PATHOLOGY
THE HEART II
Michelle Joy M. Cauan, MD March 2019
THE HEART II
I. CHRONIC ISCHEMIC HEART DISEASE
 “ischemic cardiomyopathy”
 Progressive congestive heart failure as a consequence of
accumulated ischemic myocardial damage and/or
inadequate compensatory response
 usually appears postinfarction due to the functional
decompensation of hypertrophied noninfarcted
myocardium
 severe obstructive coronary artery disease – if prior
infarction is absent
 Patients - almost 50% cardiac transplant recipients
Morphology:
 Cardiomegaly with LVH and dilatation
 Some - stenotic coronary atherosclerosis
 Discrete scars representing healed infarcts are usually
present
 patchy fibrous thickenings – mural endocardium due to
abnormal wall shear forces
 Mural thrombi +
 myocardial hypertrophy, diffuse subendocardial
vacuolization, and fibrosis
II. ARRHYTHMIAS
 Abnormalities in myocardial conduction
– Sustained
– Sporadic (paroxysmal)
Manifest as:
 Tachycardia
 Bradycardia
 Irregular rhythm with normal ventricular contraction
 Chaotic depolarization without functional ventricular
contraction (ventricular fibrillation)
 No electrical activity at all (asystole)
 Patients may be unaware: “racing heart” or palpitations;
– Loss of adequate cardiac output – light-headedness,
loss of consciousness, sudden cardiac death
Most common cause – Ischemic injury
 Direct damage or dilation of heart chambers that alters
conduction system firing
– SA node is damaged (e.g., sick sinus syndrome), other
fibers or even the AV node can take over pacemaker
function, albeit at a much slower intrinsic rate
(bradycardia)
– atrial myocytes become “irritable” and depolarize
independently and sporadically (atrial dilation)
o signals are variably transmitted through the AV
node leading to the random “irregularly irregular”
heart rate of atrial fibrillation
– AV node is dysfunctional - heart block occur
o first degree heart block - simple prolongation of
the P-R interval on the Electrocardiogram
o intermittent transmission of the signal (second
degree heart block)
o complete failure (third degree heart block
 primary electrical abnormalities of the heart that predispose
to arrhythmias:
 Channelopathies - caused by mutations in genes that are
required for normal ion channel function; AD disorders
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III. SUDDEN CARDIAC DEATH (SCD)
 unexpected death from cardiac causes either without
symptoms, or within 1 to 24 hours of symptom onset
 Coronary artery disease – leading cause – 80-90% of cases
 Often the first manifestation of IHD
 10-20% of cases – acute plaque disruption
 40% of cases – presence of healed remote MIs
 Sudden Cardiac Death (SCD)
 Other nonatherosclerotic causes in younger victims:
– Hereditary or acquired abnormalities of the cardiac
conduction system
– Congenital coronary arterial abnormalities
– Mitral valve prolapse
– Myocarditis or sarcoidosis
– Dilated or hypertrophic cardiomyopathy
– Pulmonary hypertension
– Myocardial hypertrophy – increased cardiac mass
(independent risk factor) - athletes
 Other causes:
– pericardial tamponade, pulmonary embolism, systemic
metabolic and hemodynamic alterations,
catecholamines, and drugs of abuse, particularly
cocaine and methamphetamine
Morphology:
 Marked coronary atherosclerosis with a critical (>75%
crosssectional area) stenosis involving one or more of the
three major vessels is present in 80% to 90% of SCD victims
 Acute plaque disruption – 50%
 Diagnostic changes of acute MI – 25%
 Most are thought to result from myocardial ischemia-
induced
 irritability that initiates malignant ventricular arrhythmias
 Scars of previous infarcts and subendocardial myocyte
vacuolization
 indicative of severe chronic ischemia - common
Mechanism:
 Lethal arrhythmia – asystole or ventricular fibrillation
Prognosis:
 patients vulnerable to SCD is markedly improved by
pharmaceutical intervention
 implantation of automatic cardioverter defibrillators that
can sense and electrically counteract episodes of
ventricular fibrillation
IV. HYPERTENSIVE HEART DISEASE
 consequence of the increased demands placed on the
heart by hypertension, causing pressure overload and
ventricular hypertrophy
A. Systemic (Left-Sided) Hypertensive Heart Disease
 Hypertrophy of the heart – adaptive response to pressure
overload of chronic hypertension
– May be maladaptive →myocardial dysfunction,
cardiac dilation, CHF, and in some cases sudden death
 Minimal pathologic criteria for the diagnosis of systemic
HHD:
1. Left ventricular hypertrophy (usually concentric) in the
absence of other cardiovascular pathology
2. A clinical history or pathologic evidence of
hypertension in other organs (e.g., kidney)
Morphology:
 left ventricular pressure
overload hypertrophy,
initially without ventricular
dilation → increases the
weight of the heart
disproportionately to the
increase in overall cardiac
size
– Wall thickness >2.0cm
– weight > 500g
 Increased interstitial
connective tissue – stiffness – impairs diastolic filling →
left atrial enlargement
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 Prognosis: Depending on the severity, duration, and
underlying basis of the hypertension, and on the adequacy
of therapeutic control, the patient may:
1. enjoy normal longevity and die of unrelated causes
2. develop IHD due to both the potentiating effects of
hypertension on coronary atherosclerosis and the
b)
ischemia induced by increased oxygen demand from
the hypertrophic muscle
3. suffer renal damage or cerebrovascular stroke
4. experience progressive heart failure or SCD
B. Pulmonary (Right-Sided) Hypertensive Heart Disease (Cor
Pulmonale)
 stems from right ventricular pressure overload
 Chronic cor pulmonale - right ventricular hypertrophy,
dilation, and potentially right-sided failure
– Causes: disorders of the lungs (chronic parenchymal
diseases such as emphysema, and primary pulmonary
hypertension)
– Pulmonary hypertension - most commonly occurs as a
complication of left-sided heart disease
 Acute cor pulmonale can follow massive pulmonary
embolism
Morphology:
 acute cor pulmonale -
marked dilation (ovoid) of the
right ventricle without
hypertrophy
 chronic cor pulmonale - right
ventricular wall thickens,
sometimes up to 1.0 cm or
more
 Other form of RVH
– Thickening of muscle
bundles in the outflow
tract, immediately below the pulmonary valve
– thickening of the moderator band, the muscle bundle
that connects the ventricular septum to the anterior
right ventricular papillary muscle
 regurgitation and fibrous thickening of the tricuspid valve
from compression of the left ventricular chamber
V. VALVULAR HEART DISEASE
 Stenosis
 Insufficiency (regurgitation or incompetence)
a) Valvular Heart Disease
– Stenosis - the failure of a valve to open completely, which
impedes forward flow
– Insufficiency - failure of a valve to close completely, thereby
allowing reversed flow
– Present alone or co-exist and involve single valve or more
than one valve
– Functional regurgitation - incompetence of a valve
stemming from an abnormality in one of its support
structures, as opposed to a primary valve defect
o Functional mitral valve regurgitation – IHD and dilated
cardiomyopathy
– valvular stenosis
o leads to pressure overload cardiac hypertrophy
o ejection of blood can produce high speed “jets” of
blood that injure the endocardium where they impact
o mitral or aortic valvular insufficiency leads to volume
overload
– Acquired valvular stenosis - almost always a consequence
of a remote or chronic injury of the valve cusps
– Acquired valvular insufficiency - result from intrinsic disease
of the valve cusps or damage to or distortion of the
supporting structures
Most frequent causes of the major functional valvular lesions are:
o Aortic stenosis: calcification and sclerosis of
anatomically normal or congenitally bicuspid aortic
valves
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o Aortic insufficiency: dilation of the ascending aorta,
often secondary to hypertension and/or aging
o Mitral stenosis: rheumatic heart disease
o Mitral insufficiency: myxomatous degeneration (mitral
valve prolapse)
Calcific Valvular Degeneration
– Calcific Aortic Stenosis
– Calcific Stenosis of Congenitally Bicuspid Aortic Valve
– Mitral Annular Calcification
– Causes of high levels of repetitive mechanical stress in the
heart valves:
1. 30 to 40 million or more cardiac contractions per year
2. Substantial tissue deformations during each contraction
3. transvalvular pressure gradients in the closed phase of
each contraction - approximately 120 mm Hg for the
mitral and 80 mm Hg for the aortic valve
1. Calcific Aortic Stenosis
o Most common of all valvular abnormalities
o consequence of age-associated “wear and tear” of either
anatomically normal valves (senile calcific aortic stenosis) or
congenitally bicuspid valves (in approximately 1% of the
population)
o Prevalence – 2% and increasing as the general population
ages
 Senile calcific aortic stenosis – 7th - 9th decade of life
 Stenotic bicuspid valve – 1-2decades earlier
o Aortic valve calcification - consequence of recurrent
chronic injury due to hyperlipidemia, hypertension,
inflammation, and other factors similar to those implicated
in atherosclerosis
o Bicuspid valves incur greater mechanical stress than normal
tricuspid valves
o chronic progressive injury → valvular degeneration and
incites the deposition of hydroxyapatite (same calcium salt
found in bone)
 abnormal valves contain cells resembling osteoblasts
that synthesize bone matrix proteins and promote the
deposition of calcium salts
Morphology: gross
 Hallmark of nonrheumatic, calcific aortic stenosis
(involving either tricuspid or bicuspid valves) –
mounded calcified masses within the aortic cusps that
ultimately protrude through the outflow surfaces into
the sinuses of Valsalva, and prevent cuspal opening
 commissural fusion is not usually seen
 Mitral valve is generally normal
Morphology: microscopic
 the layered architecture of the valve is largely
preserved
 calcific process begins in the valvular fibrosa on the
outflow surface of the valve, at the points of maximal
cusp flexion (near the margins of attachment)
 metaplastic bone (and even bone marrow) may be
seen
 Inflammation is variable
Clinical features:
 left ventricular (pressure overload) hypertrophy -
increasing pressure gradient across the calcified valve
 tends to be ischemic and angina pectoris may
occur
 Both systolic and diastolic myocardial function may be
impaired → cardiac decompensation, CHF or syncope
 Poor prognosis
 Untreated: patients with angina die within 5 years,
syncope – 3 years, CHF – 2 years
 Treatment – surgical valve replacement
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2) Calcific Stenosis of Congenitally Bicuspid Aortic Valve (BAV) Morphology:
o Developmental abnormality – 1% of population – Anatomic change - interchordal ballooning (hooding) of the
o Associated with loss-of-function mutations in NOTCH1 mitral leaflets or portions thereof
o there are only two functional cusps, usually of unequal size,  enlarged, redundant, thick, and rubbery
with the larger cusp having a midline raphe, resulting from – associated tendinous cords may be elongated, thinned, or even
incomplete commissural separation during development ruptured, and the annulus may be dilated
 raphe is frequently a major site of calcific deposits. – tricuspid, aortic, or pulmonary valves may also be affected
o If due to acquired deformity (e.g., rheumatic valve disease)
- fused commissure that produces a conjoined cusp that is
generally twice the size of the nonconjoined cusp
o become incompetent as a result of aortic dilation, cusp
prolapse, or infective
endocarditis
o Asymptomatic in early life
o Late complications: aortic
stenosis or regurgitation,
infective endocarditis, and
aortic dilation and/or
dissection A, Long axis view (left ventricle is on the right) demonstrating hooding
o Calcified BAV - approximately with prolapse of the posterior mitral leaflet into the left atrium (arrow).
50% of cases of aortic stenosis C, Opened valve with pronounced hooding (double arrows) in a
in adults patient who died suddenly.
One cusp has a partial fusion at its center, called a raphe (arrow)
thrombotic plaques at
3) Mitral Annular Calcification sites of leaflet left
o typically develop in the fibrous annulus atrium contact
o usually does not affect valvular function (arrows).
o Most common in women older than age 60 and individuals
with mitral valve prolapse
o Complications:
 Regurgitation by interfering with physiologic
contraction of the valve ring
 Stenosis by impairing opening of the mitral leaflets
 Arrhythmias and occasionally sudden death by
– myxomatous degeneration – marked thickening of the
penetration of calcium deposits to a depth sufficient to
spongiosa layer with deposition of mucoid (myxomatous)
impinge on the atrioventricular conduction system
material
o increased risk of embolic stroke – calcific nodules become
– attenuation of the collagenous fibrosa layer of the valve, on
site for thrombus formation
which the structural integrity of the leaflet depends
o appear as irregular, stony hard, occasionally ulcerated
nodules (2 to 5 mm in thickness) at the base of the leaflets

o Secondary changes:
(1) fibrous thickening of the valve leaflets, particularly where
Cut section of myocardium showing the lateral wall with dense they rub against each other
calcification that extends into the underlying myocardium (arrow) (2) linear fibrous thickening of the left ventricular endocardial
surface where the abnormally long cords snap or rub
calcific nodules at the base (attachment margin) of the anterior
against it
mitral leaflet
(3) thickening of the mural endocardium of the left ventricle or
c) Mitral Valve Prolapse (Myxomatous Degeneration of the Mitral atrium as a consequence of friction-induced injury induced
Valve) by the prolapsing, hypermobile leaflets
– one or both mitral valve leaflets are “floppy” and prolapse, (4) thrombi on the atrial surfaces of the leaflets or the atrial
or balloon back, into the left atrium during systole walls
– 2-3% of adults in the United States (5) focal calcifications at the base of the posterior mitral leaflet
– 7:1 female-to-male ratio Clinical features:
– most often an incidental finding on physical examination
– Most are asymptomatic
– Pathogenesis:
– Auscultation: mid-systolic clicks sometimes followed by
 Unknown in most cases
a mid to late systolic murmur – confirmed by
 Associated with heritable disorders of connective tissue
echocardiogram
including Marfan syndrome, caused by fibrillin-1 (FBN-1)
– chest pain mimicking angina – minority of patients
mutations
– Dyspnea – related to valvular insufficiency – some
– alter cell-matrix interactions and dysregulate TGF-β
patients
signaling
– approximately 3% develop one of four serious
 excess TGF-β activity can cause the
characteristic structural laxity and
myxomatous changes

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complications:
(1) infective endocarditis
(2) mitral insufficiency, sometimes with chordal rupture
(3) stroke or other systemic infarct, resulting from embolism of
leaflet thrombi
(4) arrhythmias, both ventricular and atrial
– risk of serious complications
 Very low in young asymptomatic patients
 Higher for men, older patients
 With arrhythmias or mitral regusgitation
– Valve repair or replacement surgery can be done for
symptomatic patients or those with increased risk for
significant complications
– most common cause for mitral valve surgery - US
d) Rheumatic Fever and Rheumatic Heart Disease
1. Rheumatic fever (RF)
– acute, immunologically mediated, multisystem
inflammatory disease classically occurring a few weeks
after an episode of group A streptococcal pharyngitis
o occasionally, RF can follow streptococcal
infections at other sites, such as the skin
– Acute rheumatic carditis - common manifestation of
active RF – may progress over time to chronic
rheumatic heart disease (RHD), mainly manifesting as
valvular abnormalities
2. RHD
– characterized principally by deforming fibrotic valvular
disease, particularly involving the mitral valve
– the only cause of mitral stenosis
Pathogenesis
 Acute rheumatic fever results from host immune
responses to group A streptococcal antigens that
cross-react with host proteins
 Antibodies and CD4+ T cells directed against
streptococcal M proteins can also in some cases
recognize cardiac self-antigens
 Antibody binding can activate complement, recruit Fc-
receptor bearing cells (neutrophils and macrophages);
cytokine production by the stimulated T cells leads to
macrophage activation (within Aschoff bodies)
 Damage to heart tissue
Morphology:
 acute RF - focal inflammatory lesions are found in
various tissues.
 Distinctive lesions occur in the heart, Aschoff bodies
 consisting of foci of T lymphocytes, occasional plasma
cells, and plump activated macrophages called
Anitschkow cells (pathognomonic for RF)
– abundant cytoplasm and central round-to-ovoid
nuclei occasionally binucleate) in which
thechromatin condenses into a central, slender,
wavy ribbon (hence the designation “caterpillar
cells”)
 found in any of the three layers of the heart, resulting in
pericarditis, myocarditis, or endocarditis (pancarditis)
Aschoff body
The myocardium exhibits a
circumscribed nodule of
mixed mononuclear
inflammatory cells with
associated necrosis; within
the inflammation, large
activated macrophages
show prominent nucleoli, as
well as chromatin
condensed into long, wavy
ribbons (caterpillar cells;
arrows)
 fibrinoid necrosis within the cusps or tendinous cords as
result of inflammation endocardium and the left-sided
valves
 Overlying the necrotic foci and along the lines of
closure are small (1 to 2 mm) vegetations – verrucae
 Subendocardial lesions, perhaps exacerbated by
regurgitant jets, can induce irregular thickenings called
MacCallum plaques, usually in the left atrium
Acute rheumatic mitral
valvulitis superimposed on
chronic rheumatic heart
disease. Small vegetations
(verrucae) are visible
along the line of closure of
the mitral valve leaflet
(arrows).
 Cardinal anatomic changes - leaflet thickening,
commissural fusion and shortening, and thickening and
fusion of the tendinous cords
 mitral valve is virtually always involved – chronic disease
thickening of the diffuse fibrous thickening and
chordate tendineae distortion of the valve leaflets
and commissural fusion
 rheumatic mitral stenosis -
calcification and fibrous
bridging across the valvular
commissures create “fish
mouth” or “buttonhole”
stenoses
 Long-standing congestive
changes in the lungs may
induce pulmonary vascular
and parenchymal changes
→ right ventricular hypertrophy
 Microscopically, valves show organization of the acute
inflammation, with post-inflammatory
neovascularization and transmural fibrosis that
obliterate the leaflet architecture
Clinical features:
 RF is characterized by a constellation of findings (Major
manifestations):
(1) migratory polyarthritis of the large joints
(2) pancarditis
(3) subcutaneous nodules
(4) erythema marginatum of the skin
(5) Sydenham chorea - neurologic disorder with
involuntary rapid, purposeless movements
Clinical features: diagnosis by Jones criteria:
 evidence of a preceding group A streptococcal
infection, with the presence of two of the major
manifestations or one major and two minor
manifestations (nonspecific signs and symptoms that
include fever, arthralgia, or elevated blood levels of
acute phase reactants)
Clinical features: Acute RF
 appears 10 days to 6 weeks after a group A
streptococcal infection in about 3% of patients
 children between ages 5 and 15

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 Detection of antibodies (streptolysin O and DNase B) – – occasionally erode into the underlying myocardium and
most of patients produce an abscess (ring abscess)
 Predominant clinical manifestations - carditis and – prone to embolization - embolic fragments often contain virulent
arthritis organisms, abscesses frequently develop where they lodge →
– Arthritis - typically begins with migratory polyarthritis septic infarcts or mycotic aneurysms
(with fever) - one large joint after another – vegetations of subacute endocarditis are associated with less
becomes painful and swollen for a period of days valvular destruction
→ subsides spontaneously, no residual disability  Microscopically, granulation tissue at their bases indicative
– Acute Carditis – pericardial friction rubs, of healing → fibrosis, calcification, and a chronic
tachycardia, and arrhythmias inflammatory infiltrate can develop
Other manifestations: Clinical features:
 cardiac murmurs, cardiac hypertrophy and dilation, – Acute endocarditis - rapidly developing fever, chills,
and heart failure weakness, and lassitude
 Chronic RHD – arrhythmias (atrial fibrillation in the  Adult – slight or absent fever, nonspecific fatigue, loss of
setting of mitral stenosis), hromboembolic weight, and a flulike syndrome
complications, and infective endocarditis – Left-sided IE – presence of murmurs (90%)
 Surgical repair or prosthetic replacement of diseased – Duke Criteria, requires either pathologic or clinical
valves criteria;
 if clinical criteria are used, 2 major, 1 major + 3 minor, or
e) Infective Endocarditis (IE)
5 minor criteria are required for diagnosis
– microbial infection of the heart valves or the mural
– Janeway lesions - small erythematous or hemorrhagic,
endocardium →formation of vegetations composed of
macular, nontender lesions on the palms and soles and are
thrombotic debris and organisms, often associated with
the consequence of septic embolic events
destruction of the underlying cardiac tissues
– Osler nodes - small, tender subcutaneous nodules that
– Other sites of infection : aorta, aneurysms, other blood
develop in the pulp of the digits or occasionally more
vessels, and prosthetic devices
proximally in the fingers and persist for hours to several days
– most infections - bacterial (bacterial endocarditis)
– Roth spots - oval retinal hemorrhages with pale centers
– Infective Endocarditis
– Acute infective endocarditis - infection of a previously
normal heart valve by a highly virulent organism
(Staphylococcus aureus) → rapidly produces necrotizing
and destructive lesions
 difficult to cure with antibiotics alone, and usually
require surgery
– Subacute IE - characterized by organisms with lower
virulence (viridans streptococci) that cause insidious
infections of deformed valves with overall less destruction
 cures can be achieved with antibiotics
Pathogenesis:
– Endocarditis of native but previously damaged or otherwise
abnormal valves is caused most commonly (50% to 60% of
cases) by Streptococcus viridans (normal flora of oral
cavity)
– 20% to 30% of cases - S. aureus – infect either healthy or
deformed valves
 Major offender in IE among intravenous drug abusers
– Other causes: enterococci and the so-called HACEK group
(Haemophilus, Actinobacillus, Cardiobacterium, Eikenella,
and Kingella)
– Prosthetic valve endocarditis - coagulase-negative
staphylococci (S. epidermidis)
Morphology:
– Vegetations on heart valves - classic hallmark of IE f) Noninfected (Sterile) Vegetations
 friable, bulky, potentially destructive lesions – occur in nonbacterial thrombotic endocarditis and the
containing fibrin, inflammatory cells, and bacteria endocarditis of systemic lupus erythematosus (SLE), called
or other organisms Libman-Sacks endocarditis
1. Nonbacterial Thrombotic Endocarditis (NBTE)
 deposition of small sterile thrombi on the leaflets of the
cardiac valves
 Lesions - 1 to 5 mm in size, as single or multiple
vegetations along the line of closure of the leaflets or
cusps
 comprise bland thrombi that are loosely attached to
the underlying valve
o not invasive and do not elicit any inflammatory
reaction
– aortic and mitral valves are the most common sites a. can be the source of systemic emboli
 IV drug users – valves of right heart that produce significant infarcts in the
brain, heart, or elsewhere

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Nearly complete row of surfaces of the cardiac chambers and valve leaflets
– right-sided involvement - typical findings are tricuspid
insufficiency and pulmonary stenosis
– Smooth muscle cells and sparse collagen fibers embedded
in an acid mucopolysaccharide-rich matrix material
– Underlying structures are intact
- intimal thickening
- Movat stain shows myocardial
elastic tissue (black) underlying the
thrombotic vegetations along the acid mucopolysaccharide-rich
line of closure of the mitral valve lesion (blue-green). The underlying
leaflets (arrows) myocardium is unaffected
 often encountered in debilitated patients
o cancer or sepsis
 occurs concomitantly with deep venous thromboses,
Two types of valvular prostheses:
pulmonary emboli, or other findings
– Mechanical valves - different configurations of rigid
 suggesting an underlying systemic hypercoagulable
nonphysiologic material
state
 caged balls, tilting disks, or hinged semicircular
 Associated with mucinous adenocarcinomas –
flaps (bi-leaflet tilting disk valves)
procoagulant effects of tumor-derived mucin or tissue
– Tissue valves (bioprostheses) - Porcine aortic valves
factor – cause migratory thrombophlebitis
or bovine pericardium are preserved in a dilute
 Endocardial trauma (indwelling catheter) and right-
glutaraldehyde solution and then mounted on a
sided valvular and endocardial thrombotic lesions –
prosthetic frame
predisposing conditions
 frozen human valves from deceased donors
2. Endocarditis of Systemic Lupus Erythematosus (Libman- (called cryopreserved “homografts”)
Sacks Disease)  flexible and function similarly to natural semilunar
 Libman-Sacks endocarditis - Mitral and tricuspid valves
valvulitis with small, sterile vegetations Complications of Prosthetic Valves
o Occasionally encountered in systemic lupus – Approximately 60% of substitute valve recipients
erythematosus develop a serious prosthesis-related problem within 10
o lesions are small (1 to 4 mm in diameter), single or years after the surgery
multiple, sterile, pink vegetations with a warty – Thromboembolism - consideration with mechanical
(verrucous) appearance valves
o located on the undersurfaces of the  blood flow in all mechanical devices is nonlaminar
atrioventricular valves, on the valvular - foci of turbulence and stasis are produced -
endocardium, on the chords, or on the mural predispose to thrombus formation
endocardium of atria or ventricles  Needs long-term anticoagulation
 Vegetations consist of a finely granular, fibrinous
eosinophilic material containing cellular debris
including nuclear remnants Thrombosis of a
o often associated with an intense valvulitis - fibrinoid mechanical
necrosis of the valve substance and reflecting the prosthetic valve
activation of complement and recruitment of Fc-
receptor-bearing cells
 mitral valve is more frequently involved than the aortic
valve, and regurgitation is the usual functional
abnormality
mitral
g) Carcinoid Heart Disease
– Carcinoid syndrome - systemic disorder marked by flushing, mechanical valve
diarrhea, dermatitis, and bronchoconstriction that is caused prosthesis of the
by bioactive compounds (serotonin released by carcinoid older ball-and-
tumors) cage variety
– Carcinoid heart disease - cardiac manifestations caused by
the bioactive compounds
 occurs in roughly half of the patients in whom the
– Structural deterioration –
systemic syndrome develops
bioprostheses eventually
– endocardium and valves of the right heart are primarily
become incompetent due to
affected
calcification and/or tearing
Pathogenesis:
– Infective endocarditis
– Mediators - serotonin (5-hydroxytryptamine), kallikrein,
 vegetations of prosthetic
bradykinin, histamine, prostaglandins, and tachykinins
valve endocarditis are
– Valvular plaques - patients taking fenfluramine (an appetite
usually located at the prosthesis tissue interface→
suppressant) or ergot alkaloids (for migraine headaches)
formation of a ring abscess → paravalvular
– left-sided plaques -
regurgitant blood leak
methysergide or ergotamine
 major organisms - staphylococcal skin
therapy for migraines
contaminants (e.g., S. epidermidis), S. aureus,
Morphology:
streptococci, and fungi
– Lesions - distinctive, glistening Other complications
white intimal plaquelike
– paravalvular leak - inadequate healing
thickenings of the endocardial
– obstruction - overgrowth of fibrous tissue during healing

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– valve-orifice disproportion - relative stenosis  Iron overload – from either hereditary hemochromatosis
– intravascular hemolysis - high shear forces or from multiple transfusions
– excessive noise owing to hard contacts of moving rigid o DCM - most common manifestation iron excess
parts  Supraphysiologic stress – occur with persistent
tachycardia, hyperthyroidism, or even during
VI. Cardiomyopathies
development (fetuses of insulindependent diabetic
 heterogeneous group of diseases of the myocardium
mothers)
associated with mechanical and/or electrical dysfunction
o Excess catecholamines (pheochromocytomas) -
that usually (but not invariably) exhibit inappropriate
result in multifocal myocardial contraction band
ventricular hypertrophy or dilatation and are due to a
necrosis
variety of causes that frequently are genetic
– Takotsubo cardiomyopathy - left ventricular
 either are confined to the heart or are part of generalized
contractile dysfunction following extreme
systemic disorders, often leading to cardiovascular death or
psychological stress
progressive heart failure-related disability
 Affected myocardium – show multifocal
 Primary - genetic or acquired diseases of myocardium
contraction band necrosis
 Secondary cardiomyopathies - have myocardial
 Left ventricular apex – most often
involvement as a component of a systemic or multiorgan
affected → “apical ballooning”
disorder
resembles a “takotsubo”
 Three pathologic patterns:
Morphology:
– Dilated cardiomyopathy (including arrhythmogenic right
 Heart is enlarged, heavy
ventricular cardiomyopathy) - most common (90%)
(2-3x normal weight), and
– Hypertrophic cardiomyopathy
flabby, due to dilation of
– Restrictive cardiomyopathy – least frequent
all chambers
 Mural thrombi are
common – source of
thromboemboli
 no primary valvular
alterations
 histologic abnormalities in
DCM are nonspecific and
usually do not point to a specific etiology
o Most muscle cells - hypertrophied with enlarged
nuclei, but some are attenuated, stretched, and
irregular
o Interstitial and
endocardial fibrosis -
variable degree
o small subendocardial
scars may replace
individual cells or
groups of cells -
probably reflecting
Cardiomyopathy and Indirect Myocardial Dysfunction: healing of previous
Functional Patterns and Causes (refer to last page) ischemic necrosis of myocytes caused by
hypertrophy-induced imbalance between
a) Dilated Cardiomyopathy (DCM) perfusion and demand
 Characterized morphologically and functionally by
progressive cardiac dilation and contractile (systolic) Clinical features:
dysfunction, usually with concomitant hypertrophy  Occur at any age – childhood; most affects individuals
 Many cases - familial between 20-50 years old
Pathogenesis:  Slowly progressive signs and symptoms of CHF including
 Genetic influences - familial in at leasyct 30% to 50% of dyspnea, easy fatigability, and poor exertional
cases capacity
o mutations in TTN, a gene that encodes titin – 20%  End stage - ejection fractions are typically less than 25%
of all cases (normal = 50% to 65%)
 Alcohol and other toxins  Secondary mitral regurgitation and abnormal cardiac
 Alcohol abuse - strongly associated with development rhythms
of DCM (have direct effect on myocardium)  Embolism from intracardiac thrombi
o Thiamine deficiency secondary to chronic
b) Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
alcoholism
 inherited disease of myocardium → right ventricular
 doxorubicin (Adriamycin), tyrosine kinase inhibitors
failure and rhythm disturbances (particularly ventricular
causing myocardial injury
tachycardia or fibrillation) with sudden death
 Cobalt - has caused DCM in the setting of inadvertent
 Left-sided involvement with left-sided heart failure
tainting
 right ventricular wall is severely
 Myocarditis – viral origin - detection of the genetic
 thinned due to loss of myocytes, accompanied by
fingerprints of coxsackie B and other viruses within
extensive fatty infiltration and fibrosis
myocardium
 Classic ARVC – autosomal dominant with variable
 Childbirth – “peripartum cardiomyopathy”
penetrance
o primary defect is a microvascular angiogenic
 Pathogenesis: Defective cell adhesion proteins in the
imbalance within the myocardium leading to
desmosomes that link adjacent cardiac myocytes
functional ischemic injury

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 Naxos syndrome - arrhythmogenic right ventricular features
cardiomyopathy and hyperkeratosis of plantar palmar (1) massive myocyte hypertrophy, with transverse myocyte
skin surfaces diameters frequently greater than 40 μm (normal,
approximately 15 μm)
dilation of the right (2) haphazard disarray of bundles of myocytes, individual
ventricle and near- myocytes, and contractile elements in sarcomeres
transmural replacement of within cells (termed myofiber disarray)
the right ventricular free-wall (3) interstitial and replacement fibrosis
by fat and fibrosis. The left Histologic appearance
ventricle has a virtually demonstrating
normal configuration in this myocyte disarray,
case, but can also be extreme hypertrophy,
involved by the disease and exaggerated
process myocyte branching, as
Histologic section of the well as the characteristic
right ventricular free wall, interstitial fibrosis
demonstrating (collagen is blue in this
replacement of Masson trichrome stain).
myocardium (red) by
fibrosis (blue, arrow) and Clinical Features:
fat (Masson trichrome  reduced stroke volume due to impaired diastolic filling
stain) o consequence of a reduced chamber size, as well as
the reduced compliance of the massively
c) Hypertrophic Cardiomyopathy (HCM) hypertrophied left ventricle
 clinically heterogeneous, genetic disorder characterized by  25% of patients have dynamic obstruction to the left ventricular
myocardial hypertrophy → abnormal diastolic filling, and outflow
(in about one third of cases) intermittent ventricular outflow  exertional dyspnea due to compromised cardiac output in
obstruction conjunction with a secondary increase in pulmonary venous
 Common (incidence, 1 in 500) pressure
 leading cause of left ventricular hypertrophy unexplained  Atrial fibrillation, mural thrombus formation leading to
by other clinical or pathologic causes embolization and possible stroke, intractable cardiac failure,
 thick-walled, heavy, and hypercontracting ventricular arrhythmias, and, not infrequently, sudden death
 causes primarily diastolic dysfunction o one of the most common causes of sudden, otherwise
Pathogenesis: unexplained death in young athletes
 autosomal dominant with variable penetrance – most cases d) Restrictive Cardiomyopathy
 70% - 80% - Mutations in the gene encoding β-myosin
 characterized by a primary decrease in ventricular
heavy chain (β-MHC) followed by the genes coding for
compliance, resulting in impaired ventricular filling during
cardiac TnT, α-tropomyosin, and myosin-binding protein C
diastole
(MYBP-C)
 can be idiopathic or associated with distinct diseases or
 May arise from defective energy transfer from its source of
processes that affect the myocardium
generation (mitochondria) to its site of use (sarcomeres)
o principally radiation fibrosis, amyloidosis, sarcoidosis,
 Interstitial fibrosis in HCM probably occurs secondary to
metastatic tumors, or the deposition of metabolites that
exaggerated responses of the myocardial fibroblasts to the
accumulate due to inborn errors of metabolism
primary myocardial dysfunction
Morphology: gross
 morphologic features:
 massive myocardial hypertrophy, usually without ventricular o Ventricles are of approximately normal size or slightly
dilation enlarged
 Asymmetric septal hypertrophy - disproportionate o cavities are not dilated
thickening of the ventricular septum relative to the left o the myocardium is firm and noncompliant
ventricle free wall (ratio of septum to free wall greater than o Biatrial dilation is commonly observed
3 : 1)
 left ventricular cavity may be compressed into a “banana-  Microscopically:
like” configuration by bulging of the ventricular septum into o there may be only patchy or diffuse interstitial fibrosis -
the lumen
minimal to extensive
 left ventricular outflow tract – exhibits a fibrous endocardial  Endomyocardial biopsy can often reveal a specific
plaque associated with thickening of the anterior mitral etiology:
leaflet o Endomyocardial fibrosis - fibrosis of the ventricular
 Hypertrophic cardiomyopathy with asymmetric septal endocardium and subendocardium that extends from
hypertrophy the apex upward, often involving the tricuspid and
The septal muscle bulges
mitral valves
into the left ventricular – markedly diminishes the volume and compliance
outflow tract, and the left of affected chambers causes a restrictive
atrium is enlarged. The functional defect
anterior mitral leaflet has  Loeffler endomyocarditis also results in endomyocardial
been reflected away from fibrosis, typically with large mural thrombi
the septum to reveal a o there is often a peripheral eosinophilia and eosinophilic
fibrous endocardial plaque infiltrates in multiple organs, including the heart
(arrow)  Endocardial fibroelastosis - fibroelastic thickening that
Morphology: histologic typically involves the left ventricular endocardium

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e) Myocarditis  Chagas disease - parasitization of scattered myofibers by
 diverse group of pathologic entities in which infectious trypanosomes accompanied by a mixed inflammatory
microorganisms and/or a primary inflammatory process infiltrate of neutrophils, lymphocytes, macrophages, and
cause myocardial injury occasional eosinophils
 viral infections - most common cause of myocarditis – US The myocarditis of Chagas
o Coxsackie viruses A and B and other enteroviruses disease. A myofiber
probably account for most of the cases distended with
o potentially cause myocardial injury either as a direct trypanosomes (arrow) is
cytopathic effect, or by eliciting a destructive immune present along with
response individual myofiber
 Nonviral agents: necrosis, and modest
o Trypanosoma cruzi -agent of Chagas disease amounts of inflammation
o Trichinosis (Trichinella spiralis) - most common helminthic
Clinical features:
disease associated with myocarditis
 disease is entirely asymptomatic - expect a complete
o Other causes: Lyme disease and diphtheria, AIDS-
recovery without sequelae
associated myocarditis
 If symptomatic - precipitous onset of heart failure or
 noninfectious causes of myocarditis - immunologically
arrhythmias, occasionally with sudden death
mediated (hypersensitivity myocarditis) or idiopathic
o fatigue, dyspnea, palpitations, precordial discomfort,
conditions with distinctive morphology (giant cell
and fever
myocarditis
 can mimic those of acute MI
Morphology: gross
 dilated cardiomyopathy – late complication
 Heart may appear normal
or dilated VII. PERICARDIAL DISEASE
 advanced stages the a) Pericardial Effusion and Hemopericardium
ventricular myocardium is  Normal – less than 50ml of thin, clear, straw-colored fluid
flabby and often mottled  parietal pericardium may be distended by:
by either pale foci or o pericardial effusion – serous fluid
minute hemorrhagic lesions o Hemopericardium – blood
 Mural thrombi may be o Purulent pericarditis – pus
present  chronic effusions of less than 500 mL in volume, the only
clinical significance is a characteristic globular enlargement
Morphology: microscopic of the heart shadow on chest radiographs
 Active myocarditis is characterized by an interstitial  cardiac tamponade - clinically devastating compression of
inflammatory infiltrate associated with focal myocyte the thin-walled atria and venae cavae, or the ventricles
necrosis o Caused by rapidly developing fluid collections of as little
 diffuse, mononuclear, predominantly lymphocytic infiltrate is as 200 to 300 mL (hemopericardium caused by a
most common ruptured MI or aortic dissection)
Lymphocytic b) Pericarditis
myocarditis,  Pericardial inflammation can occur secondary to a variety of
associated with cardiac, thoracic, or systemic disorders, metastases from
myocyte injury remote neoplasms, or cardiac surgical procedures
 Primary pericarditis - unusual and almost always of viral origin
1. Acute Pericarditis
i. Serous pericarditis
– produced by noninfectious inflammatory diseases,
Morphology: microscopic including rheumatic fever, SLE, and scleroderma, as well
 Hypersensitivity myocarditis has interstitial infiltrates, as tumors and uremia
principally perivascular, composed of lymphocytes, – Histologicaly: Mild inflammatory infiltrate in the
macrophages, and a high proportion of eosinophils epipericardial fat consisting predominantly of
Hypersensitivity lymphocytes; tumor-associated pericarditis may also
myocarditis, characterized by exhibit neoplastic cells
interstitial inflammatory
ii. Fibrinous and serofibrinous pericarditis
infiltrate composed largely of
– Most frequent types of pericarditis
eosinophils and mononuclear
– composed of serous fluid variably admixed with a
inflammatory cells, fibrinous exudate.
predominantly localized to – Common causes include acute MI, postinfarction
perivascular and expanded (Dressler) syndrome (an autoimmune response
interstitial spaces appearing days-weeks after an MI), uremia, chest
 giant-cell myocarditis - widespread inflammatory radiation rheumatic fever, SLE, and trauma
cellular infiltrate containing multinucleate giant cells – pain (sharp, pleuritic, and position dependent) and
(fused macrophages) interspersed with lymphocytes, fever
eosinophils, plasma cells, and macrophages – congestive failure may also be present
o Focal to frequently extensive necrosis is present – Loud pericardial friction rub is the most striking clinical
Giant-cell myocarditis, with finding
mononuclear inflammatory
iii. Purulent or suppurative pericarditis
infiltrate containing lymphocytes – reflects an active infection caused by microbial invasion
and macrophages, extensive loss of the pericardial space
of muscle, and multinucleated – Occur through:
giant cells (fused macrophages).

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 Direct extension from neighboring infections -
2. Chronic or Healed Pericarditis
empyema of the pleural cavity, lobar pneumonia,
 plaque-like fibrous thickenings of
mediastinal infections, or extension of a ring abscess
 the serosal membranes (“soldier’s plaque”) or thin,
 Seeding from the blood
delicate adhesions that rarely cause impairment of
 Lymphatic extension
cardiac function
 Direct introduction during cardiotomy
 Adhesive mediastinopericarditis - follow infectious
– exudate ranges from a thin cloudy fluid to frank pus up
pericarditis, previous cardiac surgery, or mediastinal
to 400 to 500 mL in volume
irradiation
dark, roughened o pericardial sac is obliterated, and adherence
of the external aspect of the parietal layer to
epicardial surface surrounding structures strains cardiac function
overlying an acute  constrictive pericarditis - the heart is encased in a
infarct dense, fibrous or fibrocalcific scar that limits diastolic
expansion and cardiac output
VIII. Tumors of the Heart
 Tumors of the Heart
– serosal surfaces are reddened, granular, and coated  Primary tumors – rare
with the exudate  Metastatic tumors to the heart occur in about 5% of persons
– Microscopically - acute inflammatory reaction, which dying of cancer
sometimes extends into surrounding structures to induce  most common primary cardiac tumors, in descending order
mediastinopericarditis of frequency:
– intense inflammatory response and the subsequent – myxomas, fibromas, lipomas, papillary fibroelastomas,
scarring frequently produce constrictive pericarditis - rhabdomyomas, and angiosarcomas
serious consequence  five most common tumors - all benign and collectively
Acute suppurative account for 80% to 90% of
pericarditis arising from primary tumors of the heart
direct extension of an large, firm, white tumor
adjacent pneumonia. mass is shown filling much of
Extensive purulent the left ventricle, which
exudate is evident obstructed the flow of blood

iv. Hemorrhagic pericarditis

– has an exudate
– arises in the epicardium in
composed of blood
the groove between the
mixed with a fibrinous or
right atrium and right
suppurative effusion
ventricle
– most commonly caused
– one of the most common
by the spread of a
primary malignancies in the
malignant neoplasm to
heart
the pericardial space
– variegated, hemorrhagic
– can also be found in
mass
bacterial infections, in
persons with an
underlying bleeding
diathesis, and in tuberculosis Pale, white-tan
– often follows cardiac surgery and is occasionally nodules of
responsible for significant blood loss or even metastatic
tamponade, requiring re-operation tumor are seen
over the
v. Caseous pericarditis is, until proved otherwise, surface of the
tuberculous in origin Epicardium
– infrequently, fungal infections evoke a similar reaction
– occurs by direct spread from tuberculous foci within
the tracheobronchial nodes
– Caseous pericarditis is a common antecedent of 1. Primary Cardiac Tumors
disabling, fibrocalcific, chronic constrictive pericarditis a. Myxomas
Mycobacterium  most common primary tumor of the adult heart
tuberculosis infection  benign neoplasms thought to arise from primitive
can produce multipotent mesenchymal cells
extensive  familial syndromes associated with myxomas:
granulomatous o activating mutations in the GNAS1 gene - encoding
inflammationwith a subunit of G protein (Gsα) (in association with
McCune-Albright syndrome)
resultant calcification
o null mutations in PRKAR1A, encoding a regulatory
that can severely
subunit of a cyclic-AMPdependent protein kinase
restrict cardiac motion (Carney complex)
(so-called constrictive
pericarditis

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 90% of myxomas arise in the atria, with a left-to-right ratio a) Allograft Rejection
of approximately 4:1  primary problem requiring surveillance
 tumors are usually single, but can rarely be multiple  Endomyocardial biopsy - only reliable means of diagnosing
 range from small (<1 cm) to large (≥10 cm), and can be acute cardiac rejection before substantial myocardial
sessile or pedunculated lesions damage has occurred
o vary from globular hard masses mottled with  Classic cellular rejection - interstitial lymphocytic
hemorrhage to soft, translucent, papillary, or villous inflammation with associated myocyte damage
lesions having a gelatinous appearance o There may also be interstitial edema due to vascular
o pedunculated form is often sufficiently mobile to injury, and local cytokine elaboration can impact
move during systole into the atrioventricular valve myocardial contractility without necessarily eliciting
opening, causing intermittent obstruction that may myocyte damage
be position dependent  antibody-mediated rejection - donor-specific antibodies
o Sometimes mobile tumors exert a “wrecking-ball” directed against major histocompatibility complex proteins
effect, causing damage to the valve leaflets lead to complement activation and the recruitment of Fc-
 region of the fossa ovalis in the atrial septum - site of receptor-bearing cells
origin Cardiac allograft rejection typified by lymphocytic infiltrate
 Histologically, composed of associated with cardiac myocyte damage.
stellate or globular myxoma
cells embedded within an b) Allograft
abundant acid arteriopathy
mucopolysaccharide ground  single
substance most important
 Peculiar vessel-like or gland- long-term
like structures are limitation for
characteristic cardiac
 Hemorrhage and transplantation
mononuclear inflammation  late, progressive, diffusely stenosing intimal proliferation in the
are usually present coronary arteries leading to ischemic injury
Abundant  Developed in 50% of patients within 5 years of
amorphous transplantation
 Pathogenesis: immunologic responses that induce local
extracellular matrix
production of growth factors that promote intimal smooth
contains scattered
muscle cell recruitment and proliferation with ECM synthesis
multinucleate  lead to silent MI (transplant patients have denervated hearts
myxoma and do not experience angina), progressive CHF, or sudden
cells (arrowheads) in cardiac death
various groupings, Allograft arteriopathy,
including abnormal with severe diffuse
vessel-like formations concentric intimal
(arrow) thickening producing
critical stenosis. The
IX. Cardiac Transplantation
 Transplantation of cardiac allografts internal elastic lamina
– now frequently performed (approximately 3000 per year (arrow) and media are
worldwide) for severe, intractable heart failure of diverse intact (Movat
causes—most commonly DCM and IHD pentachrome stain, elastin
– Three major factors have contributed to the improved black).
outcome of cardiac transplantation:
1. more effective immunosuppressive therapy
(including the use of cyclosporin A, glucocorticoids,
and other agents)
2. careful selection of candidates Cardiomyopathy and Indirect Myocardial Dysfunction:
3. early histopathologic diagnosis of acute allograft
Functional Patterns and Causes
rejection by endomyocardial biopsy

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