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This document discusses different types of arteriosclerosis including atherosclerosis. It defines atherosclerosis as the thickening of the arterial walls due to buildup of fatty plaques. The major risk factors for atherosclerosis include dyslipidemia, hypertension, diabetes, and smoking. The document discusses the pathogenesis of atherosclerosis, describing how abnormalities in lipoproteins and cholesterol levels contribute to plaque formation in the arteries over time. It also outlines strategies for prevention through modifying risk factors like maintaining healthy cholesterol levels.

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SAMOEI – EGERTON UNIVERSITY MBChB Y3
2 1. ARTERIOSCLEROSIS 1. DEFINATION 2. TYPES SENILE ARTERIOSCLEROSIS HYPERTENSIVE ARTERIOSCLEROSIS MONCKEBERG’S ARTERIOSCLEROSIS (MEDIAL CALCIFIC SCLEROSIS) ATHEROSCLEROSIS 2. ATHEROSCLEROSIS (AS) DEFINATION ETIOLOGY FRACTIONS OF LIPIDS IN SERUM PATHOGENESIS OF AS PROGRESSION OF AS SYMPTOMS OF AS PREVENTION OF AVD SUMMARY N/B AVD – ATHEROSCLEROTIC VASCULAR DISEASE
3 Arteriosclerosis is a general term used to include all conditions with thickening and hardening of the arterial walls. TYPES OF ARTERIOSCLEROSIS 1. Senile arteriosclerosis (affects arteries) 2. Hypertensive arteriolosclerosis (affects arterioles) 3. Mönckeberg’s arteriosclerosis (Medial calcific sclerosis) (affects arteries) 4. Atherosclerosis (affects arteries) N/B Atherosclerosis, is the most common and most important form of arteriosclerosis; if not specified, the two terms are used interchangeably with each other.
4 • Is the thickening of media and intima of the arteries seen due to ageing. • Changes are non-selective and affect most of the arteries. • Possibly induced by stress and strain on vessel wall during life. MORPHOLOGIC FEATURES The changes are as under: 1. Fibroelastosis: Intima and media are thickened due to increase in elastic and collagen tissue. 2. Elastic reduplication: Internal elastic lamina split or reduplicated so that two wavy layers are seen. Eventually, the fibrotic changes result in age-related elevation of SBP.
5 Involves 3 morphologic forms of vascular disease affecting arterioles and small muscular arteries, these are: 1. Hyaline arteriolosclerosis 2. Hyperplastic arteriolosclerosis 3. Necrotizing arteriolitis. All the three types are common in hypertension but may occur due to other causes as well. HYALINE ARTERIOSCLEROSIS • May be seen physiologically due to ageing, or may occur pathologically in: Benign nephrosclerosis in hypertensives As a part of microangiopathy in diabetics MORPHOLOGIC CHANGES The visceral arterioles are particularly involved. The vascular walls are thickened and the lumina narrowed or even obliterated. Microscopically, the thickened vessel wall shows structureless, eosinophilic, hyaline material in the intima and media. PATHOGENESIS The exact pathogenesis is not known. However, the following hypotheses have been proposed: 1. The lesions result from leakage of components of plasma across the vascular endothelium. This is substantiated by the demonstration of Igs, complement, fibrin and lipids in the lesions. The permeability of the vessel wall is increased, d/t haemodyanamic stress in HPTN and metabolic stress in diabetes, so that these plasma components leak out and get deposited in the vessel wall. 2. The lesions may also be d/t immunologic reaction. 3. It might also be d/t normal aging process exaggerated in HPTN and DM.
6 HYPERPLASTIC/PROLIFERATIVE ARTERIOSCLEROSIS • Is a characteristic lesion of malignant hypertension • Other causes include HUS, scleroderma and toxemia of pregnancy. MORPHOLOGIC FEATURES The morphologic changes affect mainly the intima, especially of the interlobular arteries in the kidneys. Three types of intimal thickening may occur. 1. Onion-skin lesion 2. Mucinous intimal thickening 3. Fibrous intimal thickening Onion-skin lesion  Consists of loosely-placed concentric layers of hyperplastic intimal smooth muscle cells like the bulb of an onion. Mucinous intimal thickening  Is the deposition of amorphous ground substance, probably proteoglycans, with scanty cells. Fibrous intimal thickening  Is less common and consists of bundles of collagen, elastic fibres and hyaline deposits in the intima.  Severe intimal sclerosis results in narrowed or obliterated lumen.  With time, the lesions become more and more fibrotic. PATHOGENESIS Unclear. Probably, the changes result following: • Endothelial injury from systemic hypertension, hypoxia or immunologic damage leading to increased permeability. • A healing reaction occurs in the form of proliferation of smooth muscle cells with fibrosis.
7 NECROTIZING ARTERIOLITIS • In cases of severe HPTN and malignant HPTN, parts of small arteries and arterioles show changes of hyaline sclerosis and parts of these show necrosis, or necrosis may be superimposed on hyaline sclerosis. • However, hyaline sclerosis may not be always present in the vessel wall. MORPHOLOGIC FEATURES Besides the changes of hyaline sclerosis, the changes of necrotizing arteriolitis include: 1. Fibrinoid necrosis of vessel wall 2. Acute inflammatory infiltrate of neutrophils in the adventitia 3. Edema and hemorrhages often surround the affected vessels. PATHOGENESIS Since necrotizing arteriolitis occurs in vessels in which there is sudden and great elevation of pressure, the changes are said to result from direct physical injury to the vessel wall.
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9 • Is calcification of the media of large and medium-sized muscular arteries, especially of the extremities and of the genital tract, in persons past the age of 50. • The condition occurs as an age-related degenerative process, and therefore, an example of dystrophic calcification, and has little or no clinical significance. • However, it also occurs in some pathological states like pseudoxanthoma elasticum and in idiopathic arterial calcification of infancy. MORPHOLOGIC FEATURES Medial calcification is often an incidental finding in X-rays of the affected sites having muscular arteries. The deposition of calcium salts in the media produces pipestem-like rigid tubes without causing narrowing of the lumen. Microscopically, It is characterised by deposits of calcium salts in the media without associated inflammatory reaction while the intima and the adventitia are spared. Often, coexistent changes of atherosclerosis are present altering the histologic appearance. PATHOGENESIS • Unknown, but it is considered as an age- related physiologic change due to prolonged effect of vasoconstriction.
10 • Is the thickening and hardening of large and medium-sized muscular arteries, primarily d/t involvement of tunica intima. • Characterised by fibro fatty 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. • Is the commonest and the most important of the arterial diseases. • Though any large and medium-sized artery may be involved in atherosclerosis, the most commonly affected are the aorta, the coronaries and the cerebral arterial systems. The major clinical syndromes resulting from ischemia d/t atherosclerosis are as under: 1. Heart (angina and MI or heart attacks) 2. Brain (transient cerebral ischemia and cerebral infarcts or strokes) 3. Other sequelae are: peripheral vascular disease, aneurysmal dilatation d/t weakened arterial wall, chronic IHD, ischemic encephalopathy and mesenteric arterial occlusion.
11 I. MAJOR RISK FACTORS A) Modifiable 1. Dyslipidemia 2. HPTN 3. DM 4. Smoking B) Constitutional 1. Increasing age 2. Male gender 3. Genetic abnormalities 4. Family history and racial factors II. EMERGING RISK FACTORS 1. Environmental influences 2. Obesity 3. Hormones: estrogen deficiency, oral contraceptives 4. Physical inactivity 5. Stressful life (Type A personality) 6. Homocystinuria 7. Role of alcohol 8. Prothrombotic factors 9. Infections (C. pneumoniae, Herpesvirus, CMV) 10.High CRP
12 A. MODIFIABLE BY LIFESTYLE AND/OR THERAPY 1. DYSLIPIDEMIA • Abnormalities in plasma lipoproteins is the most important major risk factor for atherosclerosis. • Hypercholesterolemia has directly proportionate relationship with AS and IHD. The following evidences are cited in support of this: 1. Atherosclerotic plaques contain cholesterol and cholesterol esters, derived from the LPs in blood. 2. Lesions of AS can be induced in experimental animals by feeding them with diet rich in cholesterol. 3. Individuals with hypercholesterolemia d/t various causes such as in DM, myxedema, nephrotic syndrome, von Gierke’s disease, xanthomatosis and familial hypercholesterolemia have increased risk of developing AS and IHD. 4. Populations having hypercholesterolemia have higher mortality from IHD. Dietary regulation and administration of cholesterol- lowering drugs (statins) have beneficial effect on reducing the risk of IHD.
13 Total cholesterol Desirable normal serum level is 140- 200 mg/dl Levels of borderline high are 200-240 mg/dl. Levels above 260 mg/dl in men and women between 30 and 50 years has three times higher risk of developing IHD as compared with people with cholesterol levels within normal limits. Triglycerides Normal serum level is below 150 mg/dl. Low-density lipoproteins (LDL) cholesterol Optimal serum level is <100 mg/dl. LDL is richest in cholesterol and has the maximum association with atherosclerosis. Very-low-density lipoprotein (VLDL) Carries much of the TGs and its blood levels therefore parallel with that of TGs; VLDL has less marked effect than LDL. High-density lipoproteins (HDL) cholesterol Normal desirable serum level is <50 mg/dl. It’s protective (‘good cholesterol’) against atherosclerosis. N/B 1. Total cholesterol – <200mg/dl 2. TGs/VLDL – <150mg/dl 3. LDL – <100mg/dl 4. HDL - <50mg/dl
14 PLASMA CHOLESTROL LEVELS ELEVATED BY: 1. Diet containing large quantities of saturated fats (e.g. in eggs, meat, milk, butter etc) 2. Diet containing large quantities of trans fats (i.e. unsaturated fats produced by artificial hydrogenation of polyunsaturated fats) 3. High intake of total number of calories from carbohydrates, proteins, alcohol & sweets. 4. Familial hypercholesterolemia, an autosomal codominant disorder, characterised by elevated LDL cholesterol and normal TGs and occurrence of xanthomas and premature CAD. It occurs d/t mutations in LDL receptor gene. N/B  High serum cholesterol levels increases the risk of AS PLASMA CHOLESTEROL LEVELS LOWERED BY:  Diet low in saturated fats and high in poly- unsaturated fats  Diet having omega-3 fatty acids (e.g. in fish, fish oils etc).  Use of statins, to lower LDL in particular, and total cholesterol in general, in the management of dyslipidemia (Inhibits HMG-CoA reductase)  Weight loss, exercise and use of nicotinic acid to raise HDL  Moderate consumption of ethanol to raise HDL N/B Currently, preferred term for hyperlipidemia is dyslipidemia because one risky plasma lipoprotein (LDL) is elevated and needs to be brought down, while the other good plasma lipoprotein (HDL) when low requires to be raised.
15 2. HYPERTENSION • Is a risk factor for all clinical manifestations of AS. • Doubles the risk of all forms of cardiovascular disease. • Acts probably by mechanical injury to the arterial wall d/t increased BP. • Elevation of SBP over160 mmHg or DBP over 95 mmHg is associated with five times higher risk of developing IHD than in people with BP within normal range (140/90 mmHg or less) 3. SMOKING • The extent and severity of AS are much greater in smokers than in non-smokers. • 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 AS in smokers is d/t: • Reduced level of HDL • Deranged coagulation system • Accumulation of carbon monoxide in the blood that produces carboxyHb and eventually hypoxia in the arterial wall favouring AS.
16 4. DIABETES MELLITUS Clinical manifestations of AS are far more common and develop at an early age in people with both type 1 and type 2 DM. In particular, association of type 2 DM characterised by metabolic (insulin resistance) syndrome and abnormal lipid profile termed ‘diabetic dyslipidemia’ 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. The causes of increased severity of AS are complex and numerous which include endothelial dysfunction, increased aggregation of platelets, increased LDL and decreased HDL.
17 B. CONSTITUTIONAL FACTORS 1. INCREASING AGE • AS is an age-related disease. • Though early lesions of AS 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. MALE GENDER • Premenopausal women are relatively protected against atherosclerosis and its consequences compared with men of the same age • MI and other complications of AS are uncommon in premenopausal women unless otherwise predisposed by diabetes, hyperlipidemia, or severe HPTN. • After menopause, the incidence of AS-related diseases increases and with greater age exceeds that of men. • The lower incidence of AS in women of premenopausal age, is probably d/t high levels of estrogen and HDLs, both of which have anti-atherogenic influence. 3. GENETIC ABNORMALITIES • Hereditary derangements of LP metabolism predispose individual to high blood lipid level and familial hypercholesterolemia. 4. FAMILY Hx AND RACIAL FACTORS • Familial predisposition is related to risk factors like diabetes, HPTN and hyperlipoproteinemia. • Racial differences also exist; Blacks have generally less severe AS than Whites.
18 1. Environmental influences; Theris higher incidence of AS in developed countries and low prevalence in underdeveloped countries. 2. Metabolic syndrome characterised by abdominal obesity, glucose intolerance, insulin resistance, dyslipidemia and HPTN, is associated with increased risk. 3. Use of exogenous hormones (oral contraceptives) or endogenous estrogen deficiency (in postmenopausal women) increases the risk of developing MI or stroke. 4. Physical inactivity and lack of exercise increases the risk of developing AS and its complications. 5. Stressful life style, termed as ‘type A’ behavior pattern, characterised by aggressiveness, competitive drive, ambitiousness and a sense of urgency, is associated with enhanced risk of IHD compared with ‘type B’ behavior of relaxed and happy go-lucky type. 6. Hypercystinemia d/t elevated serum homocysteine level from low folate and vit B12 have a relationship with CAD and its consequences. 7. Homocystinuria, an uncommon inborn error of metabolism, having hypercystinemia have early AS and CAD. 8. Prothrombotic factors and elevated fibrinogen levels favour formation of thrombi; the gravest complication of AS. 9. Role of infections, particularly of Chlamydia pneumoniae, herpesvirus and CMV, has been found in coronary atherosclerotic lesions by causing inflammation. Possibly, infections may be acting in combination with some other factors. 10. Elevated CRP, an acute phase reactant & a marker of inflammation, correlate with risk of developing AS.
19 The contemporary view of atherogenesis is expressed by the response-to-injury hypothesis. This model views AS as a chronic inflammatory response of the arterial wall to endothelial injury. Lesion progression occurs through interactions of modified lipoproteins, monocyte-derived macrophages, T lymphocytes, and the normal cellular constituents of the arterial wall. Endothelial injury  Endothelial injury is the initial triggering event in the development of lesions of AS.  This leads to endothelial dysfunction which initiate sequence of events.  Two of the major risk factors which act together to produce endothelial injury are: hemodynamic stress from HPTN and chronic dyslipidemia.  Other risk factors include: mechanical trauma, hemodynamic forces, immunological and chemical mechanisms, metabolic agent as chronic dyslipidemia, homocysteine, circulating toxins from systemic infections, viruses, hypoxia, radiation, carbon monoxide and tobacco products.  The role of hemodynamic forces in causing endothelial injury is supported by the distribution of atheromatous plaques at points of bifurcation of blood vessels which are under greatest shear stress.
20 Intimal smooth muscle cell proliferation  Endothelial injury causes adherence, aggregation and platelet release reaction at the site of exposed subendothelial CT and infiltration by inflammatory cells.  Proliferation of intimal SMCs and production of ECM are stimulated by IL- 1 and TNF-α released from invading monocyte-macrophages and by activated platelets at the site of endothelial injury.  These cytokines lead to local synthesis of PDGF & FGF which stimulate proliferation and migration of SMCs from their usual location in the media into the intima. • TGF-β & IFN-γ derived from activated T lymphocytes within lesions regulate the synthesis of collagen by SMCs. • SMC proliferation is also facilitated by NO and endothelin released from endothelial cells. • Intimal proliferation of SMCs is accompanied by synthesis of matrix proteins - collagen, elastic fibre proteins and proteoglycans.
21 Role of blood monocytes • Though blood monocytes do not possess receptors for normal LDL, LDL does appear in the monocyte cytoplasm to form foam cell. • Plasma LDL on entry into the intima undergoes oxidation. • Oxidised LDL attracts, proliferates, immobilizes and activate monocytes • Also, oxidized LDL is readily taken up by scavenger receptor on the monocyte to transform the monocyte to a lipid laden foam cell. • Oxidised LDL is cytotoxic to ECs & SMCs. • Death of foam cell by apoptosis releases lipid to form lipid core of plaque Role of dyslipidemia • Chronic dyslipidemia in itself may initiate endothelial injury and dysfunction by causing increased permeability. • Hypercholesterolemia with increased serum concentration of LDL promotes formation of foam cells, while high serum concentration of HDL has anti-atherogenic effect. Thrombosis • Endothelial injury exposes subendothelial CT resulting in formation of small platelet aggregates at the site and causing proliferation of SMCs. • This causes mild inflammatory reaction which together with foam cells is incorporated into the atheromatous plaque. • The lesions enlarge by attaching fibrin and cells from the blood so that thrombus becomes a part of atheromatous plaque.
22 • Atherosclerotic Plaque-The key processes in AS are intimal thickening and lipid accumulation • Atheromatous plaques (also called fibrous or fibro fatty plaques) impinge on the lumen of the artery and grossly appear white to yellow • Plaques vary from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses. Components of Atherosclerotic plaque Have three principal components: 1. Cells; SMCs, macrophages, and T cells 2. ECM; collagen, elastic fibers, and proteoglycans 3. Intracellular and extracellular lipid • These components occur in varying proportions and configurations in different lesions. Changes in Atherosclerotic Plaque Atherosclerotic plaques are susceptible to the following pathologic changes with clinical significance: 1. Rupture, ulceration, or erosion 2. Hemorrhage 3. Atheroembolism 4. Aneurysm formation • AS is a slowly evolving lesion usually requiring many decades to become significant. • However, acute plaque changes (e.g., rupture, thrombosis, or hematoma formation) can rapidly precipitate clinical sequelae (the so- called "clinical horizon“)
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24 1. Heart - MI, IHD. 2. Brain - Chronic ischemic brain damage, cerebral infarction and stroke. 3. Aorta - Aneurysm formation, thrombosis and embolization to other organs. 4. Small intestine - Ischemic bowel disease, infarction. 5. Lower extremities - Intermittent claudication, gangrene (peripheral vascular disease).
25 Primary prevention of AS Aims at the following, in persons who have not yet suffered a serious complication of AS;  Delaying atheroma formation  Encouraging regression of established lesions Involves:  Cessation of cigarette smoking  Control of hypertension  Weight loss  Exercise, and lowering total and LDL blood cholesterol levels while increasing HDL (e.g., by diet or through statins).  Statin use may also modulate the inflammatory state of the vascular wall. Risk factor stratification and reduction should even begin in childhood. Secondary prevention of AS Is intended to; Prevent recurrence of events such as MI or stroke in symptomatic patients Involves use of:  Aspirin (anti-platelet agent),  Statins, and beta blockers (to limit cardiac demand),  Surgical interventions (e.g., coronary artery bypass surgery, carotid endarterectomy). These can successfully reduce recurrent myocardial or cerebral events. N/B Atherosclerotic Vascular Disease (AVD)
26 Atherosclerosis is an intima-based lesion organized into a fibrous cap and an atheromatous (gruel-like) core and composed of SMCs, ECM, inflammatory cells, lipids, and necrotic debris. Atherogenesis is driven by an interplay of inflammation and injury to vessel wall cells. Atherosclerotic plaques accrue slowly over decades but may acutely cause symptoms d/t rupture, thrombosis, hemorrhage, or embolization. Risk factor recognition and reduction can reduce the incidence and severity of atherosclerosis-related disease.
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ARTERIOSCLEROSIS.pptx

  • 2. 2 1. ARTERIOSCLEROSIS 1. DEFINATION 2. TYPES SENILE ARTERIOSCLEROSIS HYPERTENSIVE ARTERIOSCLEROSIS MONCKEBERG’S ARTERIOSCLEROSIS (MEDIAL CALCIFIC SCLEROSIS) ATHEROSCLEROSIS 2. ATHEROSCLEROSIS (AS) DEFINATION ETIOLOGY FRACTIONS OF LIPIDS IN SERUM PATHOGENESIS OF AS PROGRESSION OF AS SYMPTOMS OF AS PREVENTION OF AVD SUMMARY N/B AVD – ATHEROSCLEROTIC VASCULAR DISEASE
  • 3. 3 Arteriosclerosis is a general term used to include all conditions with thickening and hardening of the arterial walls. TYPES OF ARTERIOSCLEROSIS 1. Senile arteriosclerosis (affects arteries) 2. Hypertensive arteriolosclerosis (affects arterioles) 3. Mönckeberg’s arteriosclerosis (Medial calcific sclerosis) (affects arteries) 4. Atherosclerosis (affects arteries) N/B Atherosclerosis, is the most common and most important form of arteriosclerosis; if not specified, the two terms are used interchangeably with each other.
  • 4. 4 • Is the thickening of media and intima of the arteries seen due to ageing. • Changes are non-selective and affect most of the arteries. • Possibly induced by stress and strain on vessel wall during life. MORPHOLOGIC FEATURES The changes are as under: 1. Fibroelastosis: Intima and media are thickened due to increase in elastic and collagen tissue. 2. Elastic reduplication: Internal elastic lamina split or reduplicated so that two wavy layers are seen. Eventually, the fibrotic changes result in age-related elevation of SBP.
  • 5. 5 Involves 3 morphologic forms of vascular disease affecting arterioles and small muscular arteries, these are: 1. Hyaline arteriolosclerosis 2. Hyperplastic arteriolosclerosis 3. Necrotizing arteriolitis. All the three types are common in hypertension but may occur due to other causes as well. HYALINE ARTERIOSCLEROSIS • May be seen physiologically due to ageing, or may occur pathologically in: Benign nephrosclerosis in hypertensives As a part of microangiopathy in diabetics MORPHOLOGIC CHANGES The visceral arterioles are particularly involved. The vascular walls are thickened and the lumina narrowed or even obliterated. Microscopically, the thickened vessel wall shows structureless, eosinophilic, hyaline material in the intima and media. PATHOGENESIS The exact pathogenesis is not known. However, the following hypotheses have been proposed: 1. The lesions result from leakage of components of plasma across the vascular endothelium. This is substantiated by the demonstration of Igs, complement, fibrin and lipids in the lesions. The permeability of the vessel wall is increased, d/t haemodyanamic stress in HPTN and metabolic stress in diabetes, so that these plasma components leak out and get deposited in the vessel wall. 2. The lesions may also be d/t immunologic reaction. 3. It might also be d/t normal aging process exaggerated in HPTN and DM.
  • 6. 6 HYPERPLASTIC/PROLIFERATIVE ARTERIOSCLEROSIS • Is a characteristic lesion of malignant hypertension • Other causes include HUS, scleroderma and toxemia of pregnancy. MORPHOLOGIC FEATURES The morphologic changes affect mainly the intima, especially of the interlobular arteries in the kidneys. Three types of intimal thickening may occur. 1. Onion-skin lesion 2. Mucinous intimal thickening 3. Fibrous intimal thickening Onion-skin lesion  Consists of loosely-placed concentric layers of hyperplastic intimal smooth muscle cells like the bulb of an onion. Mucinous intimal thickening  Is the deposition of amorphous ground substance, probably proteoglycans, with scanty cells. Fibrous intimal thickening  Is less common and consists of bundles of collagen, elastic fibres and hyaline deposits in the intima.  Severe intimal sclerosis results in narrowed or obliterated lumen.  With time, the lesions become more and more fibrotic. PATHOGENESIS Unclear. Probably, the changes result following: • Endothelial injury from systemic hypertension, hypoxia or immunologic damage leading to increased permeability. • A healing reaction occurs in the form of proliferation of smooth muscle cells with fibrosis.
  • 7. 7 NECROTIZING ARTERIOLITIS • In cases of severe HPTN and malignant HPTN, parts of small arteries and arterioles show changes of hyaline sclerosis and parts of these show necrosis, or necrosis may be superimposed on hyaline sclerosis. • However, hyaline sclerosis may not be always present in the vessel wall. MORPHOLOGIC FEATURES Besides the changes of hyaline sclerosis, the changes of necrotizing arteriolitis include: 1. Fibrinoid necrosis of vessel wall 2. Acute inflammatory infiltrate of neutrophils in the adventitia 3. Edema and hemorrhages often surround the affected vessels. PATHOGENESIS Since necrotizing arteriolitis occurs in vessels in which there is sudden and great elevation of pressure, the changes are said to result from direct physical injury to the vessel wall.
  • 8. 8
  • 9. 9 • Is calcification of the media of large and medium-sized muscular arteries, especially of the extremities and of the genital tract, in persons past the age of 50. • The condition occurs as an age-related degenerative process, and therefore, an example of dystrophic calcification, and has little or no clinical significance. • However, it also occurs in some pathological states like pseudoxanthoma elasticum and in idiopathic arterial calcification of infancy. MORPHOLOGIC FEATURES Medial calcification is often an incidental finding in X-rays of the affected sites having muscular arteries. The deposition of calcium salts in the media produces pipestem-like rigid tubes without causing narrowing of the lumen. Microscopically, It is characterised by deposits of calcium salts in the media without associated inflammatory reaction while the intima and the adventitia are spared. Often, coexistent changes of atherosclerosis are present altering the histologic appearance. PATHOGENESIS • Unknown, but it is considered as an age- related physiologic change due to prolonged effect of vasoconstriction.
  • 10. 10 • Is the thickening and hardening of large and medium-sized muscular arteries, primarily d/t involvement of tunica intima. • Characterised by fibro fatty 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. • Is the commonest and the most important of the arterial diseases. • Though any large and medium-sized artery may be involved in atherosclerosis, the most commonly affected are the aorta, the coronaries and the cerebral arterial systems. The major clinical syndromes resulting from ischemia d/t atherosclerosis are as under: 1. Heart (angina and MI or heart attacks) 2. Brain (transient cerebral ischemia and cerebral infarcts or strokes) 3. Other sequelae are: peripheral vascular disease, aneurysmal dilatation d/t weakened arterial wall, chronic IHD, ischemic encephalopathy and mesenteric arterial occlusion.
  • 11. 11 I. MAJOR RISK FACTORS A) Modifiable 1. Dyslipidemia 2. HPTN 3. DM 4. Smoking B) Constitutional 1. Increasing age 2. Male gender 3. Genetic abnormalities 4. Family history and racial factors II. EMERGING RISK FACTORS 1. Environmental influences 2. Obesity 3. Hormones: estrogen deficiency, oral contraceptives 4. Physical inactivity 5. Stressful life (Type A personality) 6. Homocystinuria 7. Role of alcohol 8. Prothrombotic factors 9. Infections (C. pneumoniae, Herpesvirus, CMV) 10.High CRP
  • 12. 12 A. MODIFIABLE BY LIFESTYLE AND/OR THERAPY 1. DYSLIPIDEMIA • Abnormalities in plasma lipoproteins is the most important major risk factor for atherosclerosis. • Hypercholesterolemia has directly proportionate relationship with AS and IHD. The following evidences are cited in support of this: 1. Atherosclerotic plaques contain cholesterol and cholesterol esters, derived from the LPs in blood. 2. Lesions of AS can be induced in experimental animals by feeding them with diet rich in cholesterol. 3. Individuals with hypercholesterolemia d/t various causes such as in DM, myxedema, nephrotic syndrome, von Gierke’s disease, xanthomatosis and familial hypercholesterolemia have increased risk of developing AS and IHD. 4. Populations having hypercholesterolemia have higher mortality from IHD. Dietary regulation and administration of cholesterol- lowering drugs (statins) have beneficial effect on reducing the risk of IHD.
  • 13. 13 Total cholesterol Desirable normal serum level is 140- 200 mg/dl Levels of borderline high are 200-240 mg/dl. Levels above 260 mg/dl in men and women between 30 and 50 years has three times higher risk of developing IHD as compared with people with cholesterol levels within normal limits. Triglycerides Normal serum level is below 150 mg/dl. Low-density lipoproteins (LDL) cholesterol Optimal serum level is <100 mg/dl. LDL is richest in cholesterol and has the maximum association with atherosclerosis. Very-low-density lipoprotein (VLDL) Carries much of the TGs and its blood levels therefore parallel with that of TGs; VLDL has less marked effect than LDL. High-density lipoproteins (HDL) cholesterol Normal desirable serum level is <50 mg/dl. It’s protective (‘good cholesterol’) against atherosclerosis. N/B 1. Total cholesterol – <200mg/dl 2. TGs/VLDL – <150mg/dl 3. LDL – <100mg/dl 4. HDL - <50mg/dl
  • 14. 14 PLASMA CHOLESTROL LEVELS ELEVATED BY: 1. Diet containing large quantities of saturated fats (e.g. in eggs, meat, milk, butter etc) 2. Diet containing large quantities of trans fats (i.e. unsaturated fats produced by artificial hydrogenation of polyunsaturated fats) 3. High intake of total number of calories from carbohydrates, proteins, alcohol & sweets. 4. Familial hypercholesterolemia, an autosomal codominant disorder, characterised by elevated LDL cholesterol and normal TGs and occurrence of xanthomas and premature CAD. It occurs d/t mutations in LDL receptor gene. N/B  High serum cholesterol levels increases the risk of AS PLASMA CHOLESTEROL LEVELS LOWERED BY:  Diet low in saturated fats and high in poly- unsaturated fats  Diet having omega-3 fatty acids (e.g. in fish, fish oils etc).  Use of statins, to lower LDL in particular, and total cholesterol in general, in the management of dyslipidemia (Inhibits HMG-CoA reductase)  Weight loss, exercise and use of nicotinic acid to raise HDL  Moderate consumption of ethanol to raise HDL N/B Currently, preferred term for hyperlipidemia is dyslipidemia because one risky plasma lipoprotein (LDL) is elevated and needs to be brought down, while the other good plasma lipoprotein (HDL) when low requires to be raised.
  • 15. 15 2. HYPERTENSION • Is a risk factor for all clinical manifestations of AS. • Doubles the risk of all forms of cardiovascular disease. • Acts probably by mechanical injury to the arterial wall d/t increased BP. • Elevation of SBP over160 mmHg or DBP over 95 mmHg is associated with five times higher risk of developing IHD than in people with BP within normal range (140/90 mmHg or less) 3. SMOKING • The extent and severity of AS are much greater in smokers than in non-smokers. • 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 AS in smokers is d/t: • Reduced level of HDL • Deranged coagulation system • Accumulation of carbon monoxide in the blood that produces carboxyHb and eventually hypoxia in the arterial wall favouring AS.
  • 16. 16 4. DIABETES MELLITUS Clinical manifestations of AS are far more common and develop at an early age in people with both type 1 and type 2 DM. In particular, association of type 2 DM characterised by metabolic (insulin resistance) syndrome and abnormal lipid profile termed ‘diabetic dyslipidemia’ 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. The causes of increased severity of AS are complex and numerous which include endothelial dysfunction, increased aggregation of platelets, increased LDL and decreased HDL.
  • 17. 17 B. CONSTITUTIONAL FACTORS 1. INCREASING AGE • AS is an age-related disease. • Though early lesions of AS 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. MALE GENDER • Premenopausal women are relatively protected against atherosclerosis and its consequences compared with men of the same age • MI and other complications of AS are uncommon in premenopausal women unless otherwise predisposed by diabetes, hyperlipidemia, or severe HPTN. • After menopause, the incidence of AS-related diseases increases and with greater age exceeds that of men. • The lower incidence of AS in women of premenopausal age, is probably d/t high levels of estrogen and HDLs, both of which have anti-atherogenic influence. 3. GENETIC ABNORMALITIES • Hereditary derangements of LP metabolism predispose individual to high blood lipid level and familial hypercholesterolemia. 4. FAMILY Hx AND RACIAL FACTORS • Familial predisposition is related to risk factors like diabetes, HPTN and hyperlipoproteinemia. • Racial differences also exist; Blacks have generally less severe AS than Whites.
  • 18. 18 1. Environmental influences; Theris higher incidence of AS in developed countries and low prevalence in underdeveloped countries. 2. Metabolic syndrome characterised by abdominal obesity, glucose intolerance, insulin resistance, dyslipidemia and HPTN, is associated with increased risk. 3. Use of exogenous hormones (oral contraceptives) or endogenous estrogen deficiency (in postmenopausal women) increases the risk of developing MI or stroke. 4. Physical inactivity and lack of exercise increases the risk of developing AS and its complications. 5. Stressful life style, termed as ‘type A’ behavior pattern, characterised by aggressiveness, competitive drive, ambitiousness and a sense of urgency, is associated with enhanced risk of IHD compared with ‘type B’ behavior of relaxed and happy go-lucky type. 6. Hypercystinemia d/t elevated serum homocysteine level from low folate and vit B12 have a relationship with CAD and its consequences. 7. Homocystinuria, an uncommon inborn error of metabolism, having hypercystinemia have early AS and CAD. 8. Prothrombotic factors and elevated fibrinogen levels favour formation of thrombi; the gravest complication of AS. 9. Role of infections, particularly of Chlamydia pneumoniae, herpesvirus and CMV, has been found in coronary atherosclerotic lesions by causing inflammation. Possibly, infections may be acting in combination with some other factors. 10. Elevated CRP, an acute phase reactant & a marker of inflammation, correlate with risk of developing AS.
  • 19. 19 The contemporary view of atherogenesis is expressed by the response-to-injury hypothesis. This model views AS as a chronic inflammatory response of the arterial wall to endothelial injury. Lesion progression occurs through interactions of modified lipoproteins, monocyte-derived macrophages, T lymphocytes, and the normal cellular constituents of the arterial wall. Endothelial injury  Endothelial injury is the initial triggering event in the development of lesions of AS.  This leads to endothelial dysfunction which initiate sequence of events.  Two of the major risk factors which act together to produce endothelial injury are: hemodynamic stress from HPTN and chronic dyslipidemia.  Other risk factors include: mechanical trauma, hemodynamic forces, immunological and chemical mechanisms, metabolic agent as chronic dyslipidemia, homocysteine, circulating toxins from systemic infections, viruses, hypoxia, radiation, carbon monoxide and tobacco products.  The role of hemodynamic forces in causing endothelial injury is supported by the distribution of atheromatous plaques at points of bifurcation of blood vessels which are under greatest shear stress.
  • 20. 20 Intimal smooth muscle cell proliferation  Endothelial injury causes adherence, aggregation and platelet release reaction at the site of exposed subendothelial CT and infiltration by inflammatory cells.  Proliferation of intimal SMCs and production of ECM are stimulated by IL- 1 and TNF-α released from invading monocyte-macrophages and by activated platelets at the site of endothelial injury.  These cytokines lead to local synthesis of PDGF & FGF which stimulate proliferation and migration of SMCs from their usual location in the media into the intima. • TGF-β & IFN-γ derived from activated T lymphocytes within lesions regulate the synthesis of collagen by SMCs. • SMC proliferation is also facilitated by NO and endothelin released from endothelial cells. • Intimal proliferation of SMCs is accompanied by synthesis of matrix proteins - collagen, elastic fibre proteins and proteoglycans.
  • 21. 21 Role of blood monocytes • Though blood monocytes do not possess receptors for normal LDL, LDL does appear in the monocyte cytoplasm to form foam cell. • Plasma LDL on entry into the intima undergoes oxidation. • Oxidised LDL attracts, proliferates, immobilizes and activate monocytes • Also, oxidized LDL is readily taken up by scavenger receptor on the monocyte to transform the monocyte to a lipid laden foam cell. • Oxidised LDL is cytotoxic to ECs & SMCs. • Death of foam cell by apoptosis releases lipid to form lipid core of plaque Role of dyslipidemia • Chronic dyslipidemia in itself may initiate endothelial injury and dysfunction by causing increased permeability. • Hypercholesterolemia with increased serum concentration of LDL promotes formation of foam cells, while high serum concentration of HDL has anti-atherogenic effect. Thrombosis • Endothelial injury exposes subendothelial CT resulting in formation of small platelet aggregates at the site and causing proliferation of SMCs. • This causes mild inflammatory reaction which together with foam cells is incorporated into the atheromatous plaque. • The lesions enlarge by attaching fibrin and cells from the blood so that thrombus becomes a part of atheromatous plaque.
  • 22. 22 • Atherosclerotic Plaque-The key processes in AS are intimal thickening and lipid accumulation • Atheromatous plaques (also called fibrous or fibro fatty plaques) impinge on the lumen of the artery and grossly appear white to yellow • Plaques vary from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses. Components of Atherosclerotic plaque Have three principal components: 1. Cells; SMCs, macrophages, and T cells 2. ECM; collagen, elastic fibers, and proteoglycans 3. Intracellular and extracellular lipid • These components occur in varying proportions and configurations in different lesions. Changes in Atherosclerotic Plaque Atherosclerotic plaques are susceptible to the following pathologic changes with clinical significance: 1. Rupture, ulceration, or erosion 2. Hemorrhage 3. Atheroembolism 4. Aneurysm formation • AS is a slowly evolving lesion usually requiring many decades to become significant. • However, acute plaque changes (e.g., rupture, thrombosis, or hematoma formation) can rapidly precipitate clinical sequelae (the so- called "clinical horizon“)
  • 23. 23
  • 24. 24 1. Heart - MI, IHD. 2. Brain - Chronic ischemic brain damage, cerebral infarction and stroke. 3. Aorta - Aneurysm formation, thrombosis and embolization to other organs. 4. Small intestine - Ischemic bowel disease, infarction. 5. Lower extremities - Intermittent claudication, gangrene (peripheral vascular disease).
  • 25. 25 Primary prevention of AS Aims at the following, in persons who have not yet suffered a serious complication of AS;  Delaying atheroma formation  Encouraging regression of established lesions Involves:  Cessation of cigarette smoking  Control of hypertension  Weight loss  Exercise, and lowering total and LDL blood cholesterol levels while increasing HDL (e.g., by diet or through statins).  Statin use may also modulate the inflammatory state of the vascular wall. Risk factor stratification and reduction should even begin in childhood. Secondary prevention of AS Is intended to; Prevent recurrence of events such as MI or stroke in symptomatic patients Involves use of:  Aspirin (anti-platelet agent),  Statins, and beta blockers (to limit cardiac demand),  Surgical interventions (e.g., coronary artery bypass surgery, carotid endarterectomy). These can successfully reduce recurrent myocardial or cerebral events. N/B Atherosclerotic Vascular Disease (AVD)
  • 26. 26 Atherosclerosis is an intima-based lesion organized into a fibrous cap and an atheromatous (gruel-like) core and composed of SMCs, ECM, inflammatory cells, lipids, and necrotic debris. Atherogenesis is driven by an interplay of inflammation and injury to vessel wall cells. Atherosclerotic plaques accrue slowly over decades but may acutely cause symptoms d/t rupture, thrombosis, hemorrhage, or embolization. Risk factor recognition and reduction can reduce the incidence and severity of atherosclerosis-related disease.