Endomyocardial Fibrosis: Still a Mystery after 60 Years
Gene Bukhman1*, John Ziegler2, Eldryd Parry3
1Division of Social Medicine and Health Inequalities, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America, 2Cancer Risk Program, University
of California San Francisco, San Francisco, California, United States of America, 3Clinical Research Unit, London School of Hygiene & Tropical Medicine, London, United
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.
September 2007 will mark the 60th anniversary of the description
of endomyocardial fibrosis (EMF) in Uganda by the pathologist Jack
N. P. Davies . Observed by Arthur Williams as early as 1938,
Davies and his colleagues at Makerere University delineated the
clinico-pathologic features of this new restrictive cardiomyopathy,
still called Davies disease by some [2,3,4]. Although virtually
unknown outside of the tropics, cases of EMF continue to surface
from parts of equatorial Asia and South America where the disease
afflicts impoverished children and young adults . The highest
prevalence of this condition likely remains, however, in regions of
sub-Saharan Africa. As a rough estimate, the burden of EMF may
well compare in scope to Chagas cardiomyopathy .
Subendocardial fibrosis of the apices and inflow tracts of the
right ventricle, left ventricle, or both defines the disease [7,8]. This
restrictive scarring prevents ventricular filling, and tethering of the
papillary muscles leads to valvular regurgitation (Figure 1; Video
S1). A review of autopsies in Uganda between 1959 and 1969
emphasized the poor prognosis of this condition, with an average
survival of 2 y after symptom onset . Later series from Brazil
and India found more variability in the course of medically treated
patients and echoed findings from southern Nigeria of both acute
and chronic forms of the disease [10,11,12]. The advent of surgical
resection and valvular replacement during the 1970s promised 10-
y survival rates as high as 68% for selected patients, but at the
price of high peri-operative mortality [13,14,15,16,17]. Unfortu-
nately, EMF has most affected those regions least equipped with
The question of whether all cases of EMF have the same
underlying cause still ranks as one of the great mysteries in
cardiology. Does the pathogenesis of this disease result from a
single process? Or does EMF represent a common pathway for
diverse insults such as those that lead to dilated cardiomyopathies?
Davies himself, who died in 1998 at the age of 83, believed to
the end that EMF had a unifying explanation . He thought the
clue perhaps lay in the similarity between the heart lesion in EMF
and the endocarditis parietalis fibroplastica that Wilhelm Lo ¨ffler and
others had described in Europe in the setting of hypereosinophilic
syndromes [19,20]. The eosinophil hypothesis—dominant though
still not well tested—has failed to convince critics who point to
other plausible alternatives [21,22,23,24]. In fact, none of the
etiologic categories first mentioned by Williams, Ball, and Davies
in 1954 have left the table of possible causes (Table 1) .
Despite uncertainty as to the cause of EMF, the volume of
publications on the subject has declined during the past decade
(Figure 2). In an effort to rekindle interest in this neglected disease,
we have undertaken a systematic review of research on this
condition. We have based this review primarily on articles in the
MEDLINE database published between January 1, 1950 and
January 1, 2007 with either ‘‘endomyocardial fibrosis’’ or
‘‘endomyocardial sclerosis’’ in the title. We limited this search to
articles in English, French, or Spanish and did not search other
databases. We consulted additional papers and books referenced
through this search strategy, and have cited those most focused on
epidemiology and etiology.
The clinical manifestations of EMF of either ventricle overlap
with other conditions that cause heart failure or ascites. For this
reason, a conclusive diagnosis of EMF depends on imaging or
surgical visualization of the heart during life, or on autopsy after
Since the first descriptions of EMF at autopsy in West and East
Africans in the late 1940s, over 2,400 cases of the disease have
been reported throughout the world [1,29]. Half of these cases
have come from sub-Saharan Africa, and a quarter have come
from Uganda alone. Connor and colleagues have questioned the
relationship between Ugandan EMF and the West African disease
. Other regions with large series include Brazil, Co ˆte d’Ivoire,
southern Nigeria, coastal Mozambique, and Kerala State in India
(Figure 3). Reporting bias skews this distribution, and in the
absence of population-based studies, worldwide prevalence can
only be estimated.
Published February 27, 2008
Funding: The authors received no specific funding for this study.
Competing Interests: The authors have declared that no competing interests
Citation: Bukhman G, Ziegler J, Parry E (2008) Endomyocardial Fibrosis: Still a
Mystery after 60 Years. PLoS Negl Trop 2(2): e97. doi:10.1371/journal.
Copyright: ? 2008 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.
Editor: John Gyapong Owusu, Ghana Health Service, Ghana
www.plosntds.org12008 | Volume 2 | Issue 2 | e97
The frequency of EMF cases in Uganda has a bimodal peak at
age 10 and age 30 . Childhood EMF in this country affects
boys and girls equally, while adult EMF affects women twice as
often as men [30,31]. In Nigeria, some studies have found a two to
one male preponderance, while others have not shown any
difference between the sexes .
The majority of EMF cases have come from low-lying, humid
parts of tropical countries (Table 2). In East Africa, Uganda has a
striking burden of EMF in contrast with Kenya and the Ethiopian
highlands. In Tanzania and Mozambique, cases have clustered
along the coastal forest [33,34,35]. Despite the frequency of EMF in
the areasaround the southerncities of Ibadan and Enugu inNigeria,
a review of cardiovascular admissions to a referral center in Zaria’s
northern savanna during the 1970s found no patients with this
Figure 1. Top, echocardiogram in a 25-y-old man with
predominantly right ventricular EMF from eastern Rwanda.
Apical four-chamber view. Note the marked dilatation of the right
atrium. RV=right ventricle, RA=right atrium, LV=left ventricle, LA=left
atrium. Bottom, massive ascites in the same patient.
Table 1. Proposed Causes of Endomyocardial Fibrosis.
Malnutrition Protein deficiency
Vitamin D 
Figure 2. Number of publications in MEDLINE between 1950 and 2006 with either ‘‘endomyocardial fibrosis’’ or ‘‘endomyocardial
sclerosis’’ in the title.
www.plosntds.org2 2008 | Volume 2 | Issue 2 | e97
disease [36,37,38,39]. In India, Kerala’s tropical rain forest has
generated one of thelargest caseseries intheworld,while otherparts
of the country have reported relatively few cases. In China, the
largest number of case reports has also come from the southern
province of Guangxi . In South America, patients with EMF
have come from Brazil and Columbia rather than Peru or Ecuador.
Theories about the etiology of EMF have tried to explain the
condition’s unusual geography and pathology. The apparent
concentration of EMF in the tropics has led to a search for infectious
or nutritional causes. In particular, the similarity of EMF lesions to
those in Lo ¨ffler endocarditis and carcinoid heart disease has
suggested a connection with serotonin or eosinophil toxicity.
Unfortunately, research on EMF peaked prior to the diffusion of
echocardiography in the much of the tropics [28,41,42,43,44].
The lack of non-invasive imaging restricted studies to small
autopsy or angiocardiographic series . Descriptions of the
clinical progression of the disease suffered from lack of diagnostic
confirmation as well [12,46]. Expansion of echocardiographic
referral centers and the development of a sub-Saharan heart
failure registry will do much to clarify the epidemiology of EMF in
this region .
At present, only a few investigators have tested the proposed
causes of EMF. Early enthusiasm for the role of serotonin in a
plantain-based diet waned by the early 1970s [48,49,50].
Encouraged at first by the demonstration of high 5-hydroxyin-
dole-acetic acid (5-HIAA) levels in the urine of West and East
Africans, this work culminated when McKinney and Crawford fed
plantains to guinea pigs, rats, and Patus monkeys [49,51,52,53,54].
They could not reproduce typical EMF lesions. With the finding
that serum 5-hydroxytryptamine (5-HT) levels failed to rise in
EMF patients fed a diet of plantains in Nigeria, investigation on
this hypothesis ceased .
The eosinophil hypothesis gained prominence in the 1960s with
reports of eosinophilic endomyocardial disease among European
visitors to tropical regions [56,57,58,59,60,61]. At the same time, Ive
and Brockington in Nigeria found filariasis (onchocerciasis or loiasis)
rates approaching 100% among 42 patients with angiographic EMF
compared with 44% of 115 controls (p,0.001) [62,63]. The
suggestion that helminth-induced eosinophiliaprecipitated a tropical
variant of the eosinophilic heart disease known as Lo ¨ffler’s found
support in later accounts of helminth-associated EMF in natives and
visitors to sub-Saharan Africa [64,65].
The case for the equivalence of end-stage Lo ¨ffler’s and EMF
rests on two formal evaluations . The first study, published by
Brockington and Olsen in 1975, compared the histology of 30
cases of Lo ¨ffler’s with 32 cases of EMF drawn from Uganda,
Nigeria, and Brazil . On the basis of this work, Olsen proposed
three stages of Lo ¨ffler’s . In patients with 1 to 2 mo of
symptoms prior to autopsy, an eosinophilic myocarditis marked
the necrotic stage. Those who died after 10 mo of symptoms had
endocardial thickening and thrombosis rather than myocarditis.
Among those 16 Lo ¨ffler patients with more than 2 y of symptoms
prior to autopsy, Olsen described a final fibrotic stage that he
found identical to EMF. In a clinical and echocardiographic study
published in 1983, Davies and colleagues confirmed these findings
. In 11 patients from the United Kingdom on the one hand,
and 47 patients from India and Brazil on the other, they found no
significant differences between fibrotic stage Lo ¨ffler’s and EMF.
Endomyocardial biopsies have failed, however, to demonstrate
an eosinophilic myocarditis in EMF. In a series of 49 patients with
EMF who underwent biopsies in Uganda, none had tissue
eosinophilia despite early presentation in several cases .
Attempts to reproduce the Nigerian filariasis findings in other
small studies have also failed to show a difference in prevalence of
parasite exposure or eosinophilia between EMF cases and controls
[69,70]. In Uganda, one study found that 60% of echocardio-
graphic cases had at least mild eosinophilia compared with 10% of
controls (odds ratio 4.6) . Another small study from this
country has not shown a difference in rates of eosinophilia .
More recently, Andy and colleagues in Nigeria have argued in
favor of the helminth-driven eosinophilia hypothesis. In a
fascinating study weakened somewhat by lack of diagnostic
confirmation, the investigators found an inverse relationship
Figure 3. Distribution by country of published cases of endomyocardial fibrosis between 1950 and 2006. Includes only those cases
diagnosed at autopsy, or confirmed by surgery or cardiac imaging. Within-country variation depicted for Brazil, China, India, Mozambique, and
www.plosntds.org3 2008 | Volume 2 | Issue 2 | e97
between eosinophil levels and duration of EMF disease . In 89
cases of EMF, only 20% of patients who presented within 6 mo of
symptom onset had normal eosinophil concentrations.
Aside from inconsistencies between the pathology of Lo ¨ffler’s
and EMF, the mismatch between the geography of EMF and the
ubiquity of parasite-induced eosinophilia calls into question the
relationship between these entities . Despite the burden of
tropical pulmonary eosinophilia on the basis of lymphatic filariasis
in Southeast Asia, for example, these countries have not reported
much EMF. Rural Haiti has not reported any EMF cases, despite
an active echocardiography service at Deschapelles in the
Artibonite Valley . Ecological research of disease causation
leaves much room for confounding.
Some have sought a more direct connection between EMF and
malarial infection. EMF cases in Uganda have disproportionately
come from Rwanda-Burundi immigrant families . While the
poverty of these migrants confounds association, others have
suggested that movement from zones of lower to higher malaria
prevalence might hold the key. Following van der Geld, during the
late 1960s Shaper and colleagues found increased levels of anti-
malarial and anti-heart antibodies among these migrants and EMF
cases in particular [74,75,76]. Ziegler, Patel, and colleagues
identified a series of familial cases of EMF among Rwanda-Burundi
migrants whohad massive splenomegaly,a condition associatedwith
malaria-induced immune hyper-reactivity [68,77]. While the
prevalence of plasmodial species does not match the geographic
possible pathway from malaria to endocardial disease.
In a separate line of inquiry in Kerala State, India, the high
prevalence of EMF along a coastal zone free of filariasis has led
investigators to pursue a geochemical hypothesis. Valiathan and
Kartha have speculated that cerium or thorium present in
monazite deposits may explain regional variation in EMF
prevalence in this region [23,78]. No empirical studies have yet
come forward to support this theory.
Investigations into nutritional factors in EMF have focused on a
possible connection with cassava toxicity. A case-control study
from Uganda has shown an association between EMF and
markers of poverty such as farming, lack of shoes, and cassava-
based diets with little animal protein . Some have suggested
Table 2. Prevalence of EMF in Africa, Latin America, South Asia, China, and the Middle East.
AuthorsCountryCity or Region Dxa
Freers et al.  UgandaKampalaE’93–94CV500AllO20%
Williams et al. UgandaKampalaN’51–53 HF231 AllI15%
Brockington and Edington NigeriaIbadanN’58–66CV 252AllI16%
CV— AllI ‘‘,5%’’
Betrand et al. Co ˆte d’Ivoire Abidjan A,N’75d
Amoah et al. GhanaAccraE ’92–95HF 572 AdultI 4%
Kimbally-Kaky Congo BrazzavilleE ’88–00 HF2,530AdultI1%
Turner and Manson-Bahr Kenya NairobiN’57–58————‘‘rare’’
Kingue et al. CameroonYaounde ´E’98–01HF 177AdultI 0%
Maru Ethiopia Addis AbabaE’85–88CV474AllO0%
Daniel and Abegaz EthiopiaAddis AbabaE’89–92 CV468
, 18O 0%
Hodes EthiopiaAddis Ababa E ’85–86CV338
. 12O 0%
Harling et al.  GambiaFajaraN’61CV 34 AllI0%
Oyoo and Ogola KenyaNairobiE’93CV91AdultI0%
Diallo et al. MaliBamakoE’00–02HF436AdultI0%
Thiam SenegalDakarE’01 HF170AdultI0%
Steenekamp et al. South AfricaKelksdorpN ’89 CV74AllI0%
Richter et al. SudanWad MedaniE’87CV33AllI0%
Latin AmericaGuimaraes BrazilBahiaN’70–91CV734AllI2%
Suarez and Suarez Venezuela CaracasN’73d
Christie (L. Christie, personal
South AsiaKutty et al. India TrivandrumE ’78–94CV22,666AllO1.5%
Datta and Aikat IndiaChandigarhN’64–72CV906AllI0.9%
Cherian et al. IndiaChennaiS ’06d
ChinaYin et al. ChinaGuangxiE’001d
Middle East Rashwan et al. EgyptAlexandriaE’91–93 CV 10,000AllO0.2%
aDx=diagnostic modality, A=angiography, E=echocardiography, N=necropsy, S=surgery.
bPop=population, CMP=only cardiomyopathy, CV=all patients with cardiovascular disease, HF=only heart failure.
cSet=setting, I=inpatient, O=outpatient.
dYear of publication.
www.plosntds.org42008 | Volume 2 | Issue 2 | e97
that cerium-mediated cassava toxicity in the setting of protein
deficiency may play a role in the pathogenesis of EMF .
Despite the known role of cyanogens from improperly processed
cassava in konzo, an upper-motor neuron disease reported from
Central and East Africa, cardiac manifestations have not had a
part in these outbreaks .
Given the difficulty of cardiovascular research in resource-poor
settings, the supply of theories about EMF has exceeded the reach
of investigation. The disease accounts for a striking proportion of
heart failure in some regions. The dissemination of echocardiog-
raphy in tropical countries should facilitate prospective studies that
clarify case definition and generate new insights into the
mechanisms of heart failure in sub-Saharan Africa. At the same
time, molecular techniques could bring new life to old ideas.
The fusion protein FIP1L1-PDGFRa, a constitutively activated
tyrosine kinase found in as many as half of those with the
idiopathic hypereosinophilic syndrome, has emerged as a
therapeutic target for imatinib . The prevalence of FIP1L1-
PDGFRa among those with EMF could give another important
clue about the etiology and treatment of this disease.
Studies that measure levels of markers, such as C-reactive
peptide or inflammatory cytokines such as tumor necrosis factor a,
could help explore the role of inflammation in EMF and suggest
therapeutic strategies in early forms of the disease .
Echocardiographic studies of patients with hyper-reactive
malarial splenomegaly could shed light on the prevalence of early
endocardial disorders in this population.
The recent finding that serotonin acts as a chemotactic factor
for eosinophils may reignite inquiries into the role of this pathway
in EMF . Zanettini and colleagues have found that some anti-
Parkinson medications induce valvular fibrosis via their action on
5HT2B receptors . Could polymorphisms in this receptor
influence susceptibility to EMF in the presence of intermittent
inantly right ventricular EMF from eastern Rwanda. Apical four-
chamber view. Note the marked dilatation of the right atrium.
Found at: doi:10.1371/journal.pntd.0000097.s001 (2.01 MB
Echocardiogram in a 25 year-old man with predom-
We would like to thank Dan Connor, Kris Somers, and three anonymous
reviewers for their comments on an earlier version of this paper. We would
also like to thank Peter Weller for his advice on eosinophilic disease in the
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.
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N Endomyocardial fibrosis, a restrictive cardiomyopathy,
has a high prevalence in tropical regions of sub-Saharan
Africa, South Asia, and South America.
N We found no conclusive evidence that parasite-induced
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but the etiological role of eosinophils remains an open
N Uncertainty continues about the distribution and causes
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