Endocardial Fibroelastosis

Endocardial fibroelastosis (EFE) refers to a pronounced, diffuse thickening of the ventricular endocardium and presents as unexplained heart failure in infants and children. The term endocardial fibroelastosis was introduced by Weinberg and Himmelfarb in 1943.[1, 2]

The disease can be primary or secondary to various congenital heart diseases, most notably hypoplastic left heart syndrome,[2] aortic stenosis, or atresia.The two pathologic forms of primary endocardial fibroelastosis are dilated, which is most common, and contracted. Primary endocardial fibroelastosis is not associated with any significant structural anomaly of the heart. Secondary endocardial fibroelastosis is associated with other congenital heart diseases. 

Once regarded as a common cause of unexplained heart failure, endocardial fibroelastosis is now considered rare. However, a study has highlighted that 25% of children who were transplanted for dilated cardiomyopathy demonstrated significant endocardial fibroelastosis on histopathology of the explanted hearts.[3]

Note the following:

• Symptoms of endocardial fibroelastosis include feeding difficulty, excessive sweating, breathlessness, failure to thrive, and wheezing.

• Onset may acute enough to produce cardiogenic shock or sudden death; it is a recognized cause of sudden death in infancy.

• Approximately 20% of patients have a history of frequent or recent respiratory tract infections.

• Echocardiography forms the mainstay to the diagnosis. Careful assessment of the heart for any associated congenital heart disease including coronary artery anomalies is essential before making a diagnosis of primary endocardial fibroelastosis.

• The treatment of endocardial fibroelastosis is essentially the same as that for chronic cardiac failure; its acute exacerbations are often precipitated by respiratory infections.

• Primary endocardial fibroelastosis prognosis is relatively poor, although the condition is not universally fatal.

The underlying pathophysiology of endocardial fibroelastosis (EFE) is believed to be deposition of acellular fibrocartilagenous tissue in the subendothelial layer of the endocardium predominantly involving the inflow tracts, apices of either left or both ventricles.[2] Endocardial fibroelastosis is characterized by diffuse endocardial thickening and myocardial dysfunction. The endocardial thickening is believed to be caused by persistent and increased wall tension in the ventricles, possibly secondary to damaged myocardium, mitral regurgitation, or both. However, endocardial fibroelastosis changes are progressive with age. The disease is usually sporadic, but familial cases have been reported (10%). Observations that favor a viral etiology include a clinical presentation similar to that of chronic myocarditis, findings of myocarditis or myocardial fibrosis in affected patients, a higher incidence following epidemics of coxsackievirus B infection, demonstration of persistent viral infection with molecular studies, and experimental production of the disease in animal models by viral infections of the myocardium. A phenotypic resemblance to dilated cardiomyopathy has also been noted. A report suggests that the epicardium-derived mesenchymal cells could be the origin of the endocardial fibroelastosis fibroblasts.[4]

Dilated endocardial fibroelastosis is characterized by a markedly enlarged globular heart, mainly involving the left ventricle (LV) and left atrium (LA). The LV endocardium is opaque, glistening, milky white, and diffusely thickened to about 1-2 mm. The thickening is most marked in the outflow tract.

Papillary muscles arise more superiorly on the ventricular wall with thickened and shortened chordae tendineae, the characteristic rolled-free edge of mitral leaflets. Papillary muscles and trabeculae carneae are flattened and partially incorporated in the fibrotic process, giving a smooth appearance to the lining of the cavity; thus, the papillary muscles exert an undesirable lateral traction on the chordae tendineae and mitral cusps, leading to faulty leaflet opposition.

Although the endocardium is thickened, the ventricular wall (myocardium) thickness is within the reference range. Endocardial thickening extends to the LA, right ventricle, and right atrium. Microthrombi may adhere to the endocardium. The right ventricle is anteriorly displaced to the right, and its cavity is usually flattened. The pulmonary artery may be enlarged, but the aorta and coronary arteries appear normal in caliber. In approximately 50% of patients, the mitral and aortic valves are involved, often producing marked deformity and either valvar regurgitation or stenosis.

The less common contracted type of primary endocardial fibroelastosis is associated with a relatively hypoplastic or normal LV size. The right and left atria and the right ventricle are markedly enlarged and hypertrophied, with minimal or no endocardial sclerosis. An early event in fetal life is believed to result in dilated endocardial fibroelastosis, which later morphoses into a contracted type. This suggests that the dilated type could appear as two different diseases while remaining a single disease. Secondary endocardial fibroelastosis, associated with cardiac malformations, is attributed to the cardiac hypertrophy and consequent imbalance in the myocardial oxygen supply-demand relationship. Resultant fibroelastotic thickening is often focal and less severe. However, the endocardial fibroelastosis may independently affect the ventricular function as shown in a study from Germany.[5]

Acute congestive heart failure (CHF) becomes progressive CHF that results in death within weeks, usually within the first 6 months of life. In a subgroup of individuals who survive from a few months to several years, a more chronic course is common. Such patients respond to medications used to treat CHF. A variable cyclical clinical course ensues, with CHF recurrences related to respiratory or other intercurrent infections or to progression of disease. Remissions can occur with intensification of medical therapy. Occasionally, cardiac arrhythmias can be the main presenting problem.[6]

Possible causative factors include intrauterine viral infection (mumps, coxsackievirus B), subendocardial ischemia, impaired lymphatic drainage of the heart, and systemic carnitine deficiency. Using polymerase chain reaction (PCR) analysis, Ni et al reported that the mumps viral genome persisted in the myocardium of children with endocardial fibroelastosis; however, this requires further study.[7]  The authors suggested cause and effect and speculated that the disease disappeared after the initiation of the measles-mumps-rubella (MMR) vaccination.

Nine patients with familial endocardial fibroelastosis were reported in 4 families, and inheritance patterns included X-linked recessive, autosomal dominant, and autosomal recessive.[8]  Relatively recently, mutation of the gene G4.5 (tafazzin) has been associated with familial X-linked endocardial fibroelastosis and Barth syndrome and has been reported to result in morphologic changes in the fetal heart as early as 18 weeks' gestation.

Dilated (primary) endocardial fibroelastosis occurs when the heart is otherwise normal and no other cause of unexplained heart failure, including systemic carnitine deficiency, is demonstrable. Dilated endocardial fibroelastosis (secondary) is associated with aortic stenosis or atresia and includes coarctation of the aorta, ventricular septal defect, anomalous origin of left coronary artery from the pulmonary artery, myocardial injury from any cause, and metabolic or carnitine deficiency. Contracted endocardial fibroelastosis (secondary) is associated with hypoplastic left heart syndrome.

United States data

The exact incidence and prevalence of endocardial fibroelastosis (EFE) is unknown owing to the relative scarcity of this condition.[2] A 1964 study demonstrated an incidence rate of 1 per 5,000 live births.[9] The incidence over subsequent years has been markedly reduced for unknown reasons, with almost no new cases in the current era. The disappearance of this condition is believed to be related to the declining prevalence of mumps.

International data

A 1978 study reported that endocardial fibroelastosis comprised 1-2% of all congenital heart diseases.[10] Currently, the number of endocardial fibroelastosis cases has dramatically fallen to almost zero. The idiopathic form of the disease is sporadic, but familial cases are also reported (10%).

Sex- and age-related demographics

Endocardial fibroelastosis equally affects both sexes.

Endocardial fibroelastosis presents during the first 3-6 months of life in 80% of cases. The typical age at diagnosis is 2-12 months. Endocardial fibroelastosis is rarely reported in adolescents and adults and is an important cause of nonimmune hydrops fetalis.

Primary endocardial fibroelastosis (EFE) has a relatively poor prognosis, although the condition is not universally fatal. The prognosis is worse if early onset of heart failure occurs.

Congestive heart failure (CHF) may be present. Note the following:

• Acute CHF becomes progressive CHF and terminates in death within weeks, usually within the first 6 months of life.

• In patients who survive from a few months to several years, a more chronic course is common. Such patients respond to medications for CHF. A variable cyclical clinical course ensues, with CHF recurrence related to respiratory or other intercurrent infections or to progression of disease. Remissions can occur through intensification of medical therapy.

• Poor prognostic signs of CHF include (1) presentation in the newborn period and (2) recurrent episodes of CHF despite adequate therapy, especially if episodes recur more than 6 months after initial onset of symptoms.

Morbidity/mortality

Progressive CHF causes deteriorating conditions that lead to death in one third of patients. One third of the patients survive and may experience persistent symptoms or have residual ECG abnormalities or evidence of cardiomegaly. Although some authorities are skeptical, some believe that approximately one third of the patients completely recover.

Early diagnosis and prompt persistent administration of digitalis may result in clinical improvement and reversion of the electrocardiogram (ECG) and cardiac enlargement (CE) to normal.

Morbidity varies depending on presentation. Infants who present with acute failure almost always die from the acute episode unless they receive a transplant. Patients with a chronic presentation have a 30-40% mortality due to resistant heart failure. Contracted endocardial fibroelastosis has a grave prognosis and is generally fatal.

Complications

Complications of endocardial fibroelastosis include the following:

• Resistant cardiac failure

• Recurrent chest infections

• Severe failure to thrive

• Cardiac cirrhosis

• Cerebral, coronary, and pulmonary thromboembolism

• Persistent collapse of left lower lobe or entire left lung

Note the following:

• Symptoms of endocardial fibroelastosis (EFE) include feeding difficulty, excessive sweating, breathlessness, failure to thrive, and wheezing.

• Onset may acute enough to produce cardiogenic shock or sudden death; it is a recognized cause of sudden death in infancy.

• Approximately 20% of patients have a history of frequent or recent respiratory tract infections.

• Episodes of severe sudden abdominal pain may indicate coronary insufficiency.

• The contracted form of endocardial fibroelastosis presents with features of left-sided obstructive disease and acute left ventricular failure.

• Endocardial fibroelastosis is one of the recognized causes of nonimmune hydrops fetalis.

Endocardial fibroelastosis manifests as the classic features of heart failure.

Tachypnea during feeding and grunting respirations with subcostal or intercostal retractions have been reported. Fine expiratory wheezes or rales in the lung bases are common.

The following may be present upon admission:

• Pallor

• Peripheral cyanosis

• Fever

• Leukocytosis

• Anemia

• Rash

Thromboembolic episodes may lead to sudden death, myocardial infarction, cerebrovascular events, or even pulmonary embolism.

The usual physical findings are as follows:

• Cardiomegaly with normal-to-faint first and second heart sounds, a gallop rhythm with an audible third heart sound, apical pansystolic murmur of mitral regurgitation, and hepatosplenomegaly

• Clinically detectable pleural or pericardial effusions (rare)

Blood tests indicated in cases of suspected endocardial fibroelastosis (EFE) include the following[2] :

• Serum electrolyte levels

• Blood urea nitrogen (BUN) and creatinine levels

• Complete blood cell (CBC) count

• Complete metabolic profile

• Blood culture tests indicated for management of acute episodes

• Autoantibody profile including anti-Ro and anti-La

• Brain natriuretic peptide

Chest radiography

Note the following:

• Cardiomegaly and cardiothoracic ratios exceed 0.65 in 50% of patients.Cardiac enlargement (CE) is present in some patients at birth. In others, the heart size is normal during the first few weeks to the first few months of life, but CE subsequently develops.

• The shape of the cardiac silhouette varies, although it is often globular.

• Pulmonary venous congestion is common.

• Left lower lobe atelectasis secondary to dilated left atrium (LA) is found in 25% of patients.

See the images below.

Endocardial Fibroelastosis. Chest radiograph, anteroposterior view, showing cardiomegaly and pulmonary venous congestion in a 6-month-old infant with endocardial fibroelastosis (EFE).

Endocardial Fibroelastosis. Chest radiograph, left lateral view, showing an enlarged heart in 6-month-old infant.

Echocardiography

Echocardiographic features may include the following:

• LA and left ventricular (LV) dimensions are increased.

• LV, septal, and posterior wall (PW) excursions are reduced.

• The ejection fraction (EF) is reduced.

• Mitral valve (MV) motion is abnormal.

• Echogenicity along the endocardium of the LV (diagnostic clue) is dense.

• Suggestive indicators include increased endocardial echo brightness and globular shape of the LV.

• The echocardiograph may depict a normalization of the shortening fraction and the LV dimensions when the clinical condition improves following medical therapy.

• A varying degree of mitral regurgitation is common.

Fetal echocardiography

Fetal echocardiography is a valuable tool for early identification, particularly of the secondary type.

One of the congenital malformations (eg, aortic stenosis) is often demonstrated at the initial study. The endocardial fibroelastosis becomes obvious in repeat studies.

Electron beam computed tomography (CT) scanning

Electron beam CT scanning has been reported to be useful in the early diagnosis of endocardial fibroelastosis because of its demonstration of calcification and fibrosis of the ventricles, especially at the apex.

Magnetic resonance imaging (MRI)

Reports highlight the role of MRI in identifying the presence of endocardial fibroelastosis.[12, 13] MRI that uses perfusion and myocardial delayed enhancement can be useful in establishing the diagnosis. Endocardial fibroelastosis gives the endocardial surface a rim of hypointense signal in the perfusion sequences and a rim of hyperintense signal in the myocardial delayed-enhancement sequences.

Twenty-four–hour Holter electrocardiography (ECG)

The 24-hour Holter study is useful for documenting ambient arrhythmias.

Electrocardiography

Findings on ECG may include the following:

• Tall R waves, deep Q waves, and T-wave inversion or flattening in the left precordial or inferior lead have been reported.

• Findings depict left ventricular (LV) hypertrophy in more than 75% of patients.

• In the first few weeks of life, right-axis deviation and isolated right ventricular hypertrophy are more common.

• Pulmonary hypertension may develop in patients who survive for a long period and appears as biventricular hypertrophy on electrocardiography.

• Patterns of left, right, or biatrial enlargement are evident in 50% of patients.

• Conduction or rhythm abnormalities include Wolff-Parkinson-White syndrome, left bundle branch block, supraventricular and ventricular arrhythmias, and varying degrees of atrioventricular block.

• Low-voltage tracings in the initial stage of heart failure and in the terminal phase are noted in 5% of patients.

• Occasionally, an infarct pattern appears, pointing to extensive myocardial fibrosis and necrosis.

Cardiac catheterization

Cardiac chambers and pulmonary arteries contain elevated pressures consistent with heart failure. Generally, systolic pulmonary artery pressure is not more than 50% of systemic pressure. Marked pulmonary hypertension may be seen in older children.

The constrictive type of endocardial fibroelastosis is rare and is associated with a left-sided atrioventricular obstructive pattern, with very high left atrial (LA) pressures from an early age. A diastolic gradient can be detected across the mitral valve (MV). Pulmonary artery pressure is elevated and often reaches systemic levels in this type of endocardial fibroelastosis.

Postcatheterization precautions include hemorrhage, vascular disruption after balloon dilation, pain, nausea and vomiting, and arterial or venous obstruction due to thrombosis or spasm.

Complications may include blood vessel rupture, tachyarrhythmias, bradyarrhythmias, and vascular occlusion.

Angiography

Angiocardiographic findings include the following:

• Marked dilation of the left ventricular (LV) cavity

• Reduced ejection fraction (EF) with little or no LV wall thickening

• Dyskinetic LV contraction

• Mitral regurgitation (common)

• In the contracted type, dilated right ventricle, right atrium, and pulmonary artery with slow clearance of the contrast from the left side of the heart

Digital subtraction angiography

This may reveal an avascular rim between the opacified LV cavity and the ventricular walls perfused by the coronary arteries. The contrast void rim can be identified even in ordinary cineangiographic films.

Biopsy

In cases in which the diagnosis is unclear, myocardial biopsy can be helpful.

Endomyocardial biopsy has its risks, especially in an infant, and it is not essential to make a diagnosis in the majority of affected babies.[14]

Endomyocardial biopsy reveals an invasion of the endocardium and subendocardium by fibroelastic tissue.

Abnormalities are largely confined to the endocardium, with marked hyperplasia of its constituents, especially collagen and elastic fibers; hence, the basic abnormality in endocardial fibroelastosis appears to involve the synthesis of abnormally large amounts of collagen and elastin rather than a qualitative change in the structure of elastic fibers.

Surface deposits of fibrin have also been detected using electron microscopy. The underlying myocardium generally appears normal.

Although no cure exists for endocardial fibroelastosis (EFE), treatment typically centers on the patient's symptoms, which frequently focuses on chronic cardiac failure[2] ; its acute exacerbations are often precipitated by respiratory infections.

Early and prolonged treatment with digoxin is suggested. Continue therapy for several years after the symptoms disappear; cessation of drug administration may result in acute cardiac failure, even when heart size has returned to normal.

Other measures for acute failure and exacerbations of failure may be required, and precipitating factors, such as infection and anemia, require attention. Invasive procedures may be required.

Although beta blockers are used frequently in adults with heart failure, a Cochrane review concluded evidence is insufficient to recommend or discourage their use in children.[15]

Anticoagulation may be required in the presence of thromboembolic complications.

Case reports in the literature cite resolution of antenatally diagnosed endocardial fibroelastosis associated with positive anti-Ro and anti-La antibodies with corticosteroid therapy.

Outpatient follow-up

Schedule regular follow-up care until symptoms subside and cardiac size and function are normal.

Educate patients about the potential for the reappearance of symptoms if therapy is withdrawn.

Permit activity to the limit of tolerance.

Both pericardial poudrage and mitral valve (MV) replacement have had disappointing results.

Cardiac transplantation may be recommended for patients with end-stage disease.

Consider consultations with the following specialists:

• Pediatric cardiologist

• Radiologist

• Nuclear medicine specialist

• Family physician

• Occupational therapist

• Physiotherapist

• Psychologist

• School teacher

• Specialist nurse

• Pharmacist

• Dietitian

Diet is dictated by the underlying heart disease and degree of malnutrition.

The Academy of Nutrition and Dietetics provides recommendations regarding heart failure and evidence-based nutrition.

Limitations to activity are dictated by the symptomatology.

If the patient is asymptomatic and his or her heart size is normal, provide early, adequate, and prolonged therapy with digitalis and diuretics for at least 2-3 years, with gradual discontinuation.

Early and prolonged treatment with digoxin is suggested. Anticoagulants may be required in the presence of thromboembolic complications.

Antibiotics for endocarditis prophylaxis are administered to patients with certain cardiac conditions, such as endocardial fibroelastosis, before procedures that may cause bacteremia are performed. For more information, see Antibiotic Prophylactic Regimens for Endocarditis.

Class Summary

These agents are used to eliminate retained fluid and to lower preload.

Furosemide (Lasix)

Inhibits reabsorption of fluid from ascending limb of Henle loop in renal tubule. IV administration has a venodilator action. Lowers preload even before diuresis sets in. DOC in acute heart failure and in exacerbations of chronic heart failure. Used for long-term management of chronic heart failure.

Spironolactone (Aldactone)

Potassium-sparing diuretic that acts on distal convoluted tubule of kidney as an aldosterone antagonist. Has synergistic action with furosemide.

Class Summary

These agents reduce afterload and decrease myocardial remodeling, which worsens chronic heart failure.

Captopril (Capoten)

Accepted as an essential part of any antifailure therapy; promotes symptomatic improvement and enhances survival.

Class Summary

These agents provide symptomatic improvement.

Digoxin (Lanoxin)

Improves myocardial contractility, reduces heart rate, and lowers sympathetic stimulation in chronic heart failure.

Class Summary

These agents prevent recurrence of thromboembolic episodes of cardiac origin.

Warfarin (Coumadin)

Prevents thrombus formation within cardiac chambers and venous circulation by antagonizing effects of vitamin K.