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Cardiology: An Integrated Approach >

Chapter 14: Myocardial Diseases

Sandeep Banga; Preeti Banga; Sudhir Mungee

Learning Objectives
Learning Objectives

By the end of this chapter the student will be able to:

Classify cardiomyopathies.

Identify the type of cardiomyopathy based on clinical features.

Describe the mechanism, natural history, and prognosis of a particular cardiomyopathy.

Understand the role of different modalities in diagnosis.

Determine the best treatment modality for a specific cardiomyopathy.

Apply the above knowledge in a clinical setting.

Introduction
Cardiomyopathies refer to a group of diseases of the heart muscle. Cardiomyopathies are divided into 3 major types: (1) hypertrophic
cardiomyopathy, (2) restrictive cardiomyopathy, and (3) dilated cardiomyopathy. While dilated cardiomyopathy is the most common type,
and the ultimate outcome of all cardiomyopathies, it is nevertheless important to recognize all 3 types as they differ in presentation,
diagnosis, and management. This chapter discusses each type of these cardiomyopathies in terms of clinical symptoms, natural history,
clinical signs, diagnoses, and treatment, including pharmacological, surgical, and device management.

Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease affecting 1 in 500 of the general population in the United States
as seen in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Hypertrophic cardiomyopathy is defined as
hypertrophy of the left ventricle that develops in the absence of hypertension, aortic valve disease, systemic infiltrative, or storage
diseases (Fig. 14.1). Microscopically, hypertrophic cardiomyopathy is characterized by a misalignment and disarray of the enlarged
myofibrils and myocytes (Fig. 14.2). The disease is caused by a mutation in 1 of 13 or more sarcomeric genes. The presentation can
vary from sudden cardiac death (SCD), ventricular arrhythmias, or insidiously with symptoms of heart failure, although the majority are
asymptomatic. Myosin heavy chain 7 (MYH7) mutations are the most common occurrence, manifesting in more than 30% of patients
with HCM, followed by myosin-binding protein C (MYBPC3C) and cardiac troponin T (TNNT2), each of which occurs in more than 20%
of cases. There are 10 major gene mutations, which are listed in Table 14.1.

Table 14.1 Major gene mutations in hypertrophic cardiomyopathy

Sarcomere genes with mutations in order of frequency of occurrence
MYH7 (β-myosin heavy chain)
MYBPC3 (myosin-binding protein C)
TNNT2 (cardiac troponin T)
TNNI3 (cardiac troponin I)
TTN (titin)
TPM1 (α-tropomyosin)
TNNC1 (cardiac troponin C)
ACTC (α-actin)
MYL2 (myosin regulatory light chain)
MYL3 (myosin essential light chain)

Figure 14.1

Gross specimen of a heart with hypertrophic cardiomyopathy. (Reproduced, with permission, from Kasper DL, Fauci AS, Hauser SL,
Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015. Image
courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)

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Figure 14.2

Microscopic image of hypertrophic cardiomyopathy. (Reproduced, with permission, from Kasper DL, Fauci AS, Hauser SL, Longo DL,
Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015. Image courtesy of
Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)

Clinical Presentation and Diagnosis

Natural History

The annual mortality for patients with HCM is estimated at 1% per year, as seen in a large epidemiological study by Maron et al (2000).
The symptoms can vary from angina as a result of a supply-demand mismatch, and palpitations from atrial or ventricular arrhythmias to
sudden cardiac death in the absence of any antecedent symptoms. The late presentation with symptoms of heart failure occurs in all
patients as fibrosis sets in, leading to end-stage heart failure with reduced ejection fraction. Heart failure can also progress even before
the end stage of dilated cardiomyopathy in patients with or without left ventricular outflow tract obstruction. The presence and degree of
the left ventricular obstruction will affect and have a direct relationship with the functional New York Heart Association (NYHA) class.
The onset of atrial fibrillation does augment the symptoms.

Physical Examination

Most patients with HCM have a normal physical examination except for the presence of dynamic obstruction. The clinical findings can
vary with the physiological state of the patient. The first of which include the jugular vein distention (JVD) findings that can show
prominent a wave. Palpation of the carotid pulse in patients with a significant outflow tract obstruction shows a brisk bifid waveform. The

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first rapid phase of ejection is followed by a second phase of deceleration caused by the midsystolic outflow tract obstruction and partial
aortic valve closure, which is seen as a spike and dome pattern.

Upon inspection of the precordium, one may find a prominent parasternal lift in patients with heart failure as a result of right ventricular
enlargement or an apical impulse. Palpation of the point of maximal impulse reveals a sustained apical impulse due to a hypertrophied
enlarged left ventricle, a presystolic apical impulse in a noncompliant ventricle due to atrial systole (S4); and an S3 that can also be
heard in patients with heart failure with reduced ejection fraction. A systolic thrill at the apex or lower left sternal border can be palpated.
A midsystolic murmur can be heard at the apex as a result of systolic anterior motion of the anterior mitral leaflet leading to a loss of
cooptation of the mitral leaflets. Another crescendo-decrescendo midsystolic murmur can be heard at the lower left sternal border as a
result of the outflow tract obstruction.

Dynamic auscultation can differentiate this disease from aortic stenosis. Maneuvers that reduce preload (eg, Valsalva, squat-to-stand)
will increase the intensity of the murmur in patients with HCM, whereas maneuvers that increase preload (stand-to-squat or passive leg
raise) will reduce the intensity of the murmur in HCM. Also maneuvers that increase myocardial contractility including exercise and
sympathomimetic amines will increase the gradient across the left ventricular outflow tract (LVOT), and hence, the intensity of the
murmur. The maneuvers that affect the afterload include squatting and sustained handgrip, which increase the afterload, and hence,
decrease the gradient across the LVOT leading to a decrease in the intensity of the murmur.

CLINICAL CORRELATION 14.1

The more the gradient across the left ventricular outflow tract, the louder the murmur across the outflow tract obstruction.

Diagnosis

Electrocardiogram

ECG reveals prominent voltages with more consistent findings resembling left ventricular hypertrophy with repolarization abnormalities.
Apical hypertrophic cardiomyopathy can show a deep T-wave inversion in the anterior leads resembling a non-ST elevation myocardial
infarction (Fig. 14.3).

Figure 14.3

Electrocardiogram showing diffuse T-wave inversions across the precordium with left ventricular hypertrophy in patient having apical
variant of hypertrophic cardiomyopathy. (Reproduced, with permission, from Fuster V, Harrington RA, Narula J, Eapen ZJ, eds. Hurst’s
The Heart. 14th ed. New York, NY: McGraw-Hill; 2017.)

Cardiac Biomarkers

Serum troponin I and T assays are prognostic in HCM. This biomarker has also been associated with an elevated risk of cardiovascular
deaths, heart failure admissions, sustained ventricular tachycardia, embolic events, and progression to NYHA functional Class III or
Class IV status over a 4-year follow-up period. B-type natriuretic peptide (BNP) levels can rise when heart failure occurs in patients with
HCM.

Imaging

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Both echocardiography and cardiac magnetic resonance imaging (MRI) have become the important imaging modalities. The presence
of left ventricular hypertrophy (LVH) with a LV wall thickness of 15 mm in diastole with no other identified cause confirms the diagnosis
of hypertrophic cardiomyopathy.

Echocardiography can be used to assess the outflow tract gradients at rest and with exercise. Different maneuvers including amyl
nitrite, isoproterenol, dobutamine, Valsalva, and exercise can be used to provoke the outflow tract gradient. MRI is often used to
evaluate LVH in atypical locations such as in the anterolateral free wall, apex, or posterior septum. Contrast MRI can also quantify the
degree of myocardial fibrosis with late gadolinium enhancement. Involvement of ≥20% of LV myocardium enhancement, which can be a
predictor for risk of sudden cardiac death.

Screening

Family screening with genetic testing for mutations in the gene encoding sarcomeric protein should be done in the first-degree relatives
of the patient with hypertrophic cardiomyopathy to identify relatives for echocardiographic screening with follow-up. The American Heart
Association (AHA) recommends screening to begin from the age of 12 every year until 18 years of age, followed by every 5 years for
the asymptomatic individual. Genetic testing should be done in the patient and the family members to identify the gene mutation and
recommend counseling for the carriers of the mutation.

Treatment

Lifestyle Recommendations

In patients with HCM, dehydration and heavy exercise should be avoided, as these can worsen the outflow tract gradient, which leads
to syncope or sudden cardiac death. During exercise, both the heart rate and contractility increases and the systemic vascular
resistance decreases, but the cardiac output falls because of the increase in the left ventricular tract obstruction. This leads to systemic
hypoperfusion in the organs including the brain causing syncope. Therefore, the recommendation is not to allow patients to participate
in most competitive sports. The treatment algorithm for HCM is depicted in Fig. 14.4.

Figure 14.4

Treatment algorithm for hypertrophic cardiomyopathy. ICD, implantable cardioverter defibrillator; LV, left ventricle. (Reproduced, with
permission, from Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine.
19th ed. New York, NY: McGraw-Hill; 2015.)

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Pharmacologic Recommendations
Role of β-Blockers

β-blockers are the mainstay of therapy in patients with hypertrophic cardiomyopathy. They play multiple roles. β-blockers reduce the
heart rate, allowing more diastolic filling of the heart, and reduces ventricular stiffness of the left ventricle. They also reduce the outflow
tract gradient across the dynamic obstruction, which leads to a reduction in the symptoms of dyspnea on exertion, angina due to a
supply-demand mismatch, and the risk of ventricular arrhythmias. Most of the earlier trials were with propranolol, but later, nadolol and
bisoprolol were used. These have been found to be effective in patients with hypertrophic cardiomyopathy, with or without gradients.

Role of Calcium Channel Blockers

Verapamil and diltiazem are the two non-dihydropyridine calcium channel blockers that are currently used in hypertrophic
cardiomyopathy patients. Of these, verapamil is the most studied calcium channel blocker. The mechanism of calcium channel blockers
is similar to β-blockers as they have a negative chronotropic and negative inotropic effect; hence prolonging the diastolic filling time and
reducing the outflow tract gradient. The calcium channel blockers do not reduce the risk of sudden cardiac death or heart failure. The
calcium channel blockers are rather contraindicated in patients with a severe outflow obstruction or patients with nonobstructive
hypertrophic cardiomyopathy or severe heart failure.

Disopyramide

Disopyramide is one of the old drugs that has been proven to be effective in hypertrophic cardiomyopathy by reducing the left
ventricular outflow tract gradient even at rest, which both β-blockers and calcium channel cannot do. But because of QTc prolongation
and the anticholinergic effect, it is not currently a preferred drug for hypertrophic cardiomyopathy. However, it remains an option in
cases where both β-blockers and calcium channel blockers fail to reduce the high outflow tract gradients in symptomatic patients
despite maximum tolerated doses, or where both of these completely fail. However, disopyramide is not effective in hypertrophic
cardiomyopathy without an obstructive gradient. So, this drug is now kept in reserve for patients when the other two pharmacological
therapies fail.

Non-pharmacological Recommendations
Septal Myectomy

Surgical septal myectomy for HCM is a gold standard treatment for obstructive HCM with symptoms and gradients that do not respond
to drug therapy. This procedure involves the resection of the septum at its proximal and mid portion, relieving the obstruction of the
outflow tract. Post-resection systolic anterior motion (SAM) of the mitral valve also improves and mitral regurgitation disappears. Often,
mitral valve replacement is done when there is an organic involvement of the mitral valve. Complications, such as heart block,
ventricular septal defect, and aortic regurgitation are seen in <1% of the patients that undergo surgery.

CLINICAL CORRELATION 14.2

Surgical septal myectomy has a better clinical outcome than alcohol septal ablation with lesser chance of iatrogenic complete heart
block.

Septal Ablation

Alcohol septal ablation is a catheter-based method. Alcohol is infused in the septal perforator arteries, producing a myocardial infarction
of the proximal septum. This infarction leads to thinning of the basal septum. The target vessel is generally a large first septal perforator.
The average gradient falls from 70 mmHg to less than 20 mmHg. A complete heart block requiring a permanent pacemaker occurs in
<10% of patients. It is more common in patients with a preexisting left bundle branch block. This method is mostly performed in patients
with a high surgical risk.

Dual-Chamber Pacing

Implantation of a dual-chamber pacemaker has been used as a treatment modality for symptomatic HCM patients. Although it was
found in initial studies that DDD pacing can decrease the outflow tract gradient during pacing by 25% to 40% of baseline, as compared
with 80% to 90% with septal myectomy. Thus, the role of dual-chamber pacing should be limited to patients who are at a high risk for
other therapeutic modalities.

Therapies for Prevention of Sudden Cardiac Death

Sudden cardiac death (SCD) occurs most frequently in asymptomatic or mildly symptomatic young patients. The risk factors include
prior cardiac arrest or spontaneous sustained ventricular tachycardia, a family history of premature SCD in a first-degree relative with
HCM, recent unexplained syncope, nonsustained ventricular tachycardia, abnormal blood pressure response to exercise, and extreme
left ventricular hypertrophy (>30 mm). Prior cardiac arrest and a history of sustained ventricular tachycardia pose the highest risk.
Delayed gadolinium enhancement in cardiovascular magnetic resonance (CMR) imaging may show enhancement but has not proven to
be a significant risk factor. The decision to recommend an implantable cardioverter defibrillator (ICD) to patients is complex and requires
a risk assessment and defining goals of treatment with the device therapy.

Role of Antiarrhythmic Drugs

There is no definite role of antiarrhythmic therapy in patients with hypertrophic cardiomyopathy in reducing the risk of ventricular
arrhythmias. But sotalol and amiodarone have been studied in many trials. Although sotalol has been found to reduce sudden cardiac

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death, its use remains controversial. As the utility of devices has been established in preventing sudden cardiac death due to ventricular
arrhythmias, pharmacological therapy is the least preferred.

Restrictive Cardiomyopathy
Restrictive cardiomyopathy (RCM) is the least common of all cardiomyopathies. This cardiomyopathy accounts for approximately 5% of
all cases of primary heart muscle disease. The World Health Organization (WHO) defines this entity as a myocardial disease
characterized by restrictive filling and reduced diastolic volumes of either the LV or the RV or both ventricles with normal or near normal
systolic function. It is necessary to rule out ischemic, hypertensive, valvular, and congenital heart disease before labeling a patient with
restrictive cardiomyopathy. These are classified into 5 different categories: inflammatory, noninfiltrative, infiltrative, storage, and
idiopathic. Division of these categories is illustrated further in Fig. 14.5.

Figure 14.5

Classification of restrictive cardiomyopathy. (Reproduced, with permission, from Crawford MH, ed. Current Diagnosis and Treatment:
Cardiology. 4th ed. New York, NY: McGraw-Hill; 2014.)

Clinical Presentation and Diagnosis

Natural History

In RCM, there is myocardial involvement and obliteration of the ventricular cavity either in isolation or in the presence of systemic or
iatrogenic disease. The ventricular stiffness leads to an elevated diastolic atrial as well as diastolic ventricular pressure. This results
clinically in biventricular backward failure. Therefore, the clinical presentation is characterized by different stages of dyspnea, beginning
with exertional dyspnea to paroxysmal nocturnal dyspnea and orthopnea. Patients also exhibit indications of raised right atrial pressure,
which leads to edema and abdominal distension. The ventricles are underfilled as a result of a reduced preload, which leads to low
cardiac output and therefore increase in fatigability.

Clinical progression is typically rapid and carries a variable prognosis depending on the etiology; the majority of patients die within few
years of presentation.

Physical Examination

The physical examination reveals elevated jugular venous pressure; prominent x and especially y descents are characteristic, often with
Kussmaul sign, peripheral edema, and ascites; with advancing disease, hepatomegaly, ascites, and anasarca. Patients typically are
limited by dyspnea on exertion attributable to left ventricular diastolic dysfunction. The precordial exam is quiet with no evidence of an
RV heave, thus ruling out pulmonary hypertension.

Patients have a low volume pulse due to low output and tachycardia. Low stroke volume combined with autonomic insufficiency as seen
in amyloidosis can present with orthostatic hypotension in some patients. Atrial dilation often leads to atrial fibrillation, which further
exacerbates diastolic dysfunction as a result of a high heart rate and loss of atrial contraction. The apical impulse is not displaced. An
S4 is present if there is no atrial fibrillation together with mitral and tricuspid valve regurgitation murmurs.

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Etiologies

Idiopathic RCM

Idiopathic RCM is seen in 50% of patients under the restrictive cardiomyopathy category and is only diagnosed after ruling out other
causes. It is more commonly seen in females than males.

Infiltrative Disorders

Cardiac Amyloid

Primary amyloidosis (AL) is a form of RCM with a deposition of amyloid in the interstitium of the cardiac muscle that gives the heart a
waxy and rubbery appearance. The progression starts with diastolic dysfunction followed by systolic dysfunction. These are further
complicated by arrhythmias and conduction abnormalities of the heart. Thick walls of the ventricles with small cavities, and a granular-
speckled appearance is nearly diagnostic on echocardiography. Cardiac magnetic resonance imaging shows subendocardial diffuse
late gadolinium enhancement throughout both ventricles.

The mainstay of treatment is decongestive therapy until hypotension is tolerated. These patients are at high risk of atrial fibrillation and
thromboembolism so should be on anticoagulation medication. Chemotherapy and stem cell transplantation, followed by cardiac
transplantation are options, however, the overall prognosis is poor.

Sarcoidosis

Sarcoidosis has multiorgan involvement; particularly in the lungs. The heart is involved in less than one-third of patients with
sarcoidosis. The granulomas have a predilection to the basal septum and posterior wall of the left ventricle. They also involve the
conduction system, which leads to conduction blocks on an ECG, including high grade AV blocks, and rarely present with heart failure.
Echocardiography reveals the segmental hypokinesia of the mid and basal free walls with septum involvement. Cardiac MRI and
positron emission tomography (PET) are more sensitive and useful modalities. Steroids and cyclophosphamide are effective treatment
options.

Storage Disorders

Glycogen Storage Diseases

Glycogen storage disorders, including Gaucher disease and Fabry disease, lead to lysosomal accumulation in the heart and other
organs. Other less common heritable storage disorders include mucopolysaccharidoses, myocardial oxalosis. Also included is
Friedreich ataxia that can present with either RCM or dilated cardiomyopathy.

Hemochromatosis

Hemochromatosis, which occurs as a result of iron overload, presents with heart failure, cirrhosis, impotence, and diabetes. The heart is
dilated with thickened ventricular walls presenting with systolic and diastolic dysfunction on echocardiography. The labs are diagnostic,
characterized by marked elevations of plasma iron, serum ferritin, and transferrin saturation, but lower than normal total iron-binding
capacity. While the endomyocardial biopsy is diagnostic, cardiac MRI is a sensitive marker of iron deposition. Clinical improvement is
achieved by subcutaneous therapy with deferoxamine.

Inflammatory Disorders

Endomyocardial Disease

There are two forms of endomyocardial disease: endomyocardial fibrosis, characterized by fibrosis of the endocardium of the ventricular
apex; and Loeffler endomyocarditis, which is primarily a hypereosinophilic state. Both have the same clinical features related to cardiac
involvement with features of diastolic dysfunction and thrombosis. The treatment involves decongestive therapy and treating the cause
if secondary.

Carcinoid Heart Disease

Carcinoid tumors are characterized by endocardial plaque on the tricuspid valve leading to regurgitation (low pressure severe tricuspid
regurgitation [TR]) or stenosis. The right side of the heart mostly involved. Management of the underlying carcinoid is the focus of
treatment.

Diagnosis

Electrocardiogram

Electrocardiogram of a patient with amyloidosis may show low voltage despite increased left ventricular wall thickness. Signs of left and
right atrial enlargement are seen on the ECG. The patients have atrial fibrillation in later stages of the disease. Atrial fibrillation is a
common arrhythmia in cardiac amyloidosis as well as in idiopathic restrictive cardiomyopathy.

Imaging

The chest radiograph mostly shows cardiomegaly with enlargement of both the atria and normal-sized ventricles. Pericardial effusion
can also present with cardiomegaly. Pulmonary congestion and pleural effusion can also be associated with the findings.

Echocardiographic findings are useful in identifying atrial enlargement with a preserved left ventricular ejection fraction to identify
restrictive cardiomyopathy. It is also useful in detecting abnormal diastolic function that progresses through the patterns of abnormal
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relaxation to a restrictive filling.

Cardiac magnetic resonance imaging can distinguish between the cardiomyopathies as seen in patients with sarcoidosis who have late
gadolinium enhancement in the basal and lateral segments. Hemochromatosis can also present with low signals on MRI. The utility of
MRI to distinguish restrictive cardiomyopathy from constrictive pericarditis with a thickened pericardium is well established.

Endomyocardial Biopsy

Endomyocardial biopsy is rarely performed as most of the diagnoses are made using imaging modalities but sometimes it is used in
patients with severe constrictive/restrictive physiology where the above modality fails and thoracostomy needs to be avoided.

Treatment

The primary causes of restrictive cardiomyopathy are rarely treatable. The main targets include the pulmonary and systemic venous
systems, which are congested, using optimal diuretic therapy. Since atrial output contributes 30% to the LV output, the occurrence of
atrial fibrillation is very detrimental. But the sinus rhythm is more important than just the rate control. Therefore, the use of amiodarone
for pharmacological cardioversion should be considered. Anticoagulation in atrial fibrillation is crucial, particularly in patients with
amyloidosis who are at a higher risk for thromboembolism. Digoxin can lead to arrhythmias especially in patients with amyloidosis, and
therefore should be avoided. Cardiac transplantation is rarely advised because of the underlying primary disease.

CLINICAL CORRELATION 14.3

It is important to distinguish restrictive cardiomyopathy from constrictive pericarditis using echocardiography, CT, and catheterization
data as both have similar clinical presentations but different treatment and outcomes.

Differentiating between Restrictive Cardiomyopathy and Constrictive Pericarditis

It is important to differentiate between these two entities as they mimic clinically but their treatment and prognosis differ significantly.

Since constrictive pericarditis is a normal heart in a constricted pericardium, the ventricular interdependence leads to ventricular
discordance. Unlike a normal pericardium, the changes in intrathoracic pressure are not transmitted to the intracardiac pressure
because of the calcium shell around the heart; the decrease in intracardiac pressure is much less than the fall in the intrathoracic
pressure during inspiration resulting in reduced filling to the left side of the heart. This reduced left ventricular filling leads to a reduction
in the mitral inflow velocity and shifting of the interventricular septum toward the left ventricle. Similarly, during expiration the increased
left ventricular filling leads to a rightward shift of the interventricular septum, which reduces the right ventricular filling with late diastolic
reversal of the hepatic venous flow. Different modalities including echocardiography can be used to detect exaggerated respiratory
interdependence and annular septal velocities, which are diagnostic of pericardial constriction. CMR or computed tomography is
essential for determining pericardial thickness and pericardial calcification (only on CT) in patients with constrictive pericarditis. On
catheterization, both the right and left ventricular end-diastolic pressure are equal or nearly equal in such patients. In addition, the
equalization of the filling pressures in the 4 cardiac chambers is a major hemodynamic criterion for the diagnosis of constrictive
pericarditis.

In patients with restrictive cardiomyopathy, the left ventricular end-diastolic pressure is usually higher than the right ventricular end-
diastolic pressure. The dip and plateau configuration of ventricular pressure (also called the square root sign) during diastole
characterizes restrictive cardiomyopathy. The presence of pulmonary hypertension, and left ventricular diastolic pressure which exceeds
that in the right ventricle by ≥5 mmHg, may favor a diagnosis of restrictive cardiomyopathy.

Dilated Cardiomyopathy
Dilated cardiomyopathy is classified under the category of heart failure with an ejection fraction less than or equal to 40% with left
ventricular enlargement in the absence of hypertension or valvular disease. Dilated cardiomyopathy occurs as a result of familial,
endocrine and metabolic issues, toxic, drug-induced, inflammatory, tachycardia-induced, peripartum, and stress-induced causes. Other
restrictive forms of cardiomyopathy in later stages can also present with dilated cardiomyopathy. One-third of cases of dilated
cardiomyopathy have a familial cause.

Clinical Presentation and Diagnosis

Natural History

The patients present with symptoms of left heart failure, which include exertional dyspnea in early stages and is later followed by
paroxysmal nocturnal dyspnea and orthopnea. A cough and frothy sputum can be the added to presentation when patients develop
pulmonary edema. Other symptoms, such as hemoptysis and syncope can also be observed. Patients can present with symptoms of
right heart failure with anasarca and abdominal distension. The later stages of heart failure can present with peripheral and central
cyanosis when severe LV dysfunction sets in. The family history is also important in patients with familial dilated cardiomyopathy. The
prognosis of dilated cardiomyopathy in the absence of heart failure is variable, but the presence of heart failure symptoms has a poor
outcome.

Physical Examination

The physical examination reveals signs of left heart failure with or without right heart failure. The patients present with rales, an elevated
jugular venous pressure (JVP) with a prominent v wave, cardiomegaly, peripheral edema, ascites, S3, and regurgitation murmurs of the
mitral and tricuspid valves. Likewise, in severe heart failure, Cheyne-Stokes breathing, pulsus alternans, and cyanosis may also be
present.

Common Etiologies

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Alcoholic Cardiomyopathy

Patients with a history of alcoholism are prone to alcoholic cardiomyopathy. Their presentation is just like familial dilated
cardiomyopathy. The gene polymorphism for alcoholic dehydrogenase increases the tendency for development of the disease. The
treatment includes abstaining from drinking alcohol.

Peripartum Cardiomyopathy

Mostly seen in multiparous African American females who become pregnant after 30 years of age especially in the last trimester and
within 6 months of delivery. Almost 50% of the patients recover completely but mortality is seen in 10% of the patients with the
diagnosis. The treatment is similar to other causes of dilated cardiomyopathy. The most important recommendation is to avoid further
pregnancies.

Cardiomyopathy Associated with Duchene Muscular Dystrophy

The mutation in the gene that expresses dystrophin causes lysis of the cardiomyocytes. The typical ECG pattern with a tall R wave in
the right precordial leads and deep Q waves in the lateral precordial leads with the limb leads is characteristic. A rapid progression of
heart failure with both atrial and ventricular tachyarrhythmia is also seen.

Cardiomyopathy Associated with Myotonic Muscular Dystrophy

The presentation is mostly syncope, sudden cardiac death due to involvement of the conduction system of the heart. Patients do
develop dilated cardiomyopathy. Treatment is with defibrillators or pacemaker implantation.

Drug-Induced Cardiomyopathy

Anthracycline derivatives, such as doxorubicin, cause dose-related cardiomyopathy. The presence of risk factors like concomitant use of
cyclophosphamide, use of radiation, hypertension, and preexisting heart disease cause an increased chance of developing
cardiomyopathy. Drug-induced cardiomyopathy generally develops within 3 months of the last dose.

Trastuzumab is a well-established receptor blocker that is used in patients with breast cancer. It has been shown to be associated with
dilated cardiomyopathy as a monotherapy or with other chemotherapeutic agents.

Takotsubo Cardiomyopathy

Most commonly seen in elderly postmenopausal syndrome, Takotsubo cardiomyopathy occurs after a major catecholamine surge in
patients with emotional or physical stress. ST elevation or deep T inversions are the findings on ECG. Patients present with acute chest
pain or shortness of breath. On catheterization, the coronaries are normal but typically show apical ballooning on LV angiography. Most
patients receive aspirin, β-blockers, and ACE inhibitors until the LV fully recovers. Complications including mitral regurgitation,
ventricular rupture, or ventricular tachycardia are seen. The LV recovers in weeks to months.

Arrhythmogenic Right Ventricular Cardiomyopathy

This is an autosomal dominant disease characterized by mutations of the genes encoding for desmosomal proteins, which causes
myocyte detachment and later, apoptosis. The myocytes are replaced by fibro-fatty tissue. The most common gene involved is
plakophilin-2. The patient presents with signs of right ventricular failure and ventricular tachyarrhythmia with a left bundle branch block
(LBBB) pattern. Cardiac MRI is diagnostic for arrhythmogenic right ventricular cardiomyopathy (ARVC). β-blockers, amiodarone,
implantable cardioverter defibrillator (ICD) implantation, and finally cardiac transplantation are the usual treatments.

CLINICAL CORRELATION 14.4

Tachycardia-induced cardiomyopathy is a reversible form of dilated cardiomyopathy. It is generally associated with more than 10,000 to
20,000 premature ventricular contractions (PVCs) in 24 hours, or with atrial fibrillation with a fast ventricular rate for more than 24 hours,
both of which can lead to this condition. Abolishing the tachycardia pharmacologically or with catheter ablation leads to clinical
improvement and recovery of the ventricular function.

Diagnosis

Electrocardiogram

Sinus tachycardia and left bundle branch block are the most common presentations on the ECG. Signs of left atrial with or without right
atrial enlargement, low voltage ECG with pericardial effusion, and nonspecific ST changes are also seen. Other common abnormalities
include atrial or ventricular arrhythmias. Atrial fibrillation is the second most common arrhythmia in dilated cardiomyopathy.

Biomarkers

BNP or N-terminal pro-BNP is a Class 1(the level of evidence is A) indication in patients with dilated cardiomyopathy to establish
prognosis and severity of disease. Other biomarkers, such as troponin I or T are not of major utility except to rule out acute coronary
event.

Imaging

The chest radiograph reveals cardiomegaly with a left ventricular contour. This cardiomegaly also involves left atrial and right atrial
enlargement features. When the late stages of heart failure sets in, there are signs of pulmonary venous hypertension that later present
as pulmonary edema when the left ventricular load rises. Pleural effusions on both sides can also be observed.

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An echocardiogram is a useful modality to show ventricular dilation of the left or both ventricles with thinned walls. This is associated
with reduced systolic LV or LV and RV function. Diastolic dysfunction of the left ventricle is also present. There is secondary pulmonary
hypertension that can be assessed during the testing. The left ventricle may contain an apical LV or LA thrombus. A stress test can be
done to rule out other etiologies.

Nuclear radionuclide ventriculography or cardiac MRI can be done to assess the ventricular function. MRI also helps to rule out
infiltrative or ischemic etiologies. Left heart catheterization is done to rule out ischemic etiology as well to estimate left ventricular end-
diastolic pressure (LVEDP). This also rule out the presence of a LV aneurysm. A right heart catheterization is usually not done but can
be useful when it is difficult to make a diagnosis.

Myocardial Biopsy

Myocardial biopsy is rarely done. The utility is only seen when the dilated cardiomyopathy is secondary to the infiltrative pathology.

Treatment

The management of patients with dilated cardiomyopathy includes ACE inhibitors or ARBs and β-blockers. Only 3 β-blockers:
bisoprolol, carvedilol, and sustained-release metoprolol, have been shown to reduce mortality in clinical trials in patients with dilated
cardiomyopathy. Patients with ischemic dilated cardiomyopathy should undergo revascularization and should be given statins in
addition to ACE inhibitors and β-blockers. An aldosterone receptor antagonist should be added to optimize medical therapy in patients
with symptoms of congestive heart failure with a low ejection fraction (EF) of less than 35% without diabetes (40% with diabetes) and
NYHA Class II to IV symptoms despite diuretics, β-blockers, and ACE inhibitors. Digoxin is also recommended as it reduces
hospitalization rates in heart failure patients. As atrial fibrillation is very common in dilated cardiomyopathy, digoxin does play a role in
controlling ventricular rates. Blood pressure control and statin therapy are also the important targets in the total pharmacological
therapy. Less than 2 g of salt a day with adequate exercise with cardiac rehabilitation are the other recommendations given to patients.
The anticoagulation in atrial fibrillation is crucial particularly in patients who are at a higher risk for thromboembolism.

Device Therapy

The indication for cardiac synchronization therapy with biventricular pacing is recommended if the patient has symptoms and a low EF
less than 35% with the QRS width greater than 150 ms. ICD is a Class IIa level of evidence (LOE) B indication in asymptomatic patients
with an EF less than 30% as a secondary prevention for sudden cardiac death. Cardiac transplantation is the surgical treatment
available for patients with end-stage heart disease as a result of dilated cardiomyopathy. But there are LV assist devices that can be a
destination therapy or a bridge to cardiac transplantation.

CLINICAL CORRELATION 14.5

Heart Mate II and Heart Mate III are the 2 left ventricular assist devices that are commonly used either as a destination therapy or
bridge therapy.

Key Points
Myocardial diseases of the heart include 3 types of cardiomyopathies: hypertrophic cardiomyopathy, restrictive cardiomyopathy,
and dilated cardiomyopathy.

The most common is dilated cardiomyopathy, which is also the endpoint of other cardiomyopathies in their end stage.

Hypertrophic cardiomyopathy presents with exertional dyspnea, ventricular arrhythmias, and sometimes with sudden cardiac
death.

β-blockers, automated implantable cardioverter defibrillator (AICD) placement, alcohol septal ablation, and surgical myectomy are
the treatment options for hypertrophic cardiomyopathy based on the type of presentation and the degree of the left ventricular
outflow obstruction.

Restrictive cardiomyopathy is associated with limited cardiac output and raised filling pressures in the ventricles leading to
symptoms of increased systemic pressure that can cause peripheral edema, ascites, and tender hepatomegaly, whereas exercise
intolerance and dyspnea are due to an elevated left ventricular diastolic pressure.

Restrictive cardiomyopathy needs to be distinguished from constrictive pericarditis using other modalities including
echocardiography, cardiac CT, and catheterization.

The most common cause of restrictive cardiomyopathy is amyloidosis. Most of the causes of restrictive cardiomyopathy are
irreversible and have a poor prognosis.

The cause of dilated cardiomyopathy is mostly familial, followed by idiopathic and other causes.

The presentation of dilated cardiomyopathy includes symptoms as a result of right and left heart failure. An enlarged heart on
chest x-ray with an LBBB pattern on the ECG is the most common finding.

Decongestive therapy using diuretics, reducing the afterload with ACE inhibitors or ARBs, using a biventricular pacemaker device
with or without an ICD, and cardiac transplantation are the available treatment options.

Case Studies
CASE 14.1 A 25-year-old male without any past medical history became unconscious while playing soccer. The patient was given
cardiac massage until the AMS arrived at which time he was given a biphasic shock of 150 J, after which he became conscious. While
in the ambulance, the paramedics found that his EKG showed signs of left ventricular hypertrophy. What should the treatment be to
prevent a recurrence of syncope?
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a. Amiodarone

b. β-blockers

c. ICD implant

d. Pacemaker placement

The correct answer is c.

The patient suffered an arrhythmia while playing soccer. This most often is ventricular tachycardia which degenerates into ventricular
fibrillation. This is a Class I indication for ICD placement in this patient.

CASE 14.2 A 50-year-old male is diagnosed with dilated cardiomyopathy with normal coronaries. He was managed on optimal doses of
metoprolol succinate, furosemide, lisinopril, and digoxin but is still having an NYHA Class IV indication. Which of the following is the
best follow-up management approach in this case?

a. BI V pacemaker

b. Starting the patient on spironolactone

c. Adding ARBs

d. Holding metoprolol succinate

The correct answer is b.

The patient has an NYHA Class IV indication despite optimal doses of β-blockers, ACE inhibitors, diuretics, and digoxin. The
aldosterone receptor blockers like spironolactone or eplerenone are an added therapy. Spironolactone has been shown to improve
symptoms of dyspnea as well as increase survival as seen in the RALES trial. Similar benefits of improved survival in patients of heart
failure on eplerenone have been demonstrated in the EPHESUS trial.

Suggested Readings
Ananthasubramaniam K. Hypertrophic cardiomyopathy. In: Crawford MH, eds. Current Diagnosis and Treatment: Cardiology. 4th ed.
New York, NY: McGraw-Hill; 2014: chap. 23.
Goldstein JA. Restrictive cardiomyopathy. In: Crawford MH, eds. Current Diagnosis and Treatment: Cardiology. 4th ed. New York, NY:
McGraw-Hill; 2014:chap. 24.
Hoit BD. Restrictive, obliterative, and infiltrative cardiomyopathies. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart.
13th ed. New York, NY: McGraw-Hill; 2011:chap. 34.
Klein K. Heart failure with reduced ejection fraction. In: Crawford MH, eds. Current Diagnosis and Treatment: Cardiology. 4th ed. New
York, NY: McGraw-Hill; 2014:chap. 26.
Lakdawala NK, Stevenson LW, Loscalzo J. Chapter 287: Cardiomyopathy and myocarditis. In: Longo DL, Fauci AS, Kasper DL,
Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012:chap.
287.
Lopes LR, Elliott PM. Hypertrophic cardiomyopathies. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New
York, NY: McGraw-Hill; 2011:chap. 59.
Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general
population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA study. Coronary artery risk development in
(young) adults. Circulation. 1995;92(4):785–789. [PubMed: 7641357]
Maron BJ, Olivotto I, Spirito P, et al. Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-
based patient population. Circulation. 2000;102:858–864. [PubMed: 10952953]
Mestroni L, Gilbert EM, Lowes BD, Bristow, MR. Dilated cardiomyopathies. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The
Heart. 13th ed. New York, NY: McGraw-Hill; 2011:chap 32.
Ommen SR, Nishimura RA, Tajik, AJ. Hypertrophic cardiomyopathy. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart.
13th ed. New York, NY: McGraw-Hill; 2011:chap. 33.

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