Session 06 : Cardiomyopathy

Long term outcomes of dilated cardiomyopathy patients

posted Jan 26, 2017, 1:34 AM by sourav ghosh

Ajay Bahl
Department of cardiology, PGIMER, Chandigarh, India

Long term outcomes of patients with dilated cardiomyopathy (DCM) have improved with medical therapy. In our cohort, with currently recommended medical therapy, one-fourth patients with non-ischemic DCM had sustained improvement, and over one-third of those who improved, relapsed. QRS duration predicted both recovery and relapse. Survival of patients in the improved group was significantly better than the non-improved groups. 
Forty DCM patients in our cohort who were very long term survivors were studied. These patients had survived for more than 10 years from initial diagnosis. A significant number of patients (45%) among this cohort had sustained recovery in ejection fraction and a large majority of our patients (90%) were either in NYHA class I or II at the end of study period. Narrow QRS at baseline, younger age at onset, smaller left atrial diameter, smaller left ventricular end diastolic diameter and lower grade of mitral regurgitation and pulmonary arterial hypertension were significant parameters in predicting good long-term outcomes. 

Genetic Basis of Idiopathic Cardiomyopathies

posted Jan 26, 2017, 1:33 AM by sourav ghosh

Madhu Khullar
Department of Experimental Medicine & Biotechnology, PGIMER, Chandigarh, India

Idiopathic cardiomyopathies are a heterogeneous group of diseases of the myocardium and are responsible for significant morbidity and mortality and leading indication for heart failure and transplant. Idiopathic cardiomyopathies are due to a variety of causes that frequently are genetic. Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and estrictive cardiomyopathy (RCM) are the major types of cardiomyopathies caused by mutant sarcomeric and non sarcomeric genes. Myosin Heavy Chain (MYH7), Myosin Binding Protein C (MYBPC3), Troponin T (TNNT2) and Troponin I (TNNI3) are frequently mutated genes in cardiomyopathy. Several of the mutant genes linked to DCM encode the same contractile sarcomeric proteins that are responsible for HCM; however, mutations in other genes encoding cytoskeletal/sarcolemmal, nuclear envelope, sarcomere, and transcriptional coactivator proteins like lamin A/C, dystrophin, desmin, caveolin, sarcoglycan, as well as the mitochondrial respiratory chain gene have been also observed. Despite advances in technology for detection of gene variants such as next generation sequencing, causal genes of cardiomyopathies remain to be identified in approximately 1/3rd of patients. Genotype-phenotype studies have shown large clinical variability and genetic heterogeneity among cardiomyopathy patients which is not solely associated with the causal mutations. Clinical phenotypes are also likely to be modified by age, sex hormones, diet and polymorphisms in many genes. Characterization and mechanistic study of cardiomyopathies are therefore challenging due to the complex protein structures, the multitude of disease-causing mutations, and modulations of pathology by genetic background.

Evaluating the combined effect of insulin like growth factor-1, transforming growth factor-ß and fibroblast growth factor on cardiac progenitor stem cells: Implications in regenerative therapeutics of acute myocardial infarction

posted Jan 26, 2017, 1:30 AM by sourav ghosh   [ updated Jan 26, 2017, 5:32 AM ]

Gururao Hariprasad
1 Department of Biophysics, 2 Department of Stem cell facility, 3 Department of Cardio Thoracic Vascular Surgery, 4 Department ofPharmacology, 5 Department ofNuclear Magnetic Resonance, 6 Department ofPathology, All India Institute of Medical Science, New Delhi, India.

Background of the Study: Cardiac stem cells trigger paracrine mechanisms mediated by cytokines that repair infracted tissue and certain cytokines in turn bestow stem cells with effective regenerative functions. We have sought to study the effect of growth factor cocktail on cardiac progenitor stem cells, and the translational value of administering growth factors along side cardiac stem cells in animal myocardial infarction models. 
Methods and Results: Cardiac stem cells were isolated from the hearts of twelve laboratory-bred female Wistar albino rats. Stem cell progeny was confirmed by flowcytometry studies and cardiac progeny was established by Immuno-electro fluorescence studies using troponin antibody. Cultured stem cells grown in the presence and absence of growth factor cocktail was compared by inverted phase contrast microscopy for cellular morphology, MTT assay for proliferative functions and, DIGE coupled with mass spectrometric experiments to delineate possible cellular pathways. Animal experiments included injecting saline, growth factors, stem cells, and combination of stem cell and growth factor cocktail in four groups of myocardial infarction rat models. Myocardial infarction was established by magnetic resonance imaging, and post-intervention follow up studies was done for four weeks by two-dimensional M-mode echocardiography. Cells grown with growth factors were seen to have distinct cardiac morphology showing elongated cells with branching fibers and centrally placed nucleus; functionally these showed 30% increase viability, and had over expression of proteins which are known to confer cardiac protection and counter oxidative stress. Rats that received combination therapy showed significant improvement in fractional shortening, stroke volume, ejection fraction and left ventricular internal dimension as compared to rats that received individual therapy of either saline, stem cells or growth factors alone. 
Conclusions: Insulin like growth factor-1, transforming growth factor-ß and fibroblast growth factors confer distinct advantages are in terms of growth, differentiation, proliferation and cell cycle signaling. These benefits have a clear translational value in regenerative therapeutics of myocardial infarction.

Differential expression and regulation of anti- hypertrophic genes Npr1 and Npr2 during β- adrenergic receptor activation- induced hypertrophic growth in rats

posted Jan 26, 2017, 1:28 AM by sourav ghosh

Elangovan Vellaichamy
Peptide Research and Molecular Cardiology Unit, Department of Biochemistry, University of Madras, Guindy campus, Chennai, India

The natriuretic peptides (NPs) family is consists of three important peptides namely atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP).ANP and BNP elicits its physiological action by specific binding to Natriureitc Peptide Receptor-A/Guanylyl cyclase-A (NPR-A/GC-A), while CNP binds to Natriureitc Peptide Receptor-B/ Guanylyl cyclase-B (NPR-B/ GC-B).Recent studies have suggested that ANP/NPR-A/GC-Aand CNP/NPR-B/GC-B system are present in the heart as a negative regulatory mechanisms to antagonize the cardiac growth response to hypertrophic stimuli.Since NPs has the potential to inhibit cardiac hypertrophic growth via NPR-A/NPR-B receptors, understanding the regulation and expression of NPR-A and –Bin the heart during the diseased conditions will help to target specific NPRs subtype to increase the physiological actions of NPs, and thus may be useful as therapy for cardiac hypertrophy and heart failure. In this context, we have studiedleft ventricular (LV) expression ofNPR-A (coded by Npr1) and NPR-B (coded by Npr2), and the functional activity of these receptors during β-adrenergic receptor (β-AR) activation induced hypertrophic growth in experimental rats. The NPR-A expression was markedly reduced (3.5-fold), while the NPR-B expression was up regulated (4-fold) in Isoproterenol (ISO)-treated heart as compared with controls.. Further, in-vitro membranes assay shows that NPR-A dependent guanylyl cyclase (GC) activity was down-regulated (2-fold), whereas NPR-B dependent GC activity was increased (5-fold) in ISO treated hearts. β –blocker (atenolol) treatment normalized the altered expression ofNPR-A and –B proteins. Our results suggests that the chronic β-AR activation differentially regulates NPR-A/GC-A and NPR-B/GC-Bin the heart. The signifcance of this finding will be discussed during the presentation.

Cardiomyopathy: genetic and evolutionary perspectives

posted Jan 26, 2017, 1:25 AM by sourav ghosh

K. Thangaraj
Centre for Cellular and Molecular Biology, Uppal Road Hyderabad, India

Cardiomyopathy due to sarcomeric gene mutations is a major cause for heart failure. However, its genetic etiology remains largely unknown, particularly in Indian subcontinent. Therefore, we have analysed sarcomeric genes, including; MYBPC3, TNNT2, TNNI3, TPM1 and MYH7 in dilated (DCM) and hypertropic cardiomypathy (HCM). We found a 25 bp deletion in the MYBPC3 that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (OR = 6.99 (3.68– 13.57), P = 4 X 10-11) and that disrupts cardiomyocyte structure in vitro. We have also screened for this mutation in different ethnic populations, who are inhabiting all the continent and found its prevalence was high (~ 4%) in populations of Indian subcontinent. We further estimated that more than 55 million people are at risk worldwide, almost 1% of the world’s population. Whereas, other mutations are either in low frequency or private, affection only single family. Apart from sarcomeric genes, we discovered rare, functional RAF1 mutations in 3 cohorts (South Indian, North Indian and Japanese). Remarkably, we found these mutations only in childhood-onset DCM. Detailed genetic study and why the frequencies of disease causing variations are different in India would be discussed at the time of presentation.

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