The objective of this non-clinical study was to examine the effects of CK-1827452 in dogs with heart failure, either with or without pre-existing left ventricular hypertrophy (LVH).
In this study, the authors observed that in dogs with severe LVH but not heart failure, a bolus followed by an infusion of CK-1827452 produced a sustained and significant increase in ejection time and systolic wall thickening with only transient effects on fractional shortening and stroke volume. After the induction of heart failure, these effects were augmented despite the presence of accompanying LVH. Thus, in dogs with heart failure in the presence of severe LVH, in addition to the increases in ejection time and systolic wall thickening, CK-1827452 produced a sustained increase in fractional shortening and stroke volume.
These changes were accompanied by decreases in left ventricular end-diastolic pressure, mean left atrial pressure and heart rate. Importantly, the endocardial to epicardial myocardial blood flow ratio and arterial and coronary sinus oxygen content were unchanged. Thus, overall myocardial oxygen consumption was unaffected even as overall systolic function improved.
The authors concluded that CK-1827452 increased left ventricular function and reduced filling pressures but, in contrast to conventional inotropic agents, did not increase myocardial oxygen consumption or reduce subendocardial blood flow in the setting of heart failure or in heart failure with severe LVH.