Systemic Pathology - Heart pathology - Peters

• Chronic hemodynamic stress
• - Endothelial cells leak plasma proteins.
• - Smooth muscle cell matrix synthesis.
• - Pink hyaline thickening narrows lumen
• Causes:
• - Hypertension
• - Elderly persons
• - Diabetic microangiopathy
• - Nephrosclerosis

• Under severe hypertension
• Smooth muscle proliferation, basement membrane and fibrin deposition
• “Onion-skin lesions"
• - Concentric, layered thickening with luminal narrowing.
• +/ - vessel wall necrosis (necrotizing arteriolitis).

• Left-sided hypertensive heart disease
• left ventricle hypertrophy, increased LV wall thickness, stiffness, and heart weight, impaired diastolic filling, minor enlarged left atrium.
• Increased myocyte diameter (early), nuclear enlargement (late)

• Right-sided HHD, Cor pulmonale
• Acute - following massive pulmonary embolism, right ventricular dilation.
• Chronic - right ventricular hypertrophy AND dilation
• Response to pressure overload

• DISEASES OF THE PULMONARY PARENCHYMA
• DISEASES OF THE PULMONARY VESSELS
• DISORDERS AFFECTING CHEST MOVEMENT
• DISORDERS INDUCING PULMONARY ARTERIAL CONSTRICTION

• Degenerative disease of large and medium sized arteries.
• Atherosclerotic plaques - Intimal lesions protrude into and narrow the vessel lumen.

• NONMODIFIABLE
• Increasing Age
• Male gender
• Family history
• Genetic abnormalities
• MODIFIABLE
• Hyperlipidmia
• Hypertension
• Cigarette smoking
• Diabetes
• C-reactive protein

hypercholesterolemia -> premature atherosclerosis; Predominant lipids in plaques, increase local O2 free radicals

• Oxidation of LDL occurs in the arterial wall when exposed to nitric oxide, macrophages, and some enzymes such as lipoxygenase.
• Oxidized LDL is :
• •Cytotoxic to endothelial cells causing
• –dysfunction and leukocyte adhesion causing
• –stimulation of endothelial cells and macrophages activation causing
• –release of growth and chemotaxic factors causing
• –smooth muscle proliferation and monocyte recruitment.
• •ingested by macrophages which
• –become foam cells
• –undergo apoptosis releasing free lipids into the intima.

• Sites of turbulence
• - Ostia
• - Branch points
• - Posterior wall of abdominal aorta

Begins at sites of intact endothelium

• produce Chemotactic factors to attract leukocytes.
• produce Cell surface adhesion molecule (VICAM 1) -> Leucocyte adhesion and emigration.
• change shape -> increased permeability -> cell, platelet and lipid migrate into the intimal space.

• Monocytes migrating into the intima transform into macrophages and engulf lipoproteins including oxidized LDL -> apoptosis -> liberating free lipid
• T lymphocytes elaborate cytokines and growth factors

• Growth factors -> smooth muscle cell (SMC) proliferation -> extracellular matrix (collagen) synthesis -> atherosclerotic plaques stabilized, fibrofatty atheroma
• Activated inflammatory cells -> SMC apoptosis -> increased ECM catabolism -> unstable plaques

• Endothelial cell injury
• Macrophage migration
• Lipid accumulation
• Smooth muscle proliferation
• Role of infection

• Hyperlipidemia
• Hemodynamic turbulence
• Hypertension
• Smoking
• Toxins
• Infectious agents
• Viruses
• Homocysteine

• Herpes, cytomegalovirus, and Chlamydia pneumoniae
• detected in atherosclerotic plaques, not normal arteries
• Increased antibody titers to C. pneumoniae in patients
• with severe atherosclerosis.
• Association with periodontal disease.
• Possible mechanisms:
• - Infect sites of early atheroma formation.
• - Drive local immune responses.
• - Add to local prothrombotic state.

• Foamy lipid-filled macrophages infiltrate the vessel wall.
• Multiple minute flat yellow spots coalesce into linear streaks.
• Earliest lesions - Virtually all children > 10 years; Minimally raised, no flow disturbance

• Gross:
• •Yellow to grey plaques.
• •0.3 to 1.5 cm in diameter - coalesce into masses.
• •Patchy, eccentric, asymmetry, a result of local hemodynamics
• •Thrombus over ulcerated plaques is red-brown.

• Necrotic lipid core - Lipid, foam cells, fibrin, thrombus, cholesterol crystal
• Superficial fibrous cap - Smooth muscle cells, lymphocytes, collagen, elastin, proteoglycans. Neovascularization.
• Shoulder - MPGs, T cells, and SMCs.

• Major targets
• •Large elastic arteries -aorta, carotid, and iliac arteries
• •Large and medium-sized muscular arteries coronary and popliteal.
• Major consequences - Myocardial Infarct, cerebral infarct, aortic aneurysms, and peripheral vascular disease - aneurysm and rupture, occlusion by thrombus, critical stenosis.
• Outcome depends on:
• •Size of the vessels.
• •Stability of the plaque.
• •Degree of degeneration of arterial wall.

• More likely to rupture
• Large areas of foam cells and extracellular lipid
• Fibrous caps are thin or contain few smooth muscle cells - Clusters of inflammatory cells.

• continuously remodeled.
• Collagen-synthesis versus degradation affects cap stability.
• Plaque inflammation increases degradation and reduces synthesis of collagen, destabilizing the fibrous cap.
• Healing plays role in the growth of atheromata

• Rupture; fissuring; erosion; ulceration; thrombosis
• Plaque hemorrhage - Further plaque disruption.
• Probably common, repetitive, and often clinically silent.

• Severe concentric lesions- no longer respond to vasodilators.
• Small arteries - occlude vessel lumina, compromise blood flow, and cause ischemic injury.
• Critical stenosis - significantly limits flow, and demand begins exceeding supply. 70% fixed occlusion
• Patients develop chest pain on exertion (stable angina).
• Bowel ischemia; ischemic encephalopathy; intermittent claudication.

• Ruptured plaque can embolize atherosclerotic debris
• - Distal vessel obstruction and acute thrombosis

Atrophy of the media and loss of elastic tissue leads to weakness, dilatation rupture, thrombosis.

• Adrenergic stimulation can increase BP and vasoconstriction, increasing stress on a plaque.
• - Waking and rising can cause blood pressure spikes and heightened platelet reactivity - Circadian periodicity of MI.
• – Intense emotional stress can contribute to plaque disruption - sudden death increases during disasters.
• Vasoconstriction
• - Compromises lumen size.
• - Potentiates plaque disruption by increasing local mechanical forces.
• - Vasoconstriction is stimulated by :
• •Circulating adrenergic agonists
• •Platelet contents released
• •Endothelial cell dysfunction - Impaired secretion of endothelial cell relaxing factors
• •? Inflammatory cells mediators

• Imbalance between the supply and demand for oxygenated blood.
• Aggravated by increased in cardiac energy demand.
• Coronary atherosclerotic lesions >90%.

• Myocardial infarction
• Angina pectoris
• Chronic IHD with heart failure.
• Sudden Cardiac Death.

• Chronic Atherosclerosis
• > 70% occlusion -> Symptomatic ischemia precipitated by exercise.
• 90% occlusion -> Inadequate perfusion at rest.
• Progressive ischemia -> protective collateral vessels
• Locations of clinically significant plaques:
• •First several centimeters of the LAD and LCX (left circumflex)
• •Entire RCA.
• •Major secondary epicardial branches.
• •Anywhere.
• Progressive atherosclerotic narrowing -> Acute plaque change, Thrombosis, Vasospasm -> Insufficient coronary perfusion

• Stable plaque abruptly converts to unstable atherothrombotic lesion.
• •Rupture, erosion, ulceration, fissuring, hemorrhage.
• •Superimposed thrombus occludes the affected artery.
• •Often associated with plaque inflammation.

• Sudden change in an atheromatous plaque.
• Platelets adhere to subendothelial collagen and necrotic plaque.
• - Activate and release granules.
• - Aggregate to form microthrombi.
• - Vasospasm stimulated by released platelets mediators.
• Tissue factors activate coagulation pathway, adding to thrombus.
• Thrombus evolves to complete occlusion within minutes.
• Some occlusions resolve due to fibrinolysis, or relaxation of spasm.
• - 4 hours of onset of MI - 90% thrombosed
• - 12 to 24 hours after onset - 60% thrombosed

• ~10%
• Vasospasm with or without coronary atherosclerosis.
• - Platelet aggregation (vasoconstrictor release)
• - Cocaine abuse (granule release -> vasoconstriction)
• Emboli from the left atrium
• - Atrial fibrillation
• - Mural thrombus
• - Vegetations of infective endocarditis
• - Prosthetic material
• Emboli from the right atrium
• - Paradoxical emboli via patent foramen ovale.
• Disorders of small vessels (intramural) -Vasculitis.
• Hematologic abnormalities - Sickle cell; amyloid deposition; apple-green stain.
• Lowered systemic blood pressure (shock).
• Inadequate myocardial “protection” during cardiac surgery.

• Normal -> atherosclerosis -> fixed coronary obstruction (FCO, typical angina) -> severe fixed coronary obstruction (SFCO, chronic ischemic heart disease)
• FCO -> platelet aggregate -> plaque disruption (PD)
• PD -> healing -> SFCO
• PD -> thrombus -> mural thrombus variable obstruction (Unstable angina, subendocardial MI, sudden death)
• PD -> thrombus -> occlusive thrombus (transmural MI, sudden death)

• Compromise of myocardial blood supply -> myocardial Ischemia, dysfunction, necrosis.
• The early biochemical consequences:
• - Cessation of aerobic metabolism within seconds leads to:
• •Inadequate production of ATP
• •Accumulation of metabolites - lactic acid
• - Myocardial function is highly oxygen dependent.
• •Loss of contractility within 60 seconds, which can precipitate acute heart failure long before myocardial cell death (irreversible at >30min).

• Within minutes of the onset of ischemia:
• •Myofibrillar relaxation
• •Glycogen depletion
• •Cell and mitochondrial swelling
• •Potentially reversible
• Severe ischemia >20-30min -> irreversible damage
• •Necrosis of cardiac myocytes.
• - Disruption of sarcolemmal membrane.
• - Intracellular macromolecules leak out of cells.

• Location, severity, and rate of obstruction.
• Size of perfused vascular bed
• Duration
• Metabolic/oxygen needs
• Collateral blood vessels
• Coronary arterial spasm
• Other - heart rate, cardiac rhythm, oxygenation.

• Irreversible injury occurs first in the subendocardial zone.
• Extended ischemia - progresses to transmural infarct.

• The coronary artery that perfuses the posterior 1/3 of the septum
• •Right coronary - Right dominant
• •Left circumflex artery - Left dominant.

• LCX (15-20% MI)
• -> Left ventricle lateral wall
• RCA (30-40% MI)
• -> Right ventricular free wall
• -> Posterior basal LV wall
• LAD (40-50% MI)
• -> Apex
• -> Anterior LV wall
• -> Anterior 2/3 of the septum
• Global hypotension -> circumferential subendocardial MI
• Small intramural vessel occlusions -> microinfarcts
• RCA -> Posterior 1/3 ventricular septum In Right Dominant Circulation (80%)
• LCX -> Posterior 1/3 ventricular septum In left Dominant Circulation (20%)

• 4–12 hr
• - Contraction bands
• - Myocytolysis
• - Wavy fibers
• - Also early coagulative necrosis, edema, and hemorrhage.
• 12-24 hr
• - Gross: Reddish blue discoloration, stagnated blood.
• - Micro: Coagulative necrosis (dead cell, architecture intact, nuclei disappear); contraction bands; edema; hemorrhage; eosinophilia; pyknosis; early neutrophilic infiltrate.
• 1-3 days
• - Gross : Mottling with softening yellow-tan infarct center
• - Micro: Coagulative necrosis, loss of nuclei and
• striations; brisk interstitial neutrophilic infiltrate.
• 7-14 days
• - Gross: Maximally yellow-tan; Depressed red-tan-gray infarct borders.
• - Micro: Phagocytosis of dead cells by MPG; Fibrovascular granulation tissue at margins; Early collagen deposition.
• 2 weeks - 2 mos
• - Gross: Gray-white scar, progresses from border
• to center.
• - Micro: Increasing collagen deposition, with decreasing cellularity; collagenous scar.

• Infarct extends beyond original borders.
• Causes of Infarct extension
• •Retrograde propagation of a thrombus.
• •Proximal vasospasm.
• •Impaired contractility causes insufficient flow through stenoses.
• •Microemboli.
• •Arrhythmia.

• Rescue – Goal: Restore myocardial blood flow as rapidly as possible by reperfusion.
• Within 20 minutes of the onset of ischemia may prevent necrosis.
• Gross: Reperfused infarcts - hemorrhagic due to vascular injury.
• Micro : Contraction bands; Myocytolysis.

• Contractile dysfunction - Heart failure -shock
• Arrhythmias
• RV infarction - Acute right-sided heart failure
• Infarct extension
• Infarct expansion – like a balloon
• Weakening of necrotic muscle allows stretching, thinning, and dilation of the infarct region.
• Papillary muscle dysfunction/rupture – Post infarct mitral regurg.
• Progressive late heart failure
• Myocardial rupture

• Necrotic myocardium – soft and weak - Usually rapidly fatal.
• - 3 to 7 days after MI ; mean 4 to 5 days.
• - Risk factors: > 60, female, hypertension.
• Ventricular free wall - hemopericardium and cardiac tamponade
• - Most common site: antero-lateral wall, midventricular level
• Rupture of the ventricular septum - acute VSD and L-R shunt

• Early: Underlying myocardial inflammation -> fibrinous pericarditis
• Late: Dressler's syndrome - Several weeks or months post-MI - autoimmune.

• Abnormal contractility and endocardial damage
• - Potential thromboembolism.

• True aneurysms bounded by scarred myocardium
• Large transmural infarcts with early expansion.
• Paradoxically bulges during systole.
• Complications - mural thrombus; arrhythmias; heart failure.

• Unexpected cardiac death without symptomatic heart disease or early after symptom onset.
• Ischemic heart disease in most cases.
• Lethal arrhythmia – Usual cause - asystole, V-fibrillation
• •Acute myocardial ischemia -> electromechanical cardiac instability of myocardium distant from the conduction system.
• •Arrythmogenic foci - often adjacent to scars of old MIs.

• Anatomic abnormalities
• •Congenital anomalies
• •Hypertrophic cardiomyopathy
• •Mitral valve prolapse
• Primary electrical disorders
• •Heritable arrhythmias - Channelopathies - Mutations in genes of ion channel function.

• •Marked coronary atherosclerosis -80% to 90%
• •Nonatherosclerotic origin -10% to 20%
• •Acute plaque disruption -50%
• •Acute MI - diagnostic changes 25%
• •Myocardial ischemia–induced irritability -> malignant ventricular arrhythmias.
• - Scars of previous infarcts and subendocardial myocyte vacuolization indicate severe chronic ischemia is common.

• Presentations - Stenosis, insufficiency or both.
• Clinical consequences vary depending on:
• •Valve involved
• •Degree of impairment
• •Rate of development
• •Rate and quality of compensatory mechanisms

• Most common of all valvular abnormalities.
• • Normal valves -70-90 y/o; Bicuspid valves- 50-70 y/o
• Wear and tear degeneration causes dystrophic and passive accumulation of calcium salt hydroxyapatite.
• • Hyperlipidemia, hypertension, inflammation play a role.
• Valve injury in CAS differs from atherosclerosis

• Heaped-up calcified masses on cusps prevent opening.
• Begins in the valvular fibrosa, near the margins of attachment.
• Ultimately protrudes into the sinuses of Valsalva.
• Commissural fusion is not usually seen.
• Microscopic – Fibrosis; calcification; lipid deposits. Layered valve architecture (fibrosa is on the top/aortic side) is largely preserved.
• Gradual narrowing of the valve orifice - Valve area: Severe aortic stenosis - 0.5-1 cm2 (normal - 4cm2 )
• Concentric LVH due to increasing pressure gradient - Hypertrophied myocardium tends to be ischemic.

• Without valve replacement:
• • 50% with angina will die within 5 years.
• • 50% with CHF will die within 2 years.

• Most frequent congenital cardiovascular malformation -1%
• Late complications: AS or AR; infective endocarditis; aortic dilation and/or dissection; cusp prolapse.
• Structural abnormalities of the aortic wall commonly accompany BAV.
• Mitral valve is generally normal.

• The raphe is a major site of calcific deposits.
• Less frequently-cusps of equal size and raphe is absent.
• Acquired Bicuspid deformity (RVD) have a fused commissure.

• Degenerative calcific deposits in the mitral annulus.
• • Most common: women > 60, mitral valve prolapse and elevated left ventricular pressure.
• • Generally does not affect valve function.
• • Uncommonly leads to regurgitation; stenosis; arrhythmias, thromboemboli and infective endocarditis.
• Gross: 2–5 mm irregular, hard nodules behind leaflets.

• One or both mitral valve leaflets are floppy and prolapse into the left atrium during systole.
• 3% of adults in the United States.
• Commonly an incidental finding on physical examination, particularly young women.
• aka mid systolic click.
• 3% develop one of four serious complications:
• - Infective endocarditis.
• - Mitral insufficiency +/- chordal rupture.
• - Stroke or systemic infarct - embolism of leaflet thrombi.
• - Arrhythmias - both ventricular and atrial.

• Interchordal ballooning of the mitral leaflets - Hooding
• Leaflets - enlarged, thickened, redundant, and rubbery.
• Tendinous cords - elongated and thinned
• Annulus may be dilated.
• May involve tricuspid, aortic, or pulmonary valves
• Secondary changes (skip):
• • Fibrous thickening of the valve leaflets.
• • Linear fibrous thickening of the LV endocardial surface.
• • Thickening of the mural endocardium of the LV or LA.
• • Thrombi on the atrial surfaces.
• • Focal calcifications at base of the posterior mitral leaflet.

• • Attenuation of the collagenous fibrosa layer of the valve.
• • Marked thickening of the spongiosa layer.
• • Deposition of mucoid “myxomatous” material
• • Can occur secondary to regurgitation of other etiologies.

• Cause unknown in most cases.
• Associated with heritable disorders of connective tissue - Marfan Syndrome.
• • Defects in FBN-1 alter cell-matrix interactions and dysregulate TGF-β signaling.
• • Excess TGF-β can cause laxity and myxomatous change.
• • Can be prevented by inhibitors of TGF-β
• Autosomal-dominant forms of MVP have been mapped to other genetic loci.

• Rheumatic fever - acute, immunologically mediated, multisystem inflammatory disease that occurs a few weeks post group A streptococcal pharyngitis.
• • RF rarely follows streptococci infections at other sites.
• • Acute rheumatic carditis is common during the active phase of RF and may progress to chronic rheumatic heart disease (RHD), and deforming fibrotic valvular disease - the only cause of mitral stenosis.

• Migratory polyarthritis
• Pancarditis
• Subcutaneous nodule
• Erythema marginatum
• Sydenham chorea

• Inflammation and Aschoff bodies - any layer of the heart.
• Pericarditis, myocarditis, or endocarditis - PANCARDITIS
• Verrucae

• granuloma lesions
• Anitschkow (catepillar) cells (Collections of the histiocyte variants) with wavy ribbon-like chromatin; lymphocytes, plasma cells and MPGs.

• Small (1-2mm) vegetations overly necrotic foci along lines of closure.
• Fibrinoid necrosis within the cusps or along chordae.

• Mitral valve - Virtually always involved.
• • Alone 65% to 70%; With aortic valve 25%.
• • Pulmonary valve - rare

• Gross Findings:
• - Leaflet thickening; Commissural fusion.
• - Shortening, thickening and fusion of chorde.
• Micro:
• - Mitral leaflets
• • Organization of acute inflammation.
• • Diffuse fibrosis and neovascularization.
• • Obliteration of leaflet architecture.

• Diffuse fibrous thickening and distortion of valve leaflets.
• Fibrous bridging of valvular commissures with calcification.
• Fish mouth or buttonhole stenoses.
• Left atrium progressively dilates.
• May harbor mural thrombi in appendage or on the wall which can then embolize.
• Long-standing pulmonary congestion leads to:
• • Pulmonary hypertensive changes.
• • RV hypertrophy.

• Cusps thickened and distorted.
• Commissures fused.
• Less than 10% of cases of acquired aortic stenosis.

• Organisms colonize or invade heart valves or endocardium.
• • Vegetations of thrombotic debris and organisms often with destruction of the underlying cardiac tissues.
• • Bacterial infections >> Fungi and other microorganism classes
• • The aorta, aneurysm sacs, other blood vessels, and prosthetic devices can also become infected.

• Predisposing factors: Cardiac and vascular abnormalities
• • Mitral valve prolapse
• • Calcific valvular stenosis
• • Bicuspid AV
• • Artificial valves
• • Congenital defects
• • Rheumatic HD
• Risk can be lowered with antibiotic prophylaxis.
• Source of the organism:
• • Infection elsewhere
• • Dental or surgical procedure
• • Contaminated needle (IVD)
• • Trivial breaks in the epithelial barriers of gut, oral cavity, or skin.

• • Rapildy progressive.
• • Highly destructive.
• • Highly virulent organisms - Staph Aureus (10-20% of cases overall)
• • Typically infects previously normal heart or deformed valves, IV drug abuser

• • More insidious protracted course.
• • Less destructive to underlying valves.
• • Less virulent organisms – Strep Viridans (50% to 60% of all cases)
• • Infects deformed valves.

• Enterococci and HACEK group (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella)
• Prosthetic valve endocarditis - coagulase-negative staphylococci
• Gram-negative bacilli and fungi.
• Culture-negative endocarditis -10% to 15% of all cases, still infective

• Gross: Friable, bulky destructive vegetations on the heart valves; single or multiple; one or more valves.
• • sub acute vegetations - less valve destruction than acute.
• Microscopic findings:
• - Vegetations - fibrin, inflammatory cells, and organisms. Underlying tissues show granulation tissue, fibrosis, calcification, and chronic
• inflammation.
• - Emboli containing bacteria can cause abscesses at sites where the emboli lodge -> Septic infarcts or mycotic aneurysms

• • Debilitated patients; cancer or sepsis - marantic endocarditis.
• • Systemic hypercoagulable state.
• • Association with mucinous adenocarcinomas - Procoagulant effects
• • Trousseau syndrome of migratory thrombophlebitis - pancreatic
• • Endocardial trauma: Indwelling catheter
• • Track along Swan-Ganz PA catheters
• Gross:
• - Small sterile thrombi on the leaflets of the cardiac valves.
• - 1 mm to 5 mm, single or multiple.
• - Along the line of closure of leaflets or cusps.
• Micro: Fibrin thrombi loosely attached to underlying valve.
• • Not invasive; no inflammation.
• • Local effect usually unimportant.
• • +/- Systemic emboli – Produce infarcts in the brain, heart, or elsewhere.

• Gross findings:
• • Mitral and tricuspid valves
• • 1–4 mm, single or multiple, pink, warty, sterile vegetations.
• • Undersurfaces of the AV valves; endocardium; chordae.
• Microcopic findings:
• • Fibrinous vegetations.
• • +/- Valvulitis with fibrinoid necrosis of the valve substance
• • +/- Hematoxylin bodies - degenerated nuclear material due to antinuclear Abs
• • Fibrosis and deformities can resemble CRHD and require surgery.

• RHD - rheumatic, at the cusps
• NBTE - nonbacterial thrombotic, sterile
• IE - infective, destructive
• LSE - SLE, undersurface

• 50% of pts. with carcinoid syndrome.
• Elaboration of bioactive products by carcinoid tumors - Products are degraded in the liver.
• Tricuspid insufficiency +/- pulmonary valve insufficiency.
• Right sided stenosis.
• Tends to spare left heart because products are also broken down in the lung.
• Left-sided valvular disease – Right to left shunting; lung tumor; Serotonergic drugs.

• Firm, plaque-like endocardial fibrous thickenings.
• Inside surfaces of the right cardiac chambers.
• Tricuspid and pulmonary valves.
• Occasionally involve IVC & PA.

• • Plaque-like thickenings.
• • Smooth muscle cells and sparse collagen fibers.
• • Acid mucopolysaccharide-rich matrix.