Background– Hypertrophic cardiomyopathy remains the most common heritable cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule inhibitors that modulate the sarcomere are promising novel therapeutics for the management of obstructive hypertrophic cardiomyopathy (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. Hypothesis/Objectives– To explore the 6-, 24-, and 48-hour post-dose, pharmacodynamic effects of the cardiac myosin inhibitor, CK-4021586 (CK-586), in cats with naturally occurring oHCM. Animals– Six purpose-bred cats bearing the A31P MYBPC3 mutation. Methods– A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of cardiac myosin inhibitor CK-586 in a feline model of oHCM. Serial plasma concentrations were obtained for dose assessments (2 -15 mg/kg, PO) and select echocardiographic variables were assessed five times over a 48-hr period. Results– Treatment with oral CK-586 relieved LVOTO in oHCM cats. In this study, we report the beneficial dose-dependent effects of CK-586 treatment by eliminating obstruction through cardiac myosin inhibition and subsequent decreases in LV FS% and EF% in the absence of impact on HR. Conclusions and Clinical Importance– At all tested doses, a single oral dose of CK-586 was well tolerated and resulted in modest, dose-dependent, reductions in LV systolic function that was associated with improved or resolved LVOTO. Further studies assessing the long-term effects of CK-586 in oHCM-affected cats are warranted. The results from this study pave the way for the potential use of this compound in both the veterinary and human clinical setting.
