Pathology of Atherosclerosis PDF

Pathology of atherosclerosis Dr. Aileen Azari-Yam M.D., Ph.D. 1 Objectives Definition and classification of arteriosclerosis Pathogenesis and stages of atherosclerosis Atherosclerosis risk factors and mechanisms by which they affect atherogenesis Morphol...

Pathology of atherosclerosis Dr. Aileen Azari-Yam M.D., Ph.D. 1 Objectives Definition and classification of arteriosclerosis Pathogenesis and stages of atherosclerosis Atherosclerosis risk factors and mechanisms by which they affect atherogenesis Morphologic and clinicopathologic changes in atherosclerosis Complications of atherosclerosis Mechanism of the effect of statins 2 3 main types of arteries Elastic arteries Have more elastic tissue than muscular arteries and are located close to the ♥. Examples: Aorta and pulmonary artery. Muscular arteries Distribute blood to various parts, have lots of smooth muscle: femoral and coronary arteries. Arterioles Small arteries that deliver blood to capillaries, important in determining the blood pressure 3 Arteriosclerosis Arteriosclerosis literally means “hardening of the arteries” A generic term for arterial wall thickening and loss of elasticity There are 4 general patterns, with different consequences: Arteriolosclerosis Mönckeberg medial sclerosis Fibromuscular intimal hyperplasia Atherosclerosis 4 Arteriolosclerosis Affects small arteries and arterioles >>> downstream ischemic injury The two anatomic variants: Hyaline arteriolosclerosis Hyperplastic arteriolosclerosis 5  Mönckeberg medial sclerosis Characterized by calcifications of the medial walls of muscular arteries, typically starting along the internal elastic membrane Adults > 50 are most commonly affected The calcifications do not advance to the lumen The calcifications are usually not clinically significant. 6 Fibromuscular intimal hyperplasia Occurs in muscular arteries larger than arterioles Cause: Inflammation (as in a healed arteritis or transplant-associated arteriopathy) or Mechanical injury (e.g., associated with stents or balloon angioplasty) Considered as a healing response The vessels become stenotic >>> in-stent restenosis Major long-term limitation of organ transplants 7 Atherosclerosis Causes more morbidity and mortality than any other disease Coronary artery disease is an important manifestation of the disease Significant morbidity and mortality are also caused by aortic and carotid atherosclerotic disease and stroke. 8 Atherosclerosis The likelihood of atherosclerosis is determined by the combination of: Acquired risk factors (e.g. cholesterol levels, smoking, hypertension) Inherited risk factors e.g. LDL receptor gene mutations Gender- and age-associated risk factors 9 Atheroma AKA atheromatous or atherosclerotic plaques Intimal lesions that protrude into vessel lumens Consists of a raised lesion with a soft core of lipid (mainly cholesterol and cholesterol esters) covered by a fibrous cap 10 Basic structure of an atherosclerotic plaque An intimal-based process with a complex interplay of cells and extracellular materials. Plaques can cause a ↓ in the underlying smooth muscle cells. 11 Atherosclerotic plaques Mechanical obstruction of the blood flow Rupture >>> catastrophic obstructive vascular thrombosis Increase the diffusion distance from the lumen to the media >>> ischemic injury of the vessel wall >>> weakening of the vessel wall >>> aneurysm formation 12 Risk Factors 13 Genetics Family history: the most important independent risk factor for atherosclerosis Certain Mendelian disorders are strongly associated with atherosclerosis (e.g., familial hypercholesterolemia), but they are rare. The more common familial predisposition to atherosclerosis and ischemic heart disease is polygenic. 14 Age MI incidence increases fivefold between ages 40 and 60 Death rates from ischemic ♥ disease rise with age. 15  Age association is more than just the accumulated vascular injury over the years. Age CHIP= clonal hematopoiesis of indeterminate potential Aging >>> outgrowth of CHIPs carrying pro-proliferative mutations >>> affect DNA modifications and transcriptional regulation (e.g., TET2 encoding an enzyme that converts methylcytosine to 5-hydroxymethylcytosine) >>> influence the risk of developing hematologic malignancies CHIP >>> impacts the inflammatory response of mononuclear cells >>> atherogenesis >>> ↑ cardiovascular mortality 16 Gender MI and other complications of atherosclerosis are uncommon in premenopausal women unless they have: Diabetes Hyperlipidemia Severe hypertension After menopause, the incidence of atherosclerosis-related diseases increases and at older ages exceeds that of men. Favorable influence of estrogen ??? Estrogen replacement did not show any benefit 17 Hyperlipidemia (hypercholesterolemia) A major risk factor for atherosclerosis LDL cholesterol (“bad cholesterol”) is associated with increased risk LDL delivers cholesterol to peripheral tissues HDL mobilizes cholesterol from the periphery (including atheromas) to the liver for catabolism and biliary excretion. Higher levels of HDL (“good cholesterol”) >>> ↓ risk 18 Hypercholesterolemia, management Dietary and pharmacologic interventions to lower LDL Exclusively raising HDL is not effective. Contribution of most dietary fats to atherosclerosis is minimal. Omega-3 fatty acids (abundant in fish oils) are beneficial. Trans fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles. 19 Types of fatty acids 20 Statins, mechanism of action Statins >>> inhibition of HMG-CoA reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis >>> ↓ cholesterol >>> ↓ MI Some of the benefit of the statins is due to reducing inflammation 21 Hypertension, Cigarette, Diabetics Hypertension >>> ↑ risk of ischemic ♥ disease by 60% Chronic hypertension is the most common cause of left ventricular hypertrophy >>> LVH is a surrogate marker for cardiovascular risk Cigarette smoking doubles the death rate from ischemic ♥ disease. Smoking cessation reduces that risk substantially. Diabetes mellitus >>> hypercholesterolemia >>> ↑ risk of atherosclerosis MI is twice as high in diabetics Increased risk of strokes Increased risk of atherosclerosis-induced gangrene of the lower extremities 22 Additional Risk Factors 20% of all cardiovascular events occur in the absence of major risk factors (e.g., hypertension, hyperlipidemia, smoking, or diabetes). Other factors : Inflammation Hyperhomocysteinemia Metabolic syndrome Lipoprotein a [Lp(a)] Factors affecting hemostasis Other factors 23 Inflammation Present in all stages of atherogenesis Assessment of systemic inflammation has become important in risk stratification. Inflammation is intimately linked with atherosclerotic plaque formation and rupture. Inflammation markers correlate with ischemic ♥ disease CRP (an acute phase reactant synthesized by the liver) is the most stable and simplest to measure 24 Inflammation, CRP level Plasma CRP is a strong marker of risk for MI, stroke, peripheral arterial disease, and sudden cardiac death, even among apparently healthy individuals CRP levels are now incorporated into risk stratification algorithms. Risk reduction measures >>> ↓ CRP Smoking cessation Weight loss Exercise Statin administration 25 Hyperhomocysteinemia Serum homocysteine levels > than 15 μmol/L correlate with: Coronary atherosclerosis Peripheral vascular disease Stroke Venous thrombosis Homocystinuria (AR) >>> ↑ circulating homocysteine (>100 μmol/L) and is associated with premature vascular disease 26 Homocystinuria 27 Metabolic syndrome A proinflammatory state associated with central obesity Characteristics: Insulin resistance Hypertension Dyslipidemia (↑ LDL and ↓ HDL) Hypercoagulability Dyslipidemia, hyperglycemia, and hypertension all are cardiac risk factors Systemic hypercoagulable and proinflammatory state >>> endothelial dysfunction and/or thrombosis. 28 Lipoprotein a [Lp(a)] An altered form of LDL that contains apolipoprotein a = apo (a) linked to the apolipoprotein B-100 Lp(a) levels are associated with coronary and cerebrovascular disease risk 29 Lp(a) level The desirable and optimal level >> ↓ clot breakdown Thrombin >>> both procoagulant and proinflammatory effects >>> local vascular pathology PAI-1 is a serine protease inhibitor (serpin) that functions as the principal inhibitor of tissue-type plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and hence fibrinolysis 31 Other factors Lack of exercise Competitive, stressful lifestyle (type A personality) Obesity (being complicated by hypertension, diabetes, hypertriglyceridemia, and decreased HDL) 32 Pathogenesis of Atherosclerosis “Response to injury” hypothesis Integrates the risk factors Views atherosclerosis as a chronic inflammatory and healing response of the arterial wall to endothelial injury Interaction of modified lipoproteins, macrophages, and T lymphocytes with ECs and SMCs of the arterial wall >>> Lesion progression 33  Atherosclerosis progression sequence Endothelial injury and dysfunction >>> ↑ vascular permeability, leukocyte adhesion, and thrombosis Accumulation of LDL and its oxidized forms in the vessel wall Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells Platelet adhesion Factor release from activated platelets, macrophages, and vascular wall cells, inducing SMC recruitment, either from the media or from circulating precursors SMC proliferation, ECM production, and recruitment of T cells Lipid accumulation extracellularly and within cells (macrophages & SMCs) Calcification of ECM and necrotic debris late in the pathogenesis 34 Endothelial injury The cornerstone of the response-to-injury hypothesis Begins at sites of morphologically intact endothelium with features of endothelial dysfunction: Increased permeability Enhanced leukocyte adhesion Altered gene expression 3 most important causes of EC dysfunction: Hemodynamic disturbances Hypercholesterolemia Other causes of EC dysfunction: Inflammation - Toxins from cigarette smoke - Homocysteine - Local production of inflammatory cytokines 35 Hemodynamic Disturbances Evidence: Plaques do not occur randomly, but locate at the ostia of exiting vessels, branch points, and along the posterior abdominal aorta where flow patterns are disturbed and non-laminar. 36 Hemodynamic Disturbances Laminar non-turbulent flow >>> ↑ production of transcription factor KLF2 that turn on atheroprotective genes and turn off inflammatory gene transcription. Some of the atheroprotective effects of statins occur through KLF2 upregulation. Turbulent, non-laminar flow >>> genetic transcription that makes those sites atheroprone. 37 Hypercholesterolemia Dyslipoproteinemias : (1) Increased LDL cholesterol levels (2) Decreased HDL cholesterol levels (3) Increased abnormal Lp(a) Causes: Mutations in apoproteins Mutations in lipoprotein receptors Underlying disorders that affect circulating lipid levels: Nephrotic syndrome Alcoholism Hypothyroidism Diabetes mellitus 38 Hypercholesterolemia The evidence implicating hypercholesterolemia in atherogenesis: The dominant lipids in atheromatous plaques are cholesterol and cholesterol esters. Genetic defects in lipoprotein uptake and metabolism that cause hyperlipoproteinemia are associated with accelerated atherosclerosis. Thus familial hypercholesterolemia, caused by mutations affecting the LDL receptors and consequent inadequate hepatic LDL uptake and catabolism, can precipitate MI before age 20 in those homozygous for the mutation. Similarly, accelerated atherosclerosis occurs in animal models with engineered deficiencies in apolipoproteins or LDL receptors. Epidemiologic analyses demonstrate a significant correlation between the severity of atherosclerosis and the levels of total plasma cholesterol or LDL. Lowering cholesterol by diet or drugs slows the rate of progression of atherosclerosis, causes regression of some plaques, and reduces the risk of cardiovascular events. 39 Mechanisms The mechanisms by which hyperlipidemia contributes to atherogenesis: Impaired EC function Modified LDL 40 Mechanisms, impaired EC function Hypercholesterolemia >>> ↑ local reactive oxygen species >>> directly impair EC function Oxygen free radicals cause Membrane damage Mitochondrial damage NO decay acceleration >>> ↓ its vasodilator activity 41 Mechanisms, modified LDL Chronic hyperlipidemia >>> lipoproteins accumulation within the intima >>> lipoprotein oxidization by free radicals produced by inflammatory cells Such modified LDL is then accumulated by macrophages through a variety of scavenger receptors (distinct from the LDL receptor). Because the modified lipoproteins cannot be completely degraded, chronic ingestion leads to the formation of lipid-filled macrophages called foam cells SMCs can similarly transform into lipid-laden foam cells by ingesting modified lipids through LDL receptor–related proteins. The binding and uptake of modified LDL also stimulate the release of growth factors, cytokines, and chemokines that create a vicious inflammatory cycle of monocyte recruitment and activation. The early lesions containing lipid-filled macrophages are called fatty streaks. Modified lipoproteins are toxic to ECs, SMCs, and macrophages 42 Inflammation Chronic inflammation contributes to the initiation and progression of atherosclerosis. Inflammation is triggered by the accumulation of cholesterol crystals and free fatty acids in macrophages and other cells. These cells sense the presence of abnormal materials via cytosolic innate immune receptors that are components of the inflammasome. Inflammasome activation leads to the production of the proinflammatory IL-1, which recruits and activates macrophages and T lymphocytes >>> local production of cytokines and chemokines >>> recruitment and activation of more inflammatory cells Activated macrophages >>> reactive oxygen species >>> LDL oxidation and elaboration of growth factors that drive SMC proliferation Activated T lymphocytes in the growing intimal lesions elaborate interferon-γ >>> activates macrophages, ECs and SMCs 43 Smooth Muscle Proliferation and Matrix Synthesis Intimal SMC proliferation and ECM deposition convert a fatty streak into a mature atheroma. Growth factors implicated in SMC proliferation and ECM synthesis: PDGF, released by locally adherent platelets & macrophages, ECs and SMCs Fibroblast growth factor TGF-α These factors also stimulate SMCs to synthesize ECM (notably collagen), which stabilizes atherosclerotic plaques. In contrast, activated inflammatory cells in atheromas may increase the breakdown of ECM components resulting in unstable plaques. 44 Overview Atherosclerosis is a chronic inflammatory response—and ultimately an attempt at vascular “healing”—driven by a variety of insults including EC injury, lipid oxidation, lipid accumulation, and inflammation. Atheromas are dynamic lesions consisting of dysfunctional ECs, proliferating SMCs, and admixed T lymphocytes and macrophages. All four cell types are capable of liberating mediators that can influence atherogenesis. At early stages, intimal plaques are just aggregates of SMCs, macrophages, and foam cells; death of these cells releases lipids and necrotic debris. 45 Overview With progression, the atheroma is modified by ECM synthesized by SMCs Connective tissue is particularly prominent on the intimal aspect forming a fibrous cap. Lesions have a central core of lipid-laden cells and fatty debris that can become calcified. The plaque grows and advances to the lumen >>> compromises blood flow The plaque can compress the media >>> degeneration of the media The plaque can erode or rupture to expose thrombogenic factors >>> thrombus formation >>> acute vascular occlusion 46 Atherogenesis 47  The role of cholesterol crystals in inflammasome activation and IL-1 production in atheroma Oxidized LDL >>> activation of subendothelial macrophages Uptake of oxidized LDL >>> cholesterol crystallization >>> assembly of the precursor components into an active inflammasome complex >>> proteolytic activation of the pro-interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) 48  Mechanism of inflammasome activation Oxidized LDL >>> activation of subendothelial macrophages through toll-like receptor (TLR) >>> activation of NF-κB transcription factor >>> production of proinflammatory mediators, including interleukin precursors and the components of the NLRP3 inflammasome 49 NLRP3 inflammasome Besides atherosclerosis, the activation of NLRP3 inflammasome is Comprises: known to contribute to the development of rheumatoid arthritis NLRP3 protein and Alzheimer disease. ASC pro-caspase-1 Multiple mechanisms activate the inflammasome such as mitochondrial dysfunction, mitochondrial active oxygen species release, lysosomal disruption, etc. Low-grade basal NLRP3 inflammasome activation promotes the development of various chronic cardiovascular diseases such as hypertension and atherosclerosis Inhibiting the activation of the NLRP3 inflammasome is crucial for the treatment of cardiovascular disease. 50  Sequence of cellular interactions in atherosclerosis Hyperlipidemia, hyperglycemia, hypertension, MCP-1: monocyte chemoattractant protein-1 etc. >>> endothelial dysfunction >>> platelet and monocyte adhesion >>> cytokine and growth factor release >>> smooth muscle cell migration and proliferation In response to cytokines and chemokines, smooth muscle cells migrate to the intima, proliferate, and produce extracellular matrix including collagen and proteoglycans. 51 Morphology, Fatty streaks Composed of lipid-filled foamy macrophages Beginning as flat yellow macules >>> coalesce into elongated streaks >= 1 cm The lesions are not raised and do not cause flow disturbance. Not all are destined to become plaques. 52  Fatty streak, a collection of foamy macrophages in the intima. Fatty streak in an hypercholesterolemic Aorta with fatty streaks at the ostia of branch vessels rabbit with intimal foamy macrophages 53 Atherosclerotic plaque The key processes in atherosclerosis: Intimal thickening Lipid accumulation Yellow-tan and are raised Thrombus over ulcerated plaques will be red-brown. Vary in size but can coalesce to form larger lesions Patchy and rarely circumferential involving only a portion of the arterial wall >>> On cross-section, the lesions appear eccentric. The focality is attributable to the differences of vascular hemodynamics. 54  Atherosclerotic plaque in the aorta (A) Mild atherosclerosis composed of fibrous plaques (B) Severe disease with diffuse, complicated lesions including an ulcerated plaque (open arrow) and a lesion with overlying thrombus (closed arrow). 55 Atherosclerotic plaque Local flow disturbances, such as non-laminar flow (turbulence) at branch points, make certain portions of a vessel wall more susceptible to plaque formation. Atherosclerotic lesions are initially focal and sparsely distributed but tend to enlarge and become more numerous and broadly distributed. Lesions at various stages coexist in any vessel. The most extensively involved vessels: Lower abdominal aorta and iliac arteries Coronary arteries Popliteal arteries Internal carotid arteries Vessels of the circle of Willis Upper extremities are relatively spared Mesenteric and renal arteries are relatively spared except at their ostia. 56 Atherosclerotic plaque Plaques have 4 principal components: (1) Cells including variable numbers of SMCs, macrophages, and T lymphocytes (2) ECM including collagen, elastic fibers, and proteoglycans (3) Intracellular and extracellular lipids (4) Calcifications in later stage plaques Typically, there is a superficial fibrous cap composed of SMCs and relatively dense collagen. Beneath and to the side of the cap (the “shoulder”) is a more cellular area containing macrophages, T lymphocytes, and SMCs. 57  Atherosclerotic plaque Deep to the fibrous cap is a necrotic core containing: Lipid (primarily cholesterol and cholesterol esters) The cholesterol content as crystalline aggregates that are washed out during routine tissue processing and leave behind only empty “clefts.” Debris from dead cells Foam cells (lipid-laden macrophages and lipid-laden SMCs) Fibrin Thrombus in varying degrees of organization Other plasma proteins 58 Atherosclerotic plaque The periphery of the lesions demonstrate neovascularization (proliferating small blood vessels) Most atheromas contain abundant lipid, but some plaques (“fibrous plaques”) are composed almost exclusively of SMCs and fibrous tissue, which can be heavily calcified. Plaques continue to change and enlarge as a consequence of superimposed thrombus, calcification, … 59  Pathologic changes of plaques Plaques are susceptible to clinically important pathologic changes. The thickness and ECM content of the overlying fibrous cap will impact the stability or fragility of the plaque and its tendency to undergo secondary changes. Rupture, ulceration, or erosion of the surface of plaques exposes the blood stream to highly thrombogenic substances and leads to thrombosis, which can occlude the lumen. If the patient survives, the thrombus may organize and become incorporated into the growing plaque. Hemorrhage into a plaque. Rupture of the fibrous cap or of the thin-walled vessels in the areas of neovascularization can cause intra-plaque hemorrhage; a hematoma may expand the plaque or induce plaque rupture. Atheroembolism. Plaque rupture can discharge atherosclerotic debris into the blood stream, producing microemboli. Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes weakness and potential rupture. 60  Histologic features of atheroma in the coronary artery Fibrous cap (F) central necrotic core (C) containing cholesterol and other lipids. The lumen (L) has been moderately compromised. A segment of the wall is plaque-free >>> the lesion is “eccentric” Collagen has been stained blue (Masson trichrome stain). 61 Histologic features of atheroma Higher power view, stained for elastin (black): the internal and external elastic membranes are attenuated and the media of the artery is thinned under the most advanced plaque (arrow). 62  Histologic features of atheroma Higher magnification at the junction of the fibrous cap and core showing scattered inflammatory cells, calcification (arrowhead), and neovascularization (small arrows). 63 Consequences of Atherosclerotic Disease MI (♥ attack) Cerebral infarction (stroke) Aortic aneurysms Peripheral vascular disease (gangrene of the legs) 64 Consequences of Atherosclerotic Disease Major targets of atherosclerosis Large elastic arteries (e.g., aorta, carotid, and iliac arteries) Large- and medium-sized muscular arteries (e.g., coronary and popliteal arteries) Symptomatic atherosclerotic disease most often involves the arteries supplying the ♥ Brain Kidneys Lower extremities 65 Features of atherosclerotic lesions that are typically responsible for the clinicopathologic manifestations: 66 Atherosclerotic Stenosis In small arteries, plaques can gradually occlude vessel lumens >>> compromising blood flow >>> ischemic injury Critical stenosis is the stage at which the occlusion is sufficiently severe to cause tissue ischemia. In the coronary (and other) circulations, this occurs when the occlusion produces a 70% to 75% decrease in luminal cross-sectional area With this degree of stenosis, chest pain may develop with exertion (stable angina). 67  Stenosis = narrowing Atherosclerotic Stenosis Chronically diminished arterial perfusion >>> Mesenteric occlusion and bowel ischemia Sudden cardiac death Chronic ischemic ♥ disease Ischemic encephalopathy Intermittent claudication (diminished perfusion of the extremities) Intermittent claudication is in the pain in calf (mostly), the thigh and buttock, induced by exercise and relieved by rest. Intermittent claudication occurs as a result of muscle ischemia during exercise caused by obstruction to arterial flow. Other examples: jaw claudication 68 Atherosclerotic Stenosis If stenosis occurs slowly >>> Enlarging of smaller adjacent vessels Creation of collateral circulation by adjacent vessels >>> partial compensation to perfuse the organ 69 Acute Plaque Change Partial or complete vascular thrombosis >>> Plaque erosion or rupture >>> acute tissue infarction (e.g., myocardial or cerebral infarction) Plaque changes fall into three general categories: Rupture/fissuring, exposing highly thrombogenic plaque constituents that activate coagulation and induce thrombosis that is often completely occlusive Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood, less-frequently inducing fully occlusive thrombosis Hemorrhage into the atheroma, expanding its volume 70 Atherosclerotic plaque rupture (A) Plaque rupture without superimposed thrombus in a patient who died suddenly. (B) Acute coronary thrombosis superimposed on an atherosclerotic plaque with focal disruption of the fibrous cap, triggering fatal MI. In both (A) and (B), an arrow points to the site of plaque rupture. 71 Plaque formation, activities, & outcomes Thin cap plaques are the most prone to plaque rupture, generally leading to sudden cardiac death. Stable plaques can undergo surface erosion and thrombosis, rapidly expanding the plaque size and leading to more prominent calcifications >>> sudden cardiac death. Extensive narrowing of the luminal diameter from large plaques generally results in critical stenosis, reducing blood supply to the heart and resulting in angina. 72 Plaques responsible for MI Often asymptomatic until a sudden, unpredictable change Most plaques that undergo abrupt disruption and coronary occlusion previously showed only mild to moderate noncritical luminal stenosis. A large number of asymptomatic adults may be at risk for a catastrophic coronary event. Standard angiography is inadequate to visualize them until after the fact. 73 Plaque rupture Plaques rupture when they are unable to withstand mechanical stresses generated by vascular shear forces. The events that trigger abrupt changes in plaques and subsequent thrombosis are complex and include both intrinsic factors (e.g., plaque structure and composition) and extrinsic elements (e.g., blood pressure, platelet reactivity, and vessel spasm). 74 Plaque rupture The fibrous cap undergoes continuous remodeling that can stabilize the plaque or, conversely, render it more susceptible to rupture. Collagen is the major structural component of the fibrous cap and accounts for its mechanical strength and stability; the balance of collagen synthesis versus degradation affects cap integrity. Thus plaques with thin fibrous caps and active inflammatory cells over a necrotic core are more likely to rupture; these are referred to as “vulnerable plaques” 75  Vulnerable and stable plaque Stable plaques have thickened and densely collagenous fibrous caps with minimal inflammation and atheromatous core. Vulnerable plaques have thin fibrous caps, large lipid cores, and increased inflammation. 76 Collagen in atherosclerotic plaque Collagen in atheromas is produced by SMCs Loss of SMCs >>> a less strong cap Macrophages and SMCs >>> matrix metalloproteinases (MMPs) >>> collagen turnover control ECs, SMCs, and macrophages >>> tissue inhibitors of metalloproteinases (TIMPs) >>> regulation of MMP activity Plaque inflammation >>> ↑ collagen degradation and ↓ collagen synthesis >>> ↓ mechanical integrity of the fibrous cap 77 Inflammation & statins Cholesterol deposits >>> inflammation >>> ↑ plaque destabilization. Statins reduce cholesterol levels >>> therapeutic effect Statins >>> ↓ inflammation in plaque >>> ↑ plaque stabilization >>> therapeutic effect 78 Pleiotropic effects of statins in atherosclerotic disease DOI: 10.2174/1568026614666141203130324 79 Influences extrinsic to plaques that contribute to acute plaque changes Adrenergic stimulation >>> ↑ systemic blood pressure or induce local vasoconstriction >>> ↑ physical stress on the plaque Intense emotional stress can also contribute to plaque disruption ↑ incidence of sudden death associated with natural or other disasters, such as earthquakes and the September 11, 2001, attack on the World Trade Center. 80  Circadian periodicity for onset of MI Morning awakening and rising >>> adrenergic stimulation >>> blood pressure spikes (followed by heightened platelet reactivity) >>> acute MI events peaking between 6 a.m. and 12 noon 81 Thrombosis, central factor in acute coronary syndromes Thrombosis, partial or total, associated with a disrupted plaque is a central factor in acute coronary syndromes. The most serious form: complete occlusion In other coronary syndromes, luminal obstruction by the thrombus is incomplete and may even wax and wane with time. Thrombin and other factors associated with thrombosis are potent activators of SMCs and can thereby contribute to the growth of lesions. 82 Vasoconstriction at sites of atheroma Vasoconstriction >>> ↓ lumen size >>> ↑ local mechanical forces >>> plaque disruption Vasoconstriction are stimulated by: (1) circulating adrenergic agonists (2) locally released platelet contents (3) EC dysfunction with impaired secretion of endothelial-derived relaxing factors (NO) relative to contracting factors (endothelin) (4) mediators released from perivascular inflammatory cells 83 Atherosclerosis, key concepts An intimal-based lesion composed of a fibrous cap and an atheromatous core Constituents of the plaque: SMCs, ECM, inflammatory cells, calcifications, lipids, and necrotic debris. Atherogenesis is driven by an interplay of vessel wall injury and inflammation. The multiple risk factors for atherosclerosis all cause EC dysfunction and influence inflammatory cell and SMC recruitment and stimulation. 84 Atherosclerosis, key concepts Atherosclerotic plaques develop and generally grow slowly over decades. Stable plaques >>> narrowing vessel lumens >>> symptoms related to chronic ischemia Unstable plaques >>> potentially fatal ischemic complications related to Acute rupture Thrombosis Embolization Stable plaques have a dense fibrous cap, minimal lipid accumulation and little inflammation “Vulnerable” unstable plaques have thin caps, large lipid cores, and dense inflammatory infiltrates. 85 Tha nk s! Shiraz., Iran 86