Basic Science and Forensic Pathology Aspects of Cardiomyopathies

Basic Science and Forensic
Pathology Aspects of
Cardiomyopathies
Luchenga Adam Mucheleng’anga
Clinical Fellow of Forensic Pathology
University of Toronto.

Disclaimer
This is not original work as it is book lifted from the
books listed at the end. This material is study notes
The PowerPoint is meant to ease the learning
process.

• Basic Science of Cardiomyopathies

Basic Science of
Cardiomyopathies
• Cardiomyopathies
• Although the term cardiomyopathy
(literally, heart muscle disease) has
been historically applied to any
cardiac dysfunction resulting from a
myocardial abnormality, a more
nuanced definition is probably
appropriate.
• Thus stimulated by the recognition of
new phenotypes and the advent of
more sophisticated molecular
characterization—an expert panel has
suggested: “Cardiomyopathies are a
heterogeneous group of diseases of
the myocardium associated with
mechanical and/or electrical
dysfunction that usually (but not
invariably) exhibit inappropriate
ventricular hypertrophy or dilatation
and are due to a variety of causes that
frequently are genetic.

Basic Science of
Cardiomyopathies
• Cardiomyopathies either are confined
to the heart or are part of generalized
systemic disorders, often leading to
cardiovascular death or progressive
heart failure-related disability.
• Thus, cardiomyopathies manifest as
failure of myocardial performance; this
can be mechanical (e.g., diastolic or
systolic dysfunction) leading to CHF, or
can culminate in life-threatening
arrhythmias.
• Primary cardiomyopathies can be
genetic or acquired diseases of
myocardium, whereas secondary
cardiomyopathies have myocardial
involvement as a component of a
systemic or multiorgan disorder.

Basic Science of
Cardiomyopathies
• Cardiomyopathies either are confined to the heart or
are part of generalized systemic disorders, often
leading to cardiovascular death or progressive heart
failure-related disability.
• Thus, cardiomyopathies manifest as failure of
myocardial performance; this can be mechanical
(e.g., diastolic or systolic dysfunction) leading to CHF,
or can culminate in life-threatening arrhythmias.
• Primary cardiomyopathies can be genetic or acquired
diseases of myocardium, whereas secondary
cardiomyopathies have myocardial involvement as a
component of a systemic or multiorgan disorder.

Basic Science of Cardiomyopathies
• A major advance in our understanding of
cardiomyopathies stems from the frequent
identification of underlying genetic causes, including
mutations in myocardial proteins involved in
contraction, cell-cell contacts, and the cytoskeleton.
• These, in turn, lead to abnormal contraction or
relaxation, or to dysregulated ion transport across
cell membranes.
• Although chronic myocardial dysfunction secondary
to ischemia, valvular abnormalities, or hypertension
can cause significant ventricular dysfunction, these
conditions should not be denoted as
cardiomyopathies.

• Cardiomyopathies can be classified according to a variety of
criteria, including the underlying genetic basis of dysfunction;
inducing channelopathies, which may be included in
cardiomyopathies.
• However, we will confine our list of cardiomyopathies to
disorders that produce anatomic abnormalities in the heart.
• These fall into three pathologic patterns; Dilated
cardiomyopathy (including arrhythmogenic right ventricular
cardiomyopathy); Hypertrophic cardiomyopathy; and
Restrictive cardiomyopathy

• Among the three major patterns, 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 in some cases clinical
features overlap among the groups.
• In addition, each of these patterns can be
caused by a specific identifiable cause, or can
be idiopathic.

Cardiomyopathy and Indirect Myocardial
Dysfunction: Functional Patterns and Causes

Basic Science of
Cardiomyopathies
• Dilated Cardiomyopathy
• Dilated cardiomyopathy (DCM) is
characterized morphologically and
functionally by progressive cardiac
dilation and contractile (systolic)
dysfunction, usually with concomitant
hypertrophy.
• Many cases are familial, but the DCM
phenotype can result from diverse
causes, both primary and secondary.

Basic Science of
Cardiomyopathies
Dilated Cardiomyopathy
Pathogenesis.
By the time of diagnosis, DCM has typically
progressed to end-stage disease; the heart is dilated
and poorly contractile.
Unfortunately, at that point, even an exhaustive
evaluation frequently fails to suggest a specific
etiology.
Increasingly, familial (genetic) forms of DCM are
recognized, but the final pathology can also result
from various acquired myocardial insults; as this
implies, several different pathways can lead to DCM.

• Pathogenesis.
• Genetic Inﬂuences.
• DCM is familial in at least 30% to 50% of cases,
in which it is caused by mutations in a diverse
group of more than 20 genes encoding proteins
involved in the cytoskeleton, sarcolemma, and
nuclear envelope (laminin A/C). In particular,
mutations in TTN, a gene that encodes titin (so-
called because it is the largest protein
expressed in humans), may account for
approximately 20% of all cases of DCM

Mutations in titin
account for
approximately 20% of
all dilated
cardiomyopathy.
Titin spans the
sarcomere and connects
the Z and M bands
thereby limiting the
passive range of motion
of the sarcomere as it
is stretched.
Titin also functions like
a molecular spring,
with domains that
unfold when the
protein is stretched and
refold when the tension
is removed, thereby
impacting the passive
elasticity of striated
muscle.

• Pathogenesis.
• In the genetic forms of DCM, autosomal dominant
inheritance is the predominant pattern; X-linked,
autosomal recessive, and mitochondrial inheritance
are less common.
• 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 β-oxidation of
fatty acids.

Basic Science of
Cardiomyopathies
• Pathogenesis.
• Mitochondrial defects typically manifest in the
pediatric population, while X-linked DCM typically
presents after puberty and into early adulthood.
• X-linked cardiomyopathy can also be associated
with mutations affecting the membrane-
associated dystrophin protein that couples
cytoskeleton to the extracellular matrix; recall
that dystrophin is mutated in the most common
skeletal myopathies (i.e., Duchenne and Becker
muscular dystrophies.

• Pathogenesis.
• Some patients and families with dystrophin
gene mutations have DCM as the primary
clinical feature.
• Interestingly, and probably resulting from the
common developmental origin of contractile
myocytes and conduction elements,
congenital abnormalities of conduction may
also be associated with DCM.

• Pathogenesis.
• Myocarditis.
• Sequential endomyocardial biopsies have
documented progression from myocarditis to
DCM.
• In other studies, the detection of the genetic
fingerprints of coxsackie B and other viruses
within myocardium of patients with DCM
suggests that viral myocarditis can be causal.

• Pathogenesis.
• Alcohol and other toxins.
• Alcohol abuse is strongly associated with the
development of DCM, raising the possibility that
ethanol toxicity or a secondary nutritional
disturbance can underlie myocardial injury.
• Alcohol or its metabolites (especially acetaldehyde)
have a direct toxic effect on the myocardium.
• Moreover, chronic alcoholism may be associated with
thiamine deficiency, which can lead to beriberi heart
disease (also indistinguishable from DCM).

Basic Science of
Cardiomyopathies
Pathogenesis.
Alcohol and other toxins.
Nevertheless, no morphologic features serve to distinguish
alcoholic cardiomyopathy from DCM of other causes.
In other cases, some other toxic insult can progress to eventual
myocardial failure.
Particularly important is myocardial injury caused by certain
chemotherapeutic agents, including doxorubicin (Adriamycin), and
even targeted cancer therapeutics (e.g., tyrosine kinase inhibitors).
Cobalt is an example of a heavy metal with cardiotoxicity and has
caused DCM in the setting of inadvertent tainting (e.g., in beer
production).

Pathogenesis.
Childbirth.
A special form of DCM, termed peripartum cardiomyopathy, can occur late in pregnancy or up to months
postpartum.
The mechanism underlying this entity is poorly understood but is probably multifactorial.
Pregnancy-associated hypertension, volume overload, nutritional deficiency, other metabolic
derangements, or an as yet poorly characterized immunological reaction have been proposed as causes.

Basic Science of
Cardiomyopathies
Pathogenesis.
Childbirth.
Recent work suggests that the primary defect is a microvascular
angiogenic imbalance within the myocardium leading to functional
ischemic injury.
Thus, peripartum cardiomyopathy can be elicited in mouse models by
increased levels of circulating antiangiogenic mediators including
vascular endothelial growth factor inhibitors (e.g., sFLT1, as occurs
with preeclampsia) or antiangiogenic cleavage products of the
hormone prolactin (which rises late in pregnancy).

Basic Science of
Cardiomyopathies
Pathogenesis.
Childbirth.
Proangiogenic approaches, including the
blockade of prolactin secretion by
bromocriptine, represent new therapeutic
strategies for treating this disease.

• Pathogenesis.
• Iron overload
• In the heart can result from either hereditary hemochromatosis or
from multiple transfusions.
• DCM is the most common manifestation of such iron excess, and
may be caused by interference with metal-dependent enzyme
systems or to injury from iron-mediated production of reactive
oxygen species.

Basic Science of
Cardiomyopathies
Pathogenesis.
Supraphysiologic stress
This can happen with persistent tachycardia, hyperthyroidism, or
even during development, as in the foetuses of insulin dependent
diabetic mothers.
Excess catecholamines, in particular, may result in multifocal
myocardial contraction band necrosis that can eventually progress
to DCM.
This can happen in individuals with pheochromocytomas, tumors
that elaborate epinephrine; use of cocaine or vasopressor agents
such as dopamine can have similar consequences.

Basic Science of
Cardiomyopathies
• Pathogenesis.
• Supraphysiologic stress
• Such “catecholamine effect” also
occurs in the setting of intense
autonomic stimulation, for example,
secondary to intracranial lesions or
emotional duress.
• Thus, takotsubo cardiomyopathy is
an entity characterized by left
ventricular contractile dysfunction
following extreme psychological
stress; affected myocardium may be
stunned or show multifocal
contraction band necrosis.

Basic Science of
Cardiomyopathies
• Pathogenesis.
• Supraphysiologic stress
• For unclear reasons, the left
ventricular apex is most often affected
leading to “apical ballooning” that
resembles a “takotsubo,”
• Japanese for “fishing pot for trapping
octopus” (hence, the name).
• The mechanism of catecholamine
cardiotoxicity is uncertain, but likely
relates either to direct myocyte toxicity
due to calcium overload or to focal
vasoconstriction in the coronary
arterial macro- or microcirculation in
the face of an increased heart rate.

Basic Science of
Cardiomyopathies
Pathogenesis.
Supraphysiologic stress
Similar changes may be encountered in individuals who
have recovered from hypotensive episodes or have
been resuscitated from a cardiac arrest; in such cases,
the damage is a result of ischemia-reperfusion with
subsequent inﬂammation.

Basic Science of
Cardiomyopathies
Morphology
In DCM the heart is usually enlarged,
heavy (often weighing two to three times
normal), and ﬂabby, due to dilation of all
chambers.
Mural thrombi are common and may be
a source of thromboemboli.
There are no primary valvular alterations; if
mitral (or tricuspid) regurgitation is present,
it results from left (or right) ventricular
chamber dilation (functional regurgitation).

Basic Science of
Cardiomyopathies
Morphology
Either the coronary arteries are free of
significant narrowing or the obstructions
present are insufficient to explain the
degree of cardiac dysfunction.
The histologic abnormalities in DCM are nonspecific and
usually do not point to a specific etiology.
Most muscle cells are hypertrophied with
enlarged nuclei, but some are attenuated,
stretched, and irregular.

Basic Science of
Cardiomyopathies
• Morphology
• Interstitial and endocardial
fibrosis of variable degree is
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.
• Moreover, the severity of
morphologic changes may not
reﬂect either the degree of
dysfunction or the patient’s
prognosis.

Basic Science of
Cardiomyopathies
Clinical Features.
DCM can occur at any age, including in
childhood, but it most commonly affects
individuals between the ages of 20 and 50.
It presents with slowly progressive signs and
symptoms of CHF including dyspnea, easy
fatigability, and poor exertional capacity.
At the end stage, ejection fractions are
typically less than 25% (normal = 50% to 65%).

Basic Science of
Cardiomyopathies
Clinical Features.
Secondary mitral regurgitation and abnormal
cardiac rhythms are common, and embolism
from intracardiac thrombi can occur.
Death usually results from progressive cardiac
failure or arrhythmia, and can occur suddenly.
Although the annual mortality is high (10% to
50%), some severely affected patients respond
well to pharmacologic therapy.

Basic Science of
Cardiomyopathies
Clinical Features.
Cardiac transplantation is also increasingly
performed, and long-term ventricular assist
can be beneficial.
Interestingly, in some patients, relatively
short-term mechanical cardiac support can
induce durable improvement of cardiac
function.

Basic Science of
Cardiomyopathies
Arrhythmogenic Right Ventricular
Cardiomyopathy
Arrhythmogenic right ventricular
cardiomyopathy (ARVC) is an inherited
disease of myocardium causing right
ventricular failure and rhythm disturbances
(particularly ventricular tachycardia or
fibrillation) with sudden death.
Left-sided involvement with left-sided heart
failure may also occur.

Basic Science of
Cardiomyopathies
Cardiomyopathy
Morphologically, the right ventricular
wall is severely thinned due to loss of
myocytes, accompanied by extensive
fatty infiltration and fibrosis.
Although myocardial inﬂammation may
be present, ARVC is not considered an
inﬂammatory cardiomyopathy.
Classical ARVC has autosomal dominant
inheritance with a variable penetrance.

Basic Science of
Cardiomyopathies
Cardiomyopathy
The disease has been attributed to defective
cell adhesion proteins in the desmosomes that
link adjacent cardiac myocytes.
Naxos syndrome is a disorder characterized by
arrhythmogenic right ventricular
cardiomyopathy and hyperkeratosis of plantar
palmar skin surfaces specifically associated
with mutations in the gene encoding the
desmosome-associated protein plakoglobin.

Basic Science of
Cardiomyopathies
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a common
(incidence, 1 in 500), clinically heterogeneous, genetic
disorder characterized by myocardial hypertrophy, poorly
compliant left ventricular myocardium leading to abnormal
diastolic filling, and (in about one third of cases)
intermittent ventricular outﬂow obstruction.
It is the leading cause of left ventricular hypertrophy
unexplained by other clinical or pathologic causes.
The heart is thick-walled, heavy, and hyper-contracting, in
striking contrast to the ﬂabby, hypo-contracting heart of
DCM.

Basic Science of
Cardiomyopathies
HCM causes primarily diastolic dysfunction; systolic
function is usually preserved.
The two most common diseases that must be
distinguished clinically from HCM are deposition
diseases (e.g., amyloidosis, Fabry disease) and
hypertensive heart disease coupled with age-
related subaortic septal hypertrophy.
Occasionally, valvular or congenital subvalvular
aortic stenosis can also mimic HCM.

Basic Science of
Cardiomyopathies
• Hypertrophic Cardiomyopathy
• Pathogenesis.
• In most cases, the pattern of transmission is
autosomal dominant with variable
penetrance.
• HCM is caused by mutations in any one of
several genes that encode sarcomeric
proteins; there are more than 400 different
known mutations in nine different genes,
most being missense mutations.
• Mutations causing HCM are found most
commonly in the gene encoding β-myosin
heavy chain (β-MHC), followed by the genes
coding for cardiac TnT, α-tropomyosin, and
myosin-binding protein C (MYBP-C); overall,
these account for 70% to 80% of all cases.

Basic Science of
Cardiomyopathies
Pathogenesis.
Different affected families may have distinct
mutations involving the same protein.
For example, approximately 50 different
mutations of β-MHC are known to cause
HCM.
The prognosis of HCM varies widely and
correlates strongly with specific mutations.

Basic Science of
Cardiomyopathies
Pathogenesis.
Although it is clear that these genetic defects
are critical to the etiology of HCM, the
sequence of events leading from mutations to
disease is still poorly understood.
HCM is a disease caused by mutations in
proteins of the sarcomere.

Basic Science of
Cardiomyopathies
Pathogenesis.
Although such sarcomeric alterations have been thought to be
pathologic on the basis of abnormal cardiac contraction causing
a secondary compensatory hypertrophy, newer evidence
suggests that HCM may instead arise from defective energy
transferfrom its source of generation (mitochondria) to its site of
use (sarcomeres).
In addition, the interstitial fibrosis in HCM probably occurs
secondary to exaggerated responses of the myocardial
fibroblasts to the primary myocardial dysfunction.

Basic Science of
Cardiomyopathies
Pathogenesis.
In contrast, DCM is mostly associated with
abnormalities of cytoskeletal proteins, and can be
conceptualized as a disease of abnormal force
generation, force transmission, or myocyte signaling.
To complicate matters, mutations in certain genes, can
give rise to either HCM or DCM, depending on the site
and nature of the mutation.

Basic Science of
Cardiomyopathies
Morphology
The essential feature of HCM is massive myocardial
hypertrophy, usually without ventricular dilation.
The classic pattern involves disproportionate thickening of
the ventricular septum relative to the left ventricle free
wall (with a ratio of septum to free wall greater than
3 : 1), termed asymmetric septal hypertrophy.
In about 10% of cases, the hypertrophy is concentric
and symmetrical.

Basic Science of
Cardiomyopathies
Morphology
On longitudinal sectioning, the normally round-to-ovoid
left ventricular cavity may be compressed into a
“banana-like” configuration by bulging of the
ventricular septum into the lumen.
Although marked hypertrophy can involve the entire
septum, it is usually most prominent in the
subaortic region.
The left ventricular outﬂow tract often exhibits a
fibrous endocardial plaque associated with thickening
of the anterior mitral leaﬂet.

Basic Science of
Cardiomyopathies
Morphology
Both findings result from contact of the
anterior mitral leaflet with the septum during
ventricular systole; they correlate with the
echocardiographic “systolic anterior motion”
of the anterior leaflet, with functional left
ventricular outflow tract obstruction during
mid-systole.

Basic Science of
Cardiomyopathies
Morphology
The most important histologic features of HCM
myocardium are:
Massive myocyte hypertrophy, with transverse
myocyte diameters frequently greater than 40 µm
(normal, approximately 15 µm);
Haphazard disarray of bundles of myocytes,
individual myocytes, and contractile elements in
sarcomeres within cells (termed myofiber disarray);
and Interstitial and replacement fibrosis.

Basic Science of
Cardiomyopathies
Clinical Features.
The central abnormality in HCM is reduced
stroke volume due to impaired diastolic
filling.
This is a consequence of a reduced chamber
size, as well as the reduced compliance of
the massively hypertrophied left ventricle.
In addition, approximately 25% of patients
with HCM have dynamic obstruction to the
left ventricular outﬂow.

Basic Science of
Cardiomyopathies
Clinical Features.
The compromised cardiac output in conjunction
with a secondary increase in pulmonary venous
pressure explains the exertional dyspnea seen
in these patients.
Auscultation discloses a harsh systolic ejection
murmur, caused by the ventricular outﬂow
obstruction as the anterior mitral leaﬂet moves
toward the ventricular septum during systole.

Basic Science of
Cardiomyopathies
Clinical Features.
Because of the massive hypertrophy, high left
ventricular chamber pressure, and frequently thick
walled intramural arteries, focal myocardial ischemia
commonly results, even in the absence of concomitant
coronary artery disease.
Major clinical problems in HCM are atrial fibrillation,
mural thrombus formation leading to embolization and
possible stroke, intractable cardiac failure, ventricular
arrhythmias, and, not infrequently, sudden death,
especially with certain specific mutations.

Basic Science of
Cardiomyopathies
Clinical Features.
Indeed, HCM is one of the most common causes of
sudden, otherwise unexplained death in young
athletes.
The natural history of HCM is highly variable.
Most patients can be helped by pharmacologic
intervention (e.g., β-adrenergic blockade) to decrease
heart rate and contractility.
Some benefit can also be gained by reducing the septal
myocardial mass, thus relieving the outﬂow tract
obstruction.
This can be achieved either by surgical excision of
muscle or by carefully controlled septal infarction
through a catheter-based infusion of alcohol.

Basic Science of
Cardiomyopathies
Restrictive Cardiomyopathy
Restrictive cardiomyopathy is characterized by a primary
decrease in ventricular compliance, resulting in impaired
ventricular filling during diastole.
Because the contractile (systolic) function of the left
ventricle is usually unaffected, the functional abnormality
can be confused with that of constrictive pericarditis or
HCM.
Restrictive cardiomyopathy can be idiopathic or
associated with distinct diseases or processes that affect
the myocardium, principally radiation fibrosis,
amyloidosis, sarcoidosis, metastatic tumors, or the
deposition of metabolites that accumulate due to inborn
errors of metabolism.

Basic Science of
Cardiomyopathies
The morphologic features are not
distinctive.
The ventricles are of approximately normal
size or slightly enlarged, the cavities are not
dilated, and the myocardium is firm and
noncompliant.
Bilatrial dilation is commonly observed.

Basic Science of
Cardiomyopathies
Microscopically, there may be only patchy
or diffuse interstitial fibrosis, which can vary
from minimal to extensive.
Endomyocardial biopsy can often reveal a
specific etiology.
An important specific subgroup is
amyloidosis.

Basic Science of
Cardiomyopathies
• Restrictive Cardiomyopathy
• Several other restrictive conditions merit brief
mention.
• Endomyocardial fibrosis is principally a disease
of children and young adults in Africa and
other tropical areas, characterized by fibrosis
of the ventricular endocardium and
subendocardium that extends from the apex
upward, often involving the tricuspid and
mitral valves.
• The fibrous tissue markedly diminishes the
volume and compliance of affected chambers
and socauses a restrictive functional defect.
• Ventricular mural thrombi sometimes develop,
and indeed the endocardial fibrosis may result
from thrombus organization.
• The etiology is unknown.

Basic Science of
Cardiomyopathies
• Several other restrictive conditions merit
brief mention.
• Loefﬂer endomyocarditis also results
in endomyocardial fibrosis, typically
with large mural thrombi, with an
overall morphology similar to the
tropical disease.
• However, in addition to the cardiac
changes, there is often a peripheral
eosinophilia and eosinophilic
infiltrates in multiple organs, including
the heart.
• The release of toxic products of
eosinophils, especially major basic
protein, is postulated to initiate
endomyocardial necrosis, followed by
scarring of the necrotic area, layering
of the endocardium by thrombus, and
finally organization of the thrombus.

Basic Science of
Cardiomyopathies
• Many patients with Loefﬂer
endomyocarditis have a
myeloproliferative disorder
associated with chromosomal
rearrangements involving either
the platelet-derived growth factor
receptor (PDGFR)-α or -β genes.
• These rearrangements produce
fusion genes that encode
constitutively active PDGFR
tyrosine kinases.
• Treatment of such patients with
the tyrosine kinase inhibitor
imatinib has resulted in
hematologic remissions
associated with reversal of the
endomyocarditis, which is
otherwise often rapidly fatal.

Basic Science of
Cardiomyopathies
• Endocardial fibroelastosis is an
uncommon heart disease
characterized by fibroelastic
thickening that typically involves the
left ventricular endocardium.
• It is most common in the first 2 years
of life; in a third of cases, it is
accompanied by aortic valve
obstruction or other congenital
cardiac anomalies.
• Endocardial fibroelastosis may actually
represent a common morphologic
endpoint of several different insults
including viral infections (e.g.,
intrauterine exposure to mumps) or
mutations in the gene for tafazzin,
which affects mitochondrial inner
membrane integrity. Diffuse
involvement may be responsible for
rapid and progressive cardiac
decompensation and death.

•Forensic Pathology
Aspects of
Cardiomyopathies

Forensic Pathology Aspects
of Cardiomyopathies
• Cardiomyopathy
• Although many cases of
cardiomyopathy come to clinical
attention due to signs and
symptoms of heart failure, in
some individuals their first
symptom will be sudden death or
their symptoms will be so
insidious as to be ignored until
death occurs.
• This is particularly true for
hypertrophic cardiomyopathy
and right ventricular
cardiomyopathy, but can
occasionally be seen in cases of
dilated cardiomyopathy.

Forensic Pathology Aspects of Cardiomyopathies
Hypertrophic cardiomyopathy
Relatively common cardiac disease, said to occur in about 1 in 500
individuals in the general population, yet it remains a relatively uncommon
cause of sudden death when compared to its overall frequency.
Its etiology lies in mutations of one of a number of genes that produce
proteins necessary for the structural integrity, contractile function, or
regulation of the cardiac sarcomere.
Unfortunately, DNA analysis for hypertrophic cardiomyopathy is not widely
available and, as such, the autopsy diagnosis still relies on anatomic
features.

The heart will exhibit either concentric or asymmetric left ventricular hypertrophy.
Asymmetric hypertrophy is said to be present when the interventricular septal
thickness is 1.3 times greater than that of the posterolateral free wall.
Left ventricular outflow tract obstruction is a feature of some cases, such that
hypertrophic cardiomyopathy has also been referred to as hypertrophic obstructive
cardiomyopathy (HOCM) and idiopathic hypertrophic subaortic stenosis (IHSS).

Anatomic features that suggest the presence of outflow tract obstruction include
thickening of the anterior mitral valve leaflet and formation of a fibrous plaque,
reflecting a mirror image of the mitral valve leaflet, on the adjacent left ventricular
outflow tract endocardium.
Histologically, most cases will exhibit a fairly characteristic bizarre branching of
myocytes, particularly prominent in the interventricular septum.
It is very important that histologic sections of the interventricular septum and the left
ventricular free walls be taken perpendicular to the long axis of the heart in order to
properly demonstrate these myocytes.

Another characteristic feature is the presence of thickened intramural coronary
arteries.
Each of these features can be present in variable degrees, such that the
diagnosis may be difficult.
Because hypertrophic cardiomyopathy is inherited as an autosomal dominant
disorder, when the diagnosis is established, it is important to recommend that
close family members undergo clinical testing for this disease.

Forensic Pathology Aspects of
Cardiomyopathies
• Hypertrophic cardiomyopathy
• A 43-year-old female collapsed and died suddenly in her
home.
• She had no significant past medical history, but a sibling had
died suddenly several years previously with an autopsy
diagnosis of “cardiac death of undetermined etiology.”
• At autopsy, the heart weight was 590 grams and there was
evidence of asymmetric hypertrophy of the left ventricle,
particularly prominent in the anterior portion of the
interventricular septum (Image). This produced left
ventricular outflow tract obstruction with thickening of the
anterior mitral valve leaflet and mirror image fibrous
thickening of the left ventricular outflow tract adjacent to
the anterior mitral valve leaflet (Image).

Evidence of asymmetric hypertrophy of the left ventricle, particularly
prominent in the anterior portion of the interventricular septum

Left ventricular outflow tract obstruction with thickening of the anterior mitral valve leaflet and mirror
image fibrous thickening of the left ventricular outflow tract adjacent to the anterior mitral valve leaflet

Cardiomyopathies
• Hypertrophic cardiomyopathy
• Another view of anterior mitral valve leaflet
thickening, from a different case, is shown in Image.
• Histologically, bizarre branching myocytes were
found throughout the left ventricular myocardium,
but were most prominent within the interventricular
septum (Image).
• Characteristic endothelial and medial thickening of
intramural coronary arteries was noted (Image).
• A diagnosis of hypertrophic cardiomyopathy was
made.
• Review of the histologic sections from the sibling
who died previously also revealed the characteristic
findings of hypertrophic cardiomyopathy.

Another view of anterior mitral valve leaflet thickening, from a different
case.

Bizarre branching myocytes were found throughout the left ventricular
myocardium

Characteristic endothelial and medial thickening of intramural coronary
arteries

Arrhythmogenic right ventricular cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy (also referred to as ARVD or
arrhythmogenic right ventricular dysplasia) is a relatively rare disorder that presents
pathologically as either paper-like thinning of the right ventricular myocardium
associated with replacement of the myocardium by a mixture of fibrous tissue and fat,
or as transmural fatty infiltration of the right ventricular myocardium extending from
the epicardium to the endocardium.
There may be evidence of patchy myocardial fibrosis and chronic inflammatory cell
infiltrates.
Occasionally, fatty infiltration will be found within the myocardium of the left ventricle.

Arrhythmogenic right ventricular cardiomyopathy
In some cases, the diagnosis is relatively straightforward.
In others, assessing the degree of fatty infiltration as being abnormal can be challenging,
particularly in the elderly.
As such, referral to a cardiac pathologist is warranted.
Because arrhythmogenic right ventricular cardiomyopathy can be a familial disorder
(primarily autosomal dominant inheritance), family members should undergo clinical
examination for the disease when the diagnosis is made.

• Arrhythmogenic right ventricular cardiomyopathy
• A 42-year-old female was found dead on a bed in a hotel room
that she had been cleaning.
• There was no known significant past medical history.
• At autopsy, there was transmural fatty infiltration and thickening
of the right ventricular myocardium (Image).
• Histologically, the fatty infiltration extended completely through
the myocardium to the endocardium (Image), with formation of
islands of myocardium completely surrounded by adipose tissue
(Image).
• A diagnosis of arrhythmogenic right ventricular cardiomyopathy
was made.

Transmural fatty infiltration and thickening of the right ventricular
myocardium

The fatty infiltration extended completely through the myocardium to
the endocardium

Formation of islands of myocardium completely surrounded by adipose
tissue

Dilated cardiomyopathy
In cases of dilated cardiomyopathy, there is dilatation of all four cardiac
chambers, with predilection for more severe disease in the left
ventricle.
Although there will be left ventricular hypertrophy, ventricular
dilatation can produce a normal or even reduced free wall thickness.
The endocardium will exhibit variable degrees of fibrous thickening and
mural thrombi are often present.

• Dilated cardiomyopathy
• The histologic changes are nonspecific, but include
endocardial fibrosis, interstitial fibrosis within the
myocardium, hypertrophy and/or actual thinning of
myocytes (as a result of ventricular dilatation), myocytolysis,
and occasional chronic inflammatory cell infiltrates.
• The diagnosis can only be made in the absence of
hypertension, coronary artery disease, and valvular disease.
• Silent or subclinical viral myocarditis is thought to be the
underlying cause of many cases of dilated cardiomyopathy.

So-called alcoholic cardiomyopathy is a form of dilated cardiomyopathy
that occurs in alcoholics, usually in the absence of alcoholic cirrhosis.
This is one of the more common reasons for a dilated cardiomyopathy
to come to the attention of a forensic pathologist.
Peripartum cardiomyopathy is a form of dilated cardiomyopathy of
unknown etiology arising in the third trimester of pregnancy or the first
6 months postpartum.

Cardiomyopathies
• Dilated cardiomyopathy
• A 35-year-old female, was found dead in bed.
• She had apparently felt unwell for an unspecified
number of days prior to her death.
• Her eighth child had been delivered 6 weeks
previously without complications.
• There was no clinical history of hypertension.
• At autopsy, the atrial and ventricular chambers
were dilated, and the myocardium was uniformly
pale in color (Image).

The atrial and ventricular chambers were dilated, and the myocardium
was uniformly pale in color.

Forensic Pathology
Aspects of
Cardiomyopathies
There was increased trabeculation of the left
ventricle, such that it had a morphologic
appearance similar to that of the right ventricle.
Histologic examination of the myocardium
revealed variable degrees of myocardial fibrosis,
with some myocyte hypertrophy and occasional
chronic inflammatory cell infiltrates (Image).
The cause of death was attributed to peripartum
cardiomyopathy.

Variable degrees of myocardial fibrosis, with some myocyte hypertrophy
and occasional chronic inflammatory cell infiltrates

Forensic Pathology
Aspects of
Cardiomyopathies
Alcoholic cardiomyopathy
Alcohol and its metabolites are directly toxic to
the heart.
In addition, chronic ethanol abusers may have
some element of thiamine deficiency, raising the
possibility of additional cardiac pathology.
Although an association between chronic ethanol
abuse and dilated cardiomyopathy is known, a
mechanism is not, and the morphology of
alcoholic dilated cardiomyopathy is no different
than any other form of dilated cardiomyopathy.

• Alcoholic cardiomyopathy
• A 65-year-old known alcoholic was found
collapsed in the hallway of his apartment
building.
• His buttocks were in the air and his pants
were around his ankles.
• There was no evidence of trauma on the
body.
• At autopsy, the only finding of note was a
prominent dilated cardiomyopathy (Image).

Prominent dilated cardiomyopathy

• Alcoholic cardiomyopathy
• Toxicology showed only a negligible
amount of alcohol.
• His cause of death was attributed to
dilated cardiomyopathy arising as a
result of chronic ethanol abuse.

• Myotonic dystrophy
• Myotonic dystrophy is an autosomal dominant disease of skeletal muscle
that can be associated with cardiomyopathy and occasionally with sudden
death.
• The pathologic appearance of the heart is actually quite nonspecific (in fact,
the heart can appear to be normal), with histologic abnormalities appearing
in skeletal muscle rather than cardiac myocytes.
• DNA hybridization is used to detect an increased number of repeats of a
trinucleotide sequence (CTG) in the gene that encodes myotonin protein
kinase.
• These studies can be performed on postmortem blood, ideally collected in a
tube containing EDTA, although definitive results become less likely with
increasing postmortem period.

• A 45-year-old male collapsed and died suddenly while
carrying wood at his worksite.
• Although he was suspected to have myotonic
dystrophy, this diagnosis had never been confirmed.
• At autopsy, there was evidence of left ventricular
hypertrophy and slight dilatation, together with
dilatation of the right ventricle.

Forensic Pathology
Aspects of
Cardiomyopathies
• Histologically, the myocardium
appeared to be relatively unremarkable,
however, sections of skeletal muscle
exhibited some central nuclei (Image)
and nuclear chains (Image), as can be
seen in myotonic dystrophy.
• Ring fibers, which are most
characteristic of this disease, were not
seen.
• Postmortem DNA hybridization studies
were consistent with a diagnosis of
myotonic dystrophy.

Skeletal muscle exhibited some central nuclei

• Do
• Search for any past medical history or histologic findings
that might suggest the underlying etiology of a dilated
cardiomyopathy. Examine the right ventricle of the heart,
looking for evidence of hypertrophy, thinning, and/or
significant fatty infiltration.
• Consider the diagnosis of hypertrophic cardiomyopathy in
cases of concentric, as well as asymmetric, left ventricular
hypertrophy.
• Take histologic sections of the interventricular septum at
right angles to its long axis in order to identify the abnormal
myocytes seen in hypertrophic cardiomyopathy.

• Do
• Look for evidence of intramural coronary artery
abnormalities as an additional histologic sign of
hypertrophic cardiomyopathy.
• Recommend clinical screening of a family when
you make a diagnosis of hypertrophic
cardiomyopathy or right ventricular
cardiomyopathy.
• Don’t
• Make a diagnosis of “cardiomyopathy” in the
presence of hypertension, significant coronary
artery disease, or valvular disease.

BOOKS
• Pathologic basis of disease
• ISBN 978-1-4557-2613-4
• I. Kumar, Vinay, 1944- editor. II. Abbas, Abul K., editor. III. Aster,
Jon C., editor.

BOOKS
• Forensic Pathology, Principles and Practice
• David Dolinak, M.D.
• Evan W. Matshes, M.D.
• Emma O. Lew, M.D.

BOOKS
• Atlas of Forensic Histopathology
Peter M. Cummings, M.D.
Darin P. Trelka M.D.
Kimberley M. Springer, M.D.

Basic Science and Forensic Pathology Aspects of Cardiomyopathies

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