Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin.

We used transient biochemical and structural kinetics to elucidate the molecular mechanism of mavacamten, an allosteric cardiac myosin inhibitor and a prospective treatment for hypertrophic cardiomyopathy. We find that mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin not found in the single-headed S1 myosin motor fragment. We determined this by measuring cardiac myosin actin-activated and actin-independent ATPase and single-ATP turnover kinetics. A two-headed myosin fragment exhibits distinct autoinhibited ATP turnover kinetics compared with a single-headed fragment. Mavacamten enhanced this autoinhibition. It also enhanced autoinhibition of ADP release. Furthermore, actin changes the structure of the autoinhibited state by forcing myosin lever-arm rotation. Mavacamten slows this rotation in two-headed myosin but does not prevent it. We conclude that cardiac myosin is regulated in solution by an interaction between its two heads and propose that mavacamten stabilizes this state.

Early remodeling of repolarizing K+ currents in the αMHC403/+ mouse model of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (HCM), linked to mutations in myosin, myosin-binding proteins and other sarcolemmal proteins, is associated with increased risk of life threatening ventricular arrhythmias, and a number of animal models have been developed to facilitate analysis of disease progression and mechanisms. In the experiments here, we use the αMHC403/+ mouse line in which one αMHC allele harbors a common HCM mutation (in ßMHC, Arg403 Gln). Here, we demonstrate marked prolongation of QT intervals in young adult (10-12week) male αMHC403/+ mice, well in advance of the onset of measurable left ventricular hypertrophy. Electrophysiological recordings from myocytes isolated from the interventricular septum of these animals revealed significantly (P<0.001) lower peak repolarizing voltage-gated K+ (Kv) current (IK,peak) amplitudes, compared with cells isolated from wild type (WT) littermate controls. Analysis of Kv current waveforms revealed that the amplitudes of the inactivating components of the total outward Kv current, Ito,f, Ito,s and IK,slow, were significantly lower in αMHC403/+, compared with WT, septum cells, whereas Iss amplitudes were similar. The amplitudes/densities of IK,peak and IK,slow were also lower in αMHC403/+, compared with WT, LV wall and LV apex myocytes, whereas Ito,f was attenuated in αMHC403/+ LV wall, but not LV apex, cells. These regional differences in the remodeling of repolarizing Kv currents in the αMHC403/+ mice would be expected to increase the dispersion of ventricular repolarization and be proarrhythmic. Quantitative RT-PCR analysis revealed reductions in the expression of transcripts encoding several K+ channel subunits in the interventricular septum, LV free wall and LV apex of (10-12week) αMHC403/+ mice, although this transcriptional remodeling was not correlated with the observed decreases in K+ current amplitudes.

Human-induced pluripotent stem cell models of inherited cardiomyopathies.

PURPOSE OF REVIEW: This article provides an overview of the latest advances in in-vitro modeling of inherited cardiomyopathies using human-induced pluripotent stem cells (iPSCs). RECENT FINDINGS: Inherited cardiomyopathies have been recently modeled by generating iPSCs from patients harboring mutations in genes associated with the pathogenesis of hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy/dysplasia. SUMMARY: Patient-specific iPSCs and their differentiated cardiomyocytes (induced pluripotent stem cell-derived cardiomyocytes) now provide a novel model to study the underlying molecular mechanism of the pathogenesis of familial cardiomyopathies as well as for in-vitro drug screening and drug discovery.

Cardiomiopatia hipertrófica: tratamento invasivo e não-invasivo / Invasive and non-invasive management of hypertrophic cardiomyopathy

O tratamento não-invasivo está dirigido aos pacientes sintomáticos, após estratificação para o risco de morte súbita. São utilizados, como primeira opção, betabloqueadores ou verapamil, assim como disopiramida. Com essas medicações, consegue-se a melhoria dos sintomas em aproximadamente 95 por cento dos pacientes. A amiodarona deverá ser utilizada na presença de arritmias ventriculares complexas ou para tratamento e prevenção da fibrilação atrial. Em caso de fibrilação atrial crônica, haverá necessidade de se utilizar a warfarina; na presença de obstrução ou insuficiência mitral, profilaxia para endocardite infecciosa. Um pequeno e importante subgrupo de pacientes é refratário ao tratamento não-invasivo. Naqueles que apresentam gradiente > 50 mmHg (formas obstrutivas), está indicada a cardiomiectomia transvalvular aórtica, que vem sendo realizada desde 1960 com bons resultados e mortalidade cirúrgica inferior a 5 por cento, ou a oclusão do ramo septal da artéria coronária descendente anterior pelo álcool. Nos pacientes sem obstrução e em fase avançada da doença, com dilatação e disfunção sistólica, a única opção é o transplante cardíaco, com indicação restrita e pequena experiência na literatura.