A Contraction Stress Model of Hypertrophic Cardiomyopathy due to Sarcomere Mutations.
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ABSTRACT:
SUBMITTER: Cohn R
PROVIDER: S-EPMC6335568 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundSarcomere protein mutations in hypertrophic cardiomyopathy induce subtle cardiac structural changes before the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic hypertrophic cardiomyopathy pre-LVH (genotype positive, LVH negative [G+LVH-]).Methods and resultsA multicenter case-control study investigated crypts and 22 other cardiovascular magnetic resonance parameters in subclinical hypertrophic cardiomyopathy to determine their strength of association with sarcomere gene mutation carriage. The G+LVH- sample (n=73) was 29 ± 13 years old and 51% were men. Crypts were related to the presence of sarcomere mutations (for ≥1 crypt, β=2.5; 95% confidence interval [CI], 0.5-4.4; P=0.014 and for ≥2 crypts, β=3.0; 95% CI, 0.8-7.9; P=0.004). In combination with 3 other parameters: anterior mitral valve leaflet elongation (β=2.1; 95% CI, 1.7-3.1; P<0.001), abnormal LV apical trabeculae (β=1.6; 95% CI, 0.8-2.5; P<0.001), and smaller LV end-systolic volumes (β=1.4; 95% CI, 0.5-2.3; P=0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95% CI, 0.8-0.9). In this G+LVH- population, cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared with the other combined mutations (47 versus 23%; odds ratio, 2.9; 95% CI, 1.1-7.9; P=0.045).ConclusionsThe subclinical hypertrophic cardiomyopathy phenotype measured by cardiovascular magnetic resonance in a multicenter environment and consisting of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and smaller LV systolic cavity is indicative of the presence of sarcomere gene mutations and highlights the need for further study.
| S-EPMC4237712 | biostudies-literature
Project description:Significance: Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by left ventricular hypertrophy, diastolic dysfunction, and myocardial disarray. Disease onset occurs between 20 and 50 years of age, thus affecting patients in the prime of their life. HCM is caused by mutations in sarcomere proteins, the contractile building blocks of the heart. Despite increased knowledge of causal mutations, the exact path from genetic defect leading to cardiomyopathy is complex and involves additional disease hits. Recent Advances: Laboratory-based studies indicate that HCM development not only depends on the primary sarcomere impairment caused by the mutation but also on secondary disease-related alterations in the heart. Here we propose a vicious mutation-induced disease cycle, in which a mutation-induced energy depletion alters cellular metabolism with increased mitochondrial work, which triggers secondary disease modifiers that will worsen disease and ultimately lead to end-stage HCM. Critical Issues: Evidence shows excessive cellular reactive oxygen species (ROS) in HCM patients and HCM animal models. Oxidative stress markers are increased in the heart (oxidized proteins, DNA, and lipids) and serum of HCM patients. In addition, increased mitochondrial ROS production and changes in endogenous antioxidants are reported in HCM. Mutant sarcomeric protein may drive excessive levels of cardiac ROS via changes in cardiac efficiency and metabolism, mitochondrial activation and/or dysfunction, impaired protein quality control, and microvascular dysfunction. Future Directions: Interventions restoring metabolism, mitochondrial function, and improved ROS balance may be promising therapeutic approaches. We discuss the effects of current HCM pharmacological therapies and potential future therapies to prevent and reverse HCM. Antioxid. Redox Signal. 31, 318-358.
| S-EPMC6602117 | biostudies-literature
Project description:BackgroundLeft atrial (LA) enlargement and dysfunction are related to clinical course in patients with hypertrophic cardiomyopathy (HCM). We aimed to investigate genetic contribution to LA structural and functional remodeling.MethodsTwo hundred twelve patients were consecutively enrolled, and echocardiography and extensive genetic analysis were performed. Cardiac magnetic resonance (CMR) was performed in 135 patients. Echocardiography was also performed in controls (n = 30).ResultsPatients with HCM had lower late-diastolic mitral annular velocity (a') and higher LA volume index (LAVI) than controls. Patients with pathogenic or likely pathogenic sarcomere gene mutations (PSM, n = 67, 32%) had higher LAVI and lower CMR-derived LA total emptying fraction (37.0 ± 18.5 vs. 44.2 ± 12.4%, p = 0.025). In patients without AF (n = 187), the PSM had lower a' (6.9 ± 2.0 vs. 7.8 ± 1.9 cm/s, p = 0.004) than others. The PSM had higher prevalence and amount of late gadolinium enhancement (LGE) in the left ventricle (LV). In multivariate analysis, PSM was significantly related to lower a' independent of E/e', LV mass index, and LAVI. However, the relation significantly attenuated after adjustment for the extent of LGE in the LV, suggesting common myopathy in the LV and LA. In addition, PSM was significantly related to lower LA total emptying fraction independent of age, E/e', s', LV ejection fraction, LV myocardial global longitudinal strain and %LGE mass.ConclusionsPSM was related to LA dysfunction independent of LV filling pressure and LAVI, suggesting its contribution to atrial myopathy in HCM.
| S-EPMC7789152 | biostudies-literature
Project description:Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Previous studies demonstrated that impaired relaxation develops before left ventricular hypertrophy (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear.Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68 preclinical (G+/LVH-), 40 overt (G+/LVH+) subjects with HCM, and 38 mutation (-) normal control relatives. All subjects had normal left ventricular ejection fraction. In preclinical HCM, global and regional peak systolic strain (epsilon(sys)) and longitudinal systolic strain rate were not significantly different from controls, but early diastolic mitral annular velocity (Ea) was reduced by 13%. In overt HCM, there was a significant 27% and 14% decrease in global longitudinal epsilon(sys) and systolic strain rate, respectively, compared with both preclinical HCM and controls (P<0.013 for all comparisons), and a 33% reduction in Ea.Sarcomere mutations have disparate initial effects on diastolic and systolic functions. Preclinical HCM is characterized by impaired relaxation but preserved systolic strain. In contrast, both diastolic and longitudinal systolic abnormalities are present in overt disease despite normal ejection fraction. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathological remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention.
| S-EPMC2773504 | biostudies-literature
Project description:BackgroundMyocardial fibrosis is an important prognostic factor in hypertrophic cardiomyopathy (HCM). However, the contribution from a wide spectrum of genetic mutations has not been well defined. We sought to investigate effect of sarcomere and mitochondria-related mutations on myocardial fibrosis in HCM.MethodsIn 133 HCM patients, comprehensive genetic analysis was performed in 82 nuclear DNA (33 sarcomere-associated genes, 5 phenocopy genes, and 44 nuclear genes linked to mitochondrial cardiomyopathy) and 37 mitochondrial DNA. In all patients, cardiovascular magnetic resonance (CMR) was performed, including 16-segmental thickness, late gadolinium enhancement (LGE), native and post-T1, extracellular volume fraction (ECV), and T2, along with echo-Doppler evaluations.ResultsPatients with sarcomere mutation (SM, n = 41) had higher LGE involved segment, % LGE mass, ECV and lower post-T1 compared to patients without SM (n = 92, all p < 0.05). When classified into, non-mutation (n = 67), only mitochondria-related mutation (MM, n = 24), only-SM (n = 36) and both SM and MM (n = 5) groups, only-SM group had higher ECV and LGE than the non-mutation group (all p < 0.05). In non-LGE-involved segments, ECV was significantly higher in patients with SM. Within non-SM group, patients with any sarcomere variants of uncertain significance had higher echocardiographic Doppler E/e' (p < 0.05) and tendency of higher LGE amount and ECV (p > 0.05). However, MM group did not have significantly higher ECV or LGE amount than non-mutation group.ConclusionsSMs are significantly related to increase in myocardial fibrosis. Although, some HCM patients had pathogenic MMs, it was not associated with an increase in myocardial fibrosis.
| S-EPMC7931545 | biostudies-literature
Project description:BackgroundPredictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM.ObjectivesThe aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers.MethodsThis was a retrospective analysis of adult and pediatric SP mutation carriers identified during family screening who did not fulfill diagnostic criteria for HCM at first evaluation.ResultsThe authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n = 123 (43.2%), MYH7 n = 69 (24.2%), TNNI3 n = 39 (13.7%), TNNT2 n = 34 (11.9%), TPM1 n = 9 (3.2%), MYL2 n = 6 (2.1%), ACTC1 n = 1 (0.4%), multiple mutations n = 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up was 46% (95% confidence interval [CI]: 38% to 54%). In a multivariable model adjusted for age and stratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91; 95% CI: 1.82 to 4.65) and abnormal electrocardiogram (ECG) (HR: 4.02; 95% CI: 2.51 to 6.44); TNNI3 variants had the lowest risk (HR: 0.19; 95% CI: 0.07 to 0.55, compared to MYBPC3).ConclusionsFollowing a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up. Male sex and an abnormal ECG are associated with a higher risk of developing HCM. Regular CMR should be considered in long-term screening.
| S-EPMC7397507 | biostudies-literature
Project description:BackgroundHeterozygous mutations in sarcomere genes in hypertrophic cardiomyopathy (HCM) are proposed to exert their effect through gain of function for missense mutations or loss of function for truncating mutations. However, allelic expression from individual mutations has not been sufficiently characterized to support this exclusive distinction in human HCM.Methods and resultsSarcomere transcript and protein levels were analyzed in septal myectomy and transplant specimens from 46 genotyped HCM patients with or without sarcomere gene mutations and 10 control hearts. For truncating mutations in MYBPC3, the average ratio of mutant:wild-type transcripts was ≈1:5, in contrast to ≈1:1 for all sarcomere missense mutations, confirming that nonsense transcripts are uniquely unstable. However, total MYBPC3 mRNA was significantly increased by 9-fold in HCM samples with MYBPC3 mutations compared with control hearts and with HCM samples without sarcomere gene mutations. Full-length MYBPC3 protein content was not different between MYBPC3 mutant HCM and control samples, and no truncated proteins were detected. By absolute quantification of abundance with multiple reaction monitoring, stoichiometric ratios of mutant sarcomere proteins relative to wild type were strikingly variable in a mutation-specific manner, with the fraction of mutant protein ranging from 30% to 84%.ConclusionsThese results challenge the concept that haploinsufficiency is a unifying mechanism for HCM caused by MYBPC3 truncating mutations. The range of allelic imbalance for several missense sarcomere mutations suggests that certain mutant proteins may be more or less stable or incorporate more or less efficiently into the sarcomere than wild-type proteins. These mutation-specific properties may distinctly influence disease phenotypes.
| S-EPMC4254656 | biostudies-literature
Project description:AimsMitral valve (MV) abnormalities are recognized features of hypertrophic cardiomyopathy (HCM), and there is preliminary evidence suggesting they are intrinsic phenotypic manifestations of sarcomere mutations, present in mutation carriers without left ventricular (LV) hypertrophy (subclinical HCM). However, further study is required to characterize the nature of these changes and their functional impact. Thus, we performed comprehensive echocardiographic analysis of MV structure and function on a genotyped population.Methods and resultsMV and papillary muscle echocardiographic parameters were measured in 192 genotyped individuals, including 50 overt HCM, 79 subclinical HCM, and 63 mutation-negative, healthy relatives as normal controls. Compared to controls, subclinical HCM subjects had elongated anterior MV leaflets relative to LV end-diastolic volume index (0.57 ± 0.02 vs. 0.51 ± 0.02 mm/mL/m2, P = 0.013) and anteriorly displaced papillary muscles [decreased papillary-septal separation (31.1 ± 0.7 vs. 34.2 ± 0.9 mm, P = 0.004) and relative antero-posterior position ratio of the papillary muscles (0.67 ± 0.01 vs. 0.71 ± 0.01, P = 0.011]. Similar findings were identified comparing overt HCM to controls. These MV changes were associated with an increased prevalence of systolic anterior motion (SAM) of the MV amongst subclinical HCM subjects.ConclusionsSarcomere mutations are associated with primary abnormalities of the MV apparatus, specifically excess anterior leaflet length relative to LV cavity size and anterior displacement of the papillary muscles; both features predisposing to SAM. These abnormalities appear to be early phenotypic consequences of sarcomere mutations, observed in mutation carriers with normal LV wall thickness.
| S-EPMC6148328 | biostudies-literature
Project description:The sarcomeres form the molecular motor of the cardiomyocyte and consist of a complex multi-protein of thick and thin filaments which are anchored to the cytoskeleton. The thick filament, composed of myosin and associated proteins, and the thin filament composed of actin, tropomyosin and the troponins develop actinmyosin crossbridges which cycle in response to calcium resulting in sliding of the filaments and contraction. The thin filament in fixed to the cardiomyocyte cytoskeleton at the Z-disc, a complex of structural and regulatory proteins. A giant protein, titin, provides an external scaffold and regulates passive force in diastole. Both genetic disorders and acquired conditions may affect proteins of the sarcomere. Genetic disorders of the thick and thin filament proteins are the predominant cause of hypertrophic cardiomyopathy. These mutations lead to abnormal sarcomere function, often an enhanced sensitivity to calcium, and impaired relaxation. This may result in secondary changes in calcium cycling and amplification of hypertrophic signaling cascades. Correcting the abnormal function of the sarcomere as well as intervening in later stages of the pathophysiologic cascades may ameliorate disease. In dilated cardiomyopathy genetic abnormalities in the sarcomere, Z-disc, calcium regulatory and cytoskeletal proteins as well as the dystrophin complex may be causal for disease. In dilated cardiomyopathy, disturbances in post-translational modifications of the sarcomere my also play a prominent role. Experimental models indicate that altered phosphorylation of sarcomeric proteins may impair systolic and diastolic function as well as the response to heart rate and afterload. Thus correcting these post-translational changes are legitimate targets for future therapeutic strategies for dilated cardiomyopathy.
| S-EPMC3032173 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.
| S-EPMC4784435 | biostudies-literature