Pathology of Cardiovascular System PDF

PATHOLOGY OF CARDIOVASCULAR SYSTEM Prof. Dr. Rafal Al-Saigh MBChB, PhD, FIBMS Pathology (Specialist Pathologist) Diseases of Blood Vessels Function of endothelial cells lined blood vessels 1. Maintenance of Permeability Barrier 2. Elaboration of Anticoagulant, Antithrombotic, Fibrino...

PATHOLOGY OF CARDIOVASCULAR SYSTEM Prof. Dr. Rafal Al-Saigh MBChB, PhD, FIBMS Pathology (Specialist Pathologist) Diseases of Blood Vessels Function of endothelial cells lined blood vessels 1. Maintenance of Permeability Barrier 2. Elaboration of Anticoagulant, Antithrombotic, Fibrinolytic 3. Regulators Prostacyclin Thrombomodulin Heparin-like molecules Plasminogen activator 4. Elaboration of Prothrombotic Molecules Von Willebrand factor Tissue factor Plasminogen activator inhibitor 5. Extracellular Matrix Production (collagen, proteoglycans) 6. Modulation of Blood Flow and Vascular Reactivity Vasconstrictors: endothelin, ACE Vasodilators: NO, prostacyclin 7. Regulation of Inflammation and Immunity IL-1, IL-6, chemokines Adhesion molecules: VCAM-1, ICAM, E-selectin P-selectin Histocompatibility antigens 8. Regulation of Cell Growth Growth stimulators: PDGF, FGF Growth inhibitors: heparin, TGF-β 9. Oxidation of LDL Endothelial cells activated cytokines & bacterial prod.  Inflammation and septic shock;  hemodynamic stresses and lipid products,  critical to the pathogenesis of atherosclerosis;  advanced glycosylation end products (important in diabetes)  viruses,  complement components,  hypoxia. Vascular smooth muscle cells vasoconstriction and dilation response to normal or pharmacologic stimuli.  synthesize collagen, elastin, and proteoglycans;  elaborate growth factors and cytokines.  migrate to the intima  proliferate following vascular injury. Vascular Structure and Function All vessels are lined by endothelium; although all endothelial cells share certain homeostatic properties, endothelial cells in specific vascular beds have special features that allow for tissue-specific functions (e.g., fenestrated endothelial cells in renal glomeruli). The relative smooth muscle cell and matrix content of vessel walls (e.g., in arteries, veins, and capillaries) vary according to hemodynamic demands (e.g., pressure, pulsatility) and functional requirements. Endothelial cell function is tightly regulated in both the basal and activated states. Various physiologic and pathophysiologic stimuli induce endothelial activation and dysfunction that alter the endothelial cell phenotype (e.g., pro- versus anticoagulative, pro- versus anti-inflammatory, nonadhesive versus adhesive).  1. Atherosclerosis Intimal lesions called atheromas, or atheromatous or fibrofatty plaques, which protrude into and obstruct vascular lumens. It is the cause of ischæmic heart disease. The American Heart Association classification divides atherosclerotic lesions into six types: Atherosclerosis is an intima-based lesion composed of a fibrous cap and an atheromatous (literally, “gruel-like”) core; the constituents of the plaque include smooth muscle cells, ECMs, inflammatory cells, lipids, and necrotic debris. Atherogenesis is driven by an interplay of vessel wall injury and inflammation. The multiple risk factors for atherosclerosis all cause endothelial cell dysfunction and influence smooth muscle cell recruitment and stimulation. Atherosclerotic plaques develop and grow slowly over decades. Stable plaques can produce symptoms related to chronic ischemia by narrowing vessels, whereas unstable plaques can cause dramatic and potentially fatal ischemic complications related to acute plaque rupture, thrombosis, or embolization. Stable plaques tend to have a dense fibrous cap, minimal lipid accumulation, and little inflammation, whereas “vulnerable” unstable plaques have thin caps, large lipid cores, and relatively dense inflammatory infiltrates. Type I lesion (The initial): increase in macrophages and formation of macrophage foam cells. Type II lesions (fatty streaks): lipid-laden smooth muscle cells. Type III: is the intermediate stage between type II and type IV (atheroma): contain scattered collections of extracellular lipid droplets Type IV: The extracellular lipid is the larger, confluent, and more disruptive core Type V: extracellular lipid contain thick layers of fibrous connective tissue lesion Type VI: extracellular lipid contains fibrous tissue, fissure, hematoma, and thrombus or largely calcified.  Fatty streaks are the earliest lesion of atherosclerosis, composed of subendothelial lipid-filled foamy cells, with few T lymphocytes and extracellular lipid, appear in the aorta in all children above the age of 10.  Some fatty streaks may progress to atheromatous plaques, developing primarily in elastic arteries (e.g., aorta, carotid, and iliac arteries) and large and medium-sized muscular arteries (e.g., coronary and popliteal arteries), resulting in partial or complete obstruction.  In small arteries plaques can undergo disruption and precipitate thrombi that further obstruct blood flow. Atherosclerotic plaques have three principal components: 1. cells, including SMCs, macrophages, and other leukocytes; 2. ECM, including collagen, elastic fibers, and proteoglycans; 3. intracellular and extracellular lipid (cholesterol and cholesterol esters). Complications:  Rupture, ulceration and erosion.  Hæmorrhage into the plaque.  Thromosis.  Aneurysmal dilatation. Risk factors of IHD: Major Minor Non-modifiable Increasing age Obesity Male gender Physical inactivity Family history Stress ("type A" personality) Genetic abnormalities Postmenopausal estrogen deficiency High carbohydrate intake Potentially Controllable Hyperlipidemia (cholesterol) Alcohol Hypertension Lipoprotein Lp(a) Cigarette smoking Hardened (trans)unsaturated fat intake Diabetes Chlamydia pneumoniæ  Pathogenesis Chronic endothelial cell injury. Accumulation of lipoproteins mainly LDL. Oxidation of lipoproteins. Migration of monocytes to the intima, phagocytosing lipids (foam cells). Adhesion of platelets. Smooth muscle cell migration to the intima and proliferation. Enhanced accumulation of lipids 2. Hypertension:  Hypertension is a common disorder affecting 25% of the population; it is a major risk factor for atherosclerosis, congestive heart failure, and renal failure. Essential hypertension represents 95% of cases and is a complex, multifactorial disorder, involving both environmental influences and genetic polymorphisms that may influence sodium resorption, aldosterone pathways, and the renin– angiotensin system. Hypertension occasionally is caused by single-gene disorders or is secondary to diseases of the kidney, adrenal, or other endocrine organs. One of the most important risk factors for both coronary artery disease and cerebrovascular accidents; it can lead to cardiac hypertrophy and, potentially, heart failure (hypertensive heart disease), aortic dissection, and renal failure. Pathogenesis multifactorial depending on genetic and environmental causes, but the main cause of hypertension remains unknown in most of the cases. Hypertension is defined as a sustained diastolic pressure greater than 90 mm Hg or a sustained systolic pressure in excess of 140 mm Hg. Types and Causes I. Essential Hypertension. II. Secondary Hypertension: 1. Renal - Acute glomerulonephritis - Chronic renal disease - Polycystic disease - Renal artery stenosis - Renal artery fibromuscular dysplasia - Renal vasculitis - Renin-producing tumors 2. Endocrine - Adrenocortical hyperfunction (Cushing syndrome, 1o aldosteronism, congenital adrenal hyperplasia, licorice ingestion) - Exogenous hormones (glucocorticoids, estrogen [pregnancy & oral contraceptives], sympathomimetics and tyramine-containing foods, monoamine oxidase inhibitors) - Pheochromocytoma - Acromegaly - Hyperthyroidism (thyrotoxicosis) - Hypothyroidism (myxœdema) 3. Pregnancy-induced 4. Cardiovascular - Coarctation of aorta - Polyarteritis nodosa (or other vasculitis) - ↑ intravascular volume & ↑ COP - Rigidity of the aorta 5. Neurologic Psychogenic Increased intracranial pressure 6. Sleep apnea 7. Acute stress, including surgery The kidneys play an important role in regulation of BP:  Renin-angiotensin system: Ang II raises BP by increasing both peripheral resistance and blood volume (stimulation of aldosterone secretion, increase in distal tubular reabsorption of sodium).  Production of PG & NO, resulting in reduction of BP.  Conservation of blood volume by reabsorption of sodium.  Natriuretic peptide inhibit sodium reabsorption and rennin-angiotensin system.  Impairment of renal excretory function will result in increased renal blood flow by increasing BP to compensate for the reduced blood volume. ETIOLOGY  ↑Vascular resistance - ↑Vascular reactivity - ↑Vascular wall thickness  ↑cardiac output - ↑ plasma & ECF vol.→ ↑ renal sod. & water retention 3. Vasculitis Vasculitis is an inflammation of vessel walls; it frequently is associated with systemic manifestations (fever, malaise, and arthralgias) and organ dysfunction that depends on the pattern of vascular involvement. Vasculitis can result from infections but more commonly has an immunologic basis such as immune complex deposition, anti-neutrophil antibodies (ANCAs), or anti–endothelial cell antibodies. Different forms of vasculitis tend to specifically affect vessels of a particular caliber and location The pathogenesis of non-infectious vasculitis is: 1. Immune complex deposition. 2. Antineutrophil cytoplasmic antibodies. 3. Anti-endothelial cell antibodies. Variants: - Giant cell (temporal) arteritis; affecting mainly the temporal arteries with destructive giant cell granuloma. - Takayasu's arteritis, involving the carotids and the subclavian arteries, with extension to the arch aorta, resulting in fibrosis of involved vessels (pulseless syndrome). - Polyarteritis nodosa, involving medium sized arteries, frequently extending to involve the renal arteries, with necrotizing fibrinous inflammation. - Kawasaki disease, happens in young children, involving the coronary arteries. - Microscopic polyangiitis (leukocytoclastic vasculitis), occur in Henoch-Schonlein purpura and Churg-Strauss syndrome, involving small arterioles, capillaries and venules. - Wegner's granulomatosis: is a destructive type of vasculitis usually involving the lungs and the kidneys, presented in the following forms: 1. Acute necrotizing granulomas of the upper and the lower respiratory tract. 2. Necrotizing or granulomatous vasculitis affecting small to medium-sized vessels. 3. Renal disease in the form of focal necrotizing, often crescentic, glomerulitis. - Thromboangiitis obliterans (Buerger's) disease; segmental, thrombosing, acute and chronic inflammation of medium-sized and small arteries, principally the tibial and radial arteries, happens almost exclusively in heavy smokers. Vascular Tumors Vascular ectasias are not neoplasms, but rather dilations of existing vessels. Vascular neoplasms can derive from either blood vessels or lymphatics, and can be composed of endothelial cells (hemangioma, lymphangioma, angiosarcoma) or other cells of the vascular wall (e.g., glomus tumor) Most vascular tumors are benign (e.g., hemangiomas), some have an intermediate, locally aggressive behavior (e.g., Kaposi sarcoma), and others are highly malignant (e.g., angiosarcoma). Benign tumors typically form obvious vascular channels lined by normal-appearing endothelial cells. Malignant tumors more often are solid and cellular, exhibit cytologic atypia, and lack well-defined vessels. 4. Congenital Cardiac Diseases Malformation % Ventricular septal defect VSD 42 VSD Atrial septal defect ASD 10 ASD Pulmonary stenosis 8 Patent ductus arteriosus PDA 7 Tetralogy of Fallot TOF 5 PS Coarctation of aorta 5 Atrioventricular septal defect AVSD 4 TOF PDA Aortic stenosis 4 Transposition of great arteries TGA 4 TGA Truncus arteriosus TA 1 TA Total anomalous pulmonary venous 1 connection TAPVC Tricuspid atresia 1 5. Ischemic Heart Disease (IHD) Pathogenesis IHD syndromes is diminished coronary perfusion relative to myocardial demand, owing largely to a complex and dynamic interaction among fixed atherosclerotic narrowing of the coronary arteries, intraluminal thrombosis overlying a disrupted atherosclerotic plaque, platelet aggregation, vasospasm. Obstruction of 75% of the coronary artery lumen by atheroma leads to symptoms on exertion, while 90% obstruction causes symptoms even on rest (angina pectoris). Acute plaque change leads to thrombosis and total occlusion of the coronary artery lumen with myocardial infarction. Acute plaque changes include: 1. Rupture/fissuring, exposing the highly thrombogenic plaque constituents. 2. Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood. 3. Hemorrhage into the atheroma, expanding its volume. Morphologic changes in acute MI Time Gross Features Light Microscope Reversible Injury 0-½ hr None None Irreversible Injury ½-4 hr None Usually none; variable waviness of fibers at border 4-12 hr Occasionally dark Beginning coagulation necrosis; edema; hemorrhage mottling 12-24 hr Dark mottling Ongoing coagulation necrosis; pyknosis of nuclei; myocyte hypereosinophilia; marginal contraction band necrosis; beginning neutrophilic infiltrate 1-3 days Mottling with yellow- Coagulation necrosis, with loss of nuclei; infiltrate of neutrophils tan infarct center 3-7 days Hyperemic; central Beginning disintegration of dead myofibers, with dying neutrophils; yellow-tan softening early phagocytosis of dead cells by macrophages at infarct border 7-10 days Maximally yellow-tan Well-developed phagocytosis of dead cells; early formation of and soft, with depressed fibrovascular granulation tissue at margins red-tan margins 10-14 days Red-gray depressed Well-established granulation tissue with new blood vessels and infarct borders collagen deposition 2-8 wk Gray-white scar, Increased collagen deposition, with decreased cellularity progressive from border toward core of infarct >2 mo Scarring complete Dense collagenous scar Consequences of MI  Contractile dysfunction.  Arrhythmias.  Myocardial rupture.  Pericarditis.  Infarct extension.  Infarct expansion.  Mural thrombus.  Ventricular aneurysm.  Papillary muscle dysfunction.  Progressive late heart failure. 6. Infective Endocarditis (IE): colonization or invasion of the heart valves or the mural endocardium by a microbe, leading to the formation of bulky, friable vegetations, composed of thrombotic debris and organisms, often associated with destruction of the underlying cardiac tissues. IE can be classified into: 1. Acute endocarditis: destructive infection of previously normal heart valve by a highly virulent MQ leading to death of more than 50% of patients within few days. Producing necrotizing, ulcerative, invasive valvular infections that are difficult to cure by antibiotics and usually require surgery. 2. Subacute endocarditis: Caused by low virulent bacterial infecting an abnormal heart (deformed valves, VSD, ASD, etc…), pursuing a long course eventually to healing. Etiology And Pathogenesis: Predisposing factors:  Rheumatic heart disease.  Myxomatous mitral valve.  Degenerative calcific valvular stenosis.  Neutropenia, and immunodeficiency  Malignancy.  Diabetes mellitus.  Alcoholism & Intravenous drug abuse. Causative microorganisms Streptococcus viridans (50-60%). Staphylococcus aureus (10-20%), especially in deformed valves. Others (enterococci, Hæmophilus, Acinetobacillus, etc…). Gram negative bacilli and fungi. Seeding of blood with microorganisms happens after dental extraction, surgical procedures, injection with contaminated needles or an occult source from the gut or oral cavity. In both forms of the disease friable, bulky, and potentially destructive vegetations containing fibrin, inflammatory cells, and bacteria or other organisms are present on the heart valves, resulting in small microabscesses in the underlying myocardium and septic emboli to distant organs, resulting in septic infarcts. 7. Rheumatic Heart Disease acute, immunologically mediated, multisystem inflammatory disease that occurs a few weeks following an episode of group A streptococcal pharyngitis. Acute rheumatic carditis during the active phase of RF may progress to chronic rheumatic heart disease (RHD). The incidence and mortality rate of RF have declined remarkably in many parts of the world over the past 30 years. During acute RF, focal inflammatory lesions are found in various tissues. They are most distinctive within the heart, where they are called Aschoff bodies. They consist of foci of swollen eosinophilic collagen surrounded by lymphocytes (primarily T cells), occasional plasma cells, and plump macrophages called Anitschkow cells (pathognomonic for RF). During acute RF, diffuse inflammation and Aschoff bodies may be found in any of the three layers of the heart- pericardium, myocardium, or endocardium- hence the lesion is called a pancarditis. Pericarditis usually resolve spontaneously without sequalae. Myocardial involvement is seen as scattered Aschoff bodies. Involvement of the endocardium by inflammation results in fibrinoid necrosis and the formation of irregular vegetations along the line of closure of valves, due to precipitation of fibrin at sites of necrosis and cause little disturbance in valvular function. Chronic RHD is characterized by organization of the acute inflammation and subsequent fibrosis. In particular, the valvular leaflets become thickened and retracted, causing permanent deformity. The cardinal anatomic changes of the mitral (or tricuspid) valve are leaflet thickening, commissural fusion and shortening, and thickening and fusion of the tendinous cords. In chronic disease, the mitral valve is virtually always abnormal, but involvement of another valve, such as the aortic, may be the most clinically important in some cases. Pathogenesis acute rheumatic fever is a hypersensitivity reaction induced by group A streptococci, but the exact pathogenesis remains uncertain despite many years of investigation. It is thought that Ab directed against the M proteins of certain strains of streptococci cross-react with glycoprotein antigens in the heart, joints, and other tissues. Clinical Features characterized by Major manifestations (1) migratory polyarthritis of the large joints, (2) carditis, (3) subcutaneous nodules, (4) erythema marginatum of the skin, (5) Sydenham chorea, a neurologic disorder with involuntary purposeless, rapid movements. After an initial attack, increased reactivation of the disease with subsequent pharyngeal infections, and the same manifestations are likely to appear with each recurrent attack. Carditis is likely to worsen with each recurrence, and damage is cumulative. 8. Varicose veins Dilatation of the superficial veins Veins: capacious, thin walled blood vessels 70% of total blood volume Upright position Bicuspid valves are responsible for unidirectional flow Muscle pump Superficial and deep system Perforant veins between deep & superf. one RELAXATION PHASE  DURING MUSCLE RELAXATION, PRESSURE WITHIN CALF  COMPARTMENT FALLS  BLOOD FROM SUPERFICIAL VEINS ENTER DEEP VEINS  SUPERFICIAL VENOUS pressure cont. To fall TILL  THRESHOLD IS REACHED  THRESHOLD IS APPROX. 30mmHg  VENOUS INFLOW NOW KEEPS PACE  WITH EJECTION FROM DEEP VEINS Symptoms  Cosmetic,  pain,  inflammation,  leg ulcer,  rupture Diagnosis: – Inspection – Doppler ultrasound – Duplex US Etiology  Congenital weakness in vessel wall  Congenital absence of valves  Congenital Valvular incompetence  Familial (FOX C2 gene)  Lysosomal enzyme activity(Haardt)  Chronic inflammatory process(Class II MHC & Macrophages)  Gender  Age  occupation and lifestyle  Ethnicity factor;  Body mass index&height smokers,  Family history constipation  Pregnancy occupations which involve prolonged standing. Deep vein incompetency Retrograde flow in deep veins Possible complications : – crural ulcer – thrombosis Etiology: – thrombosis – congenital Diagnostics Method Venography is recommended in patients with post-thrombotic disease, especially if intervention is planned. Ascending venography with injection of contrast material into the foot. (additional transfemoral injection) 9. Aneurysm and Dissections An aneurysm is a distention of an artery brought by a weakening/ destruction of the arterial wall. An aneurysm is a balloon-like bulge in an artery. Aneurysms are congenital or acquired dilations of the heart or blood vessels that involve the entire wall thickness. Complications are related to rupture, thrombosis, and embolization. Dissections occur when blood enters the wall of a vessel and separates the various layers. Complications arise as a result of rupture or obstruction of vessels branching off the aorta. Aneurysms and dissections result from structural weakness of the vessel wall caused by loss of smooth muscle cells or insufficient extracellular matrix, which can be a consequence of ischemia, genetic defects, or defective matrix remodeling  Types of Aneurysms There are two main types of aneurysms: 1. Aortic aneurysm - There are two types of aortic aneurysm - Abdominal aortic aneurysm and - Thoracic aortic aneurysm 2. Cerebral aneurysm - occurs in an artery in the brain. 3. Others: Peripheral Aneurysm Aortic Aneurysms Abdominal Aortic Aneurysms An aneurysm that occurs in the abdominal portion of the aorta is called an abdominal aortic aneurysm (AAA). Most aortic aneurysms are AAAs. Thoracic Aortic Aneurysms An aneurysm that occurs in the chest portion of the aorta (above the diaphragm) is called a thoracic aortic aneurysm (TAA). Brain Aneurysms Aneurysms in the arteries of the brain are called cereberal aneurysms or brain aneurysms. Brain aneurysms also are called berry aneurysms because they're often the size of a small berry. Peripheral Aneurysms  Aneurysms that occur in arteries other than the aorta and the brain arteries are called peripheral aneurysms.  Common locations for peripheral aneurysms include the popliteal, femoral and carotid arteries. 10. Heart Failure a clinical syndrome that results when the heart is unable to provide sufficient blood flow to meet metabolic requirements or accommodate systemic venous return. Etiology  ischemic heart disease,  hypertension,  diabetes. Less common etiologies include cardiomyopathies,  valvular disease,  myocarditis,  infections,  systemic toxins,  cardiotoxic drugs  Compensatory mechanisms Increasing cardiac output via the Frank–Starling mechanism, increasing ventricular volume and wall thickness through ventricular remodeling, maintaining tissue perfusion with augmented mean arterial pressure through activation of neurohormonal systems. In the early stages of heart failure, all of these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure Pathophysiology In heart failure, the heart may not provide tissues with adequate blood for metabolic needs, and cardiac-related elevation of pulmonary or systemic venous pressures may result in organ congestion. This condition can result from abnormalities of systolic or diastolic function or, commonly, both. Although a primary abnormality can be a change in cardiomyocyte function, there are also changes in collagen turnover of the extracellular matrix. Cardiac structural defects (eg, congenital defects, valvular disorders), rhythm abnormalities (including persistently high heart rate), and high metabolic demands (eg, due to thyrotoxicosis) also can cause HF. LV failure  CO decreases  pulmonary venous pressure increases. When pulmonary capillary pressure exceeds the oncotic pressure of plasma proteins, fluid extravasates from the capillaries into the interstitial space and alveoli, reducing pulmonary compliance and increasing the work of breathing. Marked fluid accumulation in alveoli (pulmonary edema) significantly alters ventilation-perfusion (V/Q) relationships: Deoxygenated pulmonary arterial blood passes through poorly ventilated alveoli, decreasing systemic arterial oxygenation (PaO2) and causing dyspnea. Pleural effusions characteristically develop & aggravating dyspnea. Minute ventilation increases; thus, PaCO2 decreases and blood pH increases (respiratory alkalosis). Marked interstitial edema of the small airways may interfere with ventilation, elevating PaCO2—a sign of impending respiratory failure. RV failure systemic venous pressure increases, causing fluid extravasation and consequent edema, primarily in dependent tissues (feet and ankles of ambulatory patients) and abdominal viscera. The liver is most severely affected, but the stomach and intestine also become congested; Fluid accumulation in the peritoneal cavity (ascites) can occur. Sequels 1. moderate hepatic dysfunction 2. impaired liver breaks down less aldosterone, further contributing to fluid accumulation. 3. anorexia, 4. malabsorption of nutrients and drugs, 5. protein-losing enteropathy (diarrhea & hypoalbuminemia), 6. chronic GI blood loss,