Faster cross‐bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation

Abstract

Key pointsr The R403Q mutation, located in the S1 domain of the β-myosin heavy chain, is associated with a severe phenotype of hypertrophic cardiomyopathy (HCM).r Increased cross-bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of sarcomeric tension generation; however, direct evidence is absent.r We studied the relationship between cross-bridge kinetics and energetics in single cardiac myofibrils and multicellular cardiac muscle strips in human HCM tissue with and without the R403Q mutation.r In human HCM with the R403Q mutation, cross-bridge relaxation was faster and correlated well with a rise in energetic cost of tension generation.r Our data suggest that an increase in tension cost is one of the causes underlying cardiomyopathy development in patients with the R403Q mutation.Abstract The first mutation associated with hypertrophic cardiomyopathy (HCM) is the R403Q mutation in the gene encoding β-myosin heavy chain (β-MyHC). R403Q locates in the globular head of myosin (S1), responsible for interaction with actin, and thus motor function of myosin. Increased cross-bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of tension generation; however, direct evidence is absent. Here we studied to what extent cross-bridge kinetics and energetics are related in single cardiac myofibrils and multicellular cardiac muscle strips of three HCM patients with the R403Q mutation and nine sarcomere mutation-negative HCM patients (HCM smn ). Expression of R403Q was on average 41 ± 4% of total MYH7 mRNA. Cross-bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher (P < 0.0001) than in HCM smn myofibrils (0.47 ± 0.02 and 0.30 ± 0.02 s −1 , respectively). Moreover, compared to HCM smn , tension cost was significantly higher in the muscle strips of the three R403Q patients (2.93 ± 0.25 and 1.78 ± 0.10 μmol l -1 s −1 kN −1 m −2 , respectively) which showed a positive linear correlation with relaxation kinetics in the corresponding myofibril preparations. This correlation suggests that faster cross-bridge relaxation kinetics results in an increase in energetic cost of tension generation in human HCM with the R403Q mutation compared to HCM smn . Therefore, increased tension cost might contribute to HCM disease in patients carrying the R403Q mutation.

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

“…However, myocardial stroke work was reduced to an even greater extent than oxygen consumption; myocardial efficiency (the ratio of stroke work to myocardial oxygen consumption) was, therefore, decreased. A combined in vitro and in vivo study using tissue of genotype-positive patients with HCM, and PET and cardiac MR scans, revealed an increase in energy tension-cost based on an imbalance between force-generating capacity and ATPase activity 9,14 .…”

“…Diastolic relaxation is a highly energy-dependent process; diastolic dysfunction owing to impaired relaxation is the most common phenotypic physiological abnormality in patients with HCM 33 , and diastolic dysfunction has been associated with abnormal energetics in experimental models of HCM 9,34,35 . The additional demonstration of diastolic dysfunction in HCM phenocopies and in Friedreich ataxia 36,37 has driven development and acceptance of the theory that energetic impairment, hypertrophy, and diastolic dysfunction are causally linked 23 .…”

“…See, for example, the compilation of disparate results published just for the R403Q mutation in MYH7, which encodes myosin-7 the cardiac β-myosin heavy chain 9 . Force generation with exposure to Ca 2+ and the degree of leftward displacement (in most mutations) of force-Ca 2+ curves is the method of determination.…”

“…In this Perspectives article, we focus primarily on the energy depletion hypothesis, but we also summarize the evidence for Ca 2+ sensitization, and discuss how the two theories overlap. Increasing evidence indicates that energy depletion has an important role in the development of hypertrophy and in the wider pathophysiology of HCM [9][10][11][12][13][14][15] . We summarize this evidence, and then discuss the phenotypic manifestations of energy depletion in three realms of cardiac function: diastolic dysfunction, dynamic systolic dysfunction (especially against imposed afterload), and arrhythmogenesis.…”

Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

“…At the whole heart level, HCM is characterized by hypercontractility, as indicated by an increased left ventricular ejection fraction3 and power output,4 and also diastolic dysfunction 5, 6. At the myofilament level, HCM‐related hypercontractility is often linked to enhanced sensitivity of the contractile apparatus to Ca 2+ ,7, 8 and accelerated rates of cross‐bridge (XB) cycling 9…”