Atherosclerosis

pathology of atherosclerosis for undergraduate medical and paramedical students.

1. ATHEROSCLEROSIS By Dr Utsav Parmar

2. OBJECTIVES Definition Risk factors Pathogenesis Outcome Clinical effects

3. INTRODUCTION Depending upon the calibre and certain histologic features, arteries are divided into 3 types: large (elastic) arteries, medium-sized (muscular) arteries and the smallest arterioles

4. Structure of arteries

5. The structure of a medium-sized muscular artery

6. TE R MS Arteriosclerosis is a general term describing any hardening (and loss of elasticity) of medium or large arteries Arteriolosclerosis is any hardening (and loss of elasticity) of arterioles (small arteries); Atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque. Atherogenic is used for substances or processes that cause atherosclerosis. Atherogenesis is the developmental process of atheromatous plaques

7. DEFINITION Atherosclerosis is a specific form of arteriosclerosis affecting primarily the intima of large and medium-sized muscular arteries and is characterised by fibrofatty plaques or atheromas . The term atherosclerosis is derived from athero - (meaning porridge ) referring to the soft lipid-rich material in the centre of atheroma , and sclerosis (scarring ) referring to connective tissue in the plaques

8. C a use s Atherosclerosis starts with damage or injury to the inner layer of an artery. The damage may be caused by: High blood pressure High cholesterol An irritant, such as nicotine Certain diseases, such as diabetes

9. Major risk factors Dyslipidemia : i ) The atherosclerotic plaques contain cholesterol and cholesterol esters, largely derived from the lipoproteins in the blood. ii) The lesions of atherosclerosis can be induced in experimental animals by feeding them with diet rich in cholesterol . iii) Individuals with hypercholesterolaemia due to various causes such as in diabetes mellitus, myxoedema , nephrotic syndrome , von Gierke’s disease, xanthomatosis and familial hypercholesterolaemia have increased risk of developing atherosclerosis and IHD. iv) Populations having hypercholesterolaemia have higher mortality from IHD. Dietary regulation and administration of cholesterol-lowering drugs have beneficial effect on reducing the risk of IHD.

10. 2. HYPERTENSION. Hypertension is a risk factor for all clinical manifestations of atherosclerosis. Hypertension doubles the risk of all forms of cardiovascular disease. It acts probably by mechanical injury to the arterial wall due to increased blood pressure . Elevation of systolic pressure of over 160 mmHg or a diastolic pressure of over 95 mmHg is associated with five times higher risk of developing IHD than in people with blood pressure within normal range ( 140/90 mmHg or less).

11. 3. SMOKING Cigarette smoking is associated with higher risk of atherosclerotic IHD and sudden cardiac death . Men who smoke a pack of cigarettes a day are 3-5 times more likely to die of IHD than non-smokers. The increased risk and severity of atherosclerosis in smokers is due to reduced level of HDL, deranged coagulation system and accumulation of carbon monoxide in the blood that produce carboxyhaemoglobin and eventually hypoxia in the arterial wall favouring atherosclerosis

12. 4. DIABETES MELLITUS Clinical manifestations of atherosclerosis are far more common and develop at an early age in people with both type 1 and type 2 diabetes mellitus . In particular, association of type 2 diabetes mellitus characterised by metabolic (insulin resistance) syndrome and abnormal lipid profile termed ‘diabetic dyslipidaemia ’ is common and heightens the risk of cardiovascular disease . The risk of developing IHD is doubled, tendency to develop cerebrovascular disease is high, and frequency to develop gangrene of foot is about 100 times increased.

13. Constitutional risk factors AGE . Atherosclerosis is an age-related disease. Though early lesions of atherosclerosis may be present in childhood, clinically significant lesions are found with increasing age. Fully-developed atheromatous plaques usually appear in the 4th decade and beyond. Evidence in support comes from the high death rate from IHD in this age group . 2. SEX. The incidence and severity of atherosclerosis are more in men than in women and the changes appear a decade earlier in men (>45 years) than in women (>55 years). The lower incidence of IHD in women, especially in premenopausal age, is probably due to high levels of oestrogen and high-density lipoproteins, both of which have anti- atherogenic influence .

14. 3. GENETIC FACTORS. Genetic factors play a significant role in atherogenesis . Hereditary genetic derangements of lipoprotein metabolism predispose the individual to high blood lipid level and familial hypercholesterolaemia . 4. FAMILIAL AND RACIAL FACTORS: The familial predisposition to atherosclerosis may be related to other risk factors like diabetes, hypertension and hyperlipoproteinaemia . Racial differences too exist; Blacks have generally less severe atherosclerosis than Whites.

15. PATHOGENESIS Insudation hypothesis. The concept hypothesised by Virchow in 1856 that atherosclerosis is a form of Cellular proliferation of the intimal cells resulting from increased imbibing of lipids from the blood came to be called the ‘lipid theory’. Modified form of this theory is currently known as ‘response to injury hypothesis’ and is now-a-days the most widely accepted theory

16. Encrustation hypothesis The proposal put forth by Rokitansky in 1852 that atheroma represented a form of encrustation on the arterial wall from the components in the blood forming thrombi composed of platelets, fibrin andleucocytes , was named as ‘encrustation theory’ or ‘ thrombogenic theory’. this theory has now been incorporated into the response-to-injury hypothesis mentioned above.

17. The role of four key factors Arterial smooth muscle cells, Endothelial cells, Blood monocytes Dyslipidaemia , Currently, pathogenesis of atherosclerosis is explained on the basis of the following two theories: 1. Reaction-to-injury hypothesis, 2. Monoclonal theory, based on neoplastic proliferation of smooth muscle cells

18. REACTION-TO-INJURY HYPOTHESIS

19. i ) Endothelial injury The initial triggering event Actual endothelial denudation is not an essentia lrequirement , but endothelial dysfunction may initiate the sequence of events. causes of endothelial injury in experimental animals are: mechanical trauma, haemodynamic forces, immunological and chemical mechanisms, metabolic agent as chronic dyslipidaemia , homocystine , circulating toxins from systemic infections, viruses , hypoxia , radiation, carbon monoxide and tobacco products. In man, two of the major risk factors which act together to produce endothelial injury are: haemodynamic stress from hypertension and chronic dyslipidaemia

20. ii) Intimal smooth muscle cell proliferation injury causes adherence, aggregation and platelet release reaction at the site of exposed subendothelial connective tissue and infiltration by inflammatory cells. Proliferation stimulated by IL-1, TNF- α , Platelet-derived growth factor (PDGF) , fibroblast growth factor (FGF) , Transforming growth factor-β ( TGF-β) and interferon- (IFN-γ) derived from activated T lymphocytes

21. iii) Role of blood monocytes LDL does appear in the monocyte cytoplasm to form foam cell For monocytes : Oxidised LDL acts to attract, proliferate, immobilise and activate them as well as is readily taken up by scavenger receptor on the monocyte to transform it to a lipid-laden foam cell

22. Mechanism of foam cell formation

23. iv) Role of dyslipidaemia Chronic dyslipidaemia in itself may initiate endothelial injury and dysfunction by causing increased permeability. In particular, hypercholesterolaemia with increased serum concentration of LDL promotes formation of foam cells, while high serum concentration of HDL has anti- atherogenic effect.

24. Schematic evolution of lesions in atherosclerosis

25. MORPHOLOGIC FEATURES Early lesions in the form of diffuse intimal thickening, Fatty streaks and gelatinous lesions are often the forerunners in the evolution of atherosclerotic lesions. However, the clinical disease states due to luminal narrowing in atherosclerosis are caused by fully developed Atheromatous plaques and complicated plaques

26. Histological appearance of plaque

27. COMPLICATED PLAQUES Calcification Thrombosis Ulceration Hemorrhage Aneurysm formation

28. Clinical effects Depend upon the size and type of arteries affected. 1. Slow luminal narrowing causing ischaemia and atrophy. 2. Sudden luminal occlusion causing infarction necrosis. 3. Propagation of plaque by formation of thrombi and emboli. 4. Formation of aneurysmal dilatation and eventual rupture

29. Major sites of atherosclerosis (serially numbered) in descending order of frequency

30. Major effects on organs i ) Aorta—Aneurysm formation, thrombosis and embolisation to other organs. ii) Heart—Myocardial infarction, ischaemic heart disease. iii) Brain—Chronic ischaemic brain damage, cerebral infarction. iv) Small intestine— Ischaemic bowel disease, infarction. v) Lower extremities—Intermittent claudication , gangrene.