Atherosclerosis
Chapter Atherosclerosis
Normal arterial vessel
Figure 1 normal arterial wall
Figure 2 summary of the comparison between normal and atherosclerotic arterial wall
Three layers of arterial vessel
The arterial vessel consists of intima, media and outer adventitia. (see Figure 1)
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.
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.
The outer adventitia provides nourishment to the cells of the vessel by means of nerves, lymphatics and vasa vasorum.
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)
Role of cellular components in atherogenesis
Endothelial cells
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.
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.
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.
In conclusion, the normal arterial endothelium implements good barrier with net anticoagulant properties, net relaxation of the smooth muscle and anti-inflammatory trait.
Vascular smooth muscle cells
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.
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.
Extracellular matrix
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.
Atherosclerotic arterial vessel
Figure 3 summary of 3 pathologic stages of atherosclerosis
Three pathologic stages of atherogenesis
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)
Fatty streak
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.
The distinctive hallmark of the fatty streak is the initiation of migration of leukocytes and formal cell formation caused by proinflammatory mediators.
Endothelial dysfunction
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.
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.
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.
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.
Lipoprotein entry and modification
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.
Leukocyte recruitment
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.
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
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.
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.
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.
Extracellular matrix metabolism
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
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.
Thrombogenic potential
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.
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).
Complications of atherosclerosis
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.
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:
- Atherosclerotic plaque can be calcified, which leads to higher rigidity of the vessel wall and therefore favor its fragility.
- 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.
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.
Risk factors of atherosclerosis
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
| Figure 4. Recommendations in relations to dyslipidemia. |
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General recommendations:
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Specific diet recommendations:
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Tabacco smoking
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.
Lack of physical activity / obesity
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
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.
Co-morbidity groups
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.
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.
| Figure 5. Lifestyle recommendations for hypertension. |
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* Weight reduction in overweight individuals
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Diabetes mellitus
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.
There are several possible mechanisms executed by diabetes that makes 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 myocardial infarction 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.
Metabolic syndrome
The metabolic syndrome entails a clustering of risk factors, such as hypertension, hypertriglyceridemia, reduced HDL, cellular insulin resistance and visceral obesity. Within both groups of diabetes and non-diabetes, this syndrome is associated with a high risk for atherosclerosis. Even before developing diabetes, this syndrome appears to promote atherogensis due to insulin resistance.
Biomarkers
One out of five cardiovascular events occur in patients without any of the well-established risk factors described in last sections. In order to understand this phenomenon and the pathogenesis of atherosclerosis, studies of the biomarkers of atherosclerosis have recently emerged.
Homocysteine
Homocyteine is an intermediary amino acid formed by 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 promoting oxidative stress, vascular inflammation, and platelet adhesiveness 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. Despite this observational relationship, there is no data yet that proves reducing high serum level of homocysteine will lead to marked down 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, higher serum level of lipoprotein (a) may attribute to competition with normal plasminogen activity, leading to decrease of lysis of fibrin clots. 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 atherosclerosis involves inflammation at every development stage, markers of inflammation have received a lot of attention from the researchers. Several markers of inflammation such as C-reactive protein (CRP), fibrinogen and amyloid A are produced when cytokines such as IL-6 mobilize to the liver from intima during fatty streak stage. From these markers, CRP has shown the greatest association with atherosclerosis as a marker of low-grade systemic inflammation. A large randomized trial in the healthy population, showed that higher basal CRP levels are related to increased risk of adverse cardiovascular outcomes, independent of cholesterol level in blood. Several prospective studies suggest that CRP can be an independent predictor for many cardiovascular diseases such as myocardial infarction, stroke, peripheral artery disease, and sudden cardiac death. Also,lrecent studies have shown that CRP also has a role of a mediator of atherogenesis by activating complement to sustain inflammatory state of atherosclerosis.
Infection
A variety of infectious agents such as Chlamydia were identified in the lesions of atherosclerosis and this observation raised a suggestion that these infectious agents may contribute to atherogenesis. However, to date the definite proof of this theory is lacking and also there haven’t been any clinical studies that showed significant relationship between the antibiotic treatment against these infectious agents and the risk of cardiac events of the survivors of acute coronary syndromes. Chlamydia is a strong candidate among other infectious agents, since they produce heat shock protein 60 (HSP-60) that activates macrophages and stimulates the production of matrix metalloproteinases. Furthermore, HDP-60 can also stimulate foam cell formation, lipoprotein oxidation, and increased pro-coagulant activity, which are the major attributing components of atherosclerosis. Although there is no evidence to date, some researchers believe that infections can cause endothelial injury and inflammation that can lead to initiation or exacerbation of atherosclerosis.
| Figure 6. Risk factors of atherosclerosis |
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* Dyslipidemia
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