17 Cardiomyopathies
17.1 Dilated Cardiomyopathy
17.1.1 Basics
Definition
Dilated cardiomyopathy (DCM) is a myocardial disease characterized by enlargement of all cardiac chambers (Fig. 17.1). The dilatation of the left ventricle is usually most pronounced. DCM is associated with impairment of systolic and diastolic function.
Epidemiology
DCM is rare in childhood, but is still the most common form of cardiomyopathy in children. The incidence is 0.5 to 2.6 per 100,000 children. All age groups can be affected. In children, the disease often becomes manifest within the first 2 years of life. Boys are affected slightly more often than girls.
Etiology
For the majority of patients, the cause is unknown (idiopathic DCM). The cases in which triggers are detected were formerly referred to as secondary cardiomyopathies (Table 17.1). The most common cause of secondary cardiomyopathy is myocarditis. The most important triggers of secondary DCM include metabolic disorders, chemotherapy with anthracyclines, and neuromuscular diseases (e.g., Duchenne muscular dystrophy). Long-term strain on the heart caused by an arrhythmia may also lead to the clinical features of DCM. Ischemic myocardial damage must always be ruled out as a cause of DCM. Examples for the cause of myocardial ischemia are, for example, myocardial infarction (Kawasaki syndrome), or an anomalous origin of the left coronary artery from the pulmonary artery (Bland–White–Garland syndrome).
Viral infections (myocarditis) | Coxsackie B, adenovirus, echo virus, EBV, CMV, HSV, HIV, rubella, measles, mumps, varicella, influenza, parvovirus B19, hepatitis C virus, polio, rabies |
Bacterial infections | Diphtheria, mycoplasma, tuberculosis, Lyme disease, sepsis |
Parasites | Toxoplasma gondii, Ascaris |
Fungal infections | Histoplasma, Aspergillus, Candida, Cryptococcus |
Neuromuscular diseases | Becker, Duchenne, Emery–Dreifuss, limb-girdle muscular dystrophy; myotonic dystrophy, Friedreich ataxia, Kearns–Sayre syndrome, congenital myopathy, Barth syndrome |
Deficiencies | Anorexia nervosa, copper, iron, selenium, or thiamine deficiency |
Immunological diseases | Rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Kawasaki syndrome |
Hematological diseases | Thalassemia, sickle cell anemia |
Drugs or toxins | Anthracyclines, cyclophosphamide, chloroquine, cocaine, tricyclic antidepressants, interferon, alcohol, anabolic steroids |
Endocrine disorders | Hypo/hyperthyroidism, hypoparathyroidism, pheochromocytoma, hypoglycemia |
Metabolic diseases | Glycogen storage diseases, carnitine deficiency, impaired beta-oxidation or fatty acid transport, Refsum disease, mucopolysaccharidosis, oligosaccharidosis, mitochondropathies, defects in glucose/pyruvate metabolism and defects in the citric acid cycle, hemosiderosis |
Myocardial ischemia | Bland–White–Garland-Syndrome, myocardial infarction |
Arrhythmias | Supraventricular/ventricular tachycardia |
Malformation syndromes | Cri-du-chat (cat’s cry) syndrome |
Familial DCM | Different modes of inheritance, most often autosomal dominant, affecting mainly genes that encode myocardial proteins (actin, desmin, dystrophin) |
Genetic, familial forms account for over one-third of all DCM diseases. The most common is autosomal dominant inheritance. But autosomal recessive, X-chromosomal, and mitochondrial inheritance patterns have also been described. This mainly affects genes encoding myocardial proteins such as actin, desmin, dystrophin, and tafazzin.
Note
Due to the high proportion of familial DCM, family members of affected patients must undergo investigative echocardiography. The tests must be repeated regularly since late manifestations are also possible.
Pathology
Systolic dysfunction is the main functional symptom. Dilatation of the cardiac chambers and elevated end-diastolic pressure lead to increased ventricular wall tension. The dilatation is due to structural dilation, the remodeling of the actin–myosin scaffold of the sarcomeres. There is histological evidence of hypertrophy and hyperplasia of the myocytes and of fibrosis. Progressive fibrosis causes decreased compliance of the heart and thus leads to diastolic dysfunction.
17.1.2 Diagnostic Measures
Symptoms
The main clinical symptoms are signs of congestive heart failure: fatigue, failure to thrive, increased sweating, cool, pale skin, prolonged capillary refilling time, tachypnea, dyspnea, tachycardia, exertional cyanosis, hepatomegaly, and edema. Abdominal pain (due to liver congestion) and nausea may be nonspecific signs of heart failure. Palpitations suggest supraventricular or ventricular arrhythmias. A bulge in the chest (voussure) may be visible with pronounced cardiomegaly.
Auscultation
A gallop rhythm may often be auscultated, suggesting heart failure. The first heart sound is usually soft. Pulmonary hypertension may develop as a result of pulmonary congestion. In this case, the second heart sound is pronounced. A systolic murmur can be heard at the cardiac apex if there is mitral regurgitation. Moist crackles over the lungs suggest pulmonary edema.
Laboratory
BNP (B-type natriuretic peptide) can be used as a marker of heart failure. The laboratory inflammation markers and cardiac enzymes such as troponin I or CK-MB can be elevated in myocarditis.
The basic diagnostic tools to rule out specific and secondary cardiomyopathies are the following laboratory tests:
Blood/plasma:
Differential blood count
Viral titers: Coxsackie B, adenovirus, echo virus, EBV, HSV, HIV, cytomegalovirus, rubella, measles, mumps, varicella, influenza, parvovirus B19, hepatitis C virus, polio
Iron, ferritin (hemochromatosis)
Blood gas analysis, lactate, pyruvate, beta-OH butyrate, acetoacetate (fasting and postprandial), ammonia, glucose (mitochondropathy, organ acidopathy, disorder of fatty acid transport/oxidation)
Carnitine (disorder of fatty acid transport/oxidation)
Free fatty acids, beta-OH butyrate (in hypoglycemia; disorder of fatty acid transport/oxidation)
CK (myopathy), CK-MB, troponin
BNP
AST, ALT, creatinine, urea (hepatopathy, multisystem disease)
Tandem mass spectrometry (TMS; including disorders of fatty acid oxidation)
Acidic α-glucosidosis in leukocytes (Pompe disease in infants)
Urine:
Organic acids (organ acidopathy, respiratory chain defect, defect of fatty acid oxidation)
Glycosaminoglycans, oligosaccharides in the urine (mucopolysaccharidosis, glycoproteinosis)
ECG
The ECG is usually remarkable, but the changes are nonspecific. Common ECG findings in DCM are:
Sinus tachycardia
Signs of left ventricular hypertrophy
Low voltage
Repolarization disturbances
Intraventricular conduction disturbances, left bundle branch block, first degree atrioventricular block
Pathological Q waves suggestive of ischemia (In Bland–White–Garland syndrome there is typically a pattern of anterolateral myocardial ischemia with deep Q waves and ST-segment elevation and a T inversion in leads I, aVL, V5 and V6)
Arrhythmias: ventricular arrhythmias, but also atrial flutter/fibrillation
Chest X-ray
Cardiomegaly is present, usually the result of left atrial and left ventricular enlargement. There is widening of the tracheal bifurcation and elevation of the left main bronchus due to left atrial enlargement. There may also be signs of pulmonary congestion or pulmonary edema and in some cases pleural effusion as well.
Echocardiography
Indicative findings are enlargement of the cardiac chambers, especially of the left atrium and the left ventricle, and impaired contractility (Fig. 17.2). The enlarged left ventricle contracts poorly. The fractional shortening, stroke volume, and ejection fraction are substantially reduced as a sign of left ventricular dysfunction. These parameters are also used to monitor the course of the disease. In addition, there is diastolic dysfunction with decelerated relaxation. The hepatic veins and the inferior vena cava are enlarged as a sign of right heart failure. Pericardial and pleural effusions should be noted and thrombi in the ventricles and atria must be ruled out.
The origins of the coronary arteries must be visualized to be sure Bland–White–Garland syndrome (anomalous origin of the left coronary artery from the pulmonary artery) is not overlooked. Coronary artery aneurysms must also be noted and Kawasaki syndrome ruled out.
With color Doppler ultrasound, mitral or tricuspid regurgitation can often be detected, which is the result of dilatation of the valve annulus. Right ventricular pressure can be estimated based on tricuspid regurgitation using the Bernoulli equation.
Note
In dilated cardiomyopathy, an anomalous origin of the coronary arteries must always be ruled out.
Cardiac Catheterization
Indications for cardiac catheterization are primarily to rule out coronary anomalies and perform a myocardial biopsy. A myocardial biopsy may provide information on whether the cardiomyopathy is a postmyocarditis cardiomyopathy or other specific cardiomyopathy. But it is not without risks, especially if there is significantly impaired cardiac function. Myocarditis is associated with infiltration with lymphocytes and macrophages as well as with evidence of a viral genome.
Hemodynamic measurements show elevated left ventricular and right ventricular end-diastolic pressure, elevated pressure in the atria, and reduced cardiac output and sometimes pulmonary hypertension.
MRI
MRI is sometimes used in addition to echocardiography.
Differential Diagnosis
The following diseases must be ruled out:
Coronary anomalies, particularly Bland–White–Garland syndrome
Structural heart defects that can lead to an increasing (left) ventricular dysfunction or dilatation of the cardiac chambers (e.g., severe aortic stenosis, coarctation of the aorta, mitral regurgitation)
Specific forms of DCM (Table 17.1)
17.1.3 Treatment
No specific therapy is possible for idiopathic DCM. Diuretics, aldosterone antagonists, cardiac glycosides, ACE inhibitors, and beta blockers are used to treat heart failure (see Chapter 19).
Diuretics improve the symptoms of heart failure. ACE inhibitors reduce afterload and counteract remodeling. The role of cardiac glycosides is currently not definitively known. Beta blockers, particularly carvedilol, are gaining importance in the treatment of DCM. They protect the heart from chronic adrenergic stimulation, but they must be very carefully dosed and gradually increased because they can also cause dramatic deterioration of cardiac function.
In case of acute cardiac decompensation, catecholamines and other vasoactive substances are required. Dobutamine is usually used, which not only improves contractility but also decreases afterload. A combination with a phosphodiesterase inhibitor such as milrinone is useful. Milrinone also has positive inotropic characteristics and decreases afterload. In severe cases, treatment with a calcium sensitizer (levosimendan) or a combination of adrenaline and an afterload reducer (sodium nitroprusside) can also be attempted.
To prevent thromboembolic events, anticoagulation is required for poor cardiac function and/or atrial fibrillation.
Antiarrhythmic treatment is necessary in symptomatic arrhythmias. It should be noted, however, that most antiarrhythmic drugs have negative inotropic characteristics. Therefore, amiodarone is often needed. If there is treatment-refractory ventricular tachycardia, AICD implantation should be considered, even in children.
A biventricular pacemaker may be an option to improve ventricular function in patients with a left bundle branch block. The biventricular pacing may optimize synchronicity between right and left ventricle. In children, however, this therapeutic approach is still the subject of clinical trials.
Heart transplant is the last treatment option. A DCM in children is the most common indication for heart transplantation. An “assist device” (left ventricular assist device) may be required to bridge the time until the transplant.
One of the few secondary cardiomyopathies that are treatable with medication is a DCM due to a carnitine deficiency. Administration of carnitine usually leads to a significant improvement of cardiac function (100 mg/kg carnitine for 30 min as a short infusion, then 100 mg/kg/d as a continuous infusion over 24 to 72 h, then 50 to 100 mg/kg/d in 2 single doses).
Newer therapies with growth hormones or stem cells have not yet been established in clinical practice.
17.1.4 Prognosis
The prognosis is unfavorable due to the various causes and forms of the disease but difficult to predict for an individual case. The prognosis is best when the underlying cause is treatable (e.g., carnitine deficiency). Patients who had a recent viral infection associated with the development of DCM have a better prognosis. The prognosis in idiopathic DCM depends on cardiac function, left ventricular end-diastolic pressure, and the heart size, among other factors.
17.2 Hypertrophic and Hypertrophic Obstructive Cardiomyopathy
17.2.1 Basics
Synonyms: Hypertrophic obstructive cardiomyopathy (HOCM) was formerly known as idiopathic hypertrophic subaortic stenosis or asymmetric septal hypertrophy
Definition
Hypertrophic cardiomyopathy (HCM) is a genetic myocardiac hypertrophy that cannot be explained by another cause such as valve stenosis. In principle, any region in the left ventricle can be affected, but it usually affects the interventricular septum. It is often asymmetric—that is, more pronounced on the left side—and subaortic (Fig. 17.3).
If myocardial hypertrophy results in an obstruction of the left ventricular outflow tract it is called hypertrophic obstructive cardiomyopathy (HOCM).
Epidemiology
The incidence in the general population is about 1 in 500. It is one of the most common causes of sudden cardiac death in children and adults under age 35 years.
Genetics
About half of cases are due to autosomal dominant inheritance pattern with variable penetration. More than 200 mutations have now been detected which encode almost all proteins of the sarcomere (e.g., beta MHC, myosin binding protein C, troponin T). New mutations are likely involved in at least some isolated cases. Certain mutations appear to be associated with a particularly high risk for sudden cardiac death.
Pathology and Hemodynamics
Myocardial hypertrophy, usually involving the interventricular septum, is noted on macroscopic inspection. The cavity of the left ventricle is narrowed as a result, leading to varying degrees of obstruction of the left ventricular outflow tract. The obstruction is caused on the one hand by hypertrophy of the septum, which bulges into the left ventricular outflow tract, and on the other hand, the outflow tract is often additionally constricted by an unusual anterior position of the mitral valve. The mitral valve also moves toward the hypertrophied septum during the systole (systolic anterior movement, SAM). This phenomenon is probably the result of the Venturi effect: Due to the increased flow velocity and turbulence in the left ventricular outflow tract, a maelstrom is created that “sucks” the mitral valve leaflets into the outflow tract during the systole.
The obstruction of the left ventricular outflow tract can be aggravated by an increase in contractility (e.g., by positive inotropic agents). A reduced preload and/or afterload (e.g., volume depletion, afterload reducers, Valsalva maneuver) can increase the gradient across the outflow tract.
As a result of the rigidity of the left ventricle, diastolic left ventricular dysfunction develops, which may lead to dilatation of the left atrium and to pulmonary venous congestion.
Subendocardial ischemia may be due to a relative coronary insufficiency. There is an imbalance between the oxygen demand of the hypertrophied myocardium and the oxygen supply through the coronary arteries. There is often “myocardial bridging” of the coronary arteries as well. This term refers to the finding where the coronary arteries are surrounded by myocardial bridges that may compress them. Intima and media hyperplasia or hypertrophy of the intra-myocardial coronary arteries may also develop.
In the final stage of HCM, dilated cardiomyopathy may develop as a result of the systolic dysfunction. A histological feature of HCM is myocyte and myofibrillar disorder (myocardial fiber disarray).
17.2.2 Diagnostic Measures
Symptoms
Most patients are asymptomatic, so in most cases the disease is not diagnosed. If HCM is suspected, in addition to the typical symptoms, the patients should be asked about sudden cardiac deaths and unexplained deaths in the family (30–60% of affected adolescents or young adults have a positive family history).
Typical symptoms of HCM are:
Sudden cardiac death: The highest incidence of sudden cardiac death in HCM is among (young) adolescents. It typically occurs during sport or physical exertion. Ventricular fibrillation is usually the cause triggering death. Sudden cardiac death may be the first symptom of HCM.
Dyspnea: Dyspnea is the most common complaint in symptomatic patients. Usually it is the result of diastolic dysfunction of the left ventricle with elevated filling pressures and pulmonary venous reflux into the lungs.
Syncope: Syncope may be caused by arrhythmias or a decreased cardiac output under stress. Syncopes are associated with a significantly higher risk of sudden cardiac death.
Angina pectoris: imbalance between oxygen demand of the hypertrophied muscle and coronary supply.
Palpitations occur as a result of cardiac arrhythmias.
Arrhythmias: Examples of arrhythmias in HCM are supraventricular and ventricular extrasystoles, sinus pauses, atrioventricular block, atrial fibrillation and flutter, and supraventricular and ventricular tachycardias. Ventricular tachycardia is a risk factor for sudden cardiac death.
Heart failure: Symptoms of heart failure rarely occur in childhood. In severe cases heart failure is usually a result of diastolic dysfunction and subendocardial ischemia.
Auscultation
The first heart sound is normal. A paradoxical split may be heard in the second heart sound if there is extreme obstruction of the left ventricular outflow tract, since in these cases the pulmonary valve closes before the aortic valve. There is sometimes a gallop rhythm as a sign of diastolic dysfunction or heart failure.
If the left ventricular outflow tract is obstructed, there is a harsh systolic ejection murmur with point of maximum impulse (PMI) in the 4th left parasternal intercostal space. The systolic murmur is increased by exercise or a Valsalva maneuver, because this increases the gradient across the outflow tract.
In a mitral regurgitation there is a blowing, band-shaped systolic murmur with PMI above the apex of the heart and in the mid-axillary line.
ECG
Most affected patients have abnormalities in the ECG. However, the ECG changes are not specific.
Signs of left ventricular hypertrophy, ST segment changes, deep Q waves with reduced or absent R waves in the left precordial leads, possibly a broad biphasic P wave (P mitrale)
Arrhythmias: extrasystoles, AV block, sinus pause, ectopic atrial rhythm, left bundle branch block, atrial fibrillation/flutter, supraventricular/ventricular tachycardia, rarely pre-excitation in a WPW syndrome
Holter monitor
Checkups at least once a year are recommended for affected patients. It is particular important to note any ventricular tachycardias, which have an unfavorable prognosis and are associated with an increased risk of sudden cardiac death.
Echocardiography
Echocardiography is the method of choice for confirming the diagnosis. The following findings are typical:
Hypertrophy of the interventricular septum and/or left ventricular free wall
Narrow lumen of the left ventricle
Obstruction of the left ventricular outflow tract (increase of the gradient due to measures that reduce the preload, such as the Valsalva maneuver)
Assessment of the mitral valve: Frequently, abnormalities of the attachment apparatus (papillary muscles, tendinous cords) can be detected. Mitral regurgitation should be investigated.
Systolic anterior movement (SAM): If there is an obstruction of the left ventricular outflow tract, the anterior leaflet of the mitral valve moves toward the septum during systole. This phenomenon can be readily visualized in M mode (Fig. 17.4 b).
Fig. 17.4 Systolic anterior movement in hypertrophic obstructive cardiomyopathy.
If there is obstruction of the left ventricular outflow tract, the anterior leaflet of the mitral valve protrudes into the outflow tract during systole (a). This phenomenon is probably due to the Venturi effect: as a result of the turbulent flow in the outflow tract, the anterior mitral leaflet is “sucked” into the outflow tract. This phenomenon can be readily visualized in M mode (b).43 RV, right ventricle; LV, left ventricle; LA, left atrium; IVS, ventricular septum; Ao, aorta; MV, mitral valve; RVOT, right ventricular outflow tract; RVAW, right ventricular anterior wall; LVASW, left ventricular anterior septal wall; LVPW, left ventricular posterior wall; SAM, systolic anterior movement.
Diastolic dysfunction: There is typically a reduced E wave, and thus reduced E/A ratio in the Doppler curve of transmitral inflow, however, tissue Doppler usually allows a better assessment of diastolic function.
Note
Patients with confirmed HCM should have an echocardiography examination at least once a year. Family members of HCM patients should be closely monitored even if the echocardiogram is unremarkable, as late manifestations have been described (recommendation: family members under 18 years of age annually, family members over 18 every 5 years).
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