2. • Cardiac diseases due to intrinsic myocardial
dysfunction are termed cardiomyopathies
(literally, “heart muscle diseases”); these can
be primary—that is, principally confined to
the myocardium—or secondary presenting as
the cardiac manifestation of a systemic
disorder
3. • Cardiomyopathies can be classified according
to a variety of criteria, including the
underlying genetic basis of dysfunction;
indeed, some of the arrhythmia-inducing
channelopathies that are included in some
classifications of cardiomyopathy were alluded
to earlier.
4. • For purposes of general diagnosis and therapy,
however, three time honored clinical,
functional, and pathologic patterns are
recognized.
Dilated cardiomyopathy (DCM) (including
arrhythmogenic right ventricular
cardiomyopathy)
Hypertrophic cardiomyopathy (HCM)
Restrictive cardiomyopathy
5. Dilated Cardiomyopathy
• Dilated cardiomyopathy (DCM) is
characterized by progressive cardiac dilation
and contractile (systolic) dysfunction, usually
with concurrent hypertrophy.
6.
7. Pathogenesis
• Although many individuals with DCM have a
familial (genetic) form, DCM can also result
from various acquired myocardial insults.
These include the following:
• Myocarditis (an inflammatory disorder that
precedes the development of cardiomyopathy
in at least some cases, and is sometimes
caused by viral infections)
8. • Toxicities, including adverse effects of
chemotherapeutic agents and chronic
alcoholism.
• Pregnancy, so-called “peripartum
cardiomyopathy”
• Stress-provoked
• Tachycardia-induced
9. • progressed to end-stage disease; the heart is
dilated and poorly contractile, and at autopsy
or cardiac transplant, fails to reveal any
specific pathologic features.
• Nevertheless, genetic and epidemiologic
studies suggest that at least five general
pathways can lead to end-stage DCM.
10. • Genetic causes. DCM has a hereditary basis in
20% to 50% of cases. Over 50 genes are
known to be mutated in this form of
cardiomyopathy, with autosomal dominant
inheritance being the predominant pattern;
mutations affecting cytoskeletal proteins or
proteins that link the sarcomere to the
cytoskeleton (e.g., α-cardiac actin) are most
commonly involved. X-linked DCM is most
frequently associated with mutatons
11. • Infection.
• Alcohol or other toxic exposure. Alcohol abuse is
strongly associated with the development of
DCM.
• Peripartum cardiomyopathy occurs late in
gestation or several weeks to months
postpartum. The etiology is multifactorial,
including pregnancy-associated hypertension,
volume overload, nutritional deficiency,
metabolic derangements (e.g., gestational
diabetes), and/or immunologic responses. Recent
work suggests that the primary defect is impaired
angiogenesis within the myocardium leading to
ischemic injury.
12. • Iron overload in the heart can result either
from hereditary hemochromatosis or from
multiple transfusions. Iron overload also can
cause restrictive cardiomyopathy due to
interstitial fibrosis, but DCM is the most
common manifestation; it has been attributed
to interference with metal-dependent enzyme
systems or to injury caused by iron-mediated
production of reactive oxygen species.
13. Clinical Features
• The fundamental defect in DCM is ineffective
contraction.
• Thus, in end-stage DCM, the cardiac ejection
fraction typically is less than 25% (normal is
50% to 65%). Secondary mitral regurgitation
and abnormal cardiac rhythms are common,
and embolism from intracardiac (mural)
thrombi can occur.
14. • DCM most commonly is diagnosed between
20 and 50 years of age. It typically manifests
with signs of slowly progressive CHF, including
dyspnea, easy fatigability, and poor exertional
capacity.
15. Arrhythmogenic Right Ventricular
Cardiomyopathy
• Arrhythmogenic right ventricular
cardiomyopathy is an autosomal dominant
disorder that classically manifests with right-
sided heart failure and rhythm disturbances,
which can cause sudden cardiac death.
• Morphologically, the right ventricular wall is
severely thinned owing to myocyte
replacement by fatty infiltration and lesser
amounts of fibrosis.
16. • Many of the causative mutations involve
genes encoding desmosomal junctional
proteins at the intercalated disk (e.g.,
plakoglobin), as well as proteins that interact
with the desmosome (e.g., the intermediate
filament desmin). It’s thought that myocyte
death is caused by desmosomal detachment,
particularly during strenuous exercise.
17. Hypertrophic Cardiomyopathy
• Hypertrophic cardiomyopathy (HCM) is characterized by
myocardial hypertrophy, defective diastolic filling, and—
in one third of cases—ventricular outflow obstruction.
• The heart is thick-walled, heavy, and hypercontractile, in
striking contrast to the flabby, poorly contractile heart in
DCM.
• Systolic function usually is preserved in HCM, but the
myocardium does not relax and therefore exhibits
primary diastolic dysfunction. HCM needs to be
distinguished clinically from disorders causing ventricular
stiffness (e.g., amyloid deposition) and ventricular
hypertrophy (e.g., aortic stenosis and hypertension).
18. Pathogenesis
• Most cases of HCM are caused by missense
mutations in one of several genes encoding
proteins that form the contractile apparatus.
• Although more than 400 causative mutations
in nine different genes have been identified,
all have one unifying feature: they all affect
sarcomeric proteins and increase myofilament
function.
19. • This results in myocyte hypercontractility,
increased energy use, and a net negative
energy balance. Of the various sarcomeric
proteins, β-myosin heavy chain is most
frequently involved, followed by myosin-
binding protein C and troponin T.
• Some of the genes mutated in HCM also are
mutated in DCM (e.g., beta-myosin), but in
DCM the mutations depress motor function as
opposed to the gain of function seen in HCM.
21. Clinical Features
• Although HCM can present at any age, it typically
manifests during the postpubertal growth spurt.
The clinical symptoms can be best understood in
the context of the functional abnormalities. It is
characterized by massive left ventricular
hypertorphy associated with (paradoxically) a
markedly reduced stroke volume.
• This latter occurs as a consequence of impaired
diastolic filling and overall smaller chamber size.
22. • Reduced cardiac output and a secondary
increase in pulmonary venous pressure cause
exertional dyspnea, with a harsh systolic
ejection murmur.
23. Restrictive Cardiomyopathy
• Restrictive cardiomyopathy is characterized
by a primary decrease in ventricular
compliance, resulting in impaired ventricular
filling during diastole (simply put, the wall is
stiffer).
• Three forms of restrictive cardiomyopathy
merit brief mention:
24. • Amyloidosis is caused by the deposition of
extracellular proteins with a predilection for
forming insoluble β-pleated sheets.
• In the latter case, deposition of normal (or
mutant) forms of transthyretin (a liver-
synthesized circulating protein that transports
thyroxine and retinol) in the hearts of older adult
patients results in a restrictive cardiomyopathy.
• Besides depositing as amyloid, immunoglobulin
light-chains in AL-type amyloid also are directly
cardiotoxic and can induce myocardial
dysfunction.
25. • Endomyocardial fibrosis is principally a disease of
children and young adults in Africa and other
tropical areas.
• It is characterized by dense diffuse fibrosis of the
ventricular endocardium and subendocardium,
often involving the tricuspid and mitral valves.
• The fibrous tissue markedly diminishes the
volume and compliance of affected chambers,
resulting in a restrictive physiology.
• Endomyocardial fibrosis has been linked to
nutritional deficiencies and/or inflammation
related to helminthic infections (e.g.,
hypereosinophilia); worldwide, it is the most
common form of restrictive cardiomyopathy.
26. • Loeffler endomyocarditis also exhibits
endocardial fibrosis, typically associated with
formation of large mural thrombi.
• It is characterized by peripheral
hypereosinophilia and eosinophilic tissue
infiltrates; release of eosinophil granule
contents, especially major basic protein,
probably engenders endocardial and
myocardial necrosis, followed by scarring,
layering of the endocardium by thrombus, and
finally thrombus organization.
27. • Of interest, some patients have an underlying
hypereosinophilic myeloproliferative
neoplasm driven by gene rearrangements that
lead to expression of constitutively active
tyrosine kinases.
• Treatment of such patients with tyrosine
kinase inhibitors can result in hematologic
remission and reversal of the endomyocardial
lesions.
28. Myocarditis
• Myocarditis encompasses a diverse group of
clinical entities in which infectious agents
and/or inflammatory processes target the
myocardium.
• It is important to distinguish myocarditis from
conditions such as IHD, where the
inflammatory process is secondary to some
other cause of myocardial injury.
29. Pathogenesis
• In the United States, viral infections are the
most common cause of myocarditis, with
coxsackieviruses A and B and other
enteroviruses accounting for a majority of
the cases.
• Cytomegalovirus (CMV), human
immunodeficiency virus (HIV), influenza virus,
and others are less common pathogens.
30. • Noninfectious causes of myocarditis include
systemic diseases of immune origin, such as
systemic lupus erythematosus and
polymyositis. Drug hypersensitivity reactions
affecting the heart (hypersensitivity
myocarditis) may occur with exposure to a
wide range of agents.
31. Clinical Features
• The clinical spectrum of myocarditis is broad; at
one end, the disease is asymptomatic, and
patients recover without sequelae. At the other
extreme is the precipitous onset of heart failure
or arrhythmias, occasionally with sudden death.
• Fatigue, dyspnea, palpitations, pain, and fever.
• Other causes if myocardial diseases
• Cardiotoxic Drugs
• Catecholamines
32. PERICARDIAL DISEASE
• Pericardial lesions typically are associated
with a pathologic process elsewhere in the
heart or surrounding structures, or are
secondary to a systemic disorder.
33. Pericardial Effusion and
Hemopericardium
• Normally, the pericardial sac contains less
than 50 cc of thin, clear, straw-colored fluid.
Under various circumstances, the pericardial
sac may be distended by accumulations of
serous fluid (pericardial effusion), blood
(hemopericardium), or pus (purulent
pericarditis).
34. • Pericardial effusions and their causes include
the following:
• Serous: Congestive heart failure,
hypoalbuminemia of any cause
• Serosanguineous: Blunt chest trauma,
malignancy, ruptured MI, or aortic dissection
• Chylous: Mediastinal lymphatic obstruction
35. • Thus, with chronic effusions of less than 500 cc in
volume, the only clinical significance is a
characteristic globular enlargement of the heart
shadow on chest radiograph. In contrast, rapidly
developing fluid collections of as little as 200 to
300 cc (e.g., due to hemopericardium caused by a
ruptured MI or aortic dissection) can produce
clinically devastating compression of the thin-
walled atria and venae cavae, or the ventricles
themselves; cardiac filling is thereby restricted,
producing potentially fatal cardiac tamponade.
36. Pericarditis
• Primary peri-carditis is uncommon. It is typically
due to viral infection (often with concurrent
myocarditis), although bacteria, fungi, or
parasites may also be involved.
• In most cases, pericarditis is secondary to acute
MI or cardiac surgery (so-called “Dressler’s
syndrome”), radiation to the mediastinum, or
processes involving other thoracic structures
(e.g., pneumonia or pleuritis).
37. • Pericarditis can (1) cause immediate
hemodynamic complications if it elicits a large
effusion (resulting in cardiac tamponade), (2)
resolve without significant sequelae, or 3)
progress to a chronic fibrosing process.
38. Clinical Features
• Atypical chest pain (not related to exertion
and worse in recumbency).
• Chronic constrictive pericarditis produces a
combination of right-sided venous distention
and low cardiac output, similar to the clinical
picture in restrictive cardiomyopathy.
39. CARDIAC TUMORS
Primary Neoplasms
• These are myxomas (adult heart), fibromas,
lipomas, papillary fibroelastomas, and
rhabdomyomas (tumors of the heart in infants
and children).
• Angiosarcomas constitute the most common
primary malignant tumor of the heart
40. Clinical Features
• The major clinical manifestations of myxomas
are due to valvular “ball-valve” obstruction,
embolization, or a syndrome of constitutional
signs and symptoms including fever and
malaise.
42. Pathogenesis
• The mediators elaborated by carcinoid tumors
include serotonin (5-hydroxytryptamine),
kallikrein, bradykinin, histamine,
prostaglandins, and tachykinins.
43. CARDIAC TRANSPLANTATION
• Although permanent ventricular assist device
implantation is increasingly an option for
management of end-stage heart disease,
cardiac transplantation remains the treatment
of choice for patients with intractable heart
failure.
• The major complications of cardiac
transplantation are acute cardiac rejection
and allograft arteriopathy.
44. • Rejection is characterized by interstitial
lymphocytic inflammation, myocyte damage and
a histologic pattern similar to that seen in viral
myocarditis. Both T cell- and antibody responses
to the allograft are involved in the rejection
reaction.
• Allograft arteriopathy is the single most
important longterm limitation for cardiac
transplantation. It is marked by late, progressive,
diffusely stenosing intimal proliferation in the
coronary arteries, leading to ischemic injury.
