Omecamtiv mecarbil in precision-cut living heart failure slices: A story of a double-edged sword

Abstract

Heart failure (HF) is a rapidly growing pandemic while medical treatment options remain limited. Omecamtiv mecarbil (OM) is a novel HF drug that directly targets the myosin heads of the cardiac muscle. This study used living myocardial slices (LMS) from patients with HF to evaluate the direct biomechanical effects of OM as compared to dobutamine. LMS were produced from patients with end-stage HF undergoing cardiac transplantation or left ventricular assist device implantation and cultured under electromechanical stimulation (diastolic preload: ca. 1 mN, stimulation frequency: 0.5 Hz). Dobutamine and omecamtiv mecarbil (OM) were administered on consecutive days and biomechanical effects were continuously recorded with dedicated force transducers. OM and dobutamine significantly increased contractile force to a similar maximum force, but OM also increased median time-to-peak with 48 % (p = 0.046) and time-to-relaxation with 68 % (p = 0.045). OM administration led to impaired relaxation of HF LMS with increasing stimulation frequencies, which was not observed with dobutamine. Furthermore, the functional refractory period was significantly shorter after administration of OM compared to dobutamine (235 ms (200–265) vs. 270 ms (259–283), p = 0.035). In conclusion, OM increased contractile force and systolic duration of HF LMS, indicating an improvement in cardiac function and normalization of systolic time intervals in patients with HF. Conversely, OM slowed relaxation, which could lead to diastolic filling abnormalities. As such, OM showed benefits on systolic function on one hand but potential hindrances of diastolic function on the other hand.

Keywords

• Heart failure
• Omecamtiv mecarbil
• Living myocardial slices