Key result
The R14del-PLN mutation caused depressed maximal force and increased myofilament Ca2+ sensitivity in right ventricular cardiomyocytes, a phenotype that could be reversed by omecamtiv mecarbil.
Why the study?
Underlying cellular mechanisms linked to R14del-PLN cardiac dysfunction without apparent structural remodeling remained unclear, prompting investigation into myofilament involvement and long-term cardiac effects.
Does omecamtiv mecarbil reverse the contractile dysfunction associated with the R14del-PLN mutation in cardiomyocytes?
Does omecamtiv mecarbil reverse the contractile dysfunction associated with the R14del-PLN mutation in cardiomyocytes?
The identification of myofilament dysfunction as an early characteristic of R14del-PLN cardiomyopathy suggests that myosin activators like omecamtiv mecarbil could offer a targeted therapeutic approach.
May support myosin activator therapy in R14del-PLN cardiomyopathy; hypothesis-generating from Level 5 animal data only.
Phospholamban (PLN) is a major regulator of cardiac contractility, and human mutations in this gene give rise to inherited cardiomyopathies. The deletion of Arginine 14 is the most-prevalent cardiomyopathy-related mutation, and it has been linked to arrhythmogenesis and early death. Studies in PLN-humanized mutant mice indicated an increased propensity to arrhythmias, but the underlying cellular mechanisms associated with R14del-PLN cardiac dysfunction in the absence of any apparent structural remodeling remain unclear. The present study addressed the specific role of myofilaments in the setting of R14del-PLN and the long-term effects of R14del-PLN in the heart. Maximal force was depressed in skinned cardiomyocytes from both left and right ventricles, but this effect was more pronounced in the right ventricle of R14del-PLN mice. In addition, the Ca2+ sensitivity of myofilaments was increased in both ventricles of mutant mice. However, the depressive effects of R14del-PLN on contractile parameters could be reversed with the positive inotropic drug omecamtiv mecarbil, a myosin activator. At 12 months of age, corresponding to the mean symptomatic age of R14del-PLN patients, contractile parameters and Ca2+ transients were significantly depressed in the right ventricular R14del-PLN cardiomyocytes. Echocardiography did not reveal any alterations in cardiac function or remodeling, although histological and electron microscopy analyses indicated subtle alterations in mutant hearts. These findings suggest that both aberrant myocyte calcium cycling and aberrant contractility remain specific to the right ventricle in the long term. In addition, altered myofilament activity is an early characteristic of R14del-PLN mutant hearts and the positive inotropic drug omecamtiv mecarbil may be beneficial in treating R14del-PLN cardiomyopathy.
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Kumar et al. (2023) studied R14del-Phospholamban Cardiomyopathy. R14del-PLN mutation vs. Wild-type PLN was evaluated on Maximal force and Ca2+ sensitivity in right ventricular cardiomyocytes. The R14del-PLN mutation caused depressed maximal force and increased myofilament Ca2+ sensitivity in right ventricular cardiomyocytes, a phenotype that could be reversed by omecamtiv mecarbil.
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