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European Journal of Heart Failure 2004 6(6):723-729; doi:10.1016/j.ejheart.2003.11.009
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© 2004 European Society of Cardiology

Clinico-pathological evaluation of restrictive cardiomyopathy (endomyocardial fibrosis and idiopathic restrictive cardiomyopathy) in India

Sandeep Setha, Deepak Thataia, Sanjeev Sharmab, Prem Choprac and K.K. Talwara,*

a Departments of Cardiology, Cardiothoracic Centre, All India Institute of Medical Sciences Ansari Nagar, New Delhi 110 029, India
b Departments of Cardiac Radiology, All India Institute of Medical Sciences Ansari Nagar, New Delhi 110 029, India
c Department of Pathology, All India Institute of Medical Sciences Ansari Nagar, New Delhi 110 029, India

* Corresponding author. Tel.: +91-1126594681; fax: +91-1126862663. E-mail address: kktalwar{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Restrictive heart disease is characterized by impairment of ventricular filling during diastole with preserved systolic function. The clinical and histopathological profile on endomyocardial biopsy of a cohort of patients with restrictive cardiomyopathy (RCM) is presented.

Methodology: The medical records of patients presenting with heart failure with systemic congestion, subsequently diagnosed as restrictive heart disease after evaluation including cardiac catheterisation, were studied retrospectively to determine the clinical spectrum of restrictive cardiomyopathy. The diagnosis of RCM was made, based on systemic congestion with dilated atria and near normal ventricular size and function. Only patients who had an endomyocardial biopsy were included in the study. Patients with chronic constrictive pericarditis and secondary restrictive heart disease mainly amyloidosis were excluded from the study.

Results: All 52 patients had heart failure with normal or near normal left ventricular size and function. Based on right and left ventricle angiography, patients were classified into two groups. Group I with findings suggestive of EMF (n=30) and Group II no evidence of EMF on angiography i.e. ‘idiopathic RCM’ (IRCM) (n=22). Baseline characteristics were similar in the two groups. Echocardiography revealed typical features of endomyocardial fibrosis in Group I patients, with apical obliteration of right and left ventricular apices. Group II patients had no apex obliteration (except in four patients, who were misclassified and in whom angiography did not show apex obliteration). The Group II patients had features of IRCM in the form of normal left and right ventricular size and function with restrictive features of doppler filling along with dilated left and right atria. Angiocardiography in EMF patients showed isolated RV involvement in only two patients. In the remaining 28 patients, the obliterative changes were biventricular with RV involvement more severe than LV involvement. Angiographic findings in Group II (IRCM) patients were unremarkable with preservation of normal trabecular pattern and absence of obliterative changes. Mild atrioventricular regurgitation was present in 10/22 patients. Histopathological examination revealed that endocardial thickening was more common (77% vs. 23%) in EMF patients. The presence of myocyte hypertrophy (70–80%), myocytolysis (40–50%) and interstitial fibrosis (46–56%) were similar in both groups.

Conclusions: The majority of our patients had biventricular EMF. A significant number of patients had clinical hemodynamic features of restrictive heart disease but no evidence of EMF on angiography. These IRCM patients had similar clinical profiles to EMF but on endomyocardial biopsy the endocardial thickening was minimal and seen in few patients (5/22).

Key Words: Endomyocardial fibrosis • Pathology • Idiopathic restrictive cardiomyopathy

Received February 4, 2003; Revised June 19, 2003; Accepted November 25, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Restrictive heart disease, which is characterized by impairment of ventricular filling during diastole with preserved systolic function, may be caused by disorder of any of the three layers of the heart [1]. Diastolic filling in chronic constrictive pericarditis is restricted by the rigid inelastic pericardium with indistinguishable visceral and parietal layers [2]. Restrictive cardiomyopathies (RCM) that result in decreased myocardial compliance include those associated with infiltrative disorders namely amyloidosis, sarcoidosis and hemochromatosis [3–5]. In endomyocardial fibrosis (EMF), the hemodynamic alterations are mainly due to thickened and fibrotic endocardium [6,7]. Idiopathic restrictive cardiomyopathy (IRCM) is characterized by the clinical syndrome of restrictive heart disease of unknown etiology without pericardial and endocardial pathology [8,9]. EMF is the commonest restrictive cardiomyopathy reported in India, especially from the southern zones. There are very few reports of RCM from other parts of the country, which do not fall in the geographic belt of EMF [10–14]. In the present study, we highlight the clinical and histopathological profile of patients with RCM from a large tertiary care center in North India. This is one of the largest series of patients with RCM unrelated to infiltrative disorders.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
The medical records of all patients with hemodynamic and angiographic evidence of RCM (i.e. elevated ventricular end diastolic pressures and relatively preserved systolic function) on cardiac catheterization, between 1985 and 1999 were reviewed. For a diagnosis of restrictive cardiomyopathy, it was mandatory that the patient had (1) systemic congestion along with elevated ventricular end-diastolic pressures; (2) dilated atria; and (3) normal or near normal ventricular size and function. Ventricular hypertrophy was also excluded. All patients also had hemodynamics consistent with restrictive physiology. Thus the diagnosis of restrictive cardiomyopathy was initially made on clinical evaluation along with echo and then subsequently confirmed by doing a hemodynamic study. Patients who did not have clinically significant heart failure were excluded. The information obtained from the clinical examination, electrocardiography, chest X-ray, echocardiography, cardiac catheterization and endomyocardial biopsy (EMB) were recorded. Patients with evidence of thickened pericardium on echocardiography/computerized tomographic scan of the thorax or open thoracotomy were excluded from the study population.

The angiocardiograms of all patients were reviewed by two authors’ independently and patients were classified into EMF and non-EMF groups, based upon the criteria described by Tharakan et al. [14]. The diagnosis of EMF was made if there was evidence of left or right ventricular apex obliteration. If there was no apical obliteration, and the ventricular function was near normal along with elevated end diastolic ventricular pressures, a diagnosis of IRCM was made.

Histopathology on EMB of all patients was re-studied in an effort to identify histological features differentiating between the two groups as well as to rule out infiltrative disorders. Changes in the myocardium including fibrosis, myocytolysis and inflammatory cell infiltration were graded 0 to 3+; endocardial thickening was also graded from 0 to 3+.

The investigation conforms with the principles outlined in the ‘Declaration of Helsinki’ (Br Med J 1964; ii:177)

2.1. Statistical methods
Statistical analysis was performed using X2 test to compare the two groups and a P value of <0.05 was taken as significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Seventy patients with hemodynamic evidence of restrictive cardiomyopathy (RCM) were included in the study. Eighteen had biopsy evidence of cardiac amyloidosis and were excluded from the study. Based upon angiocardiography, 30 patients who were diagnosed to have EMF were categorized as Group I. Group II consisted of the remaining 22 patients who did not have angiographic evidence of EMF and were diagnosed to have idiopathic restrictive cardiomyopathy according to the criteria mentioned above. The baseline clinical profile of the two groups of patients is summarized in Table 1. Majority of the patients in both groups were young, male and in NYHA functional class III–IV. There was no significant difference in the baseline clinical profile between the two groups.


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  		Table 1 Clinical characteristics of both groups (mean±S.D.) along with ECG and chest X-ray findings (number (%))

 
The ECGs and chest X-rays at presentation are shown in Table 1. Most of the patients were in sinus rhythm, and many had evidence of right and left atrial enlargement. The cardio thoracic ratio was slightly increased in both groups mainly due to atrial enlargement but as such there were no distinctive features differentiating the two groups.

3.1. Echocardiography Findings (Figs. 1, 2)
The diagnostic echocardiographic features of EMF including cavity obliteration and right ventricular outflow tract dilatation with varying degrees of atrioventricular valve regurgitation were present in 20 of 30 patients of Group I. The other ten patients in group I had evidence of restrictive heart disease in the form of biatrial enlargement, dilated inferior vena cava, restrictive doppler flows, relatively preserved systolic function, and tricuspid valve regurgitation. In Group II, 4/22 patients showed features of EMF including cavity obliteration, whereas in the remaining patients only a restrictive pattern was seen. Ten patients (four in Group I and six in Group II) were reported to have mildly reduced LV systolic function (mean ejection fraction (40±7%), however, ventricular cavity size was normal. No patient had evidence of intra-cavitary thrombus (Table 2) (Fig. 1 and Fig. 2).


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  		Table 2 Echocardiographic abnormalities in the two groups

 


Figure 1
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  		Fig. 1 Echocardiogram of patient with EMF, showing apex obliteration (RV) with dilated right atria and normal left ventricle.

 


Figure 2
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  		Fig. 2 Echocardiogram of patient with IRCM, showing normal sized ventricles with normal function and enlarged left and right atria.

 
3.2. Cardiac Catheterization and angiocardiography findings
Hemodynamic data from the two groups of patients are summarized in Table 3. In both the groups, patients had markedly elevated ventricular filling pressures with characteristic restrictive hemodynamic pattern. There were no characteristics differentiating features between the two groups.


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  		Table 3 Hemodynamics and angiography

 
3.3. Angiocardiography (Figs. 3, 4)
Angiocardiography formed the basis of differentiating the two groups of patients (Table 3). The left and right ventricle angiograms were unremarkable in the patients in group II. There was preservation of normal trabecular pattern and absence of obliterative changes in these patients. Mild atrioventricular regurgitation was seen in 10 out of the 22 patients. In group I most of the patients had biventricular involvement, with only two having isolated right ventricular involvement. The obliterative changes were more prominent in the right ventricle with less extensive changes in the left ventricle. Of the 28 patients with left ventricular involvement, 21 had mild to moderate mitral regurgitation whereas 21/30 patients with right ventricular involvement had significant tricuspid regurgitation (Fig. 3 and Fig. 4).


Figure 3
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  		Fig. 3 RV angiogram of a patient with RV EMF showing right ventricular outflow tract dilation, RV apex obliteration, and tricuspid regurgitation.

 


Figure 4
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  		Fig. 4 RV angiograms of a patient with RV IRCM showing normal ventricle size and normal trabecular pattern.

 
3.4. Endomyocardial Biopsy (Figs. 5, 6)
Adequate biopsy tissue was obtained in all patients with the exception of four patients in Group I.

In Group I (EMF) 17/30 patients (56%) had varying degrees of interstitial fibrosis, compared to 10/22 patients (46%) in the IRCM group (Group II) (Table 4). One patient with EMF had endocardial thickening and infiltration with lymphocytic inflammatory cells. Focal infiltration with lymphocytes was seen in 11 patients with EMF. Eosinophilic infiltration was not seen in any patients. Myocytolysis was seen in 12 (40%) EMF patients as compared to 11 (50%) IRCM patients. Mild to moderate myofibre hypertrophy was observed in a large number of patients (70% EMF and 82% IRCM). The only major difference between the two groups was in terms of endocardial thickening, 23 (77%) EMF patients had varying degrees of endocardial thickening while only five (21%) IRCM patients had mild endocardial thickening (Figs. 3 and 4). The endocardial thickening was predominantly due to cellular fibrocollagen tissue with variable amounts of elastic tissue. There was evidence of organized thrombus with endocardial thickening in two patients (Fig. 5 and Fig. 6.)


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  		Table 4 Endomyocardial biopsy

 


Figure 5
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  		Fig. 5 Histopathological specimen from the endomyocardial biopsy of a patient with endomyocardial fibrosis, showing the thick layer of endocardial thickening, along with myocyte hypertrophy and interstitial fibrosis.

 


Figure 6
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  		Fig. 6 Histopathological specimen from the endomyocardial biopsy of a patient with idiopathic restrictive cardiomyopathy, showing the absence of endocardial thickening (haematoxylin eosin staining) along with presence of myocyte hypertrophy and interstitial fibrosis.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
EMF is the commonest form of RCM encountered in tropical regions including southern parts of India [15–18]. IRCM is a recently described clinical entity and is characterized by clinical and hemodynamic findings of restrictive heart disease in the absence of discernible morphological features [8,9]. These patients have evidence of heart failure with enlarged left and right atria with both left and right ventricles being normal in size and function. The Doppler pattern is restrictive with increased rate of early filling and shortened deceleration time. The diagnosis of IRCM can be made once all known causes of restrictive cardiomyopathy have been excluded. There is very limited endomyocardial biopsy data available on this condition.

In a recent report from the Mayo clinic, data from 94 patients were presented. These patients were elderly (mean age 64 years), though the age range was from 10 to 90 years [9]. The majority of the patients were in NYHA functional class I to II (19% in class I, 53% in class II). A large number of the patients were in atrial fibrillation (74%) and 50% died during follow up. Endomyocardial biopsy data from 33 patients showed interstitial fibrosis (81%), myocyte hypertrophy (86%), myocyte attenuation (27%) and degeneration (33%). Endocardial fibrosis was present in 45% with no inflammatory changes. They had a typical restrictive filling pattern showing increased mitral E velocity, increased ratio of mitral early to late filling (EA>2) and shortened deceleration time (<150 ms). Hemodynamic data revealed elevated end diastolic pressures though typically the right ventricular end diastolic pressures were 5 mmHg lower than the left ventricular end diastolic pressures. The 5-year survival was 64% and 10-year survival was 37%.

The clinical spectrum of RCM in northern India in our report seems to have a mixed pattern. There was nearly equal representation of IRCM and EMF in RCM patients seen in a large referral hospital.

All of our patients were young and had severe form of disease as compared to the Mayo clinic study where the patients were older and less symptomatic. The majority of our patients were in sinus rhythm unlike the Mayo clinic study where three-quarters of patients were in atrial fibrillation. There were no clinical, electrocardiographic or radiological features on chest X-ray, which could differentiate between EMF and IRCM. The echocardiographic feature of ventricular cavity obliteration was a useful parameter in diagnosis of EMF. However, the cavity obliteration seen in four IRCM patients, which was absent on angiocardiography is difficult to explain. As this is a retrospective study over a decade, variability between different echocardiographers could partially account for this.

The IRCM patients with normal ventricular angiograms may represent an early stage of the disease continuum of EMF. However, the hemodynamic data of our patients (Table 3) clearly highlights the severe stage of restriction in both the groups. Moreover the age distribution and symptom duration were similar in both groups. Thus, the evidence from our observations from a large number of patients points towards a separate clinical entity of IRCM.

The degree of endocardial thickening of EMB tissue was the only histopathologically useful parameter identifying patients with EMF. Seventy seven percent of the EMF patients had endocardial thickening vs. 21% of IRCM patients. Interstitial fibrosis was present in both groups (56% of EMF patients and 46% of IRCM). The presence of myocytolysis (40% of EMF and 50% of IRCM) and mild to moderate myofiber hypertrophy (70% of EMF and 82% of IRCM) was similar in both groups. Similar kinds of histopathological changes are described in the restrictive cardiomyopathy patients from the Mayo clinic. Though EMB has no diagnostic value in patients with restrictive cardiomyopathy, it helps in excluding infiltrative disorders. Endomyocardial biopsy, which is a blinded procedure, has its limitations because tissue may be sampled from an unaffected site [19]. This may account for the seven EMF patients who had no endocardial thickening on microscopy.

An interesting feature in the EMF group was that the pattern of ventricular involvement was different to that reported from south India. Only two of our patients had isolated right ventricular EMF and all the rest had significant additional involvement of the left ventricle. In a report by Tharakan et al. [14] of 106 patients, 40 patients had isolated RV involvement. The etiology of both EMF and IRCM are unknown though a geochemical basis for EMF has been suggested by Valiathan et al. [20].

4.1. Limitation of the study
As a retrospective study extending over a decade the study is limited by multiple observer variability and controlling the quality of data collection. However, important data on which the conclusions are based, was collected by review of electrocardiogram, chest X-ray, tape recordings of echocardiographic examination, catheterization pressure trace, angiocardiography films and permanently fixed and stained tissue slides.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
EMF is not an uncommonly encountered form of RCM in North India. IRCM is equally prevalent and represents a separate clinical entity. This report highlights the usefulness of endomyocardial biopsy and angiography in differentiating these patients. Endomyocardial biopsy revealed a relatively normal endocardium in IRCM patients. The other interstitial and myocardial lesions seem to be non-specific. Endomyocardial biopsy does not contribute to the understanding of the pathogenesis of IRCM but rules out any underlying inflammatory process as none of the patients had any inflammatory cells in the histopathology. Both EMF and IRCM have similar clinical features and the patients are young and quite symptomatic. Echocardiographic evidence of apex obliteration and endocardial thickening on EMB help to distinguish EMF from IRCM. These IRCM patients differ from those seen in temperate climates where the patients are older and less symptomatic.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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