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Atherosclerosis - Pathogenesis
- 1. ATHEROSCLEROSIS 27/02/2012 Supervisor- Dr. Ndungú Presenter- Taseer Feroze Din
- 2. OBJECTIVES Introduction Definition Epidemiology Risk factors Pathogenesis Response-to-injury Hypothesis Complications
- 3. INTRODUCTION Definition : Atherosclerosis (art eriosclerotic vascular disease) is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol. In Greek, athere means gruel, and skleros means hard.
- 4. EPIDEMIOLOGY- UBIQUITOUS AMONG MOST DEVELOPED NATIONS...’’LIFESTYLE AND DIET DISEASE’’ MAJOR RISKS LESSER OR UNCERTAIN RISKS Multiplicative Nonmodifiable Obesity effect: •2 risk factors •Increasing age Physical inactivity increase risk •Male gender Stress (type A personality) fourfold •Family History Postmenopausal estrogen •3 risk factors def. increase the •Genetic Abnormalities High Carbohydrate intake rate of MI seven Potentially Controllable Lipoprotein (a) times! •Hyperlipidemia Hardened (trans) unsaturated fat intake •Hypertension Chlamydia pneumoniae infection •Cigarette smoking •Diabetes •C-reactive protein
- 5. ATHEROSCLEROSIS IN AFRICA CVD now the second most common cause of death- accounting for 11% of total deaths (WHO 1999) Projections from the Global Burden of Disease Project suggest that from 1990 to 2020, the burden of CVD faced by African countries will double. In a prospective study among elderly patients in Kenyatta National Hospital, Nairobi, Kenya, in 1991 to 1992: Clinical evidence of CVD was present in 40% of the patients evaluated; 54% were hypertensive, 53% had arrhythmia, and 49% CCF (Lodenyo, McLigeyo, and Ogola 1997)
- 6. PATHOGENESIS
- 7. PATHOGENESIS Response-to-injury hypothesis- 4 main stages to atherogenesis: 1. Chronic endothelial injury 2. Accumulation of lipoproteins 3. Resultant Inflammation & Factor release 4. Smooth muscle cell recruitment, proliferation and ECM production
- 8. RESPONSE-TO-INJURY HYPOTHESIS 1) CHRONIC ENDOTHELIAL INJURY : Hyperlipidemia Hypertension Smoking Homocysteine Hemodynamic factors Toxins Viruses Immune Reactions
- 9. ENDOTHELIAL INJURY Intimal thickening; in the presence of high- lipid diets, typical atheromas ensue. Early human lesions begin at sites of morphologically intact endothelium. Endothelial dysfunction underlies human atherosclerosis; in the setting of intact but dysfunctional ECs : increased endothelial permeability enhanced leukocyte adhesion altered gene expression.
- 10. 2) ACCUMULATION OF LIPOPROTEIN IN VESSEL WALL Dyslipoproteinemia Other underlying disorder that affects the circulating levels of lipids : • nephrotic syndrome, alcoholism, hypothyroidism, or diabetes mellitus (1) increased LDL cholesterol levels, (2) decreased HDL cholesterol levels, and (3) increased levels of the abnormal Lp(a)
- 11. HYPERLIPIDEMIA-MAJOR RISK FACTOR The mechanisms : Chronic hyperlipidemia, particularly hypercholesterolemia - increases local production of reactive oxygen species-accelerate nitric oxide decay- local shear stress. Lipoproteins accumulate within the intima- oxidized through the action of oxygen free radicals (locally generated by macrophages or ECs) Oxidized LDL is ingested by macrophages through a scavenger receptor, resulting in foam-cell formation. In addition, oxidized LDL stimulates the release of growth factors, cytokines, and chemokines by ECs and macrophages that increase monocyte recruitment into lesions. Finally, oxidized LDL is cytotoxic to ECs and SMCs- EC dysfunction.
- 12. 3) MACROPHAGE AS THE INFLAMMATORY MEDIATOR Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells.
- 13. INFLAMMATION Dysfunctional arterial ECs express VCAM-1- binds monocytes and T cells-migrate- chemokines. Monocytes transform into macrophages and avidly engulf lipoproteins, including oxidized LDL. –Activated- cytokine production (e.g., TNF)-propel mononuclear inflammatory cell recruitment. T lymphocytes recruited to the intima- elaborate inflammatory cytokines, (e.g., interferon-γ), which in turn can stimulate macrophages as well as ECs and SMCs. Activated leukocytes and vascular wall cells release growth factors that promote SMC proliferation and ECM synthesis.
- 14. 4) SMC PROLIFERATION AND ECM PRODUCTION Intimal SMC proliferation and ECM deposition convert a fatty streak to a mature atheroma. Intimal SMC-proliferative, synthetic phenotype Growth factors: 1. PDGF (platelets, macrophages, ECs, and SMCs) 2. FGF 3. TGF α. SMCs synthesize ECM (notably collagen), which stabilizes atherosclerotic plaques. Inflammatory cells in atheromas can cause intimal SMC apoptosis, and they also increase ECM catabolism, resulting in unstable plaques.
- 16. COMPLICATIONS MI Rupture, Ulceration, or Erosion- thrombus formation-downstream ischaemia Aneurysm-pressure or ischaemic atrophy of the underlying media, with loss of elastic tissue- weakness Arrthymias- due to scar formation Mural thrombus Atheroembolism- microemboli Cerebral infarct Renal infarcts Death
- 17. NATURAL HISTORY, MAIN PATHOGENIC EVENTS & CLINICAL COMPLICATIONS
- 18. THANK YOU ARMY A1
Editor's Notes
- Arteriosclerosis is an abnormal condition associated with thickening and loss of elasticity in the walls of arteries. It is a generic term and also widely referred to as hardening of the arteries. Atherosclerosis is a type of arteriosclerosis associated with fatty (lipid) deposition in the walls of arteries. The fatty deposition is uncharacteristic of other forms of arteriosclerosis such as arteriolosclerosis seen with high blood pressure (hypertension) and the rare Monckeberg's sclerosis. Atherosclerosis is the most prevalent and most important of the several types of arteriosclerosis.Atherosclerosis affects arteries throughout the body: In humans, the abdominal aorta is typically much more frequently involved than the thoracic aorta. In descending order, the most extensively involved vessels are the lower abdominal aorta, the coronary arteries, the popliteal arteries, the internal carotid arteries, and the vessels of the circle of Willis. Vessels of the upper extremities are usually spared, as are the mesenteric and renal arteries, except at their ostia.Complications associated with reduced blood supply, hence ischeamia and infarctsThe heart and the brain are the most vulnerableThe atheromatous plaque is divided into three distinct components:The atheroma ("lump of gruel," from ἀθήρα, athera, gruel in Greek), which is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of macrophages nearest the lumen of the arteryUnderlying areas of cholesterol crystalsCalcification at the outer base of older/more advanced lesions.Made up of: Cells, including SMCs, macrophages, and T cells; ECM, including collagen, elastic fibers, and proteoglycans; and Intracellular and extracellular lipid These components occur in varying proportions and configurations in different lesions. Typically, the superficial fibrous cap is 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 cells, and SMCs. Deep to the fibrous cap is a necrotic core, containing lipid (primarily cholesterol and cholesterol esters), debris from dead cells, foam cells (lipid-laden macrophages and SMCs), fibrin, variably organized thrombus, and other plasma proteins; the cholesterol content is frequently present as crystalline aggregates that are washed out during routine tissue processing and leave behind only empty "clefts." At the periphery of the lesions, there is usually neovascularization (proliferating small blood vessels). Typical atheromas contain relatively abundant lipid, but some plaques ("fibrous plaques") are composed almost exclusively of SMCs and fibrous tissue. Plaques generally continue to change and progressively enlarge through cell death and degeneration, synthesis and degradation (remodeling) of ECM, and organization of thrombi. Moreover, atheromas often undergo calcification. Patients with advanced coronary calcification appear to be at increased risk for coronary events.
- Age-slowly progressing...take decades-middle age or later. Between ages 40 & 60, incidence of MI in men increases fivefold.Gender-premenopausal women realtively protected.Genetics-multifactorial...familial clustering of risk factor e.g hypertension, diabetes, familial hypercholesterolemiaHyperlipidemia-hypercholesterolemia-LDL ‘bad’ cholesterol. HDL ‘good’ cholesterol mobilizes cholesterol from existing atheromas and transports it to the liver for excretion in the bile.High dietary intake-egg yolks, butter raises plasma cholesterol.Omega -3 fatty acids beneficial (fish oils).Raising HDL-exercise, moderate consumption of ethanol ; obesity and smoking lower it.Statins lower cholesterol.Hypertension-Increase risk of IHD by 60%Cigarette Smoking- Years of smoking one pack or more a day increases the death rate from IHD by 200%.Diabetes Mellitus- incidence of MI twice as high. Induces hypercholesterolemia.Inflammation- marked by C-reactive protein. Assess systemic inflammatory status. CRP cheap and sensitive-acute phase reactant that is synthesized by the liver. Strongly and independently predicts the risk of MI, stroke, peripheral arterial disease, sudden cardiac death. Lowering CRP-smoking cessation, weight loss, exercise, statins.Hyperhomocystinemia- strong relationship between total serum homocysteine levels and coronary artery disease, peripheral vascular disease, stroke and venous thrombosis. Elevated levels- low folate and Vitamin B intake.
- The evidence implicating hypercholesterolemia in atherogenesis includes the following observations: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, homozygous familial hypercholesterolemia, caused by defective LDL receptors and inadequate hepatic LDL uptake, can lead to myocardial infarction before the age of 20 years. Similarly, accelerated atherosclerosis occurs in animal models with engineered deficiencies in apolipoproteins or LDL receptors.Other genetic or acquired disorders (e.g., diabetes mellitus, hypothyroidism) that cause hypercholesterolemia lead to premature atherosclerosis.Epidemiologic studies demonstrate a significant correlation between the severity of atherosclerosis and the levels of total plasma cholesterol or LDL.Lowering serum cholesterol by diet or drugs slows the rate of progression of atherosclerosis, causes regression of some plaques, and reduces the risk of cardiovascular events.
- Hyperlipidemia-more specifically, hypercholesterolemia-is a major risk factor for atherosclerosis; even in the absence of other risk factors, hypercholesterolemia is sufficient to stimulate lesion development. The major component of serum cholesterol associated with increased risk is low-density lipoprotein (LDL) cholesterol ("bad cholesterol"); LDL cholesterol has an essential physiologic role delivering cholesterol to peripheral tissues. In contrast, high-density lipoprotein (HDL, "good cholesterol") mobilizes cholesterol from developing and existing atheromas and transports it to the liver for excretion in the bile. Consequently, higher levels of HDL correlate with reduced risk.Understandably, dietary and pharmacologic approaches that lower LDL or total serum cholesterol, and/or raise serum HDL are all of considerable interest. High dietary intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter, for example) raises plasma cholesterol levels. Conversely, diets low in cholesterol and/or with higher ratios of polyunsaturated fats lower plasma cholesterol levels. Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas (trans)unsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles. Exercise and moderate consumption of ethanol both raise HDL levels, whereas obesity and smoking lower it. Statins are a class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis.
- Monocyte recruitment and differentiation into macrophages (and ultimately into foam cells) is theoretically protective, since these cells remove potentially harmful lipid particles. Over time, however, progressive accumulation of oxidized LDL drives lesion progressionNormal vessels do not bind inflammatory cells-dysfunctional arterial ECs express adhesion molecules; vascular cell adhesion molecule 1 (VCAM-1) in particular binds monocytes and T cells-migrate into the intima under the influence of locally produced chemokines.Monocytes transform into macrophages and avidly engulf lipoproteins, including oxidized LDL. Thus, macrophage activation (via oxidized LDL or T cells) results in cytokine production (e.g., TNF) that further increases leukocyte adhesion and chemokine production that in turn propel mononuclear inflammatory cell recruitment.
- Hypothetical sequence of cellular interactions in atherosclerosis. Hyperlipidemia and other risk factors are thought to cause endothelial injury, resulting in adhesion of platelets and monocytes and release of growth factors, including platelet-derived growth factor (PDGF), which lead to SMC migration and proliferation. Foam cells of atheromatous plaques are derived from both macrophages and SMCs-from macrophages via the very-low-density lipoprotein (VLDL) receptor and low-density lipoprotein (LDL) modifications recognized by scavenger receptors (e.g., oxidized LDL), and from SMCs by less certain mechanisms. Extracellular lipid is derived from insudation from the vessel lumen, particularly in the presence of hypercholesterolemia, and also from degenerating foam cells. Cholesterol accumulation in the plaque reflects an imbalance between influx and efflux, and high-density lipoprotein (HDL) probably helps clear cholesterol from these accumulations. SMCs migrate to the intima, proliferate, and produce ECM, including collagen and proteoglycans.
- If the fibrous cap separating a soft atheroma from the bloodstream within the artery ruptures, tissue fragments are exposed and released. These tissue fragments are very clot-promoting, containing collagen and tissue factor; they activate platelets and activate the system of coagulation. The result is the formation of a thrombus (blood clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of oxygen and nutrients. If this is the myocardium (heart muscle), angina (cardiac chest pain) or myocardial infarction (heart attack) develops.Signs and Symptoms:Many times, people with atherosclerosis don't have any symptoms until an artery is 40% clogged with plaque. Symptoms vary depending upon which arteries are affected.Coronary Artery DiseaseSymptoms of coronary artery diseaseare usually brought on by physical exercise, sexual activity, exposure to cold weather, anger, or stress. The most common symptoms include:Chest pain (generally a heavy, squeezing, or crushing sensation with possible burning or stabbing pains)Abdominal, neck, back, jaw, or shoulder/arm painWeaknessPerspirationShortness of breathCerebrovascular DiseaseCerebrovascular diseasecan cause transient ischemic attack (a sudden loss of brain function with complete recovery within 24 hours) and stroke. Symptoms may include:Weakness or paralysis on one side of the bodyTrouble speaking or understanding speechLoss of vision in one eyeMuscle weaknessSudden trouble walkingDizzinessLoss of balance or coordinationSudden severe headachePeripheral Artery DiseasePeripheral artery disease affects the arteries that supply the arms and legs with oxygen rich blood. Symptoms may include:Pain, aching, cramps, numbness or sense of fatigue in the leg muscles (intermittent claudication)"Bruits" (blowing sounds your doctor can hear with a stethoscope that indicate turbulence in blood flow)Hair lossThickened nailsSmooth, shiny skin surfaceSkin that is cold to the touchGangrene
- Fatty StreaksFatty streaks are composed of lipid-filled foam cells but are not significantly raised and thus do not cause any disturbance in blood flow. They begin as multiple minute yellow, flat spots that can coalesce into elongated streaks, 1 cm long or longer. Fatty streaks can appear in the aortas of infants younger than 1 year and are present in virtually all children older than 10 years, regardless of geography, race, sex, or environment. Coronary fatty streaks begin to form in adolescence, at the same anatomic sites that later tend to develop plaques. The relationship of fatty streaks to atherosclerotic plaques is uncertain; although they may evolve into precursors of plaques, not all fatty streaks are destined to become advanced atherosclerotic lesions.