Understanding the Genetic and Molecular Basis of Familial Hypertrophic Cardiomyopathy and the Current Trends in Gene Therapy for Its Management.

Roshini Pradeep,Jihan A Mostafa,Matthew C Proute,Tatsiana Serhiyenia,Petros Georgiou,Mina E Kerolos,Aqsa Akram,Wangpan Shi,Nageshwar R Kothur

doi:10.7759/cureus.17548

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetically acquired disease of cardiac myocytes. Studies show that 70% of this disease is a result of different mutations in various sarcomere genes. This review aims to discuss several genetic mutations, epigenetic factors, and signal transduction pathways leading to the development of HCM. In addition, this article elaborates on recent advances in gene therapies and their implications for managing this condition. We start by discussing the founding mutations in HCM and their effect on power stroke generation. The less explored field of epigenetics including methylation, acetylation, and the role of different micro RNAs in the development of cardiac muscle hypertrophy has been highlighted in this article. The signal transduction pathways that lead to gene transcription, which in turn lead to increased protein synthesis of cardiac muscle fibers are elaborated. Finally, the microscopic events leading to the pathophysiologic macro events of cardiac failure, and the current experimental trials of gene therapy models, and the clustered regularly interspaced short palindromic repeats (CRISPR) type 2 system proteins, are discussed. We have concluded our discussion by emphasizing the need for more studies on epigenomics and experimental designs for gene therapy in HCM patients. This review focuses on the process of HCM from initial mutation to the development of phenotypic expression and various points of intervention in cardiac myocardial hypertrophy development.

Highlights

BackgroundHypertrophic cardiomyopathy (HCM), with its mortality of six percent annually, is an autosomal dominant disease due to sarcomeric-related gene mutations
This review aims to discuss several genetic mutations, epigenetic factors, and signal transduction pathways leading to the development of HCM
The less explored field of epigenetics including methylation, acetylation, and the role of different micro RNAs in the development of cardiac muscle hypertrophy has been highlighted in this article

Summary

Introduction

Hypertrophic cardiomyopathy (HCM), with its mortality of six percent annually, is an autosomal dominant disease due to sarcomeric-related gene mutations. Some of these include angiotensin 2 receptor type 1 (AGTR1), transforming growth factor (TGF) β, and fatty acid-binding protein (FABP) 3 [1,43]. The mutations and a complex hierarchy of epigenetics and environmental factors are determinants of the clinical expression of the disease (Figure 2) We show that genetic penetrance, genetic modifiers, epigenetic factors (DNA methylation, deacetylation, and miRNA expression), and environmental factors play a regulatory role after the initial mutation and determine the downstream effects, including signal transduction, alteration in sarcomere properties, cellular energy metabolism, and calcium hemostasis. We cannot deny that studies such as these have led us to explore the effect of CRISPR/Cas in treating human germline mutation, which is most likely going to be the cutting edge technology in finding a definitive cure for hereditary diseases such as HCM

Conclusions

Disclosures

33. Marian AJ

Findings

41. Bartel DP