Abstract 1439: Activating Cardiac Myosin, a Novel Inotropic Mechanism to Improve Cardiac Function in Conscious Dogs with Congestive Heart Failure
Many cardiotonic agents are not useful in the chronic treatment of heart failure (HF), either because they increase myocardial O2 consumption (MVO2) or undergo desensitization, such that their efficacy is actually reduced in HF. We examined the effects of a novel agent, CK-1827452 (CK-452), which exerts its inotropic action by activating cardiac myosin, in conscious chronically instrumented dogs in the presence and absence of HF. Dogs were instrumented with a left ventricular (LV) pressure gauge, ascending aortic flow probe, coronary flow probe, LV dimension crystals and catheters in the aorta, left atrium, and coronary sinus. HF, induced by a combination of coronary artery occlusion and ventricular pacing (240 bpm), was characterized by an increase (p<0.01) in LV end diastolic pressure (from 7±1 to 26±2 mmHg), and decreases (p<0.01) in LV dP/dt (from 3065±138 to 1730±109 mmHg/s), fractional shortening (from 14±2 to 7±1%), stroke volume (from 30±4 to 13±2 ml), and cardiac output (from 2.8±0.4 to 1.7±0.2 L/min). In normal conscious dogs, infusion of CK-452 (0.5 mg/kg/hr, iv) increased (p<0.05) LV fractional shortening (21±2%) and stroke volume (11±4%) and modestly decreased heart rate (8±2%), while cardiac output did not change significantly. After HF, infusion of CK-452 for 3 days induced sustained increases (p<0.05) in LV fractional shortening (34±7%), stroke volume (34±8%) and cardiac output (22±3%), and decreases (p<0.02) in heart rate (15±3%). Importantly, MVO2 was not altered significantly by CK-452. Interestingly, CK-452 did not increase LV dP/dt, but rather increased LV systolic ejection time by 33±2%. Thus, unlike existing inotropic agents, which generally increase LV dP/dt and MVO2, and induce desensitization, chronic infusion of the cardiac myosin activator did not induce desensitization but actually produced a greater improvement in LV function and cardiac output in HF without a change in MVO2. The unique profile of this myosin activator may provide a new therapeutic approach for patients with HF.