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## Meet the editor

Luigi Gianturco, MD, MSc, obtained his MD cum laude in Medicine and Surgery with a specialty in Cardiology from Sapienza University of Rome in July 2003 and November 2007, respectively. He also obtained an MSc in Clinical Echocardiography from the University of Milan in 2009. Currently, Dr. Gianturco works in the Cardio Rehab Unit of Passirana-Rho Hospital. Previously, he was Vice-Chief of the Cardiology Unit at Galeazzi

Orthopedic Institute, Milan, and Assistant Manager of inside clinical risk management and overall health direction unit. He has made several oral presentations at national and international conventions and published works in national and international journals. He has also served as an investigator in some important national and international studies. He has been a member of the Italian Soccer Referees' Medical Committee since 2013. Dr. Gianturco has a great passion for reading and writing, and runs a personal blog at www.luigigianturco.com.

Contents

Arteriolosclerosis *by Luigi Gianturco*

Carotid Disease

*by Lena Lavie*

**Preface III**

**Chapter 1 1**

**Chapter 2 3**

**Chapter 3 17**

**Chapter 4 29**

**Chapter 5 53**

**Chapter 6 65**

Introductory Chapter: Atherosclerosis, Arteriosclerosis, and

*by Minerva Irene Hernández Rejón and Manuel Alexis Vargas Robles*

Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms,

Interindividual Responses and Clinical Insights

*by Sabina Oreska and Michal Tomcik*

Coronary Atherosclerosis in Women *by Abhishek Ojha and Nishtha Sareen*

Atherosclerosis in Rheumatology: Old and New Insights

Atherosclerosis: A Journey around the Terminology *by Oladimeji Adebayo and Abiodun Moshood Adeoye*

### Contents

Preface

Despite a reduction in deaths over the last two decades, atherosclerosis (ATS) is still a major concern worldwide. Decreased mortality can be attributed to anti-smoking laws, especially in Western countries, as it is well established that smoking may accelerate ATS injury. Unfortunately, ATS morbidity and mortality are still quite high. Nowadays, the major cardiovascular risk (CVR) factors contributing to ATS are "metabolic" and include such conditions as dyslipidemia, diabetes, and metabolic syndrome. As such, we understand how global cardiovascular disease (CVD) determines about 30% of world deaths, and ATS is definitely a pivotal contributor to CVD. Although there is much in the literature about ATS, the discussions seem to cover most of the same topics.

This book, however, covers not only those topics but also less debated subjects.

address the linkage between them.

ing and providing new treatments.

For example, you are going to read about the link between CVD and obstructive sleep apneas (the so-called OSAs). Last evidences have linked OSAs to multiple CV disorders including diabetes and coronary artery disease (CAD). Very often, the determinants of ATS progression and OSAs are common and thus it is pivotal to

In this volume, you will also find a discussion about the consolidated and close relationship of rheumatology and CV risk. In particular, several contributing authors have been studying how and/or how much systemic rheumatic diseases might affect the heart. In their chapters, these authors attempt to define the state of the art of this topic.

The carotid artery is another conventional topic around ATS. Generally, the coronary circle is the first investigated system in patients with ATS and CAD. For this reason, we underline morbidity and mortality mainly related to carotid ATS instead of CAD.

A chapter dedicated to terminology analyzes old and new insights in order to better describe ATS manifestations, complications, and so on. New evidence needs new accurate and specific terminology, and general physicians, cardiologists, geriatricians, and other specialists involved with ATS must use the proper terms in manag-

Finally, given the growing focus on gender medicine, a chapter on ATS and women

I would like to thank my team for collaborating on this book and bringing it to fruition. In particular, I am grateful to Bruno (my expert colleague) and Aurel (my secretary) for analyzing and reading the manuscript; Vincenzo, Stefano, and Andrea for evaluating the book's language; and Rebecca (my future wife) for sustaining me

**Luigi Gianturco**

Italy

ASST Rhodense, Cardio Rehab, Passirana-Rho Hospital,

explores the differences of the disease among men and women.

in all professional activities, giving me power in daily life!

## Preface

Despite a reduction in deaths over the last two decades, atherosclerosis (ATS) is still a major concern worldwide. Decreased mortality can be attributed to anti-smoking laws, especially in Western countries, as it is well established that smoking may accelerate ATS injury. Unfortunately, ATS morbidity and mortality are still quite high. Nowadays, the major cardiovascular risk (CVR) factors contributing to ATS are "metabolic" and include such conditions as dyslipidemia, diabetes, and metabolic syndrome. As such, we understand how global cardiovascular disease (CVD) determines about 30% of world deaths, and ATS is definitely a pivotal contributor to CVD. Although there is much in the literature about ATS, the discussions seem to cover most of the same topics. This book, however, covers not only those topics but also less debated subjects.

For example, you are going to read about the link between CVD and obstructive sleep apneas (the so-called OSAs). Last evidences have linked OSAs to multiple CV disorders including diabetes and coronary artery disease (CAD). Very often, the determinants of ATS progression and OSAs are common and thus it is pivotal to address the linkage between them.

In this volume, you will also find a discussion about the consolidated and close relationship of rheumatology and CV risk. In particular, several contributing authors have been studying how and/or how much systemic rheumatic diseases might affect the heart. In their chapters, these authors attempt to define the state of the art of this topic.

The carotid artery is another conventional topic around ATS. Generally, the coronary circle is the first investigated system in patients with ATS and CAD. For this reason, we underline morbidity and mortality mainly related to carotid ATS instead of CAD.

A chapter dedicated to terminology analyzes old and new insights in order to better describe ATS manifestations, complications, and so on. New evidence needs new accurate and specific terminology, and general physicians, cardiologists, geriatricians, and other specialists involved with ATS must use the proper terms in managing and providing new treatments.

Finally, given the growing focus on gender medicine, a chapter on ATS and women explores the differences of the disease among men and women.

I would like to thank my team for collaborating on this book and bringing it to fruition. In particular, I am grateful to Bruno (my expert colleague) and Aurel (my secretary) for analyzing and reading the manuscript; Vincenzo, Stefano, and Andrea for evaluating the book's language; and Rebecca (my future wife) for sustaining me in all professional activities, giving me power in daily life!

**Chapter 1**

*Luigi Gianturco*

**1. Background**

Introductory Chapter:

and Arteriolosclerosis

literature, we have a multitude of papers about ATS.

the disease, calcify and degenerate going toward necrosis.

**2. General considerations**

ones, becomes very high.

**3. Treatment**

**1**

affect the arteries in any area of the body.

of a myocardial infarction and/or stroke.

Atherosclerosis, Arteriosclerosis,

Atherosclerosis (ATS) is still a great worldwide enemy despite the reduction of deaths due to it in the last two decades. Especially in Western countries, mortality was reduced thanks to anti-smoking laws. It is well established that smoking habits may accelerate ATS injury. Unfortunately, ATS morbidity and mortality are still high. Nowadays, the major cardiovascular (CV) risk (CVR) factors contributing to ATS are "metabolic": dyslipidemia, diabetes, and metabolic syndrome. That said, we understand how global CV disease (CVD) still determines about 30% of world deaths and ATS is definitely a pivotal contributor of CVD. For this reason, in

Let us summarize what is ATS: the term atherosclerosis refers to a generic hardening and loss of elasticity of the walls of the arteries for the formation of plaques, called atheromas or atherosclerotic plaques. Initially, they made up of lipids, including cholesterol, present in the blood and over time they tend to become getting bigger until developing a sort of "support structure" also composed of fibrous substances and connective cells. The latter, in the most advanced stage of

ATS can develop over the decades in silence, without giving any symptoms. When the first signs appear, generally after 40 years of age, the situation of the arteries is usually already compromised and the risk of complications, even serious

ATS is often considered an exclusively cardiac problem, when in fact it can

Treatment of ATS involves, first of all, lifestyle correction (low-calorie and low-

saturated fatty acid diet, exercise, smoking cessation), and pharmacological

Normally ATS does not give symptoms until an artery is so narrowed or obstructed. Then, it would no longer be able to supply organs and tissues with an adequate blood flow. In these cases, you can witness manifestations similar to those

#### **Chapter 1**

## Introductory Chapter: Atherosclerosis, Arteriosclerosis, and Arteriolosclerosis

*Luigi Gianturco*

#### **1. Background**

Atherosclerosis (ATS) is still a great worldwide enemy despite the reduction of deaths due to it in the last two decades. Especially in Western countries, mortality was reduced thanks to anti-smoking laws. It is well established that smoking habits may accelerate ATS injury. Unfortunately, ATS morbidity and mortality are still high. Nowadays, the major cardiovascular (CV) risk (CVR) factors contributing to ATS are "metabolic": dyslipidemia, diabetes, and metabolic syndrome. That said, we understand how global CV disease (CVD) still determines about 30% of world deaths and ATS is definitely a pivotal contributor of CVD. For this reason, in literature, we have a multitude of papers about ATS.

#### **2. General considerations**

Let us summarize what is ATS: the term atherosclerosis refers to a generic hardening and loss of elasticity of the walls of the arteries for the formation of plaques, called atheromas or atherosclerotic plaques. Initially, they made up of lipids, including cholesterol, present in the blood and over time they tend to become getting bigger until developing a sort of "support structure" also composed of fibrous substances and connective cells. The latter, in the most advanced stage of the disease, calcify and degenerate going toward necrosis.

ATS can develop over the decades in silence, without giving any symptoms. When the first signs appear, generally after 40 years of age, the situation of the arteries is usually already compromised and the risk of complications, even serious ones, becomes very high.

ATS is often considered an exclusively cardiac problem, when in fact it can affect the arteries in any area of the body.

Normally ATS does not give symptoms until an artery is so narrowed or obstructed. Then, it would no longer be able to supply organs and tissues with an adequate blood flow. In these cases, you can witness manifestations similar to those of a myocardial infarction and/or stroke.

#### **3. Treatment**

Treatment of ATS involves, first of all, lifestyle correction (low-calorie and lowsaturated fatty acid diet, exercise, smoking cessation), and pharmacological

treatment of concomitant cardiovascular risk factors such as high blood pressure and diabetes mellitus. In some cases, when required by the guidelines, i.e., in secondary prevention and primary prevention in subjects with high cardiovascular risk, it is possible to resort to drugs that interact with the metabolism of cholesterol, such as statins, fenofibrates, or inhibitors of absorption cholesterol.

In selected cases and always if there are indications, it is possible to treat atherosclerotic lesions invasively with some surgical techniques. We know that angioplasty implants particular devices (stents) useful for keeping the lumen of the vessel dilated over time; the bypass that uses a blood vessel taken from another area of the body or implants a synthetic tube to allow blood to get around the artery and continue to flow. Furthermore, in case of thrombus, it is possible to implement a therapy that consists of injecting an anticoagulant drug into the affected tract to dissolve the thrombus and promote the outflow of blood.

#### **Author details**

Luigi Gianturco ASST Rhodense, Cardio Rehab, Passirana-Rho Hospital, Italy

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**3**

**Chapter 2**

**Abstract**

diseases [1].

Carotid Disease

*Minerva Irene Hernández Rejón*

*and Manuel Alexis Vargas Robles*

Atherosclerotic carotid disease causes about 30% of cerebrovascular ischemia transitory or permanent in the world; the severity of symptoms is variable. The clinical manifestations are varied from focal neurological alterations to transient or permanent vascular events. The treatment of the disease will depend on the location, degree, and risk, which can be surgical, endovascular, or medical. Open surgical treatment, endarterectomy, has been preferred as the first option and, however, has been reported to have associated complications like infection, hematoma, stroke, heart attack, restenosis, etc. With the advent of new technologies, endovascular treatment has been described as an option in patients with high risk or restenosis.

**Keywords:** atherosclerotic carotid disease, carotid endarterectomy, endovascular

Atherosclerosis is a chronic disease of the arteries characterized by inflammation and plaque building in the arterial wall, eventually leading to stenosis of the vessel. Carotid atherosclerosis is associated with the increased risk of cardiovascular

Ischemic cardiovascular disease is a combination of progressive atherosclerosis

The risk factors in atherosclerosis can be modifiable or not: non-modifiable are genetic predisposition, gender, and age, and modifiable factors are blood pressure,

The earliest pathologic studies described the predilection of atherosclerosis near branch ostia, bifurcations, and bends, suggesting the important component of flow dynamics plays an important role in its initiation and development. Atherosclerotic plaque tends to form at regions where flow velocity and shear stress are reduced, in particular at the carotid bifurcation where disturbances in blood flow deviate from a laminar unidirectional pattern. Thus, the unique geometry and flow properties

Metabolic syndrome is a clinical entity characterized by multiple risk factors for cardiovascular disease and diabetes mellitus such as high-normal or elevated blood pressure, hyperglycemia, elevated triglycerides, low high-density cholesterol level,

The increase of cardiovascular risk related to metabolic syndrome is reported; over the past decades, the impact of metabolic syndrome on large arterial vessels

smoking, diabetes, cholesterol levels, obesity, and physical activity [2].

treatment, medical management of carotid disease, complications

**1. Atherosclerotic disease and carotid stenosis**

presented by the carotid bifurcation contribute [3].

and abdominal obesity [4].

has been analyzed [4].

and acute thrombotic complications [2].

### **Chapter 2** Carotid Disease

*Minerva Irene Hernández Rejón and Manuel Alexis Vargas Robles*

#### **Abstract**

treatment of concomitant cardiovascular risk factors such as high blood pressure and diabetes mellitus. In some cases, when required by the guidelines, i.e., in secondary prevention and primary prevention in subjects with high cardiovascular risk, it is possible to resort to drugs that interact with the metabolism of cholesterol,

In selected cases and always if there are indications, it is possible to treat atherosclerotic lesions invasively with some surgical techniques. We know that angioplasty implants particular devices (stents) useful for keeping the lumen of the vessel dilated over time; the bypass that uses a blood vessel taken from another area of the body or implants a synthetic tube to allow blood to get around the artery and continue to flow. Furthermore, in case of thrombus, it is possible to implement a therapy that consists of injecting an anticoagulant drug into the affected tract to

such as statins, fenofibrates, or inhibitors of absorption cholesterol.

dissolve the thrombus and promote the outflow of blood.

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

ASST Rhodense, Cardio Rehab, Passirana-Rho Hospital, Italy

\*Address all correspondence to<EMAIL_ADDRESS>
provided the original work is properly cited.

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

**Author details**

Luigi Gianturco

**2**

Atherosclerotic carotid disease causes about 30% of cerebrovascular ischemia transitory or permanent in the world; the severity of symptoms is variable. The clinical manifestations are varied from focal neurological alterations to transient or permanent vascular events. The treatment of the disease will depend on the location, degree, and risk, which can be surgical, endovascular, or medical. Open surgical treatment, endarterectomy, has been preferred as the first option and, however, has been reported to have associated complications like infection, hematoma, stroke, heart attack, restenosis, etc. With the advent of new technologies, endovascular treatment has been described as an option in patients with high risk or restenosis.

**Keywords:** atherosclerotic carotid disease, carotid endarterectomy, endovascular treatment, medical management of carotid disease, complications

#### **1. Atherosclerotic disease and carotid stenosis**

Atherosclerosis is a chronic disease of the arteries characterized by inflammation and plaque building in the arterial wall, eventually leading to stenosis of the vessel. Carotid atherosclerosis is associated with the increased risk of cardiovascular diseases [1].

Ischemic cardiovascular disease is a combination of progressive atherosclerosis and acute thrombotic complications [2].

The risk factors in atherosclerosis can be modifiable or not: non-modifiable are genetic predisposition, gender, and age, and modifiable factors are blood pressure, smoking, diabetes, cholesterol levels, obesity, and physical activity [2].

The earliest pathologic studies described the predilection of atherosclerosis near branch ostia, bifurcations, and bends, suggesting the important component of flow dynamics plays an important role in its initiation and development. Atherosclerotic plaque tends to form at regions where flow velocity and shear stress are reduced, in particular at the carotid bifurcation where disturbances in blood flow deviate from a laminar unidirectional pattern. Thus, the unique geometry and flow properties presented by the carotid bifurcation contribute [3].

Metabolic syndrome is a clinical entity characterized by multiple risk factors for cardiovascular disease and diabetes mellitus such as high-normal or elevated blood pressure, hyperglycemia, elevated triglycerides, low high-density cholesterol level, and abdominal obesity [4].

The increase of cardiovascular risk related to metabolic syndrome is reported; over the past decades, the impact of metabolic syndrome on large arterial vessels has been analyzed [4].

Carotid intima-media thickness has been proven to be a valuable predictor of myocardial infarction and ischemic stroke independent of traditional risk factor. The intima-media thickness was higher in patients with metabolic syndrome [4].

In the study IMPROVE, a multicenter observational European study, it showed that the intima-media thickness was a strong predictor of cardiovascular disease [4].

The maximum intima-media thickness of the common carotid artery, as measured by carotid artery ultrasound, has been used as a marker of atherosclerosis and cardiovascular disease. In contrast, there are reports suggesting that the predictive ability of intima-media thickness for cardiovascular disease is inferior than that of the carotid plaque score assessed by ultrasonography [5].

Recent studies have focused in adding pharmacological strategies like antithrombotic therapy, lowering lipid levels, improving glycemic control, and addressing inflammation present in the metabolic syndrome. On the other hand, patients with coronary and peripheral diseases have a high risk of cardiovascular death and disabling vascular events [2].

Carotid artery stenosis and lower limb peripheral arterial occlusive disease usually share the same pathological changes and can coexist. It has been reported that the prevalence rate of significant carotid stenosis increased with the stage of lower limb peripheral occlusive arterial disease. So the screening for significant carotid disease in these patients [6].

Screening for carotid stenosis in patients who are neurologically asymptomatic may therefore be acceptable when there are two or more risk factors or when ankle/brachial index is less than 0.4 with reevaluation of 6 months. Investigations have identified combinations of risks that identify populations in whom the risk of stenosis between 50% and 99% approaches 60%. Screening patients in these categories who are suitable operative candidates and who would undergo operation were the found to have clinically important disease [7].

#### **2. Definition and epidemiology**

Stroke diagnosis has been based on the World Health Organization's definition of a focal, occasionally global loss of neurological function lasting >24 h and which has a vascular etiology. A transient ischemic attack is defined in a similar way, but the duration is <24 h [8].

The principal causes of ischemic carotid territory stroke are thromboembolism from the internal carotid artery or middle cerebral artery (25%), small vessel intracranial disease (25%), cardiac embolism (20%), and other causes (5%). About 10–15% of all strokes follow thromboembolism from previously asymptomatic internal carotid stenosis >50% [9].

Moderate and severe carotid artery stenosis is an important public health issue; this condition affects 10% of the general population by their eighth decade and accounts for 10% of all strokes [10].

#### **3. Clinical manifestations**

The symptoms of the carotid disease were fist described by Fisher (1951). Stroke produced by carotid stenosis is caused by a combination of affection of the blood vessels, clotting system, and hemodynamics that in conjunction cause embolism or/and low cerebral flow [11].

**5**

*Carotid Disease*

hemisensory loss [12].

**4. Diagnosis**

mortality [13].

*DOI: http://dx.doi.org/10.5772/intechopen.90408*

history and physical examination [11].

can cause low flow or embolic ischemic events.

and computed tomography angiography.

wide (NASCET, ECST, and CC):

definition of asymptomatic or symptomatic carotid artery stenosis is based on the

Symptomatic symptoms include transient ischemic attacks produced by embolization that causes low flow with inadequate collateral blood supply. The symptoms depend on the cerebral artery territory involved, and total carotid artery occlusion

Various features of plaque morphology can be used to identify risk and include

A history of more than one episode of neurological alterations occurring in the same carotid territory is very suggestive of underlying carotid disease. The carotid bruit is an important sign over the site of the stenosis; however, is a poor predictor for development of stroke; and is not sufficiently predictive of high grade of carotid disease. However, 75% of patients with bruit had a moderate to severe stenosis (more than 60). Ischemic symptoms reflect ipsilateral ocular and cerebral hemisphere ischemia like partial or complete blindness, hemianopsia, hemiparesis, and

There are four diagnostic modalities to directly image the internal carotid artery: cerebral angiography, carotid duplex ultrasound, magnetic resonance angiography,

Cerebral angiography is the gold standard for imaging the carotid arteries; it permits an evaluation of the entire carotid artery system, providing information about tandem atherosclerotic disease, plaque morphology, and collateral circulation; however, it is invasive, costs high, and has a high risk of morbidity and

There are three methods to measure carotid stenosis that predominate world-

• The North American Symptomatic Carotid Endarterectomy Trial (NASCET) measures the residual lumen diameter at the most stenotic portion and com-

• The European Carotid Surgery Trial (ECST) measures the lumen diameter at the most stenotic portion of the vessel and compares this with the estimated

• Common carotid (CC) measures the residual lumen diameter at the most

Equivalent measurements for the three methods have been determined. Carotid duplex ultrasound uses B-Mode to help detect focal increases in the blood flow velocity indicative of a high-grade carotid stenosis. The peak systolic velocity is the most frequently used measurement to gauge the severity of the stenosis (end-diastolic velocity, spectral configuration, and carotid index provide additional information) and correlate with the residual lumen diameter [16]. The sensitivity reported is 89% and the specificity 84%. It is a noninvasive, safe, and relative inexpensive technique, although it has limited utility in obtaining information about plaque composition and intraplaque hemorrhage and is less precise in determining stenosis of <50% compared with stenoses of higher degrees.

stenotic portion of the vessel and compares this with the lumen diameter in the

probable original diameter at the site of maximum stenosis [15].

pares it with the normal internal carotid diameter [14].

proximal common carotid artery [15].

plaque ulceration, plaque structure and composition, and plaque volume [12].

Carotid atherosclerosis is usually most severe within 2 cm of the bifurcation of the common carotid artery and involving the posterior wall of the vessel. The

#### *Carotid Disease DOI: http://dx.doi.org/10.5772/intechopen.90408*

definition of asymptomatic or symptomatic carotid artery stenosis is based on the history and physical examination [11].

Symptomatic symptoms include transient ischemic attacks produced by embolization that causes low flow with inadequate collateral blood supply. The symptoms depend on the cerebral artery territory involved, and total carotid artery occlusion can cause low flow or embolic ischemic events.

Various features of plaque morphology can be used to identify risk and include plaque ulceration, plaque structure and composition, and plaque volume [12].

A history of more than one episode of neurological alterations occurring in the same carotid territory is very suggestive of underlying carotid disease. The carotid bruit is an important sign over the site of the stenosis; however, is a poor predictor for development of stroke; and is not sufficiently predictive of high grade of carotid disease. However, 75% of patients with bruit had a moderate to severe stenosis (more than 60). Ischemic symptoms reflect ipsilateral ocular and cerebral hemisphere ischemia like partial or complete blindness, hemianopsia, hemiparesis, and hemisensory loss [12].

#### **4. Diagnosis**

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

the carotid plaque score assessed by ultrasonography [5].

were the found to have clinically important disease [7].

disabling vascular events [2].

disease in these patients [6].

**2. Definition and epidemiology**

internal carotid stenosis >50% [9].

accounts for 10% of all strokes [10].

**3. Clinical manifestations**

or/and low cerebral flow [11].

the duration is <24 h [8].

Carotid intima-media thickness has been proven to be a valuable predictor of myocardial infarction and ischemic stroke independent of traditional risk factor. The intima-media thickness was higher in patients with metabolic syndrome [4]. In the study IMPROVE, a multicenter observational European study, it showed that the intima-media thickness was a strong predictor of cardiovascular disease [4]. The maximum intima-media thickness of the common carotid artery, as measured by carotid artery ultrasound, has been used as a marker of atherosclerosis and cardiovascular disease. In contrast, there are reports suggesting that the predictive ability of intima-media thickness for cardiovascular disease is inferior than that of

Recent studies have focused in adding pharmacological strategies like antithrombotic therapy, lowering lipid levels, improving glycemic control, and addressing inflammation present in the metabolic syndrome. On the other hand, patients with coronary and peripheral diseases have a high risk of cardiovascular death and

Carotid artery stenosis and lower limb peripheral arterial occlusive disease usually share the same pathological changes and can coexist. It has been reported that the prevalence rate of significant carotid stenosis increased with the stage of lower limb peripheral occlusive arterial disease. So the screening for significant carotid

Screening for carotid stenosis in patients who are neurologically asymptomatic

Stroke diagnosis has been based on the World Health Organization's definition of a focal, occasionally global loss of neurological function lasting >24 h and which has a vascular etiology. A transient ischemic attack is defined in a similar way, but

The principal causes of ischemic carotid territory stroke are thromboembolism

Moderate and severe carotid artery stenosis is an important public health issue; this condition affects 10% of the general population by their eighth decade and

The symptoms of the carotid disease were fist described by Fisher (1951). Stroke produced by carotid stenosis is caused by a combination of affection of the blood vessels, clotting system, and hemodynamics that in conjunction cause embolism

Carotid atherosclerosis is usually most severe within 2 cm of the bifurcation of the common carotid artery and involving the posterior wall of the vessel. The

from the internal carotid artery or middle cerebral artery (25%), small vessel intracranial disease (25%), cardiac embolism (20%), and other causes (5%). About 10–15% of all strokes follow thromboembolism from previously asymptomatic

may therefore be acceptable when there are two or more risk factors or when ankle/brachial index is less than 0.4 with reevaluation of 6 months. Investigations have identified combinations of risks that identify populations in whom the risk of stenosis between 50% and 99% approaches 60%. Screening patients in these categories who are suitable operative candidates and who would undergo operation

**4**

There are four diagnostic modalities to directly image the internal carotid artery: cerebral angiography, carotid duplex ultrasound, magnetic resonance angiography, and computed tomography angiography.

Cerebral angiography is the gold standard for imaging the carotid arteries; it permits an evaluation of the entire carotid artery system, providing information about tandem atherosclerotic disease, plaque morphology, and collateral circulation; however, it is invasive, costs high, and has a high risk of morbidity and mortality [13].

There are three methods to measure carotid stenosis that predominate worldwide (NASCET, ECST, and CC):

Equivalent measurements for the three methods have been determined.

Carotid duplex ultrasound uses B-Mode to help detect focal increases in the blood flow velocity indicative of a high-grade carotid stenosis. The peak systolic velocity is the most frequently used measurement to gauge the severity of the stenosis (end-diastolic velocity, spectral configuration, and carotid index provide additional information) and correlate with the residual lumen diameter [16].

The sensitivity reported is 89% and the specificity 84%. It is a noninvasive, safe, and relative inexpensive technique, although it has limited utility in obtaining information about plaque composition and intraplaque hemorrhage and is less precise in determining stenosis of <50% compared with stenoses of higher degrees. Transcranial Doppler is often used in conjunction with ultrasound carotid duplex to evaluate the hemodynamic significance of internal carotid artery stenosis [17].

Magnetic resonance angiography technique is used for evaluating the extracranial carotid arteries and produced a reproducible three-dimensional image of the carotid bifurcation with a good sensitivity for detecting high-grade carotid stenosis; however, it had been reported overestimated degree [18].

Computed tomography angiography provides an anatomic depiction of the carotid artery lumen, allows imaging of adjacent soft tissue structures, and is particularly useful when carotid duplex ultrasound is not reliable or when an overall view of the vascular field is required. It had a sensitivity and specificity of 97 and 99%, respectively [19].

In earlier reports, magnetic resonance, angiography, and carotid duplex ultrasound had difficulties distinguishing very severe stenosis from occlusion, so false-positive and false-negative results occurred [20].

The location most frequently affected by atherosclerosis is the carotid bifurcation. Progression of atheromatous plaque results in luminal narrowing, often accompanied by ulceration, process that can lead to ischemic stroke and transient ischemic attack from embolization, thrombosis, and hemodynamic compromise [20].

#### **5. Treatment**

#### **5.1 Endarterectomy**

The endarterectomy is the choice treatment in those patients with transient ischemic attacks or who suffered a cerebral infarction with a minimal sequel [21]. It is beneficial for symptomatic or asymptomatic patients.

The indications for carotid endarterectomy (CEA) are:

**7**

2.Stroke

*Carotid Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90408*

alternative for carotid endarterectomy.

event, and carotid plaque morphology.

cedural ipsilateral stroke was 2.3%.

1.Myocardial infarction

There are three mains risk factors:

**6.1 Surgical complications in carotid endarterectomy**

complications after carotid endarterectomy is low [25–33].

risk of cardiovascular and procedure-specific complications.

carotid symptoms within the previous 6 months.

**6. Contraindications for carotid endarterectomy**

Absolute: asymptomatic complete carotid occlusion.

Relative contraindications: history of neck radiation, concurrent tracheostomy, prior radical neck dissection with or without radiation, contralateral vocal cord paralysis from prior endarterectomy, atypical lesion location, either high or low, that is surgically inaccessible, severe recurrent carotid stenosis, unacceptably high risk [24]. Carotid endarterectomy is established as safe and effective by randomized controlled trials for reducing the risk of ischemic stroke in both symptomatic and asymptomatic patients. However, carotid angioplasty and stenting are proposed as

Symptomatic carotid disease is defined as focal neurologic symptoms that are referable to the appropriate carotid artery distribution including transient ischemic attacks or ischemic strokes. The definition is contingent on the occurrence of

Carotid endarterectomy and stenting are recommended in patients with recently

symptomatic carotid stenosis of 70–99% and a life expectancy of at least 5 years who meet all of these conditions: accessible carotid lesion, absence of clinically significant cardiac, pulmonary or other diseases that increase greatly the risk of

It is suggested that carotid endarterectomy have to be done 2 weeks after a nondisabling stroke or transitory stroke, because between the first 48 hours, the risk of recurrent stroke elevates compared with later surgery. In patients who have a large infarction with brain swelling, hemorrhagic brain infarction and progressing stroke have long been thought to have high perioperative risk and expose the patient to an increased risk of recurrent stroke, emergent CEA for progressing/fluctuating

The risk of stroke can be calculated based on patient age, patient sex, degree of carotid stenosis, type of presenting symptomatic event, time since last symptomatic

Carotid endarterectomy complications can usually be related to comorbid conditions or cardiovascular preexisting diseases and also to the surgical technique. Most common complications of CEA include myocardial infarction, perioperative stroke, postoperative bleeding, and the potential consequences of cervical hematoma, nerve injury, surgical site infection, and carotid restenosis. However, the rates of

There are two important trials in which the benefit is higher than the possible complications: the European Trial (ICSS) reports a mortality at 120 days of post-op of 0.8% and complications of 4.2%. The North American Trial (CREST) [33, 34] reported combined results for symptomatic and asymptomatic patients. In 1240 patients assigned to endarterectomy (47.3% asymptomatic), the 30-day death rate was 0.3%, and the rate of any periprocedural (30-day) stroke or death or postpro-

Appropriate perioperative medication management is important to reduce the

stroke, or crescendo transitory attack that may have a high operative risk.

anesthesia and surgery, and no prior ipsilateral endarterectomy.

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

99%, respectively [19].

compromise [20].

**5.1 Endarterectomy**

(5.6% versus 2.4%) [22].

of perioperative stroke.

**5. Treatment**

however, it had been reported overestimated degree [18].

false-positive and false-negative results occurred [20].

It is beneficial for symptomatic or asymptomatic patients. The indications for carotid endarterectomy (CEA) are:

Transcranial Doppler is often used in conjunction with ultrasound carotid duplex to evaluate the hemodynamic significance of internal carotid artery stenosis [17]. Magnetic resonance angiography technique is used for evaluating the extracranial carotid arteries and produced a reproducible three-dimensional image of the carotid bifurcation with a good sensitivity for detecting high-grade carotid stenosis;

Computed tomography angiography provides an anatomic depiction of the carotid artery lumen, allows imaging of adjacent soft tissue structures, and is particularly useful when carotid duplex ultrasound is not reliable or when an overall view of the vascular field is required. It had a sensitivity and specificity of 97 and

In earlier reports, magnetic resonance, angiography, and carotid duplex ultrasound had difficulties distinguishing very severe stenosis from occlusion, so

The location most frequently affected by atherosclerosis is the carotid bifurcation. Progression of atheromatous plaque results in luminal narrowing, often accompanied by ulceration, process that can lead to ischemic stroke and transient ischemic attack from embolization, thrombosis, and hemodynamic

The endarterectomy is the choice treatment in those patients with transient ischemic attacks or who suffered a cerebral infarction with a minimal sequel [21].

1.Bilateral carotid stenosis: in which the combined death and stroke rates in patients were almost twice than that of matched patients with unilateral disease

2.Prophylactic carotid endarterectomy: in patients with severe carotid stenosis prior to another surgery, it is rarely needed, and a decision to proceed should be individualized depending upon the clinician's best estimate of the risk

3.Coronary artery bypass surgery: a new stroke or transient ischemic attack occurs in approximately 3% of patients following coronary artery bypass grafting (CABG); also in general surgery, the incidence of stroke appears to be lower in nonvascular surgical procedures than following cardiac surgery with a reported incidence in patients undergoing general anesthesia of less than 0.5%.

4.Vascular procedures: there are not enough trials for prophylactic CEA prior to abdominal aortic aneurysm repair or other major peripheral vascular procedures, because of the involvement of significant hemodynamic fluctuations.

5.Patients with intracranial aneurysm: ipsilateral intracranial aneurysms that are distal to a cervical internal carotid artery stenosis may be susceptible to sudden hemodynamic changes associated with CEA, leading to aneurysm

**6**

rupture [23].

#### **6. Contraindications for carotid endarterectomy**

Absolute: asymptomatic complete carotid occlusion.

Relative contraindications: history of neck radiation, concurrent tracheostomy, prior radical neck dissection with or without radiation, contralateral vocal cord paralysis from prior endarterectomy, atypical lesion location, either high or low, that is surgically inaccessible, severe recurrent carotid stenosis, unacceptably high risk [24].

Carotid endarterectomy is established as safe and effective by randomized controlled trials for reducing the risk of ischemic stroke in both symptomatic and asymptomatic patients. However, carotid angioplasty and stenting are proposed as alternative for carotid endarterectomy.

Symptomatic carotid disease is defined as focal neurologic symptoms that are referable to the appropriate carotid artery distribution including transient ischemic attacks or ischemic strokes. The definition is contingent on the occurrence of carotid symptoms within the previous 6 months.

Carotid endarterectomy and stenting are recommended in patients with recently symptomatic carotid stenosis of 70–99% and a life expectancy of at least 5 years who meet all of these conditions: accessible carotid lesion, absence of clinically significant cardiac, pulmonary or other diseases that increase greatly the risk of anesthesia and surgery, and no prior ipsilateral endarterectomy.

It is suggested that carotid endarterectomy have to be done 2 weeks after a nondisabling stroke or transitory stroke, because between the first 48 hours, the risk of recurrent stroke elevates compared with later surgery. In patients who have a large infarction with brain swelling, hemorrhagic brain infarction and progressing stroke have long been thought to have high perioperative risk and expose the patient to an increased risk of recurrent stroke, emergent CEA for progressing/fluctuating stroke, or crescendo transitory attack that may have a high operative risk.

The risk of stroke can be calculated based on patient age, patient sex, degree of carotid stenosis, type of presenting symptomatic event, time since last symptomatic event, and carotid plaque morphology.

#### **6.1 Surgical complications in carotid endarterectomy**

Carotid endarterectomy complications can usually be related to comorbid conditions or cardiovascular preexisting diseases and also to the surgical technique. Most common complications of CEA include myocardial infarction, perioperative stroke, postoperative bleeding, and the potential consequences of cervical hematoma, nerve injury, surgical site infection, and carotid restenosis. However, the rates of complications after carotid endarterectomy is low [25–33].

There are two important trials in which the benefit is higher than the possible complications: the European Trial (ICSS) reports a mortality at 120 days of post-op of 0.8% and complications of 4.2%. The North American Trial (CREST) [33, 34] reported combined results for symptomatic and asymptomatic patients. In 1240 patients assigned to endarterectomy (47.3% asymptomatic), the 30-day death rate was 0.3%, and the rate of any periprocedural (30-day) stroke or death or postprocedural ipsilateral stroke was 2.3%.

Appropriate perioperative medication management is important to reduce the risk of cardiovascular and procedure-specific complications.

There are three mains risk factors:

3.Death

Others:

There are a lot of risk factors, some of them are:

#### **6.2 Myocardial infarction**

In randomized trials, myocardial infarction has occurred at a slightly higher rate for carotid endarterectomy than carotid artery stenting [25, 26, 28–31]; with a reported incidence between 0 and 2%, pooled absolute risk of perioperative (30-day) myocardial infarction was 0.87%. The risk factors for myocardial infarction included older age, coronary heart disease, peripheral artery disease, and carotid restenosis.

#### **6.3 Perioperative stroke**

Perioperative stroke is the second most common cause of death in carotid endarterectomy [25, 26, 28, 32, 33, 35, 36] with a rate of less than 3% for symptomatic patients and less than 5% for the symptomatic patients depending on the indication of the CEA and the experience of the surgeon. But also there are some factors that can contribute to postoperative stroke [28, 37–42] like plaque emboli, platelet aggregates, improper flushing, poor cerebral protection, and relative hypotension.

If perioperative stroke is suspected, ultrasound is a good option; but if it shows good flow throughout the carotid artery with no thrombosis or intimal flaps, a head computed tomography (CT) scan should be obtained to rule out intracranial bleeding [38, 43–45]. If there is access to a hybrid operating room, another approach to obtain may be head CT first, and, if no bleeding is identified, intraoperative arteriography to identify any correctable lesions is performed [28].

#### **6.4 Hyperperfusion syndrome**

It is an uncommon complication of endarterectomy, occurring after carotid revascularization in less than 1%; it causes the most postoperative intracerebral

**9**

*Carotid Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90408*

perioperative blood pressure control [46].

high-grade (80% or greater) stenosis.

endarterectomy.

this syndrome [46, 47].

**6.5 Cervical hematoma**

**6.6 Nerve injury**

than one nerve affected.

[26, 32, 36].

parotid gland.

following carotid endarterectomy [27, 33].

ptosis, anhidrosis) or partial (no anhidrosis) [29].

hemorrhages and seizures in the first 2 weeks after CEA. It is caused after the surgery; because of the small vessels that chronically compensated the patient, and after endarterectomy blood flow is restored to a normal or elevated perfusion pressure and those vessels are unable to vasoconstrict sufficiently to protect the capillary bed, causing edema and hemorrhage and clinical manifestations. Hypertension is a frequent predecessor of the syndrome, underscoring the importance of good

Hyperperfusion syndrome appears to be more likely with revascularization of a

Hyperperfusion syndrome is characterized by the following clinical features:

2.Focal motor seizures are common, sometimes with postictal Todd's paralysis

approximatelys 0.6% of patients after CEA, usually within 2 weeks of surgery.

Treatment consists of prevention, strict control of postoperative hypertension maintaining a systolic blood pressure below 150 mmHg, and using labetalol, nitroprusside, and nitroglycerin aggressively. If complication is suspected in any patient with severe headache following CAE, a head CT is required to confirm or discard

This is a catastrophic and real urgent complication, because it can result in abrupt loss of the airway, with an incidence of 4% after CAE and requiring a re-exploration of the neck. Uncontrolled hypertension during emergence from anesthesia or in the

Cranial nerve or other nerve injuries occur in approximately 5% of patients

According to the European Carotid Surgery Trial, cranial nerve injury rate declined to 3.7%. In the Vascular Study Group of New England (VSGNE) database, the overall rate of nerve injury at discharge was 5.6%; 0.7% of patients had more

Hypoglossal nerve is the most frequently injurie manifested by a deviation of the tongue to the side of the injury, the facial nerve is the second one resulting in paresis of the lateral aspect of the orbicularis oris muscle with asymmetric smile; and the vagus nerve which result in unilateral vocal cord paralysis, glossopharyngeal nerve can be damaged with excessive dissection in the carotid bifurcation

Injury to the sympathetic nerves can result in Horner's syndrome or, rarely, an entity called "first bite syndrome." Horner's syndrome can be complete (miosis,

First bite syndrome is characterized by unilateral pain in the parotid region after the first bite of each meal felt to be due to sympathetic denervation of the

postoperative period can also lead to hematoma formation [26, 35, 48].

mimicking post-endarterectomy stroke from carotid thrombosis.

3.Intracerebral hemorrhage is the most feared complication, occurring in

1.Headache ipsilateral to the revascularized internal carotid, typically improved in upright posture, may herald the syndrome in the first week after

#### *Carotid Disease DOI: http://dx.doi.org/10.5772/intechopen.90408*

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

There are a lot of risk factors, some of them are:

3.Previous stroke including transient ischemic attack

5.Special or chronic conditions such as cancer, heart diseases, hypertension, and

In randomized trials, myocardial infarction has occurred at a slightly higher rate for carotid endarterectomy than carotid artery stenting [25, 26, 28–31]; with a reported incidence between 0 and 2%, pooled absolute risk of perioperative (30-day) myocardial infarction was 0.87%. The risk factors for myocardial infarction included older age, coronary heart disease, peripheral artery disease, and carotid restenosis.

Perioperative stroke is the second most common cause of death in carotid endarterectomy [25, 26, 28, 32, 33, 35, 36] with a rate of less than 3% for symptomatic patients and less than 5% for the symptomatic patients depending on the indication of the CEA and the experience of the surgeon. But also there are some factors that can contribute to postoperative stroke [28, 37–42] like plaque emboli, platelet aggregates, improper flushing, poor cerebral protection, and relative hypotension. If perioperative stroke is suspected, ultrasound is a good option; but if it shows good flow throughout the carotid artery with no thrombosis or intimal flaps, a head computed tomography (CT) scan should be obtained to rule out intracranial bleeding [38, 43–45]. If there is access to a hybrid operating room, another approach to obtain may be head CT first, and, if no bleeding is identified, intraoperative

It is an uncommon complication of endarterectomy, occurring after carotid revascularization in less than 1%; it causes the most postoperative intracerebral

arteriography to identify any correctable lesions is performed [28].

4.Previous stenosis of carotid artery

1.Hyperperfusion syndrome

2.Cervical hematoma

3.Nerve injury

4.Infection

5.Restenosis

2.Smoking

diabetes

**6.2 Myocardial infarction**

**6.3 Perioperative stroke**

**6.4 Hyperperfusion syndrome**

1.Age (>80 years)

3.Death

Others:

**8**

hemorrhages and seizures in the first 2 weeks after CEA. It is caused after the surgery; because of the small vessels that chronically compensated the patient, and after endarterectomy blood flow is restored to a normal or elevated perfusion pressure and those vessels are unable to vasoconstrict sufficiently to protect the capillary bed, causing edema and hemorrhage and clinical manifestations. Hypertension is a frequent predecessor of the syndrome, underscoring the importance of good perioperative blood pressure control [46].

Hyperperfusion syndrome appears to be more likely with revascularization of a high-grade (80% or greater) stenosis.

Hyperperfusion syndrome is characterized by the following clinical features:

Treatment consists of prevention, strict control of postoperative hypertension maintaining a systolic blood pressure below 150 mmHg, and using labetalol, nitroprusside, and nitroglycerin aggressively. If complication is suspected in any patient with severe headache following CAE, a head CT is required to confirm or discard this syndrome [46, 47].

#### **6.5 Cervical hematoma**

This is a catastrophic and real urgent complication, because it can result in abrupt loss of the airway, with an incidence of 4% after CAE and requiring a re-exploration of the neck. Uncontrolled hypertension during emergence from anesthesia or in the postoperative period can also lead to hematoma formation [26, 35, 48].

#### **6.6 Nerve injury**

Cranial nerve or other nerve injuries occur in approximately 5% of patients following carotid endarterectomy [27, 33].

According to the European Carotid Surgery Trial, cranial nerve injury rate declined to 3.7%. In the Vascular Study Group of New England (VSGNE) database, the overall rate of nerve injury at discharge was 5.6%; 0.7% of patients had more than one nerve affected.

Hypoglossal nerve is the most frequently injurie manifested by a deviation of the tongue to the side of the injury, the facial nerve is the second one resulting in paresis of the lateral aspect of the orbicularis oris muscle with asymmetric smile; and the vagus nerve which result in unilateral vocal cord paralysis, glossopharyngeal nerve can be damaged with excessive dissection in the carotid bifurcation [26, 32, 36].

Injury to the sympathetic nerves can result in Horner's syndrome or, rarely, an entity called "first bite syndrome." Horner's syndrome can be complete (miosis, ptosis, anhidrosis) or partial (no anhidrosis) [29].

First bite syndrome is characterized by unilateral pain in the parotid region after the first bite of each meal felt to be due to sympathetic denervation of the parotid gland.

#### **6.7 Infection**

Surgical site/patch infection (SSI) rarely occurs following carotid endarterectomy, and, when they occur, most are superficial and self-limiting with antibiotic treatment. The prophylaxis is the best practice to prevent SSI.

Clinically the patient will have neck swelling and drainage from incision in acute events; in delayed infections, a draining sinus tract or pulsatile neck mass could be indicative of a carotid pseudoaneurysm. If infection persists, a patch excision is indicated with early carotid ligation, reconstruction with autogenous vein, or bypass; nowadays the use of negative pressure systems is a good option to perform a better treatment of these infections, resulting in better outcomes and reducing complications of a new exploratory surgery in these patients [3, 13, 19, 25–41].

#### **6.8 Carotid restenosis**

The pathology of the restenotic lesion is related to the time of presentation after initial surgery. Most patients with restenosis are asymptomatic and are identified with routine follow-up carotid imaging [29].

It is called early restenosis in those that occur within 2–3 years after CEA and late in those that occur more than 2–3 years after surgery. Patients at increased risk for restenosis include those below age 65, smokers, and women. Patch angioplasty appears to be associated with a decreased risk of long-term recurrent stenosis compared with primary closure [29, 31].

Reintervention is indicated in patients who develop neurologic symptoms referable to the carotid artery and those with restenosis >80% [29, 45].

#### **6.9 Endovascular treatment**

Carotid artery angioplasty and stenting are the standard for endovascular carotid intervention that is preferred for most patients with symptomatic internal carotid atherosclerosis. Patients with symptomatic carotid disease treated by endarterectomy that are considered to be less invasive have long-term benefits; nevertheless, it is reported that patients have an increased risk for poor outcomes with endarterectomy such as stroke periprocedural (30 days). So it is recommended in patients with 70–99% stenosis with the following conditions: not suitable surgical access, stenosis radiation induced, restenosis after endarterectomy, and clinically significant cardiac, pulmonary, or other disease that increment risk.

Low dose of aspirin treatment is recommended for all patients who are having an endarterectomy and have to be continued for at least 3 months after surgery; posterior only is indicated with cardiovascular disease.

The endovascular treatment is nowadays the first-line treatment for many vascular diseases. The percutaneous intraluminal angioplasty (PTA) consists in dilatation with a balloon for stenotic lesions, making a dehiscence effect, leading to fracture and separation of the arterial media from the intima; it was the first performed endovascular treatment. The introduction of stents was a major step in the evolution of the endovascular management of carotid stenosis [49].

There are a lot of diapositives that can be used in the endovascular treatment [22, 41, 50]; some of them are the following:

1.Cryoplasty is a type of balloon angioplasty that has liquid nitrous oxide to get inflated and uses cooling a-10°C (14°F) and pressure to dilate the plaque and vessel wall. It is well studied in iliac, infrainguinal, femoropopliteal, and popliteal lesions.

**11**

*Carotid Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.90408*

femoropopliteal lesions.

perforation after PTA or stenting.

used for femoropopliteal disease.

covering prostheses.

d.Multilayer stents:

ropopliteal disease and biliary applications.

now is used also for peripheral arterial beds.

5.Stent grafts

2.Focal pressure balloon was designed to reduce dissection and restenosis and to exhibit focal pressure to the lesions; it is used in infrapopliteal lesions.

3.Drug-coated balloon: drug-eluting stents (DES) achieve local administration of an agent capable of inhibiting intimal hyperplasia without systemic side effects. Cypher stents release sirolimus which has a potent immunosuppressive drug that controls intimal hyperplasia. TAXUS is a second-generation DES, with greater durability and which reduces restenosis. These devices are used in

4.Stents are a method to reduce the incidence of restenosis or address balloon PTA failure due to elastic recoil or dissection. They are classified as balloonexpanding (BES) and self-expanding stents and also either as bare metal or covered stents. Self-expanding stents are composed typically of nitinol.

a.Balloon-expanding stent grafts can be expanded beyond the stated stent diameter; they are used for tracheobronchial strictures but not for PAD, for iliac or renal artery vascular beds, for occlusive lesions, as well as for

b.Self-expanding stent grafts are used for various applications and in femo-

c.Drug-eluting stents have been associated with improved patency for the treatment of PAD compared to conventional balloon angioplasty. These are loaded with paclitaxel and sirolimus usually using polymers; these are

i.Multilayer flow modulator (MFM) is designed to exclude peripheral or visceral aneurysm while maintaining branch vessel flow. It is a threedimensional braided tube composed of multilayer wire without any

ii.Bioabsorbable stents are initially developed for coronary intervention,

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

with routine follow-up carotid imaging [29].

compared with primary closure [29, 31].

**6.9 Endovascular treatment**

Surgical site/patch infection (SSI) rarely occurs following carotid endarterectomy, and, when they occur, most are superficial and self-limiting with antibiotic

events; in delayed infections, a draining sinus tract or pulsatile neck mass could be indicative of a carotid pseudoaneurysm. If infection persists, a patch excision is indicated with early carotid ligation, reconstruction with autogenous vein, or bypass; nowadays the use of negative pressure systems is a good option to perform a better treatment of these infections, resulting in better outcomes and reducing complications of a new exploratory surgery in these patients [3, 13, 19, 25–41].

Clinically the patient will have neck swelling and drainage from incision in acute

The pathology of the restenotic lesion is related to the time of presentation after initial surgery. Most patients with restenosis are asymptomatic and are identified

It is called early restenosis in those that occur within 2–3 years after CEA and late in those that occur more than 2–3 years after surgery. Patients at increased risk for restenosis include those below age 65, smokers, and women. Patch angioplasty appears to be associated with a decreased risk of long-term recurrent stenosis

Reintervention is indicated in patients who develop neurologic symptoms refer-

Carotid artery angioplasty and stenting are the standard for endovascular carotid intervention that is preferred for most patients with symptomatic internal carotid atherosclerosis. Patients with symptomatic carotid disease treated by endarterectomy that are considered to be less invasive have long-term benefits; nevertheless, it is reported that patients have an increased risk for poor outcomes with endarterectomy such as stroke periprocedural (30 days). So it is recommended in patients with 70–99% stenosis with the following conditions: not suitable surgical access, stenosis radiation induced, restenosis after endarterectomy, and clinically significant

Low dose of aspirin treatment is recommended for all patients who are having an endarterectomy and have to be continued for at least 3 months after surgery;

The endovascular treatment is nowadays the first-line treatment for many vascular diseases. The percutaneous intraluminal angioplasty (PTA) consists in dilatation with a balloon for stenotic lesions, making a dehiscence effect, leading to fracture and separation of the arterial media from the intima; it was the first performed endovascular treatment. The introduction of stents was a major step in

There are a lot of diapositives that can be used in the endovascular treatment

1.Cryoplasty is a type of balloon angioplasty that has liquid nitrous oxide to get inflated and uses cooling a-10°C (14°F) and pressure to dilate the plaque and vessel wall. It is well studied in iliac, infrainguinal, femoropopliteal, and

the evolution of the endovascular management of carotid stenosis [49].

able to the carotid artery and those with restenosis >80% [29, 45].

cardiac, pulmonary, or other disease that increment risk.

posterior only is indicated with cardiovascular disease.

[22, 41, 50]; some of them are the following:

popliteal lesions.

treatment. The prophylaxis is the best practice to prevent SSI.

**6.7 Infection**

**6.8 Carotid restenosis**

**10**

	- i.Multilayer flow modulator (MFM) is designed to exclude peripheral or visceral aneurysm while maintaining branch vessel flow. It is a threedimensional braided tube composed of multilayer wire without any covering prostheses.
	- ii.Bioabsorbable stents are initially developed for coronary intervention, now is used also for peripheral arterial beds.

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

#### **Author details**

Minerva Irene Hernández Rejón\* and Manuel Alexis Vargas Robles Department of General Surgery, Hospital Central Norte PEMEX, Mexico City, Mexico

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**13**

75-82

*Carotid Disease*

**References**

2018:1-14

*DOI: http://dx.doi.org/10.5772/intechopen.90408*

application in clinical practice. Frontiers in Neurology. 2017;**8**(October):1-14

[9] Persoon S, Kappelle LJ, Klijn CJM. Limb-shaking transient ischaemic attacks in patients with internal carotid artery occlusion: A case-control study. Brain: A Journal of Neurology. 2010

[10] Vranic H, Hadzimehmedagic A, Haxibeqiri-karabdic I. Critical carotid artery stenosis in coronary and noncoronary patients—Frequency of risk factors. Medical Archives. 2017;**71**(2):

[11] Witteman JCM, Grobbee DE, Hofman A, Breteler MMB. Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly the rotterdam study. Circulation. 2002:2872-2877

[12] Takaya N, Yuan C, Chu B, Saam T, Underhill H, Cai J, et al. Subsequent ischemic cerebrovascular events a prospective assessment with MRI— Initial results. Stroke. 2006;**112**:818-823

[13] Hankey GJ, Warlow CP, Sellar RJ. Cerebral angiographic risk in mild cerebrovascular disease. Stroke. 1990:

[14] Commite S. Original contributions North American symptomatic carotid endarterectomy trial. Stroke. 1991

[15] James F, Toole JEC. Accurate measurement of carotid stenosis. American Society of Neuroimaging.

[16] Polak F, Leary HO. Detection and carotid artery various Doppler quantification of stenosis: Efficacy of velocity parameters. AJR. 1993;**160**:

[17] Edwards JM et al. Correlation of North American Symptomatic Carotid

110-114

209-222

1994

619-625

[2] Vanassche T, Verhamme P, Anand SS, Shestakovska O, Fox KAA, Bhatt DL, et al. Risk factors and clinical outcomes in chronic coronary and peripheral artery disease: An analysis of the randomized, double-blind COMPASS trial. European Journal of Preventive Cardiology. 2019;**27**(3):296-307

[3] Kolodgie FD, Nakazawa G, Sangiorgi G, Ladich E. Pathology of atherosclerosis and stenting. Neuroimaging Clinics of North America. 2009;**17**(3):1-25

[4] Cuspidi C et al. Metabolic syndrome and subclinical carotid damage: A metaanalysis from population-based studies. Journal of Hypertension. 2017;**36**:1-8

[5] Kawada T, Andou T, Fukumitsu M. Metabolic syndrome showed significant

atherosclerosis. Heart and Vessels.

[6] Pan Z, Wang R, Li L, Zhang H. Correlation between significant asymptomatic carotid artery stenosis and severity of peripheral arterial occlusive disease in the lower limb: A retrospective study on 200 patients.

[7] Cina CS, It SC, Safar HA. Prevalence and progression of internal carotid artery stenosis in patients with peripheral arterial occlusive disease. Journal of Vascular Surgery. 2000;**36**(1):

definitions of stroke, transient ischemic attack, and infarction for research and

relationship with carotid

BMC Neurology. 2019:4-8

[8] Abbott AL. Optimizing the

2015;**31**(5):664-670

[1] Forgo B, Medda E, Hernyes A, Szalontai L, Tarnoki DL, Tarnoki AD. Carotid artery atherosclerosis: A review on heritability and genetics. Twin Research and Human Genetics.

#### *Carotid Disease DOI: http://dx.doi.org/10.5772/intechopen.90408*

### **References**

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

**12**

**Author details**

Mexico

Minerva Irene Hernández Rejón\* and Manuel Alexis Vargas Robles

\*Address all correspondence to<EMAIL_ADDRESS>
provided the original work is properly cited.

Department of General Surgery, Hospital Central Norte PEMEX, Mexico City,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Forgo B, Medda E, Hernyes A, Szalontai L, Tarnoki DL, Tarnoki AD. Carotid artery atherosclerosis: A review on heritability and genetics. Twin Research and Human Genetics. 2018:1-14

[2] Vanassche T, Verhamme P, Anand SS, Shestakovska O, Fox KAA, Bhatt DL, et al. Risk factors and clinical outcomes in chronic coronary and peripheral artery disease: An analysis of the randomized, double-blind COMPASS trial. European Journal of Preventive Cardiology. 2019;**27**(3):296-307

[3] Kolodgie FD, Nakazawa G, Sangiorgi G, Ladich E. Pathology of atherosclerosis and stenting. Neuroimaging Clinics of North America. 2009;**17**(3):1-25

[4] Cuspidi C et al. Metabolic syndrome and subclinical carotid damage: A metaanalysis from population-based studies. Journal of Hypertension. 2017;**36**:1-8

[5] Kawada T, Andou T, Fukumitsu M. Metabolic syndrome showed significant relationship with carotid atherosclerosis. Heart and Vessels. 2015;**31**(5):664-670

[6] Pan Z, Wang R, Li L, Zhang H. Correlation between significant asymptomatic carotid artery stenosis and severity of peripheral arterial occlusive disease in the lower limb: A retrospective study on 200 patients. BMC Neurology. 2019:4-8

[7] Cina CS, It SC, Safar HA. Prevalence and progression of internal carotid artery stenosis in patients with peripheral arterial occlusive disease. Journal of Vascular Surgery. 2000;**36**(1): 75-82

[8] Abbott AL. Optimizing the definitions of stroke, transient ischemic attack, and infarction for research and

application in clinical practice. Frontiers in Neurology. 2017;**8**(October):1-14

[9] Persoon S, Kappelle LJ, Klijn CJM. Limb-shaking transient ischaemic attacks in patients with internal carotid artery occlusion: A case-control study. Brain: A Journal of Neurology. 2010

[10] Vranic H, Hadzimehmedagic A, Haxibeqiri-karabdic I. Critical carotid artery stenosis in coronary and noncoronary patients—Frequency of risk factors. Medical Archives. 2017;**71**(2): 110-114

[11] Witteman JCM, Grobbee DE, Hofman A, Breteler MMB. Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly the rotterdam study. Circulation. 2002:2872-2877

[12] Takaya N, Yuan C, Chu B, Saam T, Underhill H, Cai J, et al. Subsequent ischemic cerebrovascular events a prospective assessment with MRI— Initial results. Stroke. 2006;**112**:818-823

[13] Hankey GJ, Warlow CP, Sellar RJ. Cerebral angiographic risk in mild cerebrovascular disease. Stroke. 1990: 209-222

[14] Commite S. Original contributions North American symptomatic carotid endarterectomy trial. Stroke. 1991

[15] James F, Toole JEC. Accurate measurement of carotid stenosis. American Society of Neuroimaging. 1994

[16] Polak F, Leary HO. Detection and carotid artery various Doppler quantification of stenosis: Efficacy of velocity parameters. AJR. 1993;**160**: 619-625

[17] Edwards JM et al. Correlation of North American Symptomatic Carotid Endarterectomy Trial (NASCET) angiographic definition of 70% to 99% internal carotid artery stenosis with duplex scanning. Journal of Vascular Surgery. 1993

[18] Bowen C, Pattany M, Quencer M. Review article MR angiography head and neck: Of occlusive disease current concepts of the arteries in the. AJR. 1994:9-18

[19] Corti R, Ferrari C, Roberti M, Alerci M, Pedrazzi PL, Gallino A. Spiral computed tomography A novel diagnostic approach for investigation of the extracranial cerebral arteries and its complementary role in duplex ultrasonography. Circulation. 1998:984-989

[20] Mattle HP, Kent KC, Edelman R. Evaluation of the extracranial carotid arteries: Correlation of magnetic resonance angiography , duplex ultrasonography, and conventional angiography. Journal of Vascular Surgery. 1991;**13**(6):838-845

[21] Seara AH. Tratamiento quirúrgico de la estenosis carotídea [Surgical treatment of the carotid stenosis]. 2014;**15**(2):153-170

[22] Counsell CE, Salinas R, Naylor R, Warlow CP. A systematic review of the randomised trials of carotid patch angioplasty in carotid endarterectomy. European Journal of Vascular and Endovascular Surgery. 1997;**13**(4):345-354

[23] Da Silva AF, Mccollum P, Szymanska T, De Cossart L. Prospective study of carotid endarterectomy and contralateral carotid occlusion. The British Journal of Surgery. 1996;**83**(10):1370-1372

[24] Marcucci G, Accrocca F, Antonelli RG, Giordano A, Gabrielli R, Mounayergi F, et al. High-risk patients for carotid endarterectomy: Turned

down cases are rare. Journal of Cardiovascular Surgery. 2012;**53**:333-343

[25] Boulanger M, Camelière L, Felgueiras R, Berger L, Rerkasem K, Rothwell PM, et al. Periprocedural myocardial infarction after carotid endarterectomy and stenting: Systematic review and meta-analysis. Stroke. 2015;**46**(10):2843-2848

[26] Texakalidis P, Giannopoulos S, Charisis N, Giannopoulos S, Karasavvidis T, Koullias G, et al. A meta-analysis of randomized trials comparing bovine pericardium and other patch materials for carotid endarterectomy. Journal of Vascular Surgery. 2018;**68**(4):1241-1256.e1

[27] Kragsterman B, Björck M, Wanhainen A. EndoVAC, a novel hybrid technique to treat infected vascular reconstructions with an endograft and vacuum-assisted wound closure. Journal of Endovascular Therapy. 2011;**18**(5):666-673

[28] Krafcik BM, Cheng TW, Farber A, Kalish JA, Rybin D, Doros G, et al. Perioperative outcomes after reoperative carotid endarterectomy are worse than expected. Journal of Vascular Surgery. 2018;**67**(3):793-798

[29] Rambachan A, Smith TR, Saha S, Eskandari MK, Bendok BR, Kim JYS. Reasons for readmission after carotid endarterectomy. World Neurosurgery. 2014;**82**(6):E771-E776

[30] Bennett KM, Kent KC, Schumacher J, Greenberg CC, Scarborough JE. Targeting the most important complications in vascular surgery. Journal of Vascular Surgery. 2017;**65**(3):793-803

[31] Enomoto LM, Hill DC, Dillon PW, Han DC, Hollenbeak CS. Surgical specialty and outcomes for carotid endarterectomy: Evidence from the

**15**

*Carotid Disease*

2000;**32**(3):602-606

*DOI: http://dx.doi.org/10.5772/intechopen.90408*

National Surgical Quality Improvement Program. The Journal of Surgical Research. 2014;**188**(1):339-348

[40] Muto A, Nishibe T, Dardik H, Dardik A. Patches for carotid artery endarterectomy: Current materials and prospects. Journal of Vascular Surgery.

[41] Rangel-Castilla L, Rajah GB, Shakir HJ, Davies JM, Snyder KV, Siddiqui AH, et al. Endovascular prevention and treatment of stroke related to extracranial carotid artery disease. The Journal of Cardiovascular

[42] Perler BA, Ursin F, Shanks U, Williams GM. Carotid dacron patch angioplasty: Immediate and long-term results of a prospective series. Vascular.

[43] Hyldig N, Birke-Sorensen H, Kruse M, Vinter C, Joergensen JS, Sorensen JA, et al. Meta-analysis of negative-pressure wound therapy for closed surgical incisions. The British Journal of Surgery. 2016;**103**(5):477-486

[44] Stone PA, Srivastava M, Campbell JE, Mousa AY, Hass SH, Kazmi H, et al. A 10-year experience of infection following carotid

endarterectomy with patch angioplasty. Journal of Vascular Surgery. 2011;**53**(6):

[45] van der Slegt J, Kluytmans JAJW, de Groot HGW, van der Laan L. Treatment of surgical site infections (SSI) IN patients with peripheral arterial disease: An observational study. International Journal of Surgery. 2015;**14**:85-89

[46] Hosoda K, Kawaguchi T, Ishii K, Minoshima S, Shibata Y, Iwakura M, et al. Prediction of hyperperfusion after carotid endarterectomy by brain SPECT analysis with semiquantitative statistical mapping method. Stroke.

[47] Kablak-Ziembicka A, Przewlocki T, Pieniazek P, Musialek P, Tekieli L, Rosławiecka A, et al. Predictors of

2003;**34**(5):1187-1193

Surgery. 2017;**58**(1):35-48

1995;**3**(6):631-636

1473-1477

2009;**50**(1):206-213

[32] Rizzo A, Hertzer NR, O'Hara PJ, Krajewski LP, Beven EG. Dacron carotid patch infection: A report of eight cases. Journal of Vascular Surgery.

[33] Ederle J, Dobson J, Featherstone RL,

Bonati LH, van der Worp HB, de Borst GJ, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting

Study): An interim analysis of a randomised controlled trial. Lancet.

[34] Clark WM, Brooks W, Mackey A, Hill MD, Leimgruber PP, Sheffet AJ, et al. New England Journal. 2010:11-23

[35] Ho KJ, Nguyen LL, Menard MT. Intermediate-term outcome of carotid endarterectomy with bovine pericardial patch closure compared with Dacron patch and primary closure. Journal of Vascular Surgery. 2012;**55**(3):708-714

[36] Fatima J, Federico VP, Scali ST, Feezor RJ, Berceli SA, Giles KA, et al. Management of patch infections after carotid endarterectomy and utility of femoral vein interposition bypass graft. Journal of Vascular Surgery.

[37] Acosta S, Björck M, Wanhainen A. Negative-pressure wound therapy for prevention and treatment of surgical-site infections after vascular surgery. The British Journal of Surgery.

[38] Hammer FD. Reply. Journal of Vascular Surgery. 2001;**33**(3):662-663

[39] Inui T, Bandyk DF. Vascular surgical site infection: Risk factors and preventive measures. Seminars in Vascular Surgery. 2015;**28**(3-4):201-207

2019;**69**(6):1815-1823.e1

2017;**104**(2):e75-e84

2010;**375**(9719):985-997

#### *Carotid Disease DOI: http://dx.doi.org/10.5772/intechopen.90408*

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

down cases are rare. Journal of Cardiovascular Surgery.

[25] Boulanger M, Camelière L, Felgueiras R, Berger L, Rerkasem K, Rothwell PM, et al. Periprocedural myocardial infarction after carotid endarterectomy and stenting:

Systematic review and meta-analysis. Stroke. 2015;**46**(10):2843-2848

[26] Texakalidis P, Giannopoulos S, Charisis N, Giannopoulos S, Karasavvidis T, Koullias G, et al. A meta-analysis of randomized trials comparing bovine pericardium and other patch materials for carotid endarterectomy. Journal of Vascular Surgery. 2018;**68**(4):1241-1256.e1

[27] Kragsterman B, Björck M,

2011;**18**(5):666-673

2018;**67**(3):793-798

[29] Rambachan A, Smith TR, Saha S, Eskandari MK, Bendok BR, Kim JYS. Reasons for readmission after carotid endarterectomy. World Neurosurgery. 2014;**82**(6):E771-E776

[30] Bennett KM, Kent KC, Schumacher J, Greenberg CC, Scarborough JE. Targeting the most important complications in vascular surgery. Journal of Vascular Surgery.

[31] Enomoto LM, Hill DC, Dillon PW, Han DC, Hollenbeak CS. Surgical specialty and outcomes for carotid endarterectomy: Evidence from the

2017;**65**(3):793-803

Wanhainen A. EndoVAC, a novel hybrid technique to treat infected vascular reconstructions with an endograft and vacuum-assisted wound closure. Journal of Endovascular Therapy.

[28] Krafcik BM, Cheng TW, Farber A, Kalish JA, Rybin D, Doros G, et al. Perioperative outcomes after reoperative carotid endarterectomy are worse than expected. Journal of Vascular Surgery.

2012;**53**:333-343

Endarterectomy Trial (NASCET) angiographic definition of 70% to 99% internal carotid artery stenosis with duplex scanning. Journal of Vascular

[18] Bowen C, Pattany M, Quencer M. Review article MR angiography head and neck: Of occlusive disease current concepts of the arteries in the. AJR.

[19] Corti R, Ferrari C, Roberti M, Alerci M, Pedrazzi PL, Gallino A. Spiral

[20] Mattle HP, Kent KC, Edelman R. Evaluation of the extracranial carotid arteries: Correlation of magnetic resonance angiography , duplex ultrasonography, and conventional angiography. Journal of Vascular Surgery. 1991;**13**(6):838-845

[21] Seara AH. Tratamiento quirúrgico de la estenosis carotídea [Surgical treatment of the carotid stenosis].

[22] Counsell CE, Salinas R, Naylor R, Warlow CP. A systematic review of the randomised trials of carotid patch angioplasty in carotid

endarterectomy. European Journal of Vascular and Endovascular Surgery.

Szymanska T, De Cossart L. Prospective

Antonelli RG, Giordano A, Gabrielli R, Mounayergi F, et al. High-risk patients for carotid endarterectomy: Turned

computed tomography A novel diagnostic approach for investigation of the extracranial cerebral arteries and its complementary role in duplex ultrasonography. Circulation.

Surgery. 1993

1994:9-18

1998:984-989

2014;**15**(2):153-170

1997;**13**(4):345-354

1996;**83**(10):1370-1372

[24] Marcucci G, Accrocca F,

[23] Da Silva AF, Mccollum P,

study of carotid endarterectomy and contralateral carotid occlusion. The British Journal of Surgery.

**14**

National Surgical Quality Improvement Program. The Journal of Surgical Research. 2014;**188**(1):339-348

[32] Rizzo A, Hertzer NR, O'Hara PJ, Krajewski LP, Beven EG. Dacron carotid patch infection: A report of eight cases. Journal of Vascular Surgery. 2000;**32**(3):602-606

[33] Ederle J, Dobson J, Featherstone RL, Bonati LH, van der Worp HB, de Borst GJ, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): An interim analysis of a randomised controlled trial. Lancet. 2010;**375**(9719):985-997

[34] Clark WM, Brooks W, Mackey A, Hill MD, Leimgruber PP, Sheffet AJ, et al. New England Journal. 2010:11-23

[35] Ho KJ, Nguyen LL, Menard MT. Intermediate-term outcome of carotid endarterectomy with bovine pericardial patch closure compared with Dacron patch and primary closure. Journal of Vascular Surgery. 2012;**55**(3):708-714

[36] Fatima J, Federico VP, Scali ST, Feezor RJ, Berceli SA, Giles KA, et al. Management of patch infections after carotid endarterectomy and utility of femoral vein interposition bypass graft. Journal of Vascular Surgery. 2019;**69**(6):1815-1823.e1

[37] Acosta S, Björck M, Wanhainen A. Negative-pressure wound therapy for prevention and treatment of surgical-site infections after vascular surgery. The British Journal of Surgery. 2017;**104**(2):e75-e84

[38] Hammer FD. Reply. Journal of Vascular Surgery. 2001;**33**(3):662-663

[39] Inui T, Bandyk DF. Vascular surgical site infection: Risk factors and preventive measures. Seminars in Vascular Surgery. 2015;**28**(3-4):201-207 [40] Muto A, Nishibe T, Dardik H, Dardik A. Patches for carotid artery endarterectomy: Current materials and prospects. Journal of Vascular Surgery. 2009;**50**(1):206-213

[41] Rangel-Castilla L, Rajah GB, Shakir HJ, Davies JM, Snyder KV, Siddiqui AH, et al. Endovascular prevention and treatment of stroke related to extracranial carotid artery disease. The Journal of Cardiovascular Surgery. 2017;**58**(1):35-48

[42] Perler BA, Ursin F, Shanks U, Williams GM. Carotid dacron patch angioplasty: Immediate and long-term results of a prospective series. Vascular. 1995;**3**(6):631-636

[43] Hyldig N, Birke-Sorensen H, Kruse M, Vinter C, Joergensen JS, Sorensen JA, et al. Meta-analysis of negative-pressure wound therapy for closed surgical incisions. The British Journal of Surgery. 2016;**103**(5):477-486

[44] Stone PA, Srivastava M, Campbell JE, Mousa AY, Hass SH, Kazmi H, et al. A 10-year experience of infection following carotid endarterectomy with patch angioplasty. Journal of Vascular Surgery. 2011;**53**(6): 1473-1477

[45] van der Slegt J, Kluytmans JAJW, de Groot HGW, van der Laan L. Treatment of surgical site infections (SSI) IN patients with peripheral arterial disease: An observational study. International Journal of Surgery. 2015;**14**:85-89

[46] Hosoda K, Kawaguchi T, Ishii K, Minoshima S, Shibata Y, Iwakura M, et al. Prediction of hyperperfusion after carotid endarterectomy by brain SPECT analysis with semiquantitative statistical mapping method. Stroke. 2003;**34**(5):1187-1193

[47] Kablak-Ziembicka A, Przewlocki T, Pieniazek P, Musialek P, Tekieli L, Rosławiecka A, et al. Predictors of

cerebral reperfusion injury after carotid stenting: The role of transcranial color-coded doppler ultrasonography. Journal of Endovascular Therapy. 2010;**17**(4):556-563

[48] Illuminati G, Calio' FG, D'Urso A, Ceccanei G, Pacilè MA. Management of carotid Dacron patch infection: A case report using median sternotomy for proximal common carotid artery control and in situ polytetrafluoroethylene grafting. Annals of Vascular Surgery. 2009;**23**(6):786.e1-786.e5

[49] Eller JL, Snyder KV, Siddiqui AH. Endovascular treatment of carotid stenosis. Neurosurgery Clinics of North America. 2014;**25**(3):565-582

[50] Bederson JB, Sander Connolly E Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, et al., American Heart Association. Guidelines for the management of aneurysmal subarachnoid hemorrhage: A statement for healthcare professionals from a special writing group of the stroke council, American heart association. Stroke. 2009;**40**(3):994-1025

**17**

**Chapter 3**

*Lena Lavie*

**Abstract**

lower cardiovascular risk.

coronary collaterals

**1. Introduction**

Intermittent Hypoxia and

Obstructive Sleep Apnea:

Mechanisms, Interindividual

Responses and Clinical Insights

Obstructive sleep apnea (OSA), a nightly respiratory condition, is characterized by recurrent upper airway collapse causing intermittent hypoxia (IH) resembling ischemia and reperfusion (I/R). Consequently, blood oxygenation levels are cyclically reduced; sleep fragmentation and sympathetic activation develop, thus invoking oxidative stress and inflammation. OSA is a major risk factor for cardio-/ cerebrovascular morbidity and mortality. However, not all OSA patients develop cardio-/cerebrovascular disease, even if suffering from similar OSA severity. Possibly, this results from interindividual differences in responses to a given hypoxic stimulus involving gene polymorphism in oxygen-regulated transcription factors and downstream genes. The current review is aimed at highlighting potentially protective mechanisms induced by IH and OSA, rather than its well-established deleterious effects, while focusing on acute coronary syndromes. Therefore, protective mechanisms revealed in I/R biology and exhibited in vitro and in animal models utilizing IH followed by a severe ischemia are discussed and linked to acute myocardial infarction patients with concomitant OSA. The roles of endothelial progenitor cells, their proliferative and angiogenic properties, and collateral formation are emphasized in the clinical setting, as well as heterogenic interindividual responses to identical hypoxic stimuli. These findings might represent potential predictors to cardio-/cerebrovascular health, by identifying patients at higher or

**Keywords:** intermittent hypoxia, hypoxia, endothelial progenitor cells (EPCs), endothelial cell colony-forming units (EC-CFUs), endothelial tube formation, hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF),

Obstructive sleep apnea (OSA) is a nightly respiratory condition characterized by recurrent oropharyngeal upper airway collapse during sleep leading to multiple cycles of hypoxic episodes followed by blood reoxygenation. While blocking the respiratory system in OSA provokes hypoxic events, resuming respiration induces the reoxygenation phase. This intermittent respiration results in multiple cycles of

#### **Chapter 3**

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

cerebral reperfusion injury after carotid stenting: The role of transcranial color-coded doppler ultrasonography. Journal of Endovascular Therapy.

[48] Illuminati G, Calio' FG, D'Urso A, Ceccanei G, Pacilè MA. Management of carotid Dacron patch infection: A case report using median sternotomy for proximal common carotid artery control and in situ polytetrafluoroethylene grafting. Annals of Vascular Surgery.

[49] Eller JL, Snyder KV, Siddiqui AH. Endovascular treatment of carotid stenosis. Neurosurgery Clinics of North

2010;**17**(4):556-563

2009;**23**(6):786.e1-786.e5

America. 2014;**25**(3):565-582

Stroke. 2009;**40**(3):994-1025

[50] Bederson JB, Sander Connolly E Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, et al., American Heart Association. Guidelines for the management of aneurysmal

subarachnoid hemorrhage: A statement for healthcare professionals from a special writing group of the stroke council, American heart association.

**16**

## Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses and Clinical Insights

*Lena Lavie*

### **Abstract**

Obstructive sleep apnea (OSA), a nightly respiratory condition, is characterized by recurrent upper airway collapse causing intermittent hypoxia (IH) resembling ischemia and reperfusion (I/R). Consequently, blood oxygenation levels are cyclically reduced; sleep fragmentation and sympathetic activation develop, thus invoking oxidative stress and inflammation. OSA is a major risk factor for cardio-/ cerebrovascular morbidity and mortality. However, not all OSA patients develop cardio-/cerebrovascular disease, even if suffering from similar OSA severity. Possibly, this results from interindividual differences in responses to a given hypoxic stimulus involving gene polymorphism in oxygen-regulated transcription factors and downstream genes. The current review is aimed at highlighting potentially protective mechanisms induced by IH and OSA, rather than its well-established deleterious effects, while focusing on acute coronary syndromes. Therefore, protective mechanisms revealed in I/R biology and exhibited in vitro and in animal models utilizing IH followed by a severe ischemia are discussed and linked to acute myocardial infarction patients with concomitant OSA. The roles of endothelial progenitor cells, their proliferative and angiogenic properties, and collateral formation are emphasized in the clinical setting, as well as heterogenic interindividual responses to identical hypoxic stimuli. These findings might represent potential predictors to cardio-/cerebrovascular health, by identifying patients at higher or lower cardiovascular risk.

**Keywords:** intermittent hypoxia, hypoxia, endothelial progenitor cells (EPCs), endothelial cell colony-forming units (EC-CFUs), endothelial tube formation, hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), coronary collaterals

#### **1. Introduction**

Obstructive sleep apnea (OSA) is a nightly respiratory condition characterized by recurrent oropharyngeal upper airway collapse during sleep leading to multiple cycles of hypoxic episodes followed by blood reoxygenation. While blocking the respiratory system in OSA provokes hypoxic events, resuming respiration induces the reoxygenation phase. This intermittent respiration results in multiple cycles of

hypoxia and reoxygenation throughout the night which are termed intermittent hypoxia (IH). This intermittent respiration directly affects blood oxygenation/ deoxygenation levels altering physiological biochemical and molecular pathways [1].

The significance of OSA to human health stems from its high prevalence worldwide, the complaints regarding the quality of life, and the association with cardiovascular and other comorbidities. It is identified by a loud and intermittent snoring, excessive daytime sleepiness, and polysomnographic respiratory findings. In the general population with classical complaints, as loud snoring and excessive daytime sleepiness, OSA affects 4 and 2% of adult men and women particularly after menopause, respectively. However, these values are much higher in the general population not having the classical complaints and are estimated to be as high as 24% in men and 9% in women. Moreover, in selected populations like the obese and the elderly, this value may rise up to 60% [1, 2]. Moreover, OSA is a well-established cardiovascular and cerebrovascular risk. It is currently implicated in the etiopathogenesis of cardiovascular comorbidities, arrhythmias, congestive heart failure, hypertension, atherosclerosis, and stroke [1].

Intermittent hypoxia is in fact the hallmark of OSA. Consequently, many physiological, cellular, and biochemical alternations occur due to the cyclically reduced blood oxygenation levels, sleep becomes fragmented, and sympathetic nerve activity develops [3]. The severity of the IH and the hypoxemia in OSA are determined by the number of the hypoxic events per hour of sleep, termed Apnea-Hypopnea Index (AHI). It mostly ranges from a cutoff point of 10 events per hour of sleep for normal breathing to mild (11–20), moderate (21–30), and severe OSA (>30 events per hour of sleep). In severe patients, blood oxygenation levels can intermittently drop to as low as 60%.

Events of IH in OSA and in animal models treated with IH were shown to elicit cell and tissue injury by increasing the formation of reactive oxygen species (ROS) and promoting inflammatory pathways. Both oxidative stress and inflammation are fundamental mechanisms in various pathologies, inducing vascular dysfunction, transcriptional reprograming, inflammation, and innate and adaptive immune activation, all of which are contributors of morbidity and mortality in a vast array of cardiovascular and other morbidities [4]. This sequence of events initiated by IH is illustrated in **Figure 1**, which was adapted from Lavie [3] and published by Levy et al. [1].

To date, the deleterious effects of OSA and IH on the cardio-/cerebrovascular system are well established, many of which result from the IH-associated oxidative stress, systemic inflammation, and sympathetic nerve activation. These fundamental components are largely responsible for inducing endothelial dysfunction and vascular comorbidities in these patients [1, 3]. Specifically, IH was shown to induce activation of various leukocyte subpopulations, by increasing their ROS and inflammatory cytokine production. Moreover, increased expression of adhesion molecules, increased avidly of OSA monocytes to endothelial cells, inhibition of neutrophil apoptosis, and increased cytotoxicity of CD8+ T lymphocytes and γδ T cells toward endothelial cells were also shown to contribute to endothelial cell damage, as illustrated in **Figure 1** [3, 5–7]. Thus, the multiple cycles of IH in OSA have been shown to resemble mechanisms of ischemia and reperfusion (I/R) injury by eliciting similar fundamental mechanisms, including increased ROS production, activated leukocytes, inflammation, transcriptional reprograming, and vascular dysfunction [5, 6, 8].

Importantly, although the most prominent and notable effects of I/R reveal tissue and organ injury leading to cardiovascular and cerebrovascular morbidity, I/R was also shown to confer cardioprotection by activating adaptive mechanisms such as ischemic preconditioning (IPC), post-conditioning, and remote-conditioning [9]. Thus, since not all OSA patients develop cardiovascular and other morbidities, it is feasible that in some instances IPC may occur in OSA as well. Apparently,

**19**

**Figure 1.**

*Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses…*

genetic polymorphism in HIF-1 and downstream genes as vascular endothelial growth factor (VEGF) and erythropoietin (EPO) might influence the individual responses to a given IH stimulus. However, also environmental- and lifestyle-related variables (diet, sports, air pollution) could affect these individual responses [1, 3].

*Oxidative stress promotes sympathetic activation, cellular and systemic inflammation, and vascular comorbidities in OSA. Intermittent hypoxia induces the production of reactive oxygen species (ROS), resulting in oxidative stress by inducing mitochondrial dysfunction, activating NADPH oxidase (NOX) and xanthine oxidase (XOX), and inducing nitric oxide synthase (NOS) uncoupling. Interaction of ROS with nitric oxide (NO) further promotes oxidative stress while diminishing the bioavailability of NO and thus promoting hypertension, inflammation, endothelial dysfunction, hypercoagulability, and atherosclerosis. The ROS-dependent increase in sympathetic activation and in angiotensin II and endothelin 1 levels contribute to hypertension. Concomitantly, ROS can upregulate numerous redox-sensitive transcription factors, such as nuclear factor-κB (NF-κB), hypoxia-inducible factor-1α (HIF-1α), and nuclear factor (erythroid-derived 2)-like 2 (NF2L2). NF-κB orchestrates the various inflammatory processes that lead to endothelial dysfunction and atherosclerosis. By contrast, HIF-1α and NF2L2, which are also upregulated by ROS levels, are involved in protective mechanisms, which may counteract some of deleterious effects of ROS. Comorbidities and conditions associated with OSA, such as hypercholesterolemia, diabetes mellitus, and obesity, also have a ROS component and involve NF-κB activation and inflammation. Broken line, indirect pathway; red line, inhibition. Figure*

*adapted from Ref. [3], Elsevier and published in Lévy et al. [1].*

*DOI: http://dx.doi.org/10.5772/intechopen.86117*

*Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses… DOI: http://dx.doi.org/10.5772/intechopen.86117*

genetic polymorphism in HIF-1 and downstream genes as vascular endothelial growth factor (VEGF) and erythropoietin (EPO) might influence the individual responses to a given IH stimulus. However, also environmental- and lifestyle-related variables (diet, sports, air pollution) could affect these individual responses [1, 3].

#### **Figure 1.**

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

hypertension, atherosclerosis, and stroke [1].

drop to as low as 60%.

hypoxia and reoxygenation throughout the night which are termed intermittent hypoxia (IH). This intermittent respiration directly affects blood oxygenation/ deoxygenation levels altering physiological biochemical and molecular pathways [1]. The significance of OSA to human health stems from its high prevalence worldwide, the complaints regarding the quality of life, and the association with cardiovascular and other comorbidities. It is identified by a loud and intermittent snoring, excessive daytime sleepiness, and polysomnographic respiratory findings. In the general population with classical complaints, as loud snoring and excessive daytime sleepiness, OSA affects 4 and 2% of adult men and women particularly after menopause, respectively. However, these values are much higher in the general population not having the classical complaints and are estimated to be as high as 24% in men and 9% in women. Moreover, in selected populations like the obese and the elderly, this value may rise up to 60% [1, 2]. Moreover, OSA is a well-established cardiovascular and cerebrovascular risk. It is currently implicated in the etiopathogenesis of cardiovascular comorbidities, arrhythmias, congestive heart failure,

Intermittent hypoxia is in fact the hallmark of OSA. Consequently, many physiological, cellular, and biochemical alternations occur due to the cyclically reduced blood oxygenation levels, sleep becomes fragmented, and sympathetic nerve activity develops [3]. The severity of the IH and the hypoxemia in OSA are determined by the number of the hypoxic events per hour of sleep, termed Apnea-Hypopnea Index (AHI). It mostly ranges from a cutoff point of 10 events per hour of sleep for normal breathing to mild (11–20), moderate (21–30), and severe OSA (>30 events per hour of sleep). In severe patients, blood oxygenation levels can intermittently

Events of IH in OSA and in animal models treated with IH were shown to elicit cell and tissue injury by increasing the formation of reactive oxygen species (ROS) and promoting inflammatory pathways. Both oxidative stress and inflammation are fundamental mechanisms in various pathologies, inducing vascular dysfunction, transcriptional reprograming, inflammation, and innate and adaptive immune activation, all of which are contributors of morbidity and mortality in a vast array of cardiovascular and other morbidities [4]. This sequence of events initiated by IH is illustrated in

To date, the deleterious effects of OSA and IH on the cardio-/cerebrovascular system are well established, many of which result from the IH-associated oxidative stress, systemic inflammation, and sympathetic nerve activation. These fundamental components are largely responsible for inducing endothelial dysfunction and vascular comorbidities in these patients [1, 3]. Specifically, IH was shown to induce activation of various leukocyte subpopulations, by increasing their ROS and inflammatory cytokine production. Moreover, increased expression of adhesion molecules, increased avidly of OSA monocytes to endothelial cells, inhibition of neutrophil apoptosis, and increased cytotoxicity of CD8+ T lymphocytes and γδ T cells toward endothelial cells were also shown to contribute to endothelial cell damage, as illustrated in **Figure 1** [3, 5–7]. Thus, the multiple cycles of IH in OSA have been shown to resemble mechanisms of ischemia and reperfusion (I/R) injury by eliciting similar fundamental mechanisms, including increased ROS production, activated leukocytes, inflamma-

**Figure 1**, which was adapted from Lavie [3] and published by Levy et al. [1].

tion, transcriptional reprograming, and vascular dysfunction [5, 6, 8].

Importantly, although the most prominent and notable effects of I/R reveal tissue and organ injury leading to cardiovascular and cerebrovascular morbidity, I/R was also shown to confer cardioprotection by activating adaptive mechanisms such as ischemic preconditioning (IPC), post-conditioning, and remote-conditioning [9]. Thus, since not all OSA patients develop cardiovascular and other morbidities, it is feasible that in some instances IPC may occur in OSA as well. Apparently,

**18**

*Oxidative stress promotes sympathetic activation, cellular and systemic inflammation, and vascular comorbidities in OSA. Intermittent hypoxia induces the production of reactive oxygen species (ROS), resulting in oxidative stress by inducing mitochondrial dysfunction, activating NADPH oxidase (NOX) and xanthine oxidase (XOX), and inducing nitric oxide synthase (NOS) uncoupling. Interaction of ROS with nitric oxide (NO) further promotes oxidative stress while diminishing the bioavailability of NO and thus promoting hypertension, inflammation, endothelial dysfunction, hypercoagulability, and atherosclerosis. The ROS-dependent increase in sympathetic activation and in angiotensin II and endothelin 1 levels contribute to hypertension. Concomitantly, ROS can upregulate numerous redox-sensitive transcription factors, such as nuclear factor-κB (NF-κB), hypoxia-inducible factor-1α (HIF-1α), and nuclear factor (erythroid-derived 2)-like 2 (NF2L2). NF-κB orchestrates the various inflammatory processes that lead to endothelial dysfunction and atherosclerosis. By contrast, HIF-1α and NF2L2, which are also upregulated by ROS levels, are involved in protective mechanisms, which may counteract some of deleterious effects of ROS. Comorbidities and conditions associated with OSA, such as hypercholesterolemia, diabetes mellitus, and obesity, also have a ROS component and involve NF-κB activation and inflammation. Broken line, indirect pathway; red line, inhibition. Figure adapted from Ref. [3], Elsevier and published in Lévy et al. [1].*

The current review is aimed at highlighting potentially protective mechanisms induced by IH and OSA rather than the deleterious and well-established injurious effects described above while focusing on OSA patients with concomitant acute coronary syndromes. Thus, protective mechanisms revealed in I/R biology and also exhibited in animal models of IH after a global ischemic insult, as well as in patients with acute myocardial infarction (AMI) and concomitant OSA, are discussed and further elaborated in models of IH in vitro. A special emphasis is put on endothelial progenitor cells (EPCs), their proliferative and angiogenic properties, and their association with collateral formation. The significance of the heterogeneity in the proliferative and angiogenic functions of EPCs from healthy individuals exposed to a given identical IH stimulus is discussed with regard to potential collateral development and cardiovascular outcomes. Understanding individual differences to various forms of hypoxia and the associated molecular pathways can help in identifying patients at higher or lower cardiovascular risk.

#### **2. Protective mechanisms associated with ischemia and reperfusion**

The preconditioning effect is basically an experimental strategy. Applying brief ischemic episodes each followed by reperfusion—prior to a longer and potentially lethal duration of ischemia—can confer protection to an organ or a tissue. IPC of the heart is the best studied one. It demonstrates the heart's own self-preserving mechanism, by reducing infarct size and ventricular arrhythmias, and was shown in many of the models studied. In the first and seminal study demonstrating IPC [10], dog hearts were preconditioned by undergoing four circumflex coronary occlusions each lasting 5 min, separated each by 5 min of reperfusion (a total of 40 min), followed by a sustained 40 min occlusion and 4 days of reperfusion recovery. Control animals underwent only a single 40 min of occlusion and 4 days of reperfusion recovery after which infarct size was measured. In the controls, the infarcted area consisted 30% of the area at risk, whereas that of the preconditioned animals was only 7.5% of the area at risk (25% of the infarct size in the controls). This landmark study has paved the way to subsequent studies demonstrating the protective effects of IPC in the kidney, brain, liver, and intestine [11, 12]. Moreover, in various studies, the paradigms of IPC varied considerably ranging from intervals of minutes to seconds. Thus, when nonlethal sequential episodes of I/R—like those occurring in OSA nightly, prior to the occurrence of an acute lethal I/R episode—like in AMI or stroke, preconditioning may occur in those patients.

#### **2.1 Mechanisms of ischemic preconditioning in animal models of intermittent hypoxia**

The mechanisms involving IPC are complex and intricate, implicating various molecular, cellular, and paracrine pathways. Some of the triggers, mediators, and targets activated by I/R include Ca+2 ions, ROS, reactive nitrogen species, purinergic signaling, kinases, cytokines, and mitochondria. Transcriptional reprograming is affected as well. It involves upregulation of the redox-sensitive transcription factor hypoxia-inducible factor (HIF)-1α and its downstream genes VEGF and EPO and inducible nitric oxide synthase (iNOS) [4, 12]. The angiogenic VEGF promotes neovascularization and collateral vessel formation, while EPO is essential for protection against I/R injury. Nuclear factor kB (NF-κB) and some of its regulated inflammatory pathways are activated as well. Collectively, these transcriptional alterations invoke cellular and paracrine functions. In that context, a number of studies utilizing animal models of IH were shown to reduce infarct size in rat hearts

**21**

*Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses…*

and improve focal ischemic injury in mice. In an acute model of IH, isolated rat myocardium was exposed to 4 h or 30 min of preconditioning by IH, using hypoxic episodes of either 10 or 5% oxygen, lasting 40 s and normoxia at 21% O2 for 20 s (60 IH events per hour). After 24 h of recovery, sustained ischemia lasting 30 min was followed by 120 min of reperfusion. Only the paradigm of 4 h of IH at 10% oxygen induced a delayed preconditioning by reducing infarct size to more than 50% as compared to control hearts [13]. Moreover, besides reducing infarct size, also HIF-1α was stabilized and iNOS was activated. These effects were mediated through PKC and triggered by P38 MAPK and ERK1/ERK2 while inhibiting iNOS with aminoguanidine before the ischemic period abolished the IPC phenomenon [14]. In a chronic IH model investigating focal ischemic injury in mice, a dichotomous effect was noted. The mice were subjected to chronic IH at 10 or 6% O2 for 35 days (8 h/day 20 hypoxic episodes/hour lasting 90 s at 90 s of intervals) or to room air (sham). Then the mice were treated for focal ischemic injury for 30–35 min. Only at 10% of O2, EPO and VEGF were increased, while inflammatory markers were decreased compared to controls. At the more severe IH of 6% of O2, inflammatory markers were increased as compared to control sham animals [15]. In both the acute and the chronic IH animal models described, the IH served as a nonlethal preconditioning effect before applying the lethal I/R stimulus. Acute as well as chronic IH displayed dichotomous effects, depending on the severity of the IH applied. Moreover, the molecular mechanisms described for IH-dependent IPC concur with classical IPC mechanisms in I/R (upregulation of HIF-1α, VEGF, EPO, and iNOS). Thus, the protective effects were dependent on the severity, the frequency, and the

chronicity of the IH paradigms applied in these animal models of IH.

**ischemic stroke**

**2.2 Potential involvement of IPC in OSA patients with acute MI and acute**

**3. The role of endothelial progenitor cells in endothelial health**

Blood-derived EPCs play a pivotal role in maintaining vascular homeostasis by providing an endogenous repair mechanism by replacing dysfunctional endothelium and enhancing tissue repair after an ischemic vascular insult [20, 21]. EPCs are mobilized by hypoxia or tissue ischemia, HIF-1α- and VEGF-dependent pathways [22].

The involvement of IPC is potentially implicated in patients with OSA after an AMI or an acute ischemic stroke. For instance, peak cardiac troponin values were shown to be significantly higher in AMI patients without OSA than in AMI patients with OSA. This finding suggests that OSA might have a protective effect in the context of MI and that patients with OSA may experience less severe myocardial injury [16]. Additionally, the prevalence of non-ST-elevation myocardial infarction (NSTEMI) in AMI patients was associated with OSA and was shown to increase with the increasing severity of OSA. This finding may also suggest a cardioprotective role of OSA, which may attenuate the development of ST-elevation myocardial infarction (STEMI), perhaps through IPC [17]. In patients with OSA hospitalized because of an acute ischemic stroke, less severe neurological injury and lower unadjusted mortality rates were found than in those without a history of OSA [18]. Also, cardiac arrest survivors with OSA had better unadjusted survival rates and favorable adjusted neurological outcomes at discharge than those without OSA [19]. This latter study suggests that OSA patients may tolerate better acute brain ischemia due to preconditioning. Collectively, these recent studies favor the possibility that the presence of OSA may confer cardio-/neuroprotection in patients with AMI or acute ischemic stroke.

*DOI: http://dx.doi.org/10.5772/intechopen.86117*

*Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses… DOI: http://dx.doi.org/10.5772/intechopen.86117*

and improve focal ischemic injury in mice. In an acute model of IH, isolated rat myocardium was exposed to 4 h or 30 min of preconditioning by IH, using hypoxic episodes of either 10 or 5% oxygen, lasting 40 s and normoxia at 21% O2 for 20 s (60 IH events per hour). After 24 h of recovery, sustained ischemia lasting 30 min was followed by 120 min of reperfusion. Only the paradigm of 4 h of IH at 10% oxygen induced a delayed preconditioning by reducing infarct size to more than 50% as compared to control hearts [13]. Moreover, besides reducing infarct size, also HIF-1α was stabilized and iNOS was activated. These effects were mediated through PKC and triggered by P38 MAPK and ERK1/ERK2 while inhibiting iNOS with aminoguanidine before the ischemic period abolished the IPC phenomenon [14]. In a chronic IH model investigating focal ischemic injury in mice, a dichotomous effect was noted. The mice were subjected to chronic IH at 10 or 6% O2 for 35 days (8 h/day 20 hypoxic episodes/hour lasting 90 s at 90 s of intervals) or to room air (sham). Then the mice were treated for focal ischemic injury for 30–35 min. Only at 10% of O2, EPO and VEGF were increased, while inflammatory markers were decreased compared to controls. At the more severe IH of 6% of O2, inflammatory markers were increased as compared to control sham animals [15]. In both the acute and the chronic IH animal models described, the IH served as a nonlethal preconditioning effect before applying the lethal I/R stimulus. Acute as well as chronic IH displayed dichotomous effects, depending on the severity of the IH applied. Moreover, the molecular mechanisms described for IH-dependent IPC concur with classical IPC mechanisms in I/R (upregulation of HIF-1α, VEGF, EPO, and iNOS). Thus, the protective effects were dependent on the severity, the frequency, and the chronicity of the IH paradigms applied in these animal models of IH.

#### **2.2 Potential involvement of IPC in OSA patients with acute MI and acute ischemic stroke**

The involvement of IPC is potentially implicated in patients with OSA after an AMI or an acute ischemic stroke. For instance, peak cardiac troponin values were shown to be significantly higher in AMI patients without OSA than in AMI patients with OSA. This finding suggests that OSA might have a protective effect in the context of MI and that patients with OSA may experience less severe myocardial injury [16]. Additionally, the prevalence of non-ST-elevation myocardial infarction (NSTEMI) in AMI patients was associated with OSA and was shown to increase with the increasing severity of OSA. This finding may also suggest a cardioprotective role of OSA, which may attenuate the development of ST-elevation myocardial infarction (STEMI), perhaps through IPC [17]. In patients with OSA hospitalized because of an acute ischemic stroke, less severe neurological injury and lower unadjusted mortality rates were found than in those without a history of OSA [18]. Also, cardiac arrest survivors with OSA had better unadjusted survival rates and favorable adjusted neurological outcomes at discharge than those without OSA [19]. This latter study suggests that OSA patients may tolerate better acute brain ischemia due to preconditioning. Collectively, these recent studies favor the possibility that the presence of OSA may confer cardio-/neuroprotection in patients with AMI or acute ischemic stroke.

#### **3. The role of endothelial progenitor cells in endothelial health**

Blood-derived EPCs play a pivotal role in maintaining vascular homeostasis by providing an endogenous repair mechanism by replacing dysfunctional endothelium and enhancing tissue repair after an ischemic vascular insult [20, 21]. EPCs are mobilized by hypoxia or tissue ischemia, HIF-1α- and VEGF-dependent pathways [22].

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

patients at higher or lower cardiovascular risk.

stroke, preconditioning may occur in those patients.

The current review is aimed at highlighting potentially protective mechanisms induced by IH and OSA rather than the deleterious and well-established injurious effects described above while focusing on OSA patients with concomitant acute coronary syndromes. Thus, protective mechanisms revealed in I/R biology and also exhibited in animal models of IH after a global ischemic insult, as well as in patients with acute myocardial infarction (AMI) and concomitant OSA, are discussed and further elaborated in models of IH in vitro. A special emphasis is put on endothelial progenitor cells (EPCs), their proliferative and angiogenic properties, and their association with collateral formation. The significance of the heterogeneity in the proliferative and angiogenic functions of EPCs from healthy individuals exposed to a given identical IH stimulus is discussed with regard to potential collateral development and cardiovascular outcomes. Understanding individual differences to various forms of hypoxia and the associated molecular pathways can help in identifying

**2. Protective mechanisms associated with ischemia and reperfusion**

The preconditioning effect is basically an experimental strategy. Applying brief ischemic episodes each followed by reperfusion—prior to a longer and potentially lethal duration of ischemia—can confer protection to an organ or a tissue. IPC of the heart is the best studied one. It demonstrates the heart's own self-preserving mechanism, by reducing infarct size and ventricular arrhythmias, and was shown in many of the models studied. In the first and seminal study demonstrating IPC [10], dog hearts were preconditioned by undergoing four circumflex coronary occlusions each lasting 5 min, separated each by 5 min of reperfusion (a total of 40 min), followed by a sustained 40 min occlusion and 4 days of reperfusion recovery. Control animals underwent only a single 40 min of occlusion and 4 days of reperfusion recovery after which infarct size was measured. In the controls, the infarcted area consisted 30% of the area at risk, whereas that of the preconditioned animals was only 7.5% of the area at risk (25% of the infarct size in the controls). This landmark study has paved the way to subsequent studies demonstrating the protective effects of IPC in the kidney, brain, liver, and intestine [11, 12]. Moreover, in various studies, the paradigms of IPC varied considerably ranging from intervals of minutes to seconds. Thus, when nonlethal sequential episodes of I/R—like those occurring in OSA nightly, prior to the occurrence of an acute lethal I/R episode—like in AMI or

**2.1 Mechanisms of ischemic preconditioning in animal models of intermittent**

The mechanisms involving IPC are complex and intricate, implicating various molecular, cellular, and paracrine pathways. Some of the triggers, mediators, and targets activated by I/R include Ca+2 ions, ROS, reactive nitrogen species, purinergic signaling, kinases, cytokines, and mitochondria. Transcriptional reprograming is affected as well. It involves upregulation of the redox-sensitive transcription factor hypoxia-inducible factor (HIF)-1α and its downstream genes VEGF and EPO and inducible nitric oxide synthase (iNOS) [4, 12]. The angiogenic VEGF promotes neovascularization and collateral vessel formation, while EPO is essential for protection against I/R injury. Nuclear factor kB (NF-κB) and some of its regulated inflammatory pathways are activated as well. Collectively, these transcriptional alterations invoke cellular and paracrine functions. In that context, a number of studies utilizing animal models of IH were shown to reduce infarct size in rat hearts

**20**

**hypoxia**

In AMI patients, EPCs were shown to home at the ischemic myocardium and participate in vascular and cardiac repair, basically acting as an internal pool of endothelial cells (ECs). EPCs contribute up to 25% of ECs in newly developed vessels at ischemic sites. Hence, they promote coronary collateral formation while improving endothelial functions by integrating into newly developing capillaries or into injured blood vessels [20, 23]. Of note, low EPC numbers were shown to correlate with endothelial dysfunction, atherosclerosis, and poor cardiovascular outcome. Thus, they are currently considered in many studies to represent an independent predictor of endothelial dysfunction and long-term prognosis in patients with coronary artery disease [21, 24]. Therefore, circulating EPC levels might be used as a surrogate marker to assess clinical outcomes.

In most of the studies published thus far, EPCs were primarily identified by CD34 (primitive hematopoietic progenitors) and VEGF-R2 (a VEGF receptor) expressions [20]. Their proliferative and angiogenic capacities were demonstrated in vitro by two widely used assays: (1) the formation of endothelial colonies in culture—termed endothelial cell colony-forming units (EC-CFUs) [25]—and (2) the determination of the paracrine effects of these developed colonies on endothelial cells in culture [26].

Growing EPCs on fibronectin in vitro can induce proliferation and differentiation into EC-CFUs which are characterized by a central core of round angiogenic T cells and outgrowing spindle-shaped cells. These colonies secret angiogenic growth factors such as VEGF inducing endothelial tube formation via paracrine pathways. Moreover, in AMI patients the expression of circulating EPCs (CD34+/VEGF-R2) was positively correlated with mean endothelial tube formation [27]. Also, EC-CFUs were shown to negatively correlate with the Framingham risk score, thus adequately representing circulating EPCs [25]. Both these two in vitro measures—the formation of EC-CFUs in culture and their paracrine effects on endothelial tube formation might be considered as good surrogate markers for circulating EPCs [25, 27].

#### **3.1 Endothelial progenitor cells and their proliferative and angiogenic properties in AMI patients with OSA**

Acute MI can be a devastating I/R event and a frequent cause of sudden death. Sleep apnea is highly prevalent in AMI patients, ranging in various studies from 22 to 69%. However, in the setting of AMI, the presence of OSA is frequently not considered and therefore under diagnosed [28]. Evaluating circulating EPCs in patients diagnosed with OSA while recovering from an AMI revealed significantly higher EPC numbers than in AMI patients without OSA. Also the intracellular VEGF expression, EC-CFU numbers, and their angiogenic T cells in culture, and endothelial tube formation, were all significantly higher than those in AMI patients without OSA [27]. These findings suggest that the IH associated with OSA might have a crucial role in promoting these protective functions of EPCs in the setting of AMI. Subsequently, the development of EC-CFUs and their paracrine functions in healthy individuals were determined by exposure to IH in vitro. Indeed, the proliferative and paracrine abilities of EC-CFUs and endothelial tube formation were increased by IH, as compared to those that developed under normoxic conditions [27, 29]. Moreover, IH in vitro increased NADPH oxidase-dependent ROS production, protein carbonylation, and VEGF expression in EC-CFUs. Both EC-CFU numbers and endothelial tube formation in culture were increased by ROS-dependent mechanisms. Accordingly, ROS scavengers and NADPH oxidase inhibitors attenuated or completely abolished the formation of EC-CFUs treated by IH in vitro. It is therefore likely that IH and ROS are crucial contributors to increased EPC numbers and their proliferative and angiogenic functions [29].

**23**

*Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses…*

**4. Development of coronary collaterals in acute coronary syndromes**

A number of studies demonstrate that coronary collaterals were increased in coronary artery disease patients with high EPC numbers. Conversely, inadequate coronary collateral development was associated with reduced numbers of circulating EPCs and impaired pro-angiogenic activity, as determined by the low values of EC-CFUs and tube formation in culture [30, 31]. Moreover, increased circulating EPC levels were also associated with collateral formation in patients with NSTEMI [32]. Furthermore, reduced circulating EPC numbers also predicted future cardiovascular events, emphasizing the clinical importance of endogenous vascular repair [30, 31, 33]. Therefore, circulating EPC numbers might represent a good prognostic marker for the outcomes in the clinical context of acute coronary syndrome [20]. Interestingly in OSA patients with total coronary occlusion, collateral development was significantly higher than in non-OSA patients with the same coronary occlusion (Rentrop score 2.4 ± 0.7 vs. 1.61 ± 1.2, *p* = 0.02, respectively) [34]. Similar finding supporting increased coronary collaterals in inaugural AMI patients with

Interindividual differences are fundamental to the development of personalized medicine. Different individuals respond in a distinctively different manner to an identical hypoxic stimulus. Such diverse responses can result from a number of reasons. Specifically, however, genetic variations in the expression of oxygenregulated genes are of a particular interest in this growing field of personalized and regenerative medicine, as EPCs and their proliferative and angiogenic functions are [3]. For instance, the expression of the transcription factor HIF-1α and some of its downstream genes as VEGF and aldolase C was determined in lymphocytes from healthy adults exposed to eight different hypoxic treatments ranging from 0.1 to 20% oxygen. The sensitivity of HIF-1α expression to hypoxia varied considerably between individuals. HIF expression in the "low responders" was upregulated at 0.1% oxygen, whereas "high responders" upregulated HIF already at 5% oxygen. Moreover, also the HIF-regulated downstream genes responded in the same manner in each individual, suggesting that the source of this variation resides within the HIF system itself [36]. Furthermore, in patients with ischemic heart disease, DNA was genotyped for singlenucleotide polymorphism (C or T changes at residue 582 of HIF-1α, from proline to serine). HIF-1α polymorphism was associated with the development of collaterals in those patients and was dependent on the frequency of the T alleles. Its frequency was higher in patients without collaterals than in patients with collaterals (the presence of CT or TT was a negative predictor). Thus, variations in HIF-1α genotype may influence the development of collaterals in patients with significant coronary artery disease perhaps regardless of the severity of the ischemia they encounter [37]. In an earlier study, interindividual responses to hypoxia were also shown in coronary artery disease patients undergoing angiography. Their monocytes were harvested and exposed to an identical hypoxic stimulus. Then, mRNA levels of VEGF were determined and correlated with the presence of collaterals. Patients with no collaterals had significantly lower hypoxic induction of mRNA VEGF levels, whereas high mRNA VEGF levels were correlated with high collateral formation [38]. Collectively, these latter studies emphasize the heterogenic responses observed between different individuals exposed to an identical hypoxic stimulus, due to a different genetic background. Moreover, the significance of collateral development in the context of

*DOI: http://dx.doi.org/10.5772/intechopen.86117*

OSA was also reported more recently [35].

**5. Interindividual responses to hypoxic conditions**

individual responses and clinical outcomes is further emphasized.

*Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses… DOI: http://dx.doi.org/10.5772/intechopen.86117*

#### **4. Development of coronary collaterals in acute coronary syndromes**