Cardiomyopathy

CARDIOMYOPATHY IS A RARE FORM OF HEART
disease that affects only the heart muscle. The term
cardiomyopathy is derived from the word cardio, the heart,
and myopathy, which indicates a weakness or disturbance
of the muscle. Heart muscle diseases of unknown cause are
classified under the term cardiomyopathy.
In one form of heart muscle disease, the muscle of the
ventricle becomes considerably thickened to the point that
the cavity of the left ventricle becomes nearly filled with
muscle mass; thus less blood enters the chamber and less
blood is expelled into the circulation. Because the muscle is
enlarged, or hypertrophied, the disease is called hypertrophic
cardiomyopathy. This is a disease of young adults.
See chapter entitled ‘‘Athletes and Sudden Cardiac Death.’’
The muscle enlargement may be so severe that it
obstructs the flow of blood into the aorta, and death may
occur suddenly, particularly in individuals from age 12 to
36 years. Some athletes who have died suddenly have had
this disease. In some families, hypertrophic cardiomyopathy
is caused by mutation in the cardiac myosin gene.
Approximately 60% of cases occur in families with an
autosomal dominant pattern and 40% of cases are
sporadic.

In another form of heart muscle disease, the heart dilates
without increasing the size of the muscle. The chambers
are swollen, and the muscle becomes weak. This condition
often results in failure of the heart to pump blood, which
results in heart failure. Heart transplants are required in
some of these patients (see the chapter Heart Failure).
Other types of heart muscle diseases may be caused by
viruses. Patients with AIDS have had HIV viral infection
of the heart muscle. The heart muscle may also be
damaged by cocaine, an overload of iron (hemochromatosis),
and some inherited conditions.

With different varieties of involvement of the heart
muscle, classification became necessary. In the 1970s and
1980s cardiomyopathy was defined as heart muscle disease
of unknown cause. The current classifications are:
1. Hypertrophic cardiomyopathy
2. Dilated cardiomyopathy
3. Restrictive cardiomyopathy
4. Arrhythmogenic right ventricular cardiomyopathy
(right ventricular dysplasia)
5. Unclassified cardiomyopathy: diseases that do not have
features of 1through 4 and include fibroelastosis and
mitochondrial disease
6. Specific cardiomyopathies (specific heart muscle
diseases formerly called secondary cardiomyopathy).
Each of these cardiomyopathies will be discussed. Most
of these diseases are rare, but hypertrophic cardiomyopathy
has become well-known because it is one of the causes of
sudden death in young athletes and young individuals.

I. HYPERTROPHIC CARDIOMYOPATHY
Hypertrophic cardiomyopathy (HCM) is found throughout
the world with a prevalence in North America of
0.2%. Before the diagnosis of HCM is considered hypertensive
heart disease, a major cause of the left ventricle
hypertrophy, and other causes of hypertrophy must be
excluded. In practice HCM is defined and diagnosed
by the demonstration of unexplained left ventricular
hypertrophy.

Hypertrophic cardiomyopathy is a disease caused by a
wide variety of mutations in genes encoding cardiac
sarcomeric proteins, which leads to inappropriate and
often severe hypertrophy of the myocardium.

A. Genetics
Approximately 60% of cases are familial and are inherited
in a Mendelian single gene autosomal dominant fashion.
More than 150 mutations in 10 culprit genes that encode
sarcomeric proteins are implicated in this disease. The
most common of these culprit genes include:
1. Beta myosin heavy chain (MYH7), approximately 35%
2. Cardiac troponin-2 (TNNT2), approximately 15%
3. Myosin binding protein C genes, approximately 15%
4. Alpha tropomyosin
5. Essential myosin light chain
6. Troponins-I
7. Alpha cardiac actin
8. Regulatory myosin light chain.

Familial HCM can be caused by genetic defects at more
than one locus, therefore, it is a genetically heterogeneous
disease. The mutations of the troponins-T and some
mutations of the beta myosin heavy chain appear to be
associated with sudden death more often than other
mutations. Some mutations may be associated with a high
incidence of sudden cardiac death, whereas others appear
to have a more benign course. This has led to the hypothesis
that genotyping may facilitate the identification of
individuals at risk for sudden death. But there is extreme
variability and even mutations that were considered by
some to be malignant, MYH7 and TNNT2, often run a
benign course. In a study by Ackerman et al. so-called
‘‘malignant’’ mutation was found in only 1% of 293 study
patients. The authors concluded that given the low
prevalence of malignant MYH7 and TNNT2 mutations
in a large study, genetic testing was unlikely to contribute
significantly to risk assessment.

Mutations of the troponins-T gene usually result in only
mild or no heart muscle hypertrophy. Some of the sporadic
forms of the disease are caused by spontaneous mutations.
It is of interest that in some patients with an abnormal
gene and normal echocardiography, the most diagnostic
and least expensive test is the ECG.

B. Macroscopic Features
There is a marked increase in myocardial mass and the
ventricular cavity is encroached upon such that the
ventricular cavity becomes smaller and narrowed (see
Fig. 1). The marked thickening of the interventricular
septum obstructs the free flow of blood from the left
ventricle into the aorta, (outflow tract gradient). The left
ventricle tends to be involved much more than the right.
The degree of hypertrophy and the parts of the heart
that are involved are extremely variable. See Figure 1 in the
chapter entitled ‘‘Athletes and Sudden Cardiac Death.’’
Hypertrophy can be patchy, involving the septum only,
the apex of the anterior, and the lateral walls. This type of
hypertrophy is often referred to as asymmetric hypertrophy.
(Fig. 1). Occasionally the hypertrophy of the heart
muscle that is seen in HCM and that observed in highly
trained male athletes may be difficult to differentiate.
Hypertrophy of the apex of the heart (apical HCM) is
more common in Japan than in other parts of the world.
In apical HCM the ECG shows a highly abnormal pattern
of giant negative T waves in the precordial ECG leads.
Despite the frightfully abnormal looking ECG, patients
are often asymptomatic and the disease runs a benign
course. Figure 2 shows the ECG in a patient with apical
HCM. Figure 3 shows a patient with HCM, mild
hypertrophy of the septum, and mild free wall hypertrophy
but without significant obstruction of the outflow tract
that leads from the left ventricle to the aorta as depicted
in Fig. 1.

C. Microscopic Features
Microscopically in HCM the myocytes are hypertrophied
and in disarray and there is abundant interstitial fibrosis.
Individual myocytes demonstrate disarray in the orientation
or their myofibrillar architecture. The disorganization
in the alignment of cardiac myocytes is oriented around
loose connective tissue. Large areas of fibrosis are observed
throughout the affected muscle. This microscopic picture
may also be seen in muscle where there is no obvious
hypertrophy.

D. Pathophysiology
1. Most patients show asymmetric hypertrophy of the
septum and a hypertrophied nondilated left and or
right ventricle. The septum may be diffusely hypertrophied
or only in its upper, mid, or apical portion.
Hypertrophy extends to the free wall of the left
ventricle.
2. There is decreased compliance and incomplete relaxation
of the thickened and stiff left ventricular muscle
that causes impedance to filling of the ventricles during
diastole (diastolic dysfunction)
3. The rapid powerful contraction of hypertrophied left
ventricle expels most of its contents during the first
half of systole. This hyperdynamic systolic function
is apparent in most patients with HCM.
4. The anterior leaflet of the mitral valve is displaced
toward the hypertrophied septum. Mitral regurgitation
is virtually always present in the obstructive phase of
the disease.
5. Because of the obstruction overflow from the left
ventricle into the aorta and outflow pressure gradient
at rest, HCM is much worse during exercise in more
than 40% of patients.
6. Disease of small branches of the coronary arteries
may occur, but the major coronary arteries are not
obstructed.

E. Clinical Features
1. Shortness of breath commonly occurs but may not be
noticeable in many patients until the obstruction to
outflow of the left ventricle becomes severe.
2. Fainting, syncope, or presyncope during exercise or
during normal activities is a warning signal.
3. Chest pain may occur because of restricted flow to the
coronary arteries.
4. Abnormal heart rhythms causing palpitations may
occur.
5. On examination, hypertrophy of the heart is reflected
by a thrusting and forceful apex beat of the heart
that can be seen or felt with the palpating hand. A
murmur is heard with the stethoscope and has typical
characteristics, but the entire examination may reveal
little or no abnormalities depending on the stage of the
disease.
6. The ECG is usually abnormal with pathologic Q
waves in leads I, II, III, aVF, V5, and V6, as shown in
Fig. 3.
7. Signs of heart failure are observed in the end stages
of the disease. Figure 4 gives an outline of various
processes that lead to the end stages which culminate in
heart failure or death.

II. SUDDEN DEATH
Death is most often sudden in HCM and unfortunately
this may occur in asymptomatic patients, in those who
were unaware that they have the disease, or in individuals
with an otherwise stable course.
The mechanisms that result in sudden death remain
unresolved. The identification of patients at high risk of
sudden death presents great difficulties for the average and
expert clinicians.

A. Genotyping
Genotyping is not available as a routine clinical test, and
most important, it is currently problematic in prognostic
assessment. The findings of Ackerman et al. of only 1%
malignant mutation in 293 patients is important and is
in keeping with several other observations. Even within
so-called high-risk families there is a variable disease
expression and prognosis. Watkins et al. described a large
Scottish family with mutation in TNNT2 in which 8 died
suddenly before age 30, but 8 others lived to be 70–80
years old. Several other reports of this type have been
noted.

B. Clinical Evaluation
Because the promise held for genotyping is not likely to
materialize, assessment of risk is based mainly on clinical
evaluation and specific investigations. Clinical parameters
that may assist in the assessment of risk for sudden death,
however, remain unsystematic and haphazard. Mckenna
et al. made the point that at best, clinical risk markers are
only modestly predictive of short-to-medium term risk of
sudden death. The presence of a severe outflow tract
gradient does not correlate with the risk of sudden death.

C. Marked Left Ventricular Hypertrophy
Current evidence indicates that marked left ventricular
hypertrophy should not be relied upon for diagnosis. Some
studies indicate that left ventricular wall thickness greater
than 30 mm significantly increases the risk of sudden
death. In a study by Spirito et al. sudden death occurred
in less than 1% of patients with maximal thickness less
than 20 mm and in 16% of patients with maximal
thickness greater than 30 mm over the average follow up of
7 years. Unfortunately at least 10% of patients in most
survival studies show a left ventricular wall thickness
greater than 30 mm. Most important, the majority of
sudden cardiac death in patients with HCM occurs in
those with a wall thickness of less than 30 mm.
Survivors of cardiac arrest make up a high-risk group
that is easy to define. These are individuals who have
survived an episode of sustained ventricular tachycardia.
These patients have about an 8% chance of further cardiac
event in five years.

A history of sudden death in the family or syncope in
an individual is worrisome, and there is considerable
anecdotal evidence to suggest that these two features carry
a sizable predictive risk. The worry to the family and
individual is understandable. The outcome statistical
analyses in large series show that syncope and a previous
history of sudden death are not reliable indicators,
however, for the prediction of future sudden death.
Syncope is more sinister in children with HCM than in
adults.

Findings of nonsustained ventricular tachycardia on
Holter electrocardiographic ambulatory monitoring and
an abnormal blood pressure response on exercise along
with clinical evaluation (massive left ventricular hypertrophy)
and family history (unexplained syncope, family
history of sudden death) are useful toward a diagnosis. In a
prospective study in which these parameters were
present, there was an annual sudden death risk of
approximately 3%.

A group at low risk for sudden death may be identified
as asymptomatic patients with left ventricular thickness
less than 20 mm, absence of nonsustained ventricular
tachycardia on Holter monitoring, normal exercise blood
pressure response, and no family history of sudden death.

D. Management
1. Medical
Beta-blockers are the mainstay of medical therapy. Drug
management is used mainly in patients who are symptomatic
and in patients who present with chest pain, mild
shortness of breath, or presyncope. A marked increase in
vigorous contractions of the heart muscle (hypercontractility)
dictates the need for more oxygen by the thickened
muscle; beta-blocking drugs such as metoprolol, which
decreases the force and velocity of contraction of the
ventricle, and decreases oxygen requirement, have been
used successfully for more than 30 years to achieve
subjective and objective benefit in a significant number of
patients. Also, in patients with HCM the heart rate is slow
and this leads to improved filling of the ventricle during
diastole and increased filling of the coronary arteries that
supply the thickened muscle with blood and oxygen. Betablocking
agents, however, have not been shown to prevent
sudden death and clinical trials are difficult in patients
with HCM. Other agents used in selected cases include
verapamil, which may precipitate heart failure and hypotension
in some. Verapamil improves relaxation of the
ventricle and allows for better filling of the left ventricle,
but it should be avoided in patients who are at risk for
development of heart failure.

Diuretics may cause dehydration because of the removal
of salt and water from the body. This effect decreases the
volume of blood returned to the heart, and this may have
serious consequences in patients who already have poor
filling of the left ventricle.

2. Chemical Septal Ablation
This technique is used mainly in highly symptomatic
patients who have contraindications or are resistant to drug
treatment. In these patients the outflow tract gradient
at rest should be greater than 30 mmHg or greater than
60 mmHg with provocation. The septum usually measures
greater than 18 mm thick. Catheterization of the target
vessel (the most important proximal septal artery that
supplies the septum with blood) and ablation of the area
with the use of alcohol appears to produce satisfactory
results in selected patients. Complications include complete
heart block, damage to a coronary artery, myocardial
infarction, and pericardial tamponade. Hospital mortality
ranges from 1 to 4%.

3. Surgical Myomectomy
Surgical removal of excess muscle tissue in the region of
the thickened septum is a logical solution to reduce
outflow tract gradient and promote better flow of blood
from the left ventricle into the aorta. In 1957 Brock
advanced this method, and subsequently Morrow popularized
the technique. A portion of the thickened interventricular
septum is excised; often the mitral valve is replaced.
Symptoms are definitely improved, but the mortality rate
ranges from 2 to 5%. Surgical intervention is usually
satisfactory; long-term improvement in symptoms and
exercise capacity is observed in most patients.

4. Dual-Chamber Pacemaker
Dual-chamber pacemaker insertion is based on the observation
that excitation of the septum by pacing causes the
septum to contract away from the opposing wall reducing
the obstruction to outflow of blood from the ventricle
(reduces the left ventricular outflow tract gradient). This
strategy appeared useful in the European trial, but several
trials in the United States have failed to show significant
benefit.

III. DILATED CARDIOMYOPATHY
Heart failure is rare in individuals younger than age 20.
If congenital heart disease is excluded, the most common
cause of heart failure in the young is idiopathic dilated
cardiomyopathy (DCM). More than 50 known specific
diseases of heart muscle can produce the signs, symptoms,
and manifestations of idiopathic DCM. Some of these
diseases include the following:
1. Infectious: Coxsackie, cytomegalovirus, HIV, Chagas
disease, tuberculosis, acute rheumatic fever, toxoplasmosis,
trichinosis, echinococcus, schistosomiasis, and
Lyme disease
2. Endocrine: Thyroid diseases (thyrotoxicosis and,
hypothyroidism), diabetes, and acromegaly
3. Infiltrative diseases: Amyloidosis, hemochromatosis,
and sarcoidosis
4. Alcoholic cardiomyopathy
5. Collagen vascular disease: Lupus erythematosus, scleroderma,
mixed connective tissue disease, polyarteritis
nodosa, and rheumatoid arthritis
6. Toxic: Cocaine, heroin, amphetamines, cancer chemotherapeutic
agents, arsenic, cobalt, lead, phosphorus,
and ethylene glycol
7. Nutritional: Thiamine, protein, and selenium
8. Others: Endomyocardial fibroelastosis, peripartum, and
sleep apnea
Idiopathic DCM is transmitted in an autosomal
dominant manner although X-linked, autosomal recessive,
and mitochondrial inheritance also have been observed.

A. Genetics
Shaw et al. stated in an editorial that the genetic
heterogeneity of DCM is illustrated by the autosomal
dominant form with several foci and gene mutations
identified that include Iq32 (cardiac troponin-T), 14q11
(beta myosin heavy chain), 4q12 (beta –sarcoglycan), and
15q14(actin). Figure 5 shows some proteins involved in
DCM and their cellular location.

The mechanisms by which individual mutations cause
idiopathic DCM require further clarification. The end
result of the disease is a weakened heart muscle that leads
to heart failure. Abnormalities in force transmission and
velocity of contraction of the heart muscle appear to
result from mutations of contractile proteins, actin, alphatropomyosin,
and desmin. Cardiac beta myosin heavy
chain and troponins-T mutations are believed to result
in reduced force generation by the sarcomere. Mutations
in both sarcoglycans are believed to cause DCM.
Mutations in the mitochondrial respiratory chain also
can lead to DCM.

B. Clinical Features
1. Progressive shortness of breath on exertion appears over
weeks or months. This then progresses to shortness of
breath in bed (orthopnea) and paroxysmal nocturnal
dyspnea.
2. Signs and symptoms of right and left heart failure
become evident.
3. On auscultation gallop sounds are typically present.

D. Management
Transplantation has a role in selected individuals but does
not benefit patients worldwide. Aggressive treatment for
heart failure carries the only hope for improved survival
and must include the following medications:
1. Diuretics: Furosemide in a dosage to prevent fluid
retention, edema, signs of heart failure, and particularly
for the relief of shortness of breath.
2. ACE inhibitor therapy: Enalapril or lisinopril or similar
ACE inhibitor, see the chapter Heart Failure.
3. Beta blockers: The use of metoprolol or carvedilol is
now recognized as essential. These agents have recently
been shown to be effective in relieving symptoms as
well as improving cardiac function. Lowes et al.
reported the study of 53 patients treated with metoprolol
or carvedilol and observed significant improvement
that was associated with changes in myocardial
gene expression. A study by Cice et al. in 114 dialysis
patients with dilated cardiomyopathy treated with
carvedilol showed a reduction in left ventricular
function, left ventricular volumes, and clinical status.
4. Spironolactone: Added to the above beta-blockers
further improves clinical status survival and decreases
hospitalization for heart failure.
5. Dual-chamber electronic pacing: In patients with heart
failure and intraventricular conduction delay (IVCD),
this has shown significant benefit, reduced hospitalization,
and probably will delay the time to transplantation
in individuals on waiting lists.
6. Anticoagulants: These may be required to reduce the
risk of embolism that occurs frequently in patients with
dilated hearts.
7. Antiarrhythmics: In some of these patients implantation
of an IVCD may become necessary.

IV. RESTRICTIVE CARDIOMYOPATHY
Restrictive cardiomyopathy is rare in the western world
and in Europe. Diseases that cause damage to the muscle
and restrict the flow of blood into the ventricle include
amyloidosis, sarcoidosis, hemochromatosis, scleroderma,
Adriamycin toxicity, and heart involvement by infectious
agents. The most common cause of restrictive cardiomyopathy,
especially in tropical regions, is endomyocardial
fibrosis.

The damage to the muscle in these diseases causes the
ventricular walls to become excessively rigid and the main
abnormality is impaired relaxation and compliance that
impedes the filling of the ventricle. Less blood is held
within the ventricle and thus less blood is expelled into the
aorta and systemic circulation. When the supply of blood
to organs becomes inadequate, heart failure is diagnosed.
This situation is due mainly to poor diastolic filling of
the ventricle rather than to a decrease in the force of
contraction of the ventricular muscle (systolic dysfunction)
which is the most common cause for heart failure.

A. Clinical Features
In the tropics endomyocardial fibrosis may result in
intermittent fever, shortness of breath, cough, palpitations,
edema, and tiredness. Symptoms and signs of heart failure
must be differentiated from constrictive pericarditis.
Endomyocardial fibrosis may mimic the hemodynamic
and clinical features of constrictive peritonitis. Chest x-ray
or fluoroscopy may show calcification of the right and
left ventricular apical myocardium due to thrombus
formation, calcification of all fibrosis, and calcification of
the endocardial region. The apex of the heart may be
completely obliterated. Blood tests may reveal increased
eosinophils (hypereosinophilia). Echocardiogram typically
shows obliteration of the apices of the ventricle with
echogenic masses. Also, extensive myocardial calcification
may be detected.

B. Management
1. Steroids may be helpful to subdue inflammatory
changes.
2. Anticoagulants are advisable to prevent thromboembolism.
3. Arrhythmias may respond to small doses of a betablockers
and occasionally some beneficial response
may be obtained with ACE inhibitors.
4. Diuretics are usually not beneficial, but may be
required for symptomatic relief of shortness of breath
and other manifestations of heart failure.

V. SPECIFIC HEART MUSCLE DISEASE
Specific heart muscle disease usually produces a dilated
form of cardiomyopathy with impaired systolic function.
Restrictive physiology is seen with amyloid, sarcoid,
neoplasm, radiation, scleroderma, hemochromatosis, and
eosinophilic endomyocardial disease, in which eosinophilia
is usually present. Rarely, myocardial tuberculosis is
present with restrictive features. Amyloid heart disease and
EMF are usually considered examples of RCM, but when
cardiac involvement is associated with multiple organ
disease, they qualify as specific heart muscle disease (see
Table 1).
Endomyocardial biopsy is often required but may not
be helpful in patchy disease such as sarcoid. The presence
of systemic disease of other organs, especially the liver,
lymph nodes, and skin, which can be easily submitted to
biopsy, assist in defining the underlying cause.
Amyloidosis causes deposition of specific proteins as
insoluble fibrils in the extracellular space of several organs
including the heart. The disease affects individuals in the
fifth and sixth decade of life. The heart muscle is weakened
and mainly right heart failure ensues in more than 40%
of patients.

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