Endomyocardial fibrosis (EMF) was described as a distinct clinicopathological entity in 1948 in Uganda.^w1 Initially several terms were used to describe the disease. These included tropical endomyocardial disease, endocarditis parietalis fibroplastica, endocardial fibrosis, constrictive endocarditis and endocardial fibroelastose.

EPIDEMIOLOGY

EMF is thought to be the most common type of restrictive cardiomyopathy worldwide.1 Although most studies have been reported from Uganda, Ivory Coast, Nigeria, Brazil and India, the disease has been occasionally encountered outside the tropics.2 Geographic distribution of EMF is not uniform both in Africa and Asia.3 4 In the endemic areas of Africa, EMF is the second cause of admission for acquired cardiovascular disease in children and young adults, after rheumatic heart disease,5 ^w2 accounting for up to 20% of all causes of heart failure.

To date our knowledge of the prevalence of the disease is derived from hospital based studies with absence of data from systematic studies in the community. EMF affects predominantly children and adolescents, usually from low socioeconomic background. More than half the cases are seen in the first decade of life. Male preponderance was found in Kerala and Nigeria, while female preponderance has been described in Brazil and Uganda. A bimodal age distribution has been reported in some studies.5 ^w3

AETIOLOGY AND PATHOGENESIS

The aetiology of EMF remains unknown. Several hypotheses have been proposed and explored including cardiotoxicity of the eosinophil, infectious agents, autoimmune processes, genetic predisposition, ethnicity, diet, climate and poverty.

Hypereosinophilia

EMF appears to share some pathogenic mechanisms with the hypereosinophilic syndromes, which comprise a heterogenous group of disorders characterised by peripheral eosinophilia for at least 6 months and end organ damage related to eosinophil infiltrations. These syndromes have been classified as idiopathic, clonal and reactive. The similarity of mechanisms responsible for EMF and the hypereosinophilic syndromes could have exciting therapeutic implications.6 Eosinophils in patients with hypereosinophilia have unusual morphology, are metabolically and functionally more effective than normal, and show a preponderance of multilobed forms and evidence of degranulation. Granule proteins mediate the cardiotoxicity of the eosinophils through activation of heart mast cells.7 Eosinophils are also capable of secreting an array of pro-fibrotic mediators, including plasminogen activator inhibitor-2 (PAI-2). This mediator has a role in plasminogen–plasmin mediated tissue destruction and remodelling,^w4 and this could explain the role of eosinophils in deposition of fibrous tissue in the heart.

Severe hypereosinophilia is found in some patients with EMF and its level seems to be inversely related to the duration of the illness.^w5 Hypereosinophilia in this condition is probably induced by parasitic infestations in most cases, but this link remains difficult to establish because the eosinophil count peaks during larval migration, returning to normal thereafter.

Infection

Occurrence of EMF in people from Europe and North America after short stays in endemic areas supports the role of infection in the pathogenesis of the condition. EMF has been occasionally associated with helminths,8 schistosomiasis,^w6–8 microfilaria loa-loa,^w9 filariasis^w10 and malaria.^w11 However, several studies failed to show an increased prevalence of these infections in EMF patients when compared to the general population. The finding of endomyocardial fibrotic lesions mimicking human disease in mice infected with Plasmodium berghei supports the infection hypothesis and provides one of the best models of the disease.^{w11 w12}

Autoimmunity

The role of autoimmunity is suggested by the finding of high titres of malarial antibodies,^w13 autoantibodies,^w14 a high incidence of hyperimmune malarial splenomegaly, and raised anti-streptolysin titres^w15 in patients with EMF.

Genetic predisposition

Familial occurrence and the reported high incidence among certain ethnic groups in some countries also suggest genetic susceptibility.^{w16 w17}

Dietary factors

Prolonged ingestion of the tuber cassava (tapioca) in association with extreme deprivation of proteins, mainly tryptophan deficient diets, has been considered a risk factor for EMF. McKinney^w18 produced an experimental model of EMF and was able to show the protective role of high protein diet in guinea pigs fed on a diet consisting largely of plantains. Animal models using African green monkeys also showed that ingestion of uncooked cassava caused endomyocardial degeneration of the ventricle, apical thickening and interstitial fibrosis.^{w19 w20}

Geochemical factors

Increased levels of cerium derived from monazite soils were found in the hearts from people with EMF living in the coastal regions of the tropics.^w21 Cerium triggers a wound healing response in the cardiac tissue of rats leading to cardiac fibrosis^w22 that could result from direct stimulation of subendocardial fibroblasts by this element.^w23

EMF cannot be explained by a single cause in all areas where it has been reported. The disease appears to be triggered by several environmental factors acting upon individuals with a genetic predisposition.

PATHOPHYSIOLOGY

EMF appears to have an initial stage of febrile illness and pancarditis,9 frequently associated with hypereosinophilia, facial and peri-orbital swelling, body itching, urticaria and neurological features.6 This febrile episode, triggered by one or more unknown factors, is followed by ventricular thrombosis affecting usually the apices and the subvalvar apparatus. This causes obliteration of the ventricular cavity and interference with the valve mechanism that then evolves to organisation of thrombus and endocardial fibrosis typical of advanced stages of the disease.

The fibrosis of the mural and valvar endocardium impedes filling and causes valve distortion, both leading to restrictive physiology with atrioventricular regurgitation, and the typical small ventricles with severely dilated atria. The resulting heart failure with venous congestion and sustained low cardiac output explains most clinical findings, but there is still some controversy regarding the pathophysiology of central cyanosis, ascites and the absence of pedal oedema.

Finger and toe clubbing, growth retardation, testicular atrophy, failure to develop male secondary sexual characteristics, and cachexia are the result of sustained low cardiac output. Chronic systemic venous hypertension is the origin of most of the characteristic signs of right ventricular EMF—namely, exophthalmos, elevated jugular pressure, gross hepatomegaly, congestive splenomegaly, and voluminous ascites that can lead to ventral or inguinal hernia.^w24

Death results from complications of chronic heart failure, but can occur suddenly due to thromboembolism or arrhythmia.^w25

DIAGNOSIS

By the time of clinical presentation most patients have advanced disease with signs of longstanding heart failure, but usually give a poor history. Most patients recall a febrile episode associated with tiredness, breathlessness, cough, swelling of the face, urticaria and abdominal distension, followed by a variable interval free of symptoms—a few weeks or months in left ventricular EMF, and over 1 year in right ventricular EMF.

Clinical types

The clinical picture of EMF depends on the activity of the disease, the chamber affected and the severity of the lesions. Active disease is suggested by recent febrile episodes and the onset of heart failure, sometimes associated with urticaria and facial oedema.

Isolated or dominant left ventricular EMF

These patients have usually a good general status, pronounced dyspnoea and orthopnoea, and small displacement of the apex beat that is not particularly hyperdynamic. There is characteristically a soft and short systolic murmur confined to early systole.1 A delayed opening snap is present, due to thickening of the anterior leaflet of the mitral valve, and the pulmonary component of the second sound is loud indicating high pulmonary pressure. Occasionally, there are signs of systemic embolism.

Isolated or dominant right ventricular EMF

Most patients have proptosis, facial oedema, cyanosis, distended jugular veins and finger clubbing. Many exhibit retardation of growth and underdevelopment of secondary sexual characteristics. Some have a variable degree of jaundice; a considerable proportion present in atrial fibrillation.

A left parasternal pulsation is usually noted, and corresponds to the compensatory hypercontractile right ventricular outflow tract. The presence and intensity of the systolic murmur from the tricuspid regurgitation is variable, but a third sound is always present. Ascites is in most cases disproportionate to the almost inexistent pedal oedema (fig 1), and is associated with hepatosplenomegaly.

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Figure 1 Severe ascites without pedal oedema in a 9-year-old child with right ventricular endomyocardial fibrosis. Parental/guardian informed consent was obtained for publication of this figure.

Biventricular EMF

This group includes the majority of EMF patients. Predominance of right sided lesions is the most common form and these, by reducing pulmonary perfusion, avoid the hazards of severe pulmonary hypertension caused by left sided lesions, allowing longer survival.

Ascites is a striking feature in right ventricular EMF, but is also seen in left ventricular disease. The ascitic fluid is typically an exudate containing more proteins and leucocytes (predominantly lymphocytes) than expected with right heart failure, suggesting some role of inflammation in the pathogenesis10 and, in advanced stages, a role of protein losing enteropathy.

Laboratory findings

To date there is no specific laboratory test for diagnosing EMF. The presence of hypereosinophilia is variable and more frequent early in the disease. Characteristically the eosinophils show large granules, degranulation around the nucleus, vacuolisation and nuclear changes. Hypoalbuminaemia is rare except in advanced disease. Similarly biochemical changes secondary to liver and/or kidney dysfunction are common. The presence of procoagulant state and activation of the immune system is currently being investigated by us in Mozambique.

Chest x ray

The chest x ray in right ventricular EMF shows right atrial enlargement and a bulge over the left heart border due to dilatation of the right ventricular outflow tract, with clear lung fields (fig 2A). Pericardial effusion when present is suggested by the presence of a large globular heart shadow. In cases of isolated left disease there is evidence of pulmonary venous congestion, an enlargement of the left atrium and a prominent pulmonary artery (fig 2B). Rarely, a linear endocardial calcification may be seen.

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Figure 2 (A) Chest x ray of a patient with right ventricular EMF, showing pronounced cardiomegaly due to severe right atrial dilatation and a variable amount of pericardial effusion, with clear lung fields. (B) In left ventricular EMF, the cardiomegaly is less pronounced, there is a bulge over the left heart border, and hypervascularisation of the lung fields associated with post-capillary pulmonary hypertension.

Electrocardiography

The ECG shows no constant abnormalities. Atrial fibrillation is present in many cases at first admission. In advanced disease there are low voltage QRS complexes, non-specific ST–T wave changes, and conduction disturbances.^w26 In predominant right forms the ECG shows a tall and broad right atrial wave and a characteristic “QR” pattern in V3R or V1. In left EMF there are signs of left a trial hypertrophy and pulmonary hypertension.

Echocardiography

Echocardiography has been the main technique for the diagnosis of endomyocardial fibrosis, enabling the assessment of anatomy and cardiac function (table 1).

Criteria used for the diagnosis of right EMF are apical obliteration, reduction of the right ventricular cavity size, paradoxical movement of the interventricular septum, cleavage plane between the fibrous tissue and myocardium, parietal thrombosis, dilatation of the right ventricular outflow tract, dilatation of the right atrium, tricuspid valve adherent to the endocardium with regurgitation, diastolic opening of the pulmonary valve, dilatation of the inferior vena cava, and pericardial effusion (fig 3A).

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Figure 3 (A) Echocardiography in severe right ventricular endomyocardial fibrosis (EMF) shows apical retraction, reduction of ventricular size, aneurysmal right atrium with mural thrombi and spontaneous contrast. (B) Apical fibrosis and thrombus with calcified areas, reduction in ventricular cavity, thickening of mitral leaflet and left atrial dilatation are the main findings in this case of left ventricular EMF.

In left EMF the most important features are endocardial hyperdensity in the apex associated with reduction in the longitudinal diameter of the ventricle that becomes spherical or oval, with dilatation and hypercontractility of the basal portion.11 On Doppler evaluation there is a rapid deceleration of the E-wave with unimpressive A-wave. The posterior leaflet of the mitral valve is usually retracted or completely absent and is associated with severe eccentric valve incompetence (fig 3B) and left atrial dilatation. There is usually tricuspid regurgitation of variable degree allowing confirmation of pulmonary hypertension.

We have recently evolved and used a set of echocardiographic criteria for classifying and grading the different stages of EMF (AO Mocumbi, unpublished data).

Computed tomography

To date, computed tomography (CT) has not been used for diagnosis of EMF. The disease is suggested by the presence of linear calcification parallel to the pericardium and along the inner border of the myocardium.^w27 Further studies using multislice CT may help to elucidate several structural and functional changes at different stages of the disease.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) provides a powerful tool to define and localise many of the pathological features in the hearts of patients with EMF, including fibrosis, poor perfusion and calcification.12 In addition, MRI can be used to quantify and characterise three dimensional myocardial movements and flow patterns, which can be extremely valuable both for management and as a research tool.^w28 Unfortunately it is not easily available in most areas where EMF is endemic, an issue that needs to be urgently addressed.

Cardiac catheterisation

Invasive studies are not routinely used anymore, either for diagnosis or management, and are currently used to answer specific questions such as the degree of pulmonary hypertension and its response to pharmacological agents.

Pathology findings

Macroscopically the heart shows fibrous thickening of the ventricular endocardium which is more pronounced in the apex and the recesses behind the papillary muscles, usually sparing the leaflets and chordae (fig 4A). The atria are usually dilated and hypertrophied and, in a minority of cases, present with fibrotic endocardial patches.

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Figure 4 (A) Autopsy specimen showing endocardial whitening and thickening in the trabecular portion of the right ventricle, with viable myocardium underneath it and sparing of the leaflets and chordae. (B) Histological examination reveals subendocardial thickening due to irregular deposition of old and newly formed collagen, which penetrates the inner myocardium in the perivascular areas separating groups of myocardial fibres (Van Gieson staining, ×5).

The histology of the ventricles reveals pronounced thickening of the endocardium, which is made up of both old and newly formed collagen deposited under a lining of seemingly normal endocardium (fig 4B). There is usually chronic inflammatory infiltrate in the interface between the endocardium and the myocardium, as well as around interstitial vessels.

DIFFERENTIAL DIAGNOSIS

Due to their high prevalence in endemic areas for EMF, dilated cardiomyopathy, constrictive pericarditis, tuberculous pericarditis and rheumatic heart disease must be distinguished from this condition. Other less frequent conditions that can be misdiagnosed as EMF are amyloidosis, haemochromatosis, myocardial sarcoidosis and neoplastic infiltration of the heart. Right ventricular EMF should be distinguished from Ebstein’s disease.

MANAGEMENT

There is no specific treatment for EMF. Medical treatment is used to control the acute disease, heart failure and arrhythmias, as well as for pre- and postoperative management. Several invasive procedures also have a role in controlling the acute and chronic complications of the disease—namely, peritoneal, pleural and pericardial drainages.

Medical treatment

During acute illness, treatment is aimed at maintaining cardiac function and suppressing the eosinophilia using short courses of oral corticosteroids, usually 7–10 days. Symptomatic treatment with diuretics has been shown to be useful, although high doses are usually required. Digoxin and β-blockers are used mainly in patients with rhythm disturbances to control heart rate. Since the population affected is typically not compliant with anticoagulation regimens and has no access to effective control of this treatment, low dose aspirin frequently replaces oral anticoagulants in patients with atrial fibrillation. Due to their known effects in reducing fibrosis, spironolactone and angiotensin converting enzyme inhibitors may be useful. However, their value needs to be evaluated in prospective randomised trials.

Surgery

The most commonly used surgical technique is targeted endocardial resection combined with valve repair or replacement through atriotomy. The reported early postoperative mortality has been between 15–30%, mainly due to low cardiac output syndrome and arrhythmias, and complications of prosthetic valves and permanent pacing accounted for the late mortality seen on follow-up of earlier series.13^–15 Successful surgery has a clear benefit on symptoms, favourably affects survival,16 ^{w29 w30} and gives the best long term results on isolated left ventricular EMF.^w31

Since diagnosis is rare in western countries, and because of a lack of infrastructure for cardiac surgery in most areas where EMF is endemic, surgical experience consists of isolated episodic attempts by several groups usually involving patients with very advanced stages of the disease.17 A more systematic approach to surgical treatment requires accurate characterisation of the disease in each specific patient, with development of tailored surgical therapy combined with appropriate timing of the operation and intensive preoperative medical treatment. This approach is currently being tried at the Maputo Heart Institute18 and needs to be more widely applied in combination with integrated programmes of management.

PROGNOSIS

The overall prognosis of EMF is poor, with a high incidence of sudden death from fatal arrhythmias and thromboembolism. The prognosis of this disease can, however, be improved by early diagnosis coupled with better understanding of the pathogenesis and identification of new therapeutic targets.

Our early experience suggests that surgical treatment can be lifesaving with acceptable intermediate term results. This, however, depends critically on evolving integrated programmes for early diagnosis and management of the condition, as mentioned above.

CONCLUSIONS AND FUTURE DIRECTIONS

EMF is one of the most neglected diseases in cardiology, affecting mainly children from poor areas in developing countries. The disease has an unclear aetiology, the pathogenesis is unknown, it carries a poor prognosis, and it has no specific treatment. The availability of portable echocardiography gives an opportunity for early diagnosis and prospective studies in the affected communities, which can ultimately allow better understanding of the natural history of the disease. Research on the mechanisms of the disease is mandatory to identify new therapeutic targets and improve the outcome, as well as to explore preventive measures to avoid the disease or progression to advanced forms. Development of specific drugs aimed at preventing proliferation, migration and injury produced by eosinophils, combined with attempts at defining new therapeutic targets and proper application of tailored surgical procedures, should all continue to ameliorate the devastating effects of this neglected disease.