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Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy.

Rivas VN, Crofton AE, Jauregui CE, Wouters JR, Yang BS, Wittenburg LA, Kaplan JL, Hwee DT, Murphy AN, Morgan BP, Malik FI, Harris SP, Stern JA. Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy. Sci Rep. 2024 May 27;14(1):12038. doi: 10.1038/s41598-024-62840-3. PMID: 38802475; PMCID: PMC11130313.

Hypertrophic cardiomyopathy (HCM) is the most diagnosed cardiac disease in cats, affecting up to 14% of the population. There is a genetic predisposition to the condition as seen in some breeds such Ragdolls and Sphynx, but this does not explain all cases of the condition. This disease process primarily affects the left ventricle (LV), where the heart muscle thickens, leading to a decrease in chamber volume, and the potential for hyperdynamic contractility and pressure overload. Left ventricular outflow tract obstruction (LVOTO) has been noted in 30-60% of feline HCM cases. Congestive heart failure (CHF) and aortic thromboembolisms (ATE) are 2 possible catastrophic sequalae to patients with the disorder. Feline HCM has similar genetic, hemodynamic, and pathophysiologic aspects to human HCM and provides a unique opportunity to study the use of novel therapeutics.

There is currently only one FDA-approved cardiac sarcomere inhibitor for humans with obstructive HCM (oHCM) [Mavacamten]. This treatment binds to the cardiac sarcomere myosin to decrease ATPase activity, leading to decreased hypercontractility and reduction of LVOTO. No similar medication is currently approved for cats with HCM. Atenolol, a beta blocker that reduces systolic anterior motion (SAM) and heart rate (HR), has been commonly prescribed to cats with oHCM on an empirical basis, though it’s utility in feline HCM is controversial.

This study investigated the effects of a novel oral cardiac myosin inhibitor, CK-586, in 6 cats with oHCM & LVOTO (stage B1) that were otherwise healthy in a randomized, blinded five-treatment group. The pharmacodynamic effects of CK-586 were also evaluated up to 48 hours after dosing. The initial three randomized treatment groups were placebo, 5, and 10 mg/kg, and then randomized again to 2 mg/kg, and 15 mg/kg dosing groups. Cats received a single dose of assigned treatment, and blood was drawn at 6, 24, and 48 hrs after treatment for plasma concentration of CK-586. All patients received a sedated echocardiographic evaluation with echocardiogram performed by a single board-certified veterinary cardiologist. Additionally, an intravenous infusion of dobutamine was performed on all cats at the 6 hr timepoint to increase heart rate (HR) and contractility to induce LVOTO.

No adverse events were noted during treatment period, and the average time to maximum plasma concentration of CK-586 was estimated to be 6.6 hours. The CK-586 treatment groups showed improvement with increased measures of systolic chamber size, elimination of obstruction (LVOTmaxPG – maximum pressure gradient), as well as a decrease in specific heart function parameters (LV fractional shortening percentage and ejection fraction percentage). The greatest effects were noted at the 6-hour post drug point, with no appreciation of heart rate (HR) changes. A dose range of > 5, and < 15 mg/kg showed the most promising target dose range.

Limitations of the study include small sample size, all test subjects in stage B1 with no evidence of advanced subclinical or clinical disease states (such as left atrial enlargement or CHF), and all patients required a dobutamine challenge to induce LVOTO. Regardless, this study showed multiple promising effects of CK-586 in cats with asymptomatic oHCM where there are no similar treatments available on the market. ~BJP

For further reading:

Coleman AE, DeFrancesco TC, Griffiths EH, Lascelles BDX, Kleisch DJ, Atkins CE, Keene BW. Atenolol in cats with subclinical hypertrophic cardiomyopathy: a double-blind, placebo-controlled, randomized clinical trial of effect on quality of life, activity, and cardiac biomarkers. J Vet Cardiol. 2020 Aug;30:77-91. doi: 10.1016/j.jvc.2020.06.002. Epub 2020 Jul 1. PMID: 32707333.

Kaplan JL, Rivas VN, Connolly DJ. Advancing Treatments for Feline Hypertrophic Cardiomyopathy: The Role of Animal Models and Targeted Therapeutics. Vet Clin North Am Small Anim Pract. 2023 Nov;53(6):1293-1308. doi: 10.1016/j.cvsm.2023.05.011. Epub 2023 Jul 4. PMID: 37414693.

Ostrominski JW, Guo R, Elliott PM, Ho CY. Cardiac Myosin Inhibitors for Managing Obstructive Hypertrophic Cardiomyopathy: JACC: Heart Failure State-of-the-Art Review. JACC Heart Fail. 2023 Jul;11(7):735-748. doi: 10.1016/j.jchf.2023.04.018. PMID: 37407153.