Cardiovascular Pathology (modification of Dr. Veinot’s presentation) Michel Dionne MD FRCPC for John P. Veinot MD FRCPC Professor of Pathology University of Ottawa Pathology and Laboratory Medicine Ottawa Hospital

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Overview Atherosclerosis Aneurysms Ischemic heart disease Cardiomyopathies Valvular heart disease Hypertension

CVS Anatomy 101

Endothelium

muscular artery intima media adventitia

Aorta

Media of aorta – an elastic artery

Atherosclerosis Disease of large and medium sized arteries (elastic and muscular), particularly: aorta, iliac, coronary, popliteal, carotid, circle of Willis Develop intimal lesions called atheromas or atheromatous plaques which: protrude into the lumen resulting in stenosis (narrowing of lumen) and possibly occlusion (lumen blocked) can weaken the underlying media, possibly leading to aneurysm formation

Atherosclerosis - risk factors Hyperlipidemia high LDL low HDL Hypertension Smoking Diabetes Age Male gender Family history/ genetics Other: physical inactivity, diet, obesity etc.

Atherosclerosis - pathogenesis Chronic endothelial injury* resulting in endothelial dysfunction increased permeability increased adhesion of leukocytes (monocytes and lymphocytes) and platelets accumulation of lipids in intima Migration of monocytes into intima leading to formation of foam cells (lipid-laden macrophages) Release of cytokines and growth factors result in smooth muscle cell migration into intima, proliferation of smooth muscle cells, deposition of extracellular matrix (e.g. collagen) * From hemodynamic forces, hyperlipidemia, HTN, smoking etc.

From: Robbins and Cotran Pathologic Basis of Disease, 8th Edition

Aorta – fatty streaks

Aorta – fibrofatty/atheromatous plaques

Aorta – complicated plaques

advanced plaques causing severe stenosis Aortic arch vessels – advanced plaques causing severe stenosis

Coronary artery

Atheromatous material – foam cells (lipid laden macrophages) and cholesterol clefts

From: Robbins and Cotran Pathologic Basis of Disease, 8th Edition

Atherosclerosis - complications Calcification Plaque hemorrhage and rupture Plaque erosion/ulceration Thrombosis Embolization of atheromatous material (atheroemboli) Aneurysm formation and rupture

Renal infarct from embolization

Atherosclerosis - major consequences Symptomatic disease most often affects the heart, brain, kidneys and lower extremities Heart: angina and myocardial infarction Brain: cerebral infarction (stroke) Aorta (particularly abdominal): Aneurysms Stenosis of ostia of major branches leading to visceral ischemia Lower extremities: peripheral vascular (arterial) disease – claudication, gangrene

a localized abnormal dilatation of a vessel Aneurysm - definition a localized abnormal dilatation of a vessel

Aneurysm types Atherosclerotic aneurysms are the most common, but there are other types!

Aneurysms - complications Stasis of blood Thrombosis obstruction embolism Mass effect Rupture

Abdominal Aortic Aneurysm (AAA) thrombus

Aneurysm rupture blood lumen tear thrombus vessel wall

AAA rupture Hemorrhage into surrounding tissue

Dissecting “aneurysm”

Coronary artery aneurysms secondary to vasculitis (inflammation of blood vessels)

Left lung SVC Aorta Left atrium Pericardium Right lung Right atrium Left ventricle Right ventricle

Left atrium Right atrium Left ventricle Right ventricle Interventricular septum

Coronary artery anatomy http://www.drchander.com/diagnoseCAD.html

Coronary artery atherosclerosis affects the epicardial arteries; tends to be more pronounced in the proximal portion of these vessels can involve 1, 2 or all 3 of the main vessels +/- their large branches if degree of obstruction is significant, can result in angina (pain from myocardial ischemia) an atherosclerotic plaque can become unstable (acute plaque lesion): intraplaque hemorrhage plaque rupture or erosion resulting in thrombosis acute plaque lesions can result in an “acute coronary syndrome” (unstable angina, myocardial infarct)

Myocardial infarct terminology

Recent MI - about 24 hours old

Contraction band necrosis

Recent MI - about 3 days old

Recent MI - interstitial infiltrate of neutrophils

Recent MI - 5-7 days old

Recent MI - 7-10 days old “Sick” myocytes bordering the infarct Phagocytosis of dead cells at margin of infarct Residual necrotic myocytes

Remote myocardial infarcts

Transmural rupture

Infarct rupture and tamponade

Papillary muscle rupture

Left ventricle aneurysm

Ischemic heart disease - interventions Non-surgical thrombolysis PTCA / stenting atherectomy rotablation Surgical Coronary Artery Bypass Grafting (CABG) – typically using saphenous vein grafts and/or internal thoracic arteries endarterectomy

Atherectomy device

PTCA balloon

Angiogram pre/post PTCA

Aortic valve - normal

Mitral valve - normal

Aortic stenosis - causes

Aortic stenosis causing LVH

Mitral stenosis - rheumatic

Floppy mitral valve - mitral valve prolapse (MVP)

Hypertension PRIMARY (ESSENTIAL) SECONDARY Genetic and environmental factors Defects in sodium homeostasis, vascular smooth muscle structure, regulation of vascular tone SECONDARY renal disease vascular disease endocrinopathies drugs neurogenic etc…

Reno-vascular hypertension

Hypertension - complications enhance other diseases (risk factor) small vessel changes scarring/sclerosis microaneurysms large vessel changes ectasia / aneurysms / aortic regurgitation dissection vessel rupture cardiac hypertrophy etc…

Arteriolo-nephrosclerosis

Brain hypertensive bleed

Hypertensive brain stem bleed

LVH (look familiar?)

Cardiomyopathy - definition Heterogenous group of diseases of the myocardium associated with mechanical or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilation and are due to a variety of causes that frequently are genetic. Cardiomyopathies are either confined to the heart or are part of generalized systemic disorders often leading to cardiovascular death or progressive heart failure related disability. Circulation 2006 113:1807-1816

Cardiomyopathy types (clinical/functional/morphologic patterns) Dilated (DCM) – 90% Hypertrophic (HCM) Restrictive

Primary cardiomyopathy (confined to the heart) - etiology Genetic e.g. HCM, ARVC, mitochondrial defects, channelopathies (e.g. LQTS) Acquired e.g. due to myocarditis (inflammation of the myocardium) Mixed Idiopathic

Secondary cardiomyopathy (part of generalized systemic disorder) – examples of etiologies Amyloidosis Hemochromatosis Sarcoidosis Medication/Toxin induced - e.g. cancer chemotherapy, alcoholism Autoimmune diseases - e.g. SLE, rheumatoid arthritis Infections Endocrine disorders - e.g. hypothyroidism Neuromuscular diseases - e.g. muscular dystrophies Storage diseases - e.g. glycogen storage disease Nutritional deficiencies - e.g. thiamine

Primary dilated cardiomyopathy Primary myocardial abnormality NO SIGNIFICANT: coronary artery disease valve disease systemic arterial hypertension systemic disorder, history of toxin exposure etc.

Non-specific myocardial degenerative changes

DCM - clinical presentation Progressive heart failure systolic dysfunction 4 chamber dilatation hypokinesis Arrhythmias Thromboembolism Sudden death

Familial (genetic) DCM About 30 % of DCM Often asymptomatic LV dilatation at detection - minority progress Examples: muscular dystrophy mitochondrial defects - maternal inheritance inherited metabolic disorders

Cardiomyopathy – genetic abnormalities Dilated - cytoskeletal elements largely affected dystrophin - X-linked, some muscular dystrophies lamin desmin actin etc… mitochondrial genes Hypertrophic - contractile elements affected (sarcomeric genes) myosin troponin tropomyosin myosin binding protein C etc…

Viral myocarditis and DCM Enteroviral protease cleaves dystrophin Disrupted dystrophin / sarcoglycan complex Similar to primary genetic defects found in DCM

Hypertrophic cardiomyopathy a genetic disease; autosomal dominant, variable penetrance phenotype variations even with same mutation - ? environmental influences myocardial hypertrophy (thickened myocardium) diastolic dysfunction sub-aortic obstruction sudden death (60% of deaths are sudden)

Hypertrophic cardiomyopathy Disproportionate thickening of the interventricular septum

Myocyte disarray and hypertrophy and interstitial fibrosis

HCM - diastolic dysfunction ventricular hypertrophy myocyte disarray interstitial fibrosis myocardial microinfarcts

Cardiomyopathy - summary Gross and histopathologic findings are non- specific but may be diagnostic Most require clinicopathological correlation Many mimics and secondary diseases Molecular diagnosis / genetics developing