Genetic determinants of myocardial dysfunction

Abstract

Heart failure (HF) is a major killer with high morbidity and mortality and nearly 37.7 million people are affected by HF globally, making this a global epidemic. HF is a complex pathophysiological syndrome in which the mechanical function of heart for pumping blood is compromised. Cardiac structural and functional abnormalities culminate in decreased cardiac output along with increased intracardiac pressures under resting or stress conditions, leading to HF. Besides the acquired risk factors, the independent role of hereditary and genetic factors in the development, progression and prognosis of HF remains to be established. One of the most common causes of HF is cardiomyopathy and dilated cardiomyopathy and hypertrophic cardiomyopathy are the major forms, transmitted by autosomal dominant inheritance and often result from mutations in single or multiple genes, which predominantly code for proteins present in the cardiac sarcomere. Other inherited forms of cardiomyopathies that can trigger HF are metabolic and mitochondrial cardiomyopathies that result from mutations in proteins involved in fat or carbohydrate metabolism or mitochondrial biogenesis, affecting cardiomyocyte energy balance. Because of the inherent complications in the aetiology of HF, only a small number of genome-wide association studies (GWAS) could be conducted to identify SNPs in genes that are causally related to HF. Recent attempts to conduct GWAS in a focused approach on the HF risk factors led to identification of more SNPs. Initial attempts for gene therapy using adeno-associated viral vectors have not been successful, but more studies are needed to understand the pathophysiological and genetic basis of HF.

Keywords: Cardiovascular Medicine; Clinical genetics; Congenital heart disease; Gene therapy; Genetics.