Endomyocardial Fibrosis: an Update After 70 Years.

PURPOSE OF REVIEW: This review aims at highlighting the need to better understand the pathogenesis and natural history of endomyocardial fibrosis when set against its changing endemicity and disease burden, improvements in diagnosis, and new options for clinical management. RECENT FINDINGS: Progress in imaging diagnostic techniques and availability of new targets for drug and surgical treatment of heart failure are contributing to earlier diagnosis and may lead to improvement in patient survival. Endomyocardial fibrosis was first described in Uganda by Davies more than 70 years ago (1948). Despite its poor prognosis, the etiology of this neglected tropical restrictive cardiomyopathy still remains enigmatic nowadays. Our review reflects on the journey of scientific discovery and construction of the current guiding concepts on this mysterious and fascinating condition, bringing to light the contemporary knowledge acquired over these years. Here we describe novel tools for diagnosis, give an overview of the improvement in clinical management, and finally, suggest research themes that can help improve patient outcomes focusing (whenever possible) on novel players coming into action.

Tropical Endomyocardial Fibrosis: Natural History, Challenges, and Perspectives.

Tropical endomyocardial fibrosis (EMF) is a neglected disease of poverty that afflicts rural populations in tropical low-income countries, with some certain high-prevalence areas. Tropical EMF is characterized by the deposition of fibrous tissue in the endomyocardium, leading to restrictive physiology. Since the first descriptions in Uganda in 1948, high-frequency areas for EMF have included Africa, Asia, and South America. Although there is no clear consensus on a unified hypothesis, it seems likely that dietary, environmental, and infectious factors may combine in a susceptible individual to give rise to an inflammatory process leading to endomyocardial damage and scar formation. The natural history of EMF includes an active phase with recurrent flare-ups of inflammation evolving to a chronic phase leading to restrictive heart failure. In the chronic phase, biventricular involvement is the most common presentation, followed by isolated right-sided heart disease. Marked ascites out of proportion to peripheral edema usually develops as a typical feature of EMF. EMF carries a very poor prognosis. In addition to medical management of heart failure, early open heart surgery (endocardectomy and valve repair/replacement) appears to improve outcomes to some extent; however, surgery is technically challenging and not available in most endemic areas. Increased awareness among health workers and policy makers is the need of the hour for the unhindered development of efficient preventive and therapeutic strategies.

Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction.

BACKGROUND: Characterization of myocardial structural changes in heart failure with preserved ejection fraction (HFpEF) has been hindered by the limited availability of human cardiac tissue. Cardiac hypertrophy, coronary artery disease (CAD), coronary microvascular rarefaction, and myocardial fibrosis may contribute to HFpEF pathophysiology. METHODS AND RESULTS: We identified HFpEF patients (n=124) and age-appropriate control subjects (noncardiac death, no heart failure diagnosis; n=104) who underwent autopsy. Heart weight and CAD severity were obtained from the autopsy reports. With the use of whole-field digital microscopy and automated analysis algorithms in full-thickness left ventricular sections, microvascular density (MVD), myocardial fibrosis, and their relationship were quantified. Subjects with HFpEF had heavier hearts (median, 538 g; 169% of age-, sex-, and body size-expected heart weight versus 335 g; 112% in controls), more severe CAD (65% with ≥1 vessel with >50% diameter stenosis in HFpEF versus 13% in controls), more left ventricular fibrosis (median % area fibrosis, 9.6 versus 7.1) and lower MVD (median 961 versus 1316 vessels/mm(2)) than control (P<0.0001 for all). Myocardial fibrosis increased with decreasing MVD in controls (r=-0.28, P=0.004) and HFpEF (r=-0.26, P=0.004). Adjusting for MVD attenuated the group differences in fibrosis. Heart weight, fibrosis, and MVD were similar in HFpEF patients with CAD versus without CAD. CONCLUSIONS: In this study, patients with HFpEF had more cardiac hypertrophy, epicardial CAD, coronary microvascular rarefaction, and myocardial fibrosis than controls. Each of these findings may contribute to the left ventricular diastolic dysfunction and cardiac reserve function impairment characteristic of HFpEF.

Valvular heart diseases in the developing world: developmental biology takes center stage.

Heart valve disease is a significant and increasing global problem of which, in the developing world, the primary sufferers are the children and young adults regarded as the critical 'engine' of future economic growth. Yet, up to 10 times the current number of known sufferers remain undiagnosed in these countries. Among the most prevalent and neglected diseases are rheumatic heart disease and endomyocardial fibrosis. The etiologies of these diseases can be described in part as a dysregulation or reactivation of developmental biology pathways. Consequently, connecting mechanisms of valvulogenesis and disease etiology may represent an excellent strategy to identify therapeutic targets. These local diseases require local solutions tailored to local resources; therefore, collaboration with experienced research groups should be encouraged as a way of accelerating the creation of relevant knowledge, and its clinical translation.

Tropical endomyocardial fibrosis in India: a vanishing disease!

Tropical endomyocardial fibrosis in India was a common medical problem in the coastal districts of south India, especially the Kerala State. The clinical and autopsy studies have shown left and right ventricular apical fibrosis, with varying degree of atrioventricular valve regurgitation. Left ventricular endomyocardial fibrosis presents with severe pulmonary hypertension and right ventricular endomyocardial fibrosis presents very high systemic venous pressure and congestive cardiac failure. Surgical management improved the natural history of the disease to some extent. Various infectious and toxic factors were postulated regarding its aetiology. During the last few years, incidence of the disease has decreased considerably. The only explanation identified is the significant improvement in the living standards of the people with the corresponding decline in the childhood malnutrition, infections, worm infestation and associated eosinophilia.

Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance.

BACKGROUND: Endomyocardial biopsy (EMB) represents the gold standard for diagnosing myocarditis and nonischemic cardiomyopathies. This study focuses on the risk of complications and the respective diagnostic performance of left ventricular (LV), right ventricular (RV), or biventricular EMB in patients with suspected myocarditis and/or cardiomyopathy of unknown origin. METHODS AND RESULTS: In this 2-center study, 755 patients with clinically suspected myocarditis (n=481) and/or cardiomyopathy of nonischemic origin including those with infiltrative or connective tissue disease (n=274) underwent either selective LV-EMB (n=265; 35.1%), selective RV-EMB (n=133; 17.6%), or biventricular EMB (n=357; 47.3%) after coronary angiography and exclusion of significant coronary artery disease. Cardiovascular magnetic resonance, including late gadolinium enhancement, imaging was performed in 540 patients (71.5%). The major complication rate for LV-EMB was 0.64% and for RV-EMB, 0.82%. Considering postprocedural pericardial effusion that occurred after biventricular EMB, the minor complication rate for LV-EMB varied between 0.64% to 2.89% and for RV-EMB, between 2.24% and 5.10%. Diagnostic EMB results were achieved significantly more often in those patients who underwent biventricular EMBs (79.3%) compared to those who underwent either selective LV-EMB or selective RV-EMB (67.3%; P<0.001). In patients with biventricular EMB, myocarditis was diagnosed in LV-EMB samples in 18.7% and in RV-EMB samples in 7.9% (P=0.002) , and it was diagnosed in both ventricles in 73.4%. There were no differences in the number of positive LV-EMB, RV-EMB, or LV- and RV-EMB findings when related to the site of cardiovascular magnetic resonance-based late gadolinium enhancement. CONCLUSIONS: Both LV-EMB and RV-EMB are safe procedures if performed by experienced interventionalists. The diagnostic yield of EMB may be optimized when samples from both ventricles are available. Preferential biopsy in regions showing late gadolinium enhancement on cardiovascular magnetic resonance does not increase the number of positive diagnoses of myocarditis.

A population study of endomyocardial fibrosis in a rural area of Mozambique.

BACKGROUND: Endomyocardial fibrosis is the most common restrictive cardiomyopathy worldwide. It has no specific treatment and carries a poor prognosis, since most patients present with advanced heart failure. On the basis of clinical series, regional variations in distribution have been reported within several countries in Africa, Asia, and South America, but large-scale data are lacking on the epidemiologic features and early stages of the disease. METHODS: We used transthoracic echocardiography to determine the prevalence of endomyocardial fibrosis in a rural area of Mozambique. We screened a random sample of 1063 subjects of all age groups selected by clustering. Major and minor diagnostic criteria were defined, and a severity score was developed and applied. Cases were classified according to the distribution and severity of the lesions in the heart. RESULTS: The estimated overall prevalence of endomyocardial fibrosis was 19.8%, or 211 of 1063 subjects (95% confidence interval [CI], 17.4 to 22.2). The prevalence was highest among persons 10 to 19 years of age (28.1%, or 73 of 260 subjects [95% CI, 22.6 to 33.6]) and was higher among male than among female subjects (23.0% vs. 17.5%, P=0.03). The most common form was biventricular endomyocardial fibrosis (a prevalence of 55.5%, or 117 of 211 subjects [95% CI, 48.8 to 62.2]), followed by right-sided endomyocardial fibrosis (a prevalence of 28.0%, or 59 of 211 subjects [95% CI, 21.9 to 34.1]). Most affected subjects had mild-to-moderate structural and functional echocardiographic abnormalities. Only 48 persons with endomyocardial fibrosis (22.7%) were symptomatic. The frequency of familial occurrence was high. CONCLUSIONS: Endomyocardial fibrosis is common in a rural area of Mozambique. By using echocardiography, we were able to detect early, asymptomatic stages of the disease. These findings may aid in the study of the pathogenesis of the disease and in the development of new management strategies.

Lack of evidence of myocardial damage in children with Plasmodium falciparum severe and complicated malaria from an endemic area for endomyocardial fibrosis.

Malaria is among the factors thought to be involved in the pathogenesis of endomyocardial fibrosis (EMF), a restrictive cardiomyopathy of unclear etiology, with no specific therapy, which affects predominantly children and adolescents. In Africa, regions endemic with EMF are also areas with high prevalence of malaria. We studied 47 consecutive children aged 5- to 15-years old and concluded that myocardial damage and dysfunction are rare in severe and complicated Plasmodium falciparum malaria cases in children.

Association between depressive symptoms and fibrosis markers: the Cardiovascular Health Study.

OBJECTIVE: Fibrosis plays an important role in heart failure (HF) and other diseases that occur more frequently with increasing age. Depression is associated with an increased risk of heart failure and other age-related diseases. This study examined the association between depressive symptoms and fibrosis markers in adults aged 65 years and above. METHODS: Fibrosis markers and depressive symptoms were assessed in 870 participants (age=80.9+/-5.9 yrs, 49% women) using a case-control design based on heart failure status (307 HF patients and 563 age- and sex-matched controls, of whom 284 with CVD risk factors (hypertension, diabetes mellitus, or hypercholesterolemia) and 279 controls without these CVD risk factors). Fibrosis markers were procollagen type I (PIP), type I collagen (CITP), and procollagen type III (PIIINP). Inflammation markers included C-reactive protein, white blood cell counts and fibrinogen. Depression was assessed using the Center for Epidemiological Studies-Depression (CES-D) scale using a previously validated cut-off point for depression (CES-D > or = 8). Covariates included demographic and clinical variables. RESULTS: Depression was associated with higher levels of PIP (median=411.0, inter-quartile range (IQR)=324.4-472.7 ng/mL vs. 387.6, IQR=342.0-512.5 ng/mL, p=0.006) and CITP (4.99, IQR=3.53-6.85 vs. 4.53, IQR=3.26-6.22 microg/L, p=0.024), but not PIIIINP (4.07, IQR=2.75-5.54 microg/L vs. 3.58, IQR=2.71-5.01 microg/L, p=0.29) compared to individuals without depression. Inflammation markers were also elevated in depressed participants (CRP, p=0.014; WBC, p=0.075; fibrinogen, p=0.074), but these inflammation markers did not account for the relationship between depression and fibrosis markers. CONCLUSIONS: Depression is associated with elevated fibrosis markers and may therefore adversely affect heart failure and other age-related diseases in which extra-cellular matrix formation plays a pathophysiological role.

Cardiac and noncardiac fibrotic reactions caused by ergot-and nonergot-derived dopamine agonists.

There is growing evidence that the ergot-derived dopamine agonists cabergoline and pergolide can cause fibrotic cardiac valvulopathy. Data on other fibrotic reactions and nonergot-derived dopamine agonists are sparse. Aim of this study was to investigate whether there are signals that dopamine agonists are related to cardiac and other fibrotic reactions. We identified all reports of fibrotic reactions at the heart, lung, and retroperitoneal space associated with dopamine agonists within the US Adverse Event Reporting System database. Disproportionality analyses were used to calculate adjusted reporting odds ratios (RORs). For ergot-derived dopamine agonists (bromocriptine, cabergoline, pergolide), the RORs of all reactions under study were increased, whereas no such increases were observed for nonergot-derived drugs (apomorphine, pramipexole, ropinirole, rotigotine). Fibrotic reactions due to ergot-derived dopamine agonists may not be limited to heart valves. For nonergot-derived dopamine agonists, no drug safety signals were evident.

[Tropical endomyocardial fibrosis: Perspectives]. / Fibrose endomyocardique tropicale : perspectives.

Tropical endomyocardial fibrosis (FET) is a leading cause of heart failure and the most common restrictive cardiomyopathy worldwide. Extensive fibrosis of the ventricular endocardium causing architectural distortion, impaired filling and valvular insufficiency define the disease. Confined to peculiar and limited geographical areas, the aetiology remains blurred and it carries a grim prognosis. The changing burden reported recently in some endemic areas and the refinement of diagnostic tools have emphasized alternative routes for understanding and treatment of the disease.

Geographical variation in the clinical presentation of endomyocardial fibrosis in India?

OBJECTIVES: To compare the clinical presentation, clinical profile and survival of two groups of endomyocardial fibrosis patients. METHODS: The study was a prospective cohort study, or a prospective case series, comparing all consecutive echocardiographically proven patients with endomyocardial fibrosis seen in Medical College Trivandrum with the patients seen in Medical College Hospital, Alappuzha(Alleppey) (or TD Medical College). In all patients the clinical details like age, sex, type of endomyocardial fibrosis, the presence of anaemia, eosinophilia, neutrophilia and type of rhythm(Sinus or atrial fibrillation) etc were compared by both simple X2 and by Kaplan Meier survival curves. RESULTS: The mean age and the sex distribution was same in both places Briefly the incidence of biventricular endomyocardial fibrosis was more from Trivandrum than Alleppey, 64.9% vs 14.3% (p<0.0.001), the incidence of atrial fibrillation was more in Trivandrum 44.2% vs 16.3%. (p<0.001)The overall survival of Trivandrum patients was poorer (p<0.0001). The six year survival was 61% in the Trivandrum population whereas it was 91.5% in the Alleppey population. CONCLUSIONS: These differences may have been due to the better nutrition of the Alleppey patients due to a higher exposure to fish compared to the Trivandrum population. Better nutrition would protect against Magnesium deficiency and prevent the absorption of Cerium in the patients from Alleppey, compared to those from Trivandrum.

Echocardiographic, chest X-ray and electrocardiogram findings in children presenting with heart failure to a Ugandan paediatric ward.

The aim of this study was to describe the aetiology of congestive cardiac failure (CCF) in children with suspected structural abnormalities presenting to a regional hospital in southwestern Uganda. The method used was a prospective descriptive study of successive admissions of children with persistent cardiac signs after routine treatment of CCF. Children with severe anaemia (haemoglobin [Hb]<7 g/dL), pneumonia, sepsis or severe malnutrition were excluded. Chest X-ray, electrocardiogram and echocardiography data were validated by a paediatric cardiologist and radiologist at the Bristol Royal Hospital for Children, UK. A cohort of 58 patients was identified. The aetiology of heart failure in this cohort (n = 58) was due to congenital heart disease (35%), renal hypertensive disease (26%), rheumatic heart disease (17%), cardiomyopathies (12%), endomyocardial fibrosis (7%) and tamponade (3%). In conclusion, this study confirmed the ongoing prevalence of congenital heart disease, rheumatic heart disease and endomyocardial fibrosis in this area. The cardiac effect of renal hypertension was a new and significant finding.

[Heart failure due to non-infectious causes in developing countries: etiologic approach and therapeutic principles]. / Insuffisance cardiaque d'origine non infectieuse en zone tropicale: approche étiologique et principes thérapeutiques.

Cardiovascular disease is a major worldwide health problem with a growing impact in developing countries. Heart failure is the clinical manifestation of many advanced cardiac disorders. It can have numerous etiologies and the incidence of non-infectious causes is increasing with socio-economic development, thus illustrating the global nature of this epidemiologic transition. Several of the numerous non-infectious causes of heart failure involve cardiac diseases specific to tropical areas including dilated cardiomyopathy, endomyocardial fibrosis, and peripartum cardiomyopathy. Other widespread disorders are becoming more common as a result of the epidemiologic transition. Cardiovascular risk factors are changing particularly with regard to the incidence of coronary artery disease, ischemic cardiomyopathy, and hypertension-related complications. The purpose of this article is to provide an overview of non-infectious causes of heart failure in terms of frequency, onset, and therapeutic requirements. Symptomatic treatment of heart failure is same as in developing countries but is often delayed due to shortcomings in the care system.

Diagnosis and Management of Endomyocardial Fibrosis.

Endomyocardial fibrosis (EMF) remains an important cause of restrictive cardiomyopathy worldwide. Patients cluster in specific geographic locations and are almost universally living in extreme poverty. Specific etiology remains elusive and is likely multifactorial. Untreated EMF has a very poor prognosis. Medical management can mitigate symptoms for a time but has no curative benefit. Early surgical interventions may improve survival but are not readily available in most EMF-endemic regions. Increased awareness, advocacy, and research are needed to further understand this neglected tropical cardiomyopathy and to improve survival of those affected.

Endomyocardial fibrosis in Sudan: clinical and echocardiographic features.

OBJECTIVE: Endomyocardial fibrosis (EMF) is a rare disease and is often an underdiagnosed and forgotten cardiomyopathy. The objective of this study was to document the current frequency of EMF in Sudan by defining and selecting cases from patients attending the echocardiography laboratory. Additionally we aimed to create an EMF registry for Sudan. METHODS: The study started in January 2007 and is on-going. All the patients attending our echocardiography clinics in four different hospitals in Khartoum, Sudan, were included. Transthoracic echocardiography was used as the main diagnostic and selection tool. The diagnosis of EMF was based on predefined criteria and definitions, and was further supported by additional clinical, ECG, laboratory and chest X-ray findings. RESULTS: Out of 4 332 cases studied, 23 (0.5%) were found to have features of EMF. Females constituted 52% and the age range was 24 to 67 years. All patients presented with dyspnoea grades III-IV. Advanced heart failure with gross fluid overload was seen in 54% of cases and ascites was seen in 30%. EMF was biventricular in 53%, left ventricular in 29% and right ventricular in 18% of cases. Apical and ventricular wall fibrosis was found in all cases, followed by atrial enlargement, atrioventricular valve incompetence, ventricular cavity obliteration, restrictive flow pattern and pericardial effusion. Additional echocardiographic features are defined and discussed. CONCLUSION: Although a rare disease, cases of EMF can be identified in Sudan if a high index of suspicion is observed. New echocardiographic features of ventricular wall layering, endocardial fibrous shelf and endomyocardiopericarial fibrosis were identified and are discussed.

Epidemiology and etiology of cardiomyopathy in Africa.

BACKGROUND: Cardiomyopathy, an often irreversible form of heart muscle disease that is associated with a dismal outcome, is endemic in Africa. The primary objective of this review was to summarize the current state of knowledge on the epidemiology and etiology of cardiomyopathy in people living in Africa and to identify new avenues for research. METHODS AND RESULTS: We searched MEDLINE (January 1, 1966, through February 12, 2005) and reference lists of articles for relevant references. Unlike other parts of the world in which cardiomyopathy is rare, dilated cardiomyopathy is a major cause of heart failure throughout Africa. Similarly, peripartum cardiomyopathy is ubiquitous on the continent, with an incidence ranging from 1 in 100 to 1 in 1000 deliveries. There is an apparent marked regional variation in the pathogenesis of dilated cardiomyopathy and peripartum cardiomyopathy, underlining the heterogeneity of causative factors in these conditions. By contrast, endomyocardial fibrosis is restricted to the tropical regions of East, Central, and West Africa. Although the pathogenesis of endomyocardial fibrosis is not fully understood, it seems that the conditioning factors are geography and diet, the triggering factor may be an as yet unidentified infective agent, and the perpetuating factor is eosinophilia. Although epidemiological studies are lacking, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy seem to have characteristics similar to those of other populations elsewhere in the world. CONCLUSIONS: There is a need for large-scale epidemiological studies of the incidence, prevalence, determinants, and outcome of cardiomyopathy in Africa to inform strategies for the treatment and prevention of heart muscle disease on the continent.

Which subgroup of patients with dilated cardiomyopathy would benefit from long-term beta-blocker therapy? A histologic viewpoint.

OBJECTIVES: The purpose of this study was to elucidate whether the effectiveness of long-term beta-blocker therapy could be predicted before this therapy is started. BACKGROUND: Long-term beta-blocker therapy has recently been reported to provide a favorable effect in treatment of congestive heart failure due to dilated cardiomyopathy. METHODS: Several measurements including histologic variables before administration of metoprolol were retrospectively compared among 18 good responders (showing improvement of at least one New York Heart Association functional class or an increase in ejection fraction > or = 0.10 12 months after drug administration) and 12 poor responders without such improvement. RESULTS: Although there were no significant differences between the two groups in age, gender, functional class, heart rate, blood pressure, pulmonary capillary wedge pressure, cardiac index, left ventricular end-diastolic dimension and ejection fraction, percent fibrosis estimated by the point-counting method in endomyocardial biopsy specimens was significantly lower in good than in poor responders (7.6 +/- 5.7 vs. 14.2 +/- 9.7%, p < 0.05). Moreover, when the types of fibrosis were classified as interfascicular and intercellular by the dominance of counted points, there were 13 cases of interfascicular fibrosis and 5 cases of intercellular fibrosis in good responders and 1 case of interfascicular fibrosis and 11 cases of intercellular fibrosis in poor responders (p < 0.001, sensitivity 72%, specificity 91%, predictive accuracy 80%). These results suggest that improvement with long-term beta-blocker therapy may be more likely to occur in patients with less myocardial fibrosis, with interfascicular fibrosis the dominant type. CONCLUSIONS: The extent and type of fibrosis may be important factors in the prediction of the effectiveness of long-term beta-blocker therapy for dilated cardiomyopathy.