Pediatric Dilated Cardiomyopathy

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Dilated cardiomyopathy (DCM) refers to dilation and systolic dysfunction of the ventricles (predominantly the left ventricle) with or without congestive cardiac failure. It is the most common form of heart muscle disease in children. See the image below.

Onset of DCM is usually insidious but may be acute in as many at 25% of patients. Approximately 50% of patients with DCM have a history of preceding viral illness.

Initial presenting symptoms typically include the following:

Cough

Poor feeding

Irritability

Shortness of breath

Pallor

Sweating

Fatigability

Failure to gain weight

Decreased urine output

Wheezing may be an important clinical sign, suggesting congestive heart failure in infants.

Other symptoms at presentation, found in approximately 20% of patients, are as follows:

Chest pain

Palpitations

Orthopnea

Hemoptysis

Frothy sputum

Abdominal pain

Syncope

Neurologic deficit

See Presentation for more detail.

Echocardiography and Doppler studies form the basis for the diagnosis of DCM. They are the most informative noninvasive tests for diagnosing the type of cardiomyopathy and the degree of dysfunction in the heart muscle.

Chest radiography may reveal cardiomegaly and pulmonary edema. Cardiomegaly that is incidentally detected on a chest radiograph or an arrhythmia that is incidentally detected on an electrocardiogram (ECG) may be the basis for initial cardiac referral. ECG may show the degree of left ventricular enlargement and reveal any abnormal heart rhythm.

The complete blood count, erythrocyte sedimentation rate, and C-reactive protein level may show evidence of acute inflammation in patients with DCM in the presence of active myocarditis.

First-pass test and multiple gated acquisition (MUGA) scans help to measure the left and right ventricular stroke volumes and cardiac outputs. They are also helpful in documenting dyskinetic segments in the ventricular wall.

Invasive procedures

Invasive procedures such as cardiac catheterization should be performed by experienced pediatric cardiologists and only when absolutely essential. Children with DCM are at a particular risk for complications during cardiac catheterization studies and angiography. At present, preparation for cardiac transplantation and need for myocardial biopsy are the main indications for performing the procedure.

Myocardial biopsy is usually performed in preparation for cardiac transplant and post-transplant follow-up monitoring.

See Workup for more detail.

Pharmacologic therapy

Initial therapy in DCM is largely directed at the symptoms of the underlying heart failure. Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers are used. Diuretics may provide an improvement in symptoms, whereas ACE inhibitors appear to prolong survival. Beta-blocker therapy in children with chronic heart failure due to DCM has been shown to improve symptoms and left ventricular ejection fraction.

Device implantation

Automatic implantable cardioverter-defibrillators (ICDs) reduce sudden death, and their efficacy has been clearly demonstrated in adults with chronic congestive heart failure. However, their use in children has been limited.

Cardiac resynchronization therapy with AV synchronous biventricular pacing has been successful in some children with DCM and left bundle branch block (LBBB).

Cardiac transplantation is currently the optimal treatment for DCM-induced resistant chronic heart failure in children.

See Treatment and Medication for more detail.

Idiopathic dilated cardiomyopathy (DCM) refers to congestive cardiac failure secondary to dilatation and systolic dysfunction (with or without diastolic dysfunction) of the ventricles (predominantly the left ventricle) in the absence of congenital, valvular, or coronary artery disease or any systemic disease known to cause myocardial dysfunction. DCM is the most common type of heart muscle disease in children.

All four cardiac chambers are dilated and are sometimes hypertrophied. Dilation is more pronounced than hypertrophy, and the left ventricle is affected more often than the right ventricle. The cardiac valves are intrinsically normal, although the mitral and tricuspid valve rings are dilated, and the valve leaflets do not appose each other in systole, giving rise to varying degrees of mitral regurgitation, tricuspid regurgitation, or both.

Persistent mitral regurgitation leads to thickening of the mitral valve leaflets, and, at times, distinguishing this thickening from other causes of mitral regurgitation is difficult. Thrombus formation (secondary to the low-flow cardiac output state) is often seen in the left ventricular apex and, at times, is seen in the atria. Occasionally, the right ventricle is preferentially involved in the cardiomyopathic process; this often indicates a familial basis.

Onset is usually insidious but may be acute in as many as 25% of patients with DCM, especially if exacerbated by a complicating lower respiratory infection. Cough, poor feeding, irritability, and shortness of breath are usually the initial presenting symptoms. In a patient with established disease, features of congestive heart failure are dominant. (See Presentation.)

Echocardiography and Doppler studies form the basis for the diagnosis of dilated cardiomyopathy (DCM) in most patients (see Workup). Cardiac transplantation is currently the optimal treatment for DCM-induced resistant chronic heart failure in children (see Treatment).

Patient education is a continuous process from the time of diagnosis. Explain the disease process, management, and prognosis to parents and older patients. In cases of familial DCM, patients and their families should be told about the genetic implications. For patient education information, see the Heart Center, as well as Heart and Lung Transplant.

Injury to the myocardial cell is the initiating factor that leads to cell death. If considerable cell loss occurs, the myocardium fails to generate enough contractile force to produce adequate cardiac output. This results in the activation of the following compensatory mechanisms:

The renin-angiotensin-aldosterone system

Sympathetic stimulation

Antidiuretic hormone production

Release of atrial natriuretic peptide

These compensatory mechanisms help to maintain cardiac output in the initial phase; however, as myocardial damage progresses, persistent and excessive activation can be detrimental to cardiac function, leading to overt congestive heart failure.

The theory that left ventricular noncompaction is an underlying factor in the development of DCM in young infants has received much attention. [1, 2, 3]

Over-stretching of the ventricles causes myocardial thinning, cavity dilation, secondary valvular regurgitation, and compromised myocardial perfusion. The resulting subendocardial ischemia perpetuates myocyte damage.

Myocardial remodeling is an important contributor to worsening heart failure. [4] Lost myocyte cells are replaced with fibrous tissue, thereby decreasing the compliance of one or more ventricles and adversely affecting performance. Aldosterone, angiotensin II, catecholamines, endothelins, and mechanical factors, such as excessive myocardial stretch and ischemia, have been identified as mediators of remodeling. The degree of left ventricular dilatation has been reported to influence short-term outcome in children listed for transplant. [5]

Apoptosis (ie, programmed cell death) is now believed to play a role in the continuing loss of myocardial cells in chronic heart failure. Overloading of myocytes possibly triggers apoptosis without fibrosis.

Heightened peripheral vasoconstriction, abnormal and excessive remodeling of the peripheral vasculature, and abnormalities in endothelium-dependent vasodilation contribute to the progression of heart failure. Abnormal responses to muscarinic stimulation along with a defect in the endothelial nitric oxide pathway have been suggested as the potential underlying mechanisms.

Altered gene expressions resulting in calcium-handling abnormalities, downregulation of myosin or conversion to the less-active beta isoform, and abnormal beta-receptor signal transduction have all been identified at the molecular level in the chronically failing heart.

Various factors have been identified as causes of myocardial damage. These are presented in Table 1, below. However, in the vast majority of patients, no specific etiology is demonstrable (ie, idiopathic DCM). Systemic carnitine deficiency and anthracycline-induced cardiomyopathy are notable exceptions. Three major factors have been implicated in the pathogenesis of myocardial damage in DCM: preceding viral myocarditis, autoimmunity, and underlying genetic predisposition.

Table 1. Factors Identified as Causes of Myocardial Damage (Open Table in a new window)

Category Of Factors

Specific Factors

Viral infections (myocarditis)

Coxsackievirus B, human immunodeficiency virus, echovirus, rubella, varicella, mumps, Epstein-Barr virus, cytomegalovirus, measles, polio

Bacterial infections

Diphtheria, Mycoplasma, tuberculosis, Lyme disease, septicemia

Rickettsia

Psittacosis, Rocky Mountain spotted fever

Parasites

Toxoplasma, Toxocara, Cysticercus

Fungi

Histoplasma, coccidioidomycoses, Actinomyces

Neuromuscular disorders

Duchenne or Becker muscular dystrophies, Friedreich ataxia, Kearns-Sayre syndrome, other muscular dystrophies

Nutritional factors

Kwashiorkor, pellagra, thiamine deficiency, selenium deficiency

Collagen vascular diseases

Rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Kawasaki disease

Hematological diseases

Thalassemia, sickle cell disease, iron deficiency anemia

Coronary artery diseases

Anomalous left coronary artery from pulmonary artery, infarction

Drugs

Anthracycline, cyclophosphamide, chloroquine, iron overload

Endocrine diseases

Hypothyroidism, hyperthyroidism, hypoparathyroidism, pheochromocytoma, hypoglycemia

Metabolic disorders

Glycogen-storage diseases, carnitine deficiency, fatty acid oxidation defects, mucopolysaccharidoses

Malformation syndromes

Cri-du-chat (cat-cry) syndrome

Epidemiologic, serologic, and molecular studies have detected evidence of enteroviral infection, in particular coxsackievirus B, in 20-25% of patients. Evidence also implicates various other viruses. In fact, the most common associated viruses appear to vary over time. [6, 7] Currently, coxsackievirus B is likely a less common cause of DCM than in the past.

Currently, no methods can be used to distinguish cardiovirulent strains of enteroviruses from those that are not virulent. Furthermore, the presence of a virus in a patient with DCM does not necessarily establish a causal relationship. Demonstration of viral DNA or RNA by polymerase chain reaction (PCR) is a more reliable method for revealing viral myocarditis. Unfortunately, obtaining myocardial tissue is invasive.

The exact mechanism of myocardial damage (rapid destruction or a long-term slowing of cardiomyocyte function) also remains unclear. [8]

Animal studies have shown that DCM is an autoimmune disease in genetically predisposed strains of mice. In humans, approximately 30-40% of adult patients with DCM have organ-specific and disease-specific autoantibodies. The absence of these antibodies in the remaining patients may be related to the stage of disease progression.

It has been postulated that an insult such as viral myocarditis initiates an autoimmune process with superantigen-triggered immune responses, resulting in massive T-lymphocyte activation and myocardial damage.

Genetic causes account for 25-50% of DCM cases. [9] The role of genetic factors is exemplified by the studies on familial DCM. [10, 11, 12] Patients with familial DCM have an increased frequency of human leukocyte antigen (HLA)-DR4. The frequency of HLA-DQA1 0501 alleles has been reported to be significantly higher in patients with idiopathic DCM. [13]

Autosomal dominant and recessive inheritance, X-linked transmission, and polygenic and mitochondrial inheritance have all been documented. Presently known DCM genetic loci are summarized in Table 2, below.

Table 2. Summary of Genetic Loci and Disease Genes for Familial Dilated Cardiomyopathy (Open Table in a new window)

Clinical Pattern

Identified Genetic Loci

Identified Disease Genes

Autosomal dominant (AD)

10q21-10q23, 9q13-q22, 1q32, 15q14, 2q31, 1q11-21

Actin, desmin, lamin A/C

AD with conduction defect

1p1-1q1, 3p22-3p25

X-linked (XL)

Xp21

Dystrophin

XL cardio-skeletal (Barth syndrome)

Xq28 (gene G4.5)

Tafazzin

Mutation screening of the exons that code for actin, β myosin heavy chain (MYH7 gene), cardiac troponin T (TNNT2 gene), phospholamban (PLN gene), titin, αβ-crystallin, and the cardio-specific exon of metavinculin (VCL gene) could be helpful in detecting some forms of familial DCM.

Anthracyclines, which are widely used in the management of childhood malignancies, account for as many as 30% of cases of DCM in the United States and a lesser percentage in other countries.

Besides DCM, the other manifestations of anthracycline cardiotoxicity include restrictive cardiomyopathy (symptomatic and asymptomatic), cardiac arrhythmias [14] , asymptomatic left ventricular enlargement, and more subtle changes of cardiac function.

Cardiotoxicity has two types: early onset and late onset. The early-onset type may be acute nonprogressive or chronically progressive.

Acute-onset type is defined as left ventricular dysfunction during or immediately following infusion of anthracycline and is attenuated by discontinuation of therapy. With use of low-dose regimens, this type is becoming rare.

Electrocardiographic (ECG) changes include nonspecific ST segment and T wave changes, decreased QRS voltage, prolonged QT interval, and sinus tachycardia. Less commonly, ventricular, junctional, or supraventricular tachycardia or atrioventricular and bundle branch blocks. Blood levels of cardiac troponin T (cTnT) are a specific marker of this type of injury.

Early-onset chronically progressive toxicity presents within one year of completion of therapy and persists or progresses even after discontinuation of therapy. Clinical features are similar to any other type of cardiomyopathy and include ECG changes, left ventricular dysfunction, arrhythmias, reduced exercise-stress capacity, and even overt signs of heart failure. Blood levels of cTnT are elevated. Presence of early-onset cardiotoxicity is believed to be a harbinger of poor patient outcome.

Late-onset toxicity clinically manifests after a latent period of one or more years following completion of therapy. This type of manifestation is presumably due to diminished left ventricular contractility and an inappropriately thin left ventricular wall, resulting in elevated wall stress and progressive left ventricular dysfunction.

Myocyte loss underlies all these sequelae, and alteration of myocellular protein transcription by anthracyclines may contribute. Thus, the latent period is not latent at all, and more sensitive markers may be able to detect the changes earlier. Late-onset asymptomatic toxicity has also been reported, but more detailed questioning often reveals easy fatigability or dyspnea in many of these patients.

Risk factors contributing to the development of anthracycline cardiotoxicity include the following:

Total cumulative dose (20% mortality with cumulative dose >550 mg/m2, 65% frequency of subtle echocardiographic changes with dose >400 mg/m2, and histologic evidence of toxicity with >240 mg/m2)

Female sex (higher cellular concentrations because of higher body fat percentage)

Young age

Rate of drug administration (maximum risk with doses >50 mg/m2/dose)

Concomitant cardiac radiation exposure or use of amsacrine

Black race

Trisomy 21

In the United States, the reported incidence rate of DCM is 0.57 cases per 100,000 children. [15] The incidence rate in Finland is 2.6 cases per 100,000 children. [16] In the United Kingdom, the incidence rate is 0.87 cases per 100,000 individuals older than 16 years. [17] No reliable figures are available for the rest of the world. Genetic causes account for more than 30% of DCM cases.

DCM is reportedly more common in boys than in girls, and some forms are clearly X-linked. [15] All age groups are affected. However, studies suggest that DCM is more common in infants (age < 1 y) than in children. [15] Fetal presentation is uncommon.

Approximately one third of patients with DCM die of the disease, one third continue to have chronic heart failure requiring therapy, and one third of patients experience improvement in their condition. Causes of death include heart failure, ventricular arrhythmias, and transplantation-related complications (less common).

Children with underlying muscle disorders with progressive dilatation of the heart and worsening heart failure have a worse prognosis compared with patients with idiopathic DCM. [18] If a treatable cause is discovered, prognosis is better. A history of viral illness in the three months before onset may suggest a better prognosis. Prognosis is worst for cardiomyopathy secondary to storage diseases that do not have effective therapy.

In DCM with no obvious detectable etiology, outcome depends on severity of myocardial dysfunction, improvement during the first year after onset, compliance with therapy, and availability of timely transplant.

The degree of depression of fractional shortening or ejection fraction on initial echocardiography, elevation of left ventricular end diastolic pressure, and cardiothoracic ratio have all been applied as predictors of outcome, although they are not often predictive. Other possible prognostic factors include age at onset (better for infants), presence of symptomatic arrhythmias, and thromboembolic episodes. A recent review of outcomes from the Pediatric Cardiomyopathy Registry places the incidence of sudden cardiac deaths at 3% and suggests age at diagnosis younger than 14.3 years, left ventricular dilation, and left ventricular posterior wall thinning as predictors of risk. [19]

Arrhythmic death can occur even after the left ventricular ejection fraction has returned to normal.

Following cardiac transplant, survival rates of as much as 77% at 1 year and as much as 65% at 5 years have been reported in children.

Mortality and morbidity have greatly decreased because of advances in medical management. Studies from 1975-1990 reported 70% survival at 2 years and 52% survival at 11.5 years of follow-up. [20, 21, 22, 23, 16, 24] Studies from 1992-1997 document more than 85% survival at 5 years. However, a study from Texas that included patients diagnosed from 1990-2004 found reported a survival of only 40% at a mean followup of 6.2 years. [25]

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Category Of Factors

Specific Factors

Viral infections (myocarditis)

Coxsackievirus B, human immunodeficiency virus, echovirus, rubella, varicella, mumps, Epstein-Barr virus, cytomegalovirus, measles, polio

Bacterial infections

Diphtheria, Mycoplasma, tuberculosis, Lyme disease, septicemia

Rickettsia

Psittacosis, Rocky Mountain spotted fever

Parasites

Toxoplasma, Toxocara, Cysticercus

Fungi

Histoplasma, coccidioidomycoses, Actinomyces

Neuromuscular disorders

Duchenne or Becker muscular dystrophies, Friedreich ataxia, Kearns-Sayre syndrome, other muscular dystrophies

Nutritional factors

Kwashiorkor, pellagra, thiamine deficiency, selenium deficiency

Collagen vascular diseases

Rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Kawasaki disease

Hematological diseases

Thalassemia, sickle cell disease, iron deficiency anemia

Coronary artery diseases

Anomalous left coronary artery from pulmonary artery, infarction

Drugs

Anthracycline, cyclophosphamide, chloroquine, iron overload

Endocrine diseases

Hypothyroidism, hyperthyroidism, hypoparathyroidism, pheochromocytoma, hypoglycemia

Metabolic disorders

Glycogen-storage diseases, carnitine deficiency, fatty acid oxidation defects, mucopolysaccharidoses

Malformation syndromes

Cri-du-chat (cat-cry) syndrome

Clinical Pattern

Identified Genetic Loci

Identified Disease Genes

Autosomal dominant (AD)

10q21-10q23, 9q13-q22, 1q32, 15q14, 2q31, 1q11-21

Actin, desmin, lamin A/C

AD with conduction defect

1p1-1q1, 3p22-3p25

X-linked (XL)

Xp21

Dystrophin

XL cardio-skeletal (Barth syndrome)

Xq28 (gene G4.5)

Tafazzin

Approach

Findings

Conclusion

Clinical suspicion

Infants and young children: Shortness of breath, feeding difficulties, wheezing, failure to thrive, recurrent chest infections, hepatomegaly, cardiomegaly

Older children: Dyspnea, dependent edema, elevated jugular venous pressure, cardiomegaly

Probable heart disease with heart failure

Chest radiography

Cardiomegaly, pulmonary plethora, prominent upper lobe veins, pulmonary edema, pleural effusion, collapsed left lower lobe

High probability of heart failure with or without chest infection

Electrocardiography

Low-voltage complexes

Pericardial effusion

Presence of Q waves and inversion of T waves in leads I, II, aVL, and V4 through V6 (anterolateral infarction pattern)

Anomalous left coronary artery from pulmonary artery

Significant arrhythmia

Dilated cardiomyopathy secondary to arrhythmia

Left ventricular or biventricular hypertrophy with or without left ventricular strain pattern

Often unhelpful

Doppler echocardiographic studies*

Significant congenital heart disease

Diagnose primary disease

Significant pericardial effusion with satisfactory left ventricular ejection fraction

Diagnose pericardial effusion

Left ventricular posterior wall hypokinesia with hyperechoic papillary muscles, retrograde continuous flow into proximal pulmonary artery

Diagnose anomalous left coronary artery from pulmonary artery

Dilated left ventricle (>95th percentile) with global hypokinesia (fractional shortening < 25%, ejection fraction < 50%), and no demonstrable structural heart disease

Diagnose dilated cardiomyopathy

Approach

Findings

Conclusion

Clinical features

Positive family history

Genetic cause for dilated cardiomyopathy

Acute or chronic encephalopathy, muscle weakness, hypotonia, growth retardation, recurrent vomiting, lethargy

Inborn error of metabolism involving energy production

Coarse or dysmorphic features, organomegaly, skeletal abnormalities, short stature, chronic encephalopathy, cherry-red spot in eyes

Storage diseases

Skeletal muscle weakness without encephalopathy

Neuromuscular disorders

Blood investigations

High blood urea nitrogen and creatinine levels, low calcium and magnesium levels, electrolyte disturbances

Help in the initial management; occasionally point to a cause of dilated cardiomyopathy, especially in neonates

Elevated acute-phase reactants and cardiac enzyme levels

Myocarditis

Positive viral titers

Viral myocarditis

Low serum carnitine levels

Systemic carnitine deficiency

Hypoglycemia with low or no acidosis (ketosis)

1. High insulin levels, low free fatty acid

2. Low insulin levels, high free fatty acid

1. Infant of diabetic mother, nesidioblastosis

2. Defect in fatty acid oxidation or carnitine metabolism

Hypoglycemia with moderate or high acidosis (ketosis)

1. Low or normal lactate and abnormal urine and serum organic acid levels

1. High lactate

1. Organic (propionic, methylmalonic) acidemias, or ß-ketothiolase deficiency

2. Glycogen storage disease, Bath and Sengers syndromes, pyruvate dehydrogenase deficiency, mitochondrial enzyme deficiency

Hyperammonemia with acidosis

Organic acidemias (as above)

Specific enzyme assay

Confirms enzymatic defect

Absence of above physical and biochemical abnormalities

Post myocarditis or idiopathic dilated cardiomyopathy

Cardiac catheterization

Evaluate hemodynamics

Useful to predict prognosis and evaluate for transplant

Coronary angiography

Abnormal origin of left coronary artery from pulmonary artery

Anomalous left coronary artery from pulmonary artery

Myocardial biopsy

Myocyte hypertrophy and fibrosis without lymphocytic infiltrate

Dilated cardiomyopathy

Inflammatory cell infiltration, cell necrosis

Myocarditis

Special stains

Mitochondrial or infiltrative diseases

Molecular studies (on blood, fibroblasts, or myocardial cells)

Nucleic acid hybridization studies

Polymerase chain reaction studies

Myocarditis

DNA mutation analysis

Identifies specific genetic defect

Poothirikovil Venugopalan, MBBS, MD, FRCPCH Consultant Pediatrician with Cardiology Expertise, Department of Child Health, Brighton and Sussex University Hospitals, NHS Trust; Honorary Senior Clinical Lecturer, Brighton and Sussex Medical School, UK

Poothirikovil Venugopalan, MBBS, MD, FRCPCH is a member of the following medical societies: British Congenital Cardiac Association, Paediatrician with Cardiology Expertise Special Interest Group, Royal College of Paediatrics and Child Health

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Ameeta Martin, MD Clinical Associate Professor, Department of Pediatric Cardiology, University of Nebraska College of Medicine

Ameeta Martin, MD is a member of the following medical societies: American College of Cardiology

Disclosure: Nothing to disclose.

Syamasundar Rao Patnana, MD Professor of Pediatrics and Medicine, Division of Cardiology, Emeritus Chief of Pediatric Cardiology, University of Texas Medical School at Houston and Children’s Memorial Hermann Hospital

Syamasundar Rao Patnana, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, American College of Cardiology, American Heart Association, Society for Cardiovascular Angiography and Interventions, Society for Pediatric Research

Disclosure: Nothing to disclose.

Pediatric Dilated Cardiomyopathy

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