Molecular Genetic Basis of Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium characterized by a hypertrophic left ventricle with a preserved or increased ejection fraction. Cardiac hypertrophy is often asymmetrical, which is associated with left ventricular outflow tract obstruction. Myocyte hypertrophy, disarray, and myocardial fibrosis constitute the histological features of HCM. HCM is a relatively benign disease but an important cause of sudden cardiac death in the young and heart failure in the elderly. Pathogenic variants (PVs) in genes encoding protein constituents of the sarcomeres are the main causes of HCM. PVs exhibit a gradient of effect sizes, as reflected in their penetrance and variable phenotypic expression of HCM. MYH7 and MYBPC3 , encoding β-myosin heavy chain and myosin binding protein C, respectively, are the two most common causal genes and responsible for ≈40% of all HCM cases but a higher percentage of HCM in large families. PVs in genes encoding protein components of the thin filaments are responsible for ≈5% of the HCM cases. Whereas pathogenicity of the genetic variants in large families has been firmly established, ascertainment causality of the PVs in small families and sporadic cases is challenging. In the latter category, PVs are best considered as probabilistic determinants of HCM. Deciphering the genetic basis of HCM has enabled routine genetic testing and has partially elucidated the underpinning mechanism of HCM as increased number of the myosin molecules that are strongly bound to actin. The discoveries have led to the development of mavacamten that targets binding of the myosin molecule to actin filaments and imparts beneficial clinical effects. In the coming years, the yield of the genetic testing is expected to be improved and the so-called missing causal gene be identified. The advances are also expected to enable development of additional specific therapies and editing of the mutations in HCM.

Inflammation‐induced left ventricular fibrosis is partially mediated by tumor necrosis factor‐α

“…Although, increased deposition of collagen I and collagen III in pro-fibrotic tissues is associated with a less compliant cardiac extracellular matrix, collagen I is more fibrillar and dense in composition compared to the weaker and less mature collagen III (Husse et al, 2007;Querejeta et al, 2004). We also showed increased expression of Myh7, which codes for the βmyosin heavy chain, a well-known marker of cardiac hypertrophy (Marian, 2021) that has also been localized to areas of fibrosis in the heart (Pandya et al, 2006). However, we showed that only expression of Col1 was associated with increased RWT.…”

Single-Cell Analysis Revealed the Role of CD8+ Effector T Cells in Preventing Cardioprotective Macrophage Differentiation in the Early Phase of Heart Failure

“…To confirm the presence of the cardioprotective hypertrophy in the early stages after TAC, we performed RNAseq analysis on isolated cardiomyocytes 2 weeks after TAC treatment ( Figure 2A ). Sarcomeric cardiac β-myosin heavy chain gene ( Myh7) has been shown to be associated with myocardial hypertrophy ( 16 , 17 ). Natriuretic Peptide A ( Nppa ) has secreted by cardiac stretch stimulation, and collagen type I alpha 1 Chain ( Col1a1) is a marker of subsequent fibrosis ( 13 ).…”

Reconnoitering the Role of Long-Noncoding RNAs in Hypertrophic Cardiomyopathy: A Descriptive Review

“…Most variations occur in genes that are responsible for normal functioning of contractile sarcomeric proteins: troponin I and T, myosin binding protein C, myosin heavy and light chains, α-actin, titin and α-tropomyosin. Nevertheless, in rare cases, variations in non-sarcomeric protein coding genes have also been reported in HCM patients [19]. The genes predominantly related to the HCM development are TNNT2, MYH7, MYBPC3, ACTC1, TPMI, TNNI3, TNNC1, TNNC2, MYL2, MYL3, CSRP3, and MYOZ2 (Figure 2 and Table 1) [20].…”