Continuing Education Activity

Endocardial fibroelastosis (EFE) is primarily a disease of infants and children, but can rarely present in adulthood as well. In 1943, the endocardial fibroelastosis term was coined by Weinberg et al. in children who presented with unexplained heart failure previously known as 'fetal endocarditis'. Rare diseases are studied in a limited capacity and lack sufficient data for evidence-based medical practice. This activity outlines the updates in clinical presentation, evaluation, and management of endocardial fibroelastosis and also reviews the role of the interprofessional teams in improving the management of patients with this condition.

Objectives:

• Describe the pathophysiology of endocardial fibroelastosis.
• Review the clinical symptomology in the presentation of endocardial fibroelastosis.
• Identify the indications for medical therapies and surgical interventions for endocardial fibroelastosis.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for patients with endocardial fibroelastosis.

Introduction

Endocardial fibroelastosis (EFE) is primarily a disease of infants and children, but can rarely present in adulthood as well.[1] In 1943, the endocardial fibroelastosis term was coined by Weinberg et al. in children who presented with unexplained heart failure previously known as 'fetal endocarditis.'[2] It is broadly defined as the thickening of the endocardium due to the excessive proliferation of fibrous and elastic tissue.[3] 

The endocardium is normally a thin layer of endothelial cells lining the inner side of the heart chambers. The presentation is versatile and is often overlapping with other cardiac anomalies. It is frequently noticed with other congenital heart conditions like hypoplastic left heart syndrome.[4] Cases have been reported where anomalous left coronary artery from the pulmonary artery (ALCAPA) was initially labeled as EFE due to similar echocardiographic findings.[5] Hence, it is pertinent to know conditions that can present similar to EFE as well which is discussed in the differential diagnosis section.

Etiology

The exact etiology of EFE is still unknown. Although primary  EFE is considered idiopathic, some studies have suggested a genetic component, most notably X-linked recessive.[6] Tafazzin is a protein encoded by the gene TAZ (also known as EFE2) located on chromosome Xq28. Mutations in this gene have been implicated in the development of EFE.[7] Animal models also report a possible role of mutation in gene NEX, which produces nexilin, a novel Z-disk protein implicated in developing EFE.[8] Another possible underlying mechanism suggested has been the transition of endothelial cells to mesenchymal cells.[9][10] Infective and viral etiology has also been suggested by researchers, along with the possible autoimmune role.[11] The possible role of anti-Ro and anti-La antibodies has been established in the literature.[12] Complete regression of EFE after corticosteroids to anti-Ro/anti-La mothers in the fetus also supports this notion.[13] Although EFE can occur alone, 25% to 50% of cases have been seen alongside other genetic conditions such as hypoplastic left heart syndrome, aortic stenosis, and atresia.[11][14][15]

Epidemiology

There is not enough data on the incidence and prevalence of endocardial fibroelastosis itself in literature due to the rarity of this condition. The usual age of presentation is the first year of life.[14] Pediatric cardiomyopathy is a broad entity that includes EFE. The overall incidence of pediatric cardiomyopathies is approximately 1 in 100,000 children.[16] The incidence has been non-discriminatory between both sexes and questions the widely accepted X-linked recessive pattern of inheritance. Some studies have suggested an autosomal recessive pattern as well.[14]

Pathophysiology

The underlying pathophysiology of endocardial fibroelastosis is suggested 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.[17] Gross examination shows the glistening white appearance of the endocardium. Normally, the endocardium is transparent as the underlying pink myocardium is visible. Myocardial thickness is within the normal range in the beginning but can increase with time to compensate for the workload. Valvular involvement is seen as either thickening, adhesion of valvular leaflets, or shortening of papillary muscles leading to mitral regurgitation.[11]

Mural thrombus formation is also a common finding.[18] These findings are more noticeable in the left heart. Both dilated and restrictive cardiomyopathies have been linked to EFE in the literature.[14] The possible explanation can be the continuous strain on the left ventricle (LV) due to volume and/or pressure overload. Conversion of dilated cardiomyopathy into restrictive has also been reported in fetal surveillance.[19]

Histopathology

The endocardium is a transparent thin layer approximately 10 micrometers in thickness consisting of only 5 layers.[11] Histopathological findings in samples from the autopsies have shown thickening of all five layers, and an increase in elastin and collagen fibers deposition.[20] Neustein et al. suggested the possible mechanism as:[21]

1. The initial invasion of endocardium by dark smooth muscle cells
2. The latter invasion of endocardium by light smooth muscle cells
3. Transformation of light smooth muscle cells to leiomyoid cells
4. Transformation of these leiomyoid cells to typical fibroblasts

It is believed that light smooth muscle cells, along with leiomyoid cells, are the culprit in the production of excessive collagen and elastin in the endocardium.

History and Physical

Initial common clinical signs are feeding difficulty, excessive sweating, breathlessness, failure to thrive, respiratory distress, cough, cyanosis, and swelling of the lower limbs. The most common presentation of endocardial fibroelastosis includes signs and symptoms of left heart failure following a recent respiratory infection.[14] Furthermore, patients may have signs of cardiogenic shock, irregular pulse, gallop rhythm, the pan-systolic murmur of the atrioventricular valve regurgitation, lung crepitations, raised jugular venous pressure, hepatosplenomegaly, and pedal edema as well.[2] Sinus tachycardia and pulsus alternans are other less notable auscultatory findings.[14] The less common but pertinent presentations reported in the literature are hydrops fetalis,[22][23] congestive heart failure,[18] mural thrombi,[1] myocardial infarction,[18] congenital heart block,[12] pulmonary embolism,[24] and sudden cardiac death.[25] 

Due to a wide variety of clinical presentations, Seki et al. proposed pathological criteria to narrow down the diagnosis:[26]

• Absence of other congenital malformations
• Absence of underlying vascular, metabolic, or inflammatory disorders
• Spherical or dilated left ventricle (LV)
• Diffuse thickening of LV endocardium
• LV papillary muscles displaced upward towards the left atrium
• Thickened free edges of mitral valve leaflets
• Excessive straight elastic fibers in the endocardium (on microscopic examination)

Evaluation

Besides routine baseline investigations like serum electrolyte levels, renal function tests, complete metabolic profile, and brain natriuretic peptide, some specific investigations like an autoantibody profile including anti-Ro and anti-La are advised since management includes steroids if positive.

A chest X-ray is a quick way to assess for cardiac and pulmonary findings like cardiomegaly, pulmonary edema, pleural effusion, and pneumonia.

Electrocardiograms reveal a variety of disturbances, including tachyarrhythmias and neonatal atrial fibrillation, arrhythmias, infarct pattern, and LV hypertrophy.

Echocardiographic features of the dilated type of primary endocardial fibroelastosis include the globular shape of the LV with global hypokinesia. Increased septal and free wall thicknesses can be seen. Increased dimensions of the left atrium, left ventricle, right ventricle, and a varying degree of mitral regurgitation along with abnormal mitral inflow velocities may also be seen. An experienced eye can pick up increased brightness of the endocardium as well, which is a hallmark of endocardial involvement.

Computed tomography (CT) scan is an excellent non-invasive tool for the detection of cardiovascular calcification and ruling out pericarditis.[27][28] Electron beam CT scan picks up apex calcification with high accuracy.[27]

Magnetic resonance imaging (MRI) can be useful in the detection of EFE since biopsy is invasive. A hypointense rim in the perfusion sequence of the myocardium and a hyperintense rim in the delayed-enhancement sequence is indicative of EFE.[29]

Biopsy of endocardial tissue is the gold standard test for diagnosis but may not be the first choice due to its invasive nature and related complications.

Treatment / Management

Medical

There is no specific cure for endocardial fibroelastosis. Treatment is largely tailored around symptoms. Management commonly revolves around chronic cardiac failure with diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers. Early and long-term treatment with digoxin has been suggested.[30] It is beneficial in clinical improvement, but mortality benefits are yet unclear. Corticosteroids have shown to regress fetal endocardial fibroelastosis associated with maternal anti-Ro and anti-La antibodies. Standard therapy with steroids is not recommended in seronegative EFE as little to no benefit has been reported in those cases. Thromboembolic complications may require anticoagulation. 

Surgical

At present, surgery is only indicated in refractory cases that do not respond to medical management. Experimental procedures such as peeling off the fibrotic and thickened endocardium to restore compliance of the underlying myocardial tissue have been tried with limited improvement in outcomes.[2]

Cardiac transplantation may be recommended for those with end-stage disease.[31]

Differential Diagnosis

Several conditions have been mistaken for this disease, and an extensive workup and a vigilant clinician are required for correct diagnosis. Due to the rarity of this condition and the absence of highly sensitive/specific diagnostic tools, endocardial fibroelastosis is a diagnosis of exclusion. The following conditions have been reported in the literature so far and should be ruled out in suspected cases of EFE.[11]

• Cardiomyopathies: Dilated, hypertrophic (Noonan syndrome), restrictive, Barth syndrome
• Congenital malformations: Aortic stenosis, coarctation of the aorta, ALCAPA, hypoplastic left heart syndrome 
• Viral myocarditis: Mumps, coxsackie, adenovirus
• Lysosomal storage diseases: Pompe, Hurler, Niemann-Pick
• Other: Systemic carnitine deficiency, myocardial infarction

Rare disorders like fibroplastic parietal endocarditis, cardiovascular collagenosis, and endomyocardial fibrosis should also be included in differential diagnoses.[32]

Prognosis

Although the condition is not universally fatal, the prognosis is still relatively poor. The 4-year survival rate is 77%.[33] It is relatively worse in infants who present with acutely decompensated heart failure and they are less likely to survive unless they receive a transplant. Surviving patients often experience persistent symptoms. An ECG 'infarct' pattern in a child with endocardial fibroelastosis is usually associated with death and this pattern is a negative prognostic sign for survival.[34]

The following findings were reported by Manning et al.[30]

• Subacute or chronic symptoms at presentation have a better prognosis. 
• Response to initial therapy correlates with a better prognosis.
• Cardiothoracic ratio below 55% by the end of 2 years of therapy is indicative of a good prognosis.
• Normalization of electrocardiogram findings between 2 to 5 years after the onset of therapy supports a positive prognosis as well.

Complications

Many complications have been reported with endocardial fibroelastosis. Some of them are:

• Intracardiac thrombus precipitated by LV dysfunction and arrhythmias[1]
• Severe mitral regurge due to direct valvular involvement or chronic LV dysfunction[2]
• Thromboembolism leading to stroke, pulmonary embolism, and systemic embolization[35]
• Myocardial infarction either from ischemia or thromboembolism[18]
• Arrhythmias due to the involvement of the cardiac conduction system[36] 
• Congestive heart failure and cardiogenic shock[33]
• Right heart involvement leading to pulmonary hypertension[37][38]
• Hydrops fetalis presumably due to intrauterine cardiac failure[23] 
• Sudden cardiac death[33]

Deterrence and Patient Education

Parents with a history of a child with endocardial fibroelastosis should undergo prenatal assessment in subsequent pregnancies. Mothers with Sjögren syndrome should also remain cautious regarding the possibility of this entity in a child, so screening with anti-Ro and anti-La antibodies is warranted. Parents should be educated regarding the high morbidity and mortality of the condition. Genetic counseling should also be provided.

Enhancing Healthcare Team Outcomes

Due to the rarity of the condition and diverse clinical presentation, primary care clinicians and pediatricians seldom make the diagnosis of endocardial fibroelastosis alone. It is only after referral to a pediatric cardiologist that a diagnosis is formed. Clinical knowledge about EFE and its differential diagnosis can help early detection and intervention lower mortality. Most of the deaths in EFE occur within the first two months of presentation. Frequent follow-up and close monitoring can improve patient outcomes. Better communication among the interprofessional team, including primary clinicians, cardiologists, and healthcare staff, is required. Since the etiology is not yet clear, no preventive measures can be suggested to the public. More studies are required to understand the underlying etiology before the prognosis can be improved.

The American Heart Association, in its latest report (2006), has removed EFE from the classification of cardiomyopathy.[39] This move has further affected the future of research related to EFE. Studies are already scarce, and even those available in databases have poor evidence levels. Medical therapy for heart failure is the mainstay of management. [Level 4][30] Surgical peeling of endocardium has been advised by a few authors and is only indicated in severe and treatment-refractory cases.[2] Cardiac transplantation is advised for end-stage disease. [Level 5][31] EFE lacks evidence level 3 or better in its perspectives.