Cardiomyopathies

Cardiomyopathies are a heterogeneous group of diseases in which the major structural abnormality is limited to the myocardium. The four main cardiomyopathic groups are dilated, hypertrophic, restrictive, and arrhythmogenic right ventricular cardiomyopathy. Atrophic cardiomyopathy is a newer recognized group. Familial (genetic) and nonfamilial (acquired) forms of the diseases have been described.

Dilated Cardiomyopathy

Definition and epidemiology. Cardiac enlargement and systolic dysfunction in DCM result from a wide spectrum of genetic, inflammatory, toxic, and metabolic causes (Table 10.2), although most cases are idiopathic. Abnormal loading conditions such as hypertension, valvular disease, or coronary artery disease can lead to similar structural and functional changes; these conditions are not considered to be part of the DCM group and are discussed elsewhere.

Most cases are thought to result from acute viral myocarditis, a process described earlier. Exposures to cardiac toxins such as chemotherapeutic

agents, alcohol, cocaine, and radiation, along with deficiency of nutri- ents such as thiamine (causes beriberi), vitamin C (causes scurvy), car- nitine, selenium, phosphate, and calcium, can cause DCM. Peripartum cardiomyopathy is a rare cause of DCM that can develop during the last month of pregnancy and up to 6 months after delivery. The pathogenesis of this peripartum cardiomyopathy is not completely understood, and it is a diagnosis of exclusion. Risk factors include older maternal age, being African American, and having multiple pregnancies. Prolonged periods of supraventricular or ventricular tachycardia can lead to idiopathic DCM (i.e., tachycardia-induced cardiomyopathy). The structural and functional changes usually reverse after the rapid heart rhythm is controlled.

Familial forms of DCM may be responsible for 20% to 30% of cases. Specific mutations involve genes that encode proteins of the sarcomere, cytoskeleton, nuclear membrane, and mitochondria; many mutations remain unknown. The mode of inheritance is typically autosomal dominant, but it can be an X-linked or mitochondrial pattern.

Pathology. Marked enlargement of all four cardiac chambers is typical of DCM, although the disease sometimes is limited to the left TABLE 10.2

Disorder Description and Cause

Dilated cardiomyopathy Dilation and impaired systolic function of the left or both ventricles

Familial (genetic) Known or unknown genetic mutations

Nonfamilial Viral myocarditis, nonviral infective myocarditis, idiopathic (immune) myocarditis Toxins (drugs, alcohol)

Pregnancy (peripartum cardiomyopathy)

Nutritional (thiamine deficiency [beriberi], vitamin C deficiency [scurvy], selenium deficiency)

Endocrine (diabetes mellitus, hyperthyroidism, hypothyroidism, hyperparathyroidism, pheochromocytoma, acromegaly) Autoimmune (rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis)

Tachycardia induced

Hypertrophic cardiomyopathy Left and/or right ventricular hypertrophy, often asymmetrical (usually more prominent hypertrophy of the interventric- ular septum)

Familial (genetic) Mutations of sarcoplasmic proteins (several hundred described) Metabolic storage diseases of the myocyte

Restrictive cardiomyopathy Restrictive filling of the ventricles; ventricles are usually small, atria are markedly enlarged Familial (genetic) Mutations of sarcomeric proteins

Familial amyloidosis (transthyretin, apolipoprotein) Hemochromatosis

Desminopathy, pseudoxanthoma elasticum, glycogen storage diseases Unknown genetic mutations

Nonfamilial Amyloidosis, sarcoidosis, carcinoid, scleroderma

Endomyocardial fibrosis (hypereosinophilic syndrome, idiopathic, chromosomal defect, drugs) Radiation, metastatic cancer, anthracycline toxicity

Arrhythmogenic right ventricular Progressive fibrofatty replacement of the right and, to a lesser degree, left ventricular cardiomyopathy

Familial Unknown gene mutation

Mutations of intercalated disk protein, cardiac ryanodine receptor, transforming growth factor-β3 Unclassified Cardiomyopathies

Takotsubo (stress-induced) cardiomyopathy Transient dilation and dysfunction of the distal parts of the left ventricle (apical ballooning) in the setting of a stress- ful situation; usually resolves within weeks

Left ventricular noncompaction Characterized by prominent left ventricular trabeculae and deep intertrabecular recesses; familial in most cases, caused by arrest in the normal embryogenesis of the heart; apex and periapical regions of the left ventricle most affected; some patients remain asymptomatic, but others develop left ventricular dilation and systolic dysfunction Cardiomyopathies associated with muscular

dystrophies and neuromuscular disorders

Duchenne-Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, myotonic dystrophy, Friedreich’s ataxia, neurofibromatosis, tuberous sclerosis

Ion channelopathies Disorders caused by mutations in genes encoding ionic channel proteins; not considered cardiomyopathies because they are not associated with typical structural changes of the heart but rather manifest with electrical dysfunction;

some classifications include these disorders as cardiomyopathies: long QT syndrome, short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia

or right chambers. The dilation is out of proportion to the ventricular thickness. Histology reveals evidence of myocyte degeneration with irregular hypertrophy and atrophy of myofibers with often extensive interstitial and perivascular fibrosis.

Clinical presentation. DCM usually manifests with symptoms of heart failure such as fatigue, weakness, dyspnea, and edema. In some patients, the presenting episode is related to arrhythmia or an embolic event. On physical examination, signs of decreased cardiac output are often found, including cool extremities, narrow pulse pressure, and tachycardia. The cardiac examination reveals a laterally displaced apex. An S₃ gallop is common, along with murmurs of mitral and tricuspid regurgitation. Pulmonary edema manifests as auscultatory crackles over the lung fields, and breath sounds may be diminished if there are pleural effusions. In some patients, the clinical features of right ventricular heart failure may predominate, with jugular venous distention hepatomegaly, ascites, and peripheral edema.

Diagnosis. Standard diagnostic procedures include a chest radiograph, an electrocardiogram, serum markers, and echocardiography.

The radiograph shows cardiomegaly, pulmonary venous congestion, and pleural effusions. The electrocardiogram may reveal enlargement of the heart chambers along with other nonspecific ST- and T-wave abnormalities. Serum B-type natriuretic peptide (BNP) levels are elevated.

Echocardiography provides a comprehensive evaluation of ventricular size and function and valvular function, and it can show a ventricular thrombus. Similar information can be obtained with MRI.

A complete work-up should rule out ischemic, valvular, and hypertensive heart disease as the cause of myocardial dysfunction, and it should include evaluation for potentially reversible causes of DCM (e.g., alcohol, nutritional deficiencies). Myocardial biopsy may be considered if the cause of DCM is in question. In patients with a strong family history, a referral for genetic testing should be considered.

Treatment. Potential reversible causes of DCM should be addressed (e.g., alcohol cessation, correction of nutritional deficiencies, removal of cardiotoxic agents). Treatment should follow current ACC/AHA recommendations for the management of left ventricular systolic dysfunction and include β-adrenergic blockers, angiotensin-converting enzyme inhibitors, aldosterone receptor blockers, and diuretics.

Patients with idiopathic DCM who have persistent, moderate to severe symptoms of heart failure and a QRS duration longer than 120 milliseconds may benefit from cardiac resynchronization therapy with a biventricular pacemaker. Survival of patients with a left ventricular ejection fraction less than 35% despite maximal medical management is improved with the use of implantable cardioverter-defibrillators (ICDs). Patients with limiting heart failure symptoms despite use of the previously described therapies may be considered for heart transplantation or support with a left ventricular assist device.

Prognosis. The prognosis of patients with DCM depends on the response to medical therapy. Some patients have a significant improvement in symptoms and cardiac function, but in others, the disease is progressive and associated with a high mortality rate.

Hypertrophic Cardiomyopathy

Definition and epidemiology. Hypertrophic cardiomyopathy (HCM) is a disease state characterized by left ventricular hypertrophy with nondilated ventricular chambers in the absence of an apparent cause for hypertrophy (e.g., hypertensive disease, aortic stenosis). This is a relatively common genetic disease (1 case in 500 people in the general population) with autosomal dominant inheritance, although spontaneous mutations have been described. More than 1400 mutations identified among at least eight genes encoding proteins of the cardiac sarcomere have been described, with mutations of the β-myosin heavy chain being the most common.

Pathology. The main pathophysiologic abnormalities seen in HCM are left ventricular outflow obstruction, diastolic dysfunction, mitral regurgitation, and arrhythmias. Obstruction of left ventricular outflow occurs in roughly one half of the patients. During systole, the hypertrophied septum bulges into the left ventricular outflow tract, creating a gradient between the lower part of the left ventricular cavity and the left ventricular outflow. This causes high-velocity turbulent flow through the narrowed path, which results in a suction force (i.e., Venturi effect) that pulls the anterior leaflet of the mitral valve into the outflow tract. This worsens the obstruction and causes mitral regurgitation. Diastolic dysfunction from impaired relaxation properties of the abnormal myocardium causes marked elevation of left ventricular filling and pulmonary venous pressures, pulmonary congestion, and limitation in cardiac output. Patients with HCM are also predisposed to supraventricular and ventricular arrhythmias.

Clinical presentation. HCM is a heterogeneous cardiac disease with a diverse course and clinical manifestations. Most patients probably do not suffer sequelae from this disease during their lifetimes.

When the disease does result in complications, there are three relatively discrete but not mutually exclusive clinical manifestations: sudden cardiac death due to unpredictable ventricular tachyarrhythmia, most commonly in young asymptomatic patients (<35 years of age); heart failure characterized by exertional dyspnea (with or without chest pain) that may progress despite preserved systolic function and sinus rhythm; and atrial fibrillation that associates with various degrees of heart failure.

Heart failure symptoms result from the dynamic obstruction to left ventricular outflow and diastolic dysfunction. The most frequent symptom is dyspnea on exertion, followed by ischemic chest pain due to the increased oxygen demand by the hypertrophied ventricle and elevated wall tension that reduces blood flow to the subendocardium.

Abnormalities of the structure of small myocardial arteries in HCM can contribute to myocardial ischemia. Presyncope or syncope can result from outflow tract obstruction and an inability to increase cardiac output during exertion or from arrhythmias that can be triggered by exertion. In some, sudden death caused by ventricular arrhythmia is the initial manifestation of the disease.

Physical examination findings include pulsus bisferiens, a brisk initial upstroke in pulse followed by a midsystolic dip corresponding to the development of left ventricular outflow tract obstruction, followed by another rise in late systole. Cardiac examination may reveal a force- ful and sustained apical impulse, an audible S₄ gallop, and a harsh cre- scendo-decrescendo systolic murmur best heard along the left sternal border with radiation to the base of the heart.

Patients may also have an apical holosystolic murmur of mitral regurgitation. The intensity of the murmur of HCM varies with chang- ing degrees of obstruction. This can be observed with physiologic or pharmacologic maneuvers that change preload (i.e., left ventricular filling) or contractility. The intensity of the murmur increases with a Valsalva maneuver, with assuming a standing position, and after administration of nitroglycerin or inotropic drugs. The intensity of the murmur decreases with squatting, volume loading, and administration of β-blockers.

Diagnosis. Clinical diagnosis is made most commonly with echocardiography and increasingly with cardiac MRI. The diagnosis is based on a maximal left ventricular wall thickness of 15 mm or more; a wall thickness of 13 to 14 mm is considered borderline. The diagnosis can be made in the setting of other compelling information (e.g., family history of HCM). Genetic testing is available to confirm the diagnosis and to screen family members.

Treatment. The ACC/AHA hypertrophic cardiomyopathy guide- line recommends tailored therapy based on the individual patient. For

129 CHAPTER 10 Pericardial and Myocardial Disease

asymptomatic patients, the usefulness of β-blockade and verapamil may be considered. For patients symptomatic with dyspnea or angina, β-blockers and verapamil are recommended. If patients remain symptomatic, it is reasonable to add disopyramide to a β-blocker or verapamil.

Nonpharmacologic therapies should be considered in patients with considerable symptoms despite medical management. Septal reduction therapy is recommended only for patients with severe drug-refractory symptoms and left ventricular outflow tract obstruction (Fig. 10.3).

Use of ICD therapy for prevention of sudden death is guided by the perceived risk for ventricular arrhythmias in individual patients. Some of the characteristics that have been associated with this risk are prior cardiac arrest or sustained ventricular tachycardia; great (>30 mm) ventricular wall thickness; syncope, especially if exertional or recur- rent; and a first-degree relative with sudden cardiac death. Certain genotypes appear to convey an increased risk of sudden cardiac death.

Patients with HCM should be excluded from most competitive sports and should avoid strenuous exercise.

Prognosis. The clinical course of HCM varies. Sudden cardiac death is the leading cause of mortality. Heart failure symptoms may gradually progress and patients who are unresponsive to conventional therapy may require heart transplantation.

Restrictive Cardiomyopathies

Definition and epidemiology. RCM is an uncommon form of cardiomyopathy characterized by impaired ventricular filling of nondilated ventricles. RCM can be genetic or acquired. Causes include infiltrative disorders (e.g., amyloidosis, sarcoidosis, Gaucher’s disease, Hurler’s syndrome, fatty infiltration), storage diseases (e.g., hemochromatosis, Fabry’s disease, glycogen storage disease), other disorders (e.g., hypereosinophilic syndrome, carcinoid heart disease), drugs (e.g., serotonin, methysergide, ergotamine), and cancer treatment (e.g., irradiation, chemotherapy).

Pathology. In the purest form of the disease, the atria are disproportionately dilated compared with the normal ventricular size, and the left ventricle has normal or near-normal systolic function

in the absence of hypertrophy. Histology is normally nondistinctive and can reveal normal findings or nonspecific degenerative changes, including myocyte hypertrophy, disarray, and degrees of interstitial fibrosis.

Clinical presentation. Patients often have symptoms and signs of pulmonary and systemic congestion. The most common symptoms include dyspnea, palpitations, fatigue, weakness, and exercise intolerance due to poor cardiac output. As central venous pressure continues to increase in advanced cases, there may be hepatosplenomegaly, ascites, and anasarca. The chest radiograph shows atrial enlargement, pulmonary venous congestion, and pleural effusions.

Diagnosis. The diagnosis of RCM should be considered for patients with predominantly right ventricular heart failure without evidence of cardiomegaly or systolic dysfunction. The correct diagnosis often is not made until months or years after symptom onset. Constrictive pericarditis can mimic RCM and establishing the correct diagnosis can be challenging. Distinctive features of the two disorders are described in Table 10.3.

Treatment. Treatment of RCM focuses on alleviating the symptoms of heart failure. Diuretics are used for decongestion, but intravascular depletion may compromise ventricular filling and lead to reduced cardiac output and hypotension. Supraventricular tachyarrhythmias are poorly tolerated. In patients with conduction system disease such as advanced atrioventricular block, a permanent pacemaker may be indicated. Specific therapies for underlying disorders include chemotherapy in amyloidosis, phlebotomy and iron chelation therapy in hemochromatosis, and steroids in sarcoidosis and endomyocardial fibrosis.

Prognosis. The course of RCM depends on the pathology, and treatment is often unsatisfactory. In the adult population, the prognosis usually is poor, with progressive deterioration and death due to low- output heart failure.

Arrhythmogenic Right Ventricular Cardiomyopathy

Definition and epidemiology. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant disease characterized by specific myocardial pathology. The estimated prevalence of ARVC is about 1 case in 2000 to 5000 people, and it has a male pre- dominance.

Pathology. The myocardium of the right ventricular free wall is progressively replaced by fibrous and adipose tissue. Right ventricular function is abnormal, with regional akinesis or dyskinesis or global right ventricular dilation and dysfunction.

Clinical presentation. The disease typically manifests in young adults as palpitations, dizziness or syncope, or sudden cardiac death.

Symptoms of right ventricular failure are rare, despite evidence of right ventricular dysfunction on imaging studies.

Diagnosis. The clinical diagnosis of ARVC is suggested by integra- tion of the information from the clinical presentation (e.g., arrhythmias), electrocardiogram, family history, and imaging studies. When available, histologic examination of the right ventricle confirms the diagnosis. The resting electrocardiogram may be normal, but common abnormalities include incomplete or complete right bundle branch block, the so-called epsilon waves that follow the QRS complex, and inverted T waves in the precordial leads. Right ventricular dilation and systolic dysfunction can be seen with echocardiography and MRI. The latter modality can also show myocardial fat.

Treatment. Treatment consists of ICD therapy to prevent sudden cardiac death, but the indications for implantation are not well defined. Antiarrhythmics and radiofrequency ablation of ventricular tachycardia are used in patients with frequent arrhythmias, but they have not been shown to reduce the risk of sudden cardiac death.

Reduced outflow

Increased outflow

Incision line through hypertrophied basal septum

Mitral regurgitation

Septal myectomy

Fig. 10.3 (A to C) Schematic diagrams of a septal myectomy. (From Nishimura RA, Holmes DR Jr: Clinical practice: hypertrophic obstructive cardiomyopathy, N Engl J Med 350:1320-1327, 2004.)

Patients with a probable or definite diagnosis of ARVC should be excluded from competitive sports.

Prognosis. The prognosis for these patients remains uncertain.

Unclassified Cardiomyopathies

Some cardiomyopathies that do not fit the current categories are described in Table 10.2.

For a deeper discussion of this topic, please see Chapter 54,

“Diseases of the Myocardium and Endocardium,” in Goldman-Cecil Medicine, 26th Edition.

Differentiation of Restrictive Cardiomyopathy From Constrictive Pericarditis

Type of Evaluation Restrictive Cardiomyopathy Constrictive Pericarditis Physical examination Kussmaul sign present

Apical impulse may be prominent Regurgitant murmurs are common

Kussmaul sign may be present Apical impulse usually not palpable Pericardial knock may be present Electrocardiography Low QRS voltage (especially in amyloidosis)

Pseudoinfarction pattern Bundle branch blocks AV conduction disturbances Atrial fibrillation

Low QRS voltage

Repolarization abnormalities

Chest radiography Calcification of the pericardium may be present

Echocardiography Marked enlargement of the atria

Increased wall thickness (especially in amyloidosis)

Atria usually of normal size Normal wall thickness

Pericardial thickening may be seen Doppler echocardiography Restrictive mitral inflow (dominant E wave with short

deceleration time)

No significant variation (<10%) of transvalvular veloci- ties with respiration

Reversal of forward flow in hepatic veins during inspiration

Restrictive mitral inflow (dominant E wave with short deceleration time) Increased velocity of RV filling and decreased velocity of LV filling with

inspiration; opposite with expiration; variation in velocity exceeds 15%

Reversal of forward flow in hepatic veins during expiration

Cardiac catheterization Prominent atrial x and y descents (w sign) Dip-and-plateau appearance of ventricular diastolic

pressure

Diastolic pressures increased but not equalized; LV diastolic pressure higher than RV diastolic pressure

Prominent atrial x and y descents (w sign)

Dip-and-plateau appearance of ventricular diastolic pressure Increase and equalization of diastolic pressures

Discordance of RV and LV peak systolic pressures (with inspiration, RV systolic pressure increases and LV systolic pressure decreases) Endomyocardial biopsy May reveal specific cause of restrictive cardiomyop-

athy

No specific findings on endomyocardial biopsy Pericardial biopsy may reveal abnormality Computed tomography, magnetic

resonance imaging

Pericardial thickening

AV, Atrioventricular; LV, left ventricular; RV, right ventricular.

Dalam dokumen Cecil Essentials of Medicine(Edward J. Wing MD FACP FIDSA (editor) etc.) (Halaman 152-156)

Cardiomyopathies

Cardiomyopathies

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