Overview of heart disease Heart failure Left-sided heart failure Right-shyperreactivityure Cor pulmonale Congenital heart disease Left-to-right shunts (ASD, VSD, PDA) Right-to-left shunts (tetralogy of Fallot, transposition of the great arteries) Obstructive congenital lesions (aortic coarctation) Atherosclerosis and its pathogenesis Plaque vulnerability and acute plaque change Foam cell formation and atherogenesis Ischemic heart disease Angina pectoris (stable, unstable, variant) Myocardial infarction Coronary artery anatomy and patterns of infarction Morphologic evolution of myocardial infarction over time Reperfusion injury and contraction band necrosis Complications of myocardial infarction Chronic ischemic heart disease Systemic (left-sided) hypertensive heart disease Pulmonary hypertensive heart disease Valvular heart disease Calcific aortic stenosis Mitral valve prolapse Rheumatic fever and rheumatic valvular disease Infective endocarditis Nonbacterial thrombotic endocarditis Libman-Sacks endocarditis Cardiomyopathies Dilated cardiomyopathy Hypertrophic cardiomyopathy Restrictive cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy Myocarditis Cardiotoxic drugs Pericardial disease and cardiac tamponade Aneurysms (abdominal and thoracic) Aortic dissection Vasculitis classification by vessel size and mechanism Large vessel vasculitis (giant cell, Takayasu) Medium vessel vasculitis (polyarteritis nodosa, Kawasaki) Small vessel / ANCA-associated vasculitis Thromboangiitis obliterans (Buerger disease) Raynaud phenomenon and disorders of vascular hyperreactivity

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Cardiovascular Pathology - Complete Overview

1. Overview of Heart Disease

Heart disease is the single greatest cause of morbidity and mortality in the developed world. Cardiac disease arises from four broad categories:

Congenital abnormalities - structural defects present from birth
Ischemic heart disease - imbalance between coronary supply and myocardial demand
Hypertensive heart disease - pressure overload from elevated systemic or pulmonary pressure
Valvular, myocardial, and pericardial disease - primary structural or inflammatory pathology

The heart compensates for injury or pressure/volume overloads through hypertrophy (increased cell size, not number, since cardiomyocytes are terminally differentiated) and dilation. Sustained overload eventually exceeds compensatory capacity and leads to heart failure.

2. Heart Failure

Heart failure (HF) is a clinical state in which the heart cannot pump sufficient output to meet the body's metabolic demands, or can only do so at elevated filling pressures.

Mechanisms:

Systolic dysfunction - impaired contractility (ejection fraction <40%), as in dilated cardiomyopathy and ischemic heart disease
Diastolic dysfunction - impaired ventricular filling due to stiffness (EF preserved), as in hypertrophic and restrictive cardiomyopathy

Compensatory mechanisms include:

Frank-Starling mechanism (increased preload -> increased stroke volume)
Neurohumoral activation (RAAS, catecholamines) - initially beneficial, chronically maladaptive
Myocardial hypertrophy

Left-Sided Heart Failure

Left ventricular failure produces:

Pulmonary congestion - increased pulmonary venous/capillary pressure, transudation of fluid, pulmonary edema
Dyspnea, orthopnea, paroxysmal nocturnal dyspnea
Pleural effusions (typically bilateral but often larger on right)
Hemosiderin-laden macrophages ("heart failure cells") in alveolar spaces - due to extravasation of red cells and breakdown of hemoglobin
Reduced cardiac output: fatigue, prerenal azotemia

Right-Sided Heart Failure

Most commonly caused by left-sided HF (elevated pulmonary venous pressure elevates pulmonary arterial resistance). Also caused by primary pulmonary disease (cor pulmonale).

Consequences of right-sided failure:

Systemic venous congestion: elevated JVP, peripheral edema, hepatomegaly (congestive hepatopathy - "nutmeg liver")
Ascites and pleural effusions
Portal hypertension with bowel edema (malabsorption)

Cor Pulmonale

Right ventricular hypertrophy and dilation caused by primary pulmonary parenchymal or vascular disease (not secondary to left-heart failure or congenital disease). Causes include:

Chronic obstructive pulmonary disease (most common)
Pulmonary fibrosis/interstitial disease
Recurrent pulmonary emboli
Primary pulmonary arterial hypertension

Acute cor pulmonale: massive pulmonary embolism Chronic cor pulmonale: insidious pressure overload from long-standing pulmonary hypertension

3. Congenital Heart Disease

Congenital heart defects occur in approximately 1% of live births; most result from abnormal embryonic cardiac development during weeks 3-8.

Left-to-Right Shunts (Acyanotic)

These initially shunt oxygenated blood back to the lungs. Over time, increased pulmonary blood flow causes pulmonary hypertension and right-sided pressure elevation, which can eventually reverse the shunt direction (Eisenmenger syndrome - late cyanosis).

Atrial Septal Defect (ASD)

Failure of the atrial septum to fully close (most commonly at the fossa ovalis - ostium secundum type)
Produces left-to-right shunting proportional to the difference in ventricular compliance
Findings: right ventricular dilation and hypertrophy, pulmonary vascular changes
Often asymptomatic for decades; may present with arrhythmias or paradoxical embolism
Ostium primum ASDs are associated with AV valve abnormalities

Ventricular Septal Defect (VSD)

Most common congenital heart defect overall
Membranous VSD (80%) is the most common subtype
Small VSDs (maladie de Roger): may close spontaneously; cause a loud holosystolic murmur with little hemodynamic consequence
Large VSDs: significant left-to-right shunt -> right ventricular hypertrophy -> pulmonary hypertension -> Eisenmenger syndrome
Morphology: right ventricular and pulmonary vascular hypertrophy in large defects

Patent Ductus Arteriosus (PDA)

Persistence of the ductus arteriosus (connects the pulmonary artery to the aorta in fetal circulation) after birth
In utero, prostaglandins maintain patency; after birth, decreased prostaglandins and increased oxygen tension lead to closure
A continuous ("machinery") murmur at the left infraclavicular region
Small PDAs: well-tolerated long-term
Large PDAs: pulmonary hypertension, Eisenmenger syndrome
Treatment: indomethacin (inhibits prostaglandin synthesis) or surgical ligation

Right-to-Left Shunts (Cyanotic)

Deoxygenated blood bypasses the lungs and enters the systemic circulation -> cyanosis from birth ("blue babies"). Complications include polycythemia (secondary to hypoxia), hyperviscosity, hypertrophic osteoarthropathy, and paradoxical embolism.

Tetralogy of Fallot The most common cyanotic congenital heart defect. Four features result from a single embryologic defect - anterosuperior displacement of the infundibular septum:

Ventricular septal defect (large, perimembranous)
Right ventricular outflow tract obstruction (subpulmonic stenosis)
Overriding aorta - aorta straddles the VSD
Right ventricular hypertrophy

The pulmonic stenosis protects the pulmonary vasculature from pressure overload, so pulmonary hypertension does NOT develop. Cyanosis severity depends on the degree of right ventricular outflow obstruction.

"Boot-shaped" heart on X-ray (right ventricular hypertrophy causes upturned cardiac apex). Complications include right ventricular failure, infective endocarditis, and polycythemia. Complete surgical repair is possible.

Transposition of the Great Arteries

The aorta arises from the right ventricle; the pulmonary artery arises from the left ventricle
The systemic and pulmonary circulations are thus completely separated - incompatible with postnatal life unless a shunt exists (PDA, ASD, or VSD)
Marked right ventricular hypertrophy (as it functions as the systemic ventricle); hypoplastic left ventricle
Requires emergent surgical correction (arterial switch operation) in the first days of life

Obstructive Congenital Lesions: Coarctation of the Aorta

Narrowing of the aortic lumen, typically at the site of the ductus arteriosus (juxtaductal). Male predominance. Associated with Turner syndrome (45,X) and bicuspid aortic valve.

Two classic presentations:

Infantile (preductal): severe narrowing proximal to the ductus; pulmonary artery delivers mixed blood to the lower body via the patent ductus; lower-body cyanosis; presents with heart failure in infancy
Adult (postductal): narrowing distal to the ductus; develops extensive collateral circulation (via internal mammary and intercostal arteries) to bypass the obstruction; presents later with hypertension in the upper extremities, diminished/delayed femoral pulses, and "rib notching" on X-ray

4. Atherosclerosis and Its Pathogenesis

Atherosclerosis is the most important vascular disease, underlying coronary, cerebral, and peripheral vascular disease. It accounts for roughly half of all deaths in the Western world. It is an intima-based lesion (fibrous cap + atheromatous core) that impinges on the vascular lumen.

Pathogenesis: Response-to-Injury Hypothesis

Atherosclerosis is a chronic inflammatory response of the arterial wall to endothelial injury. Key steps:

Endothelial injury/dysfunction - caused by hyperlipidemia, hypertension, cigarette smoke, diabetes, turbulent flow at vessel bifurcations
Increased permeability - LDL enters the intima and accumulates; oxidized LDL (ox-LDL) is particularly atherogenic
Monocyte recruitment - endothelial adhesion molecules (VCAM-1, ICAM-1, selectins) attract monocytes, which differentiate into macrophages in the intima
Foam cell formation - macrophages take up ox-LDL via scavenger receptors (CD36, SR-A) and become lipid-laden foam cells; foam cells form the fatty streak (earliest visible lesion)
SMC migration and proliferation - growth factors (PDGF, FGF, TGF-β) from platelets, macrophages, and ECs drive smooth muscle cell (SMC) migration from the media into the intima, where they proliferate and produce extracellular matrix (collagen, proteoglycans), forming the fibrous cap
Chronic inflammation - T cells, macrophages, and foam cells accumulate; necrotic core enlarges from foam cell death; cholesterol crystals form

Foam cell formation (atherogenesis):

Native LDL is not taken up efficiently by macrophages via the LDL receptor (which is downregulated by intracellular cholesterol)
ox-LDL is recognized by unregulated scavenger receptors -> unlimited uptake -> lipid-laden foam cells
Foam cell accumulation is the central early event in atherogenesis
Cholesterol crystals and necrotic debris form the lipid-rich grumous core

Risk Factors (modifiable): hypercholesterolemia, hypertension, cigarette smoking, diabetes mellitus Risk Factors (non-modifiable): age, male sex (though gap narrows post-menopause), family history

Plaque Vulnerability and Acute Plaque Change

Stable plaques: thick fibrous cap, minimal lipid, few inflammatory cells - produce chronic ischemia from gradual luminal narrowing (stable angina)

Vulnerable (unstable) plaques: thin fibrous cap, large necrotic lipid core, dense inflammatory infiltrate of macrophages and T cells - prone to rupture

Acute plaque changes:

Rupture/fissuring - most common; sudden exposure of subendothelial collagen and necrotic core to blood triggers platelet aggregation and thrombus formation
Erosion - endothelial loss without frank rupture; also triggers thrombosis
Intraplaque hemorrhage - rupture of small vessels within the plaque can cause sudden expansion

Metalloproteinases (MMPs) produced by macrophages degrade collagen in the fibrous cap, reducing its mechanical strength. Inflammatory cytokines (IFN-γ from T cells) inhibit SMC collagen synthesis, further weakening the cap.

Clinical consequences of acute plaque change:

Unstable angina/NSTEMI (incomplete occlusion or transient occlusion)
STEMI (complete, sustained occlusion)
Sudden cardiac death
Atheroembolism (plaque debris embolizes distally)

5. Ischemic Heart Disease (IHD)

IHD encompasses conditions caused by myocardial ischemia - imbalance between coronary supply and demand. The overwhelming cause is coronary atherosclerosis.

Coronary anatomy and patterns of infarction:

Left anterior descending (LAD): supplies the anterior left ventricle, anterior interventricular septum, anterior papillary muscle -> occlusion causes anterior/anteroseptal infarct (most common)
Right coronary artery (RCA): supplies the right ventricle, posterior left ventricle, AV node, posterior papillary muscle -> inferior/posterior infarct; AV block
Left circumflex (LCX): lateral left ventricle -> lateral infarct

Angina Pectoris

Stable angina: predictable chest pain with exertion, relieved by rest or nitrates. Caused by >70% fixed stenosis of one or more coronary arteries. Demand exceeds supply during increased work. Reversible ischemia without necrosis.

Unstable angina: increasingly severe pain at rest or with minimal exertion. Caused by acute plaque disruption with superimposed thrombus, vasospasm, and/or distal embolization. Associated with myocyte injury (elevated troponins). Requires aggressive management.

Variant (Prinzmetal) angina: occurs at rest, unrelated to exertion. Caused by coronary artery vasospasm (often over an existing plaque but can occur in normal arteries). Responds to calcium channel blockers and nitrates. ECG shows transient ST elevation during episodes.

Myocardial Infarction

MI is necrosis of the heart muscle due to sustained ischemia. The 2018 universal definition requires abnormal cardiac biomarkers plus evidence of acute ischemia.

Pathogenesis: ~90% of MIs result from acute thrombotic occlusion of a coronary artery triggered by acute plaque rupture or erosion. In 10%: vasospasm, embolism, or small vessel disease.

Sequence of coronary occlusion:

Atheromatous plaque eroded/disrupted -> subendothelial collagen and necrotic core exposed
Platelet adherence, activation, aggregation; release of TXA2, ADP, serotonin -> vasoconstriction
Tissue factor activates coagulation cascade
Enlarging thrombus completely occludes the lumen within minutes

Transmural vs. subendocardial infarction:

Transmural (STEMI): full-thickness necrosis, usually from complete occlusion of a major epicardial artery
Subendocardial (NSTEMI): necrosis limited to the inner third (most vulnerable zone, farthest from epicardial vessels); often from transient occlusion or severe fixed stenosis

Morphologic Evolution of MI Over Time

Time	Gross	Light Microscopy
0-0.5 hr	None	None (reversible injury)
0.5-4 hr	None	Waviness of fibers at border
4-12 hr	Dark mottling	Onset coagulative necrosis; edema; hemorrhage
12-24 hr	Dark mottling	Coagulative necrosis; pyknosis; hypereosinophilic myocytes; contraction band necrosis at margins; early neutrophil infiltrate
1-3 days	Mottling with yellow-tan core	Coagulative necrosis; loss of nuclei; neutrophilic infiltrate peaks
3-7 days	Hyperemic border; central yellow-tan softening	Disintegrating myofibers; dead myocytes; macrophage infiltration begins
7-10 days	Maximally yellow-tan and soft; depressed red-tan margins	Macrophage phagocytosis; early granulation tissue at margins
10-14 days	Red-gray depressed infarct borders	Well-established granulation tissue
2-8 weeks	Gray-white fibrosis	Increased collagen deposition
>2 months	White, glistening scar	Dense collagen scar

Infarcts <12 hours old are usually grossly invisible; triphenyl tetrazolium chloride (TTC) staining can detect necrosis >3 hours old (infarcted areas appear pale/unstained because LDH leaks out).

Reperfusion Injury and Contraction Band Necrosis

When blood flow is restored (spontaneously or via thrombolytics/PCI), reperfusion itself causes additional injury through:

Reactive oxygen species generated by returning oxygen
Calcium overload from membrane damage and impaired ion pumps -> hypercontraction
Mitochondrial permeability transition pore opening

Histologically: contraction band necrosis - hypereosinophilic transverse bands of densely packed sarcomeres from myocyte hypercontraction; characteristic of reperfused myocardium. Also seen in catecholamine excess (pheochromocytoma, stress cardiomyopathy).

Complications of MI

Complication	Timing	Mechanism
Arrhythmias	Minutes to days	Electrophysiologic instability of ischemic/infarcted myocardium (most common cause of death in early MI)
Left ventricular failure / cardiogenic shock	Hours to days	Loss of contractile mass (>40% LV loss = shock)
Myocardial rupture	3-7 days (peak)	Neutrophils weaken wall during early inflammatory phase (wall softening)
Free wall rupture	3-7 days	Hemopericardium -> tamponade; usually fatal
Interventricular septal rupture	3-7 days	Sudden VSD; left-to-right shunt; right heart failure
Papillary muscle rupture	3-5 days	Posterior papillary muscle (single blood supply from RCA); acute severe mitral regurgitation
Pericarditis (fibrinous)	1-3 days	Inflammation over infarcted epicardium; friction rub
Mural thrombus	Days to weeks	Stasis + abnormal endocardium in infarcted zone; risk of systemic embolism
Ventricular aneurysm	Weeks to months	Paradoxical bulging of infarcted wall; stasis, mural thrombus, arrhythmia
Dressler syndrome	2-10 weeks	Autoimmune pericarditis after MI
Progressive CHF	Months to years	Infarct expansion, remodeling, progressive LV dysfunction

Dressler syndrome (post-MI syndrome): autoimmune fibrinous pericarditis developing weeks after MI; treated with NSAIDs or corticosteroids.

Reinfarction is also possible in the setting of incomplete revascularization.

Chronic Ischemic Heart Disease

Characterized by progressive heart failure from cumulative myocardial injury. Pathology shows:

Combination of severe coronary atherosclerosis
Previous healed infarcts (white fibrous scars)
Patchy areas of myocardial fibrosis
Compensatory hypertrophy of surviving myocardium
Often associated with LV dilation and dysfunction

6. Hypertensive Heart Disease

Systemic (Left-Sided) Hypertensive Heart Disease

Diagnosis requires: (1) left ventricular hypertrophy without other cause AND (2) evidence of hypertension elsewhere.

Morphology:

Concentric LV hypertrophy: wall thickness >2.0 cm (normal 1.2-1.4 cm); heart weight >500 g
"Boxcar nuclei" - enlarged, hyperchromatic myocyte nuclei
Interstitial fibrosis
Late: diastolic dysfunction -> left atrial dilation -> atrial fibrillation; eventual systolic failure -> LV dilation

Clinical: often asymptomatic until atrial fibrillation or CHF develops. Risk of ventricular arrhythmias, sudden death, and post-infarction mortality is increased. BP control can reverse hypertrophy.

Pulmonary Hypertensive Heart Disease (Cor Pulmonale)

Right ventricular hypertrophy/dilation + right heart failure secondary to primary pulmonary parenchymal or vascular disease. Right ventricular hypertrophy from left heart failure is excluded by definition.

7. Valvular Heart Disease

Calcific Aortic Stenosis

The most common valvular lesion in the developed world. Two main types:

Calcification of a normal tricuspid aortic valve: degenerative "wear-and-tear" calcification; presents in the 7th-8th decade. Normal leaflets develop calcific nodules at the base that limit opening but typically do not fuse the commissures.

Calcification of a congenitally bicuspid aortic valve: abnormal valve architecture causes turbulent flow -> accelerated degenerative calcification; presents 1-2 decades earlier (5th-6th decade). Bicuspid aortic valve is the most common congenital cardiac anomaly (1-2% prevalence).

Clinical triad of severe aortic stenosis: exertional dyspnea, angina, syncope. Each carries a predictable prognosis without valve replacement (average survival: angina ~5 years, syncope ~3 years, heart failure ~2 years). Harsh crescendo-decrescendo systolic murmur radiating to the neck.

Mitral Valve Prolapse (MVP)

The mitral leaflets are enlarged, soft, and billowy, with redundant myxomatous tissue. The leaflets balloon back into the left atrium during systole.

Pathology: mid-systolic click +/- late systolic murmur. Myxoid degeneration of the valve's spongiosa layer with disruption of the fibrosa. Most cases are sporadic; some are associated with Marfan syndrome.

Complications (rare, but includes): mitral regurgitation, infective endocarditis, stroke from embolism, arrhythmias, sudden death. Vast majority of patients are asymptomatic and have a benign course.

Rheumatic Fever and Rheumatic Valvular Disease

Rheumatic fever is an acute, immune-mediated multi-system inflammatory disease that occurs after group A streptococcal pharyngitis (not skin infection). The major cardiac lesion results from molecular mimicry - streptococcal antigens share epitopes with cardiac tissue.

Jones Criteria (major): carditis, polyarthritis, chorea (Sydenham chorea), erythema marginatum, subcutaneous nodules.

Cardiac pathology in acute rheumatic fever:

Pancarditis (all three layers of the heart)
Aschoff bodies - pathognomonic; perivascular foci of fibrinoid necrosis with surrounding chronic inflammatory cells; Anitschkow cells (macrophages with "caterpillar" nuclei) and Aschoff giant cells
Pericarditis - "bread and butter" fibrinous pericarditis
Myocarditis - Aschoff bodies in myocardium
Endocarditis - small (1-2 mm), warty, sterile vegetations along the line of valve closure (due to fibrin deposition on denuded endothelium)

Chronic rheumatic valvular disease: Repeated episodes of inflammation and healing lead to:

Commissural fusion (leaflets fuse at their edges)
Leaflet thickening and fibrosis
Chordae tendineae thickening, shortening, and fusion
Mitral stenosis is the most common sequela (mitral valve involved in virtually all cases); produces "fish-mouth" or "buttonhole" deformity
Aortic valve involvement in ~30%; isolated aortic disease without mitral is rare
Complications: atrial fibrillation (from left atrial dilation), pulmonary hypertension, heart failure, infective endocarditis, mural thrombus

Infective Endocarditis (IE)

Microbial colonization of the cardiac valves or mural endocardium, forming vegetations of microorganisms and inflammatory debris.

Predisposing factors: abnormal valves (rheumatic, prosthetic, bicuspid, MVP), congenital heart disease, IV drug use, immunosuppression, dental or invasive procedures.

Organisms:

Streptococcus viridans - subacute IE on previously abnormal valves (dental source)
Staphylococcus aureus - most common overall; aggressive, can infect normal valves; IV drug users, nosocomial; right-sided IE (tricuspid) in IVDU
Enterococcus - elderly patients after GI/GU procedures
HACEK organisms - culture-negative IE
Streptococcus bovis - associated with colon cancer

Morphology:

Large, friable, irregular vegetations that can be destructive (perforate leaflets, extend to chordae, annulus)
Acute IE: bulky, rapidly destructive vegetations; ring abscesses common
Subacute IE: smaller, less destructive; more organized

Complications: embolization (brain, kidney, spleen); septic emboli; immune complex-mediated glomerulonephritis; Osler nodes (tender subcutaneous nodules - immune complex vasculitis); Janeway lesions (painless palmar/plantar erythematous macules - septic emboli); Roth spots (retinal hemorrhages); splinter hemorrhages.

Modified Duke Criteria: 2 major, 1 major + 3 minor, or 5 minor. Major: positive blood cultures, positive echocardiogram (vegetation, abscess, new dehiscence of prosthetic valve, new valvular regurgitation).

Nonbacterial Thrombotic Endocarditis (NBTE)

Small (1-5 mm), sterile, bland vegetations at the line of valve closure on previously normal valves. NOT associated with inflammation - the thrombus has no inflammatory infiltrate.

Causes: hypercoagulable states; mucinous adenocarcinoma (most common malignancy), DIC, hyperestrogenic states, chronic debilitating illness.

Key distinction: easily dislodged -> thromboembolism to brain, heart, kidneys (the local valve effect is trivial). Can serve as a nidus for subsequent infective endocarditis.

Libman-Sacks Endocarditis

Occurs in systemic lupus erythematosus (SLE). Small to medium, warty, sterile vegetations that uniquely can be found on BOTH surfaces of the valve leaflets (as opposed to rheumatic disease which is on the line of closure, and IE which is on the upstream surface).

Mechanism: immune complex deposition and inflammation. Heals with scarring. May produce regurgitation. Associated with antiphospholipid antibody syndrome.

8. Cardiomyopathies

Primary myocardial diseases not caused by ischemia, hypertension, valve disease, or congenital anomalies.

Type	EF	Mechanism	Key Causes
Dilated (DCM)	<40%	Systolic dysfunction (contractility impaired)	Genetic (titin, dystrophin mutations), alcohol, peripartum, myocarditis, hemochromatosis, doxorubicin, idiopathic
Hypertrophic (HCM)	50-80%	Diastolic dysfunction (compliance impaired)	Genetic (sarcomere mutations: β-MHC, MYBPC3); Friedreich ataxia; storage diseases
Restrictive (RCM)	25-50%	Diastolic dysfunction	Amyloidosis; radiation fibrosis; idiopathic; endomyocardial fibrosis

Dilated Cardiomyopathy (DCM)

Four-chamber dilation with impaired systolic function. The most common cardiomyopathy (~90% of cases). Heart is enlarged (weight up to 2-3x normal), floppy, and pale. Microscopy shows nonspecific myocyte hypertrophy and interstitial fibrosis.

Genetic causes: mutations in titin (accounts for ~20% of all DCM - titin spans the sarcomere and connects Z to M bands), dystrophin (X-linked; leads to Duchenne/Becker muscular dystrophy-associated cardiomyopathy), lamin A/C, desmin.

Clinical: progressive heart failure, arrhythmias, sudden death, mural thrombus/embolism. Treatment: standard HF therapy; cardiac transplant in refractory cases.

Hypertrophic Cardiomyopathy (HCM)

Massive asymmetric septal hypertrophy (disproportionate thickening of the interventricular septum vs. the posterior wall). The hypertrophy impairs diastolic filling and, in obstructive HCM, causes dynamic LVOT obstruction (systolic anterior motion of the mitral valve narrows the outflow tract).

Genetics: autosomal dominant mutations in sarcomere proteins:

β-myosin heavy chain (MYH7): most studied
MYBPC3 (myosin-binding protein C): most common
Troponin T, troponin I, α-tropomyosin

Morphology: asymmetric septal hypertrophy; bizarre disarray of myocytes (myofiber disarray) - cardiomyocytes arranged at oblique and perpendicular angles (hallmark); interstitial fibrosis; thickened intramural coronary arteries.

Clinical: dyspnea, angina, syncope, sudden death (leading cause of sudden cardiac death in young athletes). Physical exam: harsh systolic ejection murmur that increases with decreased preload (Valsalva, standing) and decreases with increased preload (squatting).

Restrictive Cardiomyopathy (RCM)

Impaired diastolic filling due to excessively stiff ventricular walls. Systolic function is initially preserved (EF may be normal). Clinical picture resembles constrictive pericarditis.

Amyloidosis - most important secondary cause; AL or TTR amyloid deposits in myocardium; echocardiography shows "granular sparkling" pattern; Congo red staining with apple-green birefringence
Radiation-induced fibrosis - mediastinal radiation for lymphoma
Endomyocardial fibrosis - tropical/subtropical regions; dense fibrous thickening of the endocardium, obliterating the ventricular cavities
Hemochromatosis - iron deposition in myocardium; can also cause DCM

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Replacement of right ventricular myocardium by fatty and fibrous tissue, progressing from the epicardium inward. Caused by mutations in desmosomal proteins (plakophilin-2, desmoplakin, desmoglein-2, plakoglobin), which impair cell-cell adhesion and lead to myocyte death with fibrofatty replacement.

Clinical: right ventricular failure; ventricular arrhythmias (classically left bundle branch block morphology, originating from RV); sudden cardiac death in young people. ECG: epsilon wave (small deflection after QRS). MRI: fibrofatty replacement of RV. ICD implantation for high-risk cases.

9. Myocarditis

Inflammatory infiltrate of the myocardium with myocyte injury not due to ischemia. Most cases in Western countries are caused by viral infection.

Causes:

Viral (most common): Coxsackievirus A and B (enteroviruses), CMV, HIV, parvovirus B19
Bacterial: Corynebacterium diphtheriae (diphtheria toxin); Chagas disease (Trypanosoma cruzi - chagasic myocarditis, common in South America)
Immune-mediated: giant cell myocarditis (idiopathic, aggressive; multinucleated giant cells on biopsy); drug hypersensitivity; peripartum; systemic diseases (SLE, sarcoidosis)

Morphology: mononuclear inflammatory infiltrate (lymphocytes) with focal myocyte necrosis. In giant cell myocarditis: multinucleated giant cells and eosinophils.

Clinical: presentation ranges from asymptomatic/subclinical to acute heart failure or sudden death. Arrhythmias are common. Diagnosis via cardiac MRI (late gadolinium enhancement) or endomyocardial biopsy. Supports to DCM in some cases.

Cardiotoxic Drugs

Doxorubicin (Adriamycin): anthracycline chemotherapy; dose-dependent dilated cardiomyopathy via free radical generation and mitochondrial damage. Pathology: vacuolation of myocytes (swelling of SR and mitochondria). Cumulative dose-dependent risk (>550 mg/m² markedly increased risk).
Trastuzumab (Herceptin): reversible cardiomyopathy via HER2 (ErbB2) inhibition (HER2 signaling is cardioprotective). Additive risk with anthracyclines.
Cyclophosphamide: hemorrhagic myocarditis and necrosis at high doses.
Cocaine: vasospasm, accelerated atherosclerosis, catecholamine excess -> acute MI, arrhythmias, sudden death.
Methamphetamine: direct myocardial toxicity; dilated cardiomyopathy.

10. Pericardial Disease and Cardiac Tamponade

Pericarditis: inflammation of the pericardium. Most common cause: viral infection (Coxsackievirus). Other causes: uremia, MI, autoimmune disease (SLE, rheumatoid), radiation, malignancy, tuberculosis.

Morphology:

Fibrinous pericarditis (viral, uremia, MI): shaggy "bread-and-butter" fibrinous exudate; typically resolves
Suppurative pericarditis (bacterial): purulent exudate with pus
Hemorrhagic (malignancy, TB): bloody effusion
Constrictive pericarditis: extensive fibrosis/calcification obliterates pericardial space; impairs diastolic filling; mimics restrictive cardiomyopathy clinically (elevated JVP, edema, ascites, low cardiac output)

Clinical: sharp pleuritic chest pain (worse lying down, relieved leaning forward); pericardial friction rub (pathognomonic). ECG: diffuse saddle-shaped ST elevation and PR depression.

Cardiac Tamponade: accumulation of fluid in the pericardial space that compresses the heart, reducing filling and thus cardiac output. Even small amounts of blood (200-300 mL) can cause tamponade if accumulation is rapid. Features (Beck's triad): hypotension, distended neck veins, muffled heart sounds. Pulsus paradoxus (>10 mmHg fall in systolic BP on inspiration). Treatment: pericardiocentesis.

11. Aneurysms and Aortic Dissection

Aneurysm: abnormal dilation of a vessel or heart involving all three layers of the wall (true aneurysm). A false aneurysm (pseudoaneurysm) is a contained hematoma from a wall breach (e.g., post-MI free wall rupture contained by pericardium).

Pathogenesis: structural weakness of vessel wall from:

Loss of smooth muscle cells
Weakening of ECM (elastic tissue degradation by MMPs)
Ischemia of the media (vasa vasorum compromise)
Genetic defects in connective tissue (Marfan syndrome, Ehlers-Danlos syndrome)

Abdominal Aortic Aneurysm (AAA)

Most common site: infrarenal aorta (between renal arteries and aortic bifurcation)
Caused by atherosclerosis with medial wall degeneration; associated with male sex, age >60, smoking, hypertension
Risk of rupture increases sharply at >5 cm (normal aorta ~2 cm); rupture is often fatal (retroperitoneal hemorrhage)
Clinical: pulsatile abdominal mass; back pain if expanding; abdominal/flank pain if rupturing
Elective repair (endovascular or open) recommended at >5.5 cm (men), >5 cm (women)

Thoracic Aortic Aneurysm

Commonly associated with hypertension, bicuspid aortic valve, Marfan syndrome, syphilis (tertiary syphilis causes endarteritis of vasa vasorum -> medial ischemia -> ascending aortic aneurysm + aortic regurgitation)
Cystic medial degeneration (medial degeneration) - loss of elastic fibers and smooth muscle cells, replaced by pools of myxoid ground substance; characteristic of Marfan syndrome but also occurs with aging and hypertension
Complications: aortic regurgitation, heart failure, compression of adjacent structures, dissection

Aortic Dissection

Blood enters the aortic wall through an intimal tear and dissects along the media, creating a false lumen. A catastrophic emergency.

Risk factors: hypertension (most important), Marfan syndrome, bicuspid aortic valve, pregnancy, trauma, iatrogenic (cardiac catheterization).

Pathology: an intimal tear (usually in the proximal ascending aorta or just distal to the ligamentum arteriosum) allows blood to cleave between the inner two-thirds and outer one-third of the media. The underlying predisposing lesion is cystic medial degeneration (loss of elastic fibers, mucinous ground substance accumulation).

Classification:

Stanford A (involves ascending aorta): surgical emergency; can propagate to involve coronary arteries (MI), aortic valve (AR), pericardium (tamponade), or carotid arteries (stroke)
Stanford B (descending aorta only, distal to left subclavian): typically managed medically (IV beta-blockers to reduce heart rate and blood pressure)
DeBakey Type I: ascending + descending; Type II: ascending only; Type III: descending only

Clinical: sudden, severe "tearing" or "ripping" chest pain radiating to the back. Different pulses in upper extremities. Widened mediastinum on chest X-ray. Diagnosed with CT angiography (gold standard) or TEE.

12. Vasculitis

Vasculitis is inflammation of vessel walls, with systemic manifestations (fever, malaise, myalgias) and organ dysfunction depending on the vessels involved. Most forms have an immunologic basis.

Mechanisms:

Immune complex deposition - activates complement; attracts neutrophils; tissue destruction (e.g., hypersensitivity vasculitis, some forms of polyarteritis nodosa)
ANCA (anti-neutrophil cytoplasmic antibodies) - activate primed neutrophils, causing degranulation and endothelial damage. Two patterns:
- c-ANCA (anti-PR3): Granulomatosis with polyangiitis (Wegener)
- p-ANCA (anti-MPO): Microscopic polyangiitis, Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
Anti-endothelial cell antibodies - Kawasaki disease
T cell-mediated granulomatous inflammation - giant cell arteritis, Takayasu arteritis

Classification by Vessel Size

Large Vessel Vasculitis

Giant Cell (Temporal) Arteritis

Most common vasculitis in adults >50 years in the Western world; F>M
Affects elastic arteries: temporal artery (most common biopsy site), ophthalmic artery, aorta and its major branches
Granulomatous transmural inflammation with multinucleated giant cells; fragmentation of internal elastic lamina
Clinical: unilateral headache (temporal region), jaw claudication (masseter ischemia), scalp tenderness, visual disturbances/sudden blindness (ophthalmic artery involvement - an ophthalmologic emergency); systemic symptoms (fever, weight loss, fatigue)
Strongly associated with polymyalgia rheumatica (shoulder/hip girdle aching and stiffness)
Lab: markedly elevated ESR and CRP
Treatment: immediate high-dose corticosteroids (before biopsy confirmation to prevent irreversible blindness)
Diagnosis: temporal artery biopsy (note: treat first, biopsy within days - steroids don't abolish histologic findings for 1-2 weeks)

Takayasu Arteritis ("Pulseless Disease")

Granulomatous inflammation of the aorta and major branches
Predominantly young women (<40 years); Asian > other ethnicities
Affects: aortic arch + great vessels (subclavian, carotid, vertebral arteries); may involve the entire aorta and renal/visceral arteries
Clinical: ocular disturbances, visual loss; upper extremity claudication/weakness; absent pulses in upper extremities; asymmetric BPs; carotid artery tenderness; hypertension from renal artery stenosis
Granulomatous arteritis with giant cells; adventitial and medial involvement; fibrotic healing causes stenosis
Treatment: corticosteroids; anti-TNF agents for refractory disease; angioplasty/bypass for critical stenoses

Medium Vessel Vasculitis

Polyarteritis Nodosa (PAN)

Systemic necrotizing vasculitis of medium and small muscular arteries
Characteristically spares the lungs; no ANCA association
Associated with hepatitis B infection (~30% of cases)
Morphology: segmental, transmural, necrotizing inflammation with fibrinoid necrosis; lesions at different stages of healing in different areas ("skip lesions"); weakened vessel walls can form microaneurysms
Clinical: fever, weight loss, hypertension (renal artery involvement), abdominal pain (mesenteric ischemia), peripheral neuropathy, skin ulcers/nodules, testicular pain; renal infarcts
Does NOT involve the lungs (key distinguishing feature from ANCA-associated vasculitides)
Treatment: corticosteroids + cyclophosphamide; antiviral therapy if HBV-associated

Kawasaki Disease

Acute, febrile, self-limited illness predominantly in children <5 years
Leading cause of acquired heart disease in children in the developed world (coronary artery aneurysms)
Mechanism: anti-endothelial cell antibodies; possible superantigen-mediated T cell activation
Clinical (CRASH/FEVER criteria): fever >5 days + 4 of 5: Conjunctival injection, Rash (polymorphous), strawberry tongue/Oral changes, Swollen hands/feet (induration), cervical Lymphadenopathy
Most feared complication: coronary artery aneurysms (in ~25% if untreated; <5% with IVIG treatment)
Treatment: high-dose aspirin + IVIG (dramatically reduces aneurysm risk)

Small Vessel / ANCA-Associated Vasculitis

Granulomatosis with Polyangiitis (Wegener Granulomatosis)

c-ANCA (anti-PR3) positive in ~90%
Classic triad: upper respiratory tract (chronic sinusitis, nasal/saddle-nose deformity, otitis), lower respiratory tract (pulmonary nodules, necrotizing granulomas, hemorrhage), and kidneys (focal necrotizing pauci-immune glomerulonephritis -> rapidly progressive GN)
Necrotizing granulomatous inflammation of upper and lower airways + small vessel vasculitis
Treatment: cyclophosphamide + corticosteroids; rituximab now first-line for induction in many centers

Microscopic Polyangiitis

p-ANCA (anti-MPO) positive
Identical to PAN but affects capillaries, arterioles, and venules (not medium arteries)
Lung involvement common (pulmonary-renal syndrome); pauci-immune glomerulonephritis
No granulomas (distinguishes from Wegener)

Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)

p-ANCA (anti-MPO) in ~50%
Hallmarks: asthma + eosinophilia + granulomatous vasculitis
Three phases: allergic rhinitis/asthma -> eosinophilia -> systemic vasculitis
Peripheral and tissue eosinophilia; Charcot-Leyden crystals
Cardiac involvement (eosinophilic myocarditis) is a leading cause of death

13. Thromboangiitis Obliterans (Buerger Disease)

Segmental, thrombosing, acute and chronic inflammation of small-to-medium arteries and veins, predominantly of the extremities. Strongly associated with heavy tobacco use (almost exclusively in smokers). Young male smokers predominantly affected.

Pathology: highly cellular, occlusive thrombus with microabscesses and giant cells; the vessel wall is relatively preserved (unlike most vasculitides); the inflammation extends into adjacent veins and nerves (perineural and perivenous involvement).

Clinical: Raynaud phenomenon, foot claudication (instep claudication characteristic), superficial thrombophlebitis, digital ulcers, and gangrene of the extremities (especially toes and fingers). Affects upper and lower extremities.

Treatment: absolute smoking cessation is the only effective intervention. Continued smoking leads to progressive gangrene and amputation.

14. Raynaud Phenomenon and Disorders of Vascular Hyperreactivity

Raynaud Phenomenon: exaggerated vasoconstriction of arteries and arterioles of the extremities (digits, toes, sometimes ears, nose) in response to cold or emotional stress, producing a characteristic triphasic color change:

White (pallor) - intense vasospasm, ischemia
Blue (cyanosis) - deoxygenated blood pooling
Red (rubor) - reactive hyperemia upon rewarming

Primary Raynaud (Raynaud Disease):

No underlying cause identified; young women
Intermittent, bilateral, symmetric
Benign; reversible with warming; no tissue damage/gangrene
Mechanism: exaggerated sympathetic vasoconstriction

Secondary Raynaud (Raynaud Phenomenon):

Occurs in the setting of an underlying disease, often connective tissue disease
Major causes: systemic sclerosis (scleroderma) (most important), SLE, MCTD, polymyositis, Sjögren syndrome, Buerger disease, cryoglobulinemia, thoracic outlet syndrome, drug-induced (ergots, β-blockers)
May be severe, asymmetric, lead to digital ulceration and gangrene
In scleroderma: intimal proliferation of digital arteries contributes to structural narrowing on top of functional vasospasm

Other vascular hyperreactivity: vasospastic angina (Prinzmetal) as discussed under angina pectoris; acrocyanosis (persistent diffuse cyanosis of the extremities, less episodic than Raynaud).

*Source: Robbins & Kumar Basic Pathology (10th ed), Chapters 8-9 (Vascular Disease, Heart Disease).*The comprehensive overview above covers every topic on your list. Here is a brief map of what was covered:

Section 1 - Heart Disease Overview & Heart Failure: Mechanisms of compensation (Frank-Starling, neurohumoral, hypertrophy), left-sided vs. right-sided failure (heart failure cells, nutmeg liver), and cor pulmonale (RV hypertrophy from primary pulmonary disease).

Section 3 - Congenital Heart Disease: Left-to-right shunts (ASD, VSD, PDA) with Eisenmenger progression; right-to-left shunts - Tetralogy of Fallot (4 features from infundibular displacement, boot-shaped heart) and Transposition (aorta from RV, pulmonary from LV, requires shunt for survival); coarctation (infantile vs. adult types, rib notching, Turner syndrome association).

Section 4-5 - Atherosclerosis & IHD: Response-to-injury hypothesis, foam cell formation via scavenger receptor uptake of ox-LDL, vulnerable vs. stable plaques, plaque rupture mechanics. MI pathogenesis, coronary anatomy, the full morphologic timeline table (0 hr to >2 months), reperfusion injury and contraction band necrosis, and all major complications with their timing.

Section 7 - Valvular Disease: Calcific aortic stenosis (tricuspid vs. bicuspid); MVP (myxomatous degeneration); rheumatic fever (Aschoff bodies, Anitschkow cells, Jones criteria, fish-mouth mitral stenosis); IE organisms and Duke criteria; NBTE (hypercoagulable, embologenic); Libman-Sacks (SLE, both surfaces).

Section 8-9 - Cardiomyopathies & Myocarditis: DCM vs. HCM (asymmetric septal hypertrophy, myofiber disarray, sarcomere mutations) vs. RCM (amyloid, Congo red); ARVC (desmosomal protein mutations, fibrofatty RV replacement, epsilon wave); cardiotoxic drugs (doxorubicin free radical mechanism, trastuzumab HER2 pathway).

Section 10-11 - Pericardial Disease & Vascular: Tamponade (Beck's triad, pulsus paradoxus); AAA (infrarenal, rupture risk at >5 cm); thoracic aneurysm (cystic medial degeneration, syphilis); aortic dissection (Stanford A vs. B, management).

Section 12-14 - Vasculitis & Raynaud: Large vessel (GCA with temporal headache/blindness risk; Takayasu with absent upper extremity pulses); medium vessel (PAN - segmental, HBV-associated, no lung; Kawasaki - coronary aneurysms, IVIG+aspirin); small vessel/ANCA (Wegener = c-ANCA, upper+lower airway + GN; MPA = p-ANCA, no granulomas; Churg-Strauss = eosinophilia + asthma); Buerger disease (tobacco, extremity gangrene); Raynaud (primary vs. secondary, scleroderma most important secondary cause).

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