endomyocardial fibrosis
TRANSCRIPT
ENDOMYOCARDIAL FIBROSIS
(Davies' disease)
DR VISHWANATH HESARUR
SENIOR RESIDENTDEPT OF CARDIOLOGY
JNMC, BELGAUM.
INTRODUCTION Endomyocardial fibrosis (EMF) is a disease that is
characterized by fibrosis of the apical endocardium of the right ventricle (RV), left ventricle (LV), or both.
The clinical manifestations are largely related to the
consequences of restrictive ventricular filling, including left and right sided heart failure.
The heart failure is associated with atrioventricular-valve regurgitation.
Endomyocardial fibrosis is a major cause of illness and death in areas where it is endemic, and in its severest form carries a very poor prognosis, with an estimated survival of 2 years after diagnosis.
HISTORY 1946: Bedford and Konstam described a form of
heart disease in 40 West African soldiers -post-mortem revealed subendocardial fibrosis with features that are now associated with EMF.
1946: Davies JN first coined the term EMF and said that “he became convinced rightly or wrongly that he had met a new disease”.
1938 : Arthur Williams had described two cases
of mitral incompetence and correlated with large patches of fibrosis affecting the ventricular walls at necropsy
1946 : Davies did his MD thesis on this disease where he described the pathological features as a distinct entity.
1948 : Bedford encouraged davies to publish his observations and Arthur Williams and JD Ball were his co-authors.
Later, JD Ball, with his missionary job joined Christian Medial College Vellore in India and identified the pathological specimens at autopsy which he shipped to Davies for confirmation.
Thus, the disease was reported from India for the first time
1954 : Davies described the classical four pathological features of EMF and its distribution in Africa.
Right and left ventricular endocardial fibrosis, affecting the apex and inflow region with atrioventricular valve regurgitations
The disease came to be known as the Davies’ disease.
1960 : Samuel and Anklesaria published this initial autopsy series from south India.
1962 : CK Gopi from Trivandrum, described the
specimen kept in the hospital autopsied in 1950s as a case of right ventricular endomyocardial fibrosis with right atrial thrombi.
EPIDEMIOLOGY EMF is a disorder found typically in tropical and
subtropical Africa, notably in Uganda, Nigeria, and Mozambique
Major cause of morbidity and mortality, accounting for 25% of cases of congestive heart failure and death in equatorial Africa.
A population-based study in rural Mozambique revealed a prevalence of the disorder affecting 19.8% of the population.
The disease is increasingly recognized in other tropical and subtropical regions within 15 degrees of the equator, including India, Brazil, Colombia, and Sri Lanka.
Increased incidence among individuals of low socioeconomic status.
Male preponderance, is most common in children and young adults, but has been described in individuals into the sixth decade of life .
ETIOLOGY The cause of the underlying fibrotic process of EMF is largely
unknown; however, several theories exist and are briefly reviewed
Eosinophilia
Most commonly cited etiologic link in EMF. In support - observed that EMF resembles a late stage of
Loeffler's endocarditis (eosinophilic myocarditis) , a process known to result from sustained eosinophilia in patients with hypereosinophilic syndrome .
EMF and intraventricular thrombosis have also been observed
following a variety of other eosinophilic syndromes including hypersensitivity myocarditis , parasitic infections , eosinophilic leukemia, sarcoma, carcinoma, and lymphoma .
Despite the similarities between Loeffler’s endocarditis and EMF, serum and myocardial eosinophilia have not been consistently demonstrated in EMF.
one study from Uganda found - 60 % of patients
with EMF had at least mild eosinophilia at the time of diagnosis compared to 10 % of controls , in Kerala, India, most with EMF did not have active eosinophilia at the time of diagnosis.
Endomyocardial biopsies have not demonstrated eosinophilia in EMF, even in those suspected to have early disease .
Infectious Several infections - toxoplasmosis , rheumatic fever , malaria ,
and helminthic parasites . A consistent association with one organism, however, has not
been demonstrated.
Environmental exposure
Cerium, a rare earth element, has been postulated to play a role in the pathogenesis of EMF.
Serum levels of cerium are high in patients with EMF compared
to controls, and it is postulated that cerium is ingested from food and contaminated soil .
The incidence of EMF is decreasing in India, which corresponds with a reduction in soil cerium that has occurred with modernization.
Immunologic
The presence of anti-myosin autoantibodies has been demonstrated in EMF; however, these antibodies can be detected in other forms of heart disease such as Dresser’s syndrome, rheumatic heart disease, and in patients with post-transplant rejection.
Genetic
A familial link has been identified in many studies; however, it is not known whether this is due to an environmental or genetic cause or both.
PATHOLOGY EMF affects both the right and left ventricles in
approximately 50% of patients, purely the left in 40%, and the right ventricle alone in the remaining 10%.
The typical gross appearance is that of a normal to slightly enlarged heart.
The right atrium may be dilated in proportion to the severity of right ventricular involvement.
The hallmark feature of the disorder is fibrotic obliteration of the apex of the affected ventricle .
The fibrosis involves the papillary muscles and chordae tendineae, leading to atrioventricular valve distortion and regurgitation.
In the left ventricle, the fibrosis extends from the apex to the posterior mitral valve leaflet, usually sparing the anterior mitral leaflet and the ventricular outflow tract.
Endocardial calcific deposits can be present involving
diffuse areas of the ventricle.
The fibrotic tissue often creates a nidus for thrombus formation, which can be extensive. Atrial thrombi also occur.
The process usually does not involve the epicardium, and the coronary artery obstruction is distinctly uncommon.
End-stage endomyocardial disease . Apical ventricular thrombi form in damaged endocardium, and progressive endomyocardial
fibrosis entraps the chordae tendineae, leading to mitral and sometimes tricuspid valvular incompetence.
(Courtesy Murray Resnick, MD, PhD, Brown University, Providence, RI.)
HISTOLOGY
Histology demonstrates marked fibrotic thickening of the endocardium (arrow), with proliferation of fibrous tissue in the underlying myocardium, which is consistent with
endomyocardial fibrosis (Masson trichrome stain, original magnification ×50).
CLINICAL FEATURES
The clinical presentation of EMF depends on the chamber involved, the location of the fibrotic lesion and its severity.
Davies described three phases of the disease in his patients from Uganda.
The initial phase is an acute carditis phase, characterized by febrile illness and in severe cases with heart failure and shock.
Those who survive this acute illness, progress into a sub acute phase followed by a chronic phase.
Most of the patients come to clinical attention in this
chronic burnt-out phase
Right Ventricular Endomyocardial Fibrosis
In pure or predominant right ventricular involvement, the right ventricular apex is characterized by fibrous obliteration, which may extend to involve the supporting structures of the tricuspid valve, with ensuing tricuspid regurgitation.
Patients exhibit an elevated JVP, a prominent v wave
with rapid y descent, and a right-sided S3 gallop.
There is prominent hepatomegaly with a pulsatile
liver, ascites, splenomegaly, and peripheral edema, but pulmonary congestion is typically absent because of the lack of left-sided involvement.
Left Ventricular Endomyocardial Fibrosis
In cases of predominant left-sided disease, fibrosis involves the ventricular apex and often the chordae tendineae or the posterior mitral valve leaflet, producing mitral regurgitation.
The associated murmur may be late systolic, characteristic of a papillary muscle dysfunction murmur, or pansystolic.
Findings of pulmonary hypertension may be
prominent, and an S3protodiastolic gallop is frequently present.
Biventricular Endomyocardial Fibrosis
Biventricular EMF is more common then either isolated right- or left-sided disease.
The typical clinical presentation of EMF resembles
right ventricular EMF; however, a murmur of mitral regurgitation is indicative of left-sided involvement.
Unless left ventricular involvement is extensive, severe
pulmonary hypertension is absent and the right-sided findings are the predominant mode of presentation.
Approximately 15% of patients will experience systemic
embolization, and only 2% will have infective endocarditis.
In a study conducted in india which included 145 pts with EMF show clinical profile
The mean (SD) age of the patients at first presentation was 26±3 (14±1) years for women (n = 70) and 21±1 (11±9) years for men (n = 75); 33.1% were under 15.
Gupta PN, Valiathan MS, Balakrishnan KG, Kartha CC, Ghosh
MK. Clinical course of endomyocardial fibrosis. Br Heart
J. 1989;62:450–4.Sree
Chitra Tirunal Institute for Medical Sciences and Technology,
Trivandrum 69501 1, Kerala, Indi
A COMPARISON OF THE CLINICAL AND CARDIOLOGICAL FEATURES OF ENDOMYOCARDIAL DISEASE IN
TEMPERATE AND TROPICAL REGIONS
J. DAVIES ,G. VIJAYARAGHAVAN et al A comparison of the clinical and cardiological features of endomyocardial disease in
temperate and tropical regions,1983.
J. DAVIES ,G. VIJAYARAGHAVAN et al A comparison of the clinical and cardiological features of
endomyocardial disease intemperate and tropical regions,1983.
RV EMF Right atrial (RA) abnormality - peaking and increased P
wave amplitude in lead II
Tharakan J. Electrocardiogram in endomyocardial fibrosis. Indian J Pacing Electrophysiol.2011;11:129–33
ECGDIAGNOSIS
QR pattern with a diminutive R wave in lead V1 , attributed to RA enlargement, though this pattern is seen even in patients with atrial fibrillation (AF) .
Tharakan J. Electrocardiogram in endomyocardial fibrosis. Indian J Pacing Electrophysiol.2011;11:129–33
In isolated RV EMF - A dominant R wave in V2 in the absence of QR pattern in V1 in 14 of 25 patients resulting in early transition from a dominant S wave in right sided chest leads to dominant R wave in V2 or earlier .
Tharakan J. Electrocardiogram in endomyocardial fibrosis. Indian J Pacing Electrophysiol.2011;11:129–33
AF is seen in the end stage patients with advanced RV EMF.
It is noteworthy that patients with RV EMF and AF rarely have fast ventricular response, in striking contrast to patients with AF and LV EMF.
Patients with large pericardial effusion often have low voltage QRS, satisfying the low voltage ECG criteria.
LV EMF
LA abnormality. AF occurs in advanced and uncorrected case of
LVEMF.
The odd finding is a uniform ST segment depression and T wave inversion more evident in the lateral chest leads, similar to apical hypertrophic cardiomyopathy (HCM) and non- ST elevation acute coronary syndromes
Tharakan J. Electrocardiogram in endomyocardial fibrosis. Indian J Pacing Electrophysiol.2011;11:129–33
More than 50% patients with EMF have biventricular involvement
The ECG reflects a combination of these
abnormalities. ECG findings reported by Balakrishnan et al from
Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum - 210 patients
AF (33%), junctional rhythm or heart block (4.4%), right axis deviation (29%), intra ventricular conduction abnormality (16%) and atrial tachycardia or atrial flutter(3.5%).
Balakrishnan KG, et al. Clinical course of patients in Kerala. In: Valiathan MS, editor.Endomyocardial fibrosis. Oxford University
Press; 1993
Earlier three large studies of 60 patients, 95 patients and 50 patients, reported AF in 40%, junctional rhythm in 2%, RA enlargement in 32% and QR pattern in V1 in 25% patients .
LA enlargement was common in patients with LVEMF and 18% of LVEMF patients had LVH (left ventricular hypertrophy) with strain .
Sapru RP. Clinical profile of endomyocardial fibrosis. In: Sapru RP, editor. Endomyocardial fibrosis in India. ICMR; 1983.Vijayaraghavan G, et al. Endomyocardial fibrosis: Clinical,
ECG and radiological features. In: Sapru RP, editor. Endomyocardial fibrosis in India. ICMR; 1983.
Jacob G, et al. Endomyocardial fibrosis in Kerala. In: Sapru RP, editor. Endomyocardial fibrosis in India. ICMR; 1983.
Jacob G, et al. Endomyocardial fibrosis in Kerala. In: Sapru RP, editor. Endomyocardial fibrosis in India. ICMR; 1983
Echocardiography
Apical fibrosis of the right ventricle (RV), left ventricle (LV), or both ventricles.
Tethering the atrioventricular (AV) valve papillary muscles, leading to mitral and/or tricuspid regurgitation
Giant atrial enlargement . Restrictive filling pattern on Doppler recordings of mitral
valve inflow .
Apical thrombi are often present
In a study conducted in brazil - 12 pts with EMF were studied with Doppler echocardiography with the purpose of describing the echocardiographic features and identify the affected sites.
The average age was 41 years (range 16 to 59 years), 2 men
and 10 women.
3 (25%) had isolated right ventricular involvement, one patient (8%) left ventricular, 8 patients (66%) both ventricular.
Doppler echocardiographic findings were: right atrium enlargement (91%), right ventricle outflow dilatation (83%), paradoxical septal motion (83%), left atrial enlargement (33%), mitral and tricuspid valve prolapse (50%), pericardial effusion (41%), mitral regurgitation (75%), tricuspid regurgitation (100%), apex obliteration (50%) and a restrictive type flow pattern (50%).
Tello r Cuan et al . Doppler echocardiography in endomyocardial fibrosis , Brazil ,1994.
In a study conducted in india which included 145 pts with EMF ,Echocardiographic data were available in 86 patients.
The mean (SD) left ventricular internal dimensions in diastole and systole were 4.17 (1.19) cm and 2.9 (1. 07) cm respectively.
Pericardial effusion was present in 35
(40.7%), intracavitary thrombi in 11 (12.8%), and myocardial calcification in 16 (18. 6%) patients.Gupta PN, Valiathan MS, Balakrishnan KG, Kartha CC, Ghosh
MK. Clinical course of endomyocardial fibrosis. Br Heart J. 1989;62:450–4. Sree
Chitra Tirunal Institute for Medical Sciences and Technology,Trivandrum 69501 1, Kerala, India
An echocardiographic screening study in Mozambique included echocardiographic criteria for the diagnosis and staging of EMF
As the natural history of EMF is not well defined,
these criteria will likely aid in defining the stages of this disease and in determining the clinical significance of early EMF.
Classification of Endomyocardial Fibrosis
They defined major and minor criteria for the diagnosis of EMF on the basis of features of advanced disease and pathologic features of early stages described in postmortem studies.
Endomyocardial fibrosis was diagnosed in the presence of two major criteria or one major criterion associated with two minor criteria
Possible scores ranged from 0 to 35; cases with
scores of 8 or less were classified as mild, scores of 8 to 15 as moderate, scores of 15 or more as severe.
A Population Study of Endomyocardial Fibrosis in a Rural Area of Mozambique Ana Olga Mocumbi, M.D., Maria Beatriz Ferreira, M.D., Ph.D., Daniel Sidi, M.D., Ph.D., and
Magdi H. Yacoub, F.R.S. N Engl J Med 2008;359:43-9.
HEMODYNAMIC FINDINGS
The typical haemodynamic finding on cardiac catheterization is the dip and plateau pattern of restrictive ventricular filling.
In a study conducted in Mozambique included 21 pts showed
In patients with RV EMF, RA pressure was increased with prominent A waves, which was also seen in the right ventricular and pulmonary artery pressure tracings .
The right ventricular pressure tracing showed a dip and high end-diastolic pressure 5 mm Hg higher than the pulmonary diastolic pressure, and the contour of the right ventricular pressure tracing was distorted .
In patients with left sided involvement, left ventricular end-diastolic pressure was very high.
A dip and plateau pattern of the ventricular pressure curve present .
Pulmonary hypertension present in all patients with left and biventricular EMF
In a study conducted which included 8 pts, their hemodynamics showed
Vijayaraghavan G, Cherian G, Krishnaswami S, Sukumar IP. Left ventricular endomyocardial fibrosis in India. Br Heart
J. 1977;39:563–8
Gupta PN, Valiathan MS, Balakrishnan KG, Kartha CC, Ghosh MK. Clinical course of endomyocardial fibrosis. Br Heart
J. 1989;62:450–4. SreeChitra Tirunal Institute for Medical Sciences and Technology,
Trivandrum 69501 1, Kerala, India
Chest X-Ray
Cardiomegaly - varying degrees from mild to severe.
Right atrial enlargement in the patients with right-sided involvement, left atrial enlargement in patients with left-sided involvement, and biatrial enlargement in those with biventricular involvement.
Pulmonary venous congestion with left-sided involvement.
Endocardial calcification
Somers K, Williams AW. Intracardiac calcification in endomyocardial fibrosis. Br Heart J.1962;24:324–8
Vijayaraghavan G, Cherian G, Krishnaswami S, Sukumar IP. Left ventricular endomyocardial fibrosis in India. Br Heart
J. 1977;39:563–8
ANGIOGRAPHY
CHARACTERISTIC OBLITERATION OF THE APEX OF THE INVOLVED VENTRICLE(S) WITH VARYING DEGREE OF AV VALVE REGURGITATION
Left ventricular angiogram in the RAO view showing obliteration of the apex (arrow) in systole (top, a) and diastole (bottom, b).
Walid M. Hassan, MD, FCCP; Mohamed et al Pitfalls in Diagnosis and Clinical, Echocardiographic, and Hemodynamic Findings in Endomyocardial Fibrosis A 25-Year
Experience 2005
Right ventricular angiogram in the RAO view in a patient with right-sided EMF showing complete obliteration of the apex of the right
ventricle, dilated rightatrium, and severe TR. .
Walid M. Hassan, MD, FCCP; Mohamed et al Pitfalls in Diagnosis and Clinical, Echocardiographic, and Hemodynamic Findings in Endomyocardial Fibrosis A 25-Year
Experience 2005
CMR imaging with contrast demonstrates myocardial fibrosis.
In early disease where there is suspicion for active inflammation, CMR may be useful in identifying patients who may benefit from steroid therapy
Cardiovascular magnetic resonance imaging
CT SCAN
Endomyocardial Biopsy
Photomicrograph of endomyocardial biopsy specimenshowing marked thickening of the endocardium (E) with fibrosis
(hematoxylin-eosin, original × 200).
MANAGEMENT
Medical therapy Remains challenging. One third to one half of patients with advanced disease
die within 2 years Atrial fibrillation is a poor prognostic indicator, although
symptomatic relief can be achieved with rate control
Heart failure - difficult to control, and diuretics are effective only in early stages of disease, losing efficacy with advanced ascites.
Surgery Endomyocardial resection - endocardectomy with valve
replacement or repair - especially in subjects in advanced heart failure
Immediate postoperative mortality is high - 15 to 30 %. A surgical series of 83 patients from Brazil all in NYHA class
grade III to IV, and with a mean follow-up of 7.6 years had a survival probability at 17 years of 55 percent . 4 (5.8%) patients - recurrence of the fibrosis and were reoperated on
and in 6 (8.8%), EMF appeared in the other ventricle. 5 (7.3%) patients were reoperated on to replace either a valve
prosthesis or a native valve which had been preserved during the first procedure.
Only 24 (45%) of the 53 surviving patients are in functional class I or II.
Fernando Moraes , Cleuza et al Surgery for endomyocardial fibrosis revisited September 1998
Published series have been small, overall experience is limited, and questions remain about the appropriate timing, peri-operative mortality, and long-term prognosis .
Left ventricular angiogram in the RAO view showing a small left ventricle with apical obliteration,severe MR, and dilated
left atrium in a patient withleft-sided EMF (top, a) and after surgery with endocardectomy
and mitral valve replacement (bottom, b).Fernando Moraes , Cleuza et al Surgery for endomyocardial fibrosis revisited September 1998
CLINICAL COURSE The factors significantly affecting survival
were
Gupta PN, Valiathan MS, Balakrishnan KG, Kartha CC, Ghosh MK. Clinical course of endomyocardial fibrosis. Br Heart
J. 1989;62:450–4. SreeChitra Tirunal Institute for Medical Sciences and Technology,
Trivandrum 69501 1, Kerala, India
Gupta PN, Valiathan MS, Balakrishnan KG, Kartha CC, Ghosh MK. Clinical course of endomyocardial fibrosis. Br Heart J. 1989;62:450–4. Sree
Chitra Tirunal Institute for Medical Sciences and Technology,Trivandrum 69501 1, Kerala, India
Changing natural history of endomyocardial fibrosis
Gupta and colleagues defined the natural history of the disease in Kerala in the late 1980s.
Follow up of the initial 200 patients showed a 10
year survival of only 37 %. Ascites, atrial fibrillation and NYHA class IV were
the poor prognostic indicators.
Eighty nine patients, who underwent endocardiectomy with MVR had an actuarial survival of 55 % during the same period.
Significant decline in the number of new cases happened in the hospital admissions in Kerala in the subsequent decades.
Natural history in them was more favourable with
less than 10 per cent mortality on seven years follow up.
The average number of cases seen declined by half in the last decade, compared to the previous decade.
The mean age of the patients seen is now 33 yr compared to 25 yr in the previous decade, suggesting that people who were asymptomatic in the previous era are now being picked up on evaluation.
There are no patients below 10 yr, whereas in the previous decade, 28 per cent were below the age of 15 yr.
The patients are less symptomatic and older.
The majority are incidentally diagnosed when evaluated for electrocardiographic or echocardiographic abnormalities.
Temporal correlates of this changing natural history are worth analyzing.
The period noted in the natural history studies belong to the 30 year period of 1976 to 2007
Kerala witnessed substantial economic, nutritional and health transitions.
Cassava and plantain are no longer the staple diet for the Keralites.
The per capita calorie consumption increased from 1600 to 2100 Kcals.
The nutritional deficiency disorders were replaced by those of over nutrition and currently, Kerala is the diabetic capital for India.
Thanks to the good female literacy, health status of Kerala is
acclaimed as an example for good health at low cost.
A community survey shows that there is a substantial decline in worm load per child.
Filarial endemicity continues to be little less, with rigorous
governmental programmes initiated for its control.
Eosinophilia in children is now uncommon. There is substantial decline in rheumatic fever and
rheumatic heart disease in children of Kerala correlating with the improved health care services and quality of life.
The question which needs to be answered now is what really caused this decline; is it the change in living standards, or change in the dietary pattern or the reduction in childhood infections? By and large, endomyocardial fibrosis could be a reaction pattern of the endocardium to a variety of insults
Presence of interstitial fibrosis, myohypertrophy, and calcification speaks of the role of cytokines in its genesis.
Predominant right ventricular involvement in children could indicate an insult when the right ventricle could be more susceptible.
Right ventricle receives most of the umbilical venous return in utero and is more dominant.
But no antenatal cases are reported till date and the youngest report is that of a 4 month old baby.
The inflammatory response occurring in the younger age group could manifest as calcification in later years.
Whether this calcification has its similarity to vascular and valvar calcium occurring in older age group; if so, could it be the factor which holds the key for unraveling this mystery?
SUMMARY EMF is a restrictive cardiomyopathy observed in the tropics usually at
the end-stage of the disease. It may be indistinguishable from Loeffler’s endocarditis, observed in
temperate climates.
The pathogenesis remains unknown; however, eosinophilia may play a role.
Echocardiography may show uni- or bilateral ventricular apex obliteration with severely dilated atria and a restrictive filling pattern.
The prognosis is poor, with a mortality estimated at 25 % per year.
Surgical treatment with endomyocardial resection and valve replacement may be beneficial in patients with advanced apical obliteration and sever heart failure symptoms.