Hypertrophic Cardiomyopathy: Genetic Foundations, Outcomes, Interconnections, and Their Modifiers

Abstract

Hypertrophic cardiomyopathy (HCM) is the most prevalent heritable cardiomyopathy. HCM is considered to be caused by mutations in cardiac sarcomeric protein genes. Recent research suggests that the genetic foundation of HCM is much more complex than originally postulated. The clinical presentations of HCM are very variable. Some mutation carriers remain asymptomatic, while others develop severe HCM, terminal heart failure, or sudden cardiac death. Heterogeneity regarding both genetic mutations and the clinical course of HCM hinders the establishment of universal genotype–phenotype correlations. However, some trends have been identified. The presence of a mutation in some genes encoding sarcomeric proteins is associated with earlier HCM onset, more severe left ventricular hypertrophy, and worse clinical outcomes. There is a diversity in the mechanisms implicated in the pathogenesis of HCM. They may be classified into groups, but they are interrelated. The lack of known supplementary elements that control the progression of HCM indicates that molecular mechanisms that exist between genotype and clinical presentations may be crucial. Secondary molecular changes in pathways implicated in HCM pathogenesis, post-translational protein modifications, and epigenetic factors affect HCM phenotypes. Cardiac loading conditions, exercise, hypertension, diet, alcohol consumption, microbial infection, obstructive sleep apnea, obesity, and environmental factors are non-molecular aspects that change the HCM phenotype. Many mechanisms are implicated in the course of HCM. They are mostly interconnected and contribute to some extent to final outcomes.

Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review

“…HCM is a complex disorder that results from a combination of genetic and non-genetic factors. ( Figure 2 ) [ 2 , 31 , 32 ]. Additionally, metabolic alterations and mitochondrial dysfunction can give rise to this pathology as primary disorders or secondary conditions to the primary etiology.…”

Transcriptomics data integration and analysis to uncover hallmark genes in hypertrophic cardiomyopathy

“…Hypertrophic cardiomyopathy (HCM), a complex cardiovascular genetic disorder, is reported in one out of every 500 individuals worldwide [1,2]. In recent years, awareness of HCM has significantly improved in clinical settings [3,4].…”

“…It is important here to understand that HCM has various genotypic and phenotypic variations. HCM was linked with approximately 1400 genetic mutations across more than 10 genes responsible for producing cardiac sarcolemmal protein [2]. Mostly, HCM developed due to a single heterozygous mutation [14,15].…”