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Abstract
Endomyocardial fibrosis is the most common restrictive cardiomyopathy observed world wide. The disease occurs in its classical endemic form in the selected coastal belt in Kerala, India, affecting young people of lower socioeconomic families, and attracting worldwide attention. Geographical identification of high levels of cerium in the soil samples of this coastal belt generated a new “geochemical hypothesis” for endocardial injury. Endocardial calcification, a pathognomonic, but less common feature of the disease, may share the same pathobiology of vascular and valvar calcification occurring in other diseases. Over the past four decades, Kerala has witnessed a tremendous change in its socioeconomic and health status and a corresponding decline in new cases of endomyocardial fibrosis in the younger age group. This decline parallels the decline of rheumatic fever reported earlier in developed nations. Socioeconomic development is, therefore, a major factor in the control of this enigmatic disease
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The epidemiology of restrictive cardiomyopathy in India received worldwide attention because of a unique disease affecting the endomyocardium, endomyocardial fibrosis (EMF).1 This disease has an unusual geographical distribution around the tropics (fig 1).1–3 EMF is a rare cause of endocardial calcification in the tropics and mimics constriction occurring within the ventricular cavity, myocardial function being normal (fig 2).4 Similar to calcific pancreatitis and pericarditis, the pattern of calcification is almost diagnostic. However, these calcific disorders of the tropics are declining and may become a “clinical curiosity” of the past.5 6 The important features of this disease—namely, geographical distribution, cardiac specificity and preference for the socioeconomically poor, have evaded a complete scientific explanation despite the intense scientific scrutiny to which the disease has been subjected.1 2 7
By definition EMF is an obliterative cardiomyopathy characterised by fibrotic thickening and obliteration of either the right ventricle, left ventricle or both ventricles, with a predilection to selectively involve the ventricular apices and inflow region and spare the outflow tract.2 3 The fibrotic process does not affect the valve leaflets, the atria, or the great vessels and extracardiac involvement is not known.
EPIDEMIOLOGY
There are few hospital-based data which throw light on the epidemiology and natural history of the variety of heart diseases presenting as restrictive cardiomyopathy in India.2 8–12 Studies in children and adults presenting with heart failure show the uncommon nature of this disease. Various causes seen elsewhere in the world like infiltrative and genetic varieties of restrictive cardiomyopathies are often encountered at the referral hospitals.8 9 13 EMF comprised the vast majority in these studies and in about one-third no definite reason could be attributed and hence they were classified as idiopathic restrictive cardiomyopathy. Idiopathic restrictive cardiomyopathy can be recognised in utero and at birth, but no case of EMF has been identified at that age, the youngest age reported being 2 years.11 The peculiar geographical distribution of EMF in India is well illustrated in the paper by Ramankutty et al.14 There are reports of naturally occurring EMF occurring in cats and in animal models created in the laboratory.7 15 16
Currently, the number of new cases diagnosed in our registry has declined to 10 new cases a year in the past decade from 20 cases seen in the previous decade. Furthermore, the mean age at presentation has also changed by a decade from 25 to 33 years, suggesting late recognition of asymptomatic cases and possible decline in the incidence of new cases.2 11 12 In the current era patients with EMF have relatively stable symptomatic course on follow-up with mortality of around 10% on 3-year follow-up.
PATHOLOGY
EMF is a rare disorder characterised by fibrotic replacement of the ventricular endomyocardium, affecting the apices and the inflow.2 3 7 The pathophysiology of the disease reflects the restriction of ventricular filling caused by the endocardial fibrosis. The fibrotic process can be focal or diffuse, patchy or continuous obliterating the trabecular morphology of the endocardium. At times the 2–3 mm thick white glistening fibrotic endocardium can be separated from the underlying trabecular myocardium; this forms the basis of the surgical endocardiectomy performed in selected cases.11 12 The fibrotic process can also extend into the subendocardium with microvascular involvement and at times organised thrombi at the surface. Unaffected myocardium shows varying degrees of dilatation and myohypertrophy. Patchy calcification can be recognised in chronic cases. The pericardium is usually thin and at times contains varying amounts of transudate depending on the degree of cardiac failure.
The restrictive physiology leads to aneurysmal dilatation of the atria and pulmonary venous congestion together with pulmonary hypertension when the left ventricle is affected and systemic venous congestion when the right ventricle is involved. Extension of the fibrosis to the papillary muscles deranges the function of the atrioventricular (AV) valves by plastering it to the wall, resulting in AV valve regurgitation. Atrial fibrillation, thromboembolic complications, infective endocarditits and incidentally detected calcification on the skiagram bring the patient to the clinician’s attention.
CLINICAL FEATURES
Systemic or pulmonary venous congestion and dilated atria with near-normal ventricular size and function form the hallmark of restrictive cardiomyopathy.9 Since most published reports from India centre on the commonest cause—namely, EMF, the rest of the discussion will concentrate on this.
Clinical recognition of EMF depends on the degree of ventricular involvement. The biventricular nature of the disease is seen in more than half the patients with the remainder having isolated right or left ventricular (LV) involvement. An acute phase and a chronic phase of evolution of the disease are suspected but most patients come to clinical attention at the burnt-out stage of the disease. When either one of the ventricles is affected, long-term follow up does not show further extension of the disease to the other.2 3 17 Isolated cases of RV, outflow tract obstruction by fibrosis can occur but are rare events.2 Like constrictive pericarditis, early diastolic filling is rapid, generating a loud third heart sound. No further filling is possible by atrial contraction and henceforth heart sound cannot be clinically recognised in this disorder. A loud third heart sound and pan-systolic murmurs are the principal clinical findings.
Isolated LVEMF can present as severe idiopathic pulmonary hypertension. The presence of a loud LV third heart sound with severe pulmonary hypertension, and near-normal LV apex location with or without mitral regurgitation are the clinical clues to a diagnosis of LVEMF. Isolated RVEMF presents in an emaciated adolescent with cachexia, massive pericardial effusion and gross ascites. These types of early-onset disease with aggressive clinical course are currently not seen in this country but have been reported elsewhere in the world.18 19 Occasional patients may have cyanosis with digital clubbing because of stretched open foramen ovale. This type of presentation should be differentiated from Ebstein’s anomaly and the former from constrictive pericarditis.20 21 Clinical presentation of the disorder may vary from asymptomatic incidental detection to cardiac cachexia. Development of ascites is out of proportion to the degree of pedal oedema, which may be inflammatory, suggestive of a systemic disorder (fig 3).22–24
AETIOLOGY
The exact aetiopathogenesis of this disorder continues to be elusive. To explain the peculiar geographical distribution, malnutrition and infections were initially suggested as the cause.1–3 25 The clinical similarity to the burnt-out stage of Loeffler’s endocarditis led to a number of studies to clarify the role of eosinophils in this disease.24–26 Loeffler’s endocarditis is characterised by predominantly LV involvement and the presence of a systemic phase of vasculitis or thromboembolic phenomena, or both. Demonstration of tissue and circulating eosinophilia and/or eosinophil-derived factors is a prominent feature of Loeffler’s endocarditis, though the final fibrotic stage of the disease resembles LVEMF.25–27 Loeffler’s endocarditis continues to be sporadic and distributed in more temperate climates, whereas EMF in the tropics remains endemic and is rarely associated with the syndromic manifestations of eosinophilia. Other factors investigated were lymphatic obstruction due to filariasis and altered immunological response to streptococcal infection in hosts whose immune status had been altered by parasitic infections. Isolated RV involvement was a phenomenon seen in certain disorders like carcinoid syndrome where the lungs detoxify the toxic metabolites protecting the left side of the heart. Similar clinical features in EMF generated research on dietary toxic factors like excess of serotonin present in banana, the cyanogenic glycosides and vitamin D present in cassava.5 25 Similar dietary factors were implicated in the genesis of chronic calcific pancreatitis, suggesting mucoid changes might generate a multisystem disorder, and thus a unifying dietary concept was proposed.6 16 Isolated RV involvement in this disease suggests that the right ventricle is preferentially affected.
Research at our centre identified a geochemical basis for the pathogenesis of the disease.7 25 The peculiar geographical distribution of the disease in India correlated with the abundance of thorium and cerium in the soil.14 Tissue samples from affected people reflected the elemental excess, which is pathogenic when accompanied by magnesium deficiency.7 25 Diarrhoeal disorders common in the tropics were postulated to cause relative magnesium deficiency, which in turn aggravates the toxicity of the lanthanides. These lanthanides substitute the magnesium moiety of the metalloenzymes, resulting in abnormal cell chemistry, free radical generation and cytokine production. Cassava grown in this area naturally has a higher lanthanide content, which was the staple diet of the Keralites, three decades ago. This generated much basic research into understanding the role of these elements and enzymes in the endocardium and adjacent interstitium.
INVESTIGATIONS
There are no clear serum markers to identify the initial stages of the disease. All cardiac investigations recognise the restrictive physiology and its consequences in the late stage when the disease is clinically apparent.2 3 19 25
Cardiac catheterisation
Cardiac catheterisation discloses restrictive physiology and resembles constriction. The classical dip and plateau tracing of the end-diastolic pressure waveform occurs in both disorders, but pressure equalisation of the end-diastolic pressures, atrial mean pressures and pulmonary artery diastolic pressures does not occur in EMF. Respiratory variations between the right- and left-sided chambers are minimal and end-diastolic pressures on the right side are more than one-third greater than the systolic pressures on the right side. Still there remain times when the two conditions cannot be differentiated with certainty. In these cases surgical exploration with biopsy of the pericardium or endocardium is needed.19–21
Angiography
The angiogram in EMF has unique features (fig 4). The main features are loss of trabecular pattern, obliteration of cavity and valvar regurgitation. Transvenous endocardial biopsy is more useful to exclude other infiltrative disorders. The presence of large thrombi at times precludes catheterisation and angiography.2 13 18–21
Echocardiography
Most of the cases are currently diagnosed by echocardiography.2 3 19 Recognition of apical obliteration, endocardial thickening, calcification, atrial dilatation and varying degrees of AV valve regurgitation with plastering of the leaflets are the usual diagnostic features. Abrupt early diastolic posterior motion of the LV posterior wall with the well-described mitral inflow and atrial inflow patterns of restriction are characteristic. An unduly dilated left atrium and severe mitral regurgitation with a rather small left ventricle are diagnostic of LV involvement in EMF. Apical obliteration, RV dimpling, outflow tract dilatation, severe low-pressure tricuspid regurgitation and pericardial effusion (fig 5) are diagnostic of RV involvement. The actively contracting right atrium raises the RV pressures to cause premature opening of the pulmonary valve, resulting in end-diastolic forward flow. In such situations, true isovolumic contraction does not exist for the right ventricle, which essentially acts as a conduit. Recognition of this physiology formed the basis of the partial RV bypass surgery that has been adopted to treat this disorder.28 29
Recently, cardiac magnetic resonance imaging has also been shown to be useful, and has the potential to replace angiography.27 30 The classical features reported by echocardiography and angiocardiography can be non-invasively imaged with additional functional information and tissue characterisation. Apical obliteration seen by echocardiography may be due to thrombosis, fibrosis, tumour, calcification or myohypertrophy. Patterns of fibrosis, myohypertrophy and thrombosis can be differentiated by tissue characterisation and delayed enhancement on contrast studies using gadolinium. Cardiac MRI, therefore, could offer an excellent opportunity to identify the disease in the early stages. Electron beam computed tomographic scans an also help in non-invasive tissue characterisation and better delineation of the endocardial calcium.31
TREATMENT
Most patients are treated symptomatically with diuretics, and rate control measures with or without anticoagulant agents.2 3 Massive ascites is relieved by intermittent tapping. About one-third of the most symptomatic patients benefit from surgery, which carries 30% mortality.22 The procedures adopted are endocardiectomy, which results in AV valve replacement in the majority. Isolated RV involvement has been palliated with unilateral bidirectional Glenn procedures.2 12 17 28 29 A bidirectional Glenn procedure is offered to patients with no pulmonary hypertension, mitral regurgitation and preferably no LV diastolic dysfunction. In rare instances end-stage cardiac failure is treated by cardiac transplantation.27
THE CHANGING NATURAL HISTORY
Prevalence of the disease in India is declining. First reported cases were autopsy studies by Samuel and Ankleseria, following the original description of the disease by Davies 60 years earlier.2 3 25 These were followed by elegant angiographic echocardiographic and natural history studies.12 32 33 Intense efforts were made to identify the early stages of the disease by colour coding of myocardial tissue and this may be possible in the current era with cardiac MRI.33 A recent community survey used some echocardiographic features as the early manifestations of the disease.34 Currently, the number of new cases diagnosed in our registry has declined to 10 new cases a year in the past decade from 20 cases seen in the previous decade. Furthermore, the mean age at presentation has also changed by a decade from 25 to 33 years, suggesting late recognition of asymptomatic cases and possible decline in the incidence of new cases.2 12 During the same period Kerala has witnessed a change in diet and a steady change in its health status. Cassava is no longer the staple diet in Keralites and diarrhoeal disease in childhood is now uncommon.5 35 36 Socioeconomic status has steadily improved. Society has become westernised and diseases of civilisation like diabetes and coronary artery disease have become rampant. The decline in endomyocardial disease simulates the decline in rheumatic fever noted earlier in medical history, which can be attributed to improvement in health and living standards, reduction in childhood infections and a change in dietary pattern.36 37
In the current era, patients with EMF have a relatively stable symptomatic course on follow-up with mortality of around 10% at 3 years. A natural history study published up to 1991 on the initial 200 patients showed a 10-year survival of only 37%. The presence of ascites, New York Heart Association class III and IV symptoms and atrial fibrillation were indicators of poor prognosis. An isolated diastolic filling abnormality does not usually affect the prognosis, whereas AV valve regurgitation is progressive. Therefore, mitral valve replacement significantly improves natural history when mitral regurgitation is severe. In our series of 89 patients who underwent surgery the actuarial 17-year survival was 55%, which is much better than that achieved by medical treatment.2 11 12
CONCLUSION
Restrictive cardiomyopathy in India has exposed an enigmatic fibrotic disorder affecting the endomyocardium, which occasionally calcifies. The disease comes to clinical attention in the burnt-out phase and pathological evolution of the disease has yet to be documented. We now know that myocardial fibrosis has its origin in endothelial-to-mesenchymal transition and that cytokines can promote or retard the fibrotic process.38 39 The presence of calcification, fibrosis and myohypertrophy clearly points to the role of cytokines in its pathogenesis secondary to an endocardial injury. The disease may be a reaction pattern of the endocardium and the final common pathway for a variety of insults. Identification of the environmental, genetic or nutritional factors which cause this injury and the reason for the epidemiological transition remain to be determined.7 25 40 The decline in the disease as seen in Kerala contrasts with the continuing prevalence of the disease seen in sub-Saharan Africa.34 41 42 The endocardial inflammation obviously occurs at a younger age and the pattern of calcification that occurs in the endocardium is temporally different, but pathogenically similar to valvar and vascular calcium occurring in metabolic syndrome.43 44 The systemic inflammation of malnutrition and infection differ in their pathogenesis, and at what stage a transition in a tropical climate initiates the endocardial injury is the crucial missing link that needs to be deciphered.25 45 An epidemiological study by Mocumbi et al not only highlighted the familial and endemic nature of the disease in tropics but also identified early disease and asymptomatic subjects.34 The disease today poses more questions for scientific inquiry than those which have been answered.
REFERENCES
Footnotes
Competing interests: None.
Patient consent: Obtained.