Atherosclerosis : Causes, Risk Factors, Pathogenesis, Morphology and Clinical Manifestations

the term atherosclerosis is derived from the greek ethero meaning gruel or waxy corresponding to the necrotic lipid core at the base of the atherosclerotic plaque and sclerosis for hardening or in duration referring to the fibrous cap of the atherosclerotic plaque simply atherosclerosis is a disease in large and medium-sized arteries caused by accumulation of lipids smooth muscle cells inflammatory cells an extracellular matrix within the intimal layer of arteries leading to the formation of masses called atherosclerotic plaques plaque buildup causes thickening of arterial walls leading to narrowing of its lumen which may cause ischemia to the organ or tissue supplied by that particular artery it is important to note that plaque buildup does not occur within a day or two it is a slow process that takes years to develop a plaque that can narrow the lumen of an artery so before we begin our discussion on atherosclerosis itself we may recall the normal anatomy of blood vessels let's take an artery for example an artery has three major layers these include tunica entema which is the innermost layer tunica media which is the middle layer and tunica adventitia which is the outermost layer tunica entema consists of the endothelium connective tissue and internal elastic lamina tunica media contains smooth muscle cells tunica adventitia is composed of the external elastic lamina connective tissue nerve fibers and blood vessels supplying the artery known as vasavasaram certain risk factors are associated with the development of atherosclerotic plaques some of them are not modifiable these are referred to as constitutional risk factors they are less controllable genetics is the most important constitutional risk factor certain inherited disorders are strongly associated with atherosclerosis familial hypercholesterolemia is an example however these disorders account for only a small percentage of atherosclerosis cases advancing age is another risk factor atherosclerosis usually remains clinically silent until middle age thus incidents of myocardial infarction due to atherosclerosis increases five-fold between the ages of 40 and 60. gender is another constitutional risk factor for atherosclerosis with all other factors being equal pre-menopausal women are relatively less affected and the incidence increases after menopause and in older ages prevalence in women is higher than in men others are modifiable risk factors they are acquired and usually controllable these include hyperlipidemia and more specifically hypercholesterolemia it is a major risk factor for development of atherosclerosis and is sufficient to induce atherosclerosis in the absence of other risk factors the major cholesterol component associated with increased risk is ldl cholesterol commonly known as bad cholesterol it distributes cholesterol to peripheral tissues by contrast hdl cholesterol commonly known as good cholesterol mobilizes cholesterol from developing and existing vascular plaques and transports to the liver for biliary excretion therefore higher levels of hdl cholesterol reduce the risk for atherosclerosis hypertension is another major risk factor for development of atherosclerosis hypertension can increase the risk of ischemic heart disease due to atherosclerosis by approximately 60 percent and it is a major cause for left ventricular hypertrophy cigarette smoking is a well-established risk factor for atherosclerosis in men and for the increasing incidence and severity of atherosclerosis in women prolonged smoking of one or more packs of cigarettes a day doubles the risk of atherosclerosis while quitting smoking will reduce the risk diabetes mellitus is associated with raised circulating levels of cholesterol and markedly increase the risk for atherosclerosis incidence of myocardial infarction due to atherosclerosis in diabetic patients is twice than in non-diabetics in addition diabetes mellitus is associated with an increased risk for stroke and atherosclerosis induced gangrene in the lower extremities additional risk factors include inflammation where there is increased secretion of cytokines leading to increased levels of serious proteins which ultimately causes activation of endothelial cells increased adhesiveness and inducing a prothrombic state c reactive protein levels strongly and independently predicts the risk of myocardial infarction stroke peripheral arterial disease and sudden cardiac death hyperhomocystinemia is another one serum homocysteine levels correlate with coronary atherosclerosis peripheral vascular disease stroke and venous thrombosis metabolic syndrome is another risk factor it is a condition associated with central obesity and increased release of cytokines from adipocytes which leads to insulin resistance hypertension dyslipidemia and hypercoagulability another additional risk factor is lack of exercise and living a competitive stressful life now let's discuss about the pathogenesis of atherosclerosis there are two major layers of anatheroma fibrous cap which is mainly composed of smooth muscle cells and collagen and elastin fibers additionally macrophages foam cells lymphocytes and neovascularization deep to the fibrous cap is the necrotic center which contains cell debris cholesterol crystals foam cells and sometimes calcium it is important to note that atherosclerotic lesions occur in the tunica entema of the arterial wall the pathogenesis of atherosclerosis is not completely understood currently accepted theory is the response to injury hypothesis according to this atherosclerosis is a chronic inflammatory and healing response of the arterial wall to endothelial injury and lesion progression occurs through interaction of modified lipoproteins monocyte-derived macrophages and t lymphocytes with endothelial cells and smooth muscle cells of the arterial wall according to this hypothesis sequence of atherosclerosis progression is as follows at first there should be endothelial injury or dysfunction that leads to increased vascular permeability leukocyte adhesion and thrombosis next there is accumulation of lipoproteins in the vessel wall mainly ldl and its oxidized forms as a result of endothelial dysfunction next monocytes adhere to the endothelium and they migrate into the entema to become macrophages after that these macrophages engulf lipids in the entema and become foam cells next there will be platelet adhesion followed by factor release from activated platelets macrophages and vascular wall cells which causes smooth muscle cell recruitment into the antema then these smooth muscle cells undergo proliferation and there will be production of extracellular matrix and recruitment of t cells finally there is accumulation of lipids both extracellular and intracellularly mainly within macrophages and smooth muscle cells this image is from the robin's textbook of pathology it shows the sequence of atherosclerosis progression first there should be endothelial injury due to some kind of abnormality such as hyperlipidemia hypertension toxins from cigarette smoke hemodynamic factors immune reactions and viruses this is denoted by number one in this picture then there is accumulation of ldl in the entema as denoted by number two number three indicates monocyte adhesion and migration to the entema followed by their engulfment of lipids to become foam cells number four denotes the recruitment of smooth muscle cells followed by their proliferation and extracellular matrix synthesis which is denoted by number five and number six indicates the deposition of intracellular and extracellular lipids endothelial injury is the basis of response to injury hypothesis two most important causes of endothelial dysfunction in the pathogenesis of atherosclerosis are hemodynamic disturbances simply the turbulent blood flow and hypercholesterolemia these factors cause increased endothelial permeability leukocyte adhesion and altered gene expression of the endothelial cells atherosclerotic lesions tend to occur at sites where the blood flow is turbulent such as osteo of exiting vessels branching points of arteries and along the posterior wall of the abdominal aorta here is an image showing the lesions developed at the ostrich of exiting vessels black arrows denote the lesions in this image the area circled by the black circle indicates a mild atherosclerotic lesion red circle indicates an ulcerated atherosclerotic plaque and the green one indicates an ulcerated plaque with superimposed thrombosis hypercholesterolemia occurs due to lipoprotein abnormalities including increased ldl cholesterol levels decreased hdl cholesterol levels and increased levels of abnormal lipoproteins lipoprotein abnormalities result either from mutations that lead to defects in apoproteins or lipoprotein receptors such as familial hypercholesterolemia or other underlying disorders that affect circulating lipid levels including nephrotic syndrome alcoholism hypothyroidism and diabetes mellitus lowering serum cholesterol either by diet or taking drugs slows down the rate of progression of atherosclerosis causes regression of some plaques and reduces the risk of cardiovascular events now let's discuss about the mechanism by which hyperlipidemia contributes to atherosclerosis chronic hyperlipidemia particularly hypercholesterolemia can directly impair the function of endothelial cells by increasing local production of reactive oxygen species oxygen free radicals accelerate nitric oxide decay causing reduction in its vasodilatory activity as a result of impaired endothelial function lipoproteins tend to accumulate in the tunica entema of the affected blood vessel due to the action of reactive oxygen species these lipoproteins become oxidized then macrophages derived from blood monocytes engulf these oxidized lipoproteins and become foam cells as modified lipoproteins cannot be completely degraded they tend to accumulate within macrophages smooth muscle cells also engulf these oxidized lipoproteins and become lipid latent foam cells not only that uptake of modified lipoproteins by these cells stimulates the release of growth factors cytokines and chemokines into the area which creates a vicious cycle of monocyte recruitment and macrophage activation accumulation of cholesterol and free fatty acids within macrophages and other cells induces a chronic inflammatory response at the site as macrophages engulf modified lipoproteins they secrete pro-inflammatory cytokines mainly interleukin-1 interleukin-1 in turn causes recruitment of more leukocytes into the site mainly monocytes and t cells recruitment and activation of macrophages and t cells causes local production of large amounts of cytokines and chemokines and recruitment of more and more leukocytes to the site activated t cells secrete gamma interferon which causes activation of macrophages endothelial cells and smooth muscle cells activated macrophages secrete reactive oxygen species which enhances the oxidation of lipoproteins at this point the lesions caused by accumulation of foamy macrophages and smooth muscle cells can be seen as tiny elevations in the vessel lumen these lesions are called fatty streaks they are not large enough to cause any flow disturbances within the affected artery activated leukocytes endothelial cells and smooth muscle cells secrete growth factors that promotes smooth muscle cell proliferation and extracellular matrix production which initiates the progression of fatty streak into a fibrotheroma which is commonly known as an atherosclerotic plaque this image shows a grown atherosclerotic plaque so as we have learned so far many of the lesions of atherosclerosis are attributable to the chronic inflammatory response in the vascular wall as mentioned in the previous slide smooth muscle cell proliferation and extracellular matrix synthesis converts the fatty streak into a mature atheroma several growth factors are involved in smooth muscle cell proliferation including platelet-derived growth factor which is secreted by platelets macrophages and endothelial cells fibroblast growth factor and transforming growth factor alpha these factors also stimulate smooth muscle cells to secrete extracellular matrix proteins mainly collagen which stabilizes the plaque conversely activated inflammatory cells in the plaque may increase the breakdown of extracellular matrix leading to unstable plaques now let's discuss a bit about the morphology of atherosclerotic plaques fatty streaks are composed of lipid filled foamy macrophages and smooth muscle cells majority of these lipids are cholesterol and cholesterol esters usually they begin as multiple minutes spots and combine together to form elongated streaks as mentioned before fatty streaks are not sufficiently raised to cause significant flow disturbances and it is important to note that not all fatty streaks develop into mature atheromas bathrometers plaques are white yellow in color and they intrude the lumen of the affected vessel they vary in size and can combine together to form larger masses they involve only a portion of the arterial wall and rarely circumferential thus on a cross section the lesions appear eccentric most of the time there are numerous plaques in a given vessel and most often their ages are different most extensively involved vessels are the lower abdominal aorta coronary arteries popliteal artery internal carotid artery and vessels of the circle of willis upper extremities are usually spared three principal components can be seen in an atheromatous plaque smooth muscle cells macrophages and t cells representing the cellular component collagen elastic fibers and proteoglycans representing the extracellular matrix and intracellular and extracellular lipids these components occur in varying proportions and configurations in different lesions typically there is a superficial fibrous cap composed mainly of smooth muscle cells and dense collagen beneath and to the side of the cap is a more cellular area containing macrophages and t cells this is denoted by the two black arrows to the sides of the plaque deep to the fibrous cap is an acrotic core containing lipids mainly cholesterol and cholesterol esters cellular debris fibrin and other plasma proteins and organized thrombi the cholesterol content is frequently present as crystalline aggregates as denoted by the black arrow in the middle these crystals are washed out during routine processing leaving behind empty clefts as you can see in this picture periphery of the atheromatous lesions demonstrate neovascularization most atheromas contain abundant lipid but some plaques are composed almost exclusively of smooth muscle cells and fibrous tissue plaques generally continue to change and progressively enlarge through cell death and degradation synthesis and degradation of extracellular matrix known as remodeling and organization of any superimposed thrombus most often atheromatous plaques undergo calcification which increases the risk for coronary artery disease and other ischemic events there are two types of plaques according to their stability stable plaques and vulnerable plaques stable plaques have a thick fibrous cap with minimal atheromatous core and have little inflammation inside therefore these plaques are less likely to rupture in contrast vulnerable plaques have relatively a thin fibrous cap with high lipid content in the necrotic core and there is greater inflammation inside therefore these plaques are more likely to rupture leading to extremely fatal manifestations of atherosclerosis and superimposed thrombosis finally let's discuss about the clinical manifestations of atherosclerotic disease the major targets of atherosclerosis are large elastic arteries including the aorta carotid arteries and iliac arteries and large and medium-sized muscular arteries including coronary arteries and popliteal artery symptomatic atherosclerotic disease most often involves the arteries supplying the heart brain kidneys and lower extremities major consequences of atherosclerosis are myocardial infarction stroke aortic aneurysms and peripheral vascular disease two main changes in plaques lead to clinical consequences of atherosclerosis atherosclerotic stenosis and acute plaque change in atherosclerotic stenosis there is gradual increase in plaque size causing chronic obstruction of vessel lumen once the size of the plaque reaches a sufficient degree it can cause tissue ischemia and infarction this is known as critical stenosis of the plaque in the coronary circulation this typically occurs when the lumen of the artery is 70 obstructed at this point patient develops chest pain on exertion so-called stable angina other manifestations of atherosclerotic stenosis include mesenteric artery obstruction and bowel ischemia sudden cardiac death chronic ischemic heart disease ischemic encephalopathy and intermittent claudication as a result of reduced perfusion to the lower extremities acute plaque changes fall into three principle categories rupture or fissuring exposing the highly thrombogenic plaque constituents erosion or ulceration exposing the thrombogenic sub endothelium and bleeding into the plaque expanding its volume acute plaque change leads to thrombosis on the damaged endothelium leading to severe obstruction of the vessel lumen and this will ultimately lead to ischemia to the affected organ or tissue and if the thrombus completely occludes the vessel lumen infarction results major consequences of acute plaque change include acute coronary syndrome and stroke vulnerable plaques are more susceptible to undergo acute plaque change because they have a thin fibrous cap and increased inflammation in the core in addition extrinsic factors like hypertension increased platelet reactivity increased catecholamines in blood due to stress or other factors and vessel spasm can trigger acute plaque changes okay that's all i wish to discuss in this video hope you have learned something from it if you have any question or doubt regarding this topic feel free to post them in the comment section thanks for watching see you soon in the next video