ATHEROSCLEROSIS Dr: Wael H.Mansy, MD Assistant Professor College of Pharmacy King Saud University

ATHEROSCLEROSIS Atherosclerosis derives from “greek”: “sclerosis” = hardening - thickening “athere” = lipid accumulation An inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate and activate lesions in the arterial wall.

ATHEROSCLEROSIS Atherosclerosis is the “MOST IMPORTANT KILLER” in developed world The WHO estimates that nearly 45% of the Western world population will die due to a complicación atherosclerosis. In USA causes close to 1 million deaths p/y

ATHEROSCLEROSIS RISK FACTORS TO ATHEROSCLEROSIS Dyslipidemia: Hypercholesterolemia Low levels of H.D.L. High Levels of L.D.L. Or V.L.D.L. Mixed Systemic Hypertension Tobacco smoking ( 70% Death rate & increase 3 to 5 fold risk of CAD) Diabetes M. Type I or II Obesity

ATHEROSCLEROSIS RISK FACTORS TO ATHEROSCLEROSIS Modifiable: The 5 major risk factors plus Hyperuricemia High Na, Fat & Calories intake Physical Inactivity Increased Fibrinogen plasma levels Insulin Resistant States Type “A” personality (stress junkies) Post-menopausal state

ATHEROSCLEROSIS RISK FACTORS TO ATHEROSCLEROSIS Non-Modifiable: Genetic defects Male gender (?) Aging (?) Increase of: Lipoprotein (a) Plasminogen Activator Inhibitor-1 Homcysteine Virus (C.M.V.???) Microbial pathogens (Chlamydia???) Auto-immune inflammatory diseases

ATHEROSCLEROSIS ARTERIAL ANATOMY Three main layers: Intima: Single layer of endothelial cells Media: Smooth Muscle Cells (SMC) & connective tissue elements Adventitia: S.M.C., fibroblast & glycosaminoglycans Separating these layers, exist the internal and external elastic lamina.

The Endothelium Maintains Vascular Health Dilatation Growth inhibition Constriction Antithrombotic Growth promotion Anti-inflammatory Prothrombotic Antioxidant Proinflammatory Pro-oxidant

Endothelial Dysfunction Increased: – adhesiveness to leukocytes/platelets – permeability – procoagulant properties – formation of vasoactive molecules, cytokines, and growth factors. = Inflammation

ATHEROSCLEROSIS Steps in atherosclerosis development Fatty streak Fibrous plaque Atherosclerotic plaque (Atheroma) Calcification plaque Complication of atherosclerotic plaques.

ATHEROSCLEROSIS Fatty streak: Represents the initial lesion Results from abnormal accumulation of lipoproteins in the intima layer Mainly localized at arterial bifurcations

ATHEROSCLEROSIS Fibrous plaque: Is the most characteristic lesion of Atherosclerosis, is composed of: Monocytes Macrophages S.M.C. “Foam cells” *** Lipid-rich “Necrotic core”.

ATHEROSCLEROSIS Atherosclerotic plaque: Proliferation at the intima layer of: S.M.C. Macrophages “Foam cells” Conective Tissue elements Collagen type I Elastin Fibers Glycosaminoglycans Cholesterol uptake Calcium deposits Complication of the plaque

ATHEROSCLEROSIS COMPLICATED PLAQUE: Ulceration Thrombosis Growth Acute thrombosis with oclussion Disloging and peripheral embolism Thrombosis Acute ischemia/necrosis Growth Chronic ischemia Necrosis Aneurysm development aneurysm-rupture of the vessels wall..

ATHEROSCLEROSIS Hyperlipidemia injury the endothelium by: Induction of Growth factors synthesis by endothelial cells Increasing Monocytes attachment and migration to sub-endothelial level Increasing LDL uptake by SMC and Macrophages to develop Foam cells Oxidation and release of toxic products increasing endothelial injury.

ATHEROSCLEROSIS Rheologic forces are more marked at arterial bifurcations Chronic mechanical damage to endothelial cells leads to: Increase LDL permeability Increase Platelet adhesivity Increase Monocytes adhesivity Increase synthesis & release of cytokines, vasoactive substances so-on. Decrease synthesis & release of anti-platelet & anti-adhesivity substances. activity of these factors can induce abnormal sequencing of compensatory changes

ATHEROSCLEROSIS Monocytes Subendothelial level Macrophages Take LDL “Foam cells” abnormal presence of monocytes in teh subendotheliatl level macrophages will react and the LDL with foam cells..

ATHEROSCLEROSIS Monocytes-Macrophages-Foam cells Synthesis and release of: LDL oxidizing products Lysosomal enzymes Oxygen Free radicals Growth Factors (PDGF, PAF, EGF) Extracellular matrix synthesis Cytokines (TNFα, IL-1) abnormal increase in extracellular matrix growth factor..

ATHEROSCLEROSIS SMOOTH MUSCLE CELLS From the “media” to the “intima” layer Migrates Proliferates Turns into “Foam cells” Synthesis of connective tissue elements Synthesis of Growth factors Synthesis of Cytokines Synthesis of Vasoactive substances synthesis of connective tissue elements are due to a development of fibrotic gross cap...

ATHEROSCLEROSIS PLATELETS Adhesion and aggregation with: Release of granular content Growth factors & Cytokines Lypooxygenase pathway products Vasoactive substances Thrombus formation These enhance chemotaxis and proliferation of S.M.C. & Monocytes with platelets thrombus formation, chemotaxis adn other activities occuring in the endothelial region...Aspirin can help decrease teh risk of these thrombi formaitons

ATHEROSCLEROSIS Fibrinogen role: Fibrinogen increase blood viscosity Increases platelets & Monocytes attachment to endothelium Conversion to fibrin that causes: Endothelial cell disorganization Provides an adsorptive surface to LDL Induces SMC proliferation Fibrinopeptides causes: Increase in vascular permeability Chemotactic activity Proliferation activity Vasoconstriction. chemotactic activity involves activities with cells..

ATHEROSCLEROSIS Insulin Resistance States: Increase synthesis of LDL. Increase uptake of LDL by SMC Growth factor activity Aggravation of Hypertension

ATHEROSCLEROSIS Complications of atherosclerotic plaques SLOW GROWING WITH OCCLUSION ACUTE THROMBOSIS NECROSIS & ANURYSM DEVELOPMENT AND RUPTURE DISLOGING AND PERIPHERAL EMBOLISM

ATHEROSCLEROSIS CLINICAL SYNDROMES ASYMPTOMATIC ACUTE ISCHEMIA WITH NECROSIS CHRONIC ISCHEMIA WITH ARTERIAL INSUFFICIENCY SYNDROMES ACUTE PERIPHERAL EMBOLISM claudication-stopping of an activity due to lower extremity pains and a grade of ischemia

ATHEROSCLEROSIS CLINICAL SYNDROME DEPENDS UPON THE ARTERY AFFECTED. Carotid arteries Coronary arteries Abdominal aorta Renal arteries Mesenteric arteries Lower limb arteries Different locations of atherosclerosis…

PREVENTION & TREATMENT ATHEROSCLEROSIS PREVENTION & TREATMENT Reducing or controlling modifiable risk factors: Dyslipidemia Hypertension Tobacco smoking Diabetes Mellitus Obesity Hyperuricemia High Na, Fat & Calories intake Physical Inactivity Increased Fibrinogen plasma levels Insulin Resistant States Type “A” personality Post-menopausal state

PREVENTION & TREATMENT ATHEROSCLEROSIS PREVENTION & TREATMENT Reducing or controlling modifiable risk factors: Dyslipidemia T.Chol= < 200mg/dl LDL = < 150mg/dl HDL = > 60mg/dl Hypertension ( < 140/90mmHg) Tobacco smoking D. Mellitus (Gluc. < 127mg/dl Obesity (B.M.I. < 25 )

PREVENTION & TREATMENT ATHEROSCLEROSIS PREVENTION & TREATMENT Stabilization or regression of developed lesions: HMGCoA inhibitors ACE inhibitors Calcium Channel blockers Reduction risk of thrombosis: Primary: Aspirin 80 mg/day Secondary: Ticlopidine Clopidogrel Best example of ACE inhibitors=captopril Aspirin dose is recommended by AHA

PREVENTION & TREATMENT ATHEROSCLEROSIS PREVENTION & TREATMENT Antioxidant Vitamin supplementation Vit. C. Vit. E Estrogen replacement after menopause Under research: Cytokines Growth factor antagonists Antisense oligonucleotides Angiogenesis-blocking drugs Smooth muscle cell hyperplasia-blocking drugs Cytokines induce white cells to migrate for inflammatory response..so a drug to modify or limit this can help..