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Chapter Atherosclerosis
''Ronak Delewi, MD; Hayang Yang, MsC; John Kastelein, MD, PhD''<br /><br />
{{case|
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 />


==Normal arterial vessel==
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.
}}


Figure 1 normal arterial wall
== Introduction ==
{{multiple image
| align    = right
| direction = horizontal
| width    = 200


Figure 2 summary of the comparison between normal and atherosclerotic arterial wall
| image1    = Figure_1_-_World_map_CVD_mortality_rates_in_males.png
| caption1  = Figure 1. World map CVD mortality rates in males


===Three layers of arterial vessel===
| image2    = Figure_2_-_World_map_CVD_mortality_rates_in_females.png
| caption2  = Figure 2. World map CVD mortality rates in females


The arterial vessel consists of intima, media and outer adventitia. (see Figure 1)
| image3    = Figure 3 - Distribution of CVD death among males in 2008.png
| caption3  = Figure 3. Distribution of CVD death among males in 2008


The intima is located closest to the arterial lumen and is therefore most ‘intimate’ with the blood. It is composed of a single layer of endothelial cells. These cells function as an active metabolic barrier between blood and the arterial wall.
| image4    = Figure 4 - Distribution of CVD death among females in 2008.png
| caption4  = Figure 4. Distribution of CVD death among females in 2008
}}
Since the 20th century, cardiovascular disease (CVD’s) has grown to be the leading cause of death and disability in the world, illustrated by 17.3 million deaths per year in 2008. Amongst cardiovascular disease, coronary heart disease (46% among males, 38% among females) and cerebrovascular disease (34% among males, 37% among females) account for the largest proportion of CVD. In 2008, heart attack and stroke were responsible for 7.3 million deaths and 6.2 million deaths, respectively. Obstructive coronary and cerebrovascular diseases are caused, in the vast majority of cases, by atherosclerosis. Atherosclerotis vascular disease begins early in life and over time can eventually lead to obstructive arterial disease. Once atherosclerotic lesions become clinically significant, serious acute complications such as ischemic heart disease, MI and stroke may occur. This chapter deals with the complex pathological process of atherosclerosis, possible consequences of atherosclerosis and the most recent treatment for atherosclerosis in order to prevent CVD’s.


The media is the middle layer and is the thickest of all. It is separated from the intima by internal elastic laminae and from the adventitia by external elastic laminae. The media consists of smooth muscle cells and extracellular matrix and play its role as a contractile and elastic of the vessel. The elastic function of the media is more distinguished in large arteries such as the aorta. It allows the vessel to stretch during systole and then to contract during diastole in order to pump the blood forward. In smaller arteries such as arterioles, the muscular component is more prominent. The muscle cells act as a constrictor or relaxer of the vessel in order to alter luminal blood flow by influencing the resistance of the vessel.
== Arterial vessel in homeostasis ==
The core of the pathogenesis of atherosclerosis is a disease state of the arterial wall. In order to understand the pathogenesis of atherosclerosis, it is thus necessary to know about the function and normal morphology of non-pathological arteries.<br />


The outer adventitia provides nourishment to the cells of the vessel by means of nerves, lymphatics and vasa vasorum.  
=== Three layers of arterial vessel ===
The normal arterial vessel consists of 3 layers, namely intima, media and outer adventitia.<br />


Arterial wall is constantly concerned with dynamic interchange between its cellular components and their surrounding extra cellular matrix. By understanding the physiology of this dynamic interchange and the functions of each cellular component the dysfunction of these cellular components leading to atherogenesis are understood. (see Figure 2)
The intima is located closest to the arterial lumen and is therefore most ‘intimate’ with the blood. This layer is composed of a single layer of endothelial cells (endothelium), connective tissue, and several smooth muscle cells. The endothelium functions as an active metabolic barrier as well as a carrier between blood and the arterial wall. It plays a crucial role in atherosclerosis. Connective tissue consists of a matrix of collagen, proteoglycans and elastin. Lymphocytes, macrophages and other types of inflammatory cells may occasionally reside in the intima. <br />


==Role of cellular components in atherogenesis==
The media is the middle layer and its inner and outer boundaries are formed by the internal and external elastic laminae. The media consists of layers of smooth muscle cells with contractile and synthetic function. As for the contractile function, smooth muscle cells enable vasoconstriction and vasodilatation. As for the synthetic function, they are responsible for the growth of the vascular extracellular matrix.<br />


===Endothelial cells===
The most external vessel wall layer is called the adventitia and contains fibroblasts, connective tissue, nerves, lymphatics and vasa vasorum. Inflammatory cells may also occasionally reside in the adventitia. <br />
Normal artery wall contains endothelial cells that manage the homeostasis of the wall by structural, metabolic, and signaling functions. The endothelial cells are tightly joined with each other in order to form a suitable barrier that keeps the blood inside the vessel and inhibits the large molecules to pass from the blood to subintima (subendothelial space). It is thus an active biologic interface between the blood and other tissues. Endothelium has several important functions such as regulation of thrombosis, contraction of smooth muscle cells of the vessel, and immune response.  


The endothelium produces antithrombotic molecules in order to prevent blood from clotting. Certain molecules such as heparin sulfate, thrombomodulin, and plasminogen dwell on the endothelial surface and other molecules such as prostacyclin and nitroic oxide (NO) enter the blood. Endothelium can produce prothrombotic molecules when it encounters various stressors, however normally it maintains a net anticoagulant state.
There is a constant dynamic interchange between the arterial wall and its cellular components and the surrounding extracellular matrix. By understanding the physiology of this dynamic interchange and the function of each cellular component, the dysfunction of these cellular components leading to atherogenesis can be better understood. <br />
 
=== Cellular components involved in atherosclerosis ===
==== ''Endothelial cells'' ====
The normal artery wall contains endothelial cells that manage the homeostasis of the wall by structural, metabolic, and signaling functions. The endothelium plays a role as a barrier to elements contained in the blood, but is also an active biologic interface between the blood and other tissues, regulating cellular and nutrient trafficking. It has several important functions such as keeping certain elements in blood separated from the vessel and maintaining a balance between pro-coagulant and anticoagulant activity, pro- and anti-inflammatory response, and contracted and relaxed vasomotor tone.<br />
   
   
Another function of endothelium is to modulate contraction of smooth muscle cells in the media by releasing substances such as vasodilators and vasoconstrictors. Vasodilators (e.g. NO, prostacyclin) and vasoconstrictors (e.g. endothelin) fine-tune the resistance of the vessel and subsequently alter the arterial blood flow. Endothelium normally maintains a state of net smooth muscle relaxation with the predominance of vasodilators.  
The endothelium produces antithrombotic molecules in order to prevent blood from clotting. Certain molecules such as heparin sulfate, thrombomodulin, and plasminogen rest on the endothelial surface whereas molecules such as prostacyclin and nitric oxide (NO) enter the blood. Endothelium can produce prothrombotic molecules when it encounters stressors; however, it normally maintains a balanced anticoagulant state, maintaining blood fluidity.<br />
 
Endothelial cells also have an important function as a regulator of the immune response. In a normal situation without pathologic stimuli, endothelial cells are not capable to attract and bind patrolling leukocytes, thus maintaining an anti-inflammatory state.  When local injury or infection initiates pathologic stimulation, endothelial cells respond by secreting chemokines that attract white blood cells to the injured area. Additionally, endothelium produces cell surface adhesion molecules, which recruit mononuclear cells to the endothelium and therefore promote their migration to the injury site. This response is important for the development of atherosclerosis.<br />
 
Another function of endothelium is to modulate contraction of smooth muscle cells in the media by releasing substances such as vasodilators and vasoconstrictors. Vasodilators (e.g. NO, prostacyclin) and vasoconstrictors (e.g. endothelin) fine-tune the resistance of the vessel and subsequently alter the arterial blood flow. Endothelium normally maintains a state of net relaxed vasomotor tone with a predominance of vasodilators. Endothelium can also respond to various physical stimuli such as shear stress and can additionally dilate the blood vessel. The endothelium principally regulates such response through release of NO. This endothelial-dependent response is called flow-mediated vasodilation (FMD), which can be measured for clinical evaluation of endothelial function. For example, impairment of FMD is observed in the early stages of atherosclerosis. However, endothelial function tests are currently not recommended to be used for surrogate markers in clinical practice since the tests are technically challenging and the validation of clinical benefits in the evaluation of cardiovascular risk requires more evidence.<br />
 
As mentioned earlier, endothelial cells can respond to or in other words get ‘activated’ due to changes in the local extracellular milieu. Examples of such changes are common stresses (e.g. shear stress and mild changes in temperature), transient infections and minor trauma. The term ‘endothelial cell activation’ (EC activation) refers to a change from the normal state, illustrated by loss of barrier function, pro-adhesive (leukocyte adhesion), vasoconstriction, and procoagulant properties. EC activation is not necessarily linked to disease and can be temporary and mild or permanent and severe.<br />
 
In conclusion, the normal arterial endothelium consists of a dynamic interface with net anticoagulant properties, net relaxation of smooth muscle cells and anti-inflammatory characteristics. Endothelial cells may react to various changes in homeostasis and become ‘activated endothelial cells’.<br />
 
==== ''Vascular smooth muscle cells'' ====
As mentioned earlier, smooth muscle cells have two functions, namely contractile and synthetic. Vasoconstriction and vasodilatation are regulated by various vasoactive substances such as angiotensin II, acetylcholine, NO and endothelin, which are released by endothelium. Another element of contractile function is the elasticity of the vessel, which is regulated by the lamina elastica. They are situated between the smooth muscle cells and are responsible for the stretching of the vessel during systole and diastole. This function is crucial in the pathogenesis of atherosclerosis, because it prevents the weakening of the vessel wall that can prevail as a complication of atherosclerosis. For example, aneurysm due to weakening of the vessel wall is a serious complication of atherosclerosis.<br />
 
It is important to understand the synthetic function of smooth muscle cells since the dysfunction of it is thought to contribute to the pathogenesis of atherosclerosis. Normally the smooth muscle cells synthesize collagen, elastin and proteoglycans that form the connective tissue matrix of the vessel wall. Smooth muscle cells can also synthesize vasoactive and inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). These mediators stimulate leukocyte migration and induce the endothelial cells to express leukocyte adhesion molecules as mentioned earlier. This synthetic function is found to be more dominant in case of an atherosclerotic plaque, which is illustrated in the next section (1.2). Although smooth muscle cells rarely divide in normal circumstances, it can proliferate in response to injury, which is an important sign of atherosclerotic plaque formation. <br />
 
==== ''Extracellular matrix'' ====
Vascular extracellular matrix in the media consists of elastin, proteoglycans and fibrillar collagen, which are principally synthesized by smooth muscle cells as mentioned earlier. With the provision of flexibility by elastin and biomechanical strength by fibrillar collagen, the arterial vessel is able to maintain the structural integrity despite high pressure within the lumen.<br />
 
== 1.2 Arterial vessel with atherosclerosis ==
[[File:RCA_atherosclerosis.jpg|thumb|Atheroclerotic plaque in a coronary artery]]
=== 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 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]]


Endothelial cells have an important function as a regulator of the immune response. In a normal situation without the pathologic stimulation, endothelial cells work as anti-inflammatory by resisting leukocyte adhesion. When local injury or infection initiates pathologic stimulation, endothelial cells respond by secreting chemokines that attract white blood cells to the injured area. Additionally, endothelium produces cell surface adhesion molecules, which hold mononuclear cells to the endothelium, and therefore promote their migration to the injury site.  
=== Initiation and formation of atherosclerotic plaque ===
The earliest visible signs of atherogenesis are the fatty streak and pre-existing lesions of adaptive intimal thickening. Fatty streak is a yellow discoloration on the surface of the artery lumen, which is flat or slightly elevated in the intima and contains accumulations of intracellular and extracellular lipid. At this stage of initiation, the fatty streak doesn’t protrude substantially into the artery wall nor impedes blood flow. This process is already visible in most people by the age of 20. At this stage, there are no symptoms and this lesion may even diminish over time. Initiation of fatty streak development is most likely caused by endothelial dysfunction, since it involves entry and modification of lipids within the subintima. This modified layer of lipids creates a proinflammatory environment and initiates the migration of leukocytes and formation of foam cells (Figure 5). Intimal thickening mainly contains smooth muscle cells and proteoglycan-collagen matrix with a few or no infiltrating inflammatory cells.<br />


In conclusion, the normal arterial endothelium implements good barrier with net anticoagulant properties, net relaxation of the smooth muscle and anti-inflammatory trait.  
==== ''Endothelial dysfunction'' ====
{| class="wikitable" border="0" style='float: left'
|- align='left'
!Table 6. Factors correlated with endothelial dysfunction<br />


===Vascular smooth muscle cells===
|- align='left'
|
* Increased age
*Male sex
*Family history of coronary heart disease
*Tobacco smoking
*Elevated cholesterol
*Low HDL-cholesterol
*Diabetes mellitus
*Hypertension
*Obesity
*High fat consumption
|}
<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 />


Smooth muscle cells have two important functions; contractile and synthetic. The contractile function of these cells are stimulated or inhibited by various vasoactive substances such as angiotensin II, acetylcholine, endothelin, and NO. Such modulation results in vasoconstriction or vasodilatation.  
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 />
{| class="wikitable" border="1" style='float: right'
|-
! Table 7. Interventions that enhance endothelial function
|-
|
* L-arginine
* Estrogen
* Antioxidants
* Quit smoking
* Reducing cholesterol
* Exercise
|}<br />


Synthetic function of smooth muscle cells is important to understand, because it may contribute to the pathogenesis of atherosclerosis. Normally they synthesize collagen, elastin, and proteoglycans that form the vascular extracellular matrix. They also provide vasoactive and inflammatory mediators, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). These mediators stimulate leukocyte proliferation and induce the endothelial cells to express leukocyte adhesion molecules as mentioned earlier.  
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 />


===Extracellular matrix===
Another major factor that can impair the atheroprotective endothelial function is chemical irritants such as cigarette smoking, abnormally high circulating lipid levels and high glucose level (diabetes mellitus). They can contribute to endothelial dysfunction and are all well- known risk factors for atherosclerosis. Exposure to chemical irritants promotes endothelial dysfunction by increasing endothelial production of reactive oxygen species, which alter the metabolic and synthetic functions of endothelial cells. As a result, the endothelium become inclined to exhibit proinflammatory processes, such as secreting inflammatory cytokines.<br />


Vascular extracellular matrix in the media consists of elastin, proteoglycans and fibrillar collagen. With the provision of flexibility by elastin, and biomechanical strength by fibrillar collagen, the arterial vessel is able to maintain the structural integrity despite the high pressure within the lumen. Fibrillar collagen can also inhibit the proliferation of smooth muscle cell in vitro according to recent evidence. The matrix also plays a role in the process of cellular responses to stimuli, such as growth factors and may for example deter the cells to undergo apoptosis.
In conclusion, hemodynamic and chemical stressors contribute to disturbance of endothelial homeostasis and promote endothelial dysfunction. This results in impairment of permeability barrier function, secretion of inflammatory cytokines, stimulation of adhesion molecules on the cell surface that promote leukocyte recruitment, and altered antithrombotic properties and release of vasoactive molecules (Figure 8). Consequently, these effects establish the groundwork for further advancement of atherosclerosis.<br />
<br /><br /><br />


==Atherosclerotic arterial vessel==
==== ''Lipoprotein entry and modification'' ====
Disruption of the integrity of endothelial barrier due to endothelial dysfunction allows the passage of circulating lipoproteins (low-density lipoprotein, LDL) into the intima. By binding to proteoglycans, LDL particles start to accumulate. This accumulation is a critical process in atherogenesis since LDL may undergo chemical modifications while residing longer in the intima. It is needless to say that an elevated circulating LDL concentration strongly contributes to this accumulating process. Another major risk factor for this process is hypertension since it causes augmented vessel wall stress. Elevated vessel wall stress influences smooth muscle cells to synthesize proteoglycans in the intima, promoting LDL-binding with proteoglycans and therefore contributing to “trapping” of lipoproteins and lipid accumulation within the intima. At this point, macrophages adhere to dysfunctional endothelial cells and transmigrate into the intima. These macrophages are called ‘foam cells’ after they have taken up lipids.<br />
As mentioned earlier, chemical modification occurs with LDL when chronic accumulation takes place inside the intima. There are several types of chemical modification that may occur. One is called oxidation and it results from the chemical reaction of reactive oxygen species and pro-oxidant enzymes produced by endothelial or smooth muscle cells, or macrophages penetrating the intima. This type of oxidative stress leads to cellular dysfunction and damage in endothelial cells and macrophages. Furthermore chronic hyperglycemia can stimulate glycation of LDL that may ultimately alter LDL into an antigenic and proinflammatory molecule. This explains why diabetes mellitus is a major risk factor for atherosclerosis. The biochemical modification of LDL into a proinflammatory molecule contributes to the inflammation process established by endothelial dysfunction. Furthermore, the oxidized LDL molecule induces tissue damage, which can initiate angiogenesis, forming new vasa vasorum in the plaque. It also induces leukocyte recruitment and foam cell formation in the fatty streak throughout the plaque development.<br />


Figure 3 summary of 3 pathologic stages of atherosclerosis
==== ''Leukocyte recruitment'' ====
Leukocyte recruitment to the arterial wall is another key step in atherogenesis, which is dependent on two important factors; expression of leukocyte adhesion molecules (LAM) on the endothelial wall and chemoattractant signals that direct diapedesis (intruding of molecules through the intact vessel wall). These two factors mainly direct monocytes to the atherosclerotic lesion. T lymphocytes that play a central role in the immune system reside within plaques at all stages of atherogenesis, mainly producing cytokines. <br />


===Three pathologic stages of atherogenesis===
As mentioned earlier, modified LDL can maintain leukocyte recruitment by inducing LAM and chemokine expression. It can also stimulate endothelial and smooth muscle cells to produce proinflammatory cytokines. These proinflammatory cytokines can also induce LAM and chemoattractant cytokine expression, equivalent to the working of modified LDL. In conclusion, modified LDL can directly or indirectly promote leukocyte recruitment and atherogenesis. <br />


Endothelial cells and smooth muscle cells may respond to inflammatory mediators when normal homeostasis is disrupted. Recent research has shown that inflammatory mediators such as IL-1 and TNF-α can multiply themselves by activating vascular cells to produce such cytokines. Thus this research pointed out that not only the immune cells, but also the “activated” vascular cells can be proinflammatory. As the process of atherogenesis is believed to be caused by proinflammatory agents, it is important to discover this proinflammatory trait of vascular cells. This research also identified several other factors that contribute to atherogenesis , such as endothelial dysfunction, formation of lipid layer within the intima, migration of leukocytes and smooth muscle cells to the vessel wall, formation of foam cells, and deposition of extracellular matrix. Formation of the plaque is a chronic process of continuous interaction and competition among the cells of the lesion. This process can be identified in three stages; the fatty streak, plaque progression, and plaque disruption. (see Figure 3)
==== ''Foam cell formation'' ====
When monocytes enter the intima, they differentiate into phagocytic macrophages. These phagocytic macrophages may become foam cells when they absorb lipoproteins. They don’t phagocyte LDL with a classic cell surface LDL-receptor, since it does not recognize modified LDL, but with a family of ‘scavenger’ receptors that do bind and internalize modified LDL. Uptake by scavenger receptors avoids negative feedback inhibition from the high cholesterol content unlike the classic LDL-receptors, and allows the macrophages to imbibe cholesterol-rich lipid that results into the formation of foam cells. This uptake seems to be beneficial at first sight, since it absorbs the inflammatory modified-LDL, however since these foam cells have impaired trafficking, they will be locally accumulated in the plaque and encourage the plaque progression by serving as a source of proinflammatory cytokines.


===Fatty streak===
=== Plaque progression ===
[[File:Figure_9_-_Fibrous_cap_formation.png|thumb|left|Figure 9. Fibrous cap formation and the necrotic core.]]
<br /><br />
The atherosclerotic plaque at this stage is called fibrous cap atheroma featuring two characteristics, which are lipid-rich necrotic core and encapsulation by a fibrous cap (Figure 9). The fibrous cap is an area between the vessel lumen and the core of the plaque, which contains dead foam cells, macrophages, smooth muscle cells, lymphocytes and extracellular matrix. A distinctive hallmark of this phase is necrosis with macrophage infiltration around a lipid pool and loss of proteoglycans or collagen. At this point, the deposition of free cholesterol is not easily visible and the plaque does not always cause luminal restriction of blood flow due to a compensatory outward remodeling of the plaque wall. This remodeling preserves the diameter of the vessel lumen and thus may evade detection by angiography. Continuous plaque growth at a later stage contains cellular debris, higher free cholesterol and results into complete depletion of extracellular matrix. From this stage, the fibrous cap atheroma may go through episodes of hemorrhage with or without calcification and even fibrous cap disruption. Progressive vessel narrowing may result in ischemia and can cause ischemic symptoms such as angina pectoris or intermittent claudication.<br />


The earliest visible sign of atherogenesis is the fatty streak, which means areas of yellow discoloration on the surface of the artery lumen. At this stage, this fatty streak doesn’t protrude substantially into the artery wall nor impede blood flow. This process is already visible in most people by the age of 20. There are no symptoms and this lesion may even diminish over time. Research based on several animal models suggest that various stressors such as physical forces and chemical irritants cause early endothelial dysfunction, which allows entry and modification of lipids within the subintima. This modified layer of lipids serve as proinflammatory mediators and thus initiates the migration of leukocytes and formation of foam cells.  
==== ''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 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 />


The distinctive hallmark of the fatty streak is the initiation of migration of leukocytes and formal cell formation caused by proinflammatory mediators.
==== ''Extracellular matrix metabolism'' ====


===Endothelial dysfunction===
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 />


Endothelial dysfunction is a primary event in atherogenesis, which can be caused by various agents, such as physical stress and chemical irritants. Observations showed that atherosclerosis often forms at arterial branch points, for example at bifurcations and this result proposes that physical stress plays an important role in atherogenesis. There are several projective mechanisms against atherosclerosis by endothelial cells. One of them is NO, which is an endogenous vasodilator that works as an inhibitor of platelet aggregation and as an anti-inflammatory product. It is secreted by endothelial cells when they are stimulated by laminar flow in erect sections of arteries. Another mechanism is the expression of the antioxidant enzyme superoxide dismutase by the endothelium. This enzyme works against reactive oxygen species, produced by chemical irritants or transient ischemia in the vessel.  
=== Plaque rupture ===
==== ''Integrity of plaque'' ====
[[File:Figure_10_-_The_ruptured_plaque..png|thumb|right|Figure 10. The ruptured plaque.]]
Chronic shifting of the balance towards extracellular matrix metabolism leads to serious consequences for the plaque integrity. As mentioned earlier, it accelerates inflammatory stimulation or activation of apoptosis pathways and therefore leads to death of smooth muscle and foam cells. Cell death leads to release of cellular contents, whereby more lipids and cellular debris is absorbed to the dynamic lipid core. Due to this process, the size of the lipid core grows and as a result alters biomechanical environment and hence the stability of the plaque. One example of this is a plaque border adjacent to the normal tissue, called shoulder region, which is the main location where the hemodynamic stress is focused. As the size and the protrusion of the plaque in the vessel increase, the hemodynamic stress will also increase around the shoulder region. Furthermore, local accumulation of foam cells and lymphocytes at this site makes the plaque more susceptible to rupture by accelerating degradation of extracellular matrix. However, although shoulder area is considered as the weakest point where the fibrous cap would mostly likely rupture, there have been autopsy studies that showed an equal number of ruptures occurring at the midportion of the fibrous cap. When the fibrous cap is very thick and contains small lipid core, the plaque is called stable and it may reinforce the narrowing of the artery, but on the other hand diminishes the susceptibility to rupture. Plaques with thinner fibrous caps are called vulnerable plaques. They are identified by a large necrotic core, rich with lipid, taking about 25% of the plaque area, and a thin fibrous cap of less than 65 µM thickness, which separates the necrotic core from the vessel lumen. Vulnerable plaque is infiltrated by a large amount of macrophages and a smaller amount of T-lymphocytes. It typically lacks smooth muscle cells due to apoptosis. This type of lesion causes less obstruction in the artery, but is more fragile and has higher susceptibility to rupture and trigger thrombosis than a thick fibrous cap. At this stage, plaque hemorrhage can occur due to rupture of vasa vasorum within a plaque. Vasa vasorum is a newly formed vascularization in the plaque due to tissue damage. Due to its fragility it may rupture easily, increasing the risk to form intraplaque hemorrhage. Intraplaque hemorrhage may lead to subsequent rupture of the fibrous cap (Figure 10) or occlusion of the vessel through intramural hematoma. Plaque calcification is another factor that contributes to plaque rupture. It usually occurs in areas of necrosis and elsewhere in the plaque and can eventually lead to higher rigidity of the vessel wall. Calcification is dependent on mineral deposition and resorption by osteoblast-like and osteoclast-like cells in the vessel wall. In conclusion, there are seven important factors associated with plaque ruptures; range of inflammation area, considerable size of lipid core, fibrous cap thinner than 65 µM, apoptosis leading to fewer smooth muscle cells, disrupted balance of proteolytic enzymes and their inhibitors, plaque calcification, and hemorrhage in the plaque. Although it remains difficult to foresee the clinical consequences, progression to a complicated plaque can lead to major cardiovascular disease, mostly affecting individuals in their 60s and 70s, although it may also occur among people at an earlier age.<br />


Unfortunately, these atheroprotective endothelial functions can be impaired by several factors. For example, disturbed flow (physical stressor), typically located at arterial branch points, can impair the protective functions. This is well illustrated by the difference in prevalence of atherosclerosis deposition between branched arteries and bifurcated vessels. Bifurcation areas such as the common carotid and left coronary arteries are relatively more common deposition sites for atherosclerosis than arteries with few branches such as the internal mammary artery.
==== ''Thrombogenic potential after rupture'' ====
When the fibrous cap is ruptured, the highly thrombogenic components of the necrotic core, including tissue factor, gets in direct contact with the circulating monocytes in the blood. It is believed that these circulating monocytes in the blood play a stronger role as a source of tissue factor than the necrotic core. Tissue factor stimulates platelet activation and thus can initiate and propagate thrombus. The thrombus formed at the rupture site is called white thrombus due to its grossly white appearance of rich platelet. At the proximal and distal ends near the site of white thrombosis there is another type of thrombus composed of layers of red blood cells and fibrin and is therefore called red thrombus. Thrombosis can be healed through several processes such as penetration of smooth muscle cells, neovascularization via vasa vasorum, proliferation of extracellular matrix, inflammation and re-endothelialization on the luminal surface. Thus clinically, ruptures can be silent and heal, without major clinical complications such as MI and stroke. For example, small non-occlusive thrombi may be reabsorbed into the plaque, continuing the process of smooth cell growth and fibrous deposition. The extent of how occlusive and transient the thrombus will be is largely dependent on the thrombogenic potential of the plaque.<br />
The counter-balancing of coagulation and fibrinolysis also determines the probability of a major clinical event due to occlusive thrombosis. Inflammatory stimuli in the plaque environment incite smooth muscle cells, endothelial cells, and foam cells to release tissue factor that initiates the extrinsic coagulation pathway. Inflammatory stimuli also stimulate expression of antifibrinolytics such as plasminogen activator inhibitor-1 and consequently enhance thrombosis. As mentioned earlier, the activated endothelial cells also contribute to thrombosis and coagulation by depositing fibrin at the vascular wall. Thus, the inflammatory and dysfunctional condition of the plaque environment decreases the counterbalancing of coagulation and fibrinolysis, increasing the probability of major clinical complications of atherosclerosis. <br />


Chemical irritants such as cigarette smoking, abnormally high circulating lipid levels or high sugar levels (diabetes mellitus) can contribute to endothelial dysfunction and are all well- known risk factors for atherosclerosis. Exposure to chemical irritants promotes endothelial dysfunction by increasing endothelial production of reactive oxygen species, which alter the metabolic and synthetic functions of endothelial cells. As a result, the endothelium is inclined to exhibit proinflammatory processes.
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 />
 
{|
|-
| rowspan="2" | [[File:plaque_rupture_A.svg|100px]]
| rowspan="2" | [[File:plaque_rupture_B.svg|100px]]
| rowspan="2" | [[File:split_arrow.svg|50px]]
| [[File:plaque_rupture_C.svg|100px]] || [[File:plaque_rupture_clot.svg|100px]]
|-
| [[File:plaque_rupture_D.svg|100px]]
|-
| 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
|}


Hemodynamic and chemical stressors contribute to distorting the endothelial homeostasis and promote endothelial dysfunction. The following undesired effects result from; impairment of permeability barrier function, secretion of inflammatory cytokines, stimulation of adhesion molecules on the cell surface that promote leukocyte recruitment, and altered antithrombotic properties and release of vasoactive molecules. Consequently, these undesired effects establish the groundwork for further advancement of atherosclerosis.
== Complications of atherosclerosis ==
{| class="wikitable" border="1" style='float: left'
|- align='left'
! Figure 11. Most common locations of atherosclerosis
|-
|
* Dorsal section of the abdominal aorta
* Proximal coronary arteries
* Popliteal arteries
* Descending thoracic aorta
* Internal carotid arteries
* Renal arteries
|}
[[File:atherosclerosis_damage.svg|thumb|400px|right|Figure 12. Complications of atherosclerosis]]
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 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.).
# 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, aneurysms may suddenly rupture and result in a life-threatening situation for the patients.


===Lipoprotein entry and modification===
== Risk factors of atherosclerosis ==
{| class="wikitable" border="1" style='float: right' align='left'
|-
! Figure 13. Nine modifiable risk factors for atherosclerosis <br />
according to INTERHEART study
|-
|
* Dyslipidemia
* Tabacco smoking
* Lack of physical activity
* Abdominal obesity
* Psychosocial factors
* Daily consumption of fruits and vegetables
* Regular alcohol consumption
* Hypertension
* Diabetes Mellitus
|}
Recent studies have shown that atherosclerosis is not just the inevitable process of aging, but also a process with many modifiable components. A worldwide INTERHEART study has established the importance of nine potentially modifiable risk factors for atherosclerosis, which account for over 90% of the population-attributable risk of a first MI (figure 12). A variety of non-modifiable risk factors such as advanced age, gender and hereditary coronary heart disease are important to recognize in patients with atherosclerosis. Recently the role of several biological markers associated with the development of cardiovascular events is accentuated since one out of five cardiovascular events occurs in patients lacking the earlier mentioned risk factors. <br />
=== Common risk factors ===
==== ''Dyslipidemia'' ====
One of the major modifiable risk factors for atherosclerosis is hypercholesterolemia. Studies show that dyslipidemia (defined as an elevated apo B to apo A-1 ratio) was responsible for 49% of the population-attributable risk of a first MI. In countries with high consumption of saturated fat and high cholesterol levels (e.g. the United States), observational studies have shown that the mortality rates from coronary disease are higher compared with countries with traditionally low consumption of saturated fat and cholesterol levels (e.g. Japan). Several trials have shown that the risk of ischemic heart disease positively correlates with higher total serum cholesterol levels. For example, the impact of hypercholesterolemia can be illustrated by an observational result from the Framingham Heart Study, which shows that a person with a total cholesterol level of 240 mg/dl has twice the coronary risk a person would have with a cholesterol level of 200 mg/dl. However, it is a mistake to think that all lipoproteins consisting of cholesterol are harmful since cholesterol can provide critical functions to all cells that need to form membranes and to synthesize products such as steroid hormones and bile salts. <br />
{| class="wikitable" border="1" style='float: left'
|-
! Figure 14. Recommendations regarding dyslipidemia
|-
| General recommendations: <br />
* A varied and balanced diet
* Regular fish intake (n – 3 fatty acids)
* Fruits and vegetables, 3-5 portions per day, cereals and grain products, skimmed dairy products, and low-fat meat
* Restriction of fatty products and products with a high caloric density.
* The total fat intake should not be higher than 30% of calory intake. The saturated fat intake should not be higher than 30% of total lipids
* The cholesterol intake should be under 300 mg per day  <br />
Specific diet recommendations: <br />
* Avoid hard margarines and products of animal origin (meat, dairy products)
* Increase intake of omega-3 fatty acids from fish oils and certain vegetal oils
* Increase intake of polyunsaturated fatty acids, soluble fibres, and phytosterols
* Exercise and body weight reduction within obese group
* Normalization of glycaemia in diabetic patients
* Reduce the intake of refined sugars and replace them with complex sugars from fruits, vegetables, and grain products
|}
Incidence of atherosclerosis and coronary artery disease increases with higher levels of LDL particles. As mentioned earlier, LDL can accumulate in the intima of the artery in excess and undergo chemical modifications that activate endothelial cells to proceed to atherosclerosis. When people generally refer to ‘bad cholesterol’, they are referring to LDL particles. On the other hand, high levels of high-density lipoprotein (HDL) constitute ‘good cholesterol’ since it protects against atherosclerosis by reversing the cholesterol transport from peripheral tissues to the liver for disposal and functions as an antioxidant. In order to give additional explanation to what is ‘bad cholesterol,’ all lipid and lipoprotein abnormalities that are associated with higher coronary risk will be named subsequently: increased total cholesterol, increased LDL-cholesterol, low HDL-cholesterol, elevated total-to-HDL-cholesterol ratio, hypertriglyceridemia, increased non-HDL-cholesterol, elevated lipoprotein A, elevated apolipoprotein B (apo B is primarily found in LDL), decreased apolipoprotein A-I (apo A-1 is found in HDL), small and dense LDL particles.


Impairment of permeability barrier due to endothelial dysfunction allows the passage of circulating lipoproteins (low-density lipoprotein, LDL) into the intima. By binding to the extracellular matrix component called proteoglycans, LDL assures its place in intima and starts accumulating. This accumulation is a critical process in atherogenesis since LDL may undergo chemical modifications while residing longer in intima. It is needless to say that an elevated circulating LDL concentration strongly contributes to this accumulating process. Another major risk factor for this process is hypertension. High blood pressure influences smooth muscle cells to promote LDL-binding with proteoglycans and therefore also contributes to “trapping” of lipoproteins within the vessel wall.


As mentioned earlier, chemical modification occurs with LDL when chronic accumulation takes place inside intima. There are several types of chemical modification that may occur. One is called oxidation and it results from the chemical reaction of reactive oxygen species and pro-oxidant enzymes produced by endothelial or smooth muscle cells, or macrophages penetrating the intima. Diabetes is a major risk factor for atherosclerosis since chronic hyperglycemia can stimulate glycation of LDL that may ultimately alter LDL into an antigenic and proinflammatory molecule. In conclusion, this biochemical modification of LDL into proinflammatory molecule does not only contribute to inflammation by endothelial dysfunction, but it also maintains the promotion of leukocyte recruitment and foam cell formation throughout the plaque development.
There are several causes for persistent elevated levels of LDL, such as high fat consumption or genetic abnormalities (e.g. familial hypercholesterolemia). Familial hypercholesterolemia is a condition with deficient LDL receptors that cannot efficiently dispose LDL from the circulation. There are two types of this disease with different manifestations. Patients with the heterozygote type have only one defective gene for the receptor and suffer from high serum level of LDL, easily developing atherosclerosis. Homozygotes have a complete lack of normal LDL receptors and thus may experience cardiovascular events already in the first decade of life. In the absence of genetic abnormalities, the quantity of cholesterol in serum is strongly related to saturated fat consumption.<br />


===Leukocyte recruitment===
==== ''Lipid-Altering therapy'' ====


Leukocyte recruitment to the arterial wall is another key step in atherogensis, which is dependent on two important factors; expression of leukocyte adhesion molecules (LAM) on endothelial wall, and chemoattractant signals such as IL-8 that direct diapedesis (intruding of molecules through the intact vessel wall). These two factors mainly direct monocytes to the atherosclerotic lesion although T lymphocytes play the central role in the immune system. T-lymphocyte resides within plaques at all stages of atherogenesis, mainly producing cytokines.  
Controlling serum lipids is a key step to limit the consequences of atherosclerosis. Major clinical trials have shown that coronary events and mortality significantly decreased when total and LDL-cholesterol levels were reduced for the primary and secondary prevention of CAD events.


As mentioned earlier, modified LDL can maintain leukocyte recruitment by inducing LAM and chemokine expression. It can also stimulate endothelial and smooth muscle cells to produce proinflammatory cytokines such as IL-1 and TNF-α. These proinflammatory cytokines can also induce LAM and chemoattractant cytokine expression equivalent to modified LDL. Therfore, the dual ability of modified LDL can directly or indirectly promote leukocyte recruitment and throughout atherogenesis.


===Foam cell formation===
One of the most important strategies to reduce the complications of atherosclerosis is diet and exercise. In order to decrease cholesterol, Mediterranean diet is often recommended. Mediterranean diet consists of low animal fat, high olive oil, moderate energy consumption, nuts, vegetables, regular and moderate wine, lots of whole grains and beans. A meta-analysis of six randomized trials showed that Mediterranean diet led to greater reduction in total cholesterol than low fat diets among overweight/obese population. Mediterranean-styled diet in this context means replacement of saturated fats with polyunsaturated fats such as omega-3 fatty acid and α-linolenic acid. Polyunsaturated fats are potential anti-atherogenic due to their inhibiting action on cytokine-induced expression of leukocyte adhesion molecules at endothelial cells. Exercise and loss of excessive weight also contributes to improve abnormal lipid levels by reducing triglycerides and increasing HDL.
When monocytes enter the intima, they differentiate into phagocytic macrophages. These phagocytic macrophages may become foam cells when they absorb lipoproteins. They don’t uptake LDL from a classic cell surface LDL-receptor, since it does not recognize modified LDL, but from a family of ‘scavenger’ receptors that do bind and internalize modified LDL. Uptake by scavenger receptors avoids negative feedback inhibition from the high cholesterol content unlike the classic LDL-receptors, and allows the macrophages to imbibe cholesterol-rich lipid that results into the formation of foam cells. This uptake seems to be beneficial at first sight, since it absorbs the inflammatory modified-LDL, however when these foam cells have impaired outflow, they will be locally accumulated in the plaque and encourage the plaque progression by serving as a source of proinflammatory cytokines.


===Plaque progression===
Smooth muscle cells are the ones who play a central role in plaque progression. Atherosclerotic plaque has two typical features, which are thrombogenic lipid core and a protective fibrous cap. Plaque growth does not always cause luminal restriction of blood flow at an early stage thanks to a compensatory outward remodeling of the plaque wall. This remodeling preserves the diameter of the vessel lumen and thus may even evade detection by angiography. Nevertheless, plaque growth at a later stage may result in ischemia due to the narrowing of the vessel and can cause ischemic symptoms such as angina pectoris or intermittent claudication.  
In primary prevention, pharmacologic agents are the second option when lifestyle modifications fail to achieve targeted lipid profile. There are several groups of lipid-altering medicines such as HMG-CoA reductase inhibitors (statins), niacin, fibric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid-binding agents. In the clinical setting, statins are widely used, being the most cost-effective LDL-lowering drugs. They reduce intracellular cholesterol concentration by inhibiting HMG-CoA reductase, which is an enzyme that synthesizes cholesterol. This results into increased LDL-receptor expression and therefore leads to higher clearance of LDL molecules from blood. They also affect the liver and thereby lower the rate of VLDL synthesis, which results into lower levels of serum triglyceride. Statins also raise HDL, but this mechanism is not fully understood yet.


===Smooth muscle cell migration===
Migration of smooth muscle cell from the media to the intima is a distinctive indication of transition from fatty streak to plaque formation. After the migration, smooth muscle cells proliferate within the intima and secrete extracellular matrix macromolecules.


Additionally, foam cells, activated platelets, and endothelium stimulate the substances that signal the migration and proliferation of smooth muscle cell. 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 cell and leukocyte to reinforce inflammation in the atherosclerotic lesion.  
Large studies, which have evaluated the effects of statin therapy, showed that ischemic cardiac events, the occurrence of MI and mortality rates were significantly reduced by implementing statin therapy. This significant improvement did not only apply to people with known preexisting atherosclerotic disease, but also to people within lower ranges of LDL and without preexisting atherosclerotic disease. For example, West of Scotland Coronary Prevention Study (WOSCPS trial) evaluated the effect of pravastatin on rates of nonfatal MI or CHD death, nonfatal MI, all cardiovascular deaths and total mortality among patients with hypercholesterolemia without preexisting CVD for five years. Use of pravastatin resulted in 31% risk reduction (p<0.001) in nonfatal MI or CHD death, and a 32% risk reduction (p=0.033) in all cardiovascular deaths as compared to the control group.


Although plaque progression is traditionally known as a gradual and continuous process, recent evidence claim 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 microthrombus contains activated platelets that release additional factors such as PDGF and heparinase that can further stimulate local smooth muscle cell migration and proliferation. Heparinase stimulate smooth muscle cell migration and proliferation by degrading heparin sulfate, which normally counteracts this process.
Inhibiting HMG-CoA reductase results in several mechanisms that explain the beneficial effect of using statins. One beneficial mechanism is via lowering LDL and raising HDL. This results into less lipid content in atherosclerotic plaques and improve their biologic activity. Furthermore, the anti-thrombotic and anti-inflammatory profile is enhanced by other mechanisms such as increased NO synthesis and fibrinolytic activity, inhibition of smooth muscle proliferation and monocyte recruitment, and reduced production of matrix-degrading enzymes by macrophages. Several studies suggest that other mechanisms also contribute to the anti-inflammatory profile. For example, statins reduce endothelial expression of leukocyte adhesion molecules and macrophage tissue factor production by inhibiting the macrophage cytokines or by activating PPAR-α. Another anti-inflammatory action of statins, supported by clinical trials is reducing the serum level of C-reactive protein, which is a marker of inflammation. <br />


===Extracellular matrix metabolism===
Although statin therapy can reduce the risk of atherosclerotic cardiovascular disease by about one third, there is still a need for additional risk-reducing therapies. Thus, a new idea was developed to raise HDL cholesterol as a treatment for atherosclerosis. With the finding of the high-HDL phenotype of a human genetic deficiency of cholesteryl ester transfer protein (CETP), a new class of drugs was developed, which inhibits CETP. CETP functions as a mediator for transfer of cholesteryl ester from HDL to VLDL/LDL, which is then cleared by LDL receptors in liver. Thus when CETP is inhibited, this transfer process is inhibited and the direct hepatic HDL clearance pathway takes over. This leads to less fractional clearance of HDL from plasma, which is beneficial for atherosclerosis. Although the absolute clearance rate of HDL remains the same, the key step for atherosclerosis, which is the removal of cholesterol from macrophage foam cells in artery wall by HDL, is reduced. <br />
Metabolic process 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. Inflammatory cytokines also weakens the fibrous cap by stimulating local foam cells to secrete MMP that degrades collagen and elastin of the fibrous cap.


==Plaque disruption==
The most recently investigated CETP inhibitors are torcetrapib, anacetrapib, and dalcetrapib. In the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial, involving 15,000 patients at high risk for coronary heart disease, torcetrapib was clinically investigated. Unfortunately this trial was prematurely stopped due to the finding of an increase in cardiovascular events associated with an undiscovered off-target effect. Anacetrapib and dalcetrapib are still under active clinical investigation, since they lack the off-target effects of torcetrapib.
===Plaque integrity===
Chronic shifting of the balance of extracellular matrix metabolism leads to serious consequences to the plaque integrity. As mentioned earlier, it accelerates inflammatory stimulation or activation of apoptosis pathways and therefore leads to death of smooth muscle and foam cells. Cell death leads to release of cellular contents, whereby more lipids and cellular debris is absorbed to the dynamic lipid core. This process increases the size of the lipid core and as a result alters biomechanical environment and hence the stability of the plaque. Plaque border adjacent to the normal tissue is called shoulder region and it’s the main location where the hemodynamic stress is focused. As the size and the protrusion of the plaque in the vessel increase, the hemodynamic stress will also increase around the shoulder region. Furthermore, local accumulation of foam cells and lymphocytes at this site makes the plaque more susceptible to rupture by accelerating degradation of extracellular matrix.  


Plaque integrity and its vulnerability to rupture are highly dependent on the net balance of deposition and distribution of the fibrous cap. When the fibrous cap is very thick, the plaque is called stable plaque and it may reinforce the narrowing of the artery, but on the other hand diminish the susceptibility to rupture. Plaques with thinner fibrous caps are called vulnerable plaques and they cause less obstruction in the artery, but are more fragile and have higher susceptibility to rupture and trigger thrombosis. Characteristically, stable plaques have thick fibrous cap with small lipid core, while vulnerable plaques have thin fibrous cap with rich lipid core, extensive macrophage infiltrate and weakening smooth muscle cells. It is difficult to foresee the ‘clinical’ consequences of the plaque.
==== ''Tobacco smoking'' ====


===Thrombogenic potential===
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 />
Disruption of the fibrous cap does not always lead to major clinical events such as myocardial infarction and stroke. For example, small non-occlusive thrombi may be reabsorbed into the plaque, continuing the process of smooth cell growth and fibrous deposition. The extent of how occlusive and transient the thrombus will be is largely dependent on the thrombogenic potential of the plaque.
   
   
The counter balancing of coagulation and fibrinolysis determines the probability of a major clinical event due to occlusive thrombosis. Inflammatory stimuli in the plaque environment incite smooth muscle cells, endothelial cells, and foam cells to release tissue factor that initiates the extrinsic coagulation pathway. Inflammatory stimuli also stimulate expression of antifibrinolytics such as plasminogen activator inhibitor-1 and consequently enhance thrombosis. As mentioned earlier, the activated endothelial cells also contribute to thrombosis and coagulation by depositing fibrin at the vascular wall.
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 />


The concept of ‘vulnerable plaque’ has developed into a new concept of ‘vulnerable patient’ as the recent evidence shows that a person’s susceptibility to coagulation and thus vascular events can be influenced by many other factors such as genetics (e.g. procoagulant prothombin gene mutation), coexisting condition (e.g. diabetes), and lifestyle factors (e.g. smoking, obsesity).
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 />


=Complications of atherosclerosis =
==== ''Lack of physical activity'' ====
Developing of atherosclerotic plaques is not homogenous throughout the vasculature. The following anatomical structures are the most common areas where atherosclerosis takes place, starting from the most common region: dorsal section of the abdominal aorta, proximal coronary arteries, the popliteal arteries, descending thoracic aorta, internal carotid arteries, and renal arteries. It is needless to say that the areas perfused by these vessels are most frequently impaired by the consequences of atherosclerosis. Clinically, this can lead to thromboembolism resulting in major cardiovascular diseases such as stroke and myocardial infarction.
{| class="wikitable" border="1" style='float:right; width: 400px;'
|-
! colspan="2" | Physical Activity
|-
| colspan="2" | The following activities have similar benefits to health:
|-
| align="center" | ''Activity''
| align="center" | ''Duration''
|-
| Washing and waxing a car
| 45-60 minutes
|-
| Washing windows or floors
| 45-60 minutes
|-
| Playing volleyball
| 45 minutes
|-
| Wheeling self in wheelchair
| 30-40 minutes
|-
| Bicycling - 8 km
| 30 minutes
|-
| Pushing a pushchair - 2.5 km
| 30 minutes
|-
| Walking - 3 km
| 30 minutes
|-
| Swimming laps
| 20 minutes
|-
| Playing basketball
| 15-20 minutes
|}
INTERHEART study showed that lack of exercise accounted for 12% of the population-attributable risk of a first MI. Recent evidence shows that physical activity of even a moderate degree can protect against coronary heart disease and all-cause mortality .The beneficial effects of physical exercise are a decrease of triglyceride levels and blood pressure, elevation of HDL, enhancement of insulin sensitivity and production of NO by the endothelial cells, and of course weight loss. Although large scale randomized primary prevention trials are lacking, physical activity should be promoted to anyone with risk of developing atherosclerosis.<br />


There are several major complications, such as calcification, rupture, hemorrhage, embolization and weakening of the vessel wall that can lead to serious clinical consequences by acute restriction of blood flow or alterations in arterial wall integrity. Clinically, atherosclerosis can lead to major cardiovascular disease:
==== ''Obesity'' ====


# Atherosclerotic plaque can be calcified, which leads to higher rigidity of the vessel wall and therefore favor its fragility.  
The American Heart Association has published an article, identifying obesity as an independent risk factor for coronary heart disease. Obesity is correlated with several risk factors for atherosclerosis such as hypertension, insulin resistance, glucose intolerance, decreased HDL serum level and hypertriglyceridemia. Weight loss is an important treatment to prevent many obesity-related risk factors for atherosclerosis that has just been mentioned. <br />
# When the plaque ruptures, it will release its pro-coagulants to blood and that will lead to the formation of thrombus at the rupture site. This thrombus may cause a complete occlusion of the vessel and result in acute infarction of the involved organ. Or, the thrombus is  incorporated into another plaque and continues the process of atherogenesis.
# Fibrous cap or micro vessels, which are formed within the plaque can rupture and cause hemorrhage within the plaque. This hemorrhage results in intramural hematoma and may contribute to the occlusion of the vessel.
# Embolization is the transfer of the fragments of disrupted atheroma to distal vascular sites, which results into occlusion of those sites.
# After a chronic period, fibrous plaque can increase the pressure of the medial layer, which results into atrophy and loss of elastic tissue, forming dilatation and weakness of the artery, causing aneurysm.


Depending on where atherosclerotic plaque is located and the type of the plaque, the clinical consequences varies. For example, ‘stable plaque’ can easily result into angina pectoris due to its thick fibrous cap that directly affects occlusion 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 a physically stressed area 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’. In conclusion, you can either have an occlusion due to the growing plaque or due to the embolization of the ruptured fragments of the original plaque.
==== ''Diet'' ====


Due to the difficult detection of ‘vulnerable plaques’ while they are widely dispersed, it is important to understand that tackling the risk factors prior to plaque rupture is highly important. Thus in the following paragraph, we would like to bring attention to the critical risk factors for preventing progressive atherogenesis.
A healthy diet reduces CVD risk. In general, when following the rules for a healthy diet, no dietary supplements are needed.  N-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>


=Risk factors of atherosclerosis=
==== ''Alcohol consumption'' ====
Recent studies have shown that atherosclerosis is not just the inevitable process of aging, but can be a process with many modifiable attributes. Due to the evidence of strong correlations between specific attributes and atherosclerotic diseases, the concept of risk factors became more essential than ever. Many important studies have established the importance of modifiable risk factors for atherosclerosis, since they account for up to 90% of population-attributable cardiac risk. A variety of non-modifiable risk factors such as advanced age, gender and hereditary coronary heart disease are important to diagnosing and recognizing patients with atherosclerosis. Furthermore, recent researches accentuate the importance of recognizing several biological markers associated with the development of cardiovascular events.


=Common risk factors=
Alcohol is harmful when used chronic or excessive and can lead to various complications such as liver and heart failure, increased cancer risk, neurological complications and injuries. However despite these adverse effects, moderate drinking (US parameters; women: <2 drinks per day, men: <3 drinks per day) may have protective benefits with regards to coronary heart disease according to several prospective cohort studies. These studies showed that moderate drinking resulted in a reduction of risk in coronary heart disease by 40-70% compared to no or heavy drinkers. This beneficial effect was seen in various groups without or with known risk for coronary heart disease and adults older than 65 years old. In a meta-analysis study, alcohol drinkers had lower relative risk for CVD mortality (0.75, 95% CI 0.70-0.80), coronary heart disease mortality (0.75, 0.68-0.81) and incidence of coronary heart disease (0.71, 0.66-0.77) than nondrinkers.<br />
==Dyslipidemia==
One of the major modifiable risk factors for atherosclerosis is hypercholesterolemia. In countries with high consumption of saturated fat and high cholesterol levels (e.g. the United States), observational studies have shown that the mortality rates from coronary disease are higher compared with those in countries with traditionally low consumption of saturated fat and  cholesterol levels (e.g. Japan). Several trials have shown that the risk of ischemic heart disease positively correlates with higher total serum cholesterol levels. The impact of hypercholesterolemia can be illustrated by an observational result, which shows that a person with a total cholesterol level of 240 mg/dl has twice the coronary risk a person would have with a cholesterol level of 200 mg/dl.


However, it is a mistake to think that all lipoproteins consisting of cholesterol are harmful. Cholesterol can provide critical functions to all cells that need to form membranes and to synthesize products such as steroid hormones and bile salts.
==== '' Psychosocial factors'' ====


Incidence of atherosclerosis and coronary artery disease increases with higher levels of LDL particles. As mentioned earlier  LDL can accumulate in the intima of the artery in excess proportions, and undergo chemical modifications that activate endothelial cells to contributing atherosclerosis. When people refer to  ‘bad cholesterol’, they are referring to LDL particles. On the other hand, high level of high-density lipoprotein (HDL) is ‘good cholesterol’ since it protects against atherosclerosis by reversing the cholesterol transport from peripheral tissues to the liver for disposal and functioning as antioxidant.
Mentioned by INTERHEART study, psychosocial factors may directly contribute to the early development of atherosclerosis. Psychological stress may directly damage endothelium and indirectly aggravate other common risk factors such as smoking, dyslipidemia and hypertension. Due to the difficulty in quantifying the extent of atherosclerosis, studies showing the relationship between stress and atherosclerosis have been limited. Epidemiologic studies have shown stronger link between psychosocial factors (loss of job, depression and bereavement) and MI and sudden death. <br />


There are several causes to persistent elevated level of LDL, such as high-fat consumption or genetic abnormalities (e.g. familial cholesterolemia). Familial hypercholesterolemia is a condition with genetically defected LDL receptors that cannot efficiently dispose LDL from the circulation. There are two types of this disease with different manifestations. Patients with the heterozygote type has only one defective gene for the receptor and he/she suffers from high serum level of LDL and will easily develop atherosclerosis. Homozygotes have complete lack of normal LDL receptors and thus may experience cardiovascular events in the first decade of life.
==== ''Estrogen Status'' ====


Although not fully understood, many studies show increased triglyceride-rich lipoproteins such as very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) are positively associated with atherosclerosis. Whether triglyceride-rich lipoproteins directly participate in atherogenesis or simply accompany low HDL levels remains undetermined and seek for more research.  
Women and men have different risk for cardiovascular diseases throughout life. For example, at young age, men have an estimated four- to fivefold higher risk than women. However this difference diminishes and the age point of no difference is strongly related to the moment of menopause. From this observation, it has been suggested that estrogen may play athero-protective roles, since the levels of estrogen declines after menopause. In premenopausal women, estrogen raises HDL levels and reduces LDL levels in blood. Estrogen can even exhibit antioxidant and antithrombotic properties and can improve endothelium-dependent vasodilatation.


==Lipid-Altering therapy==
Controlling the serum lipid level is a key step to limit the consequences of atherosclerosis. Major clinical trials that form that basis of screening guidelines show that reduction of serum cholesterol by pharmacology and diet can restrict the progression of atherosclerosis significantly.  
In the past, hormone replacement therapy has been suggested by several studies due to the findings of potential athero-protective roles of estrogen. However, these findings were not confirmed in the randomized primary prevention study of the Women’s Health Initiative not in the HERS trial of secondary prevention. These studies showed that hormone replacement therapy (estrogen-progestin replacement) may increase cardiovascular risk in women and have no cardioprotective effect. Thus hormone replacement therapy is currently not recommended for reducing cardiovascular risk, due to its possible harmfulness consequences according to current clinical trials.


One of the most important strategies to reduce the complications of atherosclerosis is diet and exercise. Several studies have shown that Mediterranean-styled diet among patients with coronary disease significantly reduced the risk of recurrent cardiac events. Mediterranean-styled diet in this context means replacement of saturated fats with polyunsaturated fats such as omga-3 fatty acid and α-linolenic acid. Polyunsaturated fats are potential anti-atherogenic due to its inhibiting work on cytokine-induced expression of leukocyte adhesion molecules on endothelial cells. Exercise and loss of excessive weight also contributes to improve abnormal lipid levels by reducing triglycerides and increasing HDL.
=== Biomarkers ===


Pharmacologic agents are the second option when lifestyle modifications fail to achieve targeted lipid profile. There are several groups of lipid-altering medicines such as HMG-CoA reductase inhibitors (statins), niacin, fibric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid-binding agents. In clinical setting, statins are commonly used as the most cost-effective LDL-lowering drugs. They reduce intracellular cholesterol concentration by inhibiting HMG-CoA reductase, which is an enzyme that synthesizes cholesterol. This results into increased LDL-receptor expression and therefore leads to higher clearance of LDL molecules from blood. They also affect the liver and thereby lower the rate of VLDL synthesis, which results into lower level of serum triglyceride. Statins also raise HDL, but this mechanism is not fully understood yet.
Biomarkers can serve to identify patients with subclinical atherosclerotic disease that are at risk of developing cardiovascular events.<br />


Large studies, which have evaluated the effects of statin therapy, showed that ischemic cardiac events, the occurrence of strokes and mortality rates were significantly reduced by implementing statin therapy. This significant improvement didn’t only apply for people with known preexisting atherosclerotic disease, but also for people within lower ranges of LDL, without preexisting atherosclerotic disease.
==== ''Homocysteine'' ====


Inhibiting HMG-CoA reductase results into several mechanisms that explain the beneficial effect of using statins. One beneficial mechanism is through lowering LDL and raising HDL. This results into less lipid content in atherosclerotic plaques and improve their biologic activity. Furthermore, anti-thrombotic and anti-inflammatory condition is enhanced by other mechanisms such as increased NO synthesis and fibrinolytic antivity, inhibition of smooth muscle proliferation and monocyte recruitment, and reduced production of matrix-degrading enzymes by macrophage. Several studies suggest that other mechanisms also contribute to anti-inflammatory condition. For example, statins reduce endothelial expression of leukocyte adhesion molecules and macrophage tissue factor production by inhibiting the macrophage cytokines or by activating PPAR-α. Another anti-inflammatory working of statins, supported by clinical trials is reducing the serum level of C-reactive protein, which is a marker of inflammation.  
Homocysteine is an intermediary amino acid produced during the conversion of methionine to cysteine. A significant positive correlation was found between the serum levels of homocysteine and the incidence of cardiovascular diseases. Although the clear mechanism of this correlation is undetermined, the overall result of the most current evidence suggests that homocysteine can modestly contribute to cardiovascular risk by inducing vascular injury. Homocysteine promotes oxidative stress, intimal thickening, disruption of elastic lamina, hypertrophy of smooth muscle cells, vascular inflammation platelet accumulation and production of occlusive thrombi when elevated in blood. Several conditions can cause hyperhomocystinemia, such as genetic defects in methionine metabolism or insufficient consumption of folic acid, which is involved in the methionine pathway. Such disorders cause premature and severe atherosclerosis. Despite this observational relationship, there is no data yet that proves reducing high serum level of homocysteine will lead to a decrease in atherosclerosis or its complications.<br />


{| class="wikitable"
==== ''Lipoprotein A'' ====
|-
! Figure 4. Recommendations in relations to dyslipidemia.
|-
| General recommendations:
* A varied and balanced diet
* Regular fish intake (n – 3 fatty acids)
* Fruits and vegetables, 3-5 portions per day, cereals and grain products, skimmed dairy products, and low-fat meat
* Restriction of fatty products and products with a high caloric density.
* The total fat intake should not be higher than 30% of calorie intake. The saturated fat intake should not be higher than 30% of total lipids
* The cholesterol intake should be under 300 mg per day
|-
| Specific diet recommendations:
* Avoid hard margarines and products of animal origin (meat, dairy products)
* Increase intake of omega-3 fatty acids from fish oils and certain vegetal oils
* Increase intake of polyunsaturated fatty acids, soluble fibres, and phytosterols
* Exercise and body weight reduction within obese group
* Normalization of glycaemia in diabetic patients
|}


===Tabacco smoking===
Some studies have concluded that lipoprotein (a) is an independent risk factor for coronary artery disease. As lipoprotein (a) contains apo (a), which structurally resembles plasminogen, lipoprotein (a) interferes with fibrinolysis by competing with plasminogen binding with molecules. This leads to impairment of plasminogen activation, plasmin generation and lysis of fibrin clots. In addition, lipoprotein (a) binds with macrophages through a high-affinity receptor, promoting foam cell production and deposition of cholesterol in atherosclerotic plaques. As with homocysteine, not all studies support this theory of correlation, although increased risk of cardiovascular events appear to correlate with people with highest lipoprotein (a) serum level.<br />
Tabacco use is known to increase the risk of atherosclerosis and ischemic heart diseased based on numerous studies. Smoking is estimated to be responsible of estimated 30% of all cardiovascular diseases, and it may increase the risk even at minimal use. Tabacco smoking can lead to several mechanisms that may contribute to atherosclerosis. It enhances oxidative modification of LDL, decreases circulating HDL levels, stimulates tissue hypoxia and oxidant stress, leading to endothelial dysfunction, promotes platelet adhesiveness, increases expression of leukocyte adhesion molecules, inappropriately stimulates sympathetic nervous system, and displaces oxygen with carbon monoxide in hemoglobin. Another important component, induced by cigarette smoking is thrombosis.


According to major studies, quitting smoking is one of the most effective preventive measures of cardiovascular diseases and their complications. It decreases the risk of coronary heart disease dramatically compared to those who don’t. Not only does cessation of smoking reduce risk of CVD, but also substantially reduce the risk of all-cause mortality.
==== ''C-Reactive Protein and other markers of inflammation'' ====


===Lack of physical activity / obesity===
Since the participation of inflammatory cells and mediators in atherosclerosis is well established, markers of inflammation have received a lot of attention. Several markers of inflammation such as C-reactive protein (CRP), fibrinogen and amyloid A are produced by hepatocytes in an acute phase under the influence of cytokines such as IL-6 when they mobilize from intima to the liver during the fatty streak stage. From these markers, CRP has shown the greatest association with atherosclerosis as a marker of low-grade systemic inflammation. A significant association between elevated CRP level in blood and prevalence of atherosclerosis has been shown in more than 30 epidemiologic studies. Different studies showed that higher basal CRP levels (four-fold higher) were found in patients with MI as compared to controls. Several studies have proposed that elevated plasma CRP can be an independent predictor for many cardiovascular diseases based on the result that CRP plasma value was able to predict the long-term risk of first MI, ischemic stroke or peripheral vascular disease among the male group. In addition, recent studies have shown that CRP also has a role as a mediator in atherogenesis. By inducing adhesion molecule expression and release of IL-6 and monocyte chemoattractant protein-1 via endothelial cells, CRP sustains the inflammatory state of atherosclerosis by recruiting monocytes and lymphocytes.<br />
Recent evidence shows that physical activity can lower triglyceride levels and blood pressure, raise HDL, and can also enhance insulin sensitivity and production of NO by the endothelial cells. Several prospective studies have shown that all genders can have beneficial effects from even modest activities such as walking against cardiovascular mortality. Although large scale randomized primary prevention trials are lacking, physical activity should be promoted to anyone with risk of developing atherosclerosis.


===Estrogen Status===
==== ''Infection'' ====
Women and men have different risk for cardiovascular diseases throughout life. For example, at young age, men have estimated four- to fivefold higher risk than women. This difference diminishes with age, but even in the age range of 75 and 85, the incidence of coronary disease is almost twofold in men compared to woman. The age point of diminished difference between men and women is strongly related to the moment of menopause.  From this observation, studies suggest that estrogen may play athero-protective roles, since the levels of estrogen decline after menopause. In premenopausal women, estrogen raises HDL levels and reduces LDL levels in blood. Experiments have also shown that estrogen can exhibit antioxidant and antithrombotic properties, and can improve endothelium-dependent vasodilatation.


In the past, hormone replacement therapy has been suggested by several studies due to the findings of potential athero-protective roles of estrogen. However, the Heart and Estrogen/progestin Replacement Study, along with randomized primary prevention studies from the Women’s Health Initiative showed that such hormone replacement therapy rather increased cardiovascular risk in women. Thus hormone replace therapy is currently not recommended for reducing cardiovascular risk, due to its possible harmfulness according to current clinical trials. Further analyses are being done whether hormone replacement approaches can still be safe and effective, since some cohort studies didn’t show increased cardiovascular risk outcomes as other clinical trials, when they applied estrogen-only hormone therapy.
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 />


==Co-morbidity groups==
=== Co-morbidity groups ===
===Hypertension===
==== ''Hypertension'' ====
Hypertension is defined as a systolic blood pressure (SBP) ≥ 140mmHg and/or a diastolic blood pressure (DBP) ≥ 90mmHg. This elevated blood pressure substantially increases the risk of atherosclerosis, coronary heart disease, and stroke. For example, cardiovascular disease doubles for every 20 mmHg increase in SBP or every 10 mmHg increase in DBP.


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. As last, 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.  
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.


===Antihypertensive therapy===
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, and 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. Many large trials have shown that pharmacotherapy for hypertension can substantially reduce CVD mortality and morbidity. Drug therapy is indicated when chronic SBP ≥ 160mmHg and/or DBP ≥100mmHg, or if target organ damage is present. Hypertensive patients with lower blood pressure than the previously mentioned indication are managed according to their total risk for CVD, which usually means indications for medications, since absence of other risk factors and low risk is very unusual with hypertension.  
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.


{| class="wikitable"
==== ''Antihypertensive therapy'' ====
{| class="wikitable" border="1" style='float: right'
|-
!  Figure 16. Lifestyle recommendations for hypertension
|-
|-
! Figure 5. Lifestyle recommendations for hypertension.
|  
|-
* Weight reduction in overweight individuals
| * Weight reduction in overweight individuals
* Reduction of salt consumption to < 6g daily
* Reduction of salt consumption to < 6g daily
* Restriction of alcohol intake to < 10-30g/day (men) and < 10-20g/day (women)
* Restriction of alcohol intake to < 10-30g/day (men) and < 10-20g/day (women)
* Regular physical activity  
* Regular physical activity  
* Smoking cessation
* Smoking cessation
|}
|}
<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.
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.
==== ''Diabetes Mellitus'' ====
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 />


===Diabetes mellitus===
== References ==
With estimated global incidence of 170 million people diabetes mellitus remains 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 diabetes group is considered as high as a group with previous myocardial infarction.
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Revision as of 20:56, 8 December 2013

Ronak Delewi, MD; Hayang Yang, MsC; John Kastelein, MD, PhD

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/m2, 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.

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.


Introduction

Figure 1. World map CVD mortality rates in males
Figure 2. World map CVD mortality rates in females
Figure 3. Distribution of CVD death among males in 2008
Figure 4. Distribution of CVD death among females in 2008

Since the 20th century, cardiovascular disease (CVD’s) has grown to be the leading cause of death and disability in the world, illustrated by 17.3 million deaths per year in 2008. Amongst cardiovascular disease, coronary heart disease (46% among males, 38% among females) and cerebrovascular disease (34% among males, 37% among females) account for the largest proportion of CVD. In 2008, heart attack and stroke were responsible for 7.3 million deaths and 6.2 million deaths, respectively. Obstructive coronary and cerebrovascular diseases are caused, in the vast majority of cases, by atherosclerosis. Atherosclerotis vascular disease begins early in life and over time can eventually lead to obstructive arterial disease. Once atherosclerotic lesions become clinically significant, serious acute complications such as ischemic heart disease, MI and stroke may occur. This chapter deals with the complex pathological process of atherosclerosis, possible consequences of atherosclerosis and the most recent treatment for atherosclerosis in order to prevent CVD’s.

Arterial vessel in homeostasis

The core of the pathogenesis of atherosclerosis is a disease state of the arterial wall. In order to understand the pathogenesis of atherosclerosis, it is thus necessary to know about the function and normal morphology of non-pathological arteries.

Three layers of arterial vessel

The normal arterial vessel consists of 3 layers, namely intima, media and outer adventitia.

The intima is located closest to the arterial lumen and is therefore most ‘intimate’ with the blood. This layer is composed of a single layer of endothelial cells (endothelium), connective tissue, and several smooth muscle cells. The endothelium functions as an active metabolic barrier as well as a carrier between blood and the arterial wall. It plays a crucial role in atherosclerosis. Connective tissue consists of a matrix of collagen, proteoglycans and elastin. Lymphocytes, macrophages and other types of inflammatory cells may occasionally reside in the intima.

The media is the middle layer and its inner and outer boundaries are formed by the internal and external elastic laminae. The media consists of layers of smooth muscle cells with contractile and synthetic function. As for the contractile function, smooth muscle cells enable vasoconstriction and vasodilatation. As for the synthetic function, they are responsible for the growth of the vascular extracellular matrix.

The most external vessel wall layer is called the adventitia and contains fibroblasts, connective tissue, nerves, lymphatics and vasa vasorum. Inflammatory cells may also occasionally reside in the adventitia.

There is a constant dynamic interchange between the arterial wall and its cellular components and the surrounding extracellular matrix. By understanding the physiology of this dynamic interchange and the function of each cellular component, the dysfunction of these cellular components leading to atherogenesis can be better understood.

Cellular components involved in atherosclerosis

Endothelial cells

The normal artery wall contains endothelial cells that manage the homeostasis of the wall by structural, metabolic, and signaling functions. The endothelium plays a role as a barrier to elements contained in the blood, but is also an active biologic interface between the blood and other tissues, regulating cellular and nutrient trafficking. It has several important functions such as keeping certain elements in blood separated from the vessel and maintaining a balance between pro-coagulant and anticoagulant activity, pro- and anti-inflammatory response, and contracted and relaxed vasomotor tone.

The endothelium produces antithrombotic molecules in order to prevent blood from clotting. Certain molecules such as heparin sulfate, thrombomodulin, and plasminogen rest on the endothelial surface whereas molecules such as prostacyclin and nitric oxide (NO) enter the blood. Endothelium can produce prothrombotic molecules when it encounters stressors; however, it normally maintains a balanced anticoagulant state, maintaining blood fluidity.

Endothelial cells also have an important function as a regulator of the immune response. In a normal situation without pathologic stimuli, endothelial cells are not capable to attract and bind patrolling leukocytes, thus maintaining an anti-inflammatory state. When local injury or infection initiates pathologic stimulation, endothelial cells respond by secreting chemokines that attract white blood cells to the injured area. Additionally, endothelium produces cell surface adhesion molecules, which recruit mononuclear cells to the endothelium and therefore promote their migration to the injury site. This response is important for the development of atherosclerosis.

Another function of endothelium is to modulate contraction of smooth muscle cells in the media by releasing substances such as vasodilators and vasoconstrictors. Vasodilators (e.g. NO, prostacyclin) and vasoconstrictors (e.g. endothelin) fine-tune the resistance of the vessel and subsequently alter the arterial blood flow. Endothelium normally maintains a state of net relaxed vasomotor tone with a predominance of vasodilators. Endothelium can also respond to various physical stimuli such as shear stress and can additionally dilate the blood vessel. The endothelium principally regulates such response through release of NO. This endothelial-dependent response is called flow-mediated vasodilation (FMD), which can be measured for clinical evaluation of endothelial function. For example, impairment of FMD is observed in the early stages of atherosclerosis. However, endothelial function tests are currently not recommended to be used for surrogate markers in clinical practice since the tests are technically challenging and the validation of clinical benefits in the evaluation of cardiovascular risk requires more evidence.

As mentioned earlier, endothelial cells can respond to or in other words get ‘activated’ due to changes in the local extracellular milieu. Examples of such changes are common stresses (e.g. shear stress and mild changes in temperature), transient infections and minor trauma. The term ‘endothelial cell activation’ (EC activation) refers to a change from the normal state, illustrated by loss of barrier function, pro-adhesive (leukocyte adhesion), vasoconstriction, and procoagulant properties. EC activation is not necessarily linked to disease and can be temporary and mild or permanent and severe.

In conclusion, the normal arterial endothelium consists of a dynamic interface with net anticoagulant properties, net relaxation of smooth muscle cells and anti-inflammatory characteristics. Endothelial cells may react to various changes in homeostasis and become ‘activated endothelial cells’.

Vascular smooth muscle cells

As mentioned earlier, smooth muscle cells have two functions, namely contractile and synthetic. Vasoconstriction and vasodilatation are regulated by various vasoactive substances such as angiotensin II, acetylcholine, NO and endothelin, which are released by endothelium. Another element of contractile function is the elasticity of the vessel, which is regulated by the lamina elastica. They are situated between the smooth muscle cells and are responsible for the stretching of the vessel during systole and diastole. This function is crucial in the pathogenesis of atherosclerosis, because it prevents the weakening of the vessel wall that can prevail as a complication of atherosclerosis. For example, aneurysm due to weakening of the vessel wall is a serious complication of atherosclerosis.

It is important to understand the synthetic function of smooth muscle cells since the dysfunction of it is thought to contribute to the pathogenesis of atherosclerosis. Normally the smooth muscle cells synthesize collagen, elastin and proteoglycans that form the connective tissue matrix of the vessel wall. Smooth muscle cells can also synthesize vasoactive and inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). These mediators stimulate leukocyte migration and induce the endothelial cells to express leukocyte adhesion molecules as mentioned earlier. This synthetic function is found to be more dominant in case of an atherosclerotic plaque, which is illustrated in the next section (1.2). Although smooth muscle cells rarely divide in normal circumstances, it can proliferate in response to injury, which is an important sign of atherosclerotic plaque formation.

Extracellular matrix

Vascular extracellular matrix in the media consists of elastin, proteoglycans and fibrillar collagen, which are principally synthesized by smooth muscle cells as mentioned earlier. With the provision of flexibility by elastin and biomechanical strength by fibrillar collagen, the arterial vessel is able to maintain the structural integrity despite high pressure within the lumen.

1.2 Arterial vessel with atherosclerosis

Atheroclerotic plaque in a coronary artery

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 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.

Figure 5. Fatty streak formation

Initiation and formation of atherosclerotic plaque

The earliest visible signs of atherogenesis are the fatty streak and pre-existing lesions of adaptive intimal thickening. Fatty streak is a yellow discoloration on the surface of the artery lumen, which is flat or slightly elevated in the intima and contains accumulations of intracellular and extracellular lipid. At this stage of initiation, the fatty streak doesn’t protrude substantially into the artery wall nor impedes blood flow. This process is already visible in most people by the age of 20. At this stage, there are no symptoms and this lesion may even diminish over time. Initiation of fatty streak development is most likely caused by endothelial dysfunction, since it involves entry and modification of lipids within the subintima. This modified layer of lipids creates a proinflammatory environment and initiates the migration of leukocytes and formation of foam cells (Figure 5). Intimal thickening mainly contains smooth muscle cells and proteoglycan-collagen matrix with a few or no infiltrating inflammatory cells.

Endothelial dysfunction

Table 6. Factors correlated with endothelial dysfunction
  • Increased age
  • Male sex
  • Family history of coronary heart disease
  • Tobacco smoking
  • Elevated cholesterol
  • Low HDL-cholesterol
  • Diabetes mellitus
  • Hypertension
  • Obesity
  • High fat consumption


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.

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.

Table 7. Interventions that enhance endothelial function
  • L-arginine
  • Estrogen
  • Antioxidants
  • Quit smoking
  • Reducing cholesterol
  • Exercise


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.

Figure 8. Endothelial dysfunction: Leukocyte adhesion and migration into the deep layer of the intima.


Another major factor that can impair the atheroprotective endothelial function is chemical irritants such as cigarette smoking, abnormally high circulating lipid levels and high glucose level (diabetes mellitus). They can contribute to endothelial dysfunction and are all well- known risk factors for atherosclerosis. Exposure to chemical irritants promotes endothelial dysfunction by increasing endothelial production of reactive oxygen species, which alter the metabolic and synthetic functions of endothelial cells. As a result, the endothelium become inclined to exhibit proinflammatory processes, such as secreting inflammatory cytokines.

In conclusion, hemodynamic and chemical stressors contribute to disturbance of endothelial homeostasis and promote endothelial dysfunction. This results in impairment of permeability barrier function, secretion of inflammatory cytokines, stimulation of adhesion molecules on the cell surface that promote leukocyte recruitment, and altered antithrombotic properties and release of vasoactive molecules (Figure 8). Consequently, these effects establish the groundwork for further advancement of atherosclerosis.



Lipoprotein entry and modification

Disruption of the integrity of endothelial barrier due to endothelial dysfunction allows the passage of circulating lipoproteins (low-density lipoprotein, LDL) into the intima. By binding to proteoglycans, LDL particles start to accumulate. This accumulation is a critical process in atherogenesis since LDL may undergo chemical modifications while residing longer in the intima. It is needless to say that an elevated circulating LDL concentration strongly contributes to this accumulating process. Another major risk factor for this process is hypertension since it causes augmented vessel wall stress. Elevated vessel wall stress influences smooth muscle cells to synthesize proteoglycans in the intima, promoting LDL-binding with proteoglycans and therefore contributing to “trapping” of lipoproteins and lipid accumulation within the intima. At this point, macrophages adhere to dysfunctional endothelial cells and transmigrate into the intima. These macrophages are called ‘foam cells’ after they have taken up lipids.

As mentioned earlier, chemical modification occurs with LDL when chronic accumulation takes place inside the intima. There are several types of chemical modification that may occur. One is called oxidation and it results from the chemical reaction of reactive oxygen species and pro-oxidant enzymes produced by endothelial or smooth muscle cells, or macrophages penetrating the intima. This type of oxidative stress leads to cellular dysfunction and damage in endothelial cells and macrophages. Furthermore chronic hyperglycemia can stimulate glycation of LDL that may ultimately alter LDL into an antigenic and proinflammatory molecule. This explains why diabetes mellitus is a major risk factor for atherosclerosis. The biochemical modification of LDL into a proinflammatory molecule contributes to the inflammation process established by endothelial dysfunction. Furthermore, the oxidized LDL molecule induces tissue damage, which can initiate angiogenesis, forming new vasa vasorum in the plaque. It also induces leukocyte recruitment and foam cell formation in the fatty streak throughout the plaque development.

Leukocyte recruitment

Leukocyte recruitment to the arterial wall is another key step in atherogenesis, which is dependent on two important factors; expression of leukocyte adhesion molecules (LAM) on the endothelial wall and chemoattractant signals that direct diapedesis (intruding of molecules through the intact vessel wall). These two factors mainly direct monocytes to the atherosclerotic lesion. T lymphocytes that play a central role in the immune system reside within plaques at all stages of atherogenesis, mainly producing cytokines.

As mentioned earlier, modified LDL can maintain leukocyte recruitment by inducing LAM and chemokine expression. It can also stimulate endothelial and smooth muscle cells to produce proinflammatory cytokines. These proinflammatory cytokines can also induce LAM and chemoattractant cytokine expression, equivalent to the working of modified LDL. In conclusion, modified LDL can directly or indirectly promote leukocyte recruitment and atherogenesis.

Foam cell formation

When monocytes enter the intima, they differentiate into phagocytic macrophages. These phagocytic macrophages may become foam cells when they absorb lipoproteins. They don’t phagocyte LDL with a classic cell surface LDL-receptor, since it does not recognize modified LDL, but with a family of ‘scavenger’ receptors that do bind and internalize modified LDL. Uptake by scavenger receptors avoids negative feedback inhibition from the high cholesterol content unlike the classic LDL-receptors, and allows the macrophages to imbibe cholesterol-rich lipid that results into the formation of foam cells. This uptake seems to be beneficial at first sight, since it absorbs the inflammatory modified-LDL, however since these foam cells have impaired trafficking, they will be locally accumulated in the plaque and encourage the plaque progression by serving as a source of proinflammatory cytokines.

Plaque progression

Figure 9. Fibrous cap formation and the necrotic core.



The atherosclerotic plaque at this stage is called fibrous cap atheroma featuring two characteristics, which are lipid-rich necrotic core and encapsulation by a fibrous cap (Figure 9). The fibrous cap is an area between the vessel lumen and the core of the plaque, which contains dead foam cells, macrophages, smooth muscle cells, lymphocytes and extracellular matrix. A distinctive hallmark of this phase is necrosis with macrophage infiltration around a lipid pool and loss of proteoglycans or collagen. At this point, the deposition of free cholesterol is not easily visible and the plaque does not always cause luminal restriction of blood flow due to a compensatory outward remodeling of the plaque wall. This remodeling preserves the diameter of the vessel lumen and thus may evade detection by angiography. Continuous plaque growth at a later stage contains cellular debris, higher free cholesterol and results into complete depletion of extracellular matrix. From this stage, the fibrous cap atheroma may go through episodes of hemorrhage with or without calcification and even fibrous cap disruption. Progressive vessel narrowing may result in ischemia and can cause ischemic symptoms such as angina pectoris or intermittent claudication.

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 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.

Extracellular matrix metabolism

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.

Plaque rupture

Integrity of plaque

Figure 10. The ruptured plaque.

Chronic shifting of the balance towards extracellular matrix metabolism leads to serious consequences for the plaque integrity. As mentioned earlier, it accelerates inflammatory stimulation or activation of apoptosis pathways and therefore leads to death of smooth muscle and foam cells. Cell death leads to release of cellular contents, whereby more lipids and cellular debris is absorbed to the dynamic lipid core. Due to this process, the size of the lipid core grows and as a result alters biomechanical environment and hence the stability of the plaque. One example of this is a plaque border adjacent to the normal tissue, called shoulder region, which is the main location where the hemodynamic stress is focused. As the size and the protrusion of the plaque in the vessel increase, the hemodynamic stress will also increase around the shoulder region. Furthermore, local accumulation of foam cells and lymphocytes at this site makes the plaque more susceptible to rupture by accelerating degradation of extracellular matrix. However, although shoulder area is considered as the weakest point where the fibrous cap would mostly likely rupture, there have been autopsy studies that showed an equal number of ruptures occurring at the midportion of the fibrous cap. When the fibrous cap is very thick and contains small lipid core, the plaque is called stable and it may reinforce the narrowing of the artery, but on the other hand diminishes the susceptibility to rupture. Plaques with thinner fibrous caps are called vulnerable plaques. They are identified by a large necrotic core, rich with lipid, taking about 25% of the plaque area, and a thin fibrous cap of less than 65 µM thickness, which separates the necrotic core from the vessel lumen. Vulnerable plaque is infiltrated by a large amount of macrophages and a smaller amount of T-lymphocytes. It typically lacks smooth muscle cells due to apoptosis. This type of lesion causes less obstruction in the artery, but is more fragile and has higher susceptibility to rupture and trigger thrombosis than a thick fibrous cap. At this stage, plaque hemorrhage can occur due to rupture of vasa vasorum within a plaque. Vasa vasorum is a newly formed vascularization in the plaque due to tissue damage. Due to its fragility it may rupture easily, increasing the risk to form intraplaque hemorrhage. Intraplaque hemorrhage may lead to subsequent rupture of the fibrous cap (Figure 10) or occlusion of the vessel through intramural hematoma. Plaque calcification is another factor that contributes to plaque rupture. It usually occurs in areas of necrosis and elsewhere in the plaque and can eventually lead to higher rigidity of the vessel wall. Calcification is dependent on mineral deposition and resorption by osteoblast-like and osteoclast-like cells in the vessel wall. In conclusion, there are seven important factors associated with plaque ruptures; range of inflammation area, considerable size of lipid core, fibrous cap thinner than 65 µM, apoptosis leading to fewer smooth muscle cells, disrupted balance of proteolytic enzymes and their inhibitors, plaque calcification, and hemorrhage in the plaque. Although it remains difficult to foresee the clinical consequences, progression to a complicated plaque can lead to major cardiovascular disease, mostly affecting individuals in their 60s and 70s, although it may also occur among people at an earlier age.

Thrombogenic potential after rupture

When the fibrous cap is ruptured, the highly thrombogenic components of the necrotic core, including tissue factor, gets in direct contact with the circulating monocytes in the blood. It is believed that these circulating monocytes in the blood play a stronger role as a source of tissue factor than the necrotic core. Tissue factor stimulates platelet activation and thus can initiate and propagate thrombus. The thrombus formed at the rupture site is called white thrombus due to its grossly white appearance of rich platelet. At the proximal and distal ends near the site of white thrombosis there is another type of thrombus composed of layers of red blood cells and fibrin and is therefore called red thrombus. Thrombosis can be healed through several processes such as penetration of smooth muscle cells, neovascularization via vasa vasorum, proliferation of extracellular matrix, inflammation and re-endothelialization on the luminal surface. Thus clinically, ruptures can be silent and heal, without major clinical complications such as MI and stroke. For example, small non-occlusive thrombi may be reabsorbed into the plaque, continuing the process of smooth cell growth and fibrous deposition. The extent of how occlusive and transient the thrombus will be is largely dependent on the thrombogenic potential of the plaque.

The counter-balancing of coagulation and fibrinolysis also determines the probability of a major clinical event due to occlusive thrombosis. Inflammatory stimuli in the plaque environment incite smooth muscle cells, endothelial cells, and foam cells to release tissue factor that initiates the extrinsic coagulation pathway. Inflammatory stimuli also stimulate expression of antifibrinolytics such as plasminogen activator inhibitor-1 and consequently enhance thrombosis. As mentioned earlier, the activated endothelial cells also contribute to thrombosis and coagulation by depositing fibrin at the vascular wall. Thus, the inflammatory and dysfunctional condition of the plaque environment decreases the counterbalancing of coagulation and fibrinolysis, increasing the probability of major clinical complications of atherosclerosis.

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).

Plaque rupture A.svg Plaque rupture B.svg Split arrow.svg Plaque rupture C.svg Plaque rupture clot.svg
Plaque rupture D.svg
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

Complications of atherosclerosis

Figure 11. Most common locations of atherosclerosis
  • Dorsal section of the abdominal aorta
  • Proximal coronary arteries
  • Popliteal arteries
  • Descending thoracic aorta
  • Internal carotid arteries
  • Renal arteries
Figure 12. Complications of atherosclerosis

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.

  1. 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).
  2. 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.).
  3. 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.
  4. 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

Figure 13. Nine modifiable risk factors for atherosclerosis

according to INTERHEART study

  • Dyslipidemia
  • Tabacco smoking
  • Lack of physical activity
  • Abdominal obesity
  • Psychosocial factors
  • Daily consumption of fruits and vegetables
  • Regular alcohol consumption
  • Hypertension
  • Diabetes Mellitus

Recent studies have shown that atherosclerosis is not just the inevitable process of aging, but also a process with many modifiable components. A worldwide INTERHEART study has established the importance of nine potentially modifiable risk factors for atherosclerosis, which account for over 90% of the population-attributable risk of a first MI (figure 12). A variety of non-modifiable risk factors such as advanced age, gender and hereditary coronary heart disease are important to recognize in patients with atherosclerosis. Recently the role of several biological markers associated with the development of cardiovascular events is accentuated since one out of five cardiovascular events occurs in patients lacking the earlier mentioned risk factors.

Common risk factors

Dyslipidemia

One of the major modifiable risk factors for atherosclerosis is hypercholesterolemia. Studies show that dyslipidemia (defined as an elevated apo B to apo A-1 ratio) was responsible for 49% of the population-attributable risk of a first MI. In countries with high consumption of saturated fat and high cholesterol levels (e.g. the United States), observational studies have shown that the mortality rates from coronary disease are higher compared with countries with traditionally low consumption of saturated fat and cholesterol levels (e.g. Japan). Several trials have shown that the risk of ischemic heart disease positively correlates with higher total serum cholesterol levels. For example, the impact of hypercholesterolemia can be illustrated by an observational result from the Framingham Heart Study, which shows that a person with a total cholesterol level of 240 mg/dl has twice the coronary risk a person would have with a cholesterol level of 200 mg/dl. However, it is a mistake to think that all lipoproteins consisting of cholesterol are harmful since cholesterol can provide critical functions to all cells that need to form membranes and to synthesize products such as steroid hormones and bile salts.

Figure 14. Recommendations regarding dyslipidemia
General recommendations:
  • A varied and balanced diet
  • Regular fish intake (n – 3 fatty acids)
  • Fruits and vegetables, 3-5 portions per day, cereals and grain products, skimmed dairy products, and low-fat meat
  • Restriction of fatty products and products with a high caloric density.
  • The total fat intake should not be higher than 30% of calory intake. The saturated fat intake should not be higher than 30% of total lipids
  • The cholesterol intake should be under 300 mg per day

Specific diet recommendations:

  • Avoid hard margarines and products of animal origin (meat, dairy products)
  • Increase intake of omega-3 fatty acids from fish oils and certain vegetal oils
  • Increase intake of polyunsaturated fatty acids, soluble fibres, and phytosterols
  • Exercise and body weight reduction within obese group
  • Normalization of glycaemia in diabetic patients
  • Reduce the intake of refined sugars and replace them with complex sugars from fruits, vegetables, and grain products

Incidence of atherosclerosis and coronary artery disease increases with higher levels of LDL particles. As mentioned earlier, LDL can accumulate in the intima of the artery in excess and undergo chemical modifications that activate endothelial cells to proceed to atherosclerosis. When people generally refer to ‘bad cholesterol’, they are referring to LDL particles. On the other hand, high levels of high-density lipoprotein (HDL) constitute ‘good cholesterol’ since it protects against atherosclerosis by reversing the cholesterol transport from peripheral tissues to the liver for disposal and functions as an antioxidant. In order to give additional explanation to what is ‘bad cholesterol,’ all lipid and lipoprotein abnormalities that are associated with higher coronary risk will be named subsequently: increased total cholesterol, increased LDL-cholesterol, low HDL-cholesterol, elevated total-to-HDL-cholesterol ratio, hypertriglyceridemia, increased non-HDL-cholesterol, elevated lipoprotein A, elevated apolipoprotein B (apo B is primarily found in LDL), decreased apolipoprotein A-I (apo A-1 is found in HDL), small and dense LDL particles.


There are several causes for persistent elevated levels of LDL, such as high fat consumption or genetic abnormalities (e.g. familial hypercholesterolemia). Familial hypercholesterolemia is a condition with deficient LDL receptors that cannot efficiently dispose LDL from the circulation. There are two types of this disease with different manifestations. Patients with the heterozygote type have only one defective gene for the receptor and suffer from high serum level of LDL, easily developing atherosclerosis. Homozygotes have a complete lack of normal LDL receptors and thus may experience cardiovascular events already in the first decade of life. In the absence of genetic abnormalities, the quantity of cholesterol in serum is strongly related to saturated fat consumption.

Lipid-Altering therapy

Controlling serum lipids is a key step to limit the consequences of atherosclerosis. Major clinical trials have shown that coronary events and mortality significantly decreased when total and LDL-cholesterol levels were reduced for the primary and secondary prevention of CAD events.


One of the most important strategies to reduce the complications of atherosclerosis is diet and exercise. In order to decrease cholesterol, Mediterranean diet is often recommended. Mediterranean diet consists of low animal fat, high olive oil, moderate energy consumption, nuts, vegetables, regular and moderate wine, lots of whole grains and beans. A meta-analysis of six randomized trials showed that Mediterranean diet led to greater reduction in total cholesterol than low fat diets among overweight/obese population. Mediterranean-styled diet in this context means replacement of saturated fats with polyunsaturated fats such as omega-3 fatty acid and α-linolenic acid. Polyunsaturated fats are potential anti-atherogenic due to their inhibiting action on cytokine-induced expression of leukocyte adhesion molecules at endothelial cells. Exercise and loss of excessive weight also contributes to improve abnormal lipid levels by reducing triglycerides and increasing HDL.


In primary prevention, pharmacologic agents are the second option when lifestyle modifications fail to achieve targeted lipid profile. There are several groups of lipid-altering medicines such as HMG-CoA reductase inhibitors (statins), niacin, fibric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid-binding agents. In the clinical setting, statins are widely used, being the most cost-effective LDL-lowering drugs. They reduce intracellular cholesterol concentration by inhibiting HMG-CoA reductase, which is an enzyme that synthesizes cholesterol. This results into increased LDL-receptor expression and therefore leads to higher clearance of LDL molecules from blood. They also affect the liver and thereby lower the rate of VLDL synthesis, which results into lower levels of serum triglyceride. Statins also raise HDL, but this mechanism is not fully understood yet.


Large studies, which have evaluated the effects of statin therapy, showed that ischemic cardiac events, the occurrence of MI and mortality rates were significantly reduced by implementing statin therapy. This significant improvement did not only apply to people with known preexisting atherosclerotic disease, but also to people within lower ranges of LDL and without preexisting atherosclerotic disease. For example, West of Scotland Coronary Prevention Study (WOSCPS trial) evaluated the effect of pravastatin on rates of nonfatal MI or CHD death, nonfatal MI, all cardiovascular deaths and total mortality among patients with hypercholesterolemia without preexisting CVD for five years. Use of pravastatin resulted in 31% risk reduction (p<0.001) in nonfatal MI or CHD death, and a 32% risk reduction (p=0.033) in all cardiovascular deaths as compared to the control group.


Inhibiting HMG-CoA reductase results in several mechanisms that explain the beneficial effect of using statins. One beneficial mechanism is via lowering LDL and raising HDL. This results into less lipid content in atherosclerotic plaques and improve their biologic activity. Furthermore, the anti-thrombotic and anti-inflammatory profile is enhanced by other mechanisms such as increased NO synthesis and fibrinolytic activity, inhibition of smooth muscle proliferation and monocyte recruitment, and reduced production of matrix-degrading enzymes by macrophages. Several studies suggest that other mechanisms also contribute to the anti-inflammatory profile. For example, statins reduce endothelial expression of leukocyte adhesion molecules and macrophage tissue factor production by inhibiting the macrophage cytokines or by activating PPAR-α. Another anti-inflammatory action of statins, supported by clinical trials is reducing the serum level of C-reactive protein, which is a marker of inflammation.

Although statin therapy can reduce the risk of atherosclerotic cardiovascular disease by about one third, there is still a need for additional risk-reducing therapies. Thus, a new idea was developed to raise HDL cholesterol as a treatment for atherosclerosis. With the finding of the high-HDL phenotype of a human genetic deficiency of cholesteryl ester transfer protein (CETP), a new class of drugs was developed, which inhibits CETP. CETP functions as a mediator for transfer of cholesteryl ester from HDL to VLDL/LDL, which is then cleared by LDL receptors in liver. Thus when CETP is inhibited, this transfer process is inhibited and the direct hepatic HDL clearance pathway takes over. This leads to less fractional clearance of HDL from plasma, which is beneficial for atherosclerosis. Although the absolute clearance rate of HDL remains the same, the key step for atherosclerosis, which is the removal of cholesterol from macrophage foam cells in artery wall by HDL, is reduced.

The most recently investigated CETP inhibitors are torcetrapib, anacetrapib, and dalcetrapib. In the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial, involving 15,000 patients at high risk for coronary heart disease, torcetrapib was clinically investigated. Unfortunately this trial was prematurely stopped due to the finding of an increase in cardiovascular events associated with an undiscovered off-target effect. Anacetrapib and dalcetrapib are still under active clinical investigation, since they lack the off-target effects of torcetrapib.

Tobacco smoking

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.

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.

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.

Lack of physical activity

Physical Activity
The following activities have similar benefits to health:
Activity Duration
Washing and waxing a car 45-60 minutes
Washing windows or floors 45-60 minutes
Playing volleyball 45 minutes
Wheeling self in wheelchair 30-40 minutes
Bicycling - 8 km 30 minutes
Pushing a pushchair - 2.5 km 30 minutes
Walking - 3 km 30 minutes
Swimming laps 20 minutes
Playing basketball 15-20 minutes

INTERHEART study showed that lack of exercise accounted for 12% of the population-attributable risk of a first MI. Recent evidence shows that physical activity of even a moderate degree can protect against coronary heart disease and all-cause mortality .The beneficial effects of physical exercise are a decrease of triglyceride levels and blood pressure, elevation of HDL, enhancement of insulin sensitivity and production of NO by the endothelial cells, and of course weight loss. Although large scale randomized primary prevention trials are lacking, physical activity should be promoted to anyone with risk of developing atherosclerosis.

Obesity

The American Heart Association has published an article, identifying obesity as an independent risk factor for coronary heart disease. Obesity is correlated with several risk factors for atherosclerosis such as hypertension, insulin resistance, glucose intolerance, decreased HDL serum level and hypertriglyceridemia. Weight loss is an important treatment to prevent many obesity-related risk factors for atherosclerosis that has just been mentioned.

Diet

A healthy diet reduces CVD risk. In general, when following the rules for a healthy diet, no dietary supplements are needed. N-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.[1]

Alcohol consumption

Alcohol is harmful when used chronic or excessive and can lead to various complications such as liver and heart failure, increased cancer risk, neurological complications and injuries. However despite these adverse effects, moderate drinking (US parameters; women: <2 drinks per day, men: <3 drinks per day) may have protective benefits with regards to coronary heart disease according to several prospective cohort studies. These studies showed that moderate drinking resulted in a reduction of risk in coronary heart disease by 40-70% compared to no or heavy drinkers. This beneficial effect was seen in various groups without or with known risk for coronary heart disease and adults older than 65 years old. In a meta-analysis study, alcohol drinkers had lower relative risk for CVD mortality (0.75, 95% CI 0.70-0.80), coronary heart disease mortality (0.75, 0.68-0.81) and incidence of coronary heart disease (0.71, 0.66-0.77) than nondrinkers.

Psychosocial factors

Mentioned by INTERHEART study, psychosocial factors may directly contribute to the early development of atherosclerosis. Psychological stress may directly damage endothelium and indirectly aggravate other common risk factors such as smoking, dyslipidemia and hypertension. Due to the difficulty in quantifying the extent of atherosclerosis, studies showing the relationship between stress and atherosclerosis have been limited. Epidemiologic studies have shown stronger link between psychosocial factors (loss of job, depression and bereavement) and MI and sudden death.

Estrogen Status

Women and men have different risk for cardiovascular diseases throughout life. For example, at young age, men have an estimated four- to fivefold higher risk than women. However this difference diminishes and the age point of no difference is strongly related to the moment of menopause. From this observation, it has been suggested that estrogen may play athero-protective roles, since the levels of estrogen declines after menopause. In premenopausal women, estrogen raises HDL levels and reduces LDL levels in blood. Estrogen can even exhibit antioxidant and antithrombotic properties and can improve endothelium-dependent vasodilatation.


In the past, hormone replacement therapy has been suggested by several studies due to the findings of potential athero-protective roles of estrogen. However, these findings were not confirmed in the randomized primary prevention study of the Women’s Health Initiative not in the HERS trial of secondary prevention. These studies showed that hormone replacement therapy (estrogen-progestin replacement) may increase cardiovascular risk in women and have no cardioprotective effect. Thus hormone replacement therapy is currently not recommended for reducing cardiovascular risk, due to its possible harmfulness consequences according to current clinical trials.

Biomarkers

Biomarkers can serve to identify patients with subclinical atherosclerotic disease that are at risk of developing cardiovascular events.

Homocysteine

Homocysteine is an intermediary amino acid produced during the conversion of methionine to cysteine. A significant positive correlation was found between the serum levels of homocysteine and the incidence of cardiovascular diseases. Although the clear mechanism of this correlation is undetermined, the overall result of the most current evidence suggests that homocysteine can modestly contribute to cardiovascular risk by inducing vascular injury. Homocysteine promotes oxidative stress, intimal thickening, disruption of elastic lamina, hypertrophy of smooth muscle cells, vascular inflammation platelet accumulation and production of occlusive thrombi when elevated in blood. Several conditions can cause hyperhomocystinemia, such as genetic defects in methionine metabolism or insufficient consumption of folic acid, which is involved in the methionine pathway. Such disorders cause premature and severe atherosclerosis. Despite this observational relationship, there is no data yet that proves reducing high serum level of homocysteine will lead to a decrease in atherosclerosis or its complications.

Lipoprotein A

Some studies have concluded that lipoprotein (a) is an independent risk factor for coronary artery disease. As lipoprotein (a) contains apo (a), which structurally resembles plasminogen, lipoprotein (a) interferes with fibrinolysis by competing with plasminogen binding with molecules. This leads to impairment of plasminogen activation, plasmin generation and lysis of fibrin clots. In addition, lipoprotein (a) binds with macrophages through a high-affinity receptor, promoting foam cell production and deposition of cholesterol in atherosclerotic plaques. As with homocysteine, not all studies support this theory of correlation, although increased risk of cardiovascular events appear to correlate with people with highest lipoprotein (a) serum level.

C-Reactive Protein and other markers of inflammation

Since the participation of inflammatory cells and mediators in atherosclerosis is well established, markers of inflammation have received a lot of attention. Several markers of inflammation such as C-reactive protein (CRP), fibrinogen and amyloid A are produced by hepatocytes in an acute phase under the influence of cytokines such as IL-6 when they mobilize from intima to the liver during the fatty streak stage. From these markers, CRP has shown the greatest association with atherosclerosis as a marker of low-grade systemic inflammation. A significant association between elevated CRP level in blood and prevalence of atherosclerosis has been shown in more than 30 epidemiologic studies. Different studies showed that higher basal CRP levels (four-fold higher) were found in patients with MI as compared to controls. Several studies have proposed that elevated plasma CRP can be an independent predictor for many cardiovascular diseases based on the result that CRP plasma value was able to predict the long-term risk of first MI, ischemic stroke or peripheral vascular disease among the male group. In addition, recent studies have shown that CRP also has a role as a mediator in atherogenesis. By inducing adhesion molecule expression and release of IL-6 and monocyte chemoattractant protein-1 via endothelial cells, CRP sustains the inflammatory state of atherosclerosis by recruiting monocytes and lymphocytes.

Infection

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.

Co-morbidity groups

Hypertension

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.


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

Figure 16. Lifestyle recommendations for hypertension
  • Weight reduction in overweight individuals
  • Reduction of salt consumption to < 6g daily
  • Restriction of alcohol intake to < 10-30g/day (men) and < 10-20g/day (women)
  • Regular physical activity
  • Smoking cessation


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.

Diabetes Mellitus

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.

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.

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