Genetic and clinical profile of Indian patients of idiopathic restrictive cardiomyopathy with and without hypertrophy

Abstract

Both idiopathic restrictive cardiomyopathy (IRCM) and hypertrophic cardiomyopathy (HCM) are part of the same disease spectrum and are due to sarcomeric gene mutations. A patient with restrictive physiology without left ventricular hypertrophy (LVH) would be diagnosed as IRCM, while one with LVH would be diagnosed as HCM with restrictive physiology. We studied a group of patients with restrictive physiology for mutations in beta-myosin heavy chain (MYH7) and troponin I (TNNI3) gene. Consecutive probands in the HCM and IRCM cohort over a 4-year period were considered for this study. These included 10 IRCM and 102 HCM patients. All were Asian Indians. Among the 17 patients who had restrictive physiology 10 were IRCM patients and seven were HCM patients. Of the HCM patients, seven (6.9%) had restrictive physiology. Mean age of these 17 patients was 40.1 +/- 19.2 years (range: 15-67 ), six (35.3%) were males. Maximal left ventricular wall thickness of the seven HCM probands was 20.7 +/- 5.2 mm (range: 16-31), while 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 IRCM patient was found to have p.Arg721Lys mutation in the MYH7 gene. She died due to progressive congestive cardiac failure at the age of 47 years. One HCM proband with a maximal left ventricular 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 restrictive cardiomyopathy. IRCM and HCM with restrictive physiology, both are part of the clinical expression of MYH7 and TNNI3 mutations and lead to worse clinical onset and progression of the disease.

Animal Models of Heart Failure

“…However, for inherited restrictive cardiomyopathies, several recent studies demonstrate that specific sarcomeric protein mutations are associated with defects in myocardial function and increased myofilament calcium sensitivity. 162 Mutations involving cardiac troponin I (cTnI), [163][164][165][166][167] cardiac troponin T, [165][166][167][168][169] desmin, 170 -174 and ␣-␤-crystallin 175 have been most often associated with a restrictive cardiomyopathy phenotype, although alternative mutations of these proteins can also produce a hypertrophic cardiomyopathy phenotype. 166,176,177 The histological abnormalities observed in restrictive cardiomyopathies vary with, and are often diagnostic of, the underlying etiology.…”

Idiopathic Restrictive Cardiomyopathy - Perspectives from Genetics Studies. Is It Time to Redefine These Disorders?

“…7 They also reported a p.Arg192His mutation in TNNI3 in a adolescent Indian girl with HCM and restrictive phenotype. Two of her first degree relatives had IRC.…”

“…[4][5][6][7] Also, hypertrophic cardiomyopathy (HCM) and IRC have been found to be morphologically and genetically overlapping disorders. Use of precise parameters to define and classify any disease state is important.…”

Restrictive cardiomyopathy: A review of literature on clinical status and meta-analysis of diagnosis and clinical management

“…Similar findings were reported in another study [54], which found signs of myocardial ischemia without signs of heart failure in 15 sudden cardiac death patients. However, two other RCM studies [55,56] observed syncope, chest pain and ST segment depression in SCD patients but did not find any histological evidence of ischemia to suggest it is the underlying cause of death [55,56]. Although myocardial ischemia may occur in RCM patients, current evidence is inconclusive as to whether it is an underlying cause of sudden cardiac death in these patients suggesting the need of further autopsy studies in SCD patients or studies on coronary microcirculation to determine the role of ischemia in RCM progression and death.…”