Abstract 1440: The Cardiac Myosin Activator CK-1316719 Increases Myofibril ATPase Activity and Myocyte Contractility in a Rat Model of Heart Failure

Current inotropic therapies improve contractility by increasing the calcium transient, either via activation of the adenylyl cyclase pathway, by delaying cAMP degradation through inhibition of phosphodiesterase, or inhibition of the Na/K exchanger. However, these treatments can be detrimental to patients with heart failure and usually elicit a blunted response due to adrenergic desensitization. Improving cardiac contractility by directly activating cardiac myosin may be a preferred treatment for heart failure. We have previously reported that small molecule myosin activators increase cardiac myocyte contractility without increasing intracellular calcium or inhibiting phosphodiesterase in non-failing cells. We now report cellular and biochemical responses to the myosin activator CK-1316719 in a rat model of HF. Heart failure was confirmed in vivo by observing significant decreases in fractional shortening (M-mode echocardiography) in 12-week post myocardial infarction (MI) Sprague Dawley rats compared to sham animals. Myocytes were isolated from the left ventricle and septum for cellular contractility, myofibril ATPase, and mRNA analysis. CK-1316719 (0.4–5 uM) treatment increased cellular contractility equivalently and in a dose dependent manner in both sham and MI myocytes. In contrast, isoproterenol treatment (20 nM) resulted in a truncated response only in MI cells demonstrating β-adrenergic desensitization, a characteristic of heart failure. Increased ANF mRNA expression and increased size of MI cells corroborated heart failure at the cellular level. In fura-2 loaded myocytes, CK-1316719 increased cellular contractility in both MI and sham cells without increasing the calcium transient, consistent with the proposed mechanism of action. Sham and MI myofibrils displayed similar dose dependent increases in ATP turnover (pCa 6 and 7) with CK-1316719. In contrast to current inotropic therapies, these results indicate that myosin activators such as CK-1316719 are equally effective in non-heart failure and heart failure states and may be useful therapeutics in the treatment of human heart failure.