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''Ronak Delewi, MD; Hayang Yang, MsC; John Kastelein, MD, PhD''<br /><br />  
 
''Ronak Delewi, MD; Hayang Yang, MsC; John Kastelein, MD, PhD''<br /><br />  
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{{case|
 
{{case|
A 53 years old man, without medical history medication visits the family physician and makes an anxious impression. His friend has recently suffered from a myocardial infarction (MI) and he is worried that he might also soon face the same situation. As for family medical history, he has a father with hypertension and an uncle with diabetes mellitus. He does not seem to have any symptoms or complaints at this moment, but he has been smoking for 25 years and is overweight. Because of these characteristics he is worried that he will suffer a MI. Upon physical examination, his BMI was 29 kg/m<sup>2</sup>, RR was 152/90 mmHg and heart rate was 75 bpm. The family physician orders a blood test for lipid profile and glucose. Both turn out to be in the normal range. <br />
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A 53 years old man, without medical history or  medication visits the family physician and makes an anxious impression. His friend has recently suffered from a myocardial infarction (MI) and he is worried that he might also soon face the same situation. As for family medical history, he has a father with hypertension and an uncle with diabetes mellitus. He does not seem to have any symptoms or complaints at this moment, but he has been smoking for 25 years and is overweight. Because of these characteristics he is worried that he will suffer from a MI. Upon physical examination, his BMI was 29 kg/m<sup>2</sup>, RR was 152/90 mmHg and heart rate was 75 bpm. The family physician orders a blood test for lipid profile and glucose. Both turn out to be in the normal range. <br />
    
The family physician gives the patient advice concerning primary prevention for atherosclerosis; quit smoking, try to achieve weight reduction, do regular physical activity, restrict alcohol consumption to less than 3 drinks a day and follow a varied and balanced diet. Regarding hypertension, the advice is to keep his RR under 140/90 mmHg. Antihypertensive medication is not indicated at this moment, because his 10-years risk of death due to cardiovascular disease (Systematic Coronary Risk Evaluation)  is lower than 20%. He is advised to undergo regular checkups of cardiovascular risk profile or report to the doctor’s office in case of chest pain.
 
The family physician gives the patient advice concerning primary prevention for atherosclerosis; quit smoking, try to achieve weight reduction, do regular physical activity, restrict alcohol consumption to less than 3 drinks a day and follow a varied and balanced diet. Regarding hypertension, the advice is to keep his RR under 140/90 mmHg. Antihypertensive medication is not indicated at this moment, because his 10-years risk of death due to cardiovascular disease (Systematic Coronary Risk Evaluation)  is lower than 20%. He is advised to undergo regular checkups of cardiovascular risk profile or report to the doctor’s office in case of chest pain.
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== 1.2 Arterial vessel with atherosclerosis ==
 
== 1.2 Arterial vessel with atherosclerosis ==
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[[File:RCA_atherosclerosis.jpg|thumb|Atheroclerotic plaque in a coronary artery]]
 
=== Three pathologic stages of atherogenesis ===
 
=== Three pathologic stages of atherogenesis ===
Atherogenesis can be divided into five key steps, which are 1) endothelial dysfunction, 2) formation of lipid layer or fatty streak within the intima, 3) migration of leukocytes and smooth muscle cells in to the vessel wall, 4) foam cell formation and 5) degradation of extracellular matrix. Via these consecutive steps, an atherosclerotic plaque is formed. The formation of the plaque can also be divided into three major stages namely 1) the fatty streak, which represents the initiation 2) plaque progression, which represents adaption and 3) plaque disruption, which represents the clinical complications of atherosclerosis.<br />
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Atherogenesis can be divided into five key steps, which are 1) endothelial dysfunction, 2) formation of lipid layer or fatty streak within the intima, 3) migration of leukocytes and smooth muscle cells into the vessel wall, 4) foam cell formation and 5) degradation of extracellular matrix. Via these consecutive steps, an atherosclerotic plaque is formed. The formation of the plaque can also be divided into three major stages namely 1) the fatty streak, which represents the initiation 2) plaque progression, which represents adaption and 3) plaque disruption, which represents the clinical complication of atherosclerosis.<br />
    
[[File:Figure_7_-_Fatty_streak_formation_revealing_platelet_aggregation_on_the_endothelial_surface.png|right|thumb|Figure 5. Fatty streak formation]]
 
[[File:Figure_7_-_Fatty_streak_formation_revealing_platelet_aggregation_on_the_endothelial_surface.png|right|thumb|Figure 5. Fatty streak formation]]
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Endothelial dysfunction is a primary event in atherogenesis, which can be caused by various agents, such as physical stress and chemical irritants. Endothelial dysfunction is also observed in other pathological conditions, which are often related to atherosclerosis such as hypercholesterolemia, diabetes, hypertension, heart failure, cigarette smoking and aging.<br />
 
Endothelial dysfunction is a primary event in atherogenesis, which can be caused by various agents, such as physical stress and chemical irritants. Endothelial dysfunction is also observed in other pathological conditions, which are often related to atherosclerosis such as hypercholesterolemia, diabetes, hypertension, heart failure, cigarette smoking and aging.<br />
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Endothelial cells can display different reactions according to various levels of physical stress. There are two atheroprotective endothelial functions from physical stress. When endothelial cells are exposed to laminar flow, which contains minimal physical stress, they secrete NO. NO functions as an anti-atherosclerotic substance through vasodilation, inhibition of platelet aggregation and anti-inflammatory effects. The second function is executed, when exposed to laminar flow by an expression of the antioxidant enzyme superoxide dismutase by the endothelium. This enzyme performs anti-atherosclerotic role by acting against reactive oxygen species, which are produced by chemical irritants or transient ischemia in the vessel.<br />
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Endothelial cells can display different reactions according to various levels of physical stress. There are two atheroprotective endothelial functions from physical stress. When endothelial cells are exposed to laminar flow, which display minimal physical stress, they secrete NO. NO functions as an anti-atherosclerotic substance through vasodilation, inhibition of platelet aggregation and anti-inflammatory effects. The second function is executed, when exposed to laminar flow by an expression of the antioxidant enzyme superoxide dismutase. This enzyme performs anti-atherosclerotic role by acting against reactive oxygen species, which are produced by chemical irritants or transient ischemia in the vessel.<br />
 
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Unfortunately, these two atheroprotective endothelial functions can be impaired by several factors. The first factor is disturbed flow (low shear stress with rapid fluctuation), which is typically located at arterial branch points and bifurcations and can impair the protective functions. This is well illustrated by the difference in prevalence of atherosclerosis between branched arteries and bifurcated vessels. Bifurcation areas such as the common carotid and left coronary arteries are common deposition sites for atherosclerosis than arteries with few branches such as the internal mammary artery. Thus, many observations show that the distribution of atherosclerotic lesions is common in large vessels and they vary in location and frequency among different vascular beds. These findings encourage a belief that hemodynamic factors play an important role in atherogenesis. Furthermore, the fact that hypertension intensifies the severity of atherosclerotic lesions additionally supports this hypothesis.<br />
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Unfortunately, these two atheroprotective endothelial functions can be impaired by several factors. The first factor is disturbed flow (low shear stress with rapid fluctuations), which is typically located at arterial branch points and bifurcations and can impair the protective functions. This is well illustrated by the difference in prevalence of atherosclerosis between branched arteries and bifurcated vessels. Bifurcation areas such as the common carotid and left coronary arteries are common deposition sites for atherosclerosis than arteries with few branches such as the internal mammary artery. Thus, many observations show that the distribution of atherosclerotic lesions is common in large vessels and they vary in location and frequency among different vascular beds. These findings encourage a belief that hemodynamic factors play an important role in atherogenesis. Furthermore, the fact that hypertension intensifies the severity of atherosclerotic lesions additionally supports this hypothesis.<br />
 
[[File:Figure_8_-_Endothelial_dysfunction_-_Leukocyte_adhesion_and_migration_into_the_deep_layer_of_the_intima.png|thumb|left|Figure 8. Endothelial dysfunction: Leukocyte adhesion and migration into the deep layer of the intima.]]<br />
 
[[File:Figure_8_-_Endothelial_dysfunction_-_Leukocyte_adhesion_and_migration_into_the_deep_layer_of_the_intima.png|thumb|left|Figure 8. Endothelial dysfunction: Leukocyte adhesion and migration into the deep layer of the intima.]]<br />
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==== ''Smooth muscle cell migration'' ====
 
==== ''Smooth muscle cell migration'' ====
Smooth muscle cells play a central role at the phase of transition from fatty streak to plaque formation. During this phase, smooth muscle cells migrate from the media to the intima. After migration, smooth muscle cells proliferate within the intima and secrete extracellular matrix macromolecules. Additionally, foam cells, activated platelets and endothelium stimulate substances that induce the migration and accumulation of smooth muscle cells. For example, foam cells release platelet derived growth factor (PDGF), cytokines and growth factors that directly contribute to the migration and proliferation process, and they also activate smooth muscle cells and leukocytes to reinforce inflammation in the atherosclerotic lesion. Although plaque progression is traditionally known as a gradual and continuous process, recent evidence claims that this process can be strongly accentuated by bursts of smooth muscle replication. The observation of small ruptures within the plaque occurring without any clinical symptoms or signs supports this suggestion. These small ruptures expose tissue factor secreted by foam cells that stimulates coagulation and microthrombus formation in the lesion. Such microthromb contain activated platelets that release additional factors such as PDGF and heparinase that can further stimulate local smooth muscle cell migration and proliferation. Heparinase stimulates smooth muscle cell migration and proliferation by degrading heparan sulfate, which normally counteracts this process.<br />
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Smooth muscle cells play a central role at the phase of transition from fatty streak to plaque formation. During this phase, smooth muscle cells migrate from the media to the intima. After migration, smooth muscle cells proliferate within the intima and secrete extracellular matrix macromolecules. Additionally, foam cells, activated platelets and endothelium stimulate substances that induce the migration and accumulation of smooth muscle cells. For example, foam cells release platelet derived growth factor (PDGF), cytokines and growth factors that directly contribute to the migration and proliferation process, and they also activate smooth muscle cells and leukocytes to reinforce inflammation in the atherosclerotic lesion. Although plaque progression is traditionally known as a gradual and continuous process, recent evidence claims that this process can be strongly accentuated by bursts of smooth muscle replication. The observation of small ruptures within the plaque occurring without any clinical symptoms or signs supports this suggestion. These small ruptures expose tissue factor secreted by foam cells that stimulates coagulation and microthrombus formation in the lesion. Such microthrombi contain activated platelets that release additional factors such as PDGF and heparinase that can further stimulate local smooth muscle cell migration and proliferation. Heparinase stimulates smooth muscle cell migration and proliferation by degrading heparan sulfate, which normally counteracts this process.<br />
    
==== ''Extracellular matrix metabolism'' ====
 
==== ''Extracellular matrix metabolism'' ====
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Metabolic processes in extracellular matrix plays a central role in bridging the plaque progression to plaque rupture. Ultimately, this process weakens the fibrous cap, predisposing it to rupture. This process is influenced by the balance of matrix deposition synthesis by smooth muscle cells and degradation by matrix metalloproteinases (MMP), a class of proteolytic enzymes. For example, PDGF and TGF-β stimulate interstitial collagen production, while inflammatory cytokines such as IFN-γ inhibits collagen synthesis. TGF-β also induces formation of fibronectin and proteoglycans. It is an important regulator since it enhances the expression of protease inhibitors, leading to the inhibition of proteolytic enzymes that promote matrix degradation. On the other hand, inflammatory cytokines weaken the fibrous cap by stimulating local foam cells to secrete MMP that degrades collagen and elastin of the fibrous cap. Furthermore, the deeper parts of the thickened intima undergo necrosis due to poor nourishment.<br />
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Metabolic processes in extracellular matrix play a central role in bridging the plaque progression to plaque rupture. Ultimately, this process weakens the fibrous cap, predisposing it to rupture. This process is influenced by the balance of matrix deposition synthesis by smooth muscle cells and degradation by matrix metalloproteinases (MMP), a class of proteolytic enzymes. For example, PDGF and TGF-β stimulate interstitial collagen production, while inflammatory cytokines such as IFN-γ inhibits collagen synthesis. TGF-β also induces formation of fibronectin and proteoglycans. It is an important regulator since it enhances the expression of protease inhibitors, leading to the inhibition of proteolytic enzymes that promote matrix degradation. On the other hand, inflammatory cytokines weaken the fibrous cap by stimulating local foam cells to secrete MMP that degrades collagen and elastin of the fibrous cap. Furthermore, the deeper parts of the thickened intima undergo necrosis due to poor nourishment.<br />
    
=== Plaque rupture ===
 
=== Plaque rupture ===
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The concept of ‘vulnerable plaque’ has developed into a new concept of ‘vulnerable patient’ as the concept of pathogenesis of atherosclerosis was linked to a person’s susceptibility to coagulation and thus vascular events, which can be influenced by many personal factors such as genetics (e.g. procoagulant prothombin gene mutation), coexisting condition (e.g. diabetes), and lifestyle factors (e.g. smoking, obesity).<br />
 
The concept of ‘vulnerable plaque’ has developed into a new concept of ‘vulnerable patient’ as the concept of pathogenesis of atherosclerosis was linked to a person’s susceptibility to coagulation and thus vascular events, which can be influenced by many personal factors such as genetics (e.g. procoagulant prothombin gene mutation), coexisting condition (e.g. diabetes), and lifestyle factors (e.g. smoking, obesity).<br />
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| rowspan="2" | [[File:plaque_rupture_A.svg|100px]]
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| rowspan="2" | [[File:plaque_rupture_B.svg|100px]]
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| rowspan="2" | [[File:split_arrow.svg|50px]]
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| [[File:plaque_rupture_C.svg|100px]] || [[File:plaque_rupture_clot.svg|100px]]
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| [[File:plaque_rupture_D.svg|100px]]
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| colspan="4" width="450px" | Progression of coronary atherosclerosis can be gradual (bottom) or can lead to plaque rupture with acute occlusion of a coronary vessel due to clot formation
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== Complications of atherosclerosis ==
 
== Complications of atherosclerosis ==
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The clinical complications of atherosclerosis are highly dependent on the location and size of affected vessels, the duration of the chronic process, and the type of plaque, since the severity of impairment of atherosclerosis differs throughout the vasculature. For example, ‘stable plaque’ can easily result into angina pectoris due to its thick fibrous cap that directly affects the diameter of the relatively small coronary vessels. On the other hand, ‘vulnerable plaque’ is non-stenotic, but can easily cause acute thrombosis and therefore myocardial infarction due to its fragility towards rupture when located at physically stressed areas such as bifurcations. Often with ‘vulnerable plaques’ there are relatively few symptoms, however they are more numerous and dispersed throughout the arteries compared to ‘stable plaque’. Thus, you can either have an occlusion due to the growing plaque or due to the embolization of the ruptured fragments of the original plaque. Due to the difficult detection of ‘vulnerable plaques’ while they are widely dispersed, it is highly important to tackle the risk factors prior to plaque rupture. Thus in the following paragraph, we will highlight the clinical risk factors associated with atherosclerosis. The four major clinical consequences of atherosclerosis are listed and explained below.<br />
 
The clinical complications of atherosclerosis are highly dependent on the location and size of affected vessels, the duration of the chronic process, and the type of plaque, since the severity of impairment of atherosclerosis differs throughout the vasculature. For example, ‘stable plaque’ can easily result into angina pectoris due to its thick fibrous cap that directly affects the diameter of the relatively small coronary vessels. On the other hand, ‘vulnerable plaque’ is non-stenotic, but can easily cause acute thrombosis and therefore myocardial infarction due to its fragility towards rupture when located at physically stressed areas such as bifurcations. Often with ‘vulnerable plaques’ there are relatively few symptoms, however they are more numerous and dispersed throughout the arteries compared to ‘stable plaque’. Thus, you can either have an occlusion due to the growing plaque or due to the embolization of the ruptured fragments of the original plaque. Due to the difficult detection of ‘vulnerable plaques’ while they are widely dispersed, it is highly important to tackle the risk factors prior to plaque rupture. Thus in the following paragraph, we will highlight the clinical risk factors associated with atherosclerosis. The four major clinical consequences of atherosclerosis are listed and explained below.<br />
 
   
 
   
# Acute narrowing of the vessel lumen: When the plaque ruptures, it will release its pro-coagulants in the bloodstream and that will lead to the formation of thrombus at the rupture site. The rupture often occurs at sites of erosion and fissuring on the fibrous cap surface. This thrombus may cause a complete occlusion of a particular vessel and result in ischemic necrosis (infarction) of the tissue that this particular vessel is supplying to. Clinically this is manifested as stroke, MI, gangrene of several possible organs such as intestine, spleen or lower extremities. These occlusiosn may also dissolve spontaneously due to pro-fibrinolytic enzymes such as streptokinase and tissue plasminogen activator (TPA).  
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# Acute narrowing of the vessel lumen: When the plaque ruptures, it will release its pro-coagulants in the bloodstream and that will lead to the formation of thrombus at the rupture site. The rupture often occurs at sites of erosion and fissuring on the fibrous cap surface. This thrombus may cause a complete occlusion of a particular vessel and result in ischemic necrosis (infarction) of the tissue that this particular vessel is supplying to. Clinically this is manifested as stroke, MI, gangrene of several possible organs such as intestine, spleen or lower extremities. These occlusions may also dissolve spontaneously due to pro-fibrinolytic enzymes such as streptokinase and tissue plasminogen activator (TPA).  
 
# Chronic occlusion: When the occlusion is gradual and incomplete, it may chronically disturb the blood supply to tissues in the distribution of the affected vessel. This can result in chronic ischemia of those tissues that can additionally lead to complaints of angina pectoris or intermittent claudication or to organ atrophy (e.g. atrophy of kidney, intestines and skin due to impairment of blood flow in renal artery, mesenteric artery, peripheral vasculature among diabetics.).
 
# Chronic occlusion: When the occlusion is gradual and incomplete, it may chronically disturb the blood supply to tissues in the distribution of the affected vessel. This can result in chronic ischemia of those tissues that can additionally lead to complaints of angina pectoris or intermittent claudication or to organ atrophy (e.g. atrophy of kidney, intestines and skin due to impairment of blood flow in renal artery, mesenteric artery, peripheral vasculature among diabetics.).
 
# Embolism: Embolization is the transfer of the fragments of disrupted atheroma to distal vascular sites, which results into occlusion of those sites. For example, fragments of thrombi in abdominal aorta may transfer to the popliteal artery subsequently resulting in gangrene of the leg. Ulceration of atheroma may also produce ‘cholesterol crystal emboli’. This type of emboli is visualized as needle-shaped areas in affected tissues, mostly detected in the kidney.  
 
# Embolism: Embolization is the transfer of the fragments of disrupted atheroma to distal vascular sites, which results into occlusion of those sites. For example, fragments of thrombi in abdominal aorta may transfer to the popliteal artery subsequently resulting in gangrene of the leg. Ulceration of atheroma may also produce ‘cholesterol crystal emboli’. This type of emboli is visualized as needle-shaped areas in affected tissues, mostly detected in the kidney.  
# Aneurysm: After a chronic period, atherosclerotic lesion may extend into the medial layer, resulting into atrophy and loss of elastic tissue. This can subsequently cause dilatation and weakness of the artery, forming aneurysm. Over time, aneurysm may suddenly rupture and result in a life-threatening situation for the patients.
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# Aneurysm: After a chronic period, atherosclerotic lesion may extend into the medial layer, resulting into atrophy and loss of elastic tissue. This can subsequently cause dilatation and weakness of the artery, forming aneurysm. Over time, aneurysms may suddenly rupture and result in a life-threatening situation for the patients.
    
== Risk factors of atherosclerosis ==
 
== Risk factors of atherosclerosis ==
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==== ''Tobacco smoking'' ====
 
==== ''Tobacco smoking'' ====
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Tobacco use is known to increase the risk of atherosclerosis and ischemic heart disease based on numerous studies. For example, INTERHEART study shows that smoking is responsible for 36% of the population-attributable risk of a first MI. Other studies showed that smoking is an independent major risk factor for coronary heart disease, cerebrovascular disease and total atherosclerotic cardiovascular disease.  The Atherosclerosis Risk in Communities Study measured the direct effect of smoking on the development of atherosclerosis. They measured intima-medial thickness of the carotid artery of 10,914 patients for three years with ultrasound. Their result showed that current smokers had a 50% increased progression of atherosclerosis in comparison to nonsmokers during the study period. Also patients with environmental tobacco smoke exposure (passive smokers) had 20% higher rate of atherosclerotic progress versus patients without environmental smoke exposure.<br />
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Tobacco use, including environmental smoking exposure, is known to increase the risk of atherosclerosis and ischemic heart disease based on numerous studies. For example, INTERHEART study shows that smoking is responsible for 36% of the population-attributable risk of a first MI. Other studies showed that smoking is an independent major risk factor for coronary heart disease, cerebrovascular disease and total atherosclerotic cardiovascular disease.  The Atherosclerosis Risk in Communities Study measured the direct effect of smoking on the development of atherosclerosis. They measured intima-medial thickness of the carotid artery of 10,914 patients for three years with ultrasound. Their result showed that current smokers had a 50% increased progression of atherosclerosis in comparison to nonsmokers during the study period. Also patients with environmental tobacco smoke exposure (passive smokers) had 20% higher rate of atherosclerotic progress versus patients without environmental smoke exposure.<br />
 
   
 
   
Tobacco smoking can lead to many mechanisms that contribute to atherosclerosis. Smoking also leads to increased LDL levels, decreased HDL levels in blood and elevated insulin resistance. In addition it enhances oxidative modification of LDL by releasing free radicals and reduces generation of nitric oxide. This can promote endothelial dysfunction and thus lead to impairment of vasodilatation of coronary arteries and reduction of coronary flow reserve even in passive smokers. Tobacco smoking inappropriately stimulates sympathetic nervous system, increasing heart rate, blood pressure and perhaps coronary vasoconstriction. Smoking promotes a prothrombotic environment through inhibition of endothelial release of tissue plasminogen activator, elevation of fibrinogen concentration in blood, enhancement of platelet activity (possibility related to sympathetic activation) and  enhanced expression of tissue factor. Smoking can even damage the vessel wall and ultimately cause a decrease in the elasticity in of the artery, enhancing the stiffness of vessel wall. Smoking has been associated with increased C-reactive protein and fibrinogen, suggesting a correlation with inflammatory response, which is an important part of atherogenesis. There have also been findings that show higher expression of leukocyte adhesion molecules among smokers than nonsmokers. Smoking may additionally induce tissue hypoxia through displacement of oxygen with carbon monoxide in hemoglobin. <br />
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Tobacco smoking can lead to many mechanisms that contribute to atherosclerosis. Smoking also leads to increased LDL levels, decreased HDL levels in blood and elevated insulin resistance. In addition it enhances oxidative modification of LDL by releasing free radicals and reduces generation of nitric oxide. This can promote endothelial dysfunction and thus lead to impairment of vasodilatation of coronary arteries and reduction of coronary flow reserve even in passive smokers. Tobacco smoking inappropriately stimulates sympathetic nervous system, increasing heart rate, blood pressure and perhaps coronary vasoconstriction. Smoking promotes a prothrombotic environment through inhibition of endothelial release of tissue plasminogen activator, elevation of fibrinogen concentration in blood, enhancement of platelet activity (possibility related to sympathetic activation) and  enhanced expression of tissue factor. Smoking can even damage the vessel wall and ultimately cause a decrease in the elasticity of the artery, enhancing the stiffness of vessel wall. Smoking has been associated with increased C-reactive protein and fibrinogen, suggesting a correlation with inflammatory response, which is an important part of atherogenesis. There have also been findings that show higher expression of leukocyte adhesion molecules among smokers than nonsmokers. Smoking may additionally induce tissue hypoxia through displacement of oxygen with carbon monoxide in hemoglobin. <br />
    
To stop smoking is known as one of the most effective preventive measures of CVD and their complications. Soon after cessation, cardiac risks due to smoking decreases in a short period, and continues to diminish when cessation is permanently preserved. The risk for cardiovascular disease among patients with coronary heart disease decreases 7-47%. Not only does cessation of smoking reduce risk of CVD, but also substantially reduce the risk of all-cause mortality.<br />
 
To stop smoking is known as one of the most effective preventive measures of CVD and their complications. Soon after cessation, cardiac risks due to smoking decreases in a short period, and continues to diminish when cessation is permanently preserved. The risk for cardiovascular disease among patients with coronary heart disease decreases 7-47%. Not only does cessation of smoking reduce risk of CVD, but also substantially reduce the risk of all-cause mortality.<br />
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==== ''Diet'' ====
 
==== ''Diet'' ====
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Several studies suggest that diet, more specifically intake of fruit and vegetable can reduce the risk of coronary heart disease and stroke. In the INTERHEART study, lack of daily consumption of fruits and vegetables was responsible for 14% of the population-attributable risk of a first MI. Another meta-analysis study showed that additional daily portion of fruit reduced the risk of stroke by 11%, but no such effect was found with vegetable consumptionAnother form of diet such as high fiber consumption can also relatively reduce the risk of coronary heart disease and stroke compared to low fiber consumption. In addition, the Hale project has shown that Mediterranean-styled diet as primary prevention for CVD among elderly aged 70-90 without CVD significantly reduces all-cause, coronary heart disease and CVD mortality.<br />
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A healthy diet reduces CVD risk. In general, when following the rules for a healthy diet, no dietary supplements are neededN-3 polyunsaturated fatty acid (PUFA) consumption mainly from oily fish, is potentially associated with beneficial effects on cardiac risk factors, notably reduction in triglycerides but not all randomized, controlled trials have shown reductions in CV events Thus current recommendations are to increase PUFA intake through fish consumption, rather than from supplements. Recently, the largest study ever conducted with a so-called ‘Mediterranean’ diet, supplemented with extra-virgin olive oil or nuts, reduced the incidence of major cardiovascular events in patients at high risk of CV events but without prior CV disease.<cite>Estruch</cite>
    
==== ''Alcohol consumption'' ====
 
==== ''Alcohol consumption'' ====
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==== ''Infection'' ====
 
==== ''Infection'' ====
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A variety of infectious agents such as Chlamydia pneumonia, cytomegalovirus and Helicobacter pylori were identified in the lesions of atherosclerosis and this observation raised a suggestion that these infectious agents may contribute to atherogenesis. However, to date the definite proof of this theory is lacking and also there haven’t been any clinical studies that showed significant relationship between the antibiotic treatment against these infectious agents and the risk of cardiac events of the survivors of acute coronary syndromes. Chlamydia is a strong candidate among other infectious agents, since they produce heat shock protein 60 (HSP-60) that activates macrophages and stimulates the production of matrix metalloproteinases. Furthermore, HDP-60 can also stimulate foam cell formation, lipoprotein oxidation, and increased pro-coagulant activity, which are the major attributing components of atherosclerosis. Although there is no evidence to date, some researchers believe that exogenous pathogens can cause endothelial injury and inflammation that can lead to initiation or exacerbation of atherosclerosis.<br />
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A variety of infectious agents such as Chlamydia pneumonia, cytomegalovirus and Helicobacter pylori were identified in the lesions of atherosclerosis and this observation raised the suggestion that these infectious agents may contribute to atherogenesis. However, to date, the definite proof of this theory is lacking and also there haven’t been any clinical studies that showed significant relationship between the antibiotic treatment against these infectious agents and the risk of cardiac events of the survivors of acute coronary syndromes. Chlamydia is a strong candidate among other infectious agents, since they produce heat shock protein 60 (HSP-60) that activates macrophages and stimulates the production of matrix metalloproteinases. Furthermore, HDP-60 can also stimulate foam cell formation, lipoprotein oxidation, and increased pro-coagulant activity, which are the major attributing components of atherosclerosis. Although there is no evidence to date, some researchers believe that exogenous pathogens can cause endothelial injury and inflammation that can lead to initiation or exacerbation of atherosclerosis.<br />
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=== Co-morbidity groups ===
 
=== Co-morbidity groups ===
 
==== ''Hypertension'' ====
 
==== ''Hypertension'' ====
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Hypertension is defined as a systolic blood pressure (SBP) ≥ 140mmHg and/or a diastolic blood pressure (DBP) ≥ 90mmHg. Elevated blood pressure is a well established risk factor of atherosclerosis, including mortality from coronary heart disease and stroke. For example, cardiovascular disease doubles with every 20 mmHg increase in SBP or every 10 mmHg increase in DBP.<br />
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Hypertension is defined as a systolic blood pressure (SBP) ≥ 140mmHg and/or a diastolic blood pressure (DBP) ≥ 90mmHg. Elevated blood pressure is a well established risk factor for atherosclerosis, including mortality from coronary heart disease and stroke. For example, cardiovascular disease doubles with every 20 mmHg increase in SBP or every 10 mmHg increase in DBP.
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One of the mechanisms of hypertension in contributing to atherosclerosis is injury of vascular endothelium by elevated hemodynamic stress. Injury of endothelium may increase the permeability of the vessel wall to lipoproteins. Increased blood pressure may also increase the number of scavenger receptors on macrophages, which enhances the development of foam cells. Furthermore, increased cyclic circumferential strain in hypertensive arteries can result into promoting LDL accumulation in the intima and facilitation of their oxidative modification. Finally, hypertension can contribute to atherogenesis due to the presence of Angiotensin II, which not only works as a vasoconstrictor, but also as a pro-inflammatory cytokine. <br />
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One of the mechanisms of hypertension contributing to atherosclerosis is injury of vascular endothelium by elevated hemodynamic stress. Injury of endothelium may increase the permeability of the vessel wall to lipoproteins. Increased blood pressure may also increase the number of scavenger receptors on macrophages, which enhances the development of foam cells. Furthermore, increased cyclic circumferential strain in hypertensive arteries can result into promoting LDL accumulation in the intima and facilitation of their oxidative modification. Finally, hypertension can contribute to atherogenesis due to the presence of Angiotensin II, which not only works as a vasoconstrictor, but also as a pro-inflammatory cytokine.
    
==== ''Antihypertensive therapy'' ====
 
==== ''Antihypertensive therapy'' ====
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<br />
 
Antihypertensive therapy can either consist of lifestyle interventions or pharmacotherapy. Lifestyle modifications consist of diet, body weight reduction, increased activity, and cessation of smoking. As for diet, high consumption of fruits, vegetables, dairy products low in fat, fish oils, potassium and reduced consumption of sodium and alcohol are recommended.  
 
Antihypertensive therapy can either consist of lifestyle interventions or pharmacotherapy. Lifestyle modifications consist of diet, body weight reduction, increased activity, and cessation of smoking. As for diet, high consumption of fruits, vegetables, dairy products low in fat, fish oils, potassium and reduced consumption of sodium and alcohol are recommended.  
The indication for pharmacotherapy depends on the severity of hypertension and on the assessment of total CVD risk. Several large trials have shown that pharmacotherapy for hypertension can substantially reduce major cardiovascular events such as MI and stroke. Drug therapy is indicated when chronic SBP ≥ 160mmHg and/or DBP ≥100mmHg, or if target organ damage is present.<br />
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The indication for pharmacotherapy depends on the severity of hypertension and on the assessment of total CVD risk. Several large trials have shown that pharmacotherapy for hypertension can substantially reduce major cardiovascular events such as MI and stroke. Drug therapy is indicated when chronic SBP ≥ 160mmHg and/or DBP ≥100mmHg, or if target organ damage is present.
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==== ''Diabetes Mellitus'' ====
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With estimated global incidence of 170 million people, diabetes mellitus is a large problem worldwide. Diabetes mellitus increases the risk of acute coronary events by three- to five folds and 80% of diabetic patients will face atherosclerosis-related cardiovascular diseases. Risk for atherosclerosis among diabetics is considered to be as high as grouping patients with previous MI. Based on this observation, the National Cholesterol Education Program report from the United States and guidelines from Europe consider type 2 diabetes to be a CHD equivalent, categorizing it to the highest risk for MI.<br />
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With estimated global incidence of 170 million people, diabetes mellitus is a large problem worldwide. Diabetes mellitus increases the risk of acute coronary events by three- to five folds and 80% of diabetic patients will face atherosclerosis-related cardiovascular diseases. Risk for atherosclerosis among diabetics is considered to be as high as in patients with previous MI. Based on this observation, the National Cholesterol Education Program report from the United States and guidelines from Europe considers type 2 diabetes to be a CHD equivalent, categorizing it to the highest risk for MI.<br />
    
There are several possible mechanisms that make this group particularly vulnerable to atherosclerosis. An example of mechanism is non-enzymatic glycation of lipoproteins, which promotes uptake of cholesterol by scavenger macrophages. Furthermore, pro-thrombotic and anti-fibrinolytic properties of diabetes can also contribute to this vulnerability. The high prevalence of endothelial dysfunction among diabetes group leads to reduced bioavailability of NO and enhanced leukocyte adhesion. The most effective prevention of atherosclerosis among diabetes group is tight regulation of serum glucose levels. This intervention significantly reduces the risk of microvascular complications such as retinopathy and nephropathy. Furthermore, intense anti-diabetic regime also reduced macrovascular outcomes such as MI and stroke among a group of diabetes type 1. Additionally managing hypertension and dyslipidemia among diabetic groups also significantly reduces the risk of cardiovascular diseases.<br />
 
There are several possible mechanisms that make this group particularly vulnerable to atherosclerosis. An example of mechanism is non-enzymatic glycation of lipoproteins, which promotes uptake of cholesterol by scavenger macrophages. Furthermore, pro-thrombotic and anti-fibrinolytic properties of diabetes can also contribute to this vulnerability. The high prevalence of endothelial dysfunction among diabetes group leads to reduced bioavailability of NO and enhanced leukocyte adhesion. The most effective prevention of atherosclerosis among diabetes group is tight regulation of serum glucose levels. This intervention significantly reduces the risk of microvascular complications such as retinopathy and nephropathy. Furthermore, intense anti-diabetic regime also reduced macrovascular outcomes such as MI and stroke among a group of diabetes type 1. Additionally managing hypertension and dyslipidemia among diabetic groups also significantly reduces the risk of cardiovascular diseases.<br />
    
== References ==
 
== References ==
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