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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 1  |  Issue : 2  |  Page : 156-160

Pathobiology of cardiomyopathies: Experience at a Tertiary Care Center


1 Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication30-Sep-2015

Correspondence Address:
Dr. Uma Nahar Saikia
Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-5414.166333

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  Abstract 

Background: Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with varied pathology. Pathology data from India are scarce. Methods: A retrospective, descriptive study of autopsies, as well as endomyocardial biopsy specimens, was done of patients with cardiomyopathy. The clinical and pathological features are described. Results: There were 32 patients with dilated cardiomyopathy. Two were pediatric, and two had arrhythmogenic right ventricular cardiomyopathy. Myocarditis was seen in 12 cases. In our endomyocardial biopsy data of 32 patients with restrictive cardiomyopathy (RCM), we found amyloid in 13 and idiopathic RCM in the remainder. Our genetic studies in cardiomyopathies suggest that the same genetic mutation may lead to different phenotypic manifestations with restrictive or hypertrophic cardiomyopathies in different families. Conclusions: This study gives insight into the pathology and etiology of some of the cardiomyopathies seen in India. They differ from the west, and now with the availability of genotyping and magnetic resonance imaging, more data should soon be available from more centers.

Keywords: Arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy


How to cite this article:
Saikia UN, Bahl A, Mishra B, Sharma M, Kumari V, Talwar K K. Pathobiology of cardiomyopathies: Experience at a Tertiary Care Center. J Pract Cardiovasc Sci 2015;1:156-60

How to cite this URL:
Saikia UN, Bahl A, Mishra B, Sharma M, Kumari V, Talwar K K. Pathobiology of cardiomyopathies: Experience at a Tertiary Care Center. J Pract Cardiovasc Sci [serial online] 2015 [cited 2020 Apr 9];1:156-60. Available from: http://www.j-pcs.org/text.asp?2015/1/2/156/166333


  Introduction Top


Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes.[1],[2],[3],[4] Cardiomyopathies were originally defined as diseases of the myocardium associated with cardiac dysfunction. They were simply classified as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC). There is limited pathological data from India regarding these.

We compile our experience from autopsy, endomyocardial biopsy, and genotyping studies from these patients.

Twenty years' experience from autopsies, endomyocardial biopsy and genetic studies done at Post Graduate Institute of Medical Education and Research, Chandigarh in patients with cardiomyopathy was reviewed and is presented to give an overall picture of etiopathogeneis of cardiomyopathies in India.

The autopsy, endomyocardial biopsy and genetic studies data on cardiomyopathy from the past 20 year is compiled and presented.

Dilated cardiomyopathy

Since the mortality in DCM cases accounts up to 20–30% in India, we tried to look at our data at autopsy. In our experience of DCM at autopsy among a total of 32 cases of DCM, cardiomegaly was present in 28 and clinical signs of congestive cardiac failure were present in 25 cases. There was biventricular dilatation in 5 cases, and the remaining 27 cases had four chamber dilatation at the gross review [Figure 1]a. Right auricular thrombosis was seen in 20 cases and endocardial thickening in 8 cases. The coronaries did not show any significant narrowing, and there was no evidence of any ischemic or rheumatic heart disease. Two belonged to the pediatric age group with endocardial fibroelastosis, and two had ARVC.
Figure 1: (a) Gross photograph of a dilated heart with four chamber dilatation and mural thrombi in dilated cardiomyopathy. (b) Microphotograph showing mixed interstitial infiltrate with myocyte necrosis (H and E, ×20). (c) Goss photograph of enlarged heart with deep brown color of myocardium in amyloidosis. (d) Microphotograph showing pale eosinophilic material within interstitium and perimyocyte (H and E, ×20). (e) Microphotograph showing myofiber replacement with fat (H and E, ×20). (f) Apical cross-sectional view showing fat on the free right ventricular wall in arrhythmogenic right ventricular cardiomyopathy.

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Microscopically, the myocytes generally were hypertrophied and exhibited an extreme degree of attenuation with sarcoplasmic degeneration. The myocardial interstitium was quite cellular by stromal cells. Interstitial fibrosis was observed commonly, which was graded as mild, moderate and severe. This fibrosis can be delicate perivascular or pericellular, or there can be dense patches of replacement fibrosis. It is most extensively seen in the left ventricular (LV) subendocardium. Endocardial fibrosis when present is usually mild to moderate but may be dense with collagen deposition particularly in the areas of fibrosis. Our data revealed epicardial, myocardial, and interstitial mononuclear infiltrate in 28 cases. Interstitial fibrosis was present in 29 cases of which 22 had severe replacement fibrosis, 5 had moderate, and 5 had mild fibrosis with predominant CD68+ cells indicating histiocytic nature.

True myocarditis was seen in 12 cases with CD3+ cells. In 1 case, a mixed infiltrate admixed with eosinophils indicating hypersensitive myocarditis was seen [Figure 1]b. In some cases, lymphocytic myocarditis characterized by multiple microscopic aggregates of lymphocytes associated with degenerative or necrotic myocardial cells was seen in 12 cases only. The inflammation, however, was small and sparse in most of the cases.

Restrictive cardiomyopathy

RCM [5],[6] is defined as heart muscle disease leading to a severely impaired diastolic filling of the ventricle. Idiopathic RCM (IRCM) is the most common (50% of all cases) cause of RCM. In our experience on endomyocardial biopsies of 32 patients with restrictive clinical features, we found amyloid to be cause in 13 (40%) [Figure 1]c and [Figure 1]d and remaining were IRCM. There was none with hemochromatosis or endocardial fibrosis.

Arrhythmogenic right ventricular cardiomyopathy or arrhythmogenic right ventricular disease/dysplasia

In our experience of 20 years, we found only 2 cases of ARVC at autopsy [Figure 1]e and [Figure 1]f and none on endomyocardial biopsy.

Hypertrophic cardiomyopathy

We studied a group [7] of patients with restrictive physiology for mutations in the beta-myosin heavy chain (MYH7) and troponin I (TNNI3) gene. Among the 17 patients who had restrictive physiology, seven were HCM patients. Of the HCM patients, 7 (6.9%) had restrictive physiology. The mean age of these 17 patients was 40.1 ± 19.2 years (range: 15–67), 6 (35.3%) were males. The maximal LV wall thickness of the seven HCM probands was 20.7 ± 5.2 mm (range: 16–31), whereas it was normal in the IRCM probands. Ten probands (58.8%) were in New York Heart Association (NYHA) class III or IV. Seven patients (41.2%) had atrial fibrillation. All the probands were screened for mutations in selected exons of MYH7 and TNNI3 genes. One HCM proband with a maximal LV wall thickness of 17 mm and had p. Arg192His mutation in the TNNI3 gene. She had features consistent with restrictive physiology. Her father and sister had died of RCM.

There were 32 patients with DCM. Two were pediatric and two had ARVC. Myocarditis was seen in 12 cases. In our endomyocardial biopsy data of 32 patients with RCM, we found amyloid in 13 and IRCM in the remainder. Our genetic studies in cardiomyopathies suggest that the same genetic mutation may lead to different phenotypic manifestations with restrictive or hypertrophic cardiomyopathies in different families.

Dilated cardiomyopathy

Clinically approximately 50% of patients with congestive heart failure (CHF) of unknown etiology belong to primary or idiopathic DCM.[1] Although coronary or valvular heart disease, connective tissue disorders, toxic causes, and systemic infections have been investigated as causes of DCM.[2] However in predominant cases, the cause of DCM remains undetermined though cardiotropic viral infections have been suspected as a possible cause of myocarditis and DCM. DCM is a myocardial disorder characterized by cardiac dilatation and contractile dysfunction of the left and/or right ventricles.

Grossly the heart weight is increased 25–50% above the normal and is characterized by biventricular hypertrophy and four chamber dilatation. The ventricular wall thickness remains normal generally; however, thinning may be present due to the dilatation. There is subendocardial and transmural scarring that may be seen even in the absence of identifiable thromboembolic obstruction of the coronary arteries. The endocardial fibrosis may be prominent, particularly in children, that is, the dilated form of endocardial fibroelastosis.[3] Mural thrombi are frequently encountered in any of the cardiac chamber and may vary in size. These on getting organized, produce focal endocardial fibrosis.

In a endomyocardial biopsy study of 20 patients [8] from another center in India (age: 27 months to 45 years, mean 22 years; 15 males, 5 females) of idiopathic myocarditis histologically confirmed by endomyocardial biopsy, most common mode of presentation was CHF (16 patients) followed by arrhythmias (seven patients--five of whom had associated CHF) and chest pain resembling myocardial infarction (2 patients). Ten patients had a history of preceding upper respiratory infection. Only 1 of these patients had a significant rising serum titer for Coxsackie B3 virus pericardial involvement occurred in 1 patient. Radionuclide ventriculography showed a reduced LV ejection fraction (<50%) in 17 patients, global hypokinesia in 12 patients and regional wall motion abnormalities in 5 patients. LV and RV end diastolic pressures were elevated in 15 and 11 patients, respectively.

Restrictive cardiomyopathy

RCM is defined as heart muscle disease leading to a severely impaired diastolic filling of the ventricle. RCM results from an increase in ventricular wall stiffness that causes a steep rise in intraventricular pressure with a small rise in ventricular volume during diastole. RCM is a relatively rare form of cardiomyopathy. Approximately, 50% of cases of RCM are caused by specific clinical disorders, whereas the rest represents idiopathic form among the specific forms of RCM, amyloidosis is the most common outside the tropics. Endomyocardial fibrosis (EMF) is particularly common in the tropics, especially in parts of Africa, India, South and Central America. Elsewhere it occurs sporadically. RCM can result from various local and systemic disorders.[5],[6]

IRCM is the most common (50% of all cases) cause of RCM. Based on pathological involvement, RCM can be divided into two groups – with predominant endocardial involvement or myocardial involvement. Conditions causing predominant endocardial involvement include EMF, Loeffler's endocarditis, carcinoid heart disease, metastatic cancers, radiation, and drugs. Conditions with predominant myocardial involvement include IRCM, infiltrative disorders (amyloidosis, sarcoidosis), and storage disorders (hemochromatosis, Fabry's disease).

In our experience on endomyocardial biopsies of 32 patients with restrictive clinical features, we found amyloid to be cause in 13 (40%) [Figure 1]c and [Figure 1]d and remaining were IRCM. There was none with hemochromatosis or endocardial fibrosis.

Studies from another center are similar.[9] In their study of 52 patients, all 52 patients had heart failure with normal or near normal LV 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 that is, “idiopathic RCM” (n = 22). Echocardiography revealed typical features of EMF in Group I patients, with apical obliteration of right and LV apices. Group II patients had no apex obliteration. The Group II patients had features of IRCM in the form of normal left and RV 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 2 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. 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.

Prognosis in RCM is variable [10] depending on the underlying etiology. RCM secondary to amyloidosis has a poor prognosis with a median survival of <2 years. IRCM has intermediate prognosis with 5 years survival of 64%.[5] Overall, it carries a poor prognosis, particularly in children. Various studies have reported 66–100% rate of death or cardiac transplantation within a few years of diagnosis.

Arrhythmogenic right ventricular cardiomyopathy or arrhythmogenic right ventricular disease/dysplasia

It is characterized by fatty replacement and fibrosis of the heart affecting commonly the right ventricle apex and outflow tract. However, sometimes left ventricle can also be affected.[11]

ARVC is a progressive disease with the incidence estimated to be 1:3000–1:10,000. Manifestations are usually seen in teenagers. ARVC can occur in families; more than 9 different mutations have been described, most often with autosomal dominant inheritance.

One unique form of ARVD, called Naxos disease (after the Greek island where it was first diagnosed), had an autosomal recessive pattern of inheritance.

The diagnosis of ARVC is a difficult diagnosis to make. Therefore, the European Society of Cardiology has created a list of diagnostic criteria for the diagnosis of ARVC. Histologically, there is fatty replacement of RV myocardium by >50% with residual myocytes <60%, with fibrous replacement of the RV free wall myocardium on endomyocardial biopsy. In our experience of 20 years we found only 2 cases of ARVC at autopsy [Figure 1]e and [Figure 1]f and none on endomyocardial biopsy.

Hypertrophic cardiomyopathy

HCM is a common heart muscle disease [12] and affects people of any age. With an incidence of 1 in 500 people in western literature, it affects men and women equally.

HCM is a common cause of sudden cardiac arrest in young people, especially young athletes. In HCM there is hypertrophy of the cardiomyocytes causing thickening of LV wall including the septum. Due to irregular septal thickening, bulging of septum takes place into the left ventricle. This also can block blood flow out of the left ventricle (The septum is the wall that divides the left and right sides of the heart). Despite this thickening, the ventricle size often remains normal. Sometimes, the thickening may block blood flow out of the ventricle causing obstructive HCM. When, the thickened heart muscle does not block blood flow out of the left ventricle. This is called nonobstructive HCM. The entire ventricle may thicken, or the thickening may happen only at the bottom of the heart. In both types of HCM (obstructive and nonobstructive), the thickened muscle makes the inside of the left ventricle smaller, decreasing its capacity. The walls of the ventricle also may stiffen due to which the ventricle is less able to relax.

Rarely HCM also can affect the heart's mitral valve, causing blood to leak backward through the valve and more rarely right ventricle or only the apex of LV may be affected. Microscopically there is irregular fibrosis in the interstitium resulting in myofiber disarray and marked hypertrophy of the myocytes. Perivascular fibrosis and luminal narrowing of the vessel is a relative feature which is commonly seen in HCM cases. We studied a group [7] of patients with restrictive physiology for mutations in the beta-myosin heavy chain (MYH7) and troponin I (TNNI3) gene. Among the 17 patients who had restrictive physiology seven were HCM patients. Of the HCM patients, seven (6.9%) had restrictive physiology. The mean age of these 17 patients was 40.1 ± 19.2 years (range: 15–67), 6 (35.3%) were males. The maximal LV wall thickness of the seven HCM probands was 20.7 ± 5.2 mm (range: 16–31), whereas it was normal in the IRCM probands. Ten probands (58.8%) were in NYHA class III or IV. Seven patients (41.2%) had atrial fibrillation. All the probands were screened for mutations in selected exons of MYH7 and TNNI3 genes. One HCM proband with a maximal LV wall thickness of 17 mm had p. Arg192His mutation in the TNNI3 gene. She had features consistent with restrictive physiology. Her father and sister had died of RCM.

The classification

The classification of “hypertrophic-dilated-restrictive cardiomyopathies” has limitations and mixes anatomic designations (i.e., hypertrophic and dilated) with a functional one (i.e., restrictive). Consequently, confusion may arise because the same disease could appear in two categories. Furthermore, such a classification fails to recognize the heterogeneity of clinical expression now attributable to many of these diseases. The latest updated classification and major etiological factors proposed for cardiomyopathies is shown in [Figure 2].[13] The present classification recognizes the rapid evolution of molecular, as well as the introduction of several recently described diseases, and incorporates ion channelopathies as a primary cardiomyopathy.
Figure 2: Classification of cardiomyopathies.

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  Conclusion Top


We have presented our data on the pathobiology of cardiomyopathies in India. With the advent of genotyping and with the availability of magnetic resonance imaging, more data are expected from many centers in India in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239.  Back to cited text no. 1
    
2.
Kasper EK, Agema WR, Hutchins GM, Deckers JW, Hare JM, Baughman KL. The causes of dilated cardiomyopathy: A clinicopathologic review of 673 consecutive patients. J Am Coll Cardiol 1994;23:586-90.  Back to cited text no. 2
    
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Miller AJ. Primary endocardial fibroelastosis of the left ventricle. Tex Heart Inst J 2012;39:913-4.  Back to cited text no. 3
    
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Lane RE, Cowie MR, Chow AW. Prediction and prevention of sudden cardiac death in heart failure. Heart 2005;91:674-80.  Back to cited text no. 4
    
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Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr 2009;10:iii23-33.  Back to cited text no. 5
    
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Sen-Chowdhry S, Syrris P, McKenna WJ. Genetics of restrictive cardiomyopathy. Heart Fail Clin 2010;6:179-86.  Back to cited text no. 6
    
7.
Rai TS, Ahmad S, Ahluwalia TS, Ahuja M, Bahl A, Saikia UN, et al. Genetic and clinical profile of Indian patients of idiopathic restrictive cardiomyopathy with and without hypertrophy. Mol Cell Biochem 2009;331:187-92.  Back to cited text no. 7
    
8.
Ramamurthy S, Talwar KK, Goswami KC, Shrivastava S, Chopra P, Broor S, et al. Clinical profile of biopsy proven idiopathic myocarditis. Int J Cardiol 1993;41:225-32.  Back to cited text no. 8
    
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Seth S, Thatai D, Sharma S, Chopra P, Talwar KK. Clinico-pathological evaluation of restrictive cardiomyopathy (endomyocardial fibrosis and idiopathic restrictive cardiomyopathy) in India. Eur J Heart Fail 2004;6:723-9.  Back to cited text no. 9
    
10.
Ammash NM, Seward JB, Bailey KR, Edwards WD, Tajik AJ. Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000;101:2490-6.  Back to cited text no. 10
    
11.
Azaouagh A, Churzidse S, Konorza T, Erbel R. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: A review and update. Clin Res Cardiol 2011;100:383-94.  Back to cited text no. 11
    
12.
Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet 2013;381:242-55.  Back to cited text no. 12
    
13.
Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. Contemporary definitions and classification of the cardiomyopathies: An American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807-16.  Back to cited text no. 13
    


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