Cardiomyopathy in Children1

Cardiomyopathy is defined as any disease of the myocardium associated with cardiac dysfunction. The classification of various types of cardiomyopathies is based on the dominant pathophysiology. The latest WHO/ISFC 1996 classification, takes into account both, the etiology and pathogenesis (Table 1.1).¹

Dilated cardiomyopathy (DCM) is the most common form, accounting for 60 to 70 percent of all cardiomyopathies. It is characterized by enlargement of ventricular cavity, usually the left ventricle, and impairment of systolic function. It may be the result of myocardial damage produced by a variety of infections, toxins or metabolic agents. Enterovirus is the most common virus resulting in myocarditis. A short history, preceded by a viral infection, either respiratory or gastrointestinal, makes myocarditis more likely. Histologically, endomyocardial biopy shows myocyte necrosis with increase in number of T cells in myocarditis, and myocyte hypertrophy and fibrosis in dilated cardiomyopathy.

True prevalence in general population is difficult to assess. It generally accounts for 2 to 3 percent of children hospitalized due to cardiac causes.^2–5 In another series DCM accounted for only 1 percent of patients with pediatric cardiac diseases.⁶ Idiopathic type is most common, followed by familial cardiomyopathy. Both sexes are equally affected.

Several reports in the past have shown that about one-third of patients die, one-third improve and one-third continue to show features of DCM.²2

The mortality rate is highest (up to 54%) in the first year after the diagnosis is made. It falls progressively thereafter.^7,8 Overall, the five year survival has been reported to vary from 34 to 66 percent and 10 years survival is about 50 percent.

The etiology is not known in idiopathic types of DCM. Various workers have hypothesized genetic factors, altered immune response and a previous viral infection. It is important to exclude some of the treatable conditions that may mimic DCM, as the clinical picture is similar. The various causes of “treatable cardiomyopathies” are given in Table 1.2.

There has been an increase in the number of familial cases of DCM. In one publication, familial DCM has been reported in 20 percent of all cases.¹⁵ Inheritance can be autosomal dominant, recessive or X-linked. The affected genes are not well known. Abnormalities of chromosome 1q32¹⁶ and deletions of chromosome 1p-1q¹⁷ have been found in some of the familial cases of DCM.4

Viral infections can produce a DCM like picture, either due to direct damage by the organism or due to its toxins. Cardiomyopathy may also be an autoimmune response to viral infection. Several serological studies have shown persistent viral infection after viral myocarditis. Jin et al have shown a correlation between viral infection and DCM.¹⁸ However, others have shown a similar prevalence of virus in the myocardium in DCM patients and controls.¹⁹ Currently, the evidence for a role of enterovirus in the pathogenesis of DCM remains controversial.

There is weakening of systolic function and dilatation of all chambers. The most striking changes are seen in left ventricle. There may be secondary changes of fibroelastosis. Histological features include myocyte hypertrophy with interstitial fibrosis. Inflammatory cells and lymphocytes are usually absent or sparsely seen.

Renin angiotensin mechanism is stimulated, secondary to renal ischemia, resulting in increased aldosterone and antidiuretic hormone levels. Salt and water retension occurs. This further increases the ventricular diastolic pressures and causes systemic and pulmonary congestion. The ventricular cavity becomes more spherical creating further after load mismatch. Papillary muscles are pulled apart causing mitral regurgitation.

Infants present with tachypnea, feeding difficulties, pallor, irritability and failure to thrive. Dyspnea on exertion and fatigue are the initial presentations in older children. Later, they may have nocturnal cough, paroxysmal nocturnal dyspnea and orthopnea. Respiratory infection or anemia can precipitate heart failure in a relatively stable child with DCM as the myocardial demand increases. In advanced cases, child may present with heart failure and pulmonary edema. Around 70 to 80 percent of patients present with features of congestive heart failure.²⁰ Sometimes, the initial presentation is in cardiogenic shock.

It shows generalized cardiomegaly, at times with left ventricular apex, and pulmonary venous hypertension of varying degree.

Sinus tachycardia is invariably present, except in those being treated with digoxin and/or beta blockers. High QRS voltages in lateral chest leads suggestive of left ventricular hypertrophy are common, often associated with diffuse ST-T wave changes. The QRS duration is often normal in children with DCM. Arrhythmias, not very common on routine ECG, were seen in 46 percent of children undergoing Holter monitoring.²¹ Atrial arrhythmias like atrial fibrillation or flutter can, in turn, produce a DCM like picture. ECG also helps to diagnose conditions like anomalous origin of left coronary artery from pulmonary artery (characterized by deep q waves in I, aVL and lateral chest leads), hypocalcemia (increased QTc interval). These conditions also mimic DCM clinically.

It is the most useful investigation. It not only diagnoses left ventricular dilatation and dysfunction, it also helps to exclude some of the treatable causes of left ventricular dysfunction like anomalous left coronary artery from pulmonary artery, and severe aortic stenosis, etc. All the chambers are enlarged, but left atrium and left ventricle are more prominent (Fig. 1.2). The M mode dimensions and wall thickness of left ventricle is measured. The systolic function of left ventricle is reduced globally seen as low shortening fraction and ejection fraction. Rarely regional wall abnormalities may be seen. The ratio of left ventricular pre-ejection period to ejection time is increased, another indicator of low left ventricular function.7

Mild mitral regurgitation and/or tricuspid regurgitation as seen by pulse/color Doppler study is usually present. Mitral valve Doppler demonstrates a reduced E wave velocity and a low E/A ratio. There may be pericardial effusion. Echo is also very helpful to look for any intracavitary thrombus, seen in up to 23 percent of children.²² Due to the noninvasive nature of echocardiography, serial measurements are made during follow up of these patients.

This invasive test is not required to make a diagnosis of DCM, however it may be rarely required to rule out coronary anomalies if not clear by echocardiography. The major indication for cardiac catheterization is for performing endomyocardial biopsy (in suspected myocarditis) and prior to cardiac transplantation.

Treatment is essentially similar to that of congestive heart failure and includes attention to fluids, electrolytes and acid-base status. Anemia, chest infection and hypoxemia should be treated, if present. In a seriously ill child presenting with pulmonary edema, positive pressure ventilation may be required in addition to cardiovascular support. The approach to treatment is described below. The doses of commonly used drugs are given in Table 1.3.

Digoxin: In a relatively stable child, digoxin is used as an antifailure agent. Besides reducing the heart rate, digoxin also improves myocardial contractility. However there is no data indicating improvement in survival with its use. In children with very poor ventricular function and myocarditis, the margin of safety is very small and lower doses should be used. Digoxin is given orally in a dose of 10ug/kg/day, generally in two divided doses. Loading dose for digitalisation is not used often in the setting of DCM.

Intravenous inotropic drugs: In infants and children presenting with advanced heart failure, hypotension or shock, intravenous infusion of sympathomimetic amines is used. Dopamine and/or dobutamine are administered as continuous infusion in a dose of 5 to 20 µg/kg/minute. 9Dobutamine may offer an advantage over dopamine as it has less arrhythmogenic potential and reduces afterload because of its vasodilatory effect. In children with hypotension, dopamine may be used alone initially, dobutamine added later. Infusion of isoprenaline, and epinephrine is sometimes used in those with cardiogenic shock. Myocardial phosphodiesterase inhibitors like milrinone also have a positive inotropic effect, reducing afterload and improving relaxation.

Availability of powerful diuretics has largely obviated the need for strict restriction on salt and water intake. Diuretics give immediate and symptomatic improvement in heart failure. Furosemide is used in a dose of 0.5 to 1.0 mg/kg/dose, 2 or 3 three times a day, orally or intravenously. Higher doses can lead to fall in cardiac output, hypotension and renal dysfunction. Electrolytes should be closely monitored when on diuretics. Adverse effects include hyponatremia, hypokalemia, acidosis, hyperglycemia, hyperuricemia and hypercalciuria. As the myocardial function is poor, arrhythmias are easily precipitated by electrolyte abnormalities.

These agents reduce afterload, thereby decreasing the cardiac work and increasing cardiac output. Commonly used vasodilators are hydralazine (not available in India) and ACEI like captopril, enalapril, etc. Since renin angiotensin system is over stimulated in patients with DCM and heart failure, ACEI are ideally suited. Several prospective trials in adults have shown improved survival in patients with DCM.²⁴ Several studies in children also give the same impression. These studies showed that the mortality was reduced in those patients treated additionally with ACEI compared with those treated with digoxin and diuretic.^25,26

Recent evidence suggests beneficial effect of beta blockers in adults with DCM. Addition of these agents to conventional treatment is associated with marked improvement in ventricular function. The mechanisms of action are several and include prevention and reversion of adrenergically mediated intrinsic myocardial dysfunction and remodelling, reduction in oxygen demand, inhibition of sympathetically mediated vasoconstriction and reduction of potentially lethal arrhythmias. Carvedilol, a third generation non selective beta blocker, has additional properties. It is an alpha adrenergic blocker, antioxidant and antiendothelin. These actions further enhance its ability to attenuate the adverse effects of sympathetic nervous system on circulation. Hence carvedilol is likely to be more beneficial than other beta blockers. It has been shown to be effective in reducing hospitalization rates and improving survival in adults.²⁷ the data in children is evolving and appears promising.^29–31It is given in a low dose initially (0.1 mg/kg/day in two divided doses). The dose is increased every one to two weeks upto a maximum of 1.0 mg/kg/day. Oral clearance of digoxin may be decreased by half with concomitant use of carvedilol in chilren and hence the dose of digoxin should be reduced at least by 25 percent to avoid toxicity.³²

Thrombus in left ventricle with or without embolization is well known in adults and children with DCM. Echocardiography may not demonstrate thrombus in many of these cases. Anticoagulant therapy with coumadin or heparin is indicated if the thrombus has been demonstrated on echocardiography or one or more episodes of embolization have occurred. Others use anticoagulants in all cases of DCM with dilated and poorly contracting left ventricle because of the high frequency of embolization (84% of children, aged 7 to 20 years, at necropsy)³³. However control of anticoagulation in children is difficult and limits widespread use of these drugs.11

Arrhythmias may be treated with amiodarone which has been found to be safe and effective in children³⁴. Other agents may be used if amiodarone is contraindicated or not tolerated. In those with bradyarrhythmia, a pacemaker insertion is indicated.

The data on use of immunosuppressive drugs in children with DCM are controversial. Uncontrolled reports of benefit with steroids, azathioprine or cyclosporine A exist³⁵, but no randomized controlled trial has shown a benefit.^36,37 In fact, these drugs may be associated with serious side effects on long-term treatment. A recent study has claimed a better 13 years survival with immunosuppressive therapy for newly diagnosed DCM patients, who had acute or borderline myocarditis on endomyocardial biopsy.³⁸

Polyclonal immunoglobulin has been shown to reduce necrosis and inflammation in mice with myocarditis. They provide antibodies against the virus or alter the immune response of our body. Drucker et al have used intravenous immunoglobulins in a dose of 2 gm/kg to treat children admitted with a presumptive diagnosis of myocarditis as judged by a short history.³⁹ The control group was retrospective. Their results showed a better chance of improvement of left ventricular function in the treated group, although the results did not reach statistical significance.

Drugs: Megavitamin therapy with biotin, cyanocobalamin and carnitine supplementation are additional drugs used in patients with DCM. Their therapeutic value is not clear. Patients with mitochondrial disorders may benefit from dichloroacetate, thiamine, ascorbic acid and/or coenzyme Q 10.

Bed rest: Strict bed rest is unnecessary and normal life activities should be encouraged.

Growth hormone: A preliminary report in adults has shown that growth hormone resulted in reduction of chamber size and improved cardiac output in patients with DCM. Trend towards improvement in ejection fraction was also reported in a small study of 8 children who were treated with growth hormone.⁴⁰ There were no significant side effects.12

If there is no improvement with medical therapy, one should consider cardiac transplantation for these children. Survival is about 75 to 80 percent at one year and 65 percent at five years in various series. Organ availability, possibility of rejection and life long immunosuppression are major limiting factors for this mode of therapy. Since delayed improvement is seen in children with DCM, cardiac transplantation should be considered only when despite medical therapy, progressive deterioration in symptoms or ventricular function continues.

Other surgical options: These include Batista procedure, where a large segment of hypertrophied ventricular muscle is resected and cardiomyoplasty where skeletal muscle is used to augment cardiac function. If there is significant mitral regurgitation, mitral valve repair or replacement is helpful and should be done.

Current understanding of pathophysiology of heart failure due to DCM has shifted from management strategy from steps that directly improve myocardial function to those that modulate the neuroendocrine profile and peripheral vascular activity. The treatment of end-stage DCM is cardiac transplant.

This form of cardiomyopathy is seen primarily in infants and young children and is indistinguishable from DCM clinically. The diagnosis is histological, there is thickening of the endocardium by elastic and collagen tissue. It can be either primary, when there is no associated structural defect of the heart, or secondary when associated with lesions like aortic atresia, aortic stenosis, coarctation of aorta, anomalous origin of left coronary artery from pulmonary artery, etc. The left ventricle is dilated as in DCM, but in a small group of patients, the left ventricle is small, hypertrophied and is poorly functioning (contracted variety). The left atrium is grossly dilated in such cases.

Over 75 percent of patients present in first year of life, mostly in congestive heart failure. Examination reveals tachycardia, often with gallop rhythm, sometimes there is a systolic murmur of mitral regurgitation. The disease is rapidly progressive, more so in neonates 13resulting in high mortality. Chest infections contribute to morbidity and mortality. Clinically, the picture is that of DCM is confirmed. It is said that if diagnosis of endocardial fibroelastosis in one member of a family, other members who present with DCM like picture are also likely to be having endocardial fibroelastosis.⁵

In this type of cardiomyopathy unexplained ventricular hypertrophy, which can involve the right, left or both ventricles is the hall mark feature. The hypertrophy is often asymmetric, involving the mid and upper part of interventricular septum. The left or right ventricular outflow tracts may demonstrate obstruction, due to muscle hypertrophy. Hypertrophic cardiomyopathy (HCM) may be associated with Noonan's syndrome, Beckwith-Wiedemann syndrome, glycogen storage disease type 2 (Pompe's), Friedreich's ataxia, LEOPARD syndrome, etc. and may be transiently seen in infants of diabetic mothers.

HCM constitutes about 20 to 30 percent of all cardiomyopathies in children. It is usually a familial disease. In 30 to 60 percent of cases, HCM appears to be genetically transmitted as an autosomal dominant trait with incomplete penetrance. The disease may not be fully expressed in affected persons carrying the gene. The technique of molecular biology has revealed some abnormal genes responsible for HCM in a particular family and currently more than five separate genes are known to produce HCM.

Clinical course is variable with higher morbidity and mortality at young age. Risk factors for sudden death are young age, family history of 14sudden death, syncopal episodes and concurrent right ventricular hypertrophy. Ventricular arrhythmias are well known in patients of HCM. Absence of arrhythmia on a 24 hours Holter monitoring does not rule out the risk of sudden death. Premature death in some families is well described. Symptoms such as dyspnea on exertion, chest pain and fatigue do not predict sudden death. Overall mortality is twice as high as in adults. Children below one year of age more often present with progressive heart failure, death usually occurring within one year of presentation. Older children, on the other hand, are more prone to sudden death.

Severe ventricular hypertrophy is universally present. It is usually localized and asymmetric, but concentric left ventricular hypertrophy is also well known. Microscopic examination shows extensive myocardial disarray.

The child may be completely asymptomatic and the disease is picked up on echocardiography when he or she is being evaluated for a systolic 15murmur. There is no correlation of the severity of hypertrophy with symptoms. In others, symptoms may be non-specific and include exertional dyspnea, palpitations and fatigue. Infants and young children present with features of heart failure. Over 60 percent have both right and left ventricular outflow gradients. Older children are often asymptomatic, may not have outflow gradients or have only left ventricular outflow obstruction. Sudden death may be the first presentation in older children and adolescents.

Electrocardiogram: It is usually abnormal showing left ventricular hypertrophy, non-specific ST-T wave changes and abnormal q waves. Left atrial enlargement is also commonly seen. Infants may show predominant right ventricular hypertrophy. A prolonged QT interval is also more common in infants and young children. The QRS widens in late phase of the disease, giving a left bundle branch block in ECG.

Some amount of cardiomegaly is usually seen, caused by atrial dilatation. Lung markings are often normal.

This is the diagnostic tool. Historically M mode echocardiography has been used for identifying asymmetric hypertrophy. The ratio of thickness of interventricular septum in end diastole to the thickness of left ventricular posterior wall in end-diastole is used for making the diagnosis.16

A ratio of greater than 1.5 is considered diagnostic. In neonates however, this ratio may still be within normal limits (Fig. 1.3). One should use the absolute values of the thickness of interventricular septum and left ventricular posterior wall and compare with normograms. Cross- sectional echocardiography and Doppler give the details of ventricular hypertrophy, the degree of obstruction across the left or both ventricular outflow tracts, systolic anterior motion of mitral valve and mitral regurgitation. Doppler examination of mitral inflow demonstrates a reduced E velocity, an increase in A velocity and a reduced E/A ratio. In some of the older children, one may observe an increased myocardial echo intensity.

Cardiac catheterization and angiography: Since echocardiography is diagnostic, cardiac catheterization is rarely required to make a diagnosis. The filling pressures are high and in the obstructed variety, a pressure difference is present between the apex of the ventricle and subaortic region. Angiography shows a hypercontractile ventricle with almost complete disappearance of radiographic contrast agent from the ventricular cavity during systole. Hypertrophied papillary muscles produce an indentation during diastole. Mitral regurgitation is seen in cases with obstruction. Endomyocardial biopsy is generally not required.17

It is aimed at improving ventricular filling and decreasing the contractility.

Restrictive cardiomyopathy (RCM) is the most rare form of cardiomyopathy. It is characterized by an abnormal diastolic function with restriction to filling due to very stiff ventricular walls. It may involve either or both ventricles. About 5 percent of all cardiomyopathies in children are of restrictive variety.^45,46 It can be idiopathic or secondary to a variety of infiltrative disease, as given in Table 1.4. Characteristically the ventricles are normal in size and contractility. The atria are enlarged.

Common symptoms include exercise intolerance, fatigue and chest pain. Examination reveals features of severe congestive heart failure with absence of significant cardiomegaly and murmurs. Soft murmur of mitral and/or tricuspid regurgitation may be heard.

Characteristic findings include massive atrial dilatation with normal ventricular size and function (Fig. 1.4). The ventricular wall thickness is usually normal, but mild thickening may be seen. Atrial thrombi are sometimes present. The Doppler across mitral inflow typically shows an increased E velocity, high E/A ratio and a short deceleration time.

Variable degree of mitral and/or tricuspid valve regurgitation are often present (Fig. 1.5). The pulmonary venous atrial reversal duration is increased. In patients with endomyocardial fibrosis, there is typically obliteration of the ventricular apex and dilatation of right ventricular outflow tract (Figs 1.6 and 1.7). Pericardial effusion may be present.

This test is almost always performed. It establishes the diagnosis of a restrictive physiology. An endomyocardial biopsy helps to rule out infiltrative disorders. Cardiac catheterization is also useful to differentiate RCM from chronic constrictive pericarditis, a relatively common and treatable cause of restrictive physiology. The filling pressures are raised in both conditions and sometimes one has to resort to more investigations like a computerized tomography or magnetic resonance imaging to clarify the diagnosis.21

In doubtful cases, an exploratory thoracotomy is justified.

Conventional treatment with diuretics helps to relieve congestive symptoms, but should be cautiously used as these drugs may lead to hypotension. Drugs like digoxin, ACEI, etc are generally not useful and may produce side effects. Calcium channel blockers like verapamil have been used with short-term benefit by some. Anticoagulants are indicated to prevent thrombosis and embolization. Surgical resection of subendocardial fibrosis with or without valve replacement has been shown to improve symptoms in some cases of endomyocardial fibrosis. Since the prognosis is very poor in idiopathic form of RCM, cardiac transplantation should be considered early in the course of the disease.

The prognosis of RCM is worse in children than in adults. The four-year-survival is reported as 29 percent in symptomatic children.⁴⁵ Denfield et al also reported a 25 percent survival at 6 years after presentation.⁴⁷ The idiopathic form has the worst prognosis in children, actuarial survival being 44 to 50 percent at two years after diagnosis.^45,48

The term “cardiomyopathy” includes all diseases where myocardial dysfunction is the dominant feature. These are not uncommon in 22children, often seen at all ages. Dilated cardiomyopathy is the most common type and restrictive cardiomyopathy is least often seen. It is important to exclude structural lesions of the heart which may be treatable before labeling any child with primary myocardial dysfunction. Although cardiomyopathies have been long known, there is continuous development in regard to our understanding of etiopathogenesis, clinical diagnosis, natural history and treatment.