Background
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.
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.
Pathophysiology
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.[1] Recently, fibrosis has been suggested to facilitate focal activity by fibroblast-myocyte coupling as well.[2] 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.[3]
While in general, fibrosis in cardiac tissue has been mainly linked to increased level of a cytokine, transforming growth factor-β1[4] ; 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.[5] 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.
Epidemiology
Frequency
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.
More than 90% of reported cases of EMF have occurred in geographic locations that are within 15° of the equator. In equatorial African nations, such as Nigeria, EMF is the fourth most common cause of cardiac disease in adults, and EMF accounts for 22% of cases of heart failure in Nigerian children. EMF is 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.[6] 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.[7]
Mortality/Morbidity
- 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.
Race
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.[8]
Sex
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).[6] This study was based on a screening echocardiography and many of these patients were not symptomatic.
Age
- 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.
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