Pediatric Restrictive Cardiomyopathy

Restrictive cardiomyopathy (RCM) is a rare disorder in children that is characterized by restrictive filling and reduced diastolic volume of one or both ventricles with normal or near-normal systolic function and wall thickness.[1] The heart is grossly normal, although histologic abnormalities are often present, depending on the etiology of the restrictive cardiomyopathy.

RCM may manifest as a solitary abnormality, although restrictive filling patterns of the left ventricle can also be seen in patients with dilated or hypertrophic cardiomyopathy. Because this disease is so rare, its pathogenesis, natural history, and treatment are not well defined. Associated syndromes and noncardiac conditions include scleroderma, amyloidosis, sarcoidosis, Gaucher disease, Hurler disease, glycogen storage diseases, hypereosinophilic syndrome, and carcinoid syndrome.

Some investigators have divided RCM into the following subtypes: (1) pure restrictive cardiomyopathy, (2) hypertrophic-restrictive cardiomyopathy, and (3) mildly dilated restrictive cardiomyopathy.[2]

Therapy for idiopathic restrictive cardiomyopathy (RCM) is limited to symptomatic treatment and is often ineffective in improving outcome. Surgical options are limited to heart transplantation. A healthy lifestyle is recommended, although there is an increased risk of sudden death and worsening heart failure, which generally precludes competitive sports participation.

The pathophysiology of RCM is diverse. This condition can be associated with diseases such as amyloidosis, hemosiderosis, hypereosinophilia, and endocardial fibroelastosis; it can also occur secondary to radiation therapy and certain medications. However, these may be considered separate diseases because the etiology is known.

In true idiopathic RCM, endomyocardial biopsy and pathologic specimen findings are usually abnormal, although they may not be diagnostic for any single disease. Findings include myofibrillar disarray, myocyte hypertrophy, and interstitial fibrosis. Morphologic findings include atrial enlargement without increased ventricular wall thickness or ventricular cavity dilation, the absence of eosinophilic infiltration, and the absence of pericardial disease.[2, 3]

The physiologic consequences of RCM are more uniform than those of its diverse etiologies. Typically, there is abrupt premature cessation of ventricular filling in early diastole, causing a dip-and-plateau or square-root pattern on ventricular pressure tracings. Therefore, ventricular filling is limited to early diastole. This is probably related to decreased compliance of the ventricle and ultimately results in the development of atrial dilatation. Typical hemodynamic characteristics include normal systolic function and equalization of increased ventricular end-diastolic pressures.

The natural history of RCM varies and is at least partially dependent on the etiology, if any is identified. Because the number of patients who have subclinical RCM is unknown, the natural history can be determined only when symptoms develop. Once symptoms develop, the morbidity and mortality are high (see Prognosis and Complications).

In most pediatric cases of RCM, the etiology is unknown. Risk factors are also unknown.

RCM can be divided into two main types, myocardial and endomyocardial. The myocardial type, in turn, can be further classified into two subtypes, noninfiltrative and infiltrative.

Noninfiltrative myocardial forms of RCM include the following:

• Idiopathic (the most common type of RCM in children)

• Familial

• Post–cardiac transplant

• Diabetic cardiomyopathy with a restrictive component

Infiltrative myocardial causes of RCM include the following:

• Amyloidosis (the most common cause of RCM in adults outside of the tropics)[4]

• Sarcoidosis

• Hemochromatosis

• Lysosomal storage diseases such as Gaucher disease, Hurler disease, and Fabry disease

Endomyocardial causes of RCM include the following:

• Endomyocardial fibrosis (EMF; the most common cause of restrictive cardiomyopathy in adults and children in certain tropical areas of Africa, Asia, and South America)[5]

• Hypereosinophilic syndrome (also known as Loeffler endocarditis)

• Carcinoid heart disease

• Metastatic cancers

• Pseudoxanthoma elasticum

• Certain drugs, including anthracyclines and methysergide

• Mediastinal radiation

Most cases of RCM (including idiopathic ones) are not known to be inherited, although there have been reports of families in whom multiple members are affected by a combination of hypertrophic and restrictive cardiomyopathies.[6] Additionally, some inherited infiltrative disorders can cause restrictive cardiomyopathy. These include Fabry disease (X-linked recessive), Gaucher disease (autosomal recessive), glycogen storage diseases, and autosomal recessive hemochromatosis.

Significant progress has been made in defining the genetic causes of RCM. These causes include mutations in the following genes: troponin I, troponin T, alpha-cardiac actin, myosin, myosin-binding protein C, filamin-C, and desmin.[7, 8, 9, 10, 11, 12, 13, 14, 15, 16] Genetic mutations have also been identified in several diseases associated with RCM, including lamin A/C in Emery-Dreifuss muscular dystrophy, transthyretin in amyloidosis, and RSK2 in Coffin-Lowry syndrome.[17, 18, 19]

Although its exact prevalence is unknown, RCM is the least common cardiomyopathy and represents approximately 2-5% of pediatric cardiomyopathies in the United States.[20, 21, 22] Reports from Europe and Australia suggest similar international infrequency.[23, 24] However, in tropical areas of Africa, Asia, and South America where endomyocardial fibrosis is endemic, the prevalence may be much higher.[25, 26]

Idiopathic RCM has been described in children of all ages. Some studies suggest that idiopathic RCM may be slightly more common in girls than in boys.[27, 28] No racial predilection is known.

The prognosis of RCM can be very poor in children. Patients are at risk for various acute and chronic complications that require close monitoring. Those who ultimately require and undergo heart transplantation before development of severe, irreversible pulmonary hypertension have a reasonably good prognosis after transplantation, comparable to those with other types of cardiomyopathy.

Mortality in children with idiopathic RCM is high, particularly in the absence of heart transplantation. Rates have been reported to be as high as 63% within 3 years of diagnosis and 75% within 6 years of diagnosis.[20] Actuarial survival range is 44-50% at 1-2 years after presentation.[20, 28] This decreases to 29-39% at 3-5 years after presentation.[22, 28]

Reasons for referral in restrictive cardiomyopathy (RCM) include the following:

• Abnormal chest radiography findings during a respiratory illness

• Abnormal physical findings (see Physical Examination)

• Syncope

• Positive family history

• Peripheral edema

• Ascites

• General fatigue and weakness

• Typical history of congestive heart failure

• Respiratory symptoms, including dyspnea with exertion or at rest, paroxysmal nocturnal dyspnea, and orthopnea

Physical examination findings usually reflect the degree of congestion from the diastolic dysfunction of the affected ventricle and the resultant degree of decreased cardiac output. In patients who are only mildly affected, findings may be normal. However, patients with significant left ventricular RCM have pulmonary venous congestion with tachypnea. Older patients in this category occasionally present with rales.

Murmurs and gallop rhythms are common. The S2 may become more prominent with the development of secondary pulmonary hypertension. Evidence of right-side congestion (manifested as hepatomegaly, jugular venous distention, or both) is usually present, either because of right-side RCM or as a secondary congestion from left-side RCM. Sometimes, the jugular venous pulse fails to fall during inspiration and may actually rise (Kussmaul sign).

In more severe forms, patients can present with peripheral edema or ascites and frank congestive heart failure.

Arrhythmias may occur in RCM, including atrial fibrillation, flutter, and ventricular tachycardia. In some infiltrative forms of RCM, complete heart block may also be present.[29]

Complications include worsening congestive heart failure, arrhythmia (including sudden death), pulmonary hypertension, and thromboembolism.

If RCM results in advanced congestive heart failure, end-organ damage may result from low cardiac output.

Arrhythmias, both atrial and ventricular, may occur.

Pulmonary hypertension is more prevalent in this type of cardiomyopathy than in dilated or hypertrophic cardiomyopathy. Patients must be closely monitored because the main therapeutic intervention for RCM (cardiac transplantation) is generally contraindicated once irreversible pulmonary hypertension develops.

The incidence of thromboembolic complications is high enough that many investigators have recommended anticoagulation with warfarin or antiplatelet agents (eg, aspirin) as a preventive measure.[20]

Laboratory studies generally do not contribute to the diagnosis of restrictive cardiomyopathy (RCM). Echocardiography is often diagnostic and is very useful in distinguishing RCM from constrictive pericarditis (CP); cardiac computed tomography (CT) or magnetic resonance imaging (MRI) may also be a helpful adjunct in this respect. Cardiac catheterization is generally indicated to assess hemodynamics. Electrocardiography (ECG) usually reveals abnormalities. Endomyocardial biopsy may reveal a specific cause but appears to be much more helpful in adults than in children.

Echocardiography is often diagnostic of RCM. Results usually include marked atrial enlargement with normal left ventricular end-diastolic dimensions (see the image below). Ventricular hypertrophy and atrioventricular valve dysfunction may also be present. Atrial thrombi may be seen. Pulmonary vein atrial flow reversal duration that exceeds mitral a wave duration has also been described. Duration of pulmonary vein a wave appears to have positive correlation with degree of elevated left ventricular end-diastolic pressure; this measure seems to exhibit high degree of sensitivity and specificity.[31]

Echocardiography can be very useful in distinguishing RCM from CP.[32, 33] For example, echocardiographic evidence of minimal respiratory variation in Doppler ventricular inflow signals is observed in patients with RCM; in comparison, significant respiratory variation is observed in patients with CP.[34] Prolongation of the systole-to-diastole ratio is observed in pediatric RCM, although this abnormality is also found in children with dilated cardiomyopathy. Mid-diastolic reversal of flow across mitral and tricuspid valves is also more common in RCM.

Unfortunately, Doppler echocardiographic findings still show overlap between RCM and CP. Echocardiography may reveal a thickened pericardium in patients with CP.

ECG usually reveals evidence of atrial enlargement and ST-T wave changes. Infiltrative diseases can have low voltage changes. An arrhythmia (eg, atrial fibrillation) may be present. Familial RCM can be associated with atrioventricular block.

Because of risk of sudden deterioration and death, some investigators recommend serial ECG and Holter monitoring to observe for evidence of ischemia and arrhythmia.[35]

Pulmonary artery pressures are usually elevated. Right and left ventricular end-diastolic pressures are elevated, and the 2 ventricular end-diastolic pressures are generally discordant, with left ventricular end-diastolic pressure usually being significantly higher (>5 mm Hg) than right ventricular end-diastolic pressure.

The systolic area index, which uses the ratio of right-to-left ventricular systolic pressure-time area during inspiration and expiration as measured during cardiac catheterization, has also been proposed as a means of differentiating between RCM and CP.[36]

On chest radiography, heart size is usually increased, often with evidence of right or left atrial enlargement. Pulmonary venous congestion is often evident.

Computed tomography (CT) and magnetic resonance imaging (MRI) may be useful for assessing pericardial thickness in patients for whom CP is in the differential diagnosis.

Endomyocardial biopsy may reveal a specific cause but appears to be much more helpful in adults than in children. Thus, indications must be individualized and balanced with the risks of the procedure.[37] Guidelines for the role of endomyocardial biopsy in the management of cardiovascular disease have been proposed.[38]

Findings from biopsy or autopsy are usually abnormal but are not necessarily diagnostic. Varying degrees of myocyte hypertrophy, interstitial fibrosis, myocytolysis, and endocardial sclerosis have been found. In those patients (usually adults) with an infiltrative cause, such as amyloidosis, biopsy findings may be diagnostic.

Therapy for idiopathic restrictive cardiomyopathy (RCM) is limited to symptomatic treatment and is often ineffective in improving outcome. Secondary arrhythmias, when they occur, may require pharmacologic and/or device-related therapies that generally require evaluation by an electrophysiologist. Surgical options in children with RCM are limited to heart transplantation. The results of heart transplantation are generally quite good but depend on the degree of pulmonary hypertension and resultant postoperative complications.[39]

A normal diet is recommended. The degree of hemodynamic abnormality and the risk of sudden death are significant, and patients should be restricted from competitive athletics, despite a paucity of data on the subject.[40]

Diuretics reduce pulmonary or systemic venous congestion; however, some patients may require high ventricular filling pressures to maintain cardiac output and may actually feel worse after diuresis.

Digoxin has not been shown to be beneficial with normal systolic function and should be used with caution.

Anticoagulation should be considered because of the significant risk of thromboembolic complications.[28, 41, 3] If chosen, anticoagulation agents should be carefully administered with close supervision of coagulation parameters. Some pediatric cardiologists prefer platelet-inhibiting doses of aspirin, because no extensive monitoring of coagulation parameters is necessary.

Previous studies in pediatric patients have suggested that angiotensin-converting enzyme inhibitors (ACEIs) may acutely reduce systemic blood pressure without increasing cardiac output; therefore, they should probably be avoided.[42] Oral vasopressin–receptor antagonists may be helpful in selected cases.[43]

Experimental studies in mice suggest that catechin (epigallocatechin-3-gallate) may reverse diastolic dysfunction associated with restrictive cardiomyopathy,[44] which may hold promise for future. Clinical studies to test this hypothesis are warranted.

Children with RCM should be considered early for heart transplantation, particularly if they are symptomatic or have evidence of pulmonary hypertension. Children with RCM are at higher risk for the development of pulmonary hypertension than children with dilated or hypertrophic cardiomyopathy and therefore need to be closely monitored for progression of pulmonary hypertension.[45]

Among the greatest challenges in the management of pediatric RCM are risk stratification and the decision regarding when to list a patient for heart transplantation. Some advocate immediate transplant evaluation and listing upon diagnosis of RCM.[46] However, patients with normal or only mildly elevated pulmonary vascular resistance may remain stable for years and may not require urgent listing for heart transplantation.

In one series, longer survival from diagnosis was correlated with lower left atrial–to–aortic root ratios by echocardiography and lower cardiac filling pressures by cardiac catheterization.[22] A recent study from Mayo Clinic indicated that early referral for cardiac transplantation may improve overall survival of RCM patients[47] .

Standard techniques for heart transplantation are used in children with RCM. Results are generally good. In those with pretransplant evidence of pulmonary hypertension, special attention must be paid to monitoring and treating this complication.[48, 49, 50] Sildenafil may be beneficial in helping to manage postoperative pulmonary hypertension, even in those patients who require heterotopic heart transplantation.[51]

Some patients may require such treatments as high levels of inspired oxygen or hyperventilation. Pulmonary vasodilators, such as prostacyclin, sodium nitroprusside, and nitric oxide, have all been used with some success in this situation. In extreme cases, mechanical circulatory assistance (eg, extracorporeal membrane oxygenation [ECMO]) may be necessary. Static balloon dilatation[52] following transseptal puncture may become necessary to decompress the left atrium and reduce pulmonary hypertension.[53]

Ventricular assist devices (VADs) may be used as a bridge to transplantation.[54, 55] However, small left ventricular size may cause problems; in such situations, left atrial cannulation may be a safer in children.[56]

Therapy for idiopathic restrictive cardiomyopathy (RCM) is limited to symptomatic treatment and is often ineffective in improving outcome.

Class Summary

Diuretic agents promote excretion of water and electrolytes by the kidneys. Treatment with diuretics may improve symptoms of venous congestion. However, these agents should be used with caution, because some patients require high venous filling pressures to maintain adequate cardiac output.

Furosemide (Lasix)

Furosemide is a loop diuretic that blocks the sodium-potassium-chloride transporter and works primarily on thick ascending limb of the loop of Henle. It also inhibits sodium and chloride absorption from the proximal and distal tubules.

Chlorothiazide (Diuril)

Chlorothiazide is a thiazide diuretic that blocks the electroneutral sodium-chloride transporter.

Metolazone (Zaroxolyn)

Metolazone is a quinazoline diuretic with properties similar to those of thiazide diuretics. It inhibits sodium resorption at the cortical diluting site and the proximal convoluted tubule.

Spironolactone (Aldactone)

Spironolactone is an aldosterone antagonist that spares potassium. It competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

Class Summary

Some authors advocate the use of anticoagulation, antiplatelet agents, or both in children with RCM because of due to the high reported incidence of thromboembolic events in several small case series. If chosen, anticoagulation agents should be carefully administered with close supervision of coagulation parameters.

Heparin

Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis.

Warfarin (Coumadin)

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.

Enoxaparin (Lovenox)

Enoxaparin is a low-molecular-weight heparin that differs from unfractionated heparin by having a higher ratio of antifactor Xa to antifactor IIa.

Class Summary

Low-dose aspirin is the predominant platelet aggregation inhibitor used in children, although only limited comparative data regarding effective antiplatelet doses in pediatric populations are available.

Aspirin (Bayer Aspirin Extra Strength, Ecotrin, Aspercin)

Aspirin is a stronger inhibitor of both prostaglandin synthesis and platelet aggregation than other salicylic acid derivatives are. The acetyl group is responsible for inactivation of cyclooxygenase via acetylation. Aspirin irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to prostaglandin I2 (a potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (a potent vasoconstrictor and platelet aggregate). Platelet-inhibition lasts for the life of the cell (approximately 10 days).

Aspirin may be used in low doses to inhibit platelet aggregation and improve complications of venous stasis and thrombosis.