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?-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

ABSTRACT: Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in ?-cardiac myosin heavy chain (?-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle/environmental differences between subjects even from the same family.To characterize disease caused by ?-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice.Unlike 2 mouse lines bearing the malignant myosin mutations Arg453Cys (RC/+) or Arg719Trp (RW/+), VM/+ mice with an identical inbred genetic background lacked hallmarks of HCM such as left ventricular hypertrophy, disarray of myofibers, and interstitial fibrosis. Even homozygous VM/VM mice were indistinguishable from wild-type animals, whereas RC/RC- and RW/RW-mutant mice died within 9 days after birth. However, hypertrophic effects of the VM mutation were observed both in mice treated with cyclosporine, a known stimulator of the HCM response, and compound VM/RC heterozygous mice, which developed a severe HCM phenotype. In contrast to all heterozygous mutants, both systolic and diastolic function of VM/RC hearts was severely impaired already before the onset of cardiac remodeling.The VM mutation per se causes mild HCM-related phenotypes; however, in combination with other HCM activators it exacerbates the HCM phenotype. Double-mutant mice are suitable for assessing the severity of benign mutations.

SUBMITTER: Blankenburg R

PROVIDER: S-EPMC4086907 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

Blankenburg Robert R Hackert Katarzyna K Wurster Sebastian S Deenen René R Seidman J G JG Seidman Christine E CE Lohse Martin J MJ Schmitt Joachim P JP

Circulation research 20140514 2

<h4>Rationale</h4>Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in β-cardiac myosin heavy chain (β-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle/environmental differences between subjects even from the same family.<h4>Objective</h4>To characterize disease caused by β-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide ...[more]

PMID: 24829265

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Project description:BackgroundThe HCMR (Hypertrophic Cardiomyopathy Registry) is a National Heart, Lung, and Blood Institute-funded, prospective registry of 2,755 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 sites in 6 countries.ObjectivesThe authors sought to improve risk prediction in HCM by incorporating cardiac magnetic resonance (CMR), genetic, and biomarker data.MethodsDemographic and echocardiographic data were collected. Patients underwent CMR including cine imaging, late gadolinium enhancement imaging (LGE) (replacement fibrosis), and T1 mapping for measurement of extracellular volume as a measure of interstitial fibrosis. Blood was drawn for the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT), and genetic analysis.ResultsA total of 2,755 patients were studied. Mean age was 49 ± 11 years, 71% were male, and 17% non-white. Mean ESC (European Society of Cardiology) risk score was 2.48 ± 0.56. Eighteen percent had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg. Thirty-six percent had a sarcomere mutation identified, and 50% had any LGE. Sarcomere mutation-positive patients were more likely to have reverse septal curvature morphology, LGE, and no significant resting LVOT obstruction. Those that were sarcomere mutation negative were more likely to have isolated basal septal hypertrophy, less LGE, and more LVOT obstruction. Interstitial fibrosis was present in segments both with and without LGE. Serum NT-proBNP and cTnT levels correlated with increasing LGE and extracellular volume in a graded fashion.ConclusionsThe HCMR population has characteristics of low-risk HCM. Ninety-three percent had no or only mild functional limitation. Baseline data separated patients broadly into 2 categories. One group was sarcomere mutation positive and more likely had reverse septal curvature morphology, more fibrosis, but less resting obstruction, whereas the other was sarcomere mutation negative and more likely had isolated basal septal hypertrophy with obstruction, but less fibrosis. Further follow-up will allow better understanding of these subgroups and development of an improved risk prediction model incorporating all these markers.

Project description:AimsAtrial fibrillation (AF) and thrombo-embolism (TE) are associated with reduced survival in hypertrophic cardiomyopathy (HCM), but the absolute risk of TE in patients with and without AF is unclear. The primary aim of this study was to derive and validate a model for estimating the risk of TE in HCM. Exploratory analyses were performed to determine predictors of TE, the performance of the CHA2 DS2 -VASc score, and outcome with vitamin K antagonists (VKAs).Methods and resultsA retrospective, longitudinal cohort of seven institutions was used to develop multivariable Cox regression models fitted with pre-selected predictors. Bootstrapping was used for validation. Of 4821 HCM patients recruited between 1986 and 2008, 172 (3.6%) reached the primary endpoint of cerebrovascular accident (CVA), transient ischaemic attack (TIA), or systemic peripheral embolus within 10 years. A total of 27.5% of patients had a CHA2 DS2 -VASc score of 0, of whom 9.8% developed TE during follow-up. Cox regression revealed an association between TE and age, AF, the interaction between age and AF, TE prior to first evaluation, NYHA class, left atrial (LA) diameter, vascular disease, and maximal LV wall thickness. There was a curvilinear relationship between LA size and TE risk. The model predicted TE with a C-index of 0.75 [95% confidence interval (CI) 0.70-0.80] and the D-statistic was 1.30 (95% CI 1.05-1.56). VKA treatment was associated with a 54.8% (95% CI 31-97%, P = 0.037) relative risk reduction in HCM patients with AF.ConclusionsThe study shows that the risk of TE in HCM patients can be identified using a small number of simple clinical features. LA size, in particular, should be monitored closely, and the assessment and treatment of conventional vascular risk factors should be routine practice in older patients. Exploratory analyses show for the first time evidence for a reduction of TE with VKA treatment. The CHA2 DS2 -VASc score does not appear to correlate well with the clinical outcome in patients with HCM and should not be used to assess TE risk in this population.

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?-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

Publications

β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

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