Endomyocardial fibrosis (EMF) is an idiopathic disorder of the tropical and subtropical regions of the world that is characterized by the development of restrictive cardiomyopathy.[1]
The nosology of EMF coincides with some related disorders. EMF is sometimes considered part of a spectrum of a single disease process that includes Löeffler endocarditis (nontropical eosinophilic endomyocardial fibrosis or fibroplastic parietal endocarditis with eosinophilia).
Tropical EMF and Löeffler endocarditis should be distinguished from endocardial fibroelastosis, which is characterized by cartilaginous thickening of the mural endocardium, chiefly of the left ventricle. This disease is most common in the first 2 years of life and, in some patients, appears to be an inherited disorder that is associated with congenital cardiac malformations.
In EMF, the underlying process produces patchy fibrosis of the endocardial surface of the heart, leading to reduced compliance and, ultimately, restrictive physiology as the endomyocardial surface becomes more generally involved. Endocardial fibrosis principally involves the apices of the right and left ventricles and may affect the atrioventricular valves mainly by tethering the papillary muscles, leading to tricuspid and mitral regurgitation.
The earliest changes of EMF are not well described because most patients do not present with symptoms until relatively late in the clinical course. Olsen described 3 phases of EMF. The first phase involves eosinophilic infiltration of the myocardium with necrosis of the subendocardium and a pathologic picture consistent with acute myocarditis. This is reportedly present in the first 5 weeks of the illness. The second stage, typically observed after 10 months, is associated with thrombus formation over the initial lesions, with a decrement in the amount of inflammatory activity present. Ultimately, after several years of disease activity, the fibrotic phase is reached, when the endocardium is replaced by collagenous fibrosis. This pathomorphologic schema is not observed uniformly and has not been consistently supported by other investigators.
Myocardial fibrosis consists of collagen deposition and fibroblast proliferation. These changes can potentially explain most of the symptoms in patients with EMF. Fibrosis increases the stiffness of the heart, resulting in the restrictive physiology. Ventricular stiffness along with atrioventricular valvular regurgitation results in atrial enlargement, which has been linked to atrial arrhythmias such as atrial fibrillation. Fibrosis also reduces conduction velocity, impairs activation pattern and may provide the substrate for wave breaks and reentry.[2] Recently, fibrosis has been suggested to facilitate focal activity by fibroblast-myocyte coupling as well.[3] Atrial fibrillation has been reported in more than 30% of patients with EMF followed by other rhythm or conduction abnormalities like junctional rhythm, heart blocks, and intraventricular conduction delay.[4]
While in general, fibrosis in cardiac tissue has been mainly linked to increased level of a cytokine, transforming growth factor-β1[5] ; the underlying mechanisms of myocardial fibrosis in this specific entity remain unclear. Hypotheses include infectious, inflammatory, and nutritional processes. EMF is frequently associated with concomitant parasitic infections (eg, helminths) and their attendant eosinophilia, although the role of parasitic infections and/or the eosinophil remains speculative. The development of EMF as a sequela to toxoplasma-related myocarditis has also been described, as has a relationship of malarial infection to development of EMF. However, no specific organism has been consistently associated with EMF.
The role of the eosinophil in the pathogenesis of EMF is controversial. Whether the eosinophil actually induces myocardial necrosis and subsequent fibrosis or is attracted to the endocardial surface as a result of the initial insult is unknown. Some authors have argued that in tropical eosinophilia, where the eosinophil count does climb to levels as high as 12,500/dL, endomyocardial fibrosis is rarely seen and the cardiac manifestations are limited, while severe eosinophilia is absent in EMF.[6] In general, the eosinophil is not present as frequently in cases of tropical EMF as in Löeffler endocarditis especially at later stages of the disease when the patient is symptomatic; thus, the role of the eosinophil in the tropical disease is likely less significant.
EMF is most frequently observed in the socially disadvantaged and in children and young women. These groups frequently have malnutrition, and in regions of sub-Saharan Africa where the disease is most prevalent, the typical diet is high in a tuber called cassava, which contains relatively high concentrations of the rare earth element cerium (Ce). The combination of high Ce levels and hypomagnesemia has been shown to produce EMF-like lesions in laboratory animals.
A familial tendency has rarely been noted in Uganda and Zambia.
United States
EMF is rarely encountered in patients who have not traveled from the subtropical regions of Africa and tropical and subtropical regions elsewhere in the world, including areas in India and South America that are within 15° of the equator. Löeffler endocarditis (also called nontropical eosinophilic endocarditis) is a related condition that is observed in the United States and is considered by some authors to be a different stage of a similar process related to eosinophilia.
International
EMF occurs primarily in the subtropical regions of Africa but is also encountered in tropical and subtropical regions elsewhere in the world, including areas in India and South America that are within 15° of the equator.[7]
More than 90% of reported cases of EMF have occurred in geographic locations that are within 15° of the equator. In equatorial African nations, EMF is the fourth most common cause of cardiac disease in adults. It is also the most common type of restrictive cardiomyopathy in tropical countries and worldwide.
In a screening study in a rural area in Mozambique, approximately 20% of a random sample of 1063 subjects of all age groups had echocardiographic evidence of this disease.[8] In the same study, the prevalence was highest among persons aged 10-19 years, and the most common form was biventricular endomyocardial fibrosis followed by right-side dominant and then left-side dominant disease. Most other studies also reported higher prevalence of biventricular pattern while in some studies left ventricular dominant pattern has been more common than the right ventricular dominant pattern.[9]
Studies have, however, found reductions in the incidence of EMF in Nigeria and India. A report by Akinwusi and Odeyei, in which patient records from a teaching hospital in southwest Nigeria were reviewed, found that the disease had a prevalence of just 0.02% among medical patients in general and 0.04% among cardiac cases specifically, between January 2003 and December 2009.[10] This was a considerable reduction from the 10% prevalence among cardiovascular cases in southwest Nigeria in the 1960s and 1970s, a change that the investigators suggested was the result of health-care improvements in their country. Similarly, the decline of EMF in the coastal districts of south India, where it was common, may be related to improvements in living standards and consequent reductions in childhood malnutrition, infections, and worm infestations.[11]
The overall prognosis of patients with EMF is poor and depends on the extent and distribution of disease within the various chambers and valves of the heart. The disease is usually progressive but the time course of decline varies.
Most patients have extensive disease at the time of presentation; therefore, survival after diagnosis is relatively brief. In one study, 95% of a group of patients had died at 2 years. In a second study, 44% of patients died within 1 year after the onset of symptoms, and another 40% of patients died 1-3 years after onset. Death usually occurs as a result of progressive heart failure or associated arrhythmia and sudden cardiac death.
EMF is most commonly reported in individuals living in Nigeria and Uganda. Among residents of these countries, EMF appears to be more prevalent in certain ethnic groups. One study in Uganda showed that EMF is more common in individuals with Rwanda/Burundi ethnic origins.[12]
In general, women of reproductive age and children are more commonly affected than men. However, a recent screening study in a rural area of Mozambique reported a higher rate among male than female subjects (23.0% vs 17.5%, P =0.03).[8] This study was based on a screening echocardiography and many of these patients were not symptomatic.
EMF is not generally observed in children younger than 4 years, although the typical pathology for EMF has recently been described in a 4-month-old infant with left ventricular inflow tract obstruction.
The people most commonly affected are usually older children (aged 5-15 y) and young adults, but cases have been reported in individuals aged 70 years.
Typically, endomyocardial fibrosis (EMF) has an insidious onset, and symptoms relate to the specific chambers and valves where the disease is most extensive, including the following:
Physical findings are also dependent on the extent and distribution of disease and may include the following:
A specific single etiology of EMF has not been established. Suggested potential causes include the following:
The cardiac silhouette in endomyocardial fibrosis (EMF) may be normal in size, and generalized cardiomegaly is unusual because the ventricles are not typically dilated. The roentgenographic image may exhibit significant enlargement of the atria, and significant right atrial enlargement creates a cardiac silhouette in the shape of the African continent, which is a specific heart shadow sign that has been termed the heart of Africa.
Echocardiography is a useful tool and the diagnostic modality of choice when making the diagnosis of EMF and has been demonstrated to successfully differentiate EMF and other processes such as rheumatic heart disease and congenital heart disease. The presence and location of fibrosis as determined by echocardiography correlates well with autopsy findings.
Findings include thickening of the inferior and basal left ventricular wall, apical obliteration, and thrombi adherent to the endocardial surface.
A pericardial effusion is frequently present and may be large.
Although parameters of diastolic function by Doppler echocardiography tend to correlate with the functional status of the patient, because most patients present with later stages of EMF, a restrictive filling pattern in the left ventricle is most common.
Decreased flow propagation velocity (Vp) has been demonstrated in a large percentage of patients with EMF.
Color-flow imaging frequently exhibits tricuspid and mitral regurgitation, believed to be due to retraction or adherence of the atrioventricular valvular apparatus. Spectral Doppler analysis of tricuspid regurgitation frequently reflects an increased pulmonary artery systolic pressure.
Traditionally, angiography has been considered the criterion standard when making the diagnosis of EMF. Left and right ventriculography exhibits distortion of chamber morphology by fibrosis and obliteration and variable degrees of mitral and tricuspid regurgitation. The mushroom sign has been used to describe the shape of the affected ventricle when the apex is obliterated completely by fibrosis.
Features of EMF observed with this modality were described in the mid 1990s. The fibrotic process is delineated as a band of low attenuation within the endocardium. Obliteration of the apex and inflow tract, when present, is also demonstrated. This method reportedly assists in distinguishing EMF from constrictive pericarditis.
In relatively recent years, the use of cardiovascular magnetic resonance imaging (MRI) has been shown to demonstrate obliterative changes in the ventricles, atrial dilation, and regurgitant atrioventricular valve lesions in patients with EMF. Recent studies have evaluated the role of contrast-enhanced MRI in detecting myocardial fibrosis, which can potentially be a useful diagnostic tool in patients with EMF.[14] However, clinical use of MRI is limited by access to this technology in endemic areas.
Atrial fibrillation in approximately one third of patients with endomyocardial fibrosis.[4] ECG findings may include the following:
Cardiac catheterization likely exhibits hemodynamic findings consistent with restrictive cardiomyopathy.
Findings from endomyocardial biopsy may be diagnostic, but this procedure is typically not needed. Biopsy findings may be nondiagnostic when the disease is patchy and sampling sites do not correlate with areas of disease. Because biopsy (especially from the left ventricle) carries some risk, reserve the use of this technique until other diagnostic approaches have been used.
Diagnostic and therapeutic paracentesis, thoracentesis and pericardiocentesis may be indicated in patients with significantly large ascites, pleural effusion, and pericardial effusion, respectively, who do not respond to medical therapy.
The heart size is not usually enlarged in EMF. The ventricular cavities are frequently laden with thrombi and, in severe cases, may be nearly totally obliterated by endocardial thickening and thrombosis. The histologic findings of EMF are characterized by reactive fibrosis associated with a selective increase in type I collagen deposition, subendocardial infarction and fibrosis, and thrombus formation. Additionally, specific features of other diseases, such as those associated with hemochromatosis or glycogen storage disease, are notably absent.
Mocumbi and colleagues provided a set of echocardiographic criteria that is useful in staging the disease, studying its progression, and comparing the results of different epidemiologic studies.[8] In this classification, there are 6 major criteria and 7 minor criteria. The diagnosis is considered when 2 major criteria or 1 major and 2 minor criteria are present. A score has been assigned to each criterion and the severity of the disease is measured by this score; a total score of less than 8 indicates mild endomyocardial fibrosis, a score of 8-15 indicates moderate disease, and a score of more than 15 indicates severe disease.
The following are considered major criteria:
The following are considered minor criteria:
In general, the response to medical therapy is unproven due to lack of well-designed studies.
Because most patients with endomyocardial fibrosis (EMF) present long after any possible period of early active myocarditis may have existed, little, if any, role exists for immunosuppressive therapy as is used in some patients with Löeffler disease. If the patient presents with acute myocarditis, prednisone may be considered as medical therapy.
Symptomatic therapy with diuretics has been shown to be useful. Similar to other patients with diastolic dysfunction, these patients may also benefit from ACE inhibitors, angiotensin receptor blockers, and beta-blockers, but only to some degree.
For patients with severe symptoms, consider surgical therapy because the prognosis for these patients with continued medical therapy alone is dismal.
There is no reliable evidence on the rate of the embolic events in these patients and whether anticoagulation and antiplatelet therapy are effective in their prevention. It is reasonable to anticoagulate patients who have thrombus on echocardiography and are compliant with medical treatments. Antiplatelet therapy with aspirin or clopidogrel can be considered as an alternative approach. Those patients with atrial fibrillation should be anticoagulated, although the ability to do this safely and effectively is again limited by availability of local services in endemic regions.
Surgical therapy by endocardial decortication seems to be beneficial for many patients with advanced disease who are in functional-therapeutic class III or IV. The operative mortality rate is high (15-20%), but successful surgery has a clear benefit on symptoms and seems to favorably affect survival as well.
The most commonly used approach is endocardiectomy, combined with mitral and/or tricuspid repair or replacement (when indicated), using a midline thoracotomy and cardiopulmonary bypass. Depending on the location of the disease (right or left ventricle, apex or inflow tract), a transapical or transventricular approach can be used.
Because a well-defined plane of cleavage usually exists between the endocardium and myocardium, endocardiectomy is most frequently feasible. Because the myocardium is not usually affected, the severe hemodynamic derangement associated with EMF is relieved with successful resection of the endocardium. Common postoperative complications include low cardiac output, heart block, and ventricular arrhythmias.
No activity restrictions are recommended because activity restrictions have not been proven to alter the prognosis of this condition, and no specific activity has been shown to hasten the onset of fatal arrhythmias or sudden death.
Transfer suitable patients with severe symptoms for consideration of endomyocardial resection. Although the operative mortality rate is high (approximately 20%), prognosis is favorably altered in those that survive the surgery.
Consider heart transplant in patients who are classified in function class III or IV.
Common postoperative complications include low cardiac output, heart block, and ventricular arrhythmias.
Prognosis for this condition is poor. Incidence of sudden cardiac death from fatal arrhythmias or from progressive cardiac failure is high.
Most patients have extensive disease at the time of presentation; therefore, survival after diagnosis is relatively brief. In one study, 95% of a group of patients had died at 2 years. In a second study, 44% of patients died within 1 year after the onset of symptoms, and another 40% of patients died 1-3 years after onset.
Inform patients about the poor prognosis and increased likelihood of fatal and nonfatal arrhythmias.