Endomyocardial Fibrosis: Still a Mystery after 60 Years

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Abstract

The pathologist Jack N. P. Davies identified endomyocardial fibrosis in Uganda in 1947. Since that time, reports of this restrictive cardiomyopathy have come from other parts of tropical Africa, South Asia, and South America. In Kampala, the disease accounts for 20% of heart disease patients referred for echocardiography. We conducted a systematic review of research on the epidemiology and etiology of endomyocardial fibrosis. We relied primarily on articles in the MEDLINE database with either “endomyocardial fibrosis” or “endomyocardial sclerosis” in the title. The volume of publications on endomyocardial fibrosis has declined since the 1980s. Despite several hypotheses regarding cause, no account of the etiology of this disease has yet fully explained its unique geographical distribution.

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A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.

Jan Cools, Daniel J. DeAngelo, Jason Gotlib … (2003)

Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause. We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response. Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRalpha (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFRalpha is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib. The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins. Copyright 2003 Massachusetts Medical Society

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Peripartum cardiomyopathy.

Uri Elkayam, Karen Sliwa, James D. Fett (2006)

Peripartum cardiomyopathy (PPCM) is a disorder in which initial left ventricular systolic dysfunction and symptoms of heart failure occur between the late stages of pregnancy and the early postpartum period. It is common in some countries and rare in others. The causes and pathogenesis are poorly understood. Molecular markers of an inflammatory process are found in most patients. Clinical presentation includes usual signs and symptoms of heart failure, and unusual presentations relating to thromboembolism. Clinicians should consider PPCM in any peripartum patient with unexplained disease. Conventional heart failure treatment includes use of diuretics, beta blockers, and angiotensin-converting enzyme inhibitors. Effective treatment reduces mortality rates and increases the number of women who fully recover left ventricular systolic function. Outcomes for subsequent pregnancy after PPCM are better in women who have first fully recovered heart function. Areas for future research include immune system dysfunction, the role of viruses, non-conventional treatments such as immunosuppression, immunoadsorption, apheresis, antiviral treatment, suppression of proinflammatory cytokines, and strategies for control and prevention.

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Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution.

G Christie, Robert Carraway, James D. Fett … (2005)

To determine the incidence and prognosis of peripartum cardiomyopathy (PPCM) in rural Haiti. Prospectively identified patients with PPCM treated at the Hospital Albert Schweitzer (HAS), Deschapelles, Haiti, were included in this study. Patients who presented to HAS from February 1, 2000, to January 31, 2005, were identified through a search of the HAS PPCM Registry. Clinical and serial echocardiographic data were collected on these patients. The 5-year experience confirms the high incidence of PPCM in this area, approximately 1 case per 300 live births, which is severalfold the estimated incidence in the United States (estimated 1 case per 3000 to 4000 live births). In this population, the ratio of PPCM deaths for the 5-year period was 47.1 per 100,000 births compared with the US ratio of 0.62 per 100,000 births. The mortality rate was 15.3% (15 deaths of 98 patients), and the mean follow-up was 2.2 years (range, 1 month to 5 years). Five years after the initiation of the HAS PPCM Registry search, 26 (28%) of 92 patients with PPCM observed for at least 6 months had regained normal left ventricular function. The difference in left ventricular echocardiographic features at diagnosis between deceased patients and survivors was not statistically significant: mean end-diastolic dimension (6.2 vs 5.8 cm; P=.08), ejection fraction (22% vs 25%; P=.12), and fractional shortening (16% vs 15%; P=.46). Left ventricular echocardiographic features at diagnosis were unable to predict individually who would eventually recover, although a statistically significant difference occurred at diagnosis between the recovered group and nonrecovered group for mean ejection fraction (28% vs 23%; P<.001) and fractional shortening (17% vs 14%; P=.004). Peripartum cardiomyopathy occurs significantly more commonly in rural Haiti on a per capita basis than in the United States. Patients with PPCM have a higher mortality rate and a poorer return of normal ventricular function.

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Author and article information

Contributors

: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS Negl Trop Dis

Journal ID (publisher-id): plos

Journal ID (pmc): plosntds

Title: PLoS Neglected Tropical Diseases

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Print): 1935-2727

ISSN (Electronic): 1935-2735

Publication date Collection: February 2008

Publication date (Electronic): 27 February 2008

Volume: 2

Issue: 2

Electronic Location Identifier: e97

Affiliations

[1 ]Division of Social Medicine and Health Inequalities, Brigham and Women's Hospital, Boston, Massachusetts, United States of America

[2 ]Cancer Risk Program, University of California San Francisco, San Francisco, California, United States of America

[3 ]Clinical Research Unit, London School of Hygiene & Tropical Medicine, London, United Kingdom

Ghana Health Service, Ghana

Author notes

* E-mail: gbukhman@ 123456partners.org

Conceived and designed the experiments: GB JZ EP. Analyzed the data: GB JZ EP. Wrote the paper: GB JZ EP. Initiated this review and wrote the first draft: GB Contributed substantially to the conception and revision of the paper: JZ EP.

Article

Publisher ID: 07-PNTD-RV-0084R2

DOI: 10.1371/journal.pntd.0000097

PMC ID: 2254164

PubMed ID: 18301727

SO-VID: 48016b03-92dd-4c89-b3d5-2c211d5d681a

Copyright © Bukhman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Endomyocardial Fibrosis: Still a Mystery after 60 Years

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Most cited references 112

A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.

Peripartum cardiomyopathy.

Five-year prospective study of the incidence and prognosis of peripartum cardiomyopathy at a single institution.

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