PATHOGENIC MECHANISMS OF ATHEROSCLEROSIS

Dr.Hesham Rashid, MD

Ass.Professor of Cardiology

Benha University

Normal Artery

GENERAL COMMENTS

• Arteriosclerosis– Thickening and loss of elasticity of arterial walls – Hardening of the arteries– Greatest morbidity and mortality of all human

diseases via

Narrowing

Weakening

Three patterns of arteriosclerosis

• Atherosclerosis– The dominant pattern of arteriosclerosis– Primarily affects the elastic (aorta, carotid,

iliac) and large to medium sized muscular arteries (coronary, popliteal)

• Monckeberg medial calcific sclerosis

• Arteriolosclerosis –small arteries and arterioles (hypertension and DM)

PATHOGENESIS OF

ATHEROSCLEROSIS

Non-modifiable Risk Factors

• Age– A dominant influence– Atherosclerosis begins in the young, but does not

precipitate organ injury until later in life

• Gender– Men more prone than women, but by age 60-70 about

equal frequency

• Family History– Familial cluster of risk factors– Genetic differences

Modifiable Risk Factors(potentially controllable)

• Hyperlipidemia• Hypertension• Cigarette smoking• Diabetes Mellitus• Elevated Homocysteine• Factors that affect hemostasis and thrombosis• Infections: Herpes virus; Chlamydia pneumoniae• Obesity, sedentary lifestyle, stress

• Two theories have been suggested to explain the onset & progression of atherosclerotic lesions:

1. The chronic endothelial theory2. The lipid hypothesis.

• Both theories are interrelated & included in a multifactor-based hypothesis

Response to injury hypothesis

* Injury to the endothelium

(dysfunctional endothelium)

* Chronic imflammatory response

* Migration of SMC from media to intima

* Proliferation of SMC in intima• Excess production of ECM• Enhanced lipid accumulation

Response to injury hypothesis (I)

1. Chronic EC injury (subtle?)–EC dysfunction

–Increased permeability

–Leukocyte adhesion (via VCAM-1)

–Thrombotic potential

Response to injury hypothesis (II)

2. Accumulation of LDL (cholesterol)3. Oxidation of LDL4. Adhesion & migration of blood

monocytes; transformation into macrophages and foam cells

5. Adhesion of platelets6. Release of factors from platelets,

macrophages and ECs

Response to injury hypothesis (III)

7. Migration of SMC from media to intima

8. Proliferation of SMC

9. ECM production by SMC

10.Enhanced lipid accumulationIntracellular (SMC and macrophages)

Extracellular

Response to Injury

Endothelial Dysfunction

Initiation of Fatty Streak

Fatty Streak

Fibro-fatty Atheroma

Fig. 11.7

                                                                         

                                               

AHA Classification of atherosclerosis

Fig. 11.7

                                                                         

                                               

AHA Classification of atherosclerosis

Fatty Streak-Coronary Artery

Fibrous Plaques Complicated Lesions

ALTERED VESSEL FUNCTION• Vessel change

– Plaque narrows lumen– Wall weakened– Thrombosis– Breaking loose of plaque– Loss of elasticity

• Consequence– Ischemia, turbulence– Aneurysms, vessel rupture– Narrowing, ischemia,

embolization– Athero-embolization– Increase systolic blood pressure

Late Changes• Calcification

– An example of dystrophic calcification

• Cracking, ulceration, rupture– Usually occurs at edge of plaque

• Thrombus formation– Caused by endothelial injury,ulceration, turbulence– Organization of thrombus– More thrombus

• Encroachment– Weakens vessel wall

• Bleeding– Ulceration, cracking and angiogenesis

Summary of Atherosclerotic

Process• Multifactorial process (risk factors)

• Initiated by endothelial dysfunction

• Up regulation of endothelial and leukocyte adhesion molecules

• Macrophage diapedesis

• LDL transcytosis

• LDL oxidation

• Foam cells

• Recruitment and proliferation of smooth muscle cells (synthesis of connective tissue proteins)

• Formation and organization of arterial thrombi