Blood Vessels PDF

Systemic Pathology CVS BLOODvessels Blood VESSELS Structure of blood vessels: Vessel walls are formed of...

Systemic Pathology CVS BLOODvessels Blood VESSELS Structure of blood vessels: Vessel walls are formed of three concentric layers: Intima Media Adventitia. Arteries Capillaries Veins Lined by endothelial cells have larger diameter, surrounded by pericytes wider lumen, thinner wall, (smooth muscle like cells) with less distinct layers Large elastic arteries Medium muscular arteries Small arteries Aorta, aortic arch vessels, Coronary arteries & (< 2mm diameter), arterioles lie iliac and pulmonary arteries renal arteries within the CT of organs In the media, elastic fibers Elastic fibers are arranged in an Their media is mostly formed alternate with smooth muscle internal and external elastic of smooth muscles. cells. lamina Arterioles regulate the blood The outer 2/3 of the media is flow resistance. supplied by Small arterioles within the adventitia (vasa vasorum ) The inner third receives oxygen and nutrients by direct diffusion from the vessel lumen. Dr. Abdelrahman Khalifa M.D. PhD. 1 Systemic Pathology CVS Hypertension Definition: It is the persistent elevation of resting blood pressure above 140/90. Types of hypertension: Etiological classification Clinico-pathological classification Primary (Essential hypertension) Benign Hypertension Secondary hypertension. Malignant hypertension The rise of blood pressure is rapid. The blood pressure usually exceeds 200/120. It may start de novo, or it may appear suddenly in a person with benign hypertension (accelerated hypertension). Etiology and pathogenesis of essential hypertension: Blood pressure is a factor of total peripheral resistance and cardiac output. Impaired renal sodium excretion leads to Increased vascular resistance due to increased blood volume with increase hypersensitivity of blood vessels to circulating cardiac output. catecholamines. Genetic factors: There is familial clustering of hypertension, may be linked to specific Environmental factors as stress, obesity, variation of angiotensinogen and and excess salt intake. angiotensin II receptors. Dr. Abdelrahman Khalifa M.D. PhD. 2 Systemic Pathology CVS Causes of secondary hypertension: Renal causes Renal artery stenosis Acute and chronic glomerulonephritis Polycystic kidney Chronic pyelonephritis. Endocrine causes Adrenocortical hyperfunction: primary aldosteronism, Cushing syndrome. Exogenous corticosteroids Pheochromocytoma (adrenal medulla tumor secreting catechol amines). Hyperthyroidism Coarctation of aorta (upper half of the body) The mechanism of renal hypertension is through Excess renin secretion by the juxtaglomerular cells of the kidney converts plasma angiotensinogen to angiotensin I angiotensin I converted to angiotensin II by angiotensin-converting enzyme Angiotensin II raises blood pressure by Vasoconstriction stimulation of aldosterone secretion → ↑ in distal tubular reabsorption of Na ↑ Peripheral Resistance BB ↑ Blood Volume Dr. Abdelrahman Khalifa M.D. PhD. 3 Systemic Pathology CVS BENIGN HYPERTENSION: Pathological changes: 1. Blood vessels: a. Hyaline arteriolosclerosis: Generalized changes of small arteries and arterioles. Homogeneous pink hyaline thickening of the intima and media with narrowing of the lumen. It results due to endothelial injury by Figure 1 Diagram of vascular changes in hemodynamic stress and leakage of benign hypertension. (Left): Hyalinosis. plasma components into the intima. (Right): Fibroelastic hyperplasia b. Fibroelastic hyperplasia (elastosis): Affects larger arteries. There is duplication of internal elastic lamina with thickening of the media. 2. Heart Concentric hypertrophy of the left ventricle. Acceleration of atherosclerosis, together with increased oxygen demand due to muscle hypertrophy leads to ischemic heart disease and angina pectoris. 3. The Kidney Benign nephrosclerosis (primary contracted kidney). Gross: Both kidneys are symmetrically atrophic. The renal surface shows diffuse fine granularity (resembling leather grain) Microscopic: Hyaline arteriolosclerosis of afferent arterioles (describe), resulting in sclerosis of glomeruli, diffuse tubular atrophy, and fibrosis. The large arteries show fibroelastic hyperplasia A decrease in GFR and mild degree of proteinuria may be present. Complications and causes of death in benign hypertension: 1. Heart failure. 2. Cerebral hemorrhage. 3. Chronic renal failure (rare). Dr. Abdelrahman Khalifa M.D. PhD. 4 Systemic Pathology CVS MALIGNANT HYPERTENSION: Pathological changes 1. Blood vessels o Fibrinoid necrosis of the small arteries and arterioles (granular eosinophilic material in vessel wall). o Hyperplastic arteriolosclerosis: onion-skin Figure 2 Vascular changes of malignant appearance of vessels due to hyperplasia of hypertension (Left): Fibrinoid necrosis of smooth muscle cells and connective tissue. glomeruli and afferent arteriole (Right): hyperplastic arteriolosclerosis. 2. The kidney Gross: The kidney is usually normal in size or shrunken (in case of accelerated hypertension). The outer surface shows pin-point hemorrhages (Flea- bitten kidney) Microscopic: Arterioles show fibrinoid necrosis. Larger arteries show hyperplastic arteriolosclerosis. Necrosis may also involve the glomeruli with microthrombi. 3. The retina (hypertensive retinopathy): Retinal hemorrhages and exudates, and papilledema (edema of optic disc, leading to blurring of vision). 4. The heart is not markedly hypertrophied due to short duration. Complications and causes of death: 1. Acute renal failure. 2. Cerebral hemorrhage. 3. Heart failure (rarely). Figure 3 The kidney in hypertension (Left): Benign nephrosclerosis: kidney with leather grain surface, (Right): Kidney in malignant hypertension showing pinpoint hemorrhages (Flea -bitten kidney). Dr. Abdelrahman Khalifa M.D. PhD. 5 Systemic Pathology CVS Arteriosclerosis Arteriosclerosis means hardening of the arteries. Three distinct types are recognized: 1. Arteriolosclerosis: It affects small arteries and arteriol es in hypertension: Hyaline arteriolosclerosis and hyperplastic arteriolosclerosis. 2. Monckeberg calcific medial sclerosis: Calcific deposits in muscular arteries, in patients older than 50 years. The lesion does not encroach on vascular lumen and is of no clinical significance. 3. Atherosclerosis: Thickening and hardening of the vessel due to lipid deposition in the subintimal connective tissue. Atherosclerosis Definition: Atherosclerosis is a disease of blood vessels characterized by Patchy Intimal Thickening as a result of lipid deposition, covered by fibrous cap. Risk factors: Major risk factors ↑ low density lipoproteins (LDL) (bad cholesterol) which distributes cholesterol to peripheral tissues. ↓ high density lipoproteins (HDL) (good cholesterol), which Hyperlipidemia mobilizes cholesterol from developing plaques and transport to the (hypercholesterolemia) liver to be excreted in bile. Increased LDL may be hereditary or related to diet (increase intake of animal fat or trans fats from artificial hydrogenation of oils). Exercise and omega 3 fatty acids in fish oil increases HDL levels. Hypertension Both systolic and diastolic BP are important. The high pressure causes endothelial injury Diabetes mellitus causes hypercholesterolemia Smoking Dr. Abdelrahman Khalifa M.D. PhD. 6 Systemic Pathology CVS Constitutional risk factors Advanced age Atherosclerosis becomes clinically apparent at 40-60 years Women in child bearing age are relatively protected (by estrogen) but Gender the incidence increases after the menopause Family history is an important independent risk factor. ▪ Hereditary hypercholesterolemia accounts for a small percentage of Genetics cases. ▪ Familial risk is due to the fact that the major risk factor (diabetes and hypertension) are polygenic in nature (controlled by multiple genes). ↓ Exercise Lack of exercise and living a competitive stressful life style Pathogenesis: (interplay of endothelial injury and inflammation). a) Hyperlipidemia, hypertension, smoking and hemodynamic forces cause endothelial injury (atheromatous plaques tend to occur at ostia of vessels, at branching points of vessels where turbulence is high). The endothelial injury leads to increased permeability to LDL, which accumulates in the intima. b) Platelets adhere to the endothelium, also monocytes adhere to the endothelium and migrate into the intima and transform to macrophages. c) Endothelial cells as well as monocytes release oxygen free radicals which cause oxidation of soluble LDL to insoluble oxidized LDL. Insoluble LDL and cholesterol crystals are taken up by macrophages which change to foam cells. d) Under the effect of platelet derived growth factors, smooth muscle cells from the media migrate to the intima and proliferate. They secrete extracellular matrix (ECM) namely collagen. e) T cells are recruited to the intima, are activated and produce inflammatory cytokines which stimulate macrophages, endothelial cells and smooth muscle cells (the exact antigen and cause of T cell activation is not clear). Dr. Abdelrahman Khalifa M.D. PhD. 7 Systemic Pathology CVS Figure 4 Pathogenesis of atherosclerosis. Morphology: 1- Fatty Streaks. o Fatty streaks are the earliest lesions in atherosclerosis as early as age of 10. o They are composed of lipid-filled foamy macrophages. o They are seen grossly as elongated streaks 1 cm or more in length o These lesions are not significantly raised and do not cause any flow disturbance. 2- Atheromatous Plaque. Figure 5 Pathology of atherosclerosis: A. Fatty ▪ These are areas of intimal thickening and streaks. B. Atheromatous plaques. (Lower lipid accumulation. Left), Atheroma, C lipid core, F fibrous cap. (Lower right) Early lesions: foam cells ▪ White to yellow raised lesions 0.3-1.5 cm in diameter, but can coalesce to form larger masses. Superadded thrombosis give the lesions a red-brown color. ▪ Lesions affect only part of the circumference of vessels so on cross section the lesion appears eccentric. Dr. Abdelrahman Khalifa M.D. PhD. 8 Systemic Pathology CVS Sites: 1. In descending order, the most extensively involved vessels are the infrarenal abdominal aorta, the coronary arteries, the popliteal arteries, the internal carotid arteries, and the vessels of the circle of Willis. 2. Vessels of the upper extremities are usually spared, as are the mesenteric and renal arteries, except at their ostia. 3. Nevertheless, in an individual case, the severity of atherosclerosis in one artery does not predict its severity in another. Microscopic picture: ▪ Atheromatous plaques consist of a central lipid core covered by a fibrous cap of smooth muscle cells and collagen. ▪ The central core contains lipids, (cholesterol, necrotic debris, lipid laden macrophages (foam cells, fibrin and other plasma proteins). The cholesterol appears as needle shaped clefts (because the cholesterol dissolves during slide preparation). ▪ The shoulder region, where the fibrous cap meets the vessel wall is more cellular and contains macrophages, T cells and smooth muscle cells. Later it shows neovascularization (proliferated small blood vessels). ▪ Secondary changes include ulceration, thrombosis and calcification. ▪ The media opposite the plaques are thin due to smooth muscle atrophy and loss. Effect and Complications: A. In medium sized arteries: 1. Artery stenosis: leading to diminished tissue perfusion and ischemia e.g. ▪ Cardiac ischemia and angina pectoris. ▪ Lower limb ischemia and intermittent claudication in femoral and popliteal artery lesions. 2. Complete arterial occlusion: due to rupture of plaque or hemorrhage into the plaque from neo-vascularization, or superadded thrombosis. B. In Large arteries as aorta: 1. Atheroembolism: Plaque rupture can discharge atherosclerotic debris into the bloodstream, producing microemboli. 2. Thromboembolism: Thrombosis on top of atheromatous plaques with embolization 3. Aneurysm formation. Pressure atrophy of the media resulting in aneurysmal dilation and potential rupture. Dr. Abdelrahman Khalifa M.D. PhD. 9 Systemic Pathology CVS Vasculitis Definition: Vessel wall inflammation. Types & causes: 1. Infectious vasculitis: Bacterial or fungal infections of arterial wall (may lead to mycotic aneurysm.) Syphilitic aortitis. 2. Non-infectious vasculitis: Hypersensitivity vasculitis: These are immune mediated diseases, commonly by immune complex deposition in vessel wall. These are multisystem disorders but affecting mainly highly vascular tissues as the skin, glomerulus, lung and GIT. e.g. polyarteritis nodosa, systemic lupus erythematosus, Henoch-Schoenlein purpura. Buerger's disease (thrombo-angitis obliterans) related to smoking. POLYARTERITIS NODOSA (PAN): ▪ An immune mediated systemic disease affecting males more than female, affecting small & medium sized arteries. ▪ One third of patients have chronic hepatitis B infection, which lead to formation of immune complex deposits containing B antigens in the vessel wall. Morphology ▪ Segmental transmural fibrinoid necrosis of arterial wall, surrounded by an acute inflammatory reaction. ▪ Lesions usually affect only part of the vessel circumference. Complications: 1- Thrombosis with vascular occlusion or emboli resulting in infarctions. 2- Aneurysm due to segmental inflammatory weakening of the arterial wall. Occurs especially in coronaries, cerebral or mesenteric arteries. 3- Rupture resulting in tissue hemorrhages e.g. melena. Dr. Abdelrahman Khalifa M.D. PhD. 10 Systemic Pathology CVS THROMBANGIITIS OBLITERANS (BURGER'S DISEASE): Definition: A segmental, inflammatory disease that most commonly affects the tibial and radial arteries, adjacent veins, and nerves (neurovascular bundle). It occurs almost exclusively in heavy smokers. Morphology: There is a sharply segmental acute transmural inflammation with microabscess formation. The inflammation often extends to adjacent veins and nerves. Thrombosis, organization and recanalization often occurs. Clinical picture: it affects mainly the legs, maybe the hands, with severe pain and progressive ischemic changes which may end in gangrene. Aneurysms Definition: Localized permanent arterial wall dilatation. Pathogenesis: Weakness of the vessel wall due to one of the following Causes: 1. Congenital absence of muscle wall and replacement by fibrous tissue. 2. Loss of smooth muscle cells as in Atherosclerosis: Thickened intima may cause ischemia of the media due to decreased diffusion of nutrients. Also thickened vasa vasorum by hypertension may cause ischemia of the outer media. Common site of atherosclerotic aneurysm is abdominal aorta. Syphlitic aortitis: Inflammation of the aorta in tertiary syphilis with endarteritis obliterans of vasa vasorum causing ischemia of the media, with loss of muscle cells. Syphilitic aneurysm occurs in ascending aorta. 3. Weakening of the arterial wall secondary to infection resulting in the so-called mycotic aneurysm. Mycotic aneurysms result from Embolization of infected embolus as a complication of infective endocarditis. Commonest site is in the cerebral arteries. As an extension of an adjacent suppurative process. 4. Vasculitis. Immune mediated inflammation of arteries weaken the vessel wall leading to small arterial dilatation as in polyarteritis nodosa. Dr. Abdelrahman Khalifa M.D. PhD. 11 Systemic Pathology CVS Classification of aneurysms: Aneurysms may be classified by shape into: 1. Saccular aneurysm are outpouchings from 5 to 20 cm, from one side of arterial wall, often with a contained thrombus. 2. Fusiform aneurysms are circumferential Dilatations up to 20 cm in diameter. These commonly involve aortic arch, the abdominal aorta and iliac arteries. False aneurysms (pseudoaneurysm) arise due to a penetrating injury in arterial wall leading to the formation of an extravascular hematoma which becomes surrounded by adventitial fibrosis, forming a sac communicating with the vascular lumen (pulsating hematoma). Examples of penetrating injuries: bullets or shrapnels, femoral artery puncture during arteriography or percutaneous angioplasty. Figure 6 Types of aneurysm Aneurysms may be classified according to etiology: 1. Congenital aneurysm: Small berry aneurysm of cerebral arteries at the branching of the circle of Willis. Rupture leads to subarachnoid hemorrhage. 2. Atherosclerotic aneurysm in abdominal aorta, iliac arteries. They are saccular or fusiform in shape. 3. Syphilitic aneurysm affects ascending part or arch of aorta. Saccular in appearance. 4. Mycotic aneurysm: cerebral, coronary, mesenteric. 5. Polyarteritis nodosa. Dr. Abdelrahman Khalifa M.D. PhD. 12 Systemic Pathology CVS Complications of aneurysms: 1. Rupture causing hemorrhage. 2. Mural thrombus formation with possible occlusion of ostia of vessels branching off the aorta e.g. renal or mesenteric artery. Embolism may occur. 3. Pressure on surrounding structures (e.g. vertebrae in cases of aortic aneurysm. Acute aortic dissection (dissecting aortic aneurysm) Blood is forced through a tear in the intima of the aorta and tracks down the aorta splitting the media in two, forming a blood-filled channel within the aortic wall. Causes: 1- Hypertension is the main cause, with cases presenting at age 40-60. 2- Marfan syndrome: congenital absence of fibrillin, a glycoprotein closely associated with elastic fibers. This occurs in younger patients. Figure 7 Aortic dissection. Morphology: 1. The tear commonly start in the aorta within 10 cm of aortic valve. The dissection spreads distally or towards the heart. 2. Microscopically: cystic medial necrosis may be seen especially in cases associated with Marfan syndrome. Medial necrosis is characterized by mucoid degeneration and elastic fiber fragmentation. 3. External rupture causes massive hemorrhage or cardiac tamponade if it occurs in the pericardial cavity. Clinical picture: Sudden onset of severe pain starting in the chest, radiating to the back between the scapulae as the dissection progresses. It is associated with high mortality and treatment is surgical. Dr. Abdelrahman Khalifa M.D. PhD. 13 Systemic Pathology CVS Varicose veins Definition: Varicose veins are abnormally dilated, tortuous veins, produced by prolonged, increased intraluminal pressure leading to vessel dilation and incompetence of the venous valves. Etiology ▪ Familial predisposition. ▪ Risk factors include occupations with prolonged standing, obesity and pregnancy. Complications: 1. Pain, congestion, edema and stasis dermatitis. 2. Chronic varicose ulcer (poor wound healing and superadded infection). Varicose veins of the esophagus (esophageal varices): ▪ Esophageal varices complicate portal hypertension of any cause, cirrhosis and bilharzial periportal fibrosis. ▪ This leads to the opening of porta-systemic shunts and increased blood flow to the veins in lower esophagus. ▪ May rupture and cause massive hemorrhage. Hemorrhoids: ▪ Varicose dilatation of veins at the anorectal junction from prolonged pelvic venous congestion associated with pregnancy and straining at defecation. ▪ They are a source of bleeding per rectum, liable to thrombosis and painful ulceration. Dr. Abdelrahman Khalifa M.D. PhD. 14 Systemic Pathology CVS FORMATIVE ASSESSMENT SAQ: List risk factors for atherosclerosis MCQ 1. The most common site of atherosclerotic aneurysm is: a) Ascending aorta b) Abdominal aorta c) Femoral artery d) Carotid artery. 2. Which one of the following is not involved in the etiology of secondary hypertension a) Atherosclerosis. b) Renal artery stenosis. c) Chronic glomerulonephritis. d) Pheochromocytoma. 3. The most common cause of death in cases of malignant hypertension. a) Chronic renal failure. b) Acute renal failure. c) Heart failure. d) Cerebral thrombosis. Dr. Abdelrahman Khalifa M.D. PhD. 15 Systemic Pathology CVS The Heart Congenital Heart Disease Congenital anomalies of the heart are due to faulty embryogenesis during weeks 3-8 of gestation. The most severe anomalies are incompatible with intrauterine survival and significant heart malformations are common among premature infants and still born. Etiology: 1. Sporadic genetic abnormalities are the major known causes of congenital heart disease. They can take the form of single gene mutations, small chromosomal losses, and additions. Also in association with Trisomy 21 known as Down syndrome. Rarely these genetic abnormalities are hereditary. 2. Environmental factors (alone or in combination with genetic factors) a) Congenital rubella infection (infection of the mother with German measles during pregnancy). b) Gestational diabetes. c) Teratogen exposure: Thalidomide, alcohol, unknown teratogens. Exposure to radiation during pregnancy d) Nutritional factors may also influence risk. For instance, folate supplementation during early pregnancy may reduce congenital heart disease risk. Types Most of the structural anomalies in congenital heart disease can be organized into three major categories: ▪ Malformations causing a left-to-right shunt. ▪ Malformations causing a right-to-left shunt. ▪ Malformations causing an obstruction e.g. Aortic or pulmonary valve stenosis. Dr. Abdelrahman Khalifa M.D. PhD. 16 Systemic Pathology CVS I. CONGENITAL HEART DISEASE WITH LEFT TO RIGHT SHUNT (NON-CYANOTIC): These are the most common type of congenital heart disease. 1- Ventricular septal defect (VSD): a) Membranous VSD usually large & present in the membranous part of the septum. b) Muscular VSD usually small less than 0.5 cm (Roger's disease). Effect & complications: 1. VSDs may be isolated or associated with Fallot tetralogy. 2. Smaller lesions are generally well tolerated for years and may not be recognized until much later in life. 3. Large defects cause significant left-to-right shunting, leading to early right ventricular hypertrophy and pulmonary hypertension, resulting in shunt reversal, cyanosis, and death. 4. Infective endocarditis opposite the shunt. 2- Atrial septal defect (ASD): ▪ ASDs result in a left-to-right shunt (higher pressure in left atrium) ▪ A murmur is often present as a result of excessive flow through the pulmonary valve and/or through the ASD. ▪ ASDs are generally well tolerated and usually do not become symptomatic before age 30; irreversible pulmonary hypertension is unusual. ▪ ASD closure (surgical or catheter-based) reverses the hemodynamic abnormalities and prevents the complications, including heart failure, paradoxical embolization, and irreversible pulmonary hypertension. Dr. Abdelrahman Khalifa M.D. PhD. 17 Systemic Pathology CVS II. CONGENITAL HEART DISEASE WITH RIGHT-TO-LEFT SHUNTS (CYANOTIC CONGENITAL HEART DISEASE) 1- Fallot's Tetralogy 1. Pulmonary stenosis 2. RV hypertrophy. 3. VSD 4. Overriding of aorta (aorta opening in both Rt. & It. ventricles). Effects & complications: Right to Left Shunt with: 1. Cyanosis. 2. Secondary polycythemia. 3. Clubbing of fingers. 4. Infective endocarditis. Endocarditis & Valvular Diseases ENDOCARDITIS Definition: Inflammation of valvular & or mural endocardium. It may be infective or non-infective. Valvular endocarditis is characterized by vegetations, which are small platelet (pale) thrombi on valve cusps. Etiology & types: A) Non infective endocarditis: 1) Rheumatic endocarditis. Immune mediated (see next section). 2) Endocarditis of systemic lupus erythematosus (SLE). (Libmann Sack's endocarditis). 3) Non-bacterial thrombotic endocarditis. It occurs in prolonged debilitating diseases as chronic sepsis, uremia & malignancy. It represents a hypercoagulable state. They can be the source of systemic emboli. B) Infective endocarditis (see later). Dr. Abdelrahman Khalifa M.D. PhD. 18 Systemic Pathology CVS Rheumatic Fever & Rheumatic Heart Disease Definition: Rheumatic fever is an inflammatory, immune mediated multisystem disease affecting most importantly the heart in the form of pancarditis (inflammation of all layers of heart). It occurs as a complication of streptococcal pharyngitis & tonsillitis. Etiology This is a disease, which is endemic in Egypt and low socio-economic developing countries due to overcrowding, low resistance and an increased frequency of airborne respiratory tract infections The condition usually starts in children & adolescents 5-15 years, 2-3 weeks after streptococcal sore throat or streptococcal upper respiratory tract infection by group A, beta hemolytic streptococcus. Acute rheumatic carditis is a common manifestation of active rheumatic fever and may progress over time to chronic rheumatic heart disease (RHD), mainly manifesting as valvular abnormalities. Valvular manifestations may begin to appear years after the first attack of rheumatic fever or after repeated attacks produce significant valve deformity. Pathogenesis: Acute rheumatic fever results from abnormal host immune responses to group A streptococcal antigens that cross-react with host proteins. Such abnormal response may be genetically determined. Antibodies and CD4+ T cells directed against streptococcal M proteins recognize cardiac self- antigens. Antibody binding can activate complement, as well as recruit Fc-receptor bearing cells (neutrophils and macrophages). Cytokine production by the stimulated T cells leads to macrophage activation (e.g., within Aschoff bodies). Damage to heart tissue may thus be caused by a combination of antibody- and T cell- mediated reactions. Dr. Abdelrahman Khalifa M.D. PhD. 19 Systemic Pathology CVS Morphology: Acute Rheumatic Fever Cardiac manifestations a) Pericardium: Fibrinous pericarditis (Fibrin deposited between the visceral and parietal layers gives the appearance of bread & butter pericarditis) b) Myocardium: The distinctive lesions of rheumatic fever is called Aschoff bodies. Gross appearance: 1-2 mm grey nodules in myocardium Microscopic: Aschoff bodies are seen in the myocardial interstitial tissue, in a paravascular location. They consist of foci of fibrinoid degeneration surrounded by T lymphocytes, occasional plasma cells, and plump activated macrophages called Anitschkow cells/caterpillar cells, Some of the marcophages become multinucleated. c) Endocardium (endocarditis): Valvular endocardium: The mitral valve is the most commonly affected. This is followed in frequency by the aortic and tricuspid, rarely the pulmonary valve. Gross: ▪ Swollen cusps carrying small 1-2 mm pale brown vegetations. Figure 8 showing (Left) Aschoff bodies in a ▪ The vegetations are arranged at the line of closure of paravascular location in myocardium., (Right) the cusps in a regular linear pattern (site of most Aschoff bodies composed of lymphocytes and friction due to closure of valve and trauma of blood macrophages (caterpillar cells), around a focus passage). of fibrinoid necrosis ▪ The vegetations are adherent (firmly fixed) to the valve. They are present in face of the direction of blood flow atrial surface of mitral valve and ventricular surface of the aortic valve). Microscopic: Fibrinoid necrosis of cusps and chordae tendinae with inflammation, and overlying vegetations (platelet thrombi). The mural endocardium of the left atrium may show Aschoff bodies (AB) on the posterior wall. Figure 10 Rh. valvulitis, small vegetations on line of closure, mitral valve Dr. Abdelrahman Khalifa M.D. PhD. 20 Systemic Pathology CVS Extra cardiac manifestations Fleeting arthritis: Large joint (knee or elbow) is red, painful and swollen. As soon as the inflammation undergoes resolution another joint becomes affected. The arthritis resolves completely with no residual effect on joints. Skin rash (erythema annulare or marginatum): Reddish macules with a pale center. Seen particularly on the trunk. Subcutaneous nodules (common over bony prominence as knuckles of hand, in the form of 2-20 mm nodules with a microscopic picture similar to AB. Rheumatic chorea: spontaneous uncoordinated purposeless movements of an involuntary nature due to basal ganglia inflammation. Fibrinous pleurisy or peritonitis Rheumatic pneumonitis may occur. Rheumatic arteritis or hypersensitivity angitis: a type III hypersensitivity reaction. Clinical picture of rheumatic fever 1. Rheumatic fever is characterized by fever, fleeting arthritis of the large joints, pancarditis (tachycardia, murmurs, pericardial rub), subcutaneous nodules, erythema marginatum of the skin, and Sydenham chorea. 2. Blood tests include elevated sedimentation rate, elevated C reactive protein and high serum level of ASO titre. Fate of acute rheumatic fever: 1. Most cases of rheumatic fever show recovery. Only 1% die from fulminant myocarditis 2. Recurrent acute attacks: cause fibrosis and deformity of cardiac valves. Dr. Abdelrahman Khalifa M.D. PhD. 21 Systemic Pathology CVS Chronic Rheumatic Heart Disease Represents the healing phase of rheumatic fever and is characterized by fibrosis. a) Pericardium: Commonly heal without sequelae. Occasionally fibrosis may cause whitish patches on visceral pericardium (Milk spots), adhesions between visceral and parietal pericardium, or rarely adhesive or constrictive pericarditis. b) Myocardium: Healing of AB by fibrosis producing fine white streaks of fibrous tissue appear within the muscle. Figure 9 Mitral valve in chronic c) Endocardium: rheumatic heart disease showing thickened white irregular fused cusps with thickened short chordae tendinae Mural endocardium : Fibrosis of the AB of the posterior wall of and hypertrophied papillary muscle. left atrium resulting in a whitish patch of fibrous tissue called MacCallum patch. Valvular endocardium: Mitral valve is the most commonly affected valve by chronic rheumatic valvular disease followed by aortic valve then tricuspid valve. The pulmonary valve is the least affected (One or more valves may be diseased. The diseased valves undergo fibrosis becoming thick, opaque whitish and deformed. Mitral stenosis: Fibrosis and fusion of the commissures produces a narrow valve, which has a button hole or fish mouth appearance. Also the chordae tendinae are thickened & shortened. The papillary muscles undergo hypertrophy. The valve appears as a funnel when looked at from the atrium. Mitral incompetence: The fibrosis causes shrinkage of valve cusps so that there is improper closure with blood leaking despite closure of the valve. Double valve lesions (i.e. double mitral or double aortic). This is a lesion where the valve suffers a deformity, which produces both stenosis & incompetence. The fibrosis affects both the commissures & the leaflets producing a narrow valve, which doesn't close properly. Complications of chronic rheumatic heart disease: 1. Subacute infective endocarditis on top of deformed fibrotic valves. 2. Heart failure secondary to valvular lesions. Figure 10 Diagram representing stenosis and incompetence in aortic valve Dr. Abdelrahman Khalifa M.D. PhD. 22 Systemic Pathology CVS INFECTIVE ENDOCARDITIS A. Acute Infective Endocarditis: Caused by infection of a previously normal heart valve by a highly virulent organism (e.g., Staphylococcus aureus) that rapidly produces necrotizing and destructive lesions. Organisms reach the blood from cutaneous infections, lung infections, or genitourinary tract infections. It is rapidly fatal owing to the septicemia & the perforation of cusps which produces acute heart failure. B. Subacute Infective Endocarditis: Occurs in bactremic states, where the organism is of low virulence & non-pyogenic such as viridans streptococci These organisms reach the blood from minor surgeries as tooth extraction and tonsillectomies. Such weak organisms do not attack healthy valves only abnormal endocardium e.g. chronic rheumatic valvular disease, congenital heart disease or prosthetic valves. Usually treatable, but healing by fibrous tissue produces more valve deformity such as stenosis or incompetence. Dr. Abdelrahman Khalifa M.D. PhD. 23 Systemic Pathology CVS Table: Pathologic manifestations of infective endocarditis: Acute infective endocarditis Subacute infective endocarditis ▪ Mitral, aortic, mural ▪ Mitral & aortic commonly and mural endocardium. endocardium. Valves affected ▪ Valves on right side are affected in intravenous drug users. ▪ Large, (bulky), yellow (purulent), ▪ Large (bulky), brownish, friable vegetations friable vegetations with valve without valve perforation. perforation. ▪ Abnormal cusps showing fibrosis and Gross ▪ Cusp are thin and do not show thickening due to previous RHD. fibrosis ▪ No rupture of chordae (already thickened ▪ May cause rupture of chordae and fibrosed). tendinae. Microscopic: Platelets, fibrin, bacteria, Platelets, fibrin, bacteria, neutrophils, neutrophils, pus cells & lymphocytes, plasma cells & macrophages (No macrophages pus cells). 1.Septicemia: Fever, chills, 1. Toxemia: Fever, clubbing of fingers... weakness 2. Embolic manifestations: 2.Embolic manifestations: - Cerebral infarction - Retinal vessel emboli and hemorrhages - Septic infarctions. (Roth spots) Clinical picture - Multiple petichae in skin and splinter & - Pyaemic abscesses. hemorrhage in nail bed. Complications - Osler's nodules: painful fingertip nodules - Kidney infarctions - Splenic infarctions & splenomegaly - Mycotic aneurysms 3.Focal glomerulonephritis due to immune complex deposition. Rapidly fatal due to septicemia, Can be curable but lead to more fibrosis and Prognosis valve perforation &heart failure valve damage Dr. Abdelrahman Khalifa M.D. PhD. 24 Systemic Pathology CVS MITRAL STENOSIS Causes: 1) Chronic rheumatic heart disease (commonest cause in Egypt) 2) Healed subacute infective endocarditis. Pathology: (see Rheumatic heart disease). Effects: 1) Progressive dilatation and hypertrophy of left atrium occurs. 2) Left atrial thrombosis which can embolize. 3) Arrythmias, particularly atrial fibrillation. 4) Chronic venous congestion of the lungs, over time leads to pulmonary hypertension. 5) Pulmonary hypertension leads to right ventricular hypertrophy and later dilatation and failure. 6) The left ventricle is unaffected in isolated mitral stenosis. MITRAL INCOMPETENCE Causes: 1) Chronic rheumatic heart disease. 2) Healing of subacute infective endocarditis. 3) Dilatation of mitral ring 2ry to Lt. ventricular dilatation. 4) Rupture of papillary muscle in recent infarction. 5) Mitral valve prolapse (myxomatous degeneration of mitral valve). Effects: 1) Dilated left atrium, dilated hypertrophied left ventricle. 2) Chronic venous congestion of lung which leads to pulmonary hypertension, reflected on right side of the heart (hypertrophy and dilatation). 3) Heart failure. Dr. Abdelrahman Khalifa M.D. PhD. 25 Systemic Pathology CVS AORTIC STENOSIS Causes: 1) Rheumatic heart disease. 2) Healed subacute infective endocarditis. 3) Congenital aortic stenosis. 4) Senile calcific aortic stenosis. 5) Calcification of congenital bicuspid valve. Effects: 1) Concentric hypertrophy of left ventricle due to pressure overload. 2) The hypertrophied myocardium tends to be ischemic (as a result of diminished microcirculatory perfusion, often complicated by coronary atherosclerosis), and angina pectoris may occur. 3) Eventually cardiac decompensation occurs and congestive heart failure develops. 4) Symptoms include angina, syncope and symptoms of heart failure. AORTIC INCOMPETENCE Causes: 1. Rheumatic heart disease. 2. Infective endocarditis. 3. Syphilitic aortitis. 4. Marfan syndrome. Effects: 1) Dilatation of all chambers of the heart. The heart is more than 1 Kg (Cor Bovinum). 2) Heart failure. Dr. Abdelrahman Khalifa M.D. PhD. 26 Systemic Pathology CVS PULMONARY STENOSIS Causes: 1) Congenital. 2) Healed subacute infective endocarditis. 3) Chronic rheumatic heart disease. 4) Carcinoid syndrome. Effects: 1) Hypertrophy of right ventricle. 2) Right ventricular failure. TRICUSPID STENOSIS Causes: 1) Chronic rheumatic valvulitis. 2) Healed subacute infective endocarditis. 3) Carcinoid syndrome: serotonine released promotes valve fibrosis on the right side of the heart. Dr. Abdelrahman Khalifa M.D. PhD. 27 Systemic Pathology CVS Ischemic (Coronary) heart disease (IHD) Definition: Ischemic heart disease (IHD) represents a group of syndromes resulting from myocardial ischemia (an imbalance between myocardial supply and cardiac demand for oxygenated blood). Causes: 1) In more than 90% of cases, it is due to atherosclerosis of the coronary arteries. 2) Other causes of ischemia include: ▪ Coronary emboli. ▪ Coronary vessel inflammation. ▪ Vascular spasm. ▪ Narrowing of coronary ostia due to syphilitic aortitis. ▪ Increased oxygen demand as in myocardial hypertrophy, or tachycardia. ▪ Diminished perfusion as in shock. Clinical syndromes: ID can present as one or more of the following clinical syndromes: 1. Myocardial infarction (MI), where ischemia causes frank myocardial necrosis. 2. Angina pectoris: Chest pain precipitated by exercise. 3. Chronic HD with heart failure. 4. Sudden cardiac death (SCD). Epidemiology: HD is the leading cause of death in the developed nations. Ischemic heart disease include: Dr. Abdelrahman Khalifa M.D. PhD. 28 Systemic Pathology CVS Chronic Ischemic Heart Disease Causes: ▪ More than 90% of patients with IHD have atherosclerosis involving one or more of the coronary arteries. ▪ A fixed lesion obstructing greater than 75% of vascular cross-sectional area defines significant coronary artery disease. ▪ Patients present with angina pectoris. ▪ Clinically significant plaques can be located anywhere along the course of the coronary vessels, although they tend to predominate within the first several centimeters of the left anterior descending (LAD) and left circumflex (LCX). Pathological changes of chronic ischemic heart disease 1. The heart is normal in size, small in size (atrophy) or increased in size due to associated hypertension. 2. The myocardium shows grey fibrous streaks. 3. The left ventricle shows subendocardial fibrosis. 4. Mitral and aortic valve thickening and calcification, with normal chordae tendinae. Myocardial Infarction (Mi) Definition: Myocardial infarction indicates irreversible myocardial injury resulting in necrosis of a significant portion of myocardium. Etiology and Pathogenesis: 1. Coronary arterial sudden complete occlusion: The major cause of acute myocardial infarction (MI) is coronary atherosclerosis with superimposed luminal thrombus in 90% of the cases. The following sequence of events likely underlies most myocardial infarctions: a) A coronary artery atheromatous plaque undergoes an acute change consisting of intraplaque hemorrhage, erosion or ulceration, or rupture or fissuring. b) When exposed to subendothelial collagen and necrotic plaque contents, platelets adhere, become activated, release their granule contents, and aggregate to form microthrombi. Dr. Abdelrahman Khalifa M.D. PhD. 29 Systemic Pathology CVS c) Vasospasm is stimulated by mediators released from platelets. d) Tissue factor activates the coagulation pathway, adding to the bulk of the thrombus. e) Within minutes, the thrombus can expand to completely occlude the vessel lumen. 2. Other causes of coronary occlusion (10%): a. Vasospasm with or without coronary atherosclerosis, perhaps in association with platelet aggregation or due to drug ingestion (e.g., cocaine or ephedrine) b. Emboli from the left atrium in association with atrial fibrillation e.g. a left-sided mural thrombus, vegetations of infective endocarditis. c. Dissecting aortic aneurysm involving the coronary ostia. d. Coronary vasculitis, shock etc... Effects of the sudden coronary occlusion: 1. May be asymptomatic, if good collaterals are present. 2. Or present by sudden death due to fatal arrhythmias e.g. ventricular fibrillation. 3. Or lead to myocardial infarction. Pathological features of myocardial infarction: Ischemia is most pronounced in the subendocardium; thus, irreversible injury (necrosis) of ischemic myocytes occurs first in the subendocardial zone due to the myocardial perfusion pattern from epicardium to endocardium. Then moves through the myocardium to encompass progressively more of the transmural thickness of the myocardium. Sites of myocardial infarction: 1. Anterior infarction: The most common site (40-50%) It is due to occlusion of the left anterior descending branch (LAD) producing an infarction of the anterior ventricular wall, the anterior part of the interventricular septum & the apex of the heart. 2. Lateral infarction: due to occlusion of the left circumflex coronary artery (LCX) resulting in infarction of the lateral ventricular wall. 3. Posterior infarction: due to occlusion of the right coronary artery with infarction of the posterior wall & the posterior part of the septum. Dr. Abdelrahman Khalifa M.D. PhD. 30 Systemic Pathology CVS Patterns of myocardial infarction: 1. Transmural infarction: due to epicardial vessel occlusion (atherosclerosis, plaque rupture and thrombosis), without any therapeutic intervention. 2. Subendocardial infarction: A subendocardial infarct - typically involving the inner third of the ventricular wall - can occur due to epicardial vessel occlusion, where thrombus becomes lysed (therapeutically Or spontaneously) before necrosis extends to full thickness of myocardium. As the subendocardial region is the least perfused region, subendocardial infarcts can also result from prolonged, severe reduction of blood pressure, such as in shock, superimposed on noncritical coronary stenosis. In such case, myocardial damage is usually circumferential, rather than being limited to the distribution of a single major coronary artery. Figure 11 Showing mechanisms of complete coronary arterial occlusion Morphology of myocardial infarction: Gross: The earliest naked eye changes occur around 15 hours, when the affected muscle appears pale and swollen. By 24-48 hours there is softening and the color changes from dark red to brown to yellow After 3-4 days the infarct is more sharply defined by the Figure 12 showing acute myocardial development of a peripheral red zone of granulation tissue. infarction involving the septum and anterior wall of the left ventricle. It is pale in color Removal of dead myocytes by phagocytosis and organization and involves the whole thickness of the wall (transmural). proceeds with variable thinning of the infarcted area at 3 weeks and some fibrosis. By 3 months the scar tissue appears white. A fibrinous or haemorrhagic pericarditis is common in transmural infarction. Dr. Abdelrahman Khalifa M.D. PhD. 31 Systemic Pathology CVS Under the endocardium, a thin surviving subendocardial band of myocytes is almost invariable, these cells being nourished by blood in the ventricular lumen. After several days, mural thrombus often forms on the endocardial surface overlying the infarct. Microscopic: ▪ The infarcted tissue shows the changes of coagulative necrosis after 8-12 hours. ▪ By 24 hours, invasion by polymorphs has begun and after a few days digestion by macrophages and organization with granulation tissue formation occurs at the periphery. ▪ Over the next 2-3 months the infarcted myocardium is eventually replaced by a fibrous scar. ▪ Hypertrophy of the non- infarcted myocardium with chamber enlargement then compensate for loss of contractility caused by the healed infarct. This is known as ventricular remodeling. Complications of myocardial infarction: 1. Contractile dysfunction and some degree of heart failure with pulmonary congestion & edema. Large infarcts can cause cardiogenic shock. 2. Arrythmias: due to myocardial irritability and affection of the conduction system in the atrioventricular septum (tachycardia, heart block, ventricular fibrillation). 3. Cardiac rupture: This occurs most frequently 2 to 4 days after MI, when coagulative necrosis, neutrophilic infiltration, and lysis of the myocardial connective tissue have weakened the infarcted myocardium. 4. Pericarditis; A fibrinous or fibrino-hemorrhagic pericarditis usually develops about the second or third day following a transmural infarct as a result of underlying myocardial inflammation. 5. Mural thrombosis: due to stasis and endocardial damage. 6. Papillary muscle dysfunction: early dysfunction, leading to acute mitral incompetence, or late ischemic dysfunction, leading to post-infarct regurgitation. 7. Ventricular aneurysm is a late complication due to weak scar that bulges during the systole. Complications of ventricular aneurysms include mural thrombus, arrhythmias, and heart failure, and occasionally rupture. 8. Progressive late heart failure (CIHD). Dr. Abdelrahman Khalifa M.D. PhD. 32 Systemic Pathology CVS Clinical picture: MI is diagnosed by clinical symptoms, laboratory tests and characteristic electrocardiographic changes. ▪ Prolonged (more than 30 minutes) chest pain described as crushing, stabbing, or squeezing, associated with a rapid, weak pulse; profuse sweating (diaphoresis), and nausea and vomiting are common. ▪ Dyspnea due to impaired contractility of the ischemic myocardium and the resultant pulmonary congestion and edema is a frequent symptom. ▪ The laboratory tests: Elevation of cardiac-specific troponins and cardiac fraction of creatine kinase. Myocardial Diseases Myocarditis Definition: Inflammation of the cardiac muscle. Causes: 1. Acute rheumatic carditis. 2. Viral infections: especially Coxsackie virus, but also adenovirus, influenza and HIV. 3. Bacterial infections, e.g. diphtheria, clostridia. 4. Parasitic infections, particularly Chagas' disease (Trypanosoma cruzi) 5. ionizing radiation. 6. Drugs, especially doxorubicin. (chemotherapeutic agent) 7. Myocarditis can complicate infective endocarditis, and in some cases myocardial abscesses form around valve rings. Clinical features: ▪ In most patients, myocarditis is a self-limiting condition with only mild chest pain and fatigue. ▪ Cardiac magnetic resonance imaging is a valuable new diagnostic technique Dr. Abdelrahman Khalifa M.D. PhD. 33 Systemic Pathology CVS ▪ Fatalities are relatively uncommon. In some patients, cardiac failure develops and coronary angiography may be performed to exclude coronary artery disease. ▪ An endomyocardial biopsy is sometimes performed and may show lymphocytic infiltration and myocyte necrosis. Cardiomyopathy o Cardiomyopathies are a heterogeneous group of myocardial diseases associated with mechanical and/or electrical dysfunction of the heart. o There are a large number of underlying causes, many of which are genetic, and inheritable. o When cardiomyopathy is suspected it is essential that coronary artery disease, valvular disease, hypertension and congenital heart disease are first excluded. Types: 1. Dilated cardiomyopathy (DCM) Most common type. 2. Hypertrophic cardiomyopathy. 3. Restrictive cardiomyopathy (in systemic diseases as amyloidosis, sarcoidosis, scleroderma). Pericardial Diseases PERICARDITIS Definition: An inflammatory reaction involving the visceral and/or parietal pericardial layers. Types and causes: 1. Fibrinous pericarditis: Caused by ▪ Rheumatic fever ▪ Viral ▪ Uremia Dr. Abdelrahman Khalifa M.D. PhD. 34 Systemic Pathology CVS ▪ Overlying myocardial infarction ▪ Fibrinous pericarditis heals by resolution or adhesions between visceral and parietal layer. 2. Suppurative pericarditis caused by staphylococci and streptococci, due to spread from intrathoracic focus. Suppurative pericarditis heals by adhesions. 3. Hemorrhagic pericarditis & hemopericardium: Inflammation associated with a bloody exudate in the pericardial cavity caused by a) Surgery. b) Trauma. c) Tumor metastases Cardiac tamponade: Blood collecting suddenly & in large quantities in the pericardial sac, resulting in sudden death (acute heart failure). It occurs in rupture myocardial infarction, ventricular aneurysm or rupture aortic aneurysm. 4. Tuberculous pericarditis: due to post primary spread or as part of secondary tuberculosis. The pericardial sac is filled with caseous material and fibrous adhesions. Extensive fibrosis and calcification results in constrictive pericarditis. 5. Constrictive pericarditis: The pericardium is transformed into a thick layer of fibrous tissue with calcification which restricts diastolic filling and causes systemic venous congestion. The heart is small in size. This is the end result of caseous and severe suppurative pericarditis. 6. Adherent mediastino-pericarditis: severe fibrosis between the 2 layers of pericardium and between outer pericardial layer and mediastinum. With each ventricular contraction, the heart pulls on the mediastinal structures which causes overload on the heart leading to ventricular hypertrophy, dilatation and failure. Figure 13 Constrictive pericarditis. The heart is wrapped by a thick layer of fibrous tissue. The heart is not enlarged Dr. Abdelrahman Khalifa M.D. PhD. 35 Systemic Pathology CVS Tumors Of The Heart 1) Left atrial myxoma: Benign tumor although some consider it a myxomatous change in a ball thrombus. 2) Rhabdomyoma: benign tumor of striated muscle. 3) Rhabdomyosarcoma The malignant counterpart of rhabdomyoma. 4) Metastasis: Rare, from lung or melanoma. Route; direct or lymphatic spread to pericardium, as in bronchogenic carcinoma Heart Failure or blood borne to the muscle, as in melanoma metastasis. Definition: A condition where the cardiac output is insufficient to meet the metabolic demands of the tissues. Pathophysiology (see physiology book) Acute and chronic failure Acute heart failure can occur within minutes of a myocardial infarction, with sudden onset of shortness of breath and marked pulmonary edema. In contrast in valvular defects such as mitral stenosis or incompetence, symptoms develop over many years with gradual worsening of symptoms. Right and left heart failure: The right and left ventricles function together in a closed circuit. In early stages of heart failure, symptoms appear 'one-sided'. Causes of left sided heart failure include 1. Ischemic heart disease. 2. Systemic hypertension. 3. Valvular heart disease (mitral regurge, aortic stenosis or regurge) The immediate consequence of left heart failure is pulmonary congestion and edema. Dr. Abdelrahman Khalifa M.D. PhD. 36 Systemic Pathology CVS Causes of right sided heart failure: 1. Consequence of left side failure. 2. Mitral stenosis. 3. Cor pulmonale: right side heart failure secondary to lung disease as chronic obstructive lung disease (chronic bronchitis and emphysema) and lung fibrosis. Right side failure produce systemic venous congestion, enlargement of the liver. In congestive cardiac failure there is both right and left ventricular failure and a full combination of systemic and pulmonary signs. Clinicopathological Features of heart failure: The major symptoms and signs of heart failure are shortness of breath (dyspnea), pulmonary edema, systemic venous congestion and edema. 1) Dyspnea due to pulmonary congestion and edema: ▪ Orthopnea is dyspnea on lying flat, due to increased venous return. ▪ Paroxysmal nocturnal dyspnea (sudden and urgent shortness of breath during sleep: probably due to increased pulmonary venous congestion. 2) Systemic venous congestion and edema: Fluid retention, a compensatory mechanism in heart failure, results in volume overload on the ventricles. Veins are the reservoir for the increased blood volume, and there is wide spread congestion of systemic veins. There is distension of superficial jugular vein. The liver is enlarged with engorgement of central veins and hepatic sinusoids. Accumulation of fluids in subcutaneous tissues (edema) and in the pleural, pericardial and peritoneal cavity, due to increased transudation of fluids as a result of high venous pressure. 3) Other changes: a. Proteinuria. b. Nausea, vomiting. c. Lethargy, headache, and difficulty sleeping due to decreased cerebral blood flow. Dr. Abdelrahman Khalifa M.D. PhD. 37 Systemic Pathology CVS SELF ASSESSMENT SAQ: 1. What is the coronary vessel most commonly involved by atherosclerosis? 2. What is the part of cardiac muscle supplied by this vessel? MCQ: 1. Left ventricular hypertrophy is seen in all the following conditions except: a) Essential hypertension b) Aortic stenosis c) Aortic incompetence d) Mitral stenosis 2. Rheumatic fever is a) Suppurative disease b) Autoimmune disease c) Degenerative disease d) Metabolic disease Dr. Abdelrahman Khalifa M.D. PhD. 38