Path p 559-585
Hypertensive Heart Disease
 HHD – stems from increased demands placed on heart by hypertension, which causes pressure overload and
ventricular hypertrophy
 Systemic (left-sided) hypertensive heart disease – heart hypertrophy is adaptive response to pressure overload
that can lead to myocardial dysfunction, cardiac dilation, CHF, and in some cases sudden death
o Minimal criteria for diagnosis of systemic HHD is left ventricular hypertrophy (usually concentric) in
absence of other cardiovascular pathology and a history or pathologic evidence of hypertension
o Even mild hypertension (levels only slightly above 140/90 mm Hg), if sufficiently prolonged, induces left
ventricular hypertrophy
o Hypertension induces left ventricular pressure overload hypertrophy, initially without ventricular
dilation; as a result, left ventricular wall thickening increases weight of heart disproportionately to
increase in overall cardiac size
o In time, increased thickness of left ventricular wall imparts stiffness that impairs diastolic filling, often
inducing left atrial enlargement
o Microscopically, earliest change of systemic HHD is increase in transverse diameter of myocytes
 At more advanced stages, variable degrees of cellular and nuclear enlargement become
apparent, often accompanied by interstitial fibrosis
o Compensated systemic HHD may be asymptomatic, producing only electrocardiographic or
echocardiographic evidence of left ventricular enlargement
o In many patients, systemic HHD comes to attention due to new atrial fibrillation induced by left atrial
enlargement or CHF
o Patient may develop IHD (ischemic heart disease) due to potentiating effects of hypertension on
coronary atherosclerosis, suffer renal damage or cerebrovascular stroke as direct effects of
hypertension, live a normal life, or experience progressive heart failure or SCD (sudden cardiac death)
o Effective control of hypertension can prevent or lead to regression of cardiac hypertrophy and
associated risks
 Pulmonary (right-sided) hypertensive heart disease (cor pulmonale) – because pulmonary vasculature is low
pressure side of circulation, right ventricular has thinner, more compliant wall than left ventricle; cor pulmonale
stems from pressure overload of right ventricle and is characterized by right ventricular hypertrophy, dilation,
and potentially failure secondary to pulmonary hypertension
o Most frequent causes are disorders of lungs, especially chronic respiratory diseases such as emphysema,
or primary pulmonary hypertension
o Most commonly occurs as complication of left-sided heart diseases
o Acute cor pulmonale can follow massive pulmonary embolism; marked dilation of right ventricle without
hypertrophy (cross-section looks like dilated ovoid)
o Chronic cor pulmonale results from right ventricular hypertrophy (and dilation) secondary to prolonged
pressure overload, such as can occur with chronic lung diseases and variety of other conditions
 Right ventricular wall thickens
 More subtle right ventricular hypertrophy may take form of thickening of muscle bundles in
outflow tract, immediately below pulmonary valve, or thickening of moderator band (muscle
bundle that connects ventricular septum to anterior right ventricular papillary muscle)
 Sometimes hypertrophied right ventricle compresses left ventricular chamber or leads to
regurgitation and fibrous thickening of tricuspid valve
 Normally, myocytes of right ventricle haphazardly arranged and wall contains transmural fat; in
right ventricular hypertrophy, fat in wall disappears and myocytes align themselves
circumferentially
Valvular Heart Disease
 Can come to clinical attention due to stenosis, insufficiency (regurgitation or incompetence) or both
 Valvular insufficiency – results from failure of valve to close completely, allowing reversed flow
 Functional regurgitation – incompetence of valve stemming from abnormality in one of its support structures
(dilation of ventricle can pull ventricular papillary muscles down and outward, thereby preventing proper
closure of otherwise normal leaflets)
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Ischemic mitral regurgitation – functional mitral valve regurgitation common in IHD
Certain conditions can complicate valvular heart disease by increasing demands on heart; for example,
pregnancy can exacerbate valve disease and lead to unfavorable maternal or fetal outcome
Generally, valvular stenosis leads to pressure overload of heart, whereas valvular insufficiency leads to volume
overload of heart
Ejection of blood through narrowed stenotic valves can produce high speed jets of blood that injure
endothelium where they impact
Acquired stenoses of aortic and mitral valves account for about 2/3 of all cases of valve disease
o Valvular stenosis almost always due to chronic abnormality of valve cusp that becomes clinically evident
after many years
o Relatively few disorders produce valvular stenosis
Valvular insufficiency can result from intrinsic disease of valve cusps or damage to or distortion of supporting
structures (e.g., aorta, mitral annulus, tendonous cords, papillary muscles, ventricular free wall)
Most frequent causes of major functional valvular lesions are
o Aortic stenosis: calcification of anatomically normal and congenitally bicuspid aortic valves
o Aortic insufficiency: dilation of ascending aorta, usually related to hypertension and aging
o Mitral stenosis: rheumatic heart disease
o Mitral insufficiency: myxomatous degeneration (mitral valve prolapse)
Calcific aortic stenosis – most common of all valvular abnormalities; usually consequence of age-associated wear
and tear of valves
o Aortic stenosis of previously normal valves – senile calcific aortic stenosis; usually comes to clinical
attention between age 60-80, whereas stenotic bicuspid valves tend to present in patients age 50-70
o Chronic injury due to hyperlipidemia, hypertension, inflammation, and other factors implicated in
atherosclerosis
o Abnormal valves contain cells resembling osteoblasts that synthesize bone matrix proteins and promote
deposition of calcium salts
o Bicuspid valves incur greater mechanical stress than normal tricuspid valves (become stenotic faster)
o Morphologic hallmark of nonrheumatic, calcific aortic stenosis is heaped-up, calcified masses within
aortic cusps that ultimately protrude through outflow surfaces into sinuses of Valsalva, preventing
opening of cusps; free edges of cusps usually not involved
o Calcific process begins in valvular fibrosa, at points of maximal cusp flexion (near margins of attachment)
o Microscopically, layered architecture of valve largely preserved
o Functional valve area decreased sufficiently by large nodular calcific deposits to cause measurable
obstruction to outflow, subjecting left ventricular myocardium to progressively increasing pressure
overload
o Obstruction to left ventricular outflow leads to gradual narrowing of valve orifice and increasing
pressure gradient across calcified valve
o Left ventricular pressures rise, producing concentric left ventricular (pressure overload) hypertrophy;
hypertrophied myocardium tends to be ischemic as result of diminished microcirculatory perfusion,
often complicated by coronary atherosclerosis, and angina pectoris may appear
o Both systolic and diastolic myocardial function may be impaired, and eventually cardiac decompensation
and CHF may ensue
o Onset of symptoms (angina, syncope, CHF) heralds cardiac decompensation and carries poor prognosis
(50% with angina die within 5 years, and 50% with CHF die in 2 years) if obstruction not alleviated by
surgical valve replacement
o Medical therapy ineffective in severe symptomatic aortic stenosis
o Asymptomatic patients with aortic stenosis generally have excellent prognosis
Calcific stenosis of congenitally bicuspid aortic valve (BAV) – most frequent congenital cardiovascular
malformation in humans
o Uncomplicated early in life, but later can cause aortic stenosis or regurgitation, infective endocarditis,
and aortic dilation and/or dissection
o Predisposed to progressive degenerative calcification
o Responsible for about 50% of cases of aortic stenosis in adults
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BAV often associated with left ventricular outflow tract obstruction malformations and other
cardiovascular malformations
o Congenitally BAV – only 2 functional cusps, usually of unequal size, with larger cusp having midline
raphe, resulting from incomplete commissural separation during development; less frequently, cusps
are of equal size and raphe absent
 Raphe frequently major site of calcific deposits
o BAVs may become incompetent as result of aortic dilation, cusp prolapse, or infective endocarditis
o Mitral valve generally normal in patients with congenitally BAV
Mitral annular calcification – degenerative calcific deposits develop in peripheral fibrous ring (annulus) of mitral
valve; appear as irregular, stony hard, occasionally ulcerated nodules that lie behind leaflets
o Process generally doesn’t affect valvular function or otherwise become clinically important
o In unusual cases, mitral annular calcification may lead to
 Regurgitation by interfering with physiologic contraction of valve ring
 Stenosis by impairing opening of mitral leaflets
 Arrhythmias and occasionally sudden death by penetration of calcium deposits to depth
sufficient to impinge on AV conduction system
o Calcific nodules may provide site for thrombi that can embolize, so patients have increased risk of
stroke, and calcific nodules can also have nidus (natural reservoir) for infective endocarditis
o Heavy calcific deposits sometimes visualized on echocardiography or seen as distinctive, ring-like opacity
on chest radiographs
o Mitral annular calcification most common in women over age 60 and individuals with mitral valve
prolapse or elevated left ventricular pressure
Mitral valve prolapse (MVP) – key histologic change is myxomatous degeneration; in small minority of patients
does this lead to serious complications
o Characteristic anatomic change is interchordal ballooning (hooding) of mitral leaflets or portions thereof
o Affected leaflets often enlarged, redundant, thick, and rubbery
o Associated tendonous cords may be elongated, thinned, or ruptured, and annulus may be dilated
o Tricuspid, aortic, or pulmonary valves may also be affected
o Attenuation of collagenous fibrosa layer of valve, on which structural integrity of leaflet depends,
accompanied by marked thickening of spongiosa layer with deposition of mucoid (myxomatous)
material
o Secondary changes reflect stresses and injury incident to billowing leaflets
 Fibrous thickening of valve leaflets, particularly where they rub against each other
 Linear fibrous thickening of left ventricular endocardial surface where abnormally long cords
snap or rub against it
 Thickening of mural endocardium of left ventricle or atrium as consequence of friction-induced
injury induced by prolapsing, hyper-mobile leaflets
 Thrombi on atrial surfaces of leaflets or atrial walls
 Focal calcifications at base of posterior mitral leaflet
o MVP can be associated with Marfan syndrome; defects in FBN-1 alter cell0matrix interactions and
dysregulate TGF-β signaling; inhibitors of TGF-β can prevent MVP
o Autosomal-dominant forms of MVP have been mapped to several genetic loci involved in remodeling of
valvular ECM
o Most individuals asymptomatic, and condition discovered incidentally by detection of midsystolic click
on physical exam; diagnosis can be confirmed by echocardiography; have systolic murmur
o Minority of patients have chest pain mimicking angina, dyspnea, and fatigue
o About 3% of patients develop one of 4 serious complications
 Infective endocarditis
 Mitral insufficiency, sometimes with chordal rupture
 Stroke or other systemic infarct, resulting from embolism of leaflet thrombi
 Arrhythmias, both ventricular and atrial
o Risk of complications higher in men, older patients, and those with arrhythmias or mitral regurgitation
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For patients with symptoms or at high risk for serious complications, valve surgery often done; MVP is
presently most common cause for surgical repair or replacement of mitral valve
Rheumatic fever and rheumatic heart disease – RF is acute, immunologically mediated, multisystem
inflammatory disease that occurs a few weeks after episode of group A streptococcal pharyngitis
o Acute rheumatic carditis is frequent manifestation during active phase of RF and may progress over time
to chronic rheumatic heart disease (RHD), of which valvular abnormalities are key manifestations
o Rheumatic and congenital aortic stenosis – commissural fusion not usually seen; mitral valve generally
normal, though some patients may have direct extension of aortic valve calcific deposits onto anterior
mitral leaflet
o Valves that become bicuspid because of acquired deformity (e.g., rheumatic valve disease) have fused
commissure that produces conjoined cusp that is generally twice the size of nonconjoined cusp
o RHD characterized principally by deforming fibrotic valvular disease, particularly mitral stenosis (virtually
only cause of this)
o RF rarely follows infections by streptococci at other sites, such as skin
o During acute RF, focal inflammatory lesions found in various tissues
 Distinctive lesions occur in heart (Aschoff bodies) that consist of foci of lymphocytes (primarily T
cells), occasional plasma cells, and plump activated macrophages (Anitschkow cells) which are
pathognomonic (characteristic) for RF
 Anitschkow cells have abundant cytoplasm and central round-to-ovoid nuclei in which
chromatin disposed in central, slender, wavy ribbon (caterpillar cells) and may become
multinucleated
 Diffuse inflammation and Aschoff bodies may be found in any of the 3 layers of the heart,
causing pericarditis, myocarditis, or endocarditis (pancarditis)
 Inflammation of endocardium and left-sided valves typically results in fibrinoid necrosis in cusps
or along tendonous cords; overlying necrotic foci at small vegetations (verrucae) along lines of
closure
 Verrucae place RHD in small group of disorders that are associated with vegetative valve
disease
 Subendocardial lesions, perhaps exacerbated by regurgitant jets, may induce irregular
thickenings (MacCallum plaques), usually in left atrium
o Cardinal anatomic changes of mitral valve in chronic RHD are leaflet thickening, commissural fusion and
shortening, and thickening and fusion of tendonous cords
 Mitral valve virtually always involved in chronic disease; mitral valve alone affected in 65-70% of
cases, and mitral valve affected with aortic valve in 25% of cases; tricuspid valve involvement
infrequent, and pulmonary valve rarely affected
 Because of increase in calcific aortic stenosis and reduced frequency of RHD, rheumatic aortic
stenosis accounts for less than 10% of cases of acquired aortic stenosis
 Fibrous bridging across valvular commissures and calcification create fish mouth or buttonhole
stenoses
 With tight mitral stenosis, left atrium progressively dilates and may harbor mural thrombi in
appendage or along wall, either of which can embolize
 Long-standing congestive changes in lungs may induce pulmonary vascular and parenchymal
changes and in time lead to right ventricular hypertrophy
 Left ventricle largely unaffected by isolated mitral stenosis
 Microscopically, in mitral leaflets, there is organization of acute inflammation and subsequent
diffuse fibrosis and neovascularization that obliterate originally layered and avascular leaflet
architecture
 Aschoff bodies rarely seen in patients with chronic RHD, as a result of long times between initial
insult and development of chronic deformity
o Acute rheumatic fever results from immune responses to group A streptococci, which happen to crossreact with host tissues
 Antibodies directed against M proteins of streptococci cross-react with self-antigens in heart
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CD4+ T cells specific for strep peptides react with self-proteins in heart and produce cytokines
that activate macrophages (such as those found in Aschoff bodies)
 Damage to heart tissue may be caused by combination of antibody and T-cell-mediated
reactions
o RF characterized by migratory polyarthritis of large joints, pancarditis, subcutaneous nodules, erythema
marginatum of skin, and Sydenham chorea (neurologic disorder with involuntary, rapid, purposeless
movements)
 Diagnosis established by Jones criteria: evidence of preceding group A strep infection with
presence of 2 of the major manifestations listed above or one major and 2 minor infestations
(fever, arthralgia, or elevated blood levels of acute-phase reactants)
o Acute RF typically appears 10 days to 6 weeks after episode of pharyngitis in about 3% of patients
 Occurs most often in children between ages 5-15, but first attacks can occur later
 Pharyngeal cultures for strep are negative by time illness begins, but antibodies to one or more
strep enzymes, such as streptolysin O and DNAse B, can be detected in sera of most patients
o Clinical features related to acute carditis include pericardial friction rubs, weak heart sounds,
tachycardia, and arrhtmias
o Myocarditis may cause cardiac dilation that can evolve to functional mitral valve insufficiency or heart
failure
o About 1% ofpatients die from fulminant RF
o Arthritis typically begins with migratory polyarthritis accompanied by fever in which one large joint after
another becomes painful and swollen for period of days and then subsides spontaneously, leaving no
residual disability
o After initial attack, there is increased vulnerability to reactivation of disease with subsequent pharyngeal
infections and same manifestations likely to appear with each recurrent attack
 Damage to valves is cumulative
 Turbulence induced by ongoing valvular deformities begets additional fibrosis
 Clinical manifestations appear years or decades after initial episode of RF and depend on which
cardiac valves involved
o Individuals with chronic RHD may suffer cardiac murmurs, cardiac hypertrophy and dilation, heart
failure, arrhythmias (particularly A fib with mitral stenosis), thromboembolic complications, and
infective endocarditis
o Long-term prognosis highly variable
o Surgical repair or prosthetic replacement of diseased valves greatly improves outlook
Infective endocarditis (IE) – serious infection characterized by colonization or invasion of heart valves or mural
endocardium by microbe; leads to formation of vegetations composed of thrombotic debris and organisms,
often associated with destruction of underlying cardiac tissues
o Aorta, aneurysmal sacs, other blood vessels, and prosthetic devices can become infected
o Most cases caused by bacterial infections
o Division into acute and subacute forms reflects range of disease severity and tempo, which are
determined in large part by virulence of infecting microorganism and whether underlying cardiac
disease present
o Acute infective endocarditis – typically caused by infection of previously normal heart valve by highly
virulent organism that produces necrotizing, ulcerative, destructive lesions; difficult to cure with
antibiotics and usually require surgery
 Death in days to weeks ensues in many patients with acute IE, despite treatment
o Subacute IE – organisms of lower virulence; cause insidious infections of deformed valves that are less
destructive; disease may pursue protracted course of weeks to months, and cures often produced with
antibiotics
o RHD, MVP, degenerative calcific valvular stenosis, bicuspid aortic valve (whether calcified or not),
artificial valves, and unrepaired and repaired congenital defects can all be precursors to IE
o IE of native but previously damaged or otherwise abnormal valves caused by Streptococcus viridans (5060% of cases), which is part of normal flora of oral cavity
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More virulent Streptococcus aureus organisms commonly found on skin can infect either healthy
or deformed valves and are responsible for 10-20% of cases overall; major offender in IV drug
abusers with IE
 Can also be caused by enterococci and HACEK group (Haemophilus, Actinobacillus,
Cardiobacterium, Eikenella, and Kingella), all commensals in oral cavity
 Prosthetic valve endocarditis most commonly caused by coagulase-negative staph (e.g., S.
epidermidis)
 In about 10-15% of cases of IE, no organism can be isolated from blood (culture-negative
endocarditis)
o Foremost among factors predisposing to development of IE are those that lead to bacteremia
 Risk can be lowered in those with predisposing factors (e.g., valve abnormalities, conditions
causing bacteremia) by prophylaxis with antibiotics
o Hallmark of IE is presence of friable, bulky, potentially destructive vegetations containing fibrin,
inflammatory cells, and bacteria or other organisms on heart valves
 Aortic and mitral valves are most common sites of infection, though valves of right heart may
also be involved, particularly in IV drug abusers
 Vegetations may be single or multiple and may involve more than one valve
 Vegetations sometimes erode into underlying myocardium and produce abscess (ring abscess)
 Emboli may be shed from vegetations at any time
 Because embolic fragments may contain large numbers of virulent organisms, abscesses often
develop at sites where emboli lodge, leading to sequelae such as septic infarcts or mycotic
aneurysms
o Vegetations of subacute endocarditis associated with less valvular destruction, though distinction
between the two forms may blur
 Microscopically, vegetations often have granulation tissue indicative of healing at their bases
 With time, fibrosis, calcification, and chronic inflammatory infiltrate may develop
o Fever is most consistent sign of IE – acute endocarditis has rapidly developing fever, chills, weakness,
and lassitude (fatigue)
 Fever may be slight or absent, particularly in elderly, and only manifestations may be
nonspecific fatigue, loss of weight, and flu-like syndrome
o Complications generally begin within first few weeks of onset; may be immunologically mediated
(glomerulonephritis caused by deposition of antigen-antibody complexes
o Murmurs present in 90% of patients with left-sided IE and may stem from new valvular defect or
represent preexisting abnormality
o Duke criteria provide standardized assessment of individuals with suspected IE that takes into account
predisposing factors, physical findings, blood culture results, echocardiographic findings, and lab info
o Clinical manifestations that used to be more of a problem in patients but are now caught early enough
to usually be prevented are thromboemboli (manifest as splinter or subungual hemorrhages),
erythematous or hemorrhagic nontender lesions on palms or soles (Janeway lesions), subcutaneous
nodules in pulp of digits (Osler nodes), and retinal hemorrhages in eyes (Roth spots)
Noninfected (sterile) vegetations – caused by NBTE or endocarditis of SLE
o Nonbacterial thrombotic endocarditis (NBTE) – characterized by deposition of small sterile thrombi on
leaflets of cardiac valves; lesions can occur singly or multiply along line of closure of leaflets or cusps
 Histologically composed of bland thrombi that are loosely attached to underlying valve
 Vegetations not invasive and don’t elicit any inflammatory reaction
 May be source of systemic emboli that produce infarcts in brain, heart, or elsewhere
 Often encountered in debilitated patients, such as those with cancer or sepsis (used to be
marantic endocarditis for this reason)
 Frequently occurs concomitantly with DVT, PE, or other findings consistent with underlying
systemic hypercoagulable state
 Association with mucinous adenocarcinomas, which may relate to procoagulant effects of
tumor-derived mucin or tissue factor
 Can be part of Trousseau syndrome of migratory thrombophlebitis
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Endocardial trauma, as from indwelling catheter, is predisposing condition, and right-sided
valvular and endocardial thrombotic lesions frequently track along course of Swan-Ganz
pulmonary artery catheters
o Endocarditis of systemic lupus erythematosus (SLE) or Libman-Sacks endocarditis – mitral and tricuspid
valvulitis with small, sterile vegetations; lesions small, single or multiple, sterile, pink vegetations that
often have warty (verrucous) appearance
 Lesions may be located on undersurfaces of AV valves, on valvular endocardium, on chords, or
on mural endocardium of atria or ventricles
 Histologically, vegetations consist of finely granular, fibrinous, eosinophilic material that may
contain hematoxylin bodies, homogeneous remnants of nuclei damaged by anti-nuclear antigen
bodies
 Intense valvulitis may be present, characterized by fibrinoid necrosis of valve substance often
contiguous with vegetation
 Fibrosis and serious deformities can result that resemble chronic RHD and require surgery
 Thrombotic heart valve lesions with sterile vegetations or rarely fibrous thickening commonly
occur with antiphospholipid syndrome, which can lead to hypercoagulable state
 Mitral valve more frequently involved than aortic valve; regurgitation is usual functional
abnormality
Carcinoid heart disease – cardiac manifestation of systemic syndrome caused by carinoid tumors; generally
involves endocardium and valves of right heart
o Cardiac lesions present in ½ of patients with carcinoid syndrome characterized by episodic flushing of
skin, cramps, nausea, vomiting, and diarrhea
o Cardiovascular lesions distinctive; consist of firm plaque-like endocardial fibrous thickenings on inside
surfaces of cardiac chambers and tricuspid and pulmonary valves
 Occasionally involve major blood vessels of right side, inferior vena cava, and pulmonary artery
 Plaque-like thickenings composed predominantly of smooth muscle cells and sparse collagen
fibers embedded in acid mucopolysaccharides-rich matrix material
 Elastic fibers not present in plaques
 Structures underlying plaques intact
o Clinical and pathologic findings relate to elaboration by carcinoid tumors of variety of bioactive products
(serotonin, kallikrein, bradykinin, histamine, prostaglandins, and tachykinins); plasma levels of serotonin
and urinary excretion of serotonin metabolite 5-hydroxyindoleacetic acid correlate with severity of right
heart lesions
o Key bioactive mediators released into portal circulation by gut carcinoid tumors readily metabolized by
liver and do not reach heart in high concentration; GI carcinoids (with venous drainage via portal
system) don’t usually induce carcinoid heart disease unless there are extensive hepatic metastases that
release relevant mediators directly into inferior vena cava
o Restriction of cardiac changes to right side of heart explained by inactivation of both serotonin and
bradykinin during passage through lungs by monoamine oxidase present in pulmonary vascular
endothelium
o Primary carcinoid tumors in organs outside portal system of venous drainage that empty directly into
inferior vena cava (e.g., ovary and lung) can induce syndrome in absence of hepatic metastasis
o Most common cardiac manifestation is tricuspid insufficiency, followed by pulmonary valve
insufficiency, which usually occurs in combination with tricuspid disease
o Stenoses of right-sided valves may develop, whereas left-sided valvular disease only seen under unusual
circumstances, such as when there is patent foramen ovale with right to left shunting or primary or
metastatic carcinoid tumor involving lung
o Left-sided valvular abnormalities complicate use of drugs that have serotonergic activity (including
fenfluramine of appetite suppression, some anti-Parkinson drugs, and methysergide or ergotamine used
to treat migraines)
Complications of artificial valves – artificial valves can be mechanical prostheses (consisting of different kinds of
rigid mechanical valves, such as caged balls, tilting disks, or hinged semicircular flaps composed of
nonphysiologic material) or tissue valves (usually bioprostheses consisting of chemically treated animal tissue,
especially porcine aortic valve tissue, which has been preserved in dilute glutaraldehyde solution and
subsequently mounted on prosthetic frame); tissue valves flexible and function similarly to natural semilunar
valves
o About 60% of substitute valve recipients develop serious prosthesis-related problem in 10 years
 Thromboembolic complications – either local obstruction of prosthesis by thrombus or distant
thromboemboli; major problem with mechanical valves; necessitates long-term anticoagulation
in all individuals with mechanical valves, with attendant risk of hemorrhagic stroke or other
forms of serious bleeding
 Infective endocarditis – vegetations of prosthetic valve endocarditis usually located at
prosthesis-tissue interface and often cause formation of ring abscess, which can lead to
paravalvular regurgitant blood leak if prosthetic valve-tissue junction is disrupted
 Vegetations may directly involve tissue of bioprosthetic valvular cusps
 Major organisms causing this are Staph. epidermidis, Staph. aureus, streptococci, and
fungi
 Structural deterioration rarely causes failure of contemporary mechanical valves; bioprostheses
often eventually become incompetent due to calcification and/or tearing
 Intravascular hemolysis due to high shear forces, paravalvular leak due to inadequate healing, or
obstruction due to overgrowth of fibrous tissues during healing process
Cardiomyopathies
 Cardiomyopathy – heart disease resulting from abnormality in myocardium
o Diseases of myocardium usually produce abnormalities in cardiac wall thickness and chamber size and
mechanical and/or electrical dysfunction; associated with significant morbidity and mortality
o Chronic myocardial dysfunction secondary to ischemia, valvular abnormalities, or hypertension can
cause ventricular dysfunction, but are not considered cardiomyopathies
 Clinical manifestations either confined to heart or can be part of generalized systemic disorder; in both cases,
cardiac dysfunction is key problem
o Primary cardiomyopathies – predominantly confined to heart muscle
o Secondary cardiomyopathies – have myocardial involvement as component of systemic or multiorgan
disorder
 Many cases have underlying genetic causes
 Cardiomyopathies of diverse etiology may have similar morphologic appearance, so frequently don’t know
underlying cause of a patient presenting
o Clinical approach largely determined by which clinical, functional, and pathologic patterns present
o Can be dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), or restrictive
cardiomyopathy
o Rare form of cardiomyopathy (left ventricular noncompaction) characterized by distinctive spongy
appearance of left ventricular myocardium; congenital disorder; frequently associated with heart failure
or arrhythmias and other clinical symptomatology; may be diagnosed in children or adults as either
isolated finding or associated with other congenital heart anomalies, such as complex cyanotic CHD
o Gene mutations affecting myocardial ion channewl function included in classifications of primary
cardiomyopathy
o Arrhythmogenic right ventricular cardiomyopathy (arrhythmic right ventricular dysplasia) usually
considered a variant of DCM
 Each pattern can be idiopathic or due to one of numerous specific identifiable causes
 Endomyocardial biopsies used in diagnosis and management of individuals with myocardial disease and in
cardiac transplant recipients; involves inserting bioptome transvenously into right side of heart and using its
jaws to snip small piece of septal myocardium, which is analyzed by pathologist
 DCM – cardiomyopathy characterized by progressive cardiac dilation and contractile (systolic) dysfunction,
usually with concomitant hypertrophy; sometimes called congestive cardiomyopathy
o Heart usually enlarged, heavy, and flabby due to dilation of all chambers
o Mural thrombi common and may be source of thromboemboli
o No primary valvular alterations, and mitral (or tricuspid) regurgitation, when present, results from left
(or right) ventricular chamber dilation (functional regurgitation)
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Either coronary arteries free of significant narrowing or obstructions present are insufficient to explain
degree of cardiac dysfunction
Histologic abnormalities nonspecific and usually do not point to specific etiologic agent
Severity of morphologic changes may not reflect either degree of dysfunction or patient’s prognosis
Most muscle cells hypertrophied with enlarged nuclei, but some attenuated, stretched, and irregular
Interstitial and endocardial fibrosis of variable degree present, and small subendocardial scars may
replace individual cells or groups of cells, probably reflecting healing of previous ischemic necrosis of
myocytes caused by hypertrophy-induced imbalance between perfusion and demand
Many individuals with DCM have familial (genetic) form, but it can also result from various acquired
myocardial insults or interactions of genetics and environment that ultimately may yield similar
clinicopathologic patterns; acquired myocardial insults include
 Myocarditis – inflammatory disorder that precedes development of cardiomyopathy in at least
some cases, and is sometimes caused by viral infections
 Toxicities – including adverse effects of chemotherapeutic agents and chronic alcoholism
 Childbirth
Genetic influences – in 20-50% of cases, DCM is familial; autosomal-dominant inheritance is
predominant pattern, but X-linked, autosomal-recessive, and mitochondrial inheritance less common
 Genetic abnormalities most commonly affect genes that encode cytoskeletal proteins expressed
by myocytes
 In some families, there are deletions in mitochondrial genes that result in defects in oxidative
phosphorylation; in others, there are mutations in genes encoding enzymes involved in betaoxidation of fatty acids
 Mitochondrial defects most frequently cause dilated cardiomyopathy in children
 X-linked dilated cardiomyopathy typically presents in teenage years or early 20s and is usually
rapidly progressive
 X-linked cardiomyopathy associated with mutations in gene that encodes dystrophin, cell
membrane-associated cytoskeletal protein that plays critical role in coupling internal
cytoskeleton to ECM (dystrophin also mutated in most common skeletal myopathies, such as
Duchenne and Becker muscular dystrophies)
 Some patients have DCM as primary clinical feature
 Other forms of DCM associated with mutations in genes encoding cardiac α-actin (which
links sarcomere with dystrophin), desmin, and nuclear lamina proteins (lamin A and
lamin C)
 Congenital abnormalities of conduction may also be associated with DCM
Myocarditis – clinical studies demonstrate progression from myocarditis to DCM
 In other studies, viral nucleic acids from coxsackievirus B and other enteroviruses detected in
myocardium of patients with DCM (DCM can be consequence of myocarditis)
Alcohol and other toxins – alcohol abuse strongly associated with development of DCM, raising
possibility of ethanol toxicity or secondary nutritional disturbance that may be cause of myocardial
injury
 Alcohol or its metabolites (especially acetaldehyde) have direct toxic effect on myocardium
 No morphologic features serve to distinguish alcoholic cardiomyopathy from DCM of other
etiologies
 Chronic alcoholism may be associated with thiamine deficiency, which can lead to beriberi heart
disease (also indistinguishable from DCM)
 Non-alcoholic toxic insult can cause myocardial failure (i.e., injury caused by certain
chemotherapeutic agents, including doxorubicin (Adriamycin))
 Cobalt can also cause DCM
Childbirth – special form of DCM (peripartum cardiomyopathy) can occur late in pregnancy or several
weeks to months postpartum
 Pregnancy-associated hypertension, volume overload, nutritional deficiency, other metabolic
derangements, or immunological reaction can contribute


Relationship between elevated levels of anti-angiogenic cleavage product of prolactin and
peripartum cardiomyopathy
 Blocking prolactin secretion by bromocriptine in mice prevents peripartum cardiomyopathy
o DCM may occur at any age, including childhood, but most commonly affects individuals between ages
20-50; presents with slowly progressive signs and symtpoms of CHF such as SOB, easy fatigability, and
poor exertional capacity
 In end stage, patients often have ejection fractions of less than 25%
 50% of patients die within 2 years, and only 25% survive longer than 5 years, but some severely
affected patients may unexpectedly improve on therapy
 Secondary mitral regurgitation and abnormal cardiac rhythms common
 Death usually attributable to progressive cardiac failure or arrhythmia and can occur suddenly
 Embolism from dislodgment of intracardiac thrombus can occur
 Cardiac transplantation frequently done, and long-term ventricular assist may be beneficial in
some patients
 Mechanical cardiac assist may induce lasting regression of cardiac dysfunction in some patients
o Arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic right ventricular dysplasia –
inherited disease of cardiac muscle that causes right ventricular failure and various rhythm disturbances,
particularly ventricular tachycardia or fibrillation that can lead to sudden death, particularly in young
 Left-sided involvement with left-sided heart failure may also occur
 Right ventricular wall severely thinned because of loss of myocytes, with extensive fatty
infiltration and fibrosis
 Autosomal-dominant inheritance and variable penetrance
 Disease related to defective cell adhesion proteins in desmosomes that link adjacent cardiac
myocytes
 Naxos syndrome – disorder characterized by arrhythmogenic right ventricular cardiomyopathy
and hyperkeratosis of plantar palmar skin surfaces associated with mutations in gene encoding
plakoglobin
HCM – characterized by myocardial hypertrophy, poorly compliant left ventricular myocardium leading to
abnormal diastolic filling, and in about 1/3 of cases, intermittent ventricular outflow obstruction
o Leading cause of left ventricular hypertrophy unexplained by other clinical or pathologic causes
o Caused by mutations in genes encoding sarcomeric proteins
o Most common cardiovascular disorder caused by single gene mutations (autosomal dominant)
o Heart is thick-walled, heavy, and hypercontracting (versus flabby hypocontracting heart of DCM)
o Causes primarily diastolic dysfunction; systolic function usually preserved
o Most common diseases that must be distinguished clinically from HCM are deposition diseases of heart
(e.g., amyloidosis, Fabry’s disease) and hypertensive heart disease coupled with age-related subaortic
septal hypertrophy
 Occasionally valvular or congenital subvalvular aortic stenosis can mimic HCM
o Essential feature of HCM is massive myocardial hypertrophy, usually without ventricular dilation
 Classic pattern is disproportionate thickening of ventricular septum as compared with free wall
of left ventricle (ratio greater than 1:3), called asymmetric septal hypertrophy
 In about 10% of cases, hypertrophy is symmetrical throughout heart
o On cross-section, ventricular cavity loses its usual round-to-ovoid shape and may be compressed into
banana-like configuration by bulging of ventricular septum into lumen
o Marked hypertrophy can involve entire septum, but usually most prominent in subaortic region
o Endocardial thickening or mural plaque formation in left ventricular outflow tract and thickening of
anterior mitral leaflet often present
 Result of contact of anterior mitral leaflet with septum during ventricular systole
 Correlate with echocardiographically demonstrated functional left ventricular outflow tract
obstruction during mid-systole
o Most important histologic features of myocardium are
 Extensive myocyte hypertrophy to degree unusual in other conditions


Haphazard disarray of bundles of myocytes, individual myocytes, and contractile elements in
sarcomeres within cells (myofiber disarray)
 Interstitial and replacement fibrosis
o Most genetic causes caused by missense mutations
o Mutations causing HCM found most commonly in gene encoding β-myosin heavy chain (β-MHC), with
genes for cardiac TnT, α-tropomyosin, and myosin-binding protein C (MYBP-C) being next most
frequently mutated
 Mutations in β-MHC, MYBP-C, and TnT account for 70-80% of all cases
 Different affected families may have distinct mutations involving same protein
 Prognosis varies widely and correlates strongly with specific mutations
o Basic physiologic abnormality is reduced stroke volume due to impaired diastolic filling, which results
from reduced chamber size and compliance of massively hypertrophied left ventricle
 About 25% of patients have dynamic obstruction to left ventricular outflow
 Limitation of cardiac output and secondary increase in pulmonary venous pressure cause
exertional dyspnea
o Auscultation shows harsh systolic ejection murmur, caused by ventricular outflow obstruction as
anterior mitral leaflet moves toward ventricular septum during systole
o Because of massive hypertrophy, high left ventricular chamber pressure, and frequently abnormal
intramural arteries, focal myocardial ischemia commonly results, even in absence of concomitant
coronary artery disease; thus angina pain frequent
o Major clinical problems are atrial fibrillation, murla thrombus formation leading to embolization and
possible stroke, intractable cardiac failure, ventricular arrhythmias, and sudden death
o HCM is one of most common causes of sudden, otherwise unexplained death in young athletes
o Most patients can be helped by treatment with drugs that decrease heart rate and contractility (such as
β-adrenergic blockers)
 Some benefit may be gained from reduction of mass of septum, which relieves outflow tract
obstruction; achieved either by surgical excision of muscle or carefully controlled septal
infarction, which is induced by infusion of alcohol through catheter
o HCM may stem from defect in energy transfer from its source of generation (mitochondria) to its site of
use (sarcomeres), leading to subcellular energy deficiency
Restrictive cardiomyopathy – characterized by primary decrease in ventricular compliance, resulting in impaired
ventricular filling during diastole
o May be idiopathic or associated with distinct diseases or processes that affect myocardium, principally
radiation fibrosis, amyloidosis, sarcoidosis, metastatic tumors, or deposition of metabolites that
accumulate due to inborn errors of metabolism
o Ventricles are of approximately normal size or slightly enlarged, cavities not dilated, and myocardium
firm and noncompliant
o Biatrial dilation commonly observed
o Microscopically, there may be only patchy or diffuse interstitial fibrosis, which can vary from minimal to
extensive
o Endomyocardial biopsy often reveals specific etiology
o Endomyocardial fibrosis – principally disease of children and young adults in Africa and other tropical
areas; characterized by fibrosis of ventricular endocardium and subendocardium that extendcs from
apex upward, often involving tricuspid and mitral valves
 Fibrous tissue markedly diminishes volume and compliance of affected chambers and so induces
restrictive functional defect
 Ventricular mural thrombi sometimes develop
 Etiology unknown
o Loeffler endomyocarditis – results in endomyocardial fibrosis, typically with large mural thrombi
 In addition to cardiac changes, often peripheral eosinophilia and eosinophilic infiltrates in other
organs; release of toxic products of eosinophils (especially basic protein) initiates
endomyocardial necrosis, followed by scarring of necrotic area, layering of endocardium by
thrombus, and organization of thrombus


Some patients have myeloproliferative disorder associated with chromosomal rearrangements
involving either PDGFRα or PDGFRβ genes
 Produce fusion genes that encode constitutively active PDGFR tyrosine kinases
 Treatment of patients with tyrosine kinase inhibitor (imatinib) results in hematologic
remissions associated with reversal of endomyocarditis
 Often rapidly fatal if untreated
o Endocardial fibroelastosis – uncommon heart disease of obscure etiology characterized by focal or
diffuse fibroelastic thickening usually involving mural left ventricular endocardium
 Most common in first 2 years of life, accompanied by aortic valve obstruction or other
congenital cardiac anomalies in 1/3 of cases
 Diffuse involvement may be responsible for rapid and progressive cardiac decompensation and
death
Myocarditis – diverse group of pathologic entities in which infectious microorganisms and/or inflammatory
process cause myocardial injury
o Viral infections are most common cause (Coxsackie viruses A and B and other enteroviruses account for
most of cases); less common etiologic agents include cytomegalovirus, HIV, and others
o Responsible virus can sometimes be identified by serologic studies or identification of viral DNA or RNA
in myocardial biopsies
o Nonviral agents , such as protozoa Trypanosoma cruzi (agent of Chagas disease), can cause myocarditis
 Chagas disease – endemic in some regions of South America
 Myocardial involvement present in most infected individuals
 About 10% of patients die during acute attack; others develop chronic immunemediated myocarditis that may progress to cardiac insufficiency 10-20 years later
 Trichinosis – most common helminthic (relating to worms) disease associated with myocarditis
 Parasitic diseases, including toxoplasmosis, and bacterial infections, including Lyme disease and
diphtheria, can cause myocarditis
 In diphtheritic myocarditis, toxins released by bacteria responsible for myocardial injury
 Myocarditis occurs in 5% of patients with Lyme disease (caused by bacterial spirochete Borrelia
burgdorferi; Lyme myocarditis manifests primarily as self-limited conduction system disorder
that frequently requires temporary pacemaker
o Myocarditis occurs in many patients with AIDS; can be inflammation and myocyte damage without clear
etiologic agent or myocarditis caused by HIV directly or by opportunistic pathogen
o Noninfectious causes of myocarditis – can be caused by hypersensitivity reactions, often to drugs such
as antibiotics, diuretics, or antihypertensive agents
o Can be associated with systemic diseases of immune origin, such as RF, SLE, and polymyositis
o Cardiac sarcoidosis and rejection of transplanted heart are forms of myocarditis
o During active phase of myocarditis, heart may appear normal or dilated; some hypertrophy may be
present depending on disease duration
o In advanced stages, ventricular myocardium flabby and often mottled by either pale foci or minute
hemorrhagic lesions; mural thrombi may be present in any chamber
o During active disease, myocarditis most frequently characterized by interstitial inflammatory infiltrate
associated with focal myocyte necrosis
 Diffuse, mononuclear, predominantly lymphocytic infiltrate most common
o Biopsies can be negative because inflammatory involvement of myocardium may be focal or patchy
o If patient survives acute phase of myocarditis, inflammatory lesions either resolve, leaving no residual
changes, or heal by progressive fibrosis
o Hypersensitivity myocarditis – has interstitial infiltrates, principally perivascular, composed of
lymphocytes, macrophages, and high proportion of eosinophils
o Morphologically distinctive form of myocarditis (giant-cell myocarditis) – uncertain causes; characterized
by widespread inflammatory cellular infiltrate containing multinucleate giant cells interspersed with
lymphocytes, eosinophils, plasma cells, and macrophages
 Focal to frequently extensive necrosis present
 Carries poor prognosis
o



Myocarditis of Chagas disease rendered distinctive by parasitization of scattered myofibers by
trypanosomes accompanied by inflammatory infiltrate of neutrophils, lymphocytes, macrophages, and
occasional eosinophils
o Patients can be asymptomatic and recover completely without sequelae; others have precipitous onset
of heart failure or arrhythmias, occasionally with sudden death
 Symptoms can include fatigue, dyspnea, palpitations, precordial discomfort, and fever
 Clinical features can mimic those of AMI
 Occasionally, patients develop DCM as late complication of myocarditis
Cardiotoxic drugs – can be associated with conventional chemotherapeutic agents, targeted drugs such as
tyrosine kinase inhibitors, and certain forms of immunotherapy
o Anthracyclines doxorubicin and daunorubicin are chemotherapeutic agents most often associated with
toxic myocardial injury, which often leads to DCM and heart failure
o Anthracycline toxicity is dose-dependent and is attributed primarily to peroxidation of lipids in myocyte
membranes
o Pharmaceutical agents such as lithium, phenothiazines, chloroquine, and cocaine have been implicated
in myocardial injury and sometimes sudden death
o Common findings in hearts injured by drugs are myofiber swelling, cytoplasmic vacuolization, and fatty
change; with discontinuance of toxic agent, changes may resolve completely with no sequelae
 Sometimes, more extensive damage produces myocyte necrosis, which can evolve to dilated
cardiomyopathy
Catecholamines – foci of myocardial necrosis with contraction bands, often associated with sparse mononuclear
inflammatory infiltrate consisting mostly of macrophages, can occur in individuals with pheochromocytoma
(tumor that elaborates catecholamines) – manifestation of catecholamine effect also seen in association with
intense autonomic stimulation (secondary to intracranial lesions or stress) or exogenous administration of large
doses of vasopressor agents such as dopamine
o Sudden intense emotional or physical stress can induce acute left ventricular dysfunction due to
myocardial stunning (Takotsubo cardiomyopathy)
o Cocaine causes similar catecholamine-mediated damage
o Mononuclear cell infiltrate secondary reaction to foci of myocyte cell death
o Similar changes found in individuals who recovered from hypotensive episodes or have been
resuscitated from cardiac arrest; damage is result of ischemia-reperfusion with subsequent
inflammation
Amyloidosis – prototypical myocardial disorder caused by deposition of abnormal substance in heart; caused by
insoluble extracellular fibrillary deposits of protein fragments prone to forming β-pleated sheets
o May appear along with systemic amyloidosis or be restricted to heart, particularly in aged (senile cardiac
amyloidosis)
o In senile cardiac amyloidosis, amyloid deposits generally occur in ventricles and atria; occurs in older
individuals and is caused by deposition of transthyretin (normal serum protein synthesized in liver and is
responsible for transporting thyroxine and retinol-binding protein)
o Senile cardiac amyloidosis has far better prognosis than systemic amyloidosis
o Mutant forms of transthyretin can accelerate cardiac (and associated systemic) amyloidosis; mutant
forms of transthyretin are autosomal-dominant familial transthyretin amyloidosis
o Isolated atrial amyloidosis can occur secondary to deposition of ANP; clinical significance uncertain
o Cardiac amyloidosis most frequently produces restrictive cardiomyopathy, but can also be
asymptomatic or manifest as dilation, arrhythmias, or symptoms mimicking those of ischemic or valvular
disease; presentation depends on predominant location of deposits, which can be found in interstitium,
conduction system, vasculature, or valves
o Heart varies in consistency from normal to firm and rubbery
o Usually chambers of normal size, but in some cases, they are dilated and have thickened walls
o Numerous small, semitranslucent nodules resembling drips of wax may be seen at atrial endocardial
surface, particularly on left
o
Eosinophilic deposits of amyloid may be found in interstitium, conduction tissue, valves, endocardium,
pericardium, and small intramural coronary arteries; can be distinguished from other hyaline deposits by
Congo red (produces classic apple-green birefringence when viewed under polarized light)
o Amyloid deposits often form rings around cardiac myocytes and capillaries
o Intramural arteries and arterioles may have sufficient amyloid in walls to compress and occlude lumen,
inducing myocardial ischemia (small-vessel disease
 Iron overload – can result from hereditary hemochromatosis or multiple blood transfusions (hemosiderosis)
o Heart usually dilated
o Iron deposition more prominent in ventricles than atria and in myocardium than conduction system
o Causes systolic dysfunction by interfering with metal-dependent enzyme systems or inducing oxygen
free-radical injury
o Myocardium is rust-brown in color but usually otherwise indistinguishable from idiopathic DCM
o Microscopically, there is marked accumulation of hemosiderin in cardiac myocytes, particularly in
perinuclear region (stained by Prussian blue)
 Associated with varying degrees of cellular degeneration and fibrosis
 Cardiac myocytes contain abundant perinuclear siderosomes (iron-containing lysosomes)
 Hyperthyroidism – tachycardia, palpitations, and cardiomegaly common
o Supraventricular arrhythmias occasionally appear
o Cardiac failure uncommon; when it does occur, it’s usually superimposed on other cardiac diseases
o Gross and histologic features are those of nonspecific hypertrophy and can include ischemic foci
 Hypothyroidism – cardiac output decreased due to reductions in stroke volume and heart rate
o Increased peripheral vascular resistance and decreased blood volume result in narrowing of pulse
pressure, prolongation of circulation time, and decreased flow to peripheral tissues
o In well-advanced hypothyroidism (myxedema) heart is flabby, enlarged and dilated
o Histologic features include myofiber swelling with loss of striations and basophilic degeneration,
accompanied by interstitial mucopolysaccharides-rich edema fluid
o Fluid can sometimes accumulate in pericardial sac
Pericardial Disease
 Most important pericardial disorders cause fluid accumulation, inflammation, fibrous constriction, or some
combination of these processes, usually in association with disease elsewhere in heart or systemic disease;
isolated pericardial disease is unusual
 Pericardial effusion and hemopericardium – parietal pericardium becomes distended by serous fluid (pericardial
effusion), blood (hemopericardium), or pus (purulent pericarditis)
o With long-standing pressure or volume overload, pericardium dilates, permitting slowly accumulating
pericardial effusion to become quite large without interfering with cardiac function
 With chronic effusions of less than 500 mL in volume, only clinical significance is characteristic
globular enlargement of heart shadow on chest radiographs
o Rapidly developing fluid collections of 200-300 mL (for example, due to hemopericardium caused by
ruptured MI or aortic dissection) may produce compression of thin-walled atria and vena cavae or
ventricles themselves; cardiac filling restricted, producing potentially fatal cardiac tamponade
 Pericarditis – inflammation may occur secondary to variety of cardiac diseases, thoracic or systemic disorders,
metastases from neoplasms arising in remote sites, or surgical procedure in heart
o Primary pericarditis is unusual and almost always of viral origin
o Most of major causes of pericarditis evoke acute pericarditis; TB and fungi produce chronic reactions
o Serous pericarditis – acute pericarditis characteristically produced by noninfectious inflammatory
diseases, such as RF, SLE, and scleroderma, tumors, and uremia
 Infection in tissues contiguous to pericardium (i.e., bacterial pleuritis) may incite sufficient
irritation of parietal pericardial serosa to cause sterile serous effusion that may progress to
serofibrinous pericarditis and ultimately to frank suppurative reaction
 In some cases, well-defined viral infection elsewhere (URI, pneumonia, parotitis) antedates
pericarditis and serves as primary focus of infection
 Infrequently (but usually in young adults when it occurs) viral pericarditis occurs as apparent
primary infection that may be accompanied by myocarditis (myopericarditis)

o
o
o
o
o
o
Histologically, there is mild inflammatory infiltrate in epipericardial fat consisting predominantly
of lymphocytes
 Organization into fibrous adhesions rarely occurs
Fibrinous and serofibrinous pericarditis – 2 anatomic forms of acute pericarditis are most frequent types
and composed of serous fluid mixed with fibrinous exudate
 Common causes include AMI, postinfarction (Dressler) syndrome (probably autoimmune
condition appearing several weeks after MI), uremia, chest radiation, RF, SLE, and trauma
 Fibrinous reaction can follow routine cardiac surgery
 In fibrinous pericarditis, surface is dry with fine granular roughening
 In serofibrinous pericarditis, more intense inflammatory process induces accumulation of larger
amounts of yellow to brown turbid fluid (made brown and cloudy by presence of leukocytes and
RBCs, which may give fluid a visibly bloody appearance) and often fibrin
 Fibrin may be lysed with resolution of exudate or it may become organized
 Development of loud pericardial friction rub is most striking characteristic of fibrinous
pericarditis
 Pain, systemic febrile reactions, and signs suggestive of cardiac failure may be present
Purulent or suppurative pericarditis
 Acute pericarditis caused by invasion of pericardial space by microbes, which may reach
pericardial cavity by
 Direct extension from neighboring infections, such as empyema of pleural cavity, lobar
pneumonia, mediastinal infections, or extension of ring abscess through myocardium or
aortic root
 Seeding from blood
 Lymphatic extension
 Direct introduction during cardiotomy
 Immunosuppression predisposes to infection by all of possible pathways
 Exudate ranges from thin cloudy fluid to frank pus up to 400-500 mL in volume
 Serosal surfaces reddened, granular, and coated with exudate
 Microscopically there is acute inflammatory reaction, which sometimes extends into
surrounding structures to induce mediastinopericarditis
 Complete resolution infrequent, and organization by scarring is usual outcome
 Intense inflammatory response and subsequent scarring frequently produce constrictive
pericarditis
 Clinical findings in active phase essentially same as those present in fibrinous pericarditis, but
signs of systemic infection usually marked (i.e., spiking temperatures, chills, and fever)
Hemorrhagic pericarditis – acute pericarditis where exudate composed of blood mixed with fibrinous or
suppurative effusion
 Most commonly caused by spread of malignant neoplasm to pericardial space – cytologic
examination of fluid removed through pericardial tap often reveals presence of neoplastic cells
 Can be found in bacterial infections, in persons with underlying bleeding diathesis, and in TB
 Often follows cardiac surgery and is occasionally responsible for significant blood loss or
tamponade, requiring “second-look” operation
 Clinical significance similar to that of fibrinous or suppurative pericarditis
Caseous pericarditis – rare type of acute pericarditis that should be assumed to be of TB origin until
proved otherwise; infrequently fungal infections evoke similar reaction
 Pericardial involvement occurs by direct spread from TB foci in tracheobronchial nodes
 Frequently antecedent of disabling, fibrocalcific, chronic constrictive pericarditis
Chronic pericarditis – in some cases, organization produces plaque-like fibrous thickenings of serosal
membranes (soldier’s plaque) or thin, delicate adhesions of obscure origin observed fairly frequently at
autopsy and rarely cause impairment of cardiac function
Adhesive pericarditis – chronic fibrosis in form of delicate, stringy adhesions that completely obliterate
pericardial sac; in most instances, has no effect on cardiac function
o
Adhesive mediastinopericarditis – chronic pericarditis that may follow infectious pericarditis, previous
cardiac surgery, or irradiation to mediastinum
 Pericardial sac obliterated, and adherence of external aspect of parietal layer to surrounding
structures produces great strain on cardiac function
 With each systolic contraction, heart pulls against parietal pericardium and against attached
surrounding structures
 Systolic retraction of rib cage and diaphragm, pulsus paradoxus, and variety of other
characteristic clinical findings may be observed
 Increased workload causes cardiac hypertrophy and dilation, which may be substantial in severe
cases
o Constrictive pericarditis – chronic pericarditis in which heart is encased in dense, fibrous or fibrocalcific
scar that limits diastolic expansion and cardiac output; features mimic restrictive cardiomyopathy
 Prior history of pericarditis may or may not be present
 Scar obliterates pericardial space and sometimes calcifies; in extreme cases, it can resemble
plaster mold (concretio cordis)
 Because of dense enclosing scar, cardiac hypertrophy and dilation cannot occur
 Cardiac output may be reduced at rest, but heart has little if any capacity to increase its output
in response to increased peripheral needs
 Heart sounds distant or muffled
 Treatment consists of surgical removal of shell of constricting fibrous tissue (pericardiectomy)
 Heart disease associated with rheumatologic disorders
o Inflammatory mechanisms may cause vascular, myocardial, valvular, and pericardial manifestations
o Rheumatoid arthritis – mainly disorder of joints, but also associated with many extra-articular features
(e.g., subcutaneous rheumatoid nodules, acute vasculitis, and Felty syndrome)
 Heart involved in 20-40% of cases of severe prolonged RA
 Most common finding is fibrinous pericarditis that may progress to fibrous thickening of visceral
and parietal pericardium and dense adhesions
 Granulomatous rheumatoid nodules resembling those that occur subcutaneously may be
identifiable in myocardium
 Much less frequently, rheumatoid nodules involve endocardium, valves of heart, and root of
aorta
 Rheumatoid valvulitis can lead to marked fibrous thickening and secondary calcification of aortic
valve cusps, producing changes resembling those of chronic rheumatic valvular disease
Tumors of Heart
 Primary tumors of heart are rare; most common are myxomas, fibromas, lipomas, papillary fibroelastomas,
rhabdomyomas, angiosarcomas, and other sarcomas
o 5 most common tumors are all benign and collectively account for 80-90% of primary tumors of heart
o Myxomas – most common primary tumor of heart in adults; benign neoplasms often associated with
clonal abnormalities of chromosomes 12 and 17 thought to arise in any of 4 chambers or rarely in heart
valves; about 90% located in atria (atrial myxomas), with left-to-right ratio of about 4:1
 Tumors usually single, but rarely several occur simultaneously
 Region of fossa ovalis in atrial septum is favored site of origin
 Sessile or pedunculated lesions that vary from globular hard masses mottled with hemorrhage
to soft, translucent, papillary, or villous lesions having gelatinous appearance
 Pedunculated form often sufficiently mobile to move into or even through AV valves during
systole, causing intermittent obstruction that may be position-dependent
 Sometimes mobile tumors exert wrecking-ball effect, causing damage to valve leaflets
 Histologically composed of stellate or globular myxoma cells embedded within abundant acid
mucopolysaccharides ground substance
 Peculiar vessel-like or gland-like structures characteristic
 Hemorrhage and mononuclear inflammation usually present
 Major clinical manifestations due to valvular ball-valve obstruction, embolization, or syndrome
of constitutional symptoms, such as fever and malaise



Sometimes fragmentation and systemic embolization calls attention to lesions
Constitutional symptoms due to elaboration by some myxomas of cytokine IL-6 (major mediator
of acute-phase response)
 Echocardiography provides opportunity to identify masses noninvasively
 Surgical removal usually curative; rarely neoplasm recurs months to years later
 About 10% of individuals with myxoma have familial syndrome (Carney complex) characterized
by autosomal-dominant transmission, multiple cardiac and often extracardiac myxomas,
pigmented skin lesions, and endocrine overactivity
 PRKAR1 on chromosome 17 (encoding regulatory subunit of cAMP-dependent PKA, possibly
tumor suppressor gene) mutated in most Carney complex kindreds
o Lipomas – localized, well-circumscribed, benign tumors composed of mature fat cells that may occur in
subendocardium, subepicardium, or myocardium
 May be asymptomatic or produce ball-valve obstructions or arrhythmias
 Most often located in left ventricle, right atrium, or atrial septum
 Not necessarily neoplastic
 In atrial septum, non-neoplastic depositions of fat sometimes occur called lipomatous
hypertrophy
o Papillary fibroelastomas – usually incidental, sea-anemone-like lesions, most often identified at autopsy
 May embolize and thereby become clinically important
 Clonal cytogenetic abnormalities have been reported, suggesting that fibroelastomas are
unusual benign neoplasms; resemble much smaller, usually trivial, Lambl excrescences
frequently found on aortic valves of older individuals
 Generally located on valves, particularly ventricular surfaces of semilunar valves and atrial
surfaces of AV valves
 Consist of distinctive cluster of hair-like projections
 Histologically, projections composed of core of myxoid CT containing abundant
mucopolysaccharides matrix and elastic fibers covered by surface endothelium
o Rhabdomyomas – most frequent primary tumor of heart in infants and children; frequently discovered
in first ears of life because of obstruction of valvular orifice or cardiac chamber
 Often associated with tuberous sclerosis caused by defects in TSC1 or TSC2 tumor suppressor
genes; TSC1 and TSC2 proteins work together in complex that inhibits activity of mTOR
(stimulates cell growth and regulates cell size)
 TSC1 or TSC2 expression often completely lost in rhadmyosarcomas that occur in setting of
tuberous sclerosis, providing mechanism for myocyte overgrowth
 Because they often regress spontaneously, rhabdomyomas considered by some to be
hamartomas rather than true neoplasms
 Generally small, gray-white myocardial masses
 Usually multiple in number and involve ventricles preferentially, often protruding into chambers
 Histologically composed of bizarre, markedly enlarged myocytes
 In sections, abundant myocyte cytoplasm often reduced to thin webs or strands that extend to
cell membranes (spider cells)
o Sarcoma – cardiac angiosarcomas and other sarcomas not clinically or morphologically distinctive from
counterparts in other locations
Metastatic tumors to heart occur in 5% of persons dying of cancer; significant cardiovascular effects of noncardiac neoplasms and their therapy commonly encountered due to increased patient survival due to diagnostic
and therapeutic advances
o Most frequent metastatic tumors involving heart are carcinomas of lung and breast, melanomas,
leukemias, and lymphomas
o Metastases can reach heart and pericardium by retrograde lymphatic extension (most carcinomas), but
hematogenous seeding (many tumors), by direct contiguous extension (primary carcinoma of lung,
breast, or esophagus), or by venous extension (tumors of kidney or liver)
o Clinical symptoms most often associated with pericardial spread, which can cause symptomatic
pericardial effusions or mass-effect that is sufficient to restrict cardiac filling
o
Myocardial metastases usually clinically silent or have nonspecific features, such as generalized defect in
ventricular contractility or compliance
o Bronchogenic carcinoma or malignant lymphoma may infiltrate mediastinum extensively, causing
encasement, compression, or invasion of superior vena cava with resultant obstruction to blood coming
from head and upper extremities (superior vena cava syndrome)
o Renal cell carcinoma often invades renal vein and may grow as frond of tissue up inferior vena cava and
into right atrium, blocking venous return to heart
o Non-cardiac tumors may affect cardiac function indirectly, sometimes via circulating tumor-derived
substances (e.g., nonbacterial thrombotic endocarditis, carcinoid heart disease, pheochromocytomaassociated myocardial damage, multiple myeloma-associated AL amyloidosis)
 Radiation used to treat breast, lung, or mediastinal neoplasms can cause pericarditis, pericardial effusion,
myocardial fibrosis, and chronic pericardial disorders
o Other cardiac effects of radiation therapy include accelerated coronary artery disease and mural and
valvular endocardial fibrosis
Cardiac Transplantation
 Performed for severe, intractable heart failure of diverse causes: 2 most common reasons are DCM and IHD
 3 major factors contribute to improved outcome of cardiac transplantation since first transplant
o More effective immunosuppressive therapy, including use of cyclosporine A, glucocorticoids, and other
agents
o Careful selection of candidates
o Early histopathologic diagnosis of acute allograft rejection by endomyocardial biopsy
 Of major complications, allograft rejection is primary problem requiring surveillance
o Scheduled endomyocardial biopsy is only reliable means of diagnosing acute cardiac rejection before
substantial myocardial damage has occurred and at a stage that is reversible in majority of instances
 Rejection characterized by interstitial lymphocytic inflammation that, in more advanced stages, damages
adjacent myocytes; histology resembles myocarditis
 When myocardial injury not extensive, rejection episode usually either self-limited or successfully reversed by
increased immunosuppressive therapy; advance rejection may be irreversible and fatal if not promptly treated
 Major current limitation to long-term success of transplantation is diffuse stenosing intimal proliferation of
coronary arteries, which may involve intramural vessels (graft arteriopathy)
 Because transplanted heart denervated, patients may not experience ischemic chest pain, leading to silent MI
 In severe graft arteriopathy, CHF or sudden death is usual outcome
 Low-level, chronic rejection reactions may induce inflammatory cells and vascular wall cells to secrete growth
factors that promote recruitment and proliferation of intimal smooth muscle cells and synthesis of ECM, thereby
expanding intima
 Other postoperative problems include infection and malignancies, particularly Epstein-Barr virus-associated B
cell lymphomas that arise in setting of T-cell immunosuppression
 1 year survival is 70-80%, and 5 year survival greater than 60%