In a novel mouse model of PLN-R14del cardiomyopathy, administration of eplerenone or metoprolol did not improve cardiac function or survival, underscoring the unresponsiveness to standard heart failure therapy.
Does eplerenone or metoprolol improve cardiac function or survival in a PLN-R14del mouse model of cardiomyopathy?
Standard heart failure therapies (eplerenone and metoprolol) fail to rescue the cardiomyopathy phenotype in a novel PLN-R14del mouse model, highlighting the need for targeted therapies.
-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments.
Eijgenraam et al. (Wed,) conducted a other in PLN-R14del cardiomyopathy (n=45). Eplerenone or metoprolol vs. Vehicle was evaluated on Survival. In a novel mouse model of PLN-R14del cardiomyopathy, administration of eplerenone or metoprolol did not improve cardiac function or survival, underscoring the unresponsiveness to standard heart failure therapy.