ATHEROSCLEROSIS

WWAMI Medical Program, MSU

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)

NonNon-Modifiable Risk Factors



Age
 

A dominant influence Atherosclerosis begins in the young, but does not precipitate organ injury until later in life Men more prone than women, but by age 60-70 60about equal frequency Familial cluster of risk factors Genetic differences

Gender


Family History
 

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

AHA Classification of atherosclerosis

Fig. 11.7

Pathogenesis of atherosclerosis

Normal Artery

Atherosclerosis
  

A disease of the intima A disease of the intima A disease of the intima Atheromas, atheromatous/fibrofatty plaques, fibrous plaques Narrowing/occlusion; weakness of wall

Major components of plaque

Cells (SMC, macrophages and other WBC) ECM (collagen, elastin, and PGs) Lipid = Cholesterol (Intra/extracellular) (Often calcification)

Two major processes in plaque formation

Intimal thickening (SMC proliferation and ECM synthesis) Lipid accumulation

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 lesional LDL 4. Adhesion & migration of blood monocytes; transformation into macrophages and foam cells 5. Adhesion of platelets 6. 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 accumulation
Intracellular (SMC and macrophages) Extracellular

Response to Injury

Endothelial Dysfunction

Initiation of Fatty Streak

Fatty Streak

Fibro-fatty Atheroma

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

Consequences of plaque formation

Generalized  Narrowing/Occlusion  Rupture  Emboli


Leading to specific problems:

Myocardial and cerebral infarcts  Aortic aneurysms  Peripheral vascular disease


Is Atherosclerosis Reversible


Primate experiments


High fat diet discontinued; atherosclerotic lesions regress Decrease fat and caloric intake (wars, famine, wasting disease), atheromas decrease. Angiography after cholesterol lowering, plaque size decreases LDL lowered Mac ingest lipids Reverse cholesterol transport, depends on HDL

Humans
 

What has to happen for plaques to regress?

  

Fatty Streak-Aorta

Fatty Streak-Coronary Artery

Consequences of Atherosclerosis

Altered Vessel Function



Vessel change
 

Consequence
 

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

 

Ischemia, turbulence Aneurysms, vessel rupture Narrowing, ischemia, embolization AtheroAthero-embolization Increase systolic blood pressure

Late Changes


Calcification


An example of dystrophic calcification Usually occurs at edge of plaque Caused by endothelial injury,ulceration, turbulence Organization of thrombus More thrombus Weakens vessel wall Ulceration, cracking and angiogenesis

 

Cracking, ulceration, rupture



Thrombus formation
  

 

Encroachment


Bleeding


ATHEROSCLEROSIS: Pathology, Pathogenesis, Complications, Natural History

Fibrous Plaques

Complicated Lesions

Complicated Lesions

Fibrous cap Cholesterol clefts

Elastin membrane destroyed

Neovas. Calcification Inflam. cells

Hemorrhage into Plaque

Ulceration/Hemorrhage/Cholesterol Crystals

Complicated Lesion/Calcification

Foam Cells/Cholesterol Crystals

Cholesterol Crystals/Foam Cells

Thrombosis/Complicated Lesion

Complicated Lesion/Ulceration/Thrombosis

Common Consequences of Atherosclerosis in Specific Vessels

Aorta


Aneurysm
Pulsatile abdominal mass  Abdominal pain  Bleeding


 

Atheroembolization Narrowing of lumen



Usually not a problem

Aortic Aneurysm

Aortic Aneurysm

Coronary Arteries


Consequences of coronary artery atherosclerosis discussed next lecture

Coronary Artery Atherosclerosis

Coronary Artery Atherosclerosis

Carotids and Cerebral Circulation



  

Atherosclerosis with thrombosis can lead to brain infarction Red or white Coagulative or liquefactive Can lead to transient ischemic attacks (TIA), if narrowing is aggravated by mural thrombus or vasospasm

Celiac and Mesenteric Arteries

 

Narrowing primarily at aorta bifurcation Ischemia uncommon because of collateral circulation Ischemia can occur if more than 1 artery severely affected - ischemic entercolitis

Renal Artery


Progressive ischemic atrophy of kidney leads to gradual kidney failure (nephrosclerosis) Renal hypertension due to decreased perfusion

Iliac and Femoral Arteries

 

Aneurysms Vessel occlusion by plaque and thrombus

Ischemia of leg muscles, especially during exercise (intermittent claudication)  Ulcers of skin of legs and feet  Gangrene of feet


Atherosclerotic Disease


Prevalence
6 million Americans with CAD  3 million Americans have had strokes


Mortality
1.5 million deaths/yr in US due to myocardial infarction  0.5 million deaths/yr in US due to strokes


Normal Artery

Pathogenesis of Atherosclerosis


Cause?


Current hypothesis: Response to Injury



Initiated by endothelial dysfunction

Disease of the intima

  

Intimal thickening IntraIntra- and extra-cellular lipid accumulation extraChronic Inflammation

Basic Lesion: is termed atheroma, fibro-fatty fibroplaque, or atheromatous plaque