ATHEROSCLEROSISATHEROSCLEROSIS

Dr: Wael H.Mansy, MDAssistant Professor

College of Pharmacy

King Saud University

ATHEROSCLEROSISATHEROSCLEROSIS

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.

ATHEROSCLEROSISATHEROSCLEROSIS

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

ATHEROSCLEROSISATHEROSCLEROSIS 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

ATHEROSCLEROSISATHEROSCLEROSIS 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

ATHEROSCLEROSISATHEROSCLEROSIS 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

ATHEROSCLEROSISATHEROSCLEROSIS 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

ATHEROSCLEROSISATHEROSCLEROSIS

Steps in atherosclerosis development

Fatty streak

Fibrous plaque

Atherosclerotic plaque (Atheroma)

Calcification plaque

Complication of atherosclerotic plaques.

ATHEROSCLEROSISATHEROSCLEROSIS

Fatty streak:

Represents the initial lesion

Results from abnormal accumulation of lipoproteins in the intima layer

Mainly localized at arterial bifurcations

ATHEROSCLEROSISATHEROSCLEROSIS Fibrous plaque:

Is the most characteristic lesion of Atherosclerosis, is composed of:

Monocytes

Macrophages

S.M.C.

“Foam cells”

*** Lipid-rich “Necrotic core”.

ATHEROSCLEROSISATHEROSCLEROSIS 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

ATHEROSCLEROSISATHEROSCLEROSIS COMPLICATED PLAQUE:

Ulceration Acute thrombosis with oclussion Disloging and peripheral embolism

Thrombosis Acute ischemia/necrosis

Growth Chronic ischemia

Necrosis Aneurysm development

ATHEROSCLEROSISATHEROSCLEROSIS 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.

ATHEROSCLEROSISATHEROSCLEROSIS 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.

ATHEROSCLEROSISATHEROSCLEROSIS Monocytes

Subendothelial level

Macrophages

Take LDL

“Foam cells”

ATHEROSCLEROSISATHEROSCLEROSIS 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)

ATHEROSCLEROSISATHEROSCLEROSIS 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

ATHEROSCLEROSISATHEROSCLEROSIS 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

ATHEROSCLEROSISATHEROSCLEROSIS 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.

ATHEROSCLEROSISATHEROSCLEROSIS

Insulin Resistance States:

Increase synthesis of LDL.

Increase uptake of LDL by SMC

Growth factor activity

Aggravation of Hypertension

ATHEROSCLEROSISATHEROSCLEROSIS Complications of atherosclerotic

plaques

SLOW GROWING WITH OCCLUSION

ACUTE THROMBOSIS

NECROSIS & ANURYSM DEVELOPMENT AND RUPTURE

DISLOGING AND PERIPHERAL EMBOLISM

ATHEROSCLEROSISATHEROSCLEROSIS CLINICAL SYNDROMES

ASYMPTOMATIC

ACUTE ISCHEMIA WITH NECROSIS

CHRONIC ISCHEMIA WITH ARTERIAL INSUFFICIENCY SYNDROMES

ACUTE PERIPHERAL EMBOLISM

ATHEROSCLEROSISATHEROSCLEROSIS CLINICAL SYNDROME DEPENDS UPON THE

ARTERY AFFECTED.

Carotid arteries

Coronary arteries

Abdominal aorta

Renal arteries

Mesenteric arteries

Lower limb arteries

ATHEROSCLEROSISATHEROSCLEROSIS 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

ATHEROSCLEROSISATHEROSCLEROSIS 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 )

ATHEROSCLEROSISATHEROSCLEROSIS 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

ATHEROSCLEROSISATHEROSCLEROSIS 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