Cardiomyopathies are diseases of the heart muscle that can have various causes including genetic factors, infections like myocarditis, and systemic conditions. There are three main types - dilated cardiomyopathy where the heart chambers dilate, hypertrophic cardiomyopathy where the heart muscle thickens, and restrictive cardiomyopathy where the heart muscle stiffens. Myocarditis refers specifically to inflammation of the heart muscle which can cause cardiomyopathy in some cases. The clinical features and causes of each type are diverse.

4. CARDIOMYOPATHIES
Most cardiac disease is secondary to some other
condition (e.g., coronary atherosclerosis,
hypertension, or valvular heart disease). However,
there are some that are attributable to intrinsic
myocardial dysfunction. Such myocardial diseases
are termed cardiomyopathies (literally, heart
muscle diseases). They are a diverse group that
includes inflammatory disorders (myocarditis),
immunologic diseases (e.g., sarcoidosis), systemic
metabolic disorders (e.g., hemochromatosis),
muscular dystrophies, and genetic disorders of
cardiac muscle cells. In many cases,
cardiomyopathies are of unknown etiology
(termed idiopathic); however, several previously
"idiopathic" cardiomyopathies have been shown to
be caused by specific genetic abnormalities in
cardiac energy metabolism or structural and
contractile proteins.

5. CARDIOMYOPATHIES
classification divides cardiomyopathies
into three groups :
Dilated cardiomyopathy
Hypertrophic cardiomyopathy
Restrictive cardiomyopathy

6. CARDIOMYOPATHIES
Among these, dilated cardiomyopathy
is most common (90% of cases), and
restrictive cardiomyopathy is the least
frequent. Within each pattern there is a
spectrum of clinical severity, and each
of these three patterns can be caused by
a specific identifiable cause or can be
idiopathic (Table 11-5). While the recent
American Heart Association
classification is intellectually more
satisfying, we follow here the time-
honored clinicopathologic classification
since, at present, it is more useful for
patient management.

7. Before we go into further details, some
comments are in order about
myocarditis. They are included here
under the umbrella of
cardiomyopathies since there is
clinical overlap between some cases of
myocarditis and dilated
cardiomyopathy and in a proportion
of cases, dilated cardiomyopathy can
be shown to evolve from acute
myocarditis. Indeed, since experts at
the American Heart Association also
include myocarditis among
cardiomyopathies, we seem to be in
good company

9. Dilated cardiomyopathy (DCM) is
characterized by progressive cardiac dilation
and contractile (systolic) dysfunction,
usually with concurrent hypertrophy. It is
sometimes called congestive
cardiomyopathy. Approximately 25% to 35%
of DCM cases have a familial (genetic) basis.
Others result from a variety of acquired
myocardial insults including toxic exposures
(e.g., chronic alcoholism), myocarditis, and
pregnancy-associated changes (see later). In
some patients, the cause of DCM is
unknown. Such cases are appropriately
called idiopathic dilated cardiomyopathy.
Many in this category are likely to be of
genetic origin. Regardless of the cause, all
share a similar clinicopathologic picture.

10. The heart in DCM is characteristically
enlarged (two to three times its
normal weight) and flabby, with
dilation of all chambers .
Because of the wall thinning that
accompanies dilation, the ventricular
thickness may be less than, equal to, or
greater than normal. Mural thrombi
are common and may be a source of
thromboemboli. By definition there is
no primary valve pathology;
consequently, any valvular
insufficiency is a secondary
consequence of ventricular chamber
dilation. The coronary arteries are
usually free of significant
atherosclerotic stenosis.

11. The histologic abnormalities in
DCM are nonspecific.
Microscopically most myocytes are
hypertrophied with enlarged
nuclei, but many are attenuated,
stretched, and irregular. There is
variable interstitial and endocardial
fibrosis; scattered scars are also often
present, probably marking previous
myocyte ischemic necrosis caused by
reduced perfusion (due to poor
contractile function) and increased
demand (due to myocyte
hypertrophy). The extent of the
changes frequently does not reflect
the degree of dysfunction or the
patient's prognosis.

12. When discovered clinically, DCM is frequently at its end stage, and many hearts show
only the nonspecific findings described above. As a result the etiology can often only
be inferred by the patient's medical history, or it is based on epidemiologic evidence.
The causes of DCM can be grouped into four broad categories:
Viral. The nucleic acid "footprints" from
coxsackievirus B and other enteroviruses can
occasionally be detected in the myocardium.
Moreover, sequential endomyocardial
biopsies have documented cases where there
is progression from myocarditis to DCM.
Consequently, some cases of DCM are
attributed to myocarditis ; even without
direct evidence of inflammation, simply
finding viral transcripts may be sufficient to
invoke a myocarditis that was "missed" in its
early stages .

13. Alcohol or other toxic exposure. Alcohol
abuse is strongly associated with
development of DCM. Alcohol and its
metabolites, especially
acetaldehyde, have a direct toxic effect
on myocardium. Moreover, chronic
alcoholism can be associated with
thiamine deficiency, introducing an
element of beriberi heart disease
.Nevertheless, the cause-and-effect
relationship with alcohol alone is
debated, and no morphologic features
serve to distinguish alcoholic
cardiomyopathy from DCM of any other
cause. Nonalcoholic toxic insults
include certain chemotherapeutic
agents, particularly doxorubicin
(Adriamycin), and cobalt

14. Genetic influences. Familial forms of DCM account for 25% to 35% of
cases; autosomal dominant inheritance is the predominant pattern; X-
linked, autosomal recessive, and mitochondrial inheritances are less
common.
Most of the genetic abnormalities seem to involve the myocyte
cytoskeleton. Although not the most common form, X-linked DCM
caused by mutation in the dystrophin gene is the best understood.
Dystrophin is an intracellular structural protein that plays a critical role in
linking the cytoskeleton of striated muscle with the extracellular matrix;
indeed, dystrophin is mutated in the most common muscular dystrophies
.Interestingly, some patients with dystrophin gene mutations have DCM as
the primary clinical feature. Other cytoskeletal proteins involved in DCM
include α-cardiac actin (links the sarcomere with dystrophin), desmin (the
principal intermediate-filament protein in cardiac myocytes), and the
nuclear lamins A and C. Mitochondrial gene deletions and mutations in
genes encoding enzymes involved in fatty acid beta-oxidation can
presumably cause DCM by altering myocardial ATP generation

15. Peripartum cardiomyopathy
occurs late in gestation or several
weeks to months postpartum. The
etiology is multifactorial, including
pregnancy-associated hyper-
tension, volume overload, nutritional
deficiency, other metabolic
derangement, and/or an immunologic
response (e.g., abnormal cytokine
production).
Fortunately, approximately half of
these patients spontaneously recover
normal function

16. Clinical Features
DCM can occur at any age, including in
childhood, but it most commonly occurs
between ages 20 and 50 years. It typically
presents with slowly progressing (e.g.,
shortness of breath and poor exertional
capacity), but patients can slip precipitously
from a compensated to a decompensated
state. The fundamental defect in DCM is
ineffective contraction. Hence in end-stage
DCM, the cardiac ejection fraction is
typically less than 25%. Secondary mitral
regurgitation and abnormal cardiac rhythms
are common, and embolism from
intracardiac thrombi can occur. Fifty percent
of patients die within 2 years, and only 25%
survive longer than 5 years;
Death is usually due to progressive cardiac
failure or arrhythmia. In most cases cardiac
transplantation is the only definitive
treatment.

18. Hypertrophic cardiomyopathy (HCM)
(also known as idiopathic
hypertrophic subaortic stenosis) is
characterized by myocardial
hypertrophy, abnormal diastolic filling,
and-in a third of cases-ventricular
outflow obstruction. As discussed
below, the obstruction, in some cases,
is dynamic, caused by the anterior
leaflet of the mitral valve. The heart is
thick-walled, heavy, and hyper
contracting, in striking contrast to the
flabby, poorly contractile heart in
DCM. Systolic function is usually
preserved in HCM, but the
myocardium does not relax and
therefore shows primary diastolic
dysfunction.

19. The essential gross feature of HCM is
massive myocardial hypertrophy without
ventricular dilation .The classic pattern of
HCM involves disproportionate thickening
of the ventricular septum relative to the left
ventricle free wall (so-called asymmetrical
septal hypertrophy); nevertheless, in
about 10% of cases there is concentric
hypertrophy. On longitudinal sectioning,
the ventricular cavity loses its usual round-
to-ovoid shape and is compressed into a
"banana-like" configuration .Often present
is an endocardial plaque in the left
ventricular outflow tract, as well as a
thickening of the anterior mitral leaflet.
Both findings reflect contact of the anterior
mitral leaflet with the septum during
ventricular systole and correlate with
functional left ventricular outflow tract
obstruction.

20. The characteristic
histologic features in
HCM are severe
myocyte
hypertrophy,
myocyte (and
myofiber) disarray,
and interstitial and
replacement fibrosis

21. Almost all cases of HCM are caused Although it is clear that these
by missense point mutations in one genetic defects underlie HCM,
of several genes encoding the the sequence of events leading
sarcomeric proteins that form the from mutations to disease is still
contractile apparatus of striated poorly understood. A current
muscle .In most cases, the pattern of proposal suggests that HCM
transmission is autosomal dominant represents a compensatory
with variable expression. Greater change in response to impaired
than 100 causal mutations have been contractility. In this model,
identified in at least 12 sarcomeric ineffective myocyte contraction
genes , with the β-myosin heavy triggers exuberant growth factor
chain being most frequently release with subsequent intense
affected, followed by myosin- compensatory hypertrophy
binding protein C and troponin T. (causing myofiber disarray) and
These three genes account for 70% fibroblast proliferation (causing
to 80% of all cases of HCM. interstitial fibrosis).

22. HCM is characterized by a massively hypertrophied left
ventricle that paradoxically provides a markedly reduced
stroke volume. This pathophysiologic effect is a direct
consequence of impaired diastolic filling and overall smaller
chamber size. In addition, roughly 25% of patients have
dynamic obstruction to the left ventricular outflow by the
anterior leaflet of the mitral valve. Reduced cardiac output
and a secondary increase in pulmonary venous pressure
cause exertional dyspnea, and there is a harsh systolic
ejection murmur. A combination of massive hypertrophy,
high left ventricular pressures, and compromised
intramural coronary arteries frequently leads to myocardial
ischemia (with angina), even in the absence of concomitant
coronary artery disease. Major clinical problems include
atrial fibrillation with mural thrombus formation, IE of the
mitral valve, CHF, arrhythmias, and sudden death. Most
patients are improved by therapy that promotes ventricular
relaxation; occasionally, partial surgical excision of septal
muscle is necessary to relieve the outflow tract obstruction.

24. Restrictive cardiomyopathy is
characterized by a primary decrease in
ventricular compliance, resulting in
impaired ventricular filling during diastole
(simply put, the wall is stiffer). The
contractile (systolic) function of the left
ventricle is usually unaffected. Thus, the
functional state can be confused with that
of constrictive pericarditis or hypertrophic
cardiomyopathy. Restrictive
cardiomyopathy can be idiopathic or
associated with systemic diseases that also
happen to affect the myocardium-for
example, radiation
fibrosis, amyloidosis, hemochromatosis, sa
rcoidosis, or products of inborn errors of
metabolism. For each of these causes, the
curious reader is referred to the more
complete discussion in the relevant
chapters. Genetic factors are less clearly
defined in restrictive cardiomyopathy.

25. In idiopathic restrictive cardiomyopathy
the ventricles are of approximately
normal size or slightly enlarged, the
cavities are not dilated, and the
myocardium is firm. Biatrial dilation is
commonly observed.
Microscopically there is interstitial
fibrosis, varying from minimal and
patchy to extensive and diffuse.
Restrictive cardiomyopathy of disparate
causes may have similar gross
morphology. However, endomyocardial
biopsy can reveal disease-specific
features (e.g., amyloid, iron
overload, sarcoid granulomas).

28. In myocarditis there is
inflammation of the myocardium
with resulting injury. It is
important, however, to emphasize
that the presence of inflammation
alone is not diagnostic of
myocarditis; for example,
inflammatory infiltrates can also
occur as a secondary response to
ischemic injury. In myocarditis, the
inflammatory process is the cause
of-rather than a response to-
myocardial injury.

29. During active myocarditis the heart may
appear normal or dilated. The
ventricular myocardium is typically
flabby and often mottled by patchy or
diffuse foci of pallor and/or
hemorrhage. Mural thrombi can be
present.
Microscopically, active myocarditis
shows an interstitial inflammatory
infiltrate, with focal necrosis of
myocytes adjacent to the inflammatory
cells

30. Lymphocytic myocarditis is most
common .If the patient survives the acute
phase of myocarditis, the inflammatory
lesions either resolve, leaving no residual
changes, or heal by progressive fibrosis.
Lymphocytic myocarditis

31. Hypersensitivity myocarditis has
interstitial and perivascular infiltrates
composed of lymphocytes, macrophages,
and a high proportion of eosinophils
Hypersensitivity myocarditis

32. Giant-cell myocarditis is a
morphologically distinctive entity
characterized by widespread
inflammatory cellular infiltrates
containing multinucleate giant cells
(formed by macrophage fusion)
interspersed with lymphocytes,
eosinophils, and plasma cells. Giant-cell
myocarditis probably represents the
aggressive end of the spectrum of
lymphocytic myocarditis, and there is at
least focal-and frequently extensive-
necrosis .This variant carries a poor
prognosis
Giant-cell myocarditis

33. Chagas myocarditis is distinctive by
virtue of the parasitization of scattered
myofibers by trypanosomes
accompanied by an inflammatory
infiltrate of neutrophils, lymphocytes,
macrophages, and occasional
eosinophils
Chagas myocarditis

35. The clinical spectrum of myocarditis is
broad. At one end, the disease is
asymptomatic and patients recover
without sequelae, and at the other end is
the precipitous onset of heart failure or
arrhythmias, occasionally with sudden
death. Between these extremes are the
many forms of presentation, associated
with a variety of symptoms
(e.g., fatigue, dyspnea, palpitations, pain,
and fever). The clinical features of
myocarditis can even mimic those of
acute MI. Occasionally, over many
years, patients can progress from
myocarditis to DCM.

37. Metastatic Neoplasms
The most common tumor of the
heart is a metastatic tumor; tumor
metastases to the heart occur in
about 5% of patients dying of
cancer. Although any malignancy
can secondarily involve the heart,
certain tumors have a higher
predilection to spread to the heart.
In descending order these tumors
are carcinoma of the lung,
lymphoma, breast cancer,
leukemia, melanoma, carcinomas
of the liver, and colon.

38. Primary Neoplasms
Primary cardiac tumors are uncommon; in
addition, most primary cardiac tumors are
also (thankfully) benign. The five most
common have no malignant potential and
account for 80% to 90% of all primary heart
tumors. In descending order of frequency
(adults) the primary cardiac tumors are:
myxomas, fibromas, lipomas, papillary
fibroelastomas, rhabdomyomas, and
angiosarcomas (this last one is malignant).
Only the myxomas and rhabdomyomas will
receive any significant attention here.

39. Myxomas
Myxomas are the most common
primary tumor of the adult heart
.Roughly 90% are located in the
atria, with the left atrium
accounting for 80% of those.
Myxomas are almost always single and are
most commonly located at the fossa ovalis
(atrial septum). They range from small (<1
cm) to impressive (≤10 cm), sessile or
pedunculated masses .and can vary from
globular hard masses to soft, translucent,
villous lesions with a gelatinous appearance.
Pedunculated forms are often sufficiently
mobile to swing into the mitral or tricuspid
valves during systole, causing intermittent
obstruction. Sometimes such mobility exerts
a "wrecking-ball" effect, causing damage to
the valve leaflets.

40. Histologically myxomas are
composed of stellate,
multinucleated myxoma cells
with hyperchromatic nuclei,
admixed with cells showing
endothelial, smooth muscle,
and/or fibroblastic
differentiation, all embedded in
an abundant acid
mucopolysaccharide ground
substance .Hemorrhage, poorly
organizing thrombus, and
mononuclear inflammation are
also usually present.

41. Clinical Features
The major clinical manifestations are
due to valvular "ball-valve"
obstruction, embolization, or a
syndrome of constitutional
symptoms, such as fever and malaise.
Constitutional symptoms are
probably due to the elaboration of
interleukin-6, a major mediator of the
acute-phase response.
Echocardiography is the diagnostic
modality of choice, and surgical
resection is almost uniformly
curative.

42. Rhabdomyomas
Rhabdomyomas are the most frequent
primary tumor of the heart in infants
and children; they are frequently
discovered because of an obstruction of
a valvular orifice or cardiac chamber.
Cardiac rhabdomyomas occur with high
frequency in patients with tuberous
sclerosis .Rhabdomyomas are probably
better classified as hamartomas or
malformations rather than true
neoplasms; recent work suggests that
these lesions may be caused by
defective apoptosis during
developmental remodeling.

43. Morphology
Rhabdomyomas are generally small,
gray-white myocardial masses up to
several centimeters in diameter that
protrude into the ventricular chambers.
Histologically they have a mixed
population of cells; the most
characteristic of which are large,
rounded, or polygonal cells containing
numerous glycogen-laden vacuoles
separated by strands of cytoplasm
running from the plasma membrane to
the more or less centrally located
nucleus. These are the so-called spider
cells.

45. An estimated five million people in the
United States have heart failure, and 300,000
die each year as a direct consequence.
Cardiac transplantation is increasingly an
option for these patients (mostly for IHD and
dilated cardiomyopathy), with roughly 2000
performed annually in the U.S. (3000 a year
worldwide). A brief look at the numbers
suggests that many more patients die while
on a waiting list (estimated at 50,000 per
year) than are successfully transplanted.
Indeed, even though the demand for hearts
has doubled in the last decade, largely as a
result of better ways to support patients in
severe failure, the actual supply has dropped
Beyond the issues of supply and demand, the
major complications of cardiac
transplantation are acute cardiac rejection
and graft coronary arteriosclerosis

46. Rejection is typically diagnosed by
endomyocardial biopsy of the
transplanted heart; it is characterized
by an interstitial lymphocytic
inflammation with associated myocyte
damage .The histology is similar to that
seen in viral myocarditis .In both
instances, T-cell-mediated killing and
local cytokine production can
materially compromise cardiac
function. When myocardial injury is not
extensive, the "rejection episode" can be
reversed by immunosuppressive
therapy. Advanced rejection can be
irreversible and fatal.

47. Cardiac allograft rejection typified by lymphocytic infiltrate, with
associated damage to cardiac myocytes. Note the similarity between
rejection and typical viral myocarditis

48. Graft coronary arteriosclerosis, demonstrating severe diffuse
concentric intimal thickening producing critical stenosis. The
internal elastic lamina (arrow) and media are intact .

49. Graft coronary arteriosclerosis (GCA) is the Despite these problems,
single most important long-term limitation the outlook for
for cardiac transplantation. It is a late, transplanted patients is
progressive, diffusely stenosing intimal generally good, with a 1-
proliferation in the coronary arteries, year survival of 80% and
leading to ischemic injury. Within 5 years 5-year survivals of more
of transplantation, 50% of patients have than 60% (compared
significant GCA, and virtually all patients with 50% and <10%,
have lesions within 10 years. The respectively, in medically
pathogenesis of GCA involves immunologic managed end-stage
responses that induce local production of heart failure).
growth factors that promote intimal
smooth muscle cell recruitment and
proliferation with extracellular matrix
synthesis. GCA is a particularly vexing
problem, because it can lead to silent MI
(transplant patients have denervated
hearts and do not experience angina),
progressive CHF, or SCD.