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

2. 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.

3. 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

4. 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 ( % Death rate & increase 3 to 5 fold risk of CAD)
Diabetes M. Type I or II
Obesity

5. 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

6. 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

7. 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.

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

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

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

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

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

14. 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

15. 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..

18. 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.

19. 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

20. 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..

21. 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..

22. 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...

23. 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

24. 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..

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

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

28. 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

30. 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…

32. 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

33. 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 )

34. 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

35. 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..