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Hypertrophic Cardiomyopathy
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Ahmad Masri, Stephen B. Heitner
The vast majority of mutations in HCM affect sarcomeric proteins, with ~70% involving genes encoding cardiac β-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC). Actin-myosin cross-bridging is an active process which results in muscle fiber shortening. Mutations in MYH7 are known to affect the activity of the myosin ATPase unit, leading to increased myocardial force generation, whereas MYBPC plays a role in sarcomere organization and may serve as a brake on myofibril contraction.80,81 Therefore, HCM mutations lead to a hypercontractile state with subsequent LV stiffening. Mavacamten, a first-in-class oral small molecule, targets this process by modulating cardiac β-myosin and causing reversible inhibition of actin-myosin cross-bridging.82,83 In animal models, treatment with mavacamten reduced contractility, eliminated SAM, relieved LVOT obstruction,84 and improved the myocardial pressure-volume relationship.85 Moreover, in a histologic study, treatment with mavacamten resulted in attenuation of the HCM phenotype with suppression of hypertrophy, cardiomyocyte disarray, and profibrotic gene expression.86
Genetics and Genetic Testing in Hypertrophic Cardiomyopathy
Published in Srilakshmi M. Adhyapak, V. Rao Parachuri, Hypertrophic Cardiomyopathy, 2020
Hypertrophic cardiomyopathy is caused by dominant mutations in 11 or more genes which encode thick and thin contractile myofilament protein components of the sarcomere or the adjacent Z-disk (Figures 2.1 and 2.3) [9–12]. Seventy percent of the mutations are in two genes – the β-myosin heavy chain (MYH7) and the myosin-binding protein C (MYBPC3). To underscore the vast genetic heterogeneity of HCM, over the past 20 years more than 1,400 mutations (largely missense) have been identified [8, 9]. Pathogenic mutations that cause HCM are transmitted in an autosomal dominant pattern; every offspring of an affected relative has a 50% chance of inheritance and risk of developing disease [9–13], although sporadic cases do arise due to de novo mutations. Phenotypic heterogeneity is evident between and within families, suggesting that mutations of the sarcomere are not the sole determinant of the HCM phenotype. Age-related penetrance may result in the delayed appearance of LVH in the third decade and beyond [14, 15]. Therefore, HCM can be considered as one heterogeneous disease entity rather than a conglomeration of similar but unrelated disorders [12–15].
What role for genetic testing in sport?
Published in Silvia Camporesi, Mike McNamee, Bioethics, Genetics and Sport, 2018
Silvia Camporesi, Mike McNamee
The first chromosome locus for the familial form of HCM and subsequent mutations involving the MYH7 (beta-myosin heavy chain) were associated with the aetiology of the condition more than 20 years ago (Marian et al. 1995). Since then, hundreds of mutations in more than 30 genes encoding different proteins related to the cardiac muscle have been identified (Bos et al. 2009). HCM is not a rare disorder. It affects 1 in 500 people and is characterised by extreme heterogeneity, both at the genotype and phenotype level and at the clinical course level: symptoms range from null to dyspnea or angina pectoris refractory to pharmacological treatment, to sudden death as the first and only symptom (Maron 2002; Bos et al. 2009).
Prenatal Diagnosis of Isolated Right Ventricular Non-Compaction Cardiomyopathy with an MYH7 Likely Pathogenic Variant
Published in Fetal and Pediatric Pathology, 2023
Weiming Yu, Mary Ann Thomas, Lindsay Mills, James R. Wright
MYH7 (myosin heavy chain 7) is the most commonly associated gene in NVM [10]. The gene encodes β myosin heavy chain protein, which is expressed predominantly in normal human ventricle, and also expressed in type I skeletal muscle fibers. More than 200 mutations have been described in MYH7. Mutations are distributed throughout the gene but are predominantly clustered in the head region [11]. Pathogenic variants of MYH7 gene are considerably heterogeneous, different variants within the same sarcomere gene can result in both overlapping and divergent clinical manifestations. MYH7 mutations are associated with 13%-20% of cases of LVNC, 16% of cases of hypertrophic cardiomyopathy, 4%-5% cases of dilated cardiomyopathy, and also include myosin storage myopathy and Laing early-onset distal myopathy [11,17].
Sudden cardiac arrest as the initial presentation for left ventricular noncompaction cardiomyopathy
Published in Baylor University Medical Center Proceedings, 2019
Avaneesh Jakkoju, Rakesh Jakkoju, Vishnupriya Kuchana, Pedro R. Cox-Alomar, Frank W. Smart, D. Luke Glancy
Although LVNC had been described in patients with other congenital cardiac malformations and in a variety of muscular dystrophies, isolated LVNCC was initially described in eight patients by Chin et al in 1990.3 LVNC with or without LV dysfunction has been found in 0.14% to 0.26% of patients referred for echocardiography.4,5 Both sporadic and familial mutations have been described for LVNC. Familial mutations are most often autosomal dominant, and in rare cases inheritance has been X linked.6 Several familial mutations have been reported in genes responsible for sarcomeric and mitochondrial proteins. Beta myosin heavy chain (MYH7), alpha-cardiac actin (ACTC), cardiac troponin T (TNNT2), troponin I (TNN13), SCN5A, and G4.5 are some of the familial mutations that have been described.6,7 Murphy et al screened asymptomatic first-degree family members with echocardiography and found 25% of the screened population to have echocardiographic abnormalities, which included LVNC, enlarged LV diameter, and noncompaction of posterior wall that did not meet criteria for LVNC.8
Gene expression and gene associations during the development of heart failure with preserved ejection fraction in the Dahl salt sensitive model of hypertension
Published in Clinical and Experimental Hypertension, 2018
Jeffrey Yim, Hyokeun Cho, Simon W. Rabkin
Although our study is a comprehensive review of the gene profiling in salt-induced HF, there are several limitations that warrant discussion. First, we were not able to include relevant data from all published studies. Some studies did not provide the full dataset, standard error, or present data in a way that allowed data extraction. This is a traditional issue with meta-analysis studies. Second, this review only discusses qRT-PCR and Northern blot gene expression results. It does not address information derived from RNAseq expression analysis, alternative gene spliced transcripts, post-transcriptional modifications, or mutations/SNPs. Third, our study focused only on gene expression and did not examine protein expression. However, there is ample evidence that the genes identified have altered protein expression in the Dahl rat, such as p47phox, p22phox, gp91phox, and eNOS (84). MYH7 protein expression in patients with HF was significantly higher than control (85). Finally, the quality of any meta-analysis is dependent on the quality of the individual studies that were included in the review.