atherosclerosis
*At the End of This Lecture You should Be Able to
Appreciate the significance of atherosclerosis as the major cause of death worldwide Describe the gross and microscopic morphology of atherosclerotic plaques Appreciate the significance of plaque morphology in determining its future behavior Understand the risk factors and causes of atherosclerosis*
At the End of This Lecture You should Be Able to Know
How would atherosclerosis present you How to estimate the likelihood of developing atherosclerosis How to prevent atherosclerosis How to treat atherosclerosis*
Athereosclerosis
The major cause of morbidity & mortality worldwide Progressive inflammatory disorder of the arterial wall Focal deposition of lipid-rich material Initially clinically silent*
Athereosclerosis
Later on: they become large enough to obstruct the lumen of the blood vessel Endothelial ulceration leads to acute thrombosis Embolization of lipid material leads to distal arterial occlusion*
Manifestations of atherosclerosis
Largely clinically silent Coronary artery disease: angina pectoris, myocardial infarction, arrhythmias, sudden death, etc. Cerebrovascular disease: stroke, TIA Peripheral vascular diseae. Renal artery stenosis Often these manifestations co-exist
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PATHOGENESIS
Normal endothelial function The blood vessel wall is not a simple tubing system that merely transports blood Rather, the endothelial lining of the blood vessels is the largest endocrine system in the body*
Normal endothelial Function
Factors normally released by the endothelium include: Prostacyclin (PG I2) Nitric oxide Tissue plasminogen activator (t-PA)*
Normal Endothelial Function
Normal function is to maintain blood in a fluid state When the endothelial function is impaired, it starts to release factors that enhance inflammation and platelet-fibrin activation*
Factors Released by Diseased Endothelium
Thromboxane A2 (TX A2): promotes platelet aggregation Endothelin (ET): the most potent vasoconstrictor known to exist! Plasminogen-activator inhibitor 2 (PAI2): inhibits the degradation of thrombus*
In Atherosclerosis
In patients with hypercholesterolemia, LDL infiltrates the artery and is retained in the intima*
In Atherosclerosis
LDL undergoes oxidative and enzymatic modifications (oxidized LDL)
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In Atherosclerosis
Oxidized LDL stimulates the endothelium to release adhesion molecules: Thromboxane A2 Endothelin Plasminogen activator inhibitor (PAI-1)*
In Atherosclerosis
Monocytes are recruited through the activated endothelium to differentiate into macrophages*
Pathogenesis of atherosclerosis
The recruited macrophages engulf the oxidized LDL to become foam cells*
Pathogenesis of atherosclerosis
Also, the recruited macrophages release cytokines which promote inflammation including:Interlukin 1(IL-1)Tumor necrosis factor (TNF)Interferon γMatrix metalloproteinase *Pathogenesis of atherosclerosis
Cytokines released from macrophages and lymphocytes lead to recruitment of smooth muscle cells from the media*
Pathogenesis of atherosclerosis
These smooth muscle cells no longer function as contractile cells but as repair cells
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Pathogenesis of atherosclerosis
The end result of an atherosclertic plaque depends on the destructive effect of macrophages and the reparative role of smooth muscle cells*
Pathogenesis of atherosclerosis
A stable plaque contains small lipid core and dense cap composed of smooth muscles and collagen*
Pathogenesis of atherosclerosis
An unstable plaque has a thin fibrous cap which can be digested by enzymes released by macrophages.*
Pathogenesis of atherosclerosis
Exposure of the subendothelial tissue to the flowing blood leads to thrombosis and vessel occlusion*
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Pathogenesis of atherosclerosis
The pathological effects of the plaque do not depend only on its size but also on the relative constituents of the plaque: A plaque with thin fibrous cap may rupture & cause sudden occlusion of the artery by superimposed thrombosis even if it was of small volume*
Risk Factors for Atherosclerosis
*Risk Factors for Atherosclerosis
The effects of risk factors are multiplicative, not additive*
Risk Factors for Atherosclerosis
Hereditary (genetic) factor: multifactorial (polygenic) inheritance:Age and gender: Age is the most powerful independent risk factor Gender: premenopausal ♀< risk than age-matched ♂The beneficial effect of ♀sex disappears rapidly after menopause *Risk Factors for Atherosclerosis
Family history:Positive family history: when IHD occurs in first degree relativesFamily history is considered positive if atherosclerosis occurs in ♂ relatives < 55 years or ♀relatives < 65 yearsSmoking *Risk Factors for Atherosclerosis
Hypertension : Related both to systolic, diastolic and pulse pressure Antihypertensive therapy has been shown to reduce the incidence of coronary mortality, stroke, & heart failure*
Risk Factors for Atherosclerosis
Hypercholeserolemia: Most important is total cholesterol:HDL ratio Lowering total cholesterol & LDL cholesterol reduces the risk of cardiovascular events (death, MI, stroke, & the need for revascularization)
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Risk Factors for Atherosclerosis
Diabetes Mellitus: Often associated with diffuse disease Insulin resistance: Normal plasma glucose despite increased insulin levels Usually associated with obesity*
Risk Factors for Atherosclerosis
Physical inactivity: Regular exercise reduces risk for atherosclerosis: Lowers body weight Elevates HDL cholesterol Reduces BP Enhances Collaterals Reduces blood clotting*
Risk Factors for Atherosclerosis
Obesity Truncal (central) Alcohol? Moderate amount of alcohol has a protective role Heavy alcohol intake is associated with HT*
Risk Factors for Atherosclerosis
DIETARY FACTORS Diets deficient in fruit, vegetables, and polyunsaturated fatty acids PERSONALITY? No evidence that emotional stress is a major risk factor for IHD*
Prevention of Atherosclerosis
*Prevention of Atherosclerosis
Primary prevention Secondary prevention Tertiary prevention
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PRIMARY PREVENTION
PREVENTING THE OCCURRENCE OF THE DISEASE Population-based strategy Targeted therapy*
PRIMARY PREVENTION
Population-based strategy: Diet Avoiding saturated fat and cholesterol Increasing intake of fibers Low-fat dairy products Smoking cessation Exercise 20-30 min/day, twice or thrice a week Maintaining ideal body weight*
PRIMARY PREVENTION
Targeted therapy Identify and treat high-risk individuals Calculating the composite risk profile using special algorithms and charts*
Primary Prevention
Using the risk profile charts*
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SECONDARY PREVENTION
PREVENTING THE RECURRENCE OF THE DISEASE: drug therapyHMG Co-A reductase inhibitors: the “statins”AspirinACE inhibitors *
SECONDARY PREVENTION
HMG Co-A reductase inhibitors: “statins”(simvastatin, atorvastatin, fluvastatin, lovastatin, rosuvastatin, etc)Given to All patients with established atherosclerosis reduce the incidence of major coronary events & strokeShould be administered at night *SECONDARY PREVENTION
ACE inhibitors e.g. captopril, enalapril, lisinopril, ramipril Shown to improve survival in established atherosclerosis, even without heart failure or LV dysfunction*
Recent Drug: PCSK9 Inhibitors
Inactivation of the enzyme Preprotein convertase subtilisin-Kexin type 9 This leads to reduced degradation of LDL receptors on the surface of the hepatocytes Increased expression of LDL receptors leading to increased rate of clearance of LDL from the circulation*