Narasimhan Calambur

An In Silico Analysis of Troponin I Mutations in Hypertrophic Cardiomyopathy of Indian Origin

Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disorder of the myocardium which is hypertrophied resulting in arrhythmias and heart failure leading to sudden cardiac death (SCD). Several sarcomeric proteins and modifier genes have been implicated in this disease. Troponin I, being a part of the Troponin complex (troponin I, troponin C, troponin T), is an important gene for sarcomeric function. Four mutations (1 novel) were identified in Indian HCM cases, namely, Pro82Ser, Arg98Gln, Arg141Gln and Arg162Gln in Troponin I protein, which are in functionally significant domains. In order to analyse the effect of the mutations on protein stability and protein-protein interactions within the Troponin complex, an in silico study was carried out. The freely available X-ray crystal structure (PDB ID: 1JIE) was used as the template to model the protein followed by loop generation and development of troponin complex for both the troponin I wild type and four mutants (NCBI ID: PRJNA194382). The structural study was carried out to determine the effect of mutation on the structural stability and protein-protein interactions between three subunits in the complex. These mutations, especially the arginine to glutamine substitutions were found to result in local perturbations within the troponin complex by creating/removing inter/intra molecular hydrogen bonds with troponin T and troponin C. This has led to a decrease in the protein stability and loss of important interactions between the three subunits. It could have a significant impact on the disease progression when coupled with allelic heterogeneity which was observed in the cases carrying these mutations. However, this can be further confirmed by functional studies on protein levels in the identified cases.

Novel mutations in arrhythmogenic right ventricular cardiomyopathy from Indian population

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive condition with right ventricular myocardium being replaced by fibro-fatty tissue. The spectrum of the expression may range from benign palpitations to the most malignant sudden death. Most of the mutations identified for the condition are localized in desmosomal proteins although three other nondesmosomal genes (cardiac ryanodine receptor-2, TGF-β3, and TMEM43) have also been implicated in ARVC. Both desmosomal and nondesmosomal genes were screened in a set of patients from local population. MATERIALS AND METHODS: A set of 34 patients from local population were included in this study. Diagnosis was based on the criteria proposed by task force of European Society of Cardiology/International Society and Federation of Cardiology. Polymerase chain reaction-based single-strand conformation polymorphism analysis was carried out, and samples with abnormal band pattern were commercially sequenced. RESULTS: Screening of cardiac ryanodine receptor revealed an insertion of a base in the intronic region of exon-28 in a patient, leading to a creation of a cryptic splice site. Screening of plakohilin-2 for mutations revealed an abnormal band pattern in three patients. Two of them had similar abnormal band pattern for exon-3.1. Sequencing revealed a novel 2 base pair deletion (433_434 delCT), which would lead to premature truncation of the protein (L145EfsX8). Another patient showed abnormal band pattern for exon-3.2 and sequencing revealed a missense mutation C792T leading to amino acid change P244L, in N-terminal, and this substitution may cause disturbances in the various protein–protein interactions. CONCLUSION: This study reports novel cardiac ryanodine receptor (RyR-2) mutations and Pkp-2 for the first time from Indian population.

Epicardial Ablation of Focal Atrial Tachycardia Arising From Left Atrial Appendage in Children

Focal left atrial tachycardia (FLAT) although a common cause of supraventricular tachycardia(SVT) among children, the ones arising from left atrial appendage (LAA) present a unique challenge for successful ablation because of anatomical location. We present two children with FLAT arising from the epicardial LAA, successfully mapped and ablated through percutaneuous epicardial approach.

Consensus statement on management of chronic heart failure in India

Summary of the Consensus Statement: This statement has been prepared keeping Indian heart failure patients in mind. Optimal management of CHF improves quality of life, reduces hospitalization rates and prolongs survival for people with this condition. Echocardiography is the single most useful test in the evaluation of heart failure, and is necessary to confirm the diagnosis. Plasma B-natriuretic peptide (BNP) measurements may be useful in excluding CHF but not mandatory in India. Educate people with CHF about lifestyle changes (e.g., increase physical activity levels, reduce salt intake and manage weight). Educate people with CHF about CHF symptoms and how to manage fluid load. Avoid prescribing drugs that exacerbate CHF. Prescribe angiotensin-converting enzyme inhibitors (ACEI) at effective doses for people with all grades of systolic heart failure, and titrate to the highest recommended dose tolerated. Angiotensin II receptor antagonists (ARA) may be used as alternatives in people who cannot tolerate ACEIs. Mineralocorticoid receptor antagonists (MRAs) should also be used. For people with stabilised systolic heart failure, prescribe beta-blockers that have been shown to improve outcome in heart failure (e.g., bisoprolol, carvedilol, extended release metoprolol or nebivolol). Titrate to the highest recommended dose tolerated. Prescribe diuretics, digoxin and nitrates for people already using ACEIs and beta-blockers to manage symptoms as indicated. For people who have systolic heart failure (New York Heart Association (NYHA) Class II-IV) despite appropriate doses of ACEIs and diuretics, consider prescribing spironolactone. Eplerenone can be considered in certain setting especially post myocardial infarction though it is more expensive. Consider direct sinus node inhibition with ivabradine for people with CHF who have impaired systolic function, have had a recent heart failure hospitalisation and are in sinus rhythm with a heart rate >70 bpm despite beta blockers or where beta blockers are contraindicated Check for, and treat, iron deficiency in people with CHF to improve their symptoms, exercise tolerance and quality of life Consider assessing people with CHF for biventricular pacemakers and implantable defibrillators. Patients with end stage heart failure have an option for heart transplant and ventricular assist devices which is now available in select centers.

Inappropriate Detection of a Supraventricular Tachycardia as Dual Tachycardia by the PR Logic™ Algorithm

Tachycardia detection and therapy algorithms in Implantable Cardioverter-Defibrillators (ICD) reduce, but do not eliminate inappropriate ICD shocks. Awareness of the pros and cons of a particular algorithm helps to predict its utility in specific situations. We report a case where PR logic™, an algorithm commonly used in currently implanted ICDs to differentiate supraventricular tachycardia (SVT) from ventricular tachycardia resulted in inappropriate detection and shock for an SVT, and discuss several solutions to the problem.

Novel compound heterozygous mutations of the myosin heavy chain gene in patients with hypertrophic cardiomyopathy

background: Hypertrophic cardiomyopathy (HCM) is a multifactorial disorder, with mutations implicated in 14 sarcomeric and cytoskeletal genes, leading to genotypic and phenotypic heterogeneity, and a challenging genetic and clinical diagnosis. The genetic characteristics of HCM have been studied for more than two decades in various ethnic and racial groups, and many novel genetic variations have been reported. The myosin heavy chain gene is the most heavily implicated gene in HCM, with >200 reported mutations, the majority of which have been found in the head-rod junction. The rod portion of MYH7, coded by exons 29 to 40 and belonging to the light meromyosin (LMM) region, has not been characterized to the same extent as the head domain with respect to single-nucleotide polymorphisms (SNPs)/mutations. OBJECTIVE: To screen the conserved LMM region, constituting exons 27 to 39 (13 exons), to identify any pathogenic SNPs/variations in this region in a population of Indian patients. Methods: Molecular screening was performed by polymerase chain reaction-based single-strand conformation polymorphism analysis in 100 control individuals and 100 HCM patients. The variations were confirmed by sequencing. Insilico analysis was performed to analyze the effect of the respective variations. Results : Screening of exons 27 to 39 revealed three novel missense variations and one novel synonymous variation in exon 34. Interestingly, patients with these variations also exhibited compound heterozygosity, indicating exon 34 to be the ‘hotspot’ exon of the LMM region. Conclusion: The results of the present study emphasize the importance of the LMM (rod) region of the MYH7 gene and suggest that variations in the conserved region are likely to be more pathogenic, making screening of the entire gene for HCM diagnosis mandatory.