We have examined, for the first time, the effects of the familial hypertrophic cardiomyopathy (HCM)- associated Lys104Glu mutation in the myosin regulatory light chain (RLC). Transgenic mice expressing the Lys104Glu substitution (Tg-MUT) were generated and the results compared to Tg-WT (wild-type human ventricular RLC) mice. Echocardiography with pulse wave Doppler in 6 month-old Tg-MUT showed early signs of diastolic disturbance with significantly reduced E/A transmitral velocities ratio. Invasive hemodynamics in 6 month-old Tg-MUT mice also demonstrated a borderline significant prolonged isovolumic relaxation time (Tau) and a tendency for slower rate of pressure decline, suggesting alterations in diastolic function in Tg-MUT. Six month-old mutant animals had no LV hypertrophy; however, at >13 months they displayed significant hypertrophy and fibrosis. In skinned papillary muscles from 5-6 month-old mice a mutation induced reduction in maximal tension and slower muscle relaxation rates were observed. Mutated cross-bridges showed increased rates of binding to the thin filaments and a faster rate of the power stroke. In addition, ~2-fold lower level of RLC phosphorylation was observed in the mutant compared to Tg-WT. In line with the higher mitochondrial content seen in Tg-MUT hearts, the MUT-myosin ATPase activity was significantly higher than WT-myosin, indicating increased energy consumption. In the in vitro motility assay, MUT-myosin produced higher actin sliding velocity under zero load, but the velocity drastically decreased with applied load in the MUT vs. WT myosin. Our results suggest that diastolic disturbance (impaired muscle relaxation, lower E/A) and inefficiency of energy use (reduced contractile force and faster ATP consumption) may underlie the Lys104Glu-mediated HCM phenotype.

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BackgroundHypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease characterized by varying degrees of left ventricular outflow tract obstruction. In a large cohort, we compare the outcomes among 3 different hemodynamic groups.Methods and ResultsWe prospectively enrolled patients fulfilling standard diagnostic criteria for HCM from January 2005 to June 2015. Detailed phenotypic characterization, including peak left ventricular outflow tract pressure gradients at rest and after provocation, was measured by echocardiography. The primary outcome was a composite cardiovascular end point, which included new‐onset atrial fibrillation, new sustained ventricular tachycardia/ventricular fibrillation, new or worsening heart failure, and death. The mean follow‐up was 3.4±2.8 years. Among the 705 patients with HCM (mean age, 52±15 years; 62% men), 230 with obstructive HCM were older and had a higher body mass index and New York Heart Association class. The 214 patients with nonobstructive HCM were more likely to have a history of sustained ventricular tachycardia/ventricular fibrillation and implantable cardioverter defibrillator implantation. During follow‐up, 121 patients experienced a composite cardiovascular end point. Atrial fibrillation occurred most frequently in the obstructive group. Patients with nonobstructive HCM had more frequent sustained ventricular tachycardia/ventricular fibrillation events. In multivariate analysis, obstructive (hazard ratio, 2.80; 95% confidence interval, 1.64–4.80) and nonobstructive (hazard ratio, 1.94; 95% confidence interval, 1.09–3.45) HCM were associated with more adverse events compared with labile HCM.ConclusionsNonobstructive HCM carries notable morbidity, including a higher arrhythmic risk than the other HCM groups. Patients with labile HCM have a relatively benign clinical course. Our data suggest detailed sudden cardiac death risk stratification in nonobstructive HCM and monitoring with less aggressive management in labile HCM.

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