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  • Atherosclerosis and arteriosclerosis are often used so interchangeably, it is hardly worth differentiating them anymore, other than to know they are different! <br />
  • Atherosclerosis is a LIFELONG, even childhood, process. This chart is worth knowing. <br />
  • The streaks are more noticeable at the ostia of the aorta because that is where PRESSURE is the greatest. This simple observation makes it easier to understand the relationship between hypertension and atherosclerosis <br />
  • “Framingham” data. Please remember that these are the ONLY four MAJOR risk factors. If somebody tells you there is anything else which is a MAJOR risk factor, nominate that joker for a Nobel prize. <br />
  • It is easy for a smoker to FORGET that cigarettes cause atherosclerosis. i.e., MAJOR risk factor. I hope YOU do not forget. <br />
  • Like the sequence of events described in acute inflammation, atherosclerosis is its own Cecil B. DeMille saga! Not only should you all be familiar with these processes, but their ORDER as well. <br /> * This may be the first (i.e., earliest) microscopic and gross finding. <br />
  • A very well constructed graphic understanding of the pathogenesis of atherosclerosis. Please be expected to not only KNOW these five items, but their correct ORDER too. <br />
  • This is the VERY VERY best diagram of atherosclerosis you will ever see. The nice thing about diagrams is that you really do not have to memorize them, but just visually “recall” the concepts! <br />

Atheroscleosis Atheroscleosis Presentation Transcript

  • Arteriosclerosis • Arteriosclerosis literally means "hardening of the arteries"; it is a generic term reflecting arterial wall thickening and loss of elasticity. Three patterns are recognized, with different clinical and pathologic consequences. • Atherosclerosis • Monkeberg medial calcific sclerosis • Arteriossclerosis
  • A r te r io s c le r o s is A r te r io s c le r o s is H a r d e n in g A th e r o s c le r o s is L a rg e B V In tim a M e d ia l C a lc ific S c le r o s is M e d ia A r te r io lo s c le r o s is S m a ll v e s s e l F u ll th ic k n e s s H y a lin e H y p e r p la s tic
  • ARTERIO-SCLEROSIS • Generic term for anything which hardens arteries – Atherosclerosis (99%) – Mönckeberg medial calcific sclerosis (1%) – Arteriolosclerosis, involving small arteries and arterioles, more related to hypertension and/or diabetes View slide
  • Atherosclerosis • Definition • Natural history and consequences • Morphology • Epidemiology and risk factors • Pathogenesis • Clinical features • Prevention View slide
  • Atherosclerosis “Slowly progressive disorder of intima of large arteries characterised by formation of fibrofatty plaques called atheroma”. Atheroma protrudes into and obstruct vascular lumen and weakens the underlying media.
  • Atherosclerosis • Modern life style disease • Major cause of IHD, MI (20-25% of all death in USA), Stroke & Aortic disease • Incidence is decreasing in West • Better understanding & Change in life style.
  • Morphologic stages of atherosclerotic lesion (AHA classification) • • • • • • Type I – Fatty dots - Foam cells Type II – Fatty streak Type III – Extracellular lipid pool Type IV – Atheroma – Core of lipid Type V – Fibroatheroma – Fibrotic layer Type VI – Complicated – Ulcer, Ca+ – Possible progression to hemorrhage, ulceration, calcification, thrombus, embolism, aneurysm formation.
  • 1) FATTY STREAK (nonpalpable) 2) ATHEROMA (plaque) (palpable) 3) THROMBUS (symptomatic)
  • MORPHOLOGIC CONCEPTS • Key processes: Intimal Thickening & lipid Accumulation • Fatty streak and atheroma • SMC proliferation and migration • Fibrosis • Calcification • Rupture, ulceration or erosion • Aneurysm • Thrombosis
  • Fatty streaks • Fatty streaks can appear in the aortas of infants younger than 1 year and are present in all children older than 10 years, regardless of geography, race, sex, or environment. • Gross: They begin as multiple minute yellow, flat spots that can coalesce into elongated streaks, size: 0.5-1.5 cm in diameter. • Microscopic: composed of lipid-filled foam cells.
  • Atherosclerotic plaque • Atherosclerotic Plaque. The key processes are intimal thickening and lipid accumulation. • Atherosclerotic lesions are patchy. On cross-section, the lesions appear "eccentric". Local flow disturbances, such as turbulence at branch points, leads to certain portions of a vessel wall being more susceptible to plaque formation. • Gross: Occur on the lumen of the artery and appear white to yellow; if thrombosis prsent over the surface of ulcerated plaques, appear red-brown in color. Size: 0.3 to 1.5 cm in diameter.
  • Microscopy of Atherosclerotic plaques • (1) Cells: SMCs, macrophages, and T cells • (2) ECM: collagen, elastic fibers, and proteoglycan • (3) intracellular and extracellular lipid. • Superficial fibrous cap- composed of SMCs and dense collagen. Beneath and to the side of the cap is a more cellular zone containing macrophages, T cells, and SMCs. Central core (necrotic core) containing cholesterol and cholesterol clefts, necrotic cell debris, foam cells, fibrin, variably organized thrombus, and other plasma proteins. At the periphery of the lesions, there is usually proliferating capillaries.
  • Pathological changes of A plaque • Rupture, ulceration, or erosion- exposes the bloodstream to thrombogenic substances- induces thrombus formation • Hemorrhage- Rupture of the overlying fibrous cap or of the thin-walled vessels in the areas of neovascularization can cause intra-plaque hemorrhage. • Atheroembolism. Plaque rupture can discharge debris into the bloodstream, producing microemboli. • Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes weakness of the vessel wall and development of aneurysms.
  • Distribution of plaque • Elastic arteries (aorta, carotid and iliac), large and medium sized muscular arteries (coronary and popliteal) • The most extensively involved vessels are the lower abdominal aorta followed by 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.
  • Common Sites: • Aorta, Carotid & Iliac. (large vessels) • Major Vessels Heart, Brain & Kidney. • Coronary • Renal • Limbs
  • Stages of Atheroma - Aorta Stage VI III II
  • Morphologic types: Fatty dots Atheroma Plaques Complicated
  • Atherosclerosis Aorta, Ruptured aneurysm.
  • Thrombo-embolism
  • Aorta Dissecting Aneurysms
  • Histological findings: Lumen, Fibrous cap (fibrous plaque), Lipid core, External Elastic Membrane thinning/destruction, Calcification, Neovascularization
  • Atheroma Aorta:
  • Coronary Atheorsclerosis •Left Coronary Artery. •Anterior Descending (LAD) •Left Circumflex (LCx) •Right Coronary Artery. LCx LAD
  • Coronary Thrombosis With Infarction
  • Atheroma Coronary Artery:
  • Atheroma Coronary Artery Calcification
  • Atheroma with Thrombosis:
  • Epidemiology and risk factors • Main cause of IHD and stroke in developed nation like USA • 50-70% decrease in death rate from IHD and strokes from 19632000 in US. Why? (better prevention of RF and treatment) • Less prevalent in central and south America, Africa and Asia.
  • Risk Factors for Atherosclerosis Major NON-modifiable Minor Modifiable Increasing age Obesity Male gender Physical inactivity Family history Stress ("type A" personality) Genetic abnormalities Postmenopausal estrogen deficiency High carbohydrate intake Modifiable Hyperlipidemia Hypertension Cigarette smoking Alcohol Lipoprotein Lp(a) Hardened (trans)unsaturated fat intake Chlamydia pneumoniae
  • MAJOR FACTORS • • • • • Hyperlipidemia Hypertension Cigarette Smoking DM (Two M factors=four fold increase in risk, 3 M factors= sevenfold increase in risk)
  • Lipoprotiens - LDL & HDL • • • • • Good Fats Low LDL, High HDL Mono/Poly unsaturated FA Omega-3 fatty acids (Fish) No chol. in vegetable oil Bad fats High LDL, cholesterol, TG, Lipoprotein LP(a) Egg yolk, animal fat, butter, hardened unsaturated fat
  • HYPERLIPIDEMIA • Due to genetic, dietary, clinical condition (nephrotic syndrome, hypothyroidism) or sedentary life style. • LDL mobilizes cholesterol to peripheral tissue • HDL mobilizes cholesterol from atheromas to liver for excretion • The higher the level of HDL, the lower is the risk • LOW CHOLESTEROL diet is GOOD • UNSATURATED fatty acids GOOD • Omega-3 fatty acids GOOD • Exercise GOOD
  • CIGARETTES • What more needs to be said? (10 sticks/day: 3 fold increase in risk)
  • Non major factors • Homocysteinuria/homocysteinemia, related to low B6 and folate intake • Increase in PAI-1 and CRP • Lipoprotein Lp(a), independent of cholesterol. Lp(a) is an altered form of LDL • Inadequate exercise, Type “A” personality, obesity (independent of diabetes) • Protective effect of moderate alcohol?
  • Pathogenesis • Response to injury hypothesis • Oligoclonality of cells in plaque • Infection: chlamydia, CMV as endothelial injurers • (The hypotheses are not mutually exclusive)
  • Response to injury hypothesis • “Atherosclerosis is defined as chronic inflammatory response of the arterial wall initiated by injury to the endothelium” • Key players: Modified lipoprotein, macrophages, T-lymphocytes, normal cellular constituents of arterial wall
  • Response to injury hypothesis • • • • • • Chronic endothelial injury LDL, Cholesterol accumulation in arterial wall Oxidation of LDL Monocytes migrate endotheliumfoam cells Platelet adhesion and activation Migration of smooth muscle cells from media to intima • Proliferation of smooth muscle cells and ECM
  • Role of endothelial injury • Endothelial loss due to - hemodynamic forces, immune complex deposition, irradiation, or chemicals-results in intimal thickening in the presence of high-lipid diets, typical atheromas ensue. • The specific causes of endothelial dysfunction in early atherosclerosis are toxins from cigarette smoke, homocysteine, and infectious agents. Inflammatory cytokines (e.g., TNF) can also stimulate the expression of pro-atherogenic genes in EC.
  • Role of inflammation • ECs express adhesion molecules that encourage leukocyte adhesion. VCAM-1 binds monocytes and T cells. After these cells adhere to the endothelium, they migrate into the intima under the influence of locally produced chemokines. • Monocytes transform into macrophages and engulf oxidized LDL. Macrophage activation via oxidized LDL or T cells results in cytokine production that in turn propel mononuclear inflammatory cell recruitment. • Activated macrophages produce ROIS, aggravating LDL oxidation. T lymphocytes recruited to the intima interact with macrophages and can generate a chronic immune inflammatory state.
  • Role of inflammation • Activated T cells elaborate inflammatory cytokines, (e.g., interferon-γ), which in turn can stimulate macrophages as well as ECs and SMCs. As a consequence of the chronic inflammatory state, activated leukocytes and vascular wall cells release growth factors that promote SMC proliferation and ECM synthesis. • Infections drive the local inflammatory process that results in atherosclerotic plaque. Herpes virus, CMV, and C. pneumoniae have been detected in atherosclerotic plaque.
  • Role of hyperlipidemia • Hypercholesterolemia impair EC function by increasing local production of reactive oxygen species. • Oxygen free radicals accelerate NO decay, damping its vasodilator activity and thereby increasing local shear stress. With chronic hyperlipidemia, lipoproteins accumulate within the intima. These lipids are oxidized through the action of oxygen free radicals locally generated by macrophages or ECs.
  • Role of hyperlipidemia • Oxidized LDL is ingested by macrophages through a scavenger receptor, resulting in foam-cell formation. • Oxidized LDL stimulates the release of growth factors, cytokines, and chemokines by ECs and macrophages that increase monocyte recruitment into lesions. • Oxidized LDL is cytotoxic to ECs and SMCs and can induce EC dysfunction. • The importance of oxidized LDL in atherogenesis is suggested by its accumulation within macrophages at all stages of plaque formation
  • LDL metabolism
  • Familial hypercholesterolemia
  • Role of SMC • Intimal SMC proliferation and ECM deposition convert a fatty streak into a mature atheroma. • Several growth factors are implicated in SMC proliferation and ECM synthesis, includingPDGF, fibroblast growth factor, and TGF-α. • The recruited SMCs synthesize ECM (collagen), which stabilizes atherosclerotic plaques. • However, activated inflammatory cells in atheromas can cause intimal SMC apoptosis, and they also increase ECM catabolism,
  • Clinical features Aorta: aneurysm, embolism ICA: TIA, stroke Circles of Willis: Rupture of Berry aneurysm Coronary artery: MI, angina pectoris Mesenteric artery: Intestinal infarction Renal artery: Stenosis, renovascular HTN Iliofemoral artery: Gangrene, Peripheral vascular disease
  • Complications • • • • • • Thrombosis, Thrombo-embolism Rupture – Haemorrhage Aneurism – Fusiform, dissecting, berry etc. Fibrosis & Calcification Ischemia / Infarction – end organ damage. Stroke, Myocardial Infarctions, Renal infarction, Mesentric vein thrombosis, gangrene etc.
  • Clinical complication
  • Summary • Atherosclerosis is an intima-based lesion organized into a fibrous cap and an atheromatous core and composed of SMCs, ECM, inflammatory cells, lipids, and necrotic debris. • Atherogenesis is driven by an interplay of inflammation and injury to vessel wall cells. Atherosclerotic plaques may acutely cause symptoms due to rupture, thrombosis, hemorrhage, or embolization. • Risk factor recognition and reduction can reduce the incidence and severity of
  • PREVENTION PRINCIPLES • Know what is preventable • Know what is MAJOR (vs. minor) • Know PRIMARY vs. SECONDARY principles • Understand atherosclerosis begins in CHILDHOOD • Risk factors in CHILDREN predict the ADULT profile • Understand SEX, ETHNIC differences