilities of Its Correction in Silent Myocardial Ischemia and Diabetes Mellitus**

I.P. Tatarchenko, N.V. Pozdnyakova, O.I. Morozova, A.G. Mordovina, S.A. Sekerko and I.A. Petrushin

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53445

#### **1. Introduction**

The high rate of disability and mortality among patients with Diabetes Mellitus (DM) is mainly caused by cardiovascular disorders. The pathogenic effect of a number of specific factors (hyperglycemia, hyperinsulinemia, insulin resistance) accelerates the development and progression of the diseases connected with atherosclerosis. They are the main causes of death among population of industrialized countries. The incidence of cardiovascular disease is 3-4 times higher among patients with Type II DM in comparison with patients having normal carbohydrate metabolism. However, atypical clinical course of coronary heart disease makes diagnosis of coronary insufficiency among patients with DM rather difficult. It results in later detection of disease, i.e. the disease is often detected on the stage of severe complications such as sudden death or circulatory failure [1]. According to Thomas Killip [2], asymptomatic myocardial ischemia occurs 2-4 times more often in diabetes, while Cohn P.F. and Fox K.M. [3] say about 5-fold increased risk of cardiac mortality among patients with asymptomatic myocardial ischemia. It should be noted that the presence of silent myocardial ischemia increases the risk of complications such as acute myocardial infarction and unstable angina [4].

Although pathogenetic mechanisms of the appearance of silent and pain ischemia are consid‐ ered to be the same and they are caused by mismatch between myocardial oxygen demand and coronary blood flow we still do not have a clear answer on the question about causes of asymptomatic myocardial ischemia.

The absence of pain among patients with DM is connected with loss of sensitivity of opioid receptors to adenosine which is one of the mediators of cardiac pain [3]. Other researchers

© 2013 Tatarchenko et al.; licensee InTech. This is an open access article 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. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

believe that the main cause of the development of silent myocardial ischemia is diabetic autonomic neuropathy [5;6]. According to Kempler P. [7], 24-hour monitoring showed that 64.7% patients having DM with diabetic autonomic neuropathy suffered silent ischemia while only 4.1% patients having DM without diabetic autonomic neuropathy suffered silent ischemia.

Endothelial dysfunction of the coronary arteries manifests in reduced coronary flow re‐ serve, inability of vessels to adequate expansion with an increase in myocardial oxygen demand. It has a significant influence on the occurrence and progression of ischemia. Changes in vascular reactivity have an impact on atherogenesis processes, hyperglycemia provokes the primary foci of atheromatous lesions of the vascular wall and creates the conditions for the formation of specific cellular component atheroma [19]. Violation of en‐ dothelial function is believed to be an important independent risk factor for coronary heart disease [20], that is why the correction of endothelial dysfunction and control of tra‐ ditional risk factors for atherosclerosis should be considered as a strategic line of the ef‐

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According to Schachinger V. and colleages [21], patients with risk of coronary atherosclerosis traditionally suffer endothelial dysfunction of the coronary vessels, but it functions as a longterm marker of the progression of atherosclerosis and cardiovascular events when coronary heart disease is diagnosed. However, this assumption is not supported by all the researchers. A significant difference in the prevalence of silent myocardial ischemia, depending on the

Having conducted our research, we investigated the relationship between the severity of silent myocardial ischemia and functional state of arteries endothelium, we studied the significance of violations of vasomotor function with the loss of the ability to flow-dependent vasodilation as a risk factor, which increases the probability of the episodes of silent myocardial ischemia

To conduct the research we formed a group of patients with stable clinical course of coronary heart disease during the previous month. All patients including people with Type II DM had stable sinus rhythm. The research was conducted on condition that the patients took oral antidiabetic drugs. The elimination criteria were Grade 3 hypertension (blood pressure was above 180/110 mmHg); the presence of valvular heart disease and congestive heart failure 3-4 functional class; the presence of chronic liver and renal failure; chronic lung disease with

We observed 128 patients (66 male and 62 female), average age was 59.3±4.7. Each patient signed an agreement to take part in our research as a volunteer. The agreement was adopted

We included patients with coronary heart disease and Type II DM into group 1 (n=60). Duration of diabetes was 6.4±1.5 years. The level of fasting plasma glucose was 7.7±1.5 mmol/ l. Group 2 (n=68) was formed by patients having coronary heart disease without violation of

fective prevention of cardiovascular complications.

**2. The subject and the methods of the research**

presence of DM is a matter of opinion too.

among patients with Type II DM.

by the local ethics committee.

carbohydrate metabolism (table 1).

respiratory failure; a history of cerebral stroke.

Undoubtedly, diagnostic methods allowing the detection of disease before the development of dangerous conditions are important in the absence of characteristic clinical symptoms among patients with DM. Early diagnosis of coronary heart disease is particularly necessary.

The role of endothelial dysfunction in the formation of vascular complications attracts attention of clinicians. The vascular endothelium certainly plays a key role in maintaining normal vascular tone and structure, local homeostasis and processes of cell proliferation of the vascular wall [8, 9]. The vascular endothelium is considered to be metabolically active tissue formed by a corporation of specialized cells. It secretes both vasoconstrictors (angiotensin II, endothelin, free radicals of incompletely oxidized fatty acids, prostaglandin F2 alpha, throm‐ boxane) and vasodilators (nitric oxide (NO), endothelial hyperpolarizing factor, prostacyclin), their effects are balanced under physiological conditions. The dysfunction of endothelial cells causes increased vascular permeability for macromolecules [10], changes in the level of vasoactive substances and vascular expansion and vasospasm respectively [11; 12] and change in the balance of coagulation and anticoagulation systems [13]. However, endothelial dys‐ function most often leads to changes in the vascular lumen. Endothelial cell dysfunction is considered to be the change in the vascular response to the delivery acetylcholine into the bloodstream and hyperemia which normally lead to vasodilatation due to release of NO.

In DM the ability of endothelial cells to synthesize NO is reduced [14; 15], the ability of endothelial cells to release relaxing factors decreases while the formation of vasoconstric‐ tive factors persists or increases, i.e. the imbalance between the neurotransmitters provid‐ ing the best rate for all endothelium-dependent processes is formed. This condition is defined as endothelial dysfunction. The major manifestations of endothelial dysfunction are violation of the endothelium relaxation of blood vessels and increased adhesiveness of endothelial lining [16].

As Tooke J. noted, insulin may affect the endothelium of blood vessels in two ways causing them to either expand or spasm [17]. Binding to its receptors on the surface of endothelial cells insulin may act in two ways. The first way is an activation of NO secretion through the insulin receptor substrate 1 and substrate 2 (IRS-1, IRS-2) and phosphatidylinositol-3-kinase (PI3-K). This mechanism provides a vasodilator and antiatherogenic properties of insulin; it is involved in insulin-dependent delivery of glucose into cells. The second way is implementation of the mitogenic properties of insulin through a cascade of mediators (ras, raf, MEK) that increase the activity of mitogen-activated protein kinase, which ends with cell proliferation and migration of smooth muscle cells, activation of vasoconstrictor factor endothelin-1 and increased blood pressure [18]. The first mechanism appeared not to function in conditions of insulin resistance. It was the first way which was resistant to insulin; therefore, NO molecule was not synthesized. At the same time, the second mechanism retains its high activity, so, hyperinsulinemia has atherogenic effects.

Endothelial dysfunction of the coronary arteries manifests in reduced coronary flow re‐ serve, inability of vessels to adequate expansion with an increase in myocardial oxygen demand. It has a significant influence on the occurrence and progression of ischemia. Changes in vascular reactivity have an impact on atherogenesis processes, hyperglycemia provokes the primary foci of atheromatous lesions of the vascular wall and creates the conditions for the formation of specific cellular component atheroma [19]. Violation of en‐ dothelial function is believed to be an important independent risk factor for coronary heart disease [20], that is why the correction of endothelial dysfunction and control of tra‐ ditional risk factors for atherosclerosis should be considered as a strategic line of the ef‐ fective prevention of cardiovascular complications.

According to Schachinger V. and colleages [21], patients with risk of coronary atherosclerosis traditionally suffer endothelial dysfunction of the coronary vessels, but it functions as a longterm marker of the progression of atherosclerosis and cardiovascular events when coronary heart disease is diagnosed. However, this assumption is not supported by all the researchers. A significant difference in the prevalence of silent myocardial ischemia, depending on the presence of DM is a matter of opinion too.

## **2. The subject and the methods of the research**

believe that the main cause of the development of silent myocardial ischemia is diabetic autonomic neuropathy [5;6]. According to Kempler P. [7], 24-hour monitoring showed that 64.7% patients having DM with diabetic autonomic neuropathy suffered silent ischemia while only 4.1% patients having DM without diabetic autonomic neuropathy suffered silent

Undoubtedly, diagnostic methods allowing the detection of disease before the development of dangerous conditions are important in the absence of characteristic clinical symptoms among patients with DM. Early diagnosis of coronary heart disease is particularly necessary. The role of endothelial dysfunction in the formation of vascular complications attracts attention of clinicians. The vascular endothelium certainly plays a key role in maintaining normal vascular tone and structure, local homeostasis and processes of cell proliferation of the vascular wall [8, 9]. The vascular endothelium is considered to be metabolically active tissue formed by a corporation of specialized cells. It secretes both vasoconstrictors (angiotensin II, endothelin, free radicals of incompletely oxidized fatty acids, prostaglandin F2 alpha, throm‐ boxane) and vasodilators (nitric oxide (NO), endothelial hyperpolarizing factor, prostacyclin), their effects are balanced under physiological conditions. The dysfunction of endothelial cells causes increased vascular permeability for macromolecules [10], changes in the level of vasoactive substances and vascular expansion and vasospasm respectively [11; 12] and change in the balance of coagulation and anticoagulation systems [13]. However, endothelial dys‐ function most often leads to changes in the vascular lumen. Endothelial cell dysfunction is considered to be the change in the vascular response to the delivery acetylcholine into the bloodstream and hyperemia which normally lead to vasodilatation due to release of NO.

In DM the ability of endothelial cells to synthesize NO is reduced [14; 15], the ability of endothelial cells to release relaxing factors decreases while the formation of vasoconstric‐ tive factors persists or increases, i.e. the imbalance between the neurotransmitters provid‐ ing the best rate for all endothelium-dependent processes is formed. This condition is defined as endothelial dysfunction. The major manifestations of endothelial dysfunction are violation of the endothelium relaxation of blood vessels and increased adhesiveness of

As Tooke J. noted, insulin may affect the endothelium of blood vessels in two ways causing them to either expand or spasm [17]. Binding to its receptors on the surface of endothelial cells insulin may act in two ways. The first way is an activation of NO secretion through the insulin receptor substrate 1 and substrate 2 (IRS-1, IRS-2) and phosphatidylinositol-3-kinase (PI3-K). This mechanism provides a vasodilator and antiatherogenic properties of insulin; it is involved in insulin-dependent delivery of glucose into cells. The second way is implementation of the mitogenic properties of insulin through a cascade of mediators (ras, raf, MEK) that increase the activity of mitogen-activated protein kinase, which ends with cell proliferation and migration of smooth muscle cells, activation of vasoconstrictor factor endothelin-1 and increased blood pressure [18]. The first mechanism appeared not to function in conditions of insulin resistance. It was the first way which was resistant to insulin; therefore, NO molecule was not synthesized. At the same time, the second mechanism retains its high activity, so,

ischemia.

42 Ischemic Heart Disease

endothelial lining [16].

hyperinsulinemia has atherogenic effects.

Having conducted our research, we investigated the relationship between the severity of silent myocardial ischemia and functional state of arteries endothelium, we studied the significance of violations of vasomotor function with the loss of the ability to flow-dependent vasodilation as a risk factor, which increases the probability of the episodes of silent myocardial ischemia among patients with Type II DM.

To conduct the research we formed a group of patients with stable clinical course of coronary heart disease during the previous month. All patients including people with Type II DM had stable sinus rhythm. The research was conducted on condition that the patients took oral antidiabetic drugs. The elimination criteria were Grade 3 hypertension (blood pressure was above 180/110 mmHg); the presence of valvular heart disease and congestive heart failure 3-4 functional class; the presence of chronic liver and renal failure; chronic lung disease with respiratory failure; a history of cerebral stroke.

We observed 128 patients (66 male and 62 female), average age was 59.3±4.7. Each patient signed an agreement to take part in our research as a volunteer. The agreement was adopted by the local ethics committee.

We included patients with coronary heart disease and Type II DM into group 1 (n=60). Duration of diabetes was 6.4±1.5 years. The level of fasting plasma glucose was 7.7±1.5 mmol/ l. Group 2 (n=68) was formed by patients having coronary heart disease without violation of carbohydrate metabolism (table 1).

The complex survey included clinical and laboratory studies, 12-lead electrocardiography, Holter ECG monitoring, stress testing (Bruce R. protocol), echocardiography, and ultrasound vascular assessment of endothelium-dependent vasodilation of the brachial artery (BA).

In B-mode we studied the following parameters: vascular permeability; vascular geometry (the correspondence of vascular duct to the anatomical vessel trajectory); the diameter of the vessel (intraluminal); the condition of the vascular wall (the integrity, the thickness of the intima-media (Figure 1.), echogenicity, the degree of differentiation of the layers, the shape of the surface); the state of the vessel lumen (presence, location, length, echogenicity of intralu‐ minal structures, the degree of obstruction); the state of the perivascular tissue (presence, shape, extent, cause extravasal impact). In spectral Doppler mode, we analyzed quantitative indicators of blood flow: peak systolic blood flow velocity (Vps, cm/s); the maximum end diastolic blood flow velocity (Ved, cm/s); diastolic blood flow velocity (Vd, cm/s), evaluated in arteries with high peripheral resistance; maximum blood flow velocity, averaged over time

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(TAMX, cm/s); peripheral resistance index - RI.

**Figure 1.** Assessment of intima-media for ultrasound scanning in B-mode

following formula:

To assess vasomotor function of vascular endothelium, we used a test with reactive hyperemia, i.e. detection of endothelium-dependent vasodilation of the BA by the method of Celermaer D.S. and Sorensen K.E. [22]. The sensor was located in the longitudinal section of a 3 - 4 cm above the elbow. First, the diameter of the BA and the velocity of blood flow through it were measured. Reactive hyperemia was produced by applying a sphygmomanometer cuff on the upper third of the shoulder. During 3-4 minutes we maintained the cuff pressure in this patient greater than systolic pressure by 40 mm Hg. After decompression, the next measurements were carried out in 60 seconds. Endothelium dependent vasodilatation was calculated by the


Note: BMI - Body Mass Index; CHF - Chronic Heart Failure; CD - Cardiovascular Disease; hyper Dyslipidemia- total cholesterol is more than 5.0 mmol/l and/or low-density lipoprotein cholesterol is more than 3 mmol/l when high density lipoprotein cholesterol is less than 1 mmol/l; n - the absolute number of individuals with this figure; % - number of persons with this figure from the total number of persons enrolled in the study.

#### **Table 1.** Clinical characteristics of patients

Vascular Doppler ultrasound was conducted before 10 a.m. when a patient was fasting. The patient had a 10-minute rest before the test. During the test the patient was lying on his/her back. Having scanned the common carotid artery, the brachial artery, common femoral artery and tibial arteries we used a linear detector with the ability to visualize the image in the frequency range 5-12 Hz.

In B-mode we studied the following parameters: vascular permeability; vascular geometry (the correspondence of vascular duct to the anatomical vessel trajectory); the diameter of the vessel (intraluminal); the condition of the vascular wall (the integrity, the thickness of the intima-media (Figure 1.), echogenicity, the degree of differentiation of the layers, the shape of the surface); the state of the vessel lumen (presence, location, length, echogenicity of intralu‐ minal structures, the degree of obstruction); the state of the perivascular tissue (presence, shape, extent, cause extravasal impact). In spectral Doppler mode, we analyzed quantitative indicators of blood flow: peak systolic blood flow velocity (Vps, cm/s); the maximum end diastolic blood flow velocity (Ved, cm/s); diastolic blood flow velocity (Vd, cm/s), evaluated in arteries with high peripheral resistance; maximum blood flow velocity, averaged over time (TAMX, cm/s); peripheral resistance index - RI.

**Figure 1.** Assessment of intima-media for ultrasound scanning in B-mode

The complex survey included clinical and laboratory studies, 12-lead electrocardiography, Holter ECG monitoring, stress testing (Bruce R. protocol), echocardiography, and ultrasound vascular assessment of endothelium-dependent vasodilation of the brachial artery (BA).

n= 60

35 / 58.3 21 / 35

14 24 22

48 / 80 52 / 86.7

6.4 ± 1.5 12.3 ± 3.5 8.7 ± 2.2

Note: BMI - Body Mass Index; CHF - Chronic Heart Failure; CD - Cardiovascular Disease; hyper Dyslipidemia- total cholesterol is more than 5.0 mmol/l and/or low-density lipoprotein cholesterol is more than 3 mmol/l when high density lipoprotein cholesterol is less than 1 mmol/l; n - the absolute number of individuals with this figure; % - number of persons

Vascular Doppler ultrasound was conducted before 10 a.m. when a patient was fasting. The patient had a 10-minute rest before the test. During the test the patient was lying on his/her back. Having scanned the common carotid artery, the brachial artery, common femoral artery and tibial arteries we used a linear detector with the ability to visualize the image in the

Group 2 n= 68

20 / 69.7 10 / 30.3

15 28 25

8 / 11.8 61 / 89.7

5.9 ± 3.2 13.4 ± 3.5 -

**Rate** Group 1

Arterial hypertension degree (n/%) I

44 Ischemic Heart Disease

Stable angina (n): I Functional Class II Functional Class III Functional Class

DM (n/%) CD (n/%)

Burdened hereditary history

Duration of illness (years) coronary heart disease arterial hypertension diabetes mellitus

II

Male/Female (n) 26 / 34 40 / 28 Age (years) 59.8 ± 4.3 58.7 ± 4.8 Smoking (Male/Female, n) 24 / 5 32 / 4 BMI (kg/м²) 33.1 ± 3.6 28.7 ± 3.1

hyper Dyslipidemia (n/%) 54 / 90 53 / 77.9 signs of CHF,% 42 / 60 37 / 54.4

with this figure from the total number of persons enrolled in the study.

**Table 1.** Clinical characteristics of patients

frequency range 5-12 Hz.

To assess vasomotor function of vascular endothelium, we used a test with reactive hyperemia, i.e. detection of endothelium-dependent vasodilation of the BA by the method of Celermaer D.S. and Sorensen K.E. [22]. The sensor was located in the longitudinal section of a 3 - 4 cm above the elbow. First, the diameter of the BA and the velocity of blood flow through it were measured. Reactive hyperemia was produced by applying a sphygmomanometer cuff on the upper third of the shoulder. During 3-4 minutes we maintained the cuff pressure in this patient greater than systolic pressure by 40 mm Hg. After decompression, the next measurements were carried out in 60 seconds. Endothelium dependent vasodilatation was calculated by the following formula:

Endothelium dependent vasodilatation= ((BA diameter after the test - initial diameter of the BA)/initial diameter of the BA)×100%.

Statistical processing and analysis of the results obtained are presented in the system of statistical analysis STATISTIKA (the package of applied programs STATISTIKA by company

Significance of Arterial Endothelial Dysfunction and Possibilities of Its Correction in Silent Myocardial...

In countries that have achieved significant success in treatment and prevention of coronary heart disease, patients with DM are the only group in which the death rate from this disease has slightly decreased among men and increases among women [24]. In this connection, the data of clinical analysis and comparative evaluation of ischemic episodes based on the results of daily monitoring of ECG and stress testing in groups I and II (Table 2) are of considerable

n=60

1.53 ± 0.4 2.5 ± 0.2\*

116 ± 2.3 97 ± 1.9\*

Note: DMI - Daily Myocardial Ischemia (duration of ischemic episodes per day); SMI - Silent Myocardial Ischemia; PEMI -

Painful Episode of Myocardial Ischemia; VA - Ventricular Arrhythmia; \*- р < 0.05 – a significant difference.

The presence of SMI (n) 56 / 93.3%\* 40 / 58.8% Number of painful episode of myocardial ischemia 2.1 ± 0.3 2.1 ± 0.43 Number of silent myocardial ischemia 2.8 ± 0.4\* 1.1 ± 0.3 DMI (min) 45.3 ± 3.2\* 33.6 ± 2.4 PEMI (min) 14.7 ± 2.5 15.2 ± 1.7 Silent myocardial ischemia (min) 31.1 ± 2.1\* 18.6 ± 2.2

VA during episodes of ischemia (n/%) 12 / 20\* 8 / 11.8 The volume of work done (Watt) 400 ± 20\* 580 ± 20 The threshold power of load (Watt) 66.5 ± 2.3\* 83.3 ± 2.8

ST segment depression (min) 6.7 ± 0.3\* 8.6 ± 0.4 Time of pain occurrence (min) 7.3 ± 0.4 8.5 ± 0.7 The number of leads with ST depression 6.3 ± 0.4\* 4.4 ± 0.2

Group 2 n=68

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47

1.5 ± 0.2 1.8 ± 0.3

122 ± 1.8 108 ± 3.1

StatSoft Inc., Version 6.0.).

interest.

average maximum

**3. The results of the research and the discussion**

**Rate** Group 1

The depth of ST segment depression (mm)

**Table 2.** Comparative analysis of functional methods

Average heart rate(beats / min) at the beginning of PEMI at the beginning of SMI

Time of occurrence

The degree of increase in BA diameter of more than 10% was regarded as a preserved endo‐ thelium dependent vasodilatation. In violation of endothelium vasomotor function of BA diameter increase was less than 10%. We got more information on the status of endothelial vasomotor function using the method of transcranial duplex scanning with the stress test, which activates the metabolic mechanisms of influence on the endothelium, i.e. breath holding test. We analyzed the nature of response to the functional stress test, taking into account the index of reactivity:


ECG monitoring was conducted in the ordinary daily routine of a patient. The patient was to keep a diary during ECG recording; he or she recorded the nature of his/her activities and his/ her state of health in detail. Besides a computer decoding, the analysis of the results of our research included visual viewing of individual fragments of the ECG recording, which increased the reliability of conclusions. We analyzed ischemic changes, taking into account corrections of the original position in ST segment whether it was ST segment elevation or depression (Figure 2.).

**Figure 2.** Variant of ischemic ST segment depression

When evaluating each episode, we noted the presence or absence of pain (according to a patient's diary or a marker on the monitor records; we calculated the total duration of daily depression of ST segment (daily myocardial ischemia), a maximum depth of ST segment depression (↓STmax), heart rate (HR) at the beginning of painful and painless episodes of ST displacement.

Statistical processing and analysis of the results obtained are presented in the system of statistical analysis STATISTIKA (the package of applied programs STATISTIKA by company StatSoft Inc., Version 6.0.).

## **3. The results of the research and the discussion**

Endothelium dependent vasodilatation= ((BA diameter after the test - initial diameter of the

The degree of increase in BA diameter of more than 10% was regarded as a preserved endo‐ thelium dependent vasodilatation. In violation of endothelium vasomotor function of BA diameter increase was less than 10%. We got more information on the status of endothelial vasomotor function using the method of transcranial duplex scanning with the stress test, which activates the metabolic mechanisms of influence on the endothelium, i.e. breath holding test. We analyzed the nature of response to the functional stress test, taking into account the

ECG monitoring was conducted in the ordinary daily routine of a patient. The patient was to keep a diary during ECG recording; he or she recorded the nature of his/her activities and his/ her state of health in detail. Besides a computer decoding, the analysis of the results of our research included visual viewing of individual fragments of the ECG recording, which increased the reliability of conclusions. We analyzed ischemic changes, taking into account corrections of the original position in ST segment whether it was ST segment elevation or

When evaluating each episode, we noted the presence or absence of pain (according to a patient's diary or a marker on the monitor records; we calculated the total duration of daily depression of ST segment (daily myocardial ischemia), a maximum depth of ST segment depression (↓STmax), heart rate (HR) at the beginning of painful and painless episodes of ST

BA)/initial diameter of the BA)×100%.

**1.** positive - the index of reactivity was from 1.1 to 1.4;

**3.** paradoxical - the index of reactivity was less than 0.9 [23].

**2.** negative - the index of reactivity was 0.9 to 1.1;

index of reactivity:

46 Ischemic Heart Disease

depression (Figure 2.).

**Figure 2.** Variant of ischemic ST segment depression

displacement.

In countries that have achieved significant success in treatment and prevention of coronary heart disease, patients with DM are the only group in which the death rate from this disease has slightly decreased among men and increases among women [24]. In this connection, the data of clinical analysis and comparative evaluation of ischemic episodes based on the results of daily monitoring of ECG and stress testing in groups I and II (Table 2) are of considerable interest.


Note: DMI - Daily Myocardial Ischemia (duration of ischemic episodes per day); SMI - Silent Myocardial Ischemia; PEMI - Painful Episode of Myocardial Ischemia; VA - Ventricular Arrhythmia; \*- р < 0.05 – a significant difference.

**Table 2.** Comparative analysis of functional methods

In group 1 we observed periods of silent ischemia among 93.3% patients, painful episodes of myocardial ischemia were detected in the form of compressive retrosternal pain, discomfort in the chest and dyspnea among 66.7% patients. When analyzing daily trend of ST segment and patients' diary records, we registered a combination of painful episodes of myocardial ischemia and silent myocardial ischemia in 60% cases. Only 6.7% patients with Type II DM had painful episodes of myocardial ischemia while 33.3% patients had ischemic depression episodes of ST segment without any subjective manifestations. That was a significant differ‐ ence in comparison with the corresponding figures in group 2, χ<sup>2</sup> =5.4 (p<0.05).

patients having coronary heart disease and DM than among patients with coronary heart disease without violation of carbohydrate metabolism. Ratio silent myocardial ischemia/ painful episodes of myocardial ischemia was 1.29 in group 1, and it exceeded the same

However, in our opinion, the pathogenesis of silent myocardial ischemia with violation of carbohydrate metabolism is complex; it appears to be related not only to autonomous cardiac neuropathy, but also to the development of angiopathy, microcirculation disturbance.

It should be noted that the presence and severity of endothelial dysfunction among patients with documented lesions of coronary arteries is a proven marker of poor prognosis [25]. However, this large-scale destruction of the vascular bed does not occur for any other disease, like DM; this is due to the influence of hyperglycemia on the primary target cell, vascular endothelium. Studies carried out in a clinical setting, showed that in DM endothelial dysfunc‐

When studying functional characteristics of vascular endothelium in the analyzed groups we paid special attention to the results on detecting endothelium-dependent vasodilation of the

Diameter of the BA (mm) 3.8 ± 0.19 3.94 ± 0.11\*\* 4.07 ± 0.18 4.57 ± 0.12\* Vps (m/s) 0.62 ± 0.04 0.84 ± 0.06 0.64 ± 0.05 0.92 ± 0.04\* Ved (m/s) 0.10 ± 0.05 0.13 ± 0.03 0.12 ± 0.06 0.16 ± 0.03\* ТАМX (m/s) 0.12 ± 0.03 0.29 ± 0.06\*\* 0.13± 0.02 0.43 ± 0.04\*

Note: Vps - Peak systolic blood flow velocity; Ved - maximum end diastolic flow velocity; ТАМX - the time-averaged maximum velocity of blood flow; EDV BA - endothelium dependent vasodilation of brachial artery; \*- р< 0.05 - reliability of differences between parameters obtained initially and after the test; \*\* - р< 0.05 - difference is reliable between

The original diameter of the BA did not differ significantly in the analyzed groups; it was 3.8±0.19 mm and 4.07±0.18 mm, respectively. Evaluating the mechanism of endothelial regulation of vascular tone among patients in group 1, in the presence of DM, we diagnosed vasomotor endothelial dysfunction induced by shear stress in all cases. The diameter of the BA increased after removal of the cuff by only 3.7±1.1% of the initial indicator in the group. At the same time 53.3% (32) of patients had violation of endothelial vasomotor function as a lack of vasodilating effect, i.e., less than 10% of the original value, 26.7% (16) of patients had violation of endothelial vasomotor function as the lack of increase in BA diameter, and 20%

EDV BA (%) 3.7 ± 1.1\*\* 12.3 ± 2.1%

**Table 3.** Performance test with reactive hyperemia in groups of patients

**Group 1 Group 2 initially after the test initially after the test**

tion is associated with microangiopathy and atherosclerosis [26; 27].

=3.84, р<0.05).

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indicator among patients of group 2 – 0.52 (χ<sup>2</sup>

BA (Table 3).

**Rate**

indicators of group 1 and group 2.

In group 2 episodes of silent myocardial ischemia were detected in 9 (13.2%) cases during a day, the detection rate of painful episodes of myocardial ischemia was 59 (88.6%) cases, 28 (41.2%) patients having had only painful episodes of myocardial ischemia. According to diary records, 51.7% patients with coronary heart disease had a combination of painful episodes of myocardial ischemia and silent myocardial ischemia. A significant difference was obtained by assessing the duration of all episodes of myocardial ischemia during the day in group 1 and group 2, it was 45.3±3.2 min and 33.6±2.4 min< p<0.03 accordingly.

The average depth of ST segment depression did not differ significantly among patients of both groups. However, maximum depth of ST depression in group 1 exceeded the same indicator in group 2, it was 2.4±0.2 mm and 1.6±0.3 mm, p<0.05 accordingly. The value of heart rate at the beginning of pain and painless episodes did not differ significantly according to groups.

The amount of work done and threshold power were lower among patients of group 1 than patients of group 2. 85% patients of group 1 had ischemic displacement of ST segment, it was detected in more than 6-lead ECG during stress testing.

Measuring the ability to perceive pain which is associated with transient myocardial ischemia has a prognostic value in stable angina. Angina/the equivalent of angina is a signal for patients to regulate their daily physical activity.

We should note that later attack of pain with a delay relatively to the ischemic ST segment shift was detected among 27(45%) patients of group 1 during stress test. In 31 (51.7%) cases the emergence of pain coincided with the appearance of ischemic symptoms on the electrocar‐ diogram. However, in 2 cases the pain occurred before the appearance of ST depression. Having analyzed the results, we obtained different data in group 2: the number of patients with premature/simultaneous appearance of angina/its equivalent was 85.3% and it exceeded the number of patients with late appearance of pain attack (14.7%), p<0.02. We assume that data on the detection rate during stress testing of patients with the later occurrence of the attack/equivalent of angina with respect to ischemic ST segment shift (45% and 14.7% - p<0.03 respectively), obtained in group 1 in comparison with group 2 may be explained by increased sensitivity to pain among patients with insulin resistant diabetes. It is associated with a change in neuronal component of pain inhibition system, which includes not only the conductors of pain sensitivity, but peripheral receptors in the myocardium.

The data obtained are consistent with the results of daily monitoring of the ECG. The proba‐ bility of occurrence of asymptomatic episodes of ST depression is significantly higher among patients having coronary heart disease and DM than among patients with coronary heart disease without violation of carbohydrate metabolism. Ratio silent myocardial ischemia/ painful episodes of myocardial ischemia was 1.29 in group 1, and it exceeded the same indicator among patients of group 2 – 0.52 (χ<sup>2</sup> =3.84, р<0.05).

In group 1 we observed periods of silent ischemia among 93.3% patients, painful episodes of myocardial ischemia were detected in the form of compressive retrosternal pain, discomfort in the chest and dyspnea among 66.7% patients. When analyzing daily trend of ST segment and patients' diary records, we registered a combination of painful episodes of myocardial ischemia and silent myocardial ischemia in 60% cases. Only 6.7% patients with Type II DM had painful episodes of myocardial ischemia while 33.3% patients had ischemic depression episodes of ST segment without any subjective manifestations. That was a significant differ‐

In group 2 episodes of silent myocardial ischemia were detected in 9 (13.2%) cases during a day, the detection rate of painful episodes of myocardial ischemia was 59 (88.6%) cases, 28 (41.2%) patients having had only painful episodes of myocardial ischemia. According to diary records, 51.7% patients with coronary heart disease had a combination of painful episodes of myocardial ischemia and silent myocardial ischemia. A significant difference was obtained by assessing the duration of all episodes of myocardial ischemia during the day in group 1 and

The average depth of ST segment depression did not differ significantly among patients of both groups. However, maximum depth of ST depression in group 1 exceeded the same indicator in group 2, it was 2.4±0.2 mm and 1.6±0.3 mm, p<0.05 accordingly. The value of heart rate at the beginning of pain and painless episodes did not differ significantly according to

The amount of work done and threshold power were lower among patients of group 1 than patients of group 2. 85% patients of group 1 had ischemic displacement of ST segment, it was

Measuring the ability to perceive pain which is associated with transient myocardial ischemia has a prognostic value in stable angina. Angina/the equivalent of angina is a signal for patients

We should note that later attack of pain with a delay relatively to the ischemic ST segment shift was detected among 27(45%) patients of group 1 during stress test. In 31 (51.7%) cases the emergence of pain coincided with the appearance of ischemic symptoms on the electrocar‐ diogram. However, in 2 cases the pain occurred before the appearance of ST depression. Having analyzed the results, we obtained different data in group 2: the number of patients with premature/simultaneous appearance of angina/its equivalent was 85.3% and it exceeded the number of patients with late appearance of pain attack (14.7%), p<0.02. We assume that data on the detection rate during stress testing of patients with the later occurrence of the attack/equivalent of angina with respect to ischemic ST segment shift (45% and 14.7% - p<0.03 respectively), obtained in group 1 in comparison with group 2 may be explained by increased sensitivity to pain among patients with insulin resistant diabetes. It is associated with a change in neuronal component of pain inhibition system, which includes not only the conductors of

The data obtained are consistent with the results of daily monitoring of the ECG. The proba‐ bility of occurrence of asymptomatic episodes of ST depression is significantly higher among

=5.4 (p<0.05).

ence in comparison with the corresponding figures in group 2, χ<sup>2</sup>

group 2, it was 45.3±3.2 min and 33.6±2.4 min< p<0.03 accordingly.

detected in more than 6-lead ECG during stress testing.

pain sensitivity, but peripheral receptors in the myocardium.

to regulate their daily physical activity.

groups.

48 Ischemic Heart Disease

However, in our opinion, the pathogenesis of silent myocardial ischemia with violation of carbohydrate metabolism is complex; it appears to be related not only to autonomous cardiac neuropathy, but also to the development of angiopathy, microcirculation disturbance.

It should be noted that the presence and severity of endothelial dysfunction among patients with documented lesions of coronary arteries is a proven marker of poor prognosis [25]. However, this large-scale destruction of the vascular bed does not occur for any other disease, like DM; this is due to the influence of hyperglycemia on the primary target cell, vascular endothelium. Studies carried out in a clinical setting, showed that in DM endothelial dysfunc‐ tion is associated with microangiopathy and atherosclerosis [26; 27].

When studying functional characteristics of vascular endothelium in the analyzed groups we paid special attention to the results on detecting endothelium-dependent vasodilation of the BA (Table 3).


Note: Vps - Peak systolic blood flow velocity; Ved - maximum end diastolic flow velocity; ТАМX - the time-averaged maximum velocity of blood flow; EDV BA - endothelium dependent vasodilation of brachial artery; \*- р< 0.05 - reliability of differences between parameters obtained initially and after the test; \*\* - р< 0.05 - difference is reliable between indicators of group 1 and group 2.

**Table 3.** Performance test with reactive hyperemia in groups of patients

The original diameter of the BA did not differ significantly in the analyzed groups; it was 3.8±0.19 mm and 4.07±0.18 mm, respectively. Evaluating the mechanism of endothelial regulation of vascular tone among patients in group 1, in the presence of DM, we diagnosed vasomotor endothelial dysfunction induced by shear stress in all cases. The diameter of the BA increased after removal of the cuff by only 3.7±1.1% of the initial indicator in the group. At the same time 53.3% (32) of patients had violation of endothelial vasomotor function as a lack of vasodilating effect, i.e., less than 10% of the original value, 26.7% (16) of patients had violation of endothelial vasomotor function as the lack of increase in BA diameter, and 20% (12) of patients had violation of endothelial vasomotor function in the form of pathological vasoconstriction.

**Rate** Group 1

The presence of atherosclerotic plaques in the arteries of

between indicators of group 1 and group 2

negative only in 5 (7.35%) cases.

reaction with reduced velocity parameters of the MCA.

cerebrovascular reactivity

and SFA).

the lower limbs (n/%)

Thickness of IMC of the CFA (mm) 1.32 ± 0.07 1.18 ± 0.09

Thickness of IMC of CCA (mm) 1.24 ± 0,06 1.12 ± 0.08 The presence of atherosclerotic plaques in CCA (n/%) 40 / 66.7 29 / 42.6

Vps (cm/s) 75.3 ± 11.4\*\* 79.2 ± 9.2 TAMX (cm/s) 37. 7 ± 8.5\*\* 39.6 ± 7.63 RI 0.52 ± 0.06\*\* 0.6 ± 0.05

Vps (cm/s) 76.2 ± 12.2\*\* 96.2 ± 10.61\* TAMX (cm/s) 38.2 ± 4.9\*\* 57.02 ± 11.2\* RI 0.51 ±0.10\*\* 0.55 ± 0.09\*

**Table 4.** Analysis of the intima-media complex of the arteries in the two groups with the assessment of

*initial indices of blood flow in the MCA*

*indices of blood flow in the MCA after the test with breath-holding*

Note: CFA - common femoral artery; CCA - common carotid artery; MCA - middle cerebral artery; Vps - Peak systolic blood flow velocity; ТАМX - the time-averaged maximum velocity of blood flow; RI - index of peripheral resistance; \*- р< 0.05 reliability of differences between parameters obtained initially and after the test; \*\* - р< 0.05 - difference is reliable

Atherosclerotic vascular changes suffered by patients without DM differed from those of patients with DM. In group 2 we recorded diffuse irregular thickening of the intima-media complex with an increase of its echogenicity, sometimes with loss of differentiation of the layers mainly in large arteries (55.9% cases were in the CCA, 70.6% were in the CFA and SFA, 54.4% were in the PA, 45.6% were in the PTA and ATA), combined with abnormal thickening and the presence of atherosclerotic plaques (42.6% cases were in the CCA, 57.4% were in the CFA

The analysis of cerebral reactivity in group 1 showed that the response on the metabolic stimulation was negative among 52 (86.7%) patients; 6 (10%) patients had a paradoxical

Initial indices in group 2 did not differ significantly from the corresponding figures in group 1. However, having done breath holding test, we had a reliable increase by 16% in Vps and by 30% in TAMX (p<0.05). The reaction on the metabolic vasodilating test in the MCA was

These data suggest that patients with coronary heart disease and violation of carbohydrate metabolism in the peripheral blood vessels suffered the changes which had two-side and

n=60

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57 / 95 39 / 57.4\*

An interesting fact is that endothelial dysfunction induced by shear stress was detected in the form of lack of increase in BA diameter and pathological vasoconstriction among patients with Type II DM (33.3% of the total number of patients in group 1) having episodes of silent myocardial ischemia without subjective symptoms, it was 15% и 18.3% of cases accordingly.

Correlation analysis showed a significant negative correlation between endothelial dysfunc‐ tion and the presence of silent myocardial ischemia (R= -0.68, p<0.01), duration of episodes of silent myocardial ischemia (R= -0.53, p<0.01), lag time of pain in relation to coronary ST depression (R= -0.61, p<0.01) in group 1.

We have received reliable dependence of endothelium dependent vasodilation from the functional class (FC) of angina (R= -0.4215, p <0.04): endothelium dependent vasodilation was 2.4±0.3% in stable angina of FC III, that was significantly less than similar indicator among patients with angina of FC I and FC II, it was 5.2± 0.2% and 4.05±0.15% (p <0.03), respectively.

In group 2 index of endothelium dependent vasodilation of BA was 12.3±2.1%. We did not reveal any violations of the vasomotor function of vascular endothelium among 44.1% (30) of patients of this group (endothelium dependent vasodilation was more than 10%). Endothelial dysfunction was registered in 38 (40%) cases: in 29 (42.6%) cases patients suffered lack of growth in BA diameter (endothelium dependent vasodilation was less than 10%), 7 (10.3%) patients had no increase in BA diameter and only 2(3%) patients suffered pathological vasoconstriction.

In Doppler test of linear velocity rates of blood flow of BA (peak systolic blood flow velocity (Vps), maximum end diastolic flow velocity (Ved)), the time-averaged maximum velocity of blood flow (ТАМX) did not differ significantly in the groups. However, the degree of increase of the velocity indicators in comparison with reactive hyperemia test was significantly higher in group 2, which also shows a decrease in vasodilating reserve in group 2.

Table 4 presents the results of the analysis of quantitative and qualitative assessment of intimamedia complex (IMC) of the arteries of the lower limb arteries, common carotid artery (CCA) and the analysis of cerebrovascular reactivity in these tests with breath-holding.

The thickness of IMC of patients in group 1 was 1.24±0,06 mm in the CCA, in the common femoral artery (CFA) it was 1.32±0.07 mm, the numerical values of these indices were higher than similar indicators among patients of group 2, p<0.05. Doing a qualitative analysis of the IMC state we revealed three different types of changes among patients with Type II DM: diffuse uniform thickening of the IMC with the appearance of additional layers of high and low echogenicity in the structure of the intima-media in the CFA, the superficial femoral artery (SFA), the popliteal artery (PA), the posterior tibial artery (PTA), the anterior tibial artery (ATA) (100% patients); in the CCA (95% patients); presence of multiple local zones of increased echogenicity with visualization of atherosclerotic plaques in the structure of IMC (95% were in the PTA and the ATA, 80% were in the PA, 71.7% were in the CFA and SFA; 66.7% patients had it the CCA), increased echogenicity of IMC with the complete loss of its differentiation into the layers (13% of cases were in the CCA).

Significance of Arterial Endothelial Dysfunction and Possibilities of Its Correction in Silent Myocardial... http://dx.doi.org/10.5772/53445 51


(12) of patients had violation of endothelial vasomotor function in the form of pathological

An interesting fact is that endothelial dysfunction induced by shear stress was detected in the form of lack of increase in BA diameter and pathological vasoconstriction among patients with Type II DM (33.3% of the total number of patients in group 1) having episodes of silent myocardial ischemia without subjective symptoms, it was 15% и 18.3% of cases accordingly. Correlation analysis showed a significant negative correlation between endothelial dysfunc‐ tion and the presence of silent myocardial ischemia (R= -0.68, p<0.01), duration of episodes of silent myocardial ischemia (R= -0.53, p<0.01), lag time of pain in relation to coronary ST

We have received reliable dependence of endothelium dependent vasodilation from the functional class (FC) of angina (R= -0.4215, p <0.04): endothelium dependent vasodilation was 2.4±0.3% in stable angina of FC III, that was significantly less than similar indicator among patients with angina of FC I and FC II, it was 5.2± 0.2% and 4.05±0.15% (p <0.03), respectively. In group 2 index of endothelium dependent vasodilation of BA was 12.3±2.1%. We did not reveal any violations of the vasomotor function of vascular endothelium among 44.1% (30) of patients of this group (endothelium dependent vasodilation was more than 10%). Endothelial dysfunction was registered in 38 (40%) cases: in 29 (42.6%) cases patients suffered lack of growth in BA diameter (endothelium dependent vasodilation was less than 10%), 7 (10.3%) patients had no increase in BA diameter and only 2(3%) patients suffered pathological

In Doppler test of linear velocity rates of blood flow of BA (peak systolic blood flow velocity (Vps), maximum end diastolic flow velocity (Ved)), the time-averaged maximum velocity of blood flow (ТАМX) did not differ significantly in the groups. However, the degree of increase of the velocity indicators in comparison with reactive hyperemia test was significantly higher

Table 4 presents the results of the analysis of quantitative and qualitative assessment of intimamedia complex (IMC) of the arteries of the lower limb arteries, common carotid artery (CCA)

The thickness of IMC of patients in group 1 was 1.24±0,06 mm in the CCA, in the common femoral artery (CFA) it was 1.32±0.07 mm, the numerical values of these indices were higher than similar indicators among patients of group 2, p<0.05. Doing a qualitative analysis of the IMC state we revealed three different types of changes among patients with Type II DM: diffuse uniform thickening of the IMC with the appearance of additional layers of high and low echogenicity in the structure of the intima-media in the CFA, the superficial femoral artery (SFA), the popliteal artery (PA), the posterior tibial artery (PTA), the anterior tibial artery (ATA) (100% patients); in the CCA (95% patients); presence of multiple local zones of increased echogenicity with visualization of atherosclerotic plaques in the structure of IMC (95% were in the PTA and the ATA, 80% were in the PA, 71.7% were in the CFA and SFA; 66.7% patients had it the CCA), increased echogenicity of IMC with the complete loss of its differentiation

in group 2, which also shows a decrease in vasodilating reserve in group 2.

and the analysis of cerebrovascular reactivity in these tests with breath-holding.

vasoconstriction.

50 Ischemic Heart Disease

vasoconstriction.

depression (R= -0.61, p<0.01) in group 1.

into the layers (13% of cases were in the CCA).

Note: CFA - common femoral artery; CCA - common carotid artery; MCA - middle cerebral artery; Vps - Peak systolic blood flow velocity; ТАМX - the time-averaged maximum velocity of blood flow; RI - index of peripheral resistance; \*- р< 0.05 reliability of differences between parameters obtained initially and after the test; \*\* - р< 0.05 - difference is reliable between indicators of group 1 and group 2

**Table 4.** Analysis of the intima-media complex of the arteries in the two groups with the assessment of cerebrovascular reactivity

Atherosclerotic vascular changes suffered by patients without DM differed from those of patients with DM. In group 2 we recorded diffuse irregular thickening of the intima-media complex with an increase of its echogenicity, sometimes with loss of differentiation of the layers mainly in large arteries (55.9% cases were in the CCA, 70.6% were in the CFA and SFA, 54.4% were in the PA, 45.6% were in the PTA and ATA), combined with abnormal thickening and the presence of atherosclerotic plaques (42.6% cases were in the CCA, 57.4% were in the CFA and SFA).

The analysis of cerebral reactivity in group 1 showed that the response on the metabolic stimulation was negative among 52 (86.7%) patients; 6 (10%) patients had a paradoxical reaction with reduced velocity parameters of the MCA.

Initial indices in group 2 did not differ significantly from the corresponding figures in group 1. However, having done breath holding test, we had a reliable increase by 16% in Vps and by 30% in TAMX (p<0.05). The reaction on the metabolic vasodilating test in the MCA was negative only in 5 (7.35%) cases.

These data suggest that patients with coronary heart disease and violation of carbohydrate metabolism in the peripheral blood vessels suffered the changes which had two-side and diffuse nature with many sections of lesions, whereas patients without diabetes usually had changes occurring on one side of the peripheral arteries and/or lesion of a single segment of arterial tree. We calculated a negative correlation of thickness of IMC and endothelium dependent vasodilatation (R= -0.8743, р<0.01).

14.3 ± 1.1 episodes) in angina attacks per week and a reduced need (from 12.8 ± 1.3 to 5.3 ±

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According to clinical measurements of blood pressure (BP) a significant reduction in office systolic (SBP) blood pressure and diastolic blood pressure (DBP) was observed among patients being treated with telmisartan during the test appearances, 95% of patients having target BP

According to the ambulatory blood pressure monitoring (ABPM), abnormal profile of blood pressure trend was observed among 88.3% of patients, most of them (75%) forming the category of "non-dippers" (patients with lack of normal physiological reduction in blood pressure at night). However, we identified cases of distorted circadian rhythm with a pre‐

After 40 weeks of the therapy we received reduction in daily average SBP and DBP, time index

We observed a normalization of circadian BP profile among 85% of patients that was 96.2% of patients with abnormal circadian rhythm (non-dipper and night-picker). Therapy with telmisartan allowed us to reduce indicators of the magnitude and rate of morning increase in BP. Thus, the magnitude of morning increase in SBP decreased by 49% and the magnitude of morning increase in DBP decreased by 51.4% while the rate of morning increase in SBP decreased by 69% and the rate of morning increase in DBP decreased by 62.9% (p<0,03).

*circadian blood pressure monitoring indicators* Daily average SBP (mmHg) 148.4 ± 11.3\* 127.1 ± 3.3 Daily average DBP (mmHg) 89.3 ± 6.7\* 77.2 ± 3.1 The daily variability of SBP (mmHg) 21.9 ± 2.8\* 15.2 ± 1.7 The daily variability of DBP (mmHg) 16.4 ± 2.3\* 9.9 ± 1.1 Time index of systolic hypertension in 24 hours (%) 80.4 ± 5.3\* 32.3 ± 5.2 Time index of diastolic hypertension in 24 hours (%) 66.7 ± 3.4\* 22.3 ± 2.5 The rate morning increase of SBP (mmHg/h) 29.7 ± 3.2 9.2 ± 1.4 The rate morning increase of DBP (mmHg/h) 17.8 ± 3.1 6.6 ± 1.0

*circadian ECG monitoring indicators*

Note: differences were significant between the numerical values of initial rates and rates after 40 weeks of therapy with

DMI (min) 45.3 ± 3.2\* 20.7± 1.4 PEMI (min) 14.7 ± 2.5 11.3 ± 1.3 SMI (min) 31.1 ± 2.1\* 9.5 ± 1.5

**Table 5.** Dynamics of functional parameters during therapy with telmisartan

telmisartan.

**Rate Initial After 40 weeks**

1.1 tablets) for short-nitroglycerin per week by the 40th week of observation.

dominantly nocturnal hypertension (13.3%), i.e. the group of "night-pickers".

of hypertension for 24 hours, the variability in SBP and DBP (p<0.05) (Table 5).

level of SBP. Target BP level of DBP was in 96.7% cases, p <0.05.

Neurohumoral disorders should be taken into account in the process of remodeling of the heart and blood vessels. Renin-angiotensin-aldosterone system (RAAS) is very important in the pathophysiological processes that eventually lead to cardiovascular remodeling, increasing the risk of cardiovascular complications [28]. Drug effect on the RAAS should be considered the standard therapeutic procedure. In this connection, study and discussion of metabolic, vascular and organ-protective effects of drugs, suppressing the activity of the RAAS are of special importance. To exclude the development of left ventricular remodeling, impaired left ventricular diastolic function and vasomotor endothelial dysfunction of the arteries from the life of patients with Type II DM is not possible. However, when treating the patients, specific efforts should be directed to slow the progression of these disorders.

We evaluated the effect of antagonist of telmisartan angiotensin II receptor on blood pressure (BP), carbohydrate and lipid metabolism, the parameters of intracardiac hemodynamics and left ventricular remodeling, endothelial vasomotor function of arteries. For 40 weeks Telmi‐ sartan - Mikardis (Boehringer Ingelheim Pharma) was prescribed to 60 patients with coronary heart disease and Type II DM in addition to standard therapy (antiplatelet, statins, peripheral vasodilators, and calcium antagonist in the pro re nata mode, oral hypoglycemic agents). The average dose for the group was 80 mg per day during the first weeks, 40 mg/day were prescribed to 24 patients during the next weeks and 36 patients took 80 mg/day).

The choice of telmisartan which is from the group of angiotensin receptor antagonists (ARA) is dictated by the results of investigations, according to which there may be a substantial difference in the influence of drugs on metabolic processes within the ARA drug group [29; 30]. This difference is explained by different ability of individual ARA to activate proliferator activation receptors by peroxisome of γ type (PPAR-γ), i.e. nuclear factors discovered by their ability to respond to xenobiotics by peroxisomal proliferation in the liver. According to Bakris G. [29], attention to PPAR is paid due to their key role in the regulation of lipid and carbohy‐ drate metabolism in general and in the formation of insulin resistance and Type II DM in particular. The synthesis of PPAR-γ activators gives additional possibilities in the treatment of Type II DM and metabolic syndrome. However, the breadth of the spectrum of their effects allows us to think about the potential of their use in primary and secondary prevention of cardiovascular complications.

To assess the degree of compensation of carbohydrate metabolism, we measured the following indicators: levels of fasting and postprandial (2 hours after eating) blood glucose (mmol/l) at each visit, glycated hemoglobin (HbA1c, %), initially and after 40 weeks of observation.

85% of patients with Type II DM and stable angina who took telmisartan in addition to standard therapy showed subjective improvement in physical condition. Having done the analysis of anginal attacks in the group, we noted a significant reduction (from 21.7 ± 2.1 to

14.3 ± 1.1 episodes) in angina attacks per week and a reduced need (from 12.8 ± 1.3 to 5.3 ± 1.1 tablets) for short-nitroglycerin per week by the 40th week of observation.

diffuse nature with many sections of lesions, whereas patients without diabetes usually had changes occurring on one side of the peripheral arteries and/or lesion of a single segment of arterial tree. We calculated a negative correlation of thickness of IMC and endothelium

Neurohumoral disorders should be taken into account in the process of remodeling of the heart and blood vessels. Renin-angiotensin-aldosterone system (RAAS) is very important in the pathophysiological processes that eventually lead to cardiovascular remodeling, increasing the risk of cardiovascular complications [28]. Drug effect on the RAAS should be considered the standard therapeutic procedure. In this connection, study and discussion of metabolic, vascular and organ-protective effects of drugs, suppressing the activity of the RAAS are of special importance. To exclude the development of left ventricular remodeling, impaired left ventricular diastolic function and vasomotor endothelial dysfunction of the arteries from the life of patients with Type II DM is not possible. However, when treating the patients, specific

We evaluated the effect of antagonist of telmisartan angiotensin II receptor on blood pressure (BP), carbohydrate and lipid metabolism, the parameters of intracardiac hemodynamics and left ventricular remodeling, endothelial vasomotor function of arteries. For 40 weeks Telmi‐ sartan - Mikardis (Boehringer Ingelheim Pharma) was prescribed to 60 patients with coronary heart disease and Type II DM in addition to standard therapy (antiplatelet, statins, peripheral vasodilators, and calcium antagonist in the pro re nata mode, oral hypoglycemic agents). The average dose for the group was 80 mg per day during the first weeks, 40 mg/day were

The choice of telmisartan which is from the group of angiotensin receptor antagonists (ARA) is dictated by the results of investigations, according to which there may be a substantial difference in the influence of drugs on metabolic processes within the ARA drug group [29; 30]. This difference is explained by different ability of individual ARA to activate proliferator activation receptors by peroxisome of γ type (PPAR-γ), i.e. nuclear factors discovered by their ability to respond to xenobiotics by peroxisomal proliferation in the liver. According to Bakris G. [29], attention to PPAR is paid due to their key role in the regulation of lipid and carbohy‐ drate metabolism in general and in the formation of insulin resistance and Type II DM in particular. The synthesis of PPAR-γ activators gives additional possibilities in the treatment of Type II DM and metabolic syndrome. However, the breadth of the spectrum of their effects allows us to think about the potential of their use in primary and secondary prevention of

To assess the degree of compensation of carbohydrate metabolism, we measured the following indicators: levels of fasting and postprandial (2 hours after eating) blood glucose (mmol/l) at each visit, glycated hemoglobin (HbA1c, %), initially and after 40 weeks of observation.

85% of patients with Type II DM and stable angina who took telmisartan in addition to standard therapy showed subjective improvement in physical condition. Having done the analysis of anginal attacks in the group, we noted a significant reduction (from 21.7 ± 2.1 to

prescribed to 24 patients during the next weeks and 36 patients took 80 mg/day).

efforts should be directed to slow the progression of these disorders.

dependent vasodilatation (R= -0.8743, р<0.01).

52 Ischemic Heart Disease

cardiovascular complications.

According to clinical measurements of blood pressure (BP) a significant reduction in office systolic (SBP) blood pressure and diastolic blood pressure (DBP) was observed among patients being treated with telmisartan during the test appearances, 95% of patients having target BP level of SBP. Target BP level of DBP was in 96.7% cases, p <0.05.

According to the ambulatory blood pressure monitoring (ABPM), abnormal profile of blood pressure trend was observed among 88.3% of patients, most of them (75%) forming the category of "non-dippers" (patients with lack of normal physiological reduction in blood pressure at night). However, we identified cases of distorted circadian rhythm with a pre‐ dominantly nocturnal hypertension (13.3%), i.e. the group of "night-pickers".

After 40 weeks of the therapy we received reduction in daily average SBP and DBP, time index of hypertension for 24 hours, the variability in SBP and DBP (p<0.05) (Table 5).

We observed a normalization of circadian BP profile among 85% of patients that was 96.2% of patients with abnormal circadian rhythm (non-dipper and night-picker). Therapy with telmisartan allowed us to reduce indicators of the magnitude and rate of morning increase in BP. Thus, the magnitude of morning increase in SBP decreased by 49% and the magnitude of morning increase in DBP decreased by 51.4% while the rate of morning increase in SBP decreased by 69% and the rate of morning increase in DBP decreased by 62.9% (p<0,03).


Note: differences were significant between the numerical values of initial rates and rates after 40 weeks of therapy with telmisartan.

**Table 5.** Dynamics of functional parameters during therapy with telmisartan

We indicated the positive dynamics of indicators characterizing the process of left ventricular remodeling: a decrease in end-diastolic volume (EDV) and end-systolic volume (ESV) by 7.5% and 8.4%, respectively, and an increase in ejection fraction by 6.6%, p<0.05. The fraction of systolic shortening of the anterior-posterior size of the left ventricular increased by 8.2%.

Daily rates of myocardial ischemia have undergone significant changes: number of ischemic episodes decreased from 4.8±0.34 to 2.3±0.3; maximum depth of ST segment depression decreased from 2.5 ± 0.2 mm to 1.7 ± 0.1 mm; duration of ischemic episodes decreased from 45.3±3.2 min to 20.7 ± 1.4 min. We should emphasize that the positive dynamics was indicated in most cases when we analyzed data on silent myocardial ischemia: duration of all episodes of silent myocardial ischemia decreased during the day (p<0.05) and the number of episodes of silent myocardial ischemia decreased from 2.8±0.4 to 1.2±0.2 per day too.

We explain the result obtained not only by improved circadian BP profile and adequate control, but also by the presumable ability of the drug to effect myocardial blood flow making coronary vasodilation and redistributing blood flow towards the subendocardial layers of myocardium, which are particularly vulnerable to ischemia. We established the correlation of the duration of painless ST segment depression and a daily index of SBP (R= -0.53, p<0.02), daily index of DBP (R= -0.61, p<0.03).

Note: The data are presented in percents, VF - vasomotor function.

hemoglobin (R= -0.56, p <0.05).

of lipids in the body.

for 24 hours (R= -0.64, p<0.003) and the daily index (R= 0.54, p<0.02).

**Figure 3.** Correction of endothelial vasomotor dysfunction of arteries during the course therapy with telmisartan.

We also associate the resulting effect of telmisartan to improve vasomotor endothelial function with the complicated mechanism of regulation of the circadian blood pressure variability. In this sense, control of blood pressure with ARA group drugs can be considered reasonable in terms of impact on the pathophysiological mechanisms leading to the morning increase of BP, and in terms of protection of patients at the beginning of drug action during the regular morning drug intake. This fact may be proved by revealed correlation dependence of the endothelium dependent vasodilatation dynamics from the time index of hypertension on DBP

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Conducting therapy with telmisartan, we noted a significant decrease in glycated hemoglobin level from 8.41±0.2% to 6.5±0.4%, a decrease of fasting plasma glucose from 8.72±0.35 mmol/l to 6.67±0.4 mmol/l (p<0.02) and a decrease of postprandial blood glucose level from 9.2±1.68 to 8.5±1.38 mmol/l (p<0.05). The number of patients who achieved compensation of carbohy‐ drate metabolism in three indices of "glycemic triad" rose from 10% to 23.3%. We indicated the correlation dependence of endothelium dependent vasodilation dynamics from glycated

We evaluated the dynamics of lipid metabolism indices among patients with Type II DM during therapy with telmisartan. After 40 weeks we noted an improvement of laboratory parameters which showed a decrease in total cholesterol by 23%, low-density lipoprotein cholesterol by 21%, triglycerides by 26% (p<0.05). We explain it by the increase in sensitivity of tissues to insulin and decreased hyperinsulinemia, which largely determine the metabolism

The data obtained allow us to state that telmisartan has a positive metabolic effect, which has an additional metabolic effect along with mechanisms of local pancreatic RAAS blocking being common for all the ARA drugs [33], i.e. agonistic effect on PPAR-ɣ-receptors, which control the activity of cytokines - the regulators of intercellular interactions, leading to a positive

These reactive hyperemia tests allowed us to indicate the improvement of vasomotor function induced by shear stress, endothelium dependent vasodilatation increasing from 3.7±1.1% to 7.2±1.1%. We had positive dynamics of velocity indicators: peak systolic blood flow velocity increased from 0.84±0.06 m/s to 0.94±0.04 m/s (р<0.05); maximum diastolic blood flow velocity increased from 0.13±0.03 m/s to 0.18±0.03 m/s (р<0.05); time-averaged maximum flow velocity increased from 0.29±0.06 to 0.46±0.04 (р<0.05).

Individual analysis of the endothelium dependent vasodilatation dynamics during treat‐ ment with telmisartan showed that the number of patients with impaired endothelial function decreased to 51.7%, while the number of persons with pathological vasoconstric‐ tion/vasodilation in the absence of performing the test with reactive hyperemia decreased by 23.3% (Figure 3.).

Recovery of adequate dilatation response of vessels to reactive hyperemia test is a necessary link in the chain of effective therapeutic intervention aimed at reducing of cardiovascular risk. It is known that activation of the RAAS is an indispensable part of the pathogenesis of endothelial dysfunction, so the use of these drugs in its correction seems most reasonable at present. The mechanism of endothelial function improvement by drugs blocking the RAAS is explained at present by the elimination of the adverse effects of ATII [31; 32] having a powerful vasoconstriction influence by stimulating of AT1-receptor of vascular smooth muscle cells. It is also considered as an inducer of oxidative stress with production of superoxide anion by simulation of nicotinamide-adenine-dinucleotide-phosphate; the action of angiotensin II is opposite to the action of nitric oxide, i.e. oxidase.

Note: The data are presented in percents, VF - vasomotor function.

We indicated the positive dynamics of indicators characterizing the process of left ventricular remodeling: a decrease in end-diastolic volume (EDV) and end-systolic volume (ESV) by 7.5% and 8.4%, respectively, and an increase in ejection fraction by 6.6%, p<0.05. The fraction of systolic shortening of the anterior-posterior size of the left ventricular increased by 8.2%.

Daily rates of myocardial ischemia have undergone significant changes: number of ischemic episodes decreased from 4.8±0.34 to 2.3±0.3; maximum depth of ST segment depression decreased from 2.5 ± 0.2 mm to 1.7 ± 0.1 mm; duration of ischemic episodes decreased from 45.3±3.2 min to 20.7 ± 1.4 min. We should emphasize that the positive dynamics was indicated in most cases when we analyzed data on silent myocardial ischemia: duration of all episodes of silent myocardial ischemia decreased during the day (p<0.05) and the number of episodes

We explain the result obtained not only by improved circadian BP profile and adequate control, but also by the presumable ability of the drug to effect myocardial blood flow making coronary vasodilation and redistributing blood flow towards the subendocardial layers of myocardium, which are particularly vulnerable to ischemia. We established the correlation of the duration of painless ST segment depression and a daily index of SBP (R= -0.53, p<0.02), daily index of

These reactive hyperemia tests allowed us to indicate the improvement of vasomotor function induced by shear stress, endothelium dependent vasodilatation increasing from 3.7±1.1% to 7.2±1.1%. We had positive dynamics of velocity indicators: peak systolic blood flow velocity increased from 0.84±0.06 m/s to 0.94±0.04 m/s (р<0.05); maximum diastolic blood flow velocity increased from 0.13±0.03 m/s to 0.18±0.03 m/s (р<0.05); time-averaged maximum flow velocity

Individual analysis of the endothelium dependent vasodilatation dynamics during treat‐ ment with telmisartan showed that the number of patients with impaired endothelial function decreased to 51.7%, while the number of persons with pathological vasoconstric‐ tion/vasodilation in the absence of performing the test with reactive hyperemia decreased

Recovery of adequate dilatation response of vessels to reactive hyperemia test is a necessary link in the chain of effective therapeutic intervention aimed at reducing of cardiovascular risk. It is known that activation of the RAAS is an indispensable part of the pathogenesis of endothelial dysfunction, so the use of these drugs in its correction seems most reasonable at present. The mechanism of endothelial function improvement by drugs blocking the RAAS is explained at present by the elimination of the adverse effects of ATII [31; 32] having a powerful vasoconstriction influence by stimulating of AT1-receptor of vascular smooth muscle cells. It is also considered as an inducer of oxidative stress with production of superoxide anion by simulation of nicotinamide-adenine-dinucleotide-phosphate; the action of angiotensin II is

of silent myocardial ischemia decreased from 2.8±0.4 to 1.2±0.2 per day too.

DBP (R= -0.61, p<0.03).

54 Ischemic Heart Disease

by 23.3% (Figure 3.).

increased from 0.29±0.06 to 0.46±0.04 (р<0.05).

opposite to the action of nitric oxide, i.e. oxidase.

We also associate the resulting effect of telmisartan to improve vasomotor endothelial function with the complicated mechanism of regulation of the circadian blood pressure variability. In this sense, control of blood pressure with ARA group drugs can be considered reasonable in terms of impact on the pathophysiological mechanisms leading to the morning increase of BP, and in terms of protection of patients at the beginning of drug action during the regular morning drug intake. This fact may be proved by revealed correlation dependence of the endothelium dependent vasodilatation dynamics from the time index of hypertension on DBP for 24 hours (R= -0.64, p<0.003) and the daily index (R= 0.54, p<0.02).

Conducting therapy with telmisartan, we noted a significant decrease in glycated hemoglobin level from 8.41±0.2% to 6.5±0.4%, a decrease of fasting plasma glucose from 8.72±0.35 mmol/l to 6.67±0.4 mmol/l (p<0.02) and a decrease of postprandial blood glucose level from 9.2±1.68 to 8.5±1.38 mmol/l (p<0.05). The number of patients who achieved compensation of carbohy‐ drate metabolism in three indices of "glycemic triad" rose from 10% to 23.3%. We indicated the correlation dependence of endothelium dependent vasodilation dynamics from glycated hemoglobin (R= -0.56, p <0.05).

We evaluated the dynamics of lipid metabolism indices among patients with Type II DM during therapy with telmisartan. After 40 weeks we noted an improvement of laboratory parameters which showed a decrease in total cholesterol by 23%, low-density lipoprotein cholesterol by 21%, triglycerides by 26% (p<0.05). We explain it by the increase in sensitivity of tissues to insulin and decreased hyperinsulinemia, which largely determine the metabolism of lipids in the body.

The data obtained allow us to state that telmisartan has a positive metabolic effect, which has an additional metabolic effect along with mechanisms of local pancreatic RAAS blocking being common for all the ARA drugs [33], i.e. agonistic effect on PPAR-ɣ-receptors, which control the activity of cytokines - the regulators of intercellular interactions, leading to a positive influence on carbohydrate and lipid metabolism and reduction of severity of insulin resistance (IR) phenomenon.

of endothelial function. It leads to the concurrent positive therapeutic effects of telmisartan on major links in the chain of cardiovascular complications in Type II DM improving glucose and blood lipid profile indices, a more pronounced organ protective effect. In addition, it directly

Significance of Arterial Endothelial Dysfunction and Possibilities of Its Correction in Silent Myocardial...

http://dx.doi.org/10.5772/53445

57

The development of ischemic episodes in the absence of pain or angina equivalents (e.g., dyspnea, arrhythmias) is possible when a patient has coronary heart disease. Atypical clinical course makes diagnosis of coronary insufficiency with disorders of carbohydrate metabolism rather difficult. Having done the analysis of the daily trend of ST segment and the diary records of patients with DM we have identified a silent myocardial ischemia in 93.3% cases, 60% patients having a combination of painful and painless episodes of myocardial ischemia. 33.3% from 93.3% cases of ischemic episodes of ST segment depression were not accompanied by any subjective symptoms. Patients with coronary heart disease and DM have reduced endothelium-dependent vasodilation reaction (endothelium-dependent vasodilation =3.7±1.1%). Violation of the functional state of the vascular endothelium correlates with the registration frequency (R= -0.68, p<0.05) and duration of episodes of silent myocardial ischemia

prevents the development of ischemia and its main clinical manifestation.

**Summary**

(R= -0.53, p<0.01).

**Abbreviations**

ATII - angiotensin II BP - blood pressure

ABPM - ambulatory blood pressure monitoring

ARA - angiotensin receptor antagonists

CHD - Coronary Heart Disease

DB2 - Type 2 Diabetes Mellitus

CHF - chronic heart failure

DM - Diabetes Mellitus

ECG – electrocardiogram

FC - Functional Class

IR - insulin resistance

ED - endothelial dysfunction

IMC - Intima-Media Complex

## **4. The conclusion**

So, patients with coronary heart disease and Type II DM had silent myocardial ischemia 2 times more often than patients with coronary heart disease who had no disorders of carbohy‐ drate metabolism. Patients with coronary heart disease and Type II DM had dominating daily duration of episodes of myocardial ischemia and a maximum depth of ST segment depression. Besides, they had reduced endothelium-dependent vasodilation reaction (endotheliumdependent vasodilation =3.7±1.1%). Violation of the functional state of the vascular endothe‐ lium correlates with the registration frequency (R= -0.68, p<0.05) and duration of episodes of silent myocardial ischemia (R= -0.53, p<0.01). Endothelial dysfunction of the coronary arteries which is manifested by blood vessels inability to adequate increase in conditions of increased myocardial oxygen demand has an influence on the genesis and progression of ischemia.

The results obtained during our research prove that metabolic factors play a significant role in the development of endothelial dysfunction. To predict vascular complications it is neces‐ sary to assess vasomotor function of arteries endothelium among patients with Type II DM.

Prescribing receptor antagonists of angiotensin II, we take into account organ-protective effects of drugs, manifested by the selective blockade of the tissue RAAS and indirect stimulation of the AT2-receptors during their long-term intake.

It is considered to be a proved fact [34; 35] that the increased activity of tissue RAAS causes long-term effects of angiotensin II (AII), which are manifested in structural and functional changes in target organs and lead to the development of a number of pathological processes such as hypertrophy, miofibroz, atherosclerotic lesion of vessels. The research [36] showed that a human body had alternative ways with chymase, cathepsin G, serine proteases in addition to ACE-dependent pathway of conversion of angiotensin I to angiotensin II. Accord‐ ing to Elmfeldt D. and colleagues [37], chymase dependent formation of AII prevails in myocardial interstitium and adventitia and media of vessels, whereas ACE-dependent formation prevails in blood plasma. This fact explains the risk of AII escape phenomenon during the long-term intake of ACE (angiotensin-converting enzyme).

Additional metabolic effect of selective antagonist of AT1-receptor of telmisartan is agonistic effect on PPAR-ɣ-receptors, which is manifested in a significantly improved glucose and lipid profiles indices. This effect allows us to consider it as the drug of choice in the treatment of patients suffering a combination of metabolic disorders, hypertension in clinical manifesta‐ tions of stable angina. Correlation analysis showed the dependence of HbA1c on the daily duration of ST depression episodes (R=0.66, p<0.01) and the duration of asymptomatic ST depression (R=0.75, p<0.02).

Modern methods in treatment of patients with coronary heart disease and DM allow using a scheme of the multi-component therapy, in which much attention is given to the improvement of endothelial function. It leads to the concurrent positive therapeutic effects of telmisartan on major links in the chain of cardiovascular complications in Type II DM improving glucose and blood lipid profile indices, a more pronounced organ protective effect. In addition, it directly prevents the development of ischemia and its main clinical manifestation.

## **Summary**

influence on carbohydrate and lipid metabolism and reduction of severity of insulin resistance

So, patients with coronary heart disease and Type II DM had silent myocardial ischemia 2 times more often than patients with coronary heart disease who had no disorders of carbohy‐ drate metabolism. Patients with coronary heart disease and Type II DM had dominating daily duration of episodes of myocardial ischemia and a maximum depth of ST segment depression. Besides, they had reduced endothelium-dependent vasodilation reaction (endotheliumdependent vasodilation =3.7±1.1%). Violation of the functional state of the vascular endothe‐ lium correlates with the registration frequency (R= -0.68, p<0.05) and duration of episodes of silent myocardial ischemia (R= -0.53, p<0.01). Endothelial dysfunction of the coronary arteries which is manifested by blood vessels inability to adequate increase in conditions of increased myocardial oxygen demand has an influence on the genesis and progression of ischemia.

The results obtained during our research prove that metabolic factors play a significant role in the development of endothelial dysfunction. To predict vascular complications it is neces‐ sary to assess vasomotor function of arteries endothelium among patients with Type II DM. Prescribing receptor antagonists of angiotensin II, we take into account organ-protective effects of drugs, manifested by the selective blockade of the tissue RAAS and indirect stimulation of

It is considered to be a proved fact [34; 35] that the increased activity of tissue RAAS causes long-term effects of angiotensin II (AII), which are manifested in structural and functional changes in target organs and lead to the development of a number of pathological processes such as hypertrophy, miofibroz, atherosclerotic lesion of vessels. The research [36] showed that a human body had alternative ways with chymase, cathepsin G, serine proteases in addition to ACE-dependent pathway of conversion of angiotensin I to angiotensin II. Accord‐ ing to Elmfeldt D. and colleagues [37], chymase dependent formation of AII prevails in myocardial interstitium and adventitia and media of vessels, whereas ACE-dependent formation prevails in blood plasma. This fact explains the risk of AII escape phenomenon

Additional metabolic effect of selective antagonist of AT1-receptor of telmisartan is agonistic effect on PPAR-ɣ-receptors, which is manifested in a significantly improved glucose and lipid profiles indices. This effect allows us to consider it as the drug of choice in the treatment of patients suffering a combination of metabolic disorders, hypertension in clinical manifesta‐ tions of stable angina. Correlation analysis showed the dependence of HbA1c on the daily duration of ST depression episodes (R=0.66, p<0.01) and the duration of asymptomatic ST

Modern methods in treatment of patients with coronary heart disease and DM allow using a scheme of the multi-component therapy, in which much attention is given to the improvement

during the long-term intake of ACE (angiotensin-converting enzyme).

(IR) phenomenon.

56 Ischemic Heart Disease

**4. The conclusion**

the AT2-receptors during their long-term intake.

depression (R=0.75, p<0.02).

The development of ischemic episodes in the absence of pain or angina equivalents (e.g., dyspnea, arrhythmias) is possible when a patient has coronary heart disease. Atypical clinical course makes diagnosis of coronary insufficiency with disorders of carbohydrate metabolism rather difficult. Having done the analysis of the daily trend of ST segment and the diary records of patients with DM we have identified a silent myocardial ischemia in 93.3% cases, 60% patients having a combination of painful and painless episodes of myocardial ischemia. 33.3% from 93.3% cases of ischemic episodes of ST segment depression were not accompanied by any subjective symptoms. Patients with coronary heart disease and DM have reduced endothelium-dependent vasodilation reaction (endothelium-dependent vasodilation =3.7±1.1%). Violation of the functional state of the vascular endothelium correlates with the registration frequency (R= -0.68, p<0.05) and duration of episodes of silent myocardial ischemia (R= -0.53, p<0.01).

## **Abbreviations**

ABPM - ambulatory blood pressure monitoring ARA - angiotensin receptor antagonists ATII - angiotensin II BP - blood pressure CHD - Coronary Heart Disease CHF - chronic heart failure DM - Diabetes Mellitus DB2 - Type 2 Diabetes Mellitus ECG – electrocardiogram ED - endothelial dysfunction FC - Functional Class IMC - Intima-Media Complex IR - insulin resistance


#### **Author details**

I.P. Tatarchenko, N.V. Pozdnyakova, O.I. Morozova, A.G. Mordovina, S.A. Sekerko and I.A. Petrushin

[11] Bassenge, E, & Zanziger, J. Nitrates in different vascular beds, nitrate tolerance, and

Significance of Arterial Endothelial Dysfunction and Possibilities of Its Correction in Silent Myocardial...

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59

[12] Cacoub, P, Dorent, R, Nataf, P, et al. Endothelin-1 in the lungs of patients with pulmo‐

[13] Kario, K, Matsuo, T, Kobayashi, H, et al. Hyperinsulinemia and hemostatic abnormal‐ ities are associated with silent lacunar cerebral infarcts in elderly hypertensive subjects.

[14] Luscher, T, Wenzel, R. R, & Noll, G. Local regulation of the coronary circulation in health and disease: role of nitric oxide and endothelin. Europ Heart J (1995). Suppl. C): ,

[15] Cipolla, M. Diabetes and Endothelial Dysfunction: A Clinical Perspective. Endocr Rev

[16] Vanhoutte, P. M, & Boulanger, C. M. Endotheliumdependent responses in hyperten‐

[17] Tooke, J. E. The association between insulin resistance and endotheliopathy. Diab Obes

[18] Folli, F, Saad, M. J, Velloso, L, et al. Crosstalk between insulin and angiotensin II

[19] Ceriello, A, Cavarape, A, Martinelli, L, et al. The post-prandial state in type 2 diabetes and endothelial dysfunction: effects of insulin aspart. Diabet Med (2004). , 21, 171-75.

[20] Hinderliter, A. L, & Caugher, M. Assessing endothelial function as a risk factor for

[21] Schachinger, V, Britten, M. B, & Zeiher, A. M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation

[22] Celermajer, D. S, & Sorensen, K. E. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet (1992). , 340, 1111-15.

[23] Lelyuk, V. G, & Lelyuk, S. E. The technique of ultrasound examination of the vascular system: scanning technology and regulatory indicators. Textbook: (2002).

[24] Campbell, I. Type 2 diabetes mellitus: «The silent killer». Practical Diabetes Int (2001). ,

[25] Suwaidi, J. A, Hamasaki, S, Higano, S. T, et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation (2000). , 101,

[26] Zateyshchikova, A. A, & Zateyshchikov, D. A. Endothelial regulation of vascular tone:

setting, and clinical significance. Cardiology (1998). , 9, 68-80.

signaling systems. Exp Clin Endocrinol Diabetes (1999). , 107, 133-39.

cardiovascular disease. Curr Atheroscler Rep (2003). , 5(6), 506-13.

interactions with endothelial function. Am. J. Cardiol (1992). , 28, 371-74.

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Penza Extension Course Institute for Medical Practitioners, Russia

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NO - Nitrogen Oxide

58 Ischemic Heart Disease

**Author details**

I.A. Petrushin

**References**

1000-12.

PEMI - Painful Episode of Myocardial Ischemia PPAR - peroxisome proliferator activating ɣ-receptor

RAAS - Renin-angiotensin-aldosterone system

I.P. Tatarchenko, N.V. Pozdnyakova, O.I. Morozova, A.G. Mordovina, S.A. Sekerko and

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[2] Killip, T. Silent Myocardial Ischemia: Some good news. Circulation (1997). , 95, 1992-93.

[3] Cohn, P. F, & Fox, K. M. Silent myocardial ischemia. Circulation (2003). , 108, 1263-90.

[4] Schoenenberger, A. W, Jamshidi, P, Kobza, R, et al. Progression of coronary artery disease during long-term follow-up of the Swiss Interventional Study on Silent

[5] Jermendy, G, & Davidovits, Z. Khoor S: Silent coronary artery disease in diabetic patients with cardiac autonomic neuropathy. Diabetes Care (1994). , 17, 1231-32.

[6] Gokcel, A, Aydin, M, & Yalcin, F. Silent coronary artery disease in patients with type

[7] Kempler, P. Neuropathies. Pathomechanism, clinical presentation, diagnosis, therapy/

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[9] Celermajer, D. S. Endothelial dysfunction: does it matter? Is it relevant? J Amer Coll

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**Chapter 4**

**Sex Differences in Sudden Cardiac Death**

Ischemic heart disease continues to be the leading cause of death in most countries and a major health burden, with approximately 50% of deaths due to sudden cardiac death (SCD) [Zipes & Wellens, 1998; Wong et al. 2001; Mazeika 2001]. The increasing prevalence of diabetes will also impact on SCD incidence. Patients with either type 1 or type 2 diabetes have significantly higher mortality and morbidity following acute myocardial infarction (AMI) than do the rest of the population. Other conditions such as hypertension, hypertrophic cardiomyopathy, aortic stenosis and aging may also increase the risk of SCD. Sex differences in prevalence and clinical outcomes are recognised [Bairey et al. 2006; Wake et al. 2007], although many random‐ ized clinical trials do not have adequate numbers of women to allow sex-specific analyses [Xhyheri & Bugiardini 2010; Melloni et al. 2010]. Ischemic heart disease is the primary cause of death for women at all ages, with annual mortality rates for women 35-55 years greater than breast cancer [Bell et al. 2000] and approximately 81% of deaths in low- and middle-income countries [Mosca et al. 2011]. The incidence of SCD differs according to geographical region depending on the prevalence of coronary or ischemic heart disease [Priori et al. 2001]. In the United States, during 1989 to 1998, there was markedly less of a decline in SCD rates among women than for men - women aged 35 to 44 years had a 21% increased SCD rate compared with a 2.8% decline for men of the same age group [Zheng et al. 2001]. During the same period, women were dying of a cardiac arrest before hospital arrival (52%) compared with 42% for men [Shaw et al. 2006]. Compared to males women are generally older when presenting with AMI [Canto et al. 2012] and with women's longer life expectancy, the estimates are expected to rise even further in future decades. Although risk factors for IHD and SCD are often assumed to be similar in women and men, there are also differences. For instance, SCD will occur before any other signs of coronary heart disease in women [de Vreede-Swagemakers et al. 1997; Kannel et al. 1998; Albert et al. 2003] whereas ventricular dysrhythmias following AMI,

> © 2013 Mihailidou et al.; licensee InTech. This is an open access article 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.

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

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

Anastasia Susie Mihailidou, Rebecca Ritchie and

Additional information is available at the end of the chapter

Anthony W. Ashton

**1. Introduction**

http://dx.doi.org/10.5772/55631


## **Sex Differences in Sudden Cardiac Death**

Anastasia Susie Mihailidou, Rebecca Ritchie and Anthony W. Ashton

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55631

## **1. Introduction**

[27] Tatarchenko, I. P, Pozdnyakova, N. V, Mordovina, A. G, & Morozova, O. I. Dysfunction of vascular endothelium in the evaluation of episodes of myocardial ischemia in type

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[33] Lau, T, Carlsson, P. O, & Leung, P. S. Evidence for local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II

[34] Chung, O, & Unger, T. Angiotensin II receptor blockade and end organ protection.

[35] Tatarchenko, I. P, Pozdnyakova, N. V, Mordovina, A. G, Morozova, O. I, Sekerko, S. A, & Petrushin, I. A. Clinical and functional assessment of organ-protective effectiveness of enalapril and telmisartan among patients with hypertension. Cardiology (2011). , 4,

[36] Burnier, M, & Brunner, H. Angiotensin II receptor antagonists. Lancet (2000). , 355,

[37] Elmfeld, D, Olofsson, B, & Meredith, P. The relationships between dose and antihy‐ pertensive effect of four AT1-receptor blockers. Differenc in potency and efficacy. Blood

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Suppl. 1): 26-31.

60 Ischemic Heart Disease

890-99.

16-21.

637-45.

Ischemic heart disease continues to be the leading cause of death in most countries and a major health burden, with approximately 50% of deaths due to sudden cardiac death (SCD) [Zipes & Wellens, 1998; Wong et al. 2001; Mazeika 2001]. The increasing prevalence of diabetes will also impact on SCD incidence. Patients with either type 1 or type 2 diabetes have significantly higher mortality and morbidity following acute myocardial infarction (AMI) than do the rest of the population. Other conditions such as hypertension, hypertrophic cardiomyopathy, aortic stenosis and aging may also increase the risk of SCD. Sex differences in prevalence and clinical outcomes are recognised [Bairey et al. 2006; Wake et al. 2007], although many random‐ ized clinical trials do not have adequate numbers of women to allow sex-specific analyses [Xhyheri & Bugiardini 2010; Melloni et al. 2010]. Ischemic heart disease is the primary cause of death for women at all ages, with annual mortality rates for women 35-55 years greater than breast cancer [Bell et al. 2000] and approximately 81% of deaths in low- and middle-income countries [Mosca et al. 2011]. The incidence of SCD differs according to geographical region depending on the prevalence of coronary or ischemic heart disease [Priori et al. 2001]. In the United States, during 1989 to 1998, there was markedly less of a decline in SCD rates among women than for men - women aged 35 to 44 years had a 21% increased SCD rate compared with a 2.8% decline for men of the same age group [Zheng et al. 2001]. During the same period, women were dying of a cardiac arrest before hospital arrival (52%) compared with 42% for men [Shaw et al. 2006]. Compared to males women are generally older when presenting with AMI [Canto et al. 2012] and with women's longer life expectancy, the estimates are expected to rise even further in future decades. Although risk factors for IHD and SCD are often assumed to be similar in women and men, there are also differences. For instance, SCD will occur before any other signs of coronary heart disease in women [de Vreede-Swagemakers et al. 1997; Kannel et al. 1998; Albert et al. 2003] whereas ventricular dysrhythmias following AMI,

© 2013 Mihailidou et al.; licensee InTech. This is an open access article 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. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

contribute to increased risk in men but not women [Dahlberg, 1990; Kim et al. 2001]. There may are also be differences in mechanisms for SCD between older and premenopausal or middle aged women. This chapter will review the sex differences in mechanism of SCD and possible treatment strategies.

The prevalence of SCD varies depending on the definition used between different studies. Another confounder is that many sudden deaths are not witnessed, and without cardiac monitoring at the time of death. Prevalence may vary from 13% when SCD is defined as death suddenly or unexpectedly within an hour of onset of symptoms, to 18.5% of all deaths when this period is extended to 24 hours after onset of symptoms [de Vreede-Swagemakers et al. 1997]. Most studies report that SCD results from a fatal cardiac arrhythmia, either degeneration of ventricular tachycardia (VT) into ventricular fibrillation(VF), leading to disorganized ventricular contraction or severe bradycardia or pulseless electrical activity [Lane et al. 2005]. Ventricular arrhythmias have been documented in 85% of patients with severe congestive heart failure [Singh et al. 1997]. Dilated nonischemic and hypertrophic cardiomyopathies contribute to the next largest number of SCDs, whereas other cardiac disorders, including congenital heart defects and genetically determined ion channel anomalies, contribute 5–10%

Sex Differences in Sudden Cardiac Death http://dx.doi.org/10.5772/55631 63

To determine the risk factors for SCD many studies examine the same traditional factors associated with IHD, which include systolic blood pressure, dyslipidemia, smoking, obesity, heavy alcohol consumption, diabetes mellitus and age [Kannel et al. 1985; Jouven et al. 1999; Khot et al. 2003; Sandhu et al. 2012], summarised in Table 1. Subjects with inherited arrhyth‐ mogenic disorders such as long-QT syndrome and Brugada syndrome are also at increased risk for SCD. Similar risk factors for men and women were identified in the Framingham Study which compared 2873 women with 2336 men aged 30 to 62 years [Schatzkln et al.1984; Kannel et al. 1998]. Similar to IHD, the presence of hypertension and diabetes increased the risk of SCD at all ages, whereas at all ages, sudden death risk ratios associated with diabetes were greater in women than men. Interestingly, the risk factors of hematocrit and vital capacity, predicted SCD in women but not men [Schatzkln et al. 1984]. Risk factors may also differ between premenopausal and older women. For instance, coronary heart disease (CHD) death in premenopausal women is due to plaque erosions with minimal coronary artery narrowing, whereas older women have high cholesterol levels and plaque rupture, with severe coronary

As noted in Table 1, the risk factors for SCD are not consistently recorded and ventricular ectopy is one risk factor which is omitted since some of the deaths may have occurred in the absence of monitoring. Trials which have targeted only suppressing this ectopy to prevent SCD have not been successful and possibly hazardous [Akiyama et al. 1991]. Parental history of MI before age 60 years has also been identified as a risk factor for SCD, but only among women younger than age 60 years. The traditional factors for IHD also elevate the risk of SCD by 2- to 4-fold and include hypertension, diabetes and smoking [Albert et al. 2003]. Smoking was identified as a strong risk factor for SCD among young women (<60 years). Since it is a modifiable risk factor, Sandhu and colleagues (2012) recently reported a prospective study showing that smoking cessation significantly reduced and eliminated

of SCDs [Lane et al. 2005].

**3. Risk factors for sudden cardiac death**

artery narrowing [Canto et al. 2012].

excess SCD risk [Sandhu et al. 2012].

## **2. Ischemic heart disease and sudden cardiac death**

Cardiovascular disease (CVD) is the primary cause of death globally with 17.3 million deaths in 2008, representing approximately 50% of non-communicable disease deaths [World Health Report (WHO), 2012]. Of these deaths, approximately 7.3 million (42%) were due to ischemic heart disease (IHD). Figure 1 shows the proportion of IHD deaths according to income status (data adapted from WHO Report 2012]. In middle- and high-income countries, IHD was the primary cause of deaths, whereas it was fourth highest in low-income countries. In the United States, coronary heart disease (CHD) resulted in 1 of every 6 deaths in 2008. According to the recent American Heart Association report [Roger et al. 2012], there is a coronary event approximately every 25 seconds, and approximately one death every minute. More women (64%) than men (50%) die suddenly of coronary heart disease without any previous symptoms of this disease, while people with previous AMI have sudden death rates 4 to 6 times that of the general population [Roger et al. 2012].

**Figure 1.** Ischemic heart disease deaths according to income status

The prevalence of SCD varies depending on the definition used between different studies. Another confounder is that many sudden deaths are not witnessed, and without cardiac monitoring at the time of death. Prevalence may vary from 13% when SCD is defined as death suddenly or unexpectedly within an hour of onset of symptoms, to 18.5% of all deaths when this period is extended to 24 hours after onset of symptoms [de Vreede-Swagemakers et al. 1997]. Most studies report that SCD results from a fatal cardiac arrhythmia, either degeneration of ventricular tachycardia (VT) into ventricular fibrillation(VF), leading to disorganized ventricular contraction or severe bradycardia or pulseless electrical activity [Lane et al. 2005]. Ventricular arrhythmias have been documented in 85% of patients with severe congestive heart failure [Singh et al. 1997]. Dilated nonischemic and hypertrophic cardiomyopathies contribute to the next largest number of SCDs, whereas other cardiac disorders, including congenital heart defects and genetically determined ion channel anomalies, contribute 5–10% of SCDs [Lane et al. 2005].

### **3. Risk factors for sudden cardiac death**

contribute to increased risk in men but not women [Dahlberg, 1990; Kim et al. 2001]. There may are also be differences in mechanisms for SCD between older and premenopausal or middle aged women. This chapter will review the sex differences in mechanism of SCD and

Cardiovascular disease (CVD) is the primary cause of death globally with 17.3 million deaths in 2008, representing approximately 50% of non-communicable disease deaths [World Health Report (WHO), 2012]. Of these deaths, approximately 7.3 million (42%) were due to ischemic heart disease (IHD). Figure 1 shows the proportion of IHD deaths according to income status (data adapted from WHO Report 2012]. In middle- and high-income countries, IHD was the primary cause of deaths, whereas it was fourth highest in low-income countries. In the United States, coronary heart disease (CHD) resulted in 1 of every 6 deaths in 2008. According to the recent American Heart Association report [Roger et al. 2012], there is a coronary event approximately every 25 seconds, and approximately one death every minute. More women (64%) than men (50%) die suddenly of coronary heart disease without any previous symptoms of this disease, while people with previous AMI have sudden death rates 4 to 6 times that of

**2. Ischemic heart disease and sudden cardiac death**

possible treatment strategies.

62 Ischemic Heart Disease

the general population [Roger et al. 2012].

**Figure 1.** Ischemic heart disease deaths according to income status

To determine the risk factors for SCD many studies examine the same traditional factors associated with IHD, which include systolic blood pressure, dyslipidemia, smoking, obesity, heavy alcohol consumption, diabetes mellitus and age [Kannel et al. 1985; Jouven et al. 1999; Khot et al. 2003; Sandhu et al. 2012], summarised in Table 1. Subjects with inherited arrhyth‐ mogenic disorders such as long-QT syndrome and Brugada syndrome are also at increased risk for SCD. Similar risk factors for men and women were identified in the Framingham Study which compared 2873 women with 2336 men aged 30 to 62 years [Schatzkln et al.1984; Kannel et al. 1998]. Similar to IHD, the presence of hypertension and diabetes increased the risk of SCD at all ages, whereas at all ages, sudden death risk ratios associated with diabetes were greater in women than men. Interestingly, the risk factors of hematocrit and vital capacity, predicted SCD in women but not men [Schatzkln et al. 1984]. Risk factors may also differ between premenopausal and older women. For instance, coronary heart disease (CHD) death in premenopausal women is due to plaque erosions with minimal coronary artery narrowing, whereas older women have high cholesterol levels and plaque rupture, with severe coronary artery narrowing [Canto et al. 2012].

As noted in Table 1, the risk factors for SCD are not consistently recorded and ventricular ectopy is one risk factor which is omitted since some of the deaths may have occurred in the absence of monitoring. Trials which have targeted only suppressing this ectopy to prevent SCD have not been successful and possibly hazardous [Akiyama et al. 1991]. Parental history of MI before age 60 years has also been identified as a risk factor for SCD, but only among women younger than age 60 years. The traditional factors for IHD also elevate the risk of SCD by 2- to 4-fold and include hypertension, diabetes and smoking [Albert et al. 2003]. Smoking was identified as a strong risk factor for SCD among young women (<60 years). Since it is a modifiable risk factor, Sandhu and colleagues (2012) recently reported a prospective study showing that smoking cessation significantly reduced and eliminated excess SCD risk [Sandhu et al. 2012].


estrogen. In the Women's Ischemia Syndrome Evaluation (WISE) Study premenopausal women that had a stress-induced disruption in ovulatory cycling with resulting low levels of estrogen had a 7.4-fold increased risk of obstructive coronary artery disease [Shaw et al. 2006]. Although there is increased focus on the lack of estrogen, the role of androgens should also be considered, given that they activate atherosclerotic-related genes in men but not women and activate androgen receptors in cardiac myocytes of both men and women, to produce

Sex Differences in Sudden Cardiac Death http://dx.doi.org/10.5772/55631 65

The risk factors for IHD common in postmenopausal women, include obesity, hypertension, and dyslipidemia. Menopausal women also have a greater loss in physical functioning com‐ paredtomen[Poehlman2002], whichaggravates weight gain,insulinresistance, andhyperten‐ sion [Shaw et al. 2006]. Loss of ovarian estrogen during menopause is also associated with redistribution of abdominal fat, further increasing the risk of IHD [Lamon-Fava et al. 1996]. The role of hormone replacement therapy (HRT) for postmenopausal women has been controver‐ sial. This is due to conflicting results from observational trials performed prior to 2002 which showed a reduction in risk of cardiovascular disease, osteoporosis, and colon cancer whereas large randomized clinical trials such as the Women's Health Initiative showed no cardiovascu‐ lar benefit from hormone replacement therapy [Schierbeck et al. 2012]. The timing of initiating hormone therapy has been suggested as a possible explanation for these conflicting results. The observational studies started hormone therapy shortly after menopause, whereas the large randomised studies, which showed no or negative cardiovascular effects, initiated hormone therapy 5 to 20 years after menopause. The recent prospective, multicentre, HRT study, the Danish Osteoporosis Prevention Study (DOPS) was initiated to evaluate HRT as primary prevention for osteoporotic fractures [Schierbeck et al. 2012]. Healthy, recently postmenopaus‐ alwomen(within7months)aged45-58wererecruitedtothestudyandwererandomlyallocated to receive HRT or no treatment (control). Treatment ceased after 11 years although partici‐ pants were followed for death, cardiovascular disease, and cancer for a further 5 years (total 16 years).Following 10 years randomised treatment, women receiving HRT early after meno‐ pausehadsignificantlyreducedriskofmortality,heartfailure,ormyocardialinfarction,without

Sustained VT and VF are responsible for at least two thirds of sudden cardiac deaths [Huikuri et al. 2001] with sex-differences in arrhythmic SCD reported [Orencia et al. (1993); Kannel et al. (1998); Zheng et al. (2001); Abildstrom et al. (2002); Adabag et al. (2008); Verheugt et al. (2008)]. Pre-existing coronary heart disease significantly contributes to SCD in men [Lane et al. 2005] whereas women are 66% less likely to be diagnosed with coronary heart disease before SCD [Albert et al. 1996; Chiuve et al. (2011)]. Several studies have investigated whether sex dispari‐ ties in the risk factors for SCD may contribute to thesedifferences.Atherogenic risk factors were found to be predictive in men but not women. Similarly, asymptomatic ventricular dysrhyth‐ mias are an independent risk for death in men but have not been shown to be a risk for women [Dahlberg,1990].Patientswithcongestiveheartfailureduetocardiomyopathyorischemicheart

any increase in risk of cancer, venous thromboembolism, or stroke.

**4. Mechanism of sudden cardiac death**

hypertrophy [Marsh et al. 1999].

**Table 1.** Relative risk for factors associated with Sudden Cardiac Death

In considering risk factors for IHD and SCD, one cannot overlook how endogenous levels of sex hormones may be contributing. Men and women show differences in ECG repolarization with QT prolongation in women, while male hearts from many species are hypertrophied relative to female hearts [Marsh et al. 1998]. In premenopausal women with normal ovulation, estrogen and other endogenous hormones provide cardioprotection and lower incidence of IHD compared to age-matched men. In contrast, during menopause, there is a fall in estrogen levels to approximately one-tenth that of premenopausal levels [Paoletti et al. 1997] and estrone, produced by peripheral conversion of androgens in the adipose tissue, is the main estrogen. In the Women's Ischemia Syndrome Evaluation (WISE) Study premenopausal women that had a stress-induced disruption in ovulatory cycling with resulting low levels of estrogen had a 7.4-fold increased risk of obstructive coronary artery disease [Shaw et al. 2006]. Although there is increased focus on the lack of estrogen, the role of androgens should also be considered, given that they activate atherosclerotic-related genes in men but not women and activate androgen receptors in cardiac myocytes of both men and women, to produce hypertrophy [Marsh et al. 1999].

The risk factors for IHD common in postmenopausal women, include obesity, hypertension, and dyslipidemia. Menopausal women also have a greater loss in physical functioning com‐ paredtomen[Poehlman2002], whichaggravates weight gain,insulinresistance, andhyperten‐ sion [Shaw et al. 2006]. Loss of ovarian estrogen during menopause is also associated with redistribution of abdominal fat, further increasing the risk of IHD [Lamon-Fava et al. 1996]. The role of hormone replacement therapy (HRT) for postmenopausal women has been controver‐ sial. This is due to conflicting results from observational trials performed prior to 2002 which showed a reduction in risk of cardiovascular disease, osteoporosis, and colon cancer whereas large randomized clinical trials such as the Women's Health Initiative showed no cardiovascu‐ lar benefit from hormone replacement therapy [Schierbeck et al. 2012]. The timing of initiating hormone therapy has been suggested as a possible explanation for these conflicting results. The observational studies started hormone therapy shortly after menopause, whereas the large randomised studies, which showed no or negative cardiovascular effects, initiated hormone therapy 5 to 20 years after menopause. The recent prospective, multicentre, HRT study, the Danish Osteoporosis Prevention Study (DOPS) was initiated to evaluate HRT as primary prevention for osteoporotic fractures [Schierbeck et al. 2012]. Healthy, recently postmenopaus‐ alwomen(within7months)aged45-58wererecruitedtothestudyandwererandomlyallocated to receive HRT or no treatment (control). Treatment ceased after 11 years although partici‐ pants were followed for death, cardiovascular disease, and cancer for a further 5 years (total 16 years).Following 10 years randomised treatment, women receiving HRT early after meno‐ pausehadsignificantlyreducedriskofmortality,heartfailure,ormyocardialinfarction,without any increase in risk of cancer, venous thromboembolism, or stroke.

## **4. Mechanism of sudden cardiac death**

In considering risk factors for IHD and SCD, one cannot overlook how endogenous levels of sex hormones may be contributing. Men and women show differences in ECG repolarization with QT prolongation in women, while male hearts from many species are hypertrophied relative to female hearts [Marsh et al. 1998]. In premenopausal women with normal ovulation, estrogen and other endogenous hormones provide cardioprotection and lower incidence of IHD compared to age-matched men. In contrast, during menopause, there is a fall in estrogen levels to approximately one-tenth that of premenopausal levels [Paoletti et al. 1997] and estrone, produced by peripheral conversion of androgens in the adipose tissue, is the main

34% 40% 38.4% 55.9%

**Age (yr) M:F High**

30-62 30-62 45:55

1.87 (<60) 1.36 ("/ >60)

<55 <65

66.1 (11.2)

M= males and F= females; \*Same cohort as Schatzkln et al. (1984)

**Table 1.** Relative risk for factors associated with Sudden Cardiac Death

59.9 (11.6) 30-62 45:55 44M:63F 56M:37F

With prior CHD 143±24 158±29

(2003) - 30- 55 100F 1.33 3.17 4.9

35-64 yr 1.3 1.4 1.9 1.7 3.9 1.5 1 1.4 65-94 yr 1 1.4 2.2 1.7 4 1.3 0.9 1.2

Kannel et al. (1998)\*

64 Ischemic Heart Disease

Schatzkln et al. (1984)

Without prior

Albert et al.

Parental history

CHD

of MI

Shaw et al. (2006)

CHD

Family History of

Khot et al (2003)

Age threshold ≥45 ≥55

**cholesterol Prior CHD (%) Hypertension Diabetes Smoking**

135±21 137±25

↑ **- -** ↑ ↑

15.3 %

23.2 %

29.5 %

41.6 %

**M F % M F without with M F M F M F**

Sustained VT and VF are responsible for at least two thirds of sudden cardiac deaths [Huikuri et al. 2001] with sex-differences in arrhythmic SCD reported [Orencia et al. (1993); Kannel et al. (1998); Zheng et al. (2001); Abildstrom et al. (2002); Adabag et al. (2008); Verheugt et al. (2008)]. Pre-existing coronary heart disease significantly contributes to SCD in men [Lane et al. 2005] whereas women are 66% less likely to be diagnosed with coronary heart disease before SCD [Albert et al. 1996; Chiuve et al. (2011)]. Several studies have investigated whether sex dispari‐ ties in the risk factors for SCD may contribute to thesedifferences.Atherogenic risk factors were found to be predictive in men but not women. Similarly, asymptomatic ventricular dysrhyth‐ mias are an independent risk for death in men but have not been shown to be a risk for women [Dahlberg,1990].Patientswithcongestiveheartfailureduetocardiomyopathyorischemicheart disease have the highest rate of SCD, although the contributing factors remain poorly defined. Recent studies have suggested that genetic or environmental factors may predispose to fatal ventricular arrhythmia, particularly in women. However, mutations or rare variants in the cardiac sodium channel SCN5A were found in <2% cases screened and further studies are required [Albert et al. 2008]. Stress cardiomyopathy, also known as takotsubo cardiomyop‐ athy, transient apical ballooning or broken heart syndrome is found predominantly in postme‐ nopausal women [Nef et al. 2010]. Emotional or physical stress trigger symptom onset, which is similar to those in AMI, including sudden onset of chest pain associated with ST-segment elevation, and moderate increases in creatine kinase and troponin levels. Prognosis for stress cardiomyopathy is favorable, although fatal complications may occur, including cardiogenic shock, malignant arrhythmias and left ventricular free wall rupture.

Pascaud et al. 2005] and sodium [Mihailidou et al. 2000] as well as producing hypokalemia and hypomagnesemia [Mihailidou et al. 2002]. These electrolyte imbalances have been translated clinically with the Framingham Heart Study showing that low serum concentrations of potassium and magnesium were linked to increased risk of SCD. A decrease in potassium of 0.48 mEq/litre or magnesium of 0.16 mEq/litre level was associated with a 27% (C.I. 6% - 51%) and a 20% (C.I. 3% - 41%) greater odds of complex or frequent ventricular premature

Sex Differences in Sudden Cardiac Death http://dx.doi.org/10.5772/55631 67

Possible other targets include the gap junction connexins and identifying whether they are regulated differently between males and females. Connexins allow rapid and coordinated electricalexcitationandfacilitateintercellularexchangeofsmallmolecules.Experimentalstudies have shown that normal gap junction expression and phosphorylation in the heart is essential fororganizedmyocellularelectricalactivity[Staufferetal.2011].Interestinglyfemaleheartshave higher levels of cardiac connexin 43 (Cx43) [Tribulova et al. 2005] and lower lethal arrhythmia susceptibility [Knezl et al. 2008]. Further studies are required to confirm whether abnormali‐ ties in cardiac Cx43 expression and phosphorylation are the primary trigger of arrhythmogene‐

sis, since this occurs prior to other structural remodelling changes [Stauffer et al. 2011].

Kir2.1 and GJA1 which encode connexin 43 gap junction channels [Yang et al. 2007].

Primary prevention of SCD continues to be a public health challenge since most deaths are among people who were not identified as high risk prior to the event. Implantable cardiovert‐ er–defibrillator (ICD) therapy is the current recommended treatment strategy for high risk patients with severe left ventricular dysfunction (Sudden Cardiac Death in Heart Failure Trial (SCDHeFT), [Bardy et al. 2005]. Subgroup analysis in SCDHeFT as well as in another primary prevention trial, the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) [Kadish et al. 2004] suggested that women may receive less benefit from ICD therapy than men. Interestingly in both these large trials, only 24%-30% of participants and since women have a lower incidence of VF compared to men [Kim et al. 2001; Wigginton et al. 2002] and therefore may not have been adequately powered to determine the influence of

ICDs treat (but do not prevent) the ventricular arrhythmias and therefore increased morbidity remains. ICD therapy is rarely considered where LV function is preserved, except in specific

Recent studies have explored the role of microRNAs (miRNAs) in many biological and pathological processes and the role of circulating miRNAs as sensitive biomarkers with aberrant expression of miRNA directly reflecting disease state. Ai and colleagues (2010), recently found upregulated cardiac miR-1 in an animal model of AMI, with similar increases in plasma in patients with AMI. These increased miR-1 levels correlated with abnormal QRS widening in AMI [Ai et al. 2010]. Over-expression of miR-1 has been shown to induce and aggravate arrhythmogenesis. The mechanism proposed is by impairing cardiac conduction by post-transcriptional repression of KCNJ2 that encodes the inward rectifier K+ channel subunit

contractions [Tsuji et al. 1994].

**5. Treatment strategies**

gender on outcome for ICD therapy.

Cardiac remodelling following either ischemia or AMI initially develops to compensate for failing cardiac function with evidence of hypertrophy, cardiomyocyte apoptosis, inflammation and fibrosis. Initially these changes are beneficial but ultimately transition to deteriorating cardiac function and lead to heart failure [Abel et al. 2008]. Although left ventricular (LV) dysfunction significantly increases the risk of SCD [Anand et al. 2006; Stecker et al. 2006], other risk factors need to be considered since women are 50% less likely to exhibit severe LV dysfunction, with structurally normal hearts identified at autopsy [Chugh et al. 2003]. Alternative mechanisms of SCD therefore need to be considered, given that women with coronary heart disease have significantly lower risk for SCD.

The renin-angiotensin-aldosterone system (RAAS) plays a significant role in ischemic heart disease and AMI and blockade of this system has emerged as an important therapeutic intervention. Elevated plasma aldosterone levels are an independent risk factor for mortality during AMI [Beygui et al. 2006; Palmer et al. 2008] and are predictive of cardiovascular events in acute coronary syndrome in the presence or absence of AMI [Tomaschitz et al. 2010]. Aldosterone exerts its actions by interacting with its receptor, the mineralocorticoid receptor (MR) or "aldosterone" receptor. Both aldosterone and the physiological glucocorticoids (cortisol (humans)/corticosterone (rodents), which are at 100-fold higher circulating levels bind to the MR. Selective activation of MR in target tissues is achieved by co-expression of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HDS2). In contrast with vascular and renal tissues, 11βHSD2 is not expressed in cardiomyocytes [Sheppard & Autelitano 2002], and therefore endogenous glucocorticoids normally do not mimic aldosterone, but act as MR antagonists [Gomez et al 1990; Sato & Funder, 1996; Young & Funder, 1996]. Redox regulation has been shown to modulate glucocorticoid hormone action *in vivo* [Makino et al. 1999] and expression of oestrogen receptors [Tamir et al. 2002]. For every molecule of cortisol converted to cortisone, one molecule of the pyridine nucleotide NAD is reduced to NADH. Since NADH has been shown to activate corepressors for other transcription factors in various systems [Zhang et al. 2002; Fjeld et al. 2003], and changes in redox state may determine cardiomyocyte MR activation by glucocorticoids [Mihailidou et al. 2009].

Elevated aldosterone levels promote electrical remodelling through activation of MR or "aldosterone" receptors, thus potentially increasing the incidence of sudden cardiac death. In experimental studies, aldosterone has a direct effect on cardiomyocyte calcium [OuvrardPascaud et al. 2005] and sodium [Mihailidou et al. 2000] as well as producing hypokalemia and hypomagnesemia [Mihailidou et al. 2002]. These electrolyte imbalances have been translated clinically with the Framingham Heart Study showing that low serum concentrations of potassium and magnesium were linked to increased risk of SCD. A decrease in potassium of 0.48 mEq/litre or magnesium of 0.16 mEq/litre level was associated with a 27% (C.I. 6% - 51%) and a 20% (C.I. 3% - 41%) greater odds of complex or frequent ventricular premature contractions [Tsuji et al. 1994].

Possible other targets include the gap junction connexins and identifying whether they are regulated differently between males and females. Connexins allow rapid and coordinated electricalexcitationandfacilitateintercellularexchangeofsmallmolecules.Experimentalstudies have shown that normal gap junction expression and phosphorylation in the heart is essential fororganizedmyocellularelectricalactivity[Staufferetal.2011].Interestinglyfemaleheartshave higher levels of cardiac connexin 43 (Cx43) [Tribulova et al. 2005] and lower lethal arrhythmia susceptibility [Knezl et al. 2008]. Further studies are required to confirm whether abnormali‐ ties in cardiac Cx43 expression and phosphorylation are the primary trigger of arrhythmogene‐ sis, since this occurs prior to other structural remodelling changes [Stauffer et al. 2011].

Recent studies have explored the role of microRNAs (miRNAs) in many biological and pathological processes and the role of circulating miRNAs as sensitive biomarkers with aberrant expression of miRNA directly reflecting disease state. Ai and colleagues (2010), recently found upregulated cardiac miR-1 in an animal model of AMI, with similar increases in plasma in patients with AMI. These increased miR-1 levels correlated with abnormal QRS widening in AMI [Ai et al. 2010]. Over-expression of miR-1 has been shown to induce and aggravate arrhythmogenesis. The mechanism proposed is by impairing cardiac conduction by post-transcriptional repression of KCNJ2 that encodes the inward rectifier K+ channel subunit Kir2.1 and GJA1 which encode connexin 43 gap junction channels [Yang et al. 2007].

## **5. Treatment strategies**

disease have the highest rate of SCD, although the contributing factors remain poorly defined. Recent studies have suggested that genetic or environmental factors may predispose to fatal ventricular arrhythmia, particularly in women. However, mutations or rare variants in the cardiac sodium channel SCN5A were found in <2% cases screened and further studies are required [Albert et al. 2008]. Stress cardiomyopathy, also known as takotsubo cardiomyop‐ athy, transient apical ballooning or broken heart syndrome is found predominantly in postme‐ nopausal women [Nef et al. 2010]. Emotional or physical stress trigger symptom onset, which is similar to those in AMI, including sudden onset of chest pain associated with ST-segment elevation, and moderate increases in creatine kinase and troponin levels. Prognosis for stress cardiomyopathy is favorable, although fatal complications may occur, including cardiogenic

Cardiac remodelling following either ischemia or AMI initially develops to compensate for failing cardiac function with evidence of hypertrophy, cardiomyocyte apoptosis, inflammation and fibrosis. Initially these changes are beneficial but ultimately transition to deteriorating cardiac function and lead to heart failure [Abel et al. 2008]. Although left ventricular (LV) dysfunction significantly increases the risk of SCD [Anand et al. 2006; Stecker et al. 2006], other risk factors need to be considered since women are 50% less likely to exhibit severe LV dysfunction, with structurally normal hearts identified at autopsy [Chugh et al. 2003]. Alternative mechanisms of SCD therefore need to be considered, given that women with

The renin-angiotensin-aldosterone system (RAAS) plays a significant role in ischemic heart disease and AMI and blockade of this system has emerged as an important therapeutic intervention. Elevated plasma aldosterone levels are an independent risk factor for mortality during AMI [Beygui et al. 2006; Palmer et al. 2008] and are predictive of cardiovascular events in acute coronary syndrome in the presence or absence of AMI [Tomaschitz et al. 2010]. Aldosterone exerts its actions by interacting with its receptor, the mineralocorticoid receptor (MR) or "aldosterone" receptor. Both aldosterone and the physiological glucocorticoids (cortisol (humans)/corticosterone (rodents), which are at 100-fold higher circulating levels bind to the MR. Selective activation of MR in target tissues is achieved by co-expression of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HDS2). In contrast with vascular and renal tissues, 11βHSD2 is not expressed in cardiomyocytes [Sheppard & Autelitano 2002], and therefore endogenous glucocorticoids normally do not mimic aldosterone, but act as MR antagonists [Gomez et al 1990; Sato & Funder, 1996; Young & Funder, 1996]. Redox regulation has been shown to modulate glucocorticoid hormone action *in vivo* [Makino et al. 1999] and expression of oestrogen receptors [Tamir et al. 2002]. For every molecule of cortisol converted to cortisone, one molecule of the pyridine nucleotide NAD is reduced to NADH. Since NADH has been shown to activate corepressors for other transcription factors in various systems [Zhang et al. 2002; Fjeld et al. 2003], and changes in redox state may determine cardiomyocyte

Elevated aldosterone levels promote electrical remodelling through activation of MR or "aldosterone" receptors, thus potentially increasing the incidence of sudden cardiac death. In experimental studies, aldosterone has a direct effect on cardiomyocyte calcium [Ouvrard-

shock, malignant arrhythmias and left ventricular free wall rupture.

66 Ischemic Heart Disease

coronary heart disease have significantly lower risk for SCD.

MR activation by glucocorticoids [Mihailidou et al. 2009].

Primary prevention of SCD continues to be a public health challenge since most deaths are among people who were not identified as high risk prior to the event. Implantable cardiovert‐ er–defibrillator (ICD) therapy is the current recommended treatment strategy for high risk patients with severe left ventricular dysfunction (Sudden Cardiac Death in Heart Failure Trial (SCDHeFT), [Bardy et al. 2005]. Subgroup analysis in SCDHeFT as well as in another primary prevention trial, the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) [Kadish et al. 2004] suggested that women may receive less benefit from ICD therapy than men. Interestingly in both these large trials, only 24%-30% of participants and since women have a lower incidence of VF compared to men [Kim et al. 2001; Wigginton et al. 2002] and therefore may not have been adequately powered to determine the influence of gender on outcome for ICD therapy.

ICDs treat (but do not prevent) the ventricular arrhythmias and therefore increased morbidity remains. ICD therapy is rarely considered where LV function is preserved, except in specific conditions with increased SCD risk such as hypertrophic obstructive cardiomyopathy, long QT and Brugada syndromes, and idiopathic VF [DiMarco 2003]. A community-based study conducted by Stecker and colleagues (2006) showed that only 30% of patients that died from SCD previously had sufficiently decreased LV systolic function to meet the criteria for ICD implantation.Patients with normalLV systolic function were generally younger,predominant‐ ly female and less likely to have an established diagnosis of coronary heart disease. Since ICDs treat the arhythmia but not prevent the underlying cause, there is a need to find new treat‐ ment strategies that target the cellular mechanisms involved. Standard antiarrhythmic medica‐ tion has not reduced (and in some cases, has increased), the incidence of SCD [Lane et al. 2005]. Suitable adjunct treatment in the primary and secondary prevention of SCD includes beta blockers andnon-anti-arrhythmic agents,i.e.,those thatdonotdirectlytargetthe electrophysio‐ logical action in cardiac muscle or specialized conduction system, such as angiotensin convert‐ ing enzyme inhibitors (ACEI), angiotensin receptor–blockers, lipid-lowering agents, aldosterone or MR antagonists, thrombolytic and antithrombotic agents [Lane et al. 2005].

**Author details**

**References**

Anastasia Susie Mihailidou1\*, Rebecca Ritchie2

tal & University of Sydney, Sydney, Australia

death. *Heart*. 86: 624–625.

*Coll Cardiol.* 47(3): SS29., 21.

*Outcomes*. , 3, 135-142.

*J.* 77: 363–370.

Hospital & University of Sydney, Sydney, Australia

\*Address all correspondence to: anastasia.mihailidou@sydney.edu.au

2 Baker IDI Heart & Diabetes Institute, Melbourne, Australia

1 Department of Cardiology & Kolling Medical Research Institute Royal North Shore Hospi‐

3 Perinatal Research Laboratories, Kolling Medical Research Institute Royal North Shore

[1] Zipes, D. P. Wellens HJJ ((1998). Sudden cardiac death. *Circulation. 98*, 2334-2351.

[2] Wong SH, Mulvihill NT, Norton M (2001). Assessing the risk of sudden cardiac

[3] Mazeika P (2001). Aborted sudden cardiac death: a clinical perspective. *Postgrad Med*

[4] Bairey Merz CN, Shaw LJ, Reis SE, et al ((2006). Insights from the NHLBI- Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study. Part II: Gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiolo‐ gy of atherosclerosis and macrovascular and microvascular coronary disease. *J Am*

[5] Wake, R, Takeuchi, M, Yoshikawa, J, & Yoshiyama, M. (2007). Effects of gender on prognosis of patients with known or suspected coronary artery disease undergoing contrast-enhanced dobutamine stress echocardiography. *Circ J.* , 71(7), 1060-1066. [6] Xhyheri, B, & Bugiardini, R. (2010). Diagnosis and Treatment of Heart Disease: Are Women Different From Men? *Progress in Cardiovascular Diseases.* , 53, 227-236.

[7] Melloni, C, Berger, J. S, Wang, T. Y, Gunes, F, Stebbins, A, Pieper, K. S, Dolor, R. J, Douglas, P. S, Mark, D. B, & Newby, L. K. (2010). Representation of women in randomized clinical trials of cardiovascular disease prevention. *Circ. Cardiovasc. Qual.*

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[9] Mosca, L, Benjamin, E. J, Berra, K, Bezanson, J. L, Dolor, R. J, Lloyd-jones, D. M, Newby, L. K, Pina, I. L, Roger, V. L, Shaw, L. J, & Zhao, D. (2011). Effectiveness-

gender differences in outcomes. *Pharmacotherapy. 20*, 1034-1044.

and Anthony W. Ashton3

Sex Differences in Sudden Cardiac Death http://dx.doi.org/10.5772/55631 69

It is worth considering the role of aldosterone or MR blockade for both primary prevention of SCD for those at high-risk and as an adjunct therapy based on the important findings from the large randomized clinical studies, the Randomized ALdactone Evaluation Study (RALES) [Pitt et al. 1999] and the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) [Pitt et al. 2003], which showed a significant reduction in SCD. The first of these trials, RALES, was a double blind study in patients who had severe heart failure with left ventricular systolic dysfunction and were receiving standard therapy including ACE inhibitor treatment, a loop diuretic, and digoxin. Patients were randomly assigned to receive low dose MR antagonist, spironolactone or placebo added to their standard treatment. The trial was discontinued early due to an interim analysis showing the addition of spironolactone resulted in a 30% reduction in mortality and reducing SCD by 29%. In the next study, EPHESUS [Pitt et al. 2003] was designed to determine whether selective MR blockade with eplerenone could be tolerated by patients with acute myocardial infarction (AMI) complicated by heart failure due to systolic left ventricular dysfunction. Addition of the selective MR antagonist, eplerenone, substantially increased survival (15% reduction in mortality) and decreased hospitalization, and had a 21% reduction in SCD.

#### **6. Conclusion**

Since women do not present with severe left ventricular dysfunction and diagnosed CHD before SCD, they will not receive the current recommended treatment. Prospective studies are required that have the same proportion of women to men with ischemic heart disease to identify the sex-specific risk factors and pathophysiology of ischemic heart disease in women which leads to an adverse cardiovascular outcome [Malenka et al. 2002]. Further investigations are required to examine whether women will show the same benefit to adjunct treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor–blocking agents, lipidlowering agents, mineralocorticoid receptor antagonists, thrombolytic and antithrombotic agents.

## **Author details**

conditions with increased SCD risk such as hypertrophic obstructive cardiomyopathy, long QT and Brugada syndromes, and idiopathic VF [DiMarco 2003]. A community-based study conducted by Stecker and colleagues (2006) showed that only 30% of patients that died from SCD previously had sufficiently decreased LV systolic function to meet the criteria for ICD implantation.Patients with normalLV systolic function were generally younger,predominant‐ ly female and less likely to have an established diagnosis of coronary heart disease. Since ICDs treat the arhythmia but not prevent the underlying cause, there is a need to find new treat‐ ment strategies that target the cellular mechanisms involved. Standard antiarrhythmic medica‐ tion has not reduced (and in some cases, has increased), the incidence of SCD [Lane et al. 2005]. Suitable adjunct treatment in the primary and secondary prevention of SCD includes beta blockers andnon-anti-arrhythmic agents,i.e.,those thatdonotdirectlytargetthe electrophysio‐ logical action in cardiac muscle or specialized conduction system, such as angiotensin convert‐ ing enzyme inhibitors (ACEI), angiotensin receptor–blockers, lipid-lowering agents, aldosterone or MR antagonists, thrombolytic and antithrombotic agents [Lane et al. 2005].

It is worth considering the role of aldosterone or MR blockade for both primary prevention of SCD for those at high-risk and as an adjunct therapy based on the important findings from the large randomized clinical studies, the Randomized ALdactone Evaluation Study (RALES) [Pitt et al. 1999] and the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) [Pitt et al. 2003], which showed a significant reduction in SCD. The first of these trials, RALES, was a double blind study in patients who had severe heart failure with left ventricular systolic dysfunction and were receiving standard therapy including ACE inhibitor treatment, a loop diuretic, and digoxin. Patients were randomly assigned to receive low dose MR antagonist, spironolactone or placebo added to their standard treatment. The trial was discontinued early due to an interim analysis showing the addition of spironolactone resulted in a 30% reduction in mortality and reducing SCD by 29%. In the next study, EPHESUS [Pitt et al. 2003] was designed to determine whether selective MR blockade with eplerenone could be tolerated by patients with acute myocardial infarction (AMI) complicated by heart failure due to systolic left ventricular dysfunction. Addition of the selective MR antagonist, eplerenone, substantially increased survival (15% reduction in mortality) and decreased

Since women do not present with severe left ventricular dysfunction and diagnosed CHD before SCD, they will not receive the current recommended treatment. Prospective studies are required that have the same proportion of women to men with ischemic heart disease to identify the sex-specific risk factors and pathophysiology of ischemic heart disease in women which leads to an adverse cardiovascular outcome [Malenka et al. 2002]. Further investigations are required to examine whether women will show the same benefit to adjunct treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor–blocking agents, lipidlowering agents, mineralocorticoid receptor antagonists, thrombolytic and antithrombotic

hospitalization, and had a 21% reduction in SCD.

**6. Conclusion**

68 Ischemic Heart Disease

agents.

Anastasia Susie Mihailidou1\*, Rebecca Ritchie2 and Anthony W. Ashton3

\*Address all correspondence to: anastasia.mihailidou@sydney.edu.au

1 Department of Cardiology & Kolling Medical Research Institute Royal North Shore Hospi‐ tal & University of Sydney, Sydney, Australia

2 Baker IDI Heart & Diabetes Institute, Melbourne, Australia

3 Perinatal Research Laboratories, Kolling Medical Research Institute Royal North Shore Hospital & University of Sydney, Sydney, Australia

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**Chapter 5**

**Costs of Hospitalizations with a Primary Diagnosis of**

Acute Myocardial Infarction (AMI) is both a common and deadly type of cardiac event in the United States. Although the age-adjusted hospitalization rate for AMI and its in-hospital case fatality rates have both declined since the mid-1990s, there were still 634,000 inpatient admissions in 2009 for which AMI was listed as the primary diagnosis [1, 2]. Moreover, Americans suffered an estimated 610,000 first-time AMIs and 325,000 recurrent attacks, and 133,958 deaths in 2008 [2]. Because the declines in hospitalization and in-hospital mortality rates have been associated with more aggressive therapeutic interventions [1], it is impor‐

To evaluate specifically the cost-effectiveness of various interventions against AMI, direct cost estimates of AMI are required [3-5]. Surprisingly, however, these cost estimates have not been comprehensively examined in the U.S. Many studies have investigated the economic burden of AMI, but all had some limitations [6-17]. Furthermore, in part because of limitations in avail‐ able studies, the costs of coronary heart disease (CHD) were used in one study to represent the costs for AMI [6], albeit this is inappropriate. For example, a previous study of insured adults aged 18-64 years found that only about 30% of CHD cases represented AMI [9]. Moreover, the American Heart Association recently estimated that the total prevalence of CHD among per‐ sons aged ≥20 years was 7% but the AMI prevalence of AMI in this group was 3.1% [2]. In addi‐ tion, in 2005, hospitalization costs for AMI admissions among adults aged 18-64 years were about \$5000 more than those for CHD admissions of non-AMI [9]. Clearly, information on costs that does not clearly distinguish between AMI and non-AMI admissions is of little use in

> © 2013 Wang et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

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

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

**Acute Myocardial Infarction Among Patients Aged**

**18-64 Years in the United States**

Guijing Wang, Zefeng Zhang, Carma Ayala,

Additional information is available at the end of the chapter

tant to evaluate the cost-effectiveness of these interventions.

evaluating the cost-effectiveness of interventions to treat AMI [18].

Diane Dunet and Jing Fang

http://dx.doi.org/10.5772/53499

**1. Introduction**
