Myosin activators increased metabolic rates in human cardiac slices compared to vehicle (danicamtiv: 3.48 mW/g, omecamtiv: 3.28 mW/g vs 2.51 mW/g), whereas mavacamten decreased it (1.38 mW/g).
Living cardiac slices capture the inotropic, lusitropic, and metabolic effects of myosin modulators, demonstrating that danicamtiv has a more favorable relaxation profile than omecamtiv.
Abstract Introduction Modulation of the contractile machinery as a therapy in heart failure is emerging, but the interplay between sarcomere activation, myocardial metabolism, and contraction kinetics is not well characterized. Here, we used human and animal myocardial slice culture as a platform to detect drug-induced alterations in contractile force, kinetics, and energy metabolism. Methods Left-ventricular tissue from failing human hearts was obtained during assist device implantation or from explanted hearts. The use of human tissues was approved by institutional ethics committees, all patients or legal guardians gave written informed consent. Left-ventricular tissue from healthy minipigs was obtained following national and institutional animal welfare regulations. We prepared slices of 300 µm thickness and cultured them for 6 d with constant pacing and force recordings at 30 bpm. Slices were treated with either vehicle as control, danicamtiv (3 µM), omecamtiv (3 µM) or mavacamten (1 µM). The culture medium was analyzed to quantify glucose utilization, lactate production and metabolic rate. After culture, whole-slice Ca2+ imaging was performed. Results Myosin activators increased contraction force in minipig and failing human myocardium (relative changes vs CTRL: danicamtiv: 3.84±1.25; omecamtiv: 2.29±0.37, n/N=4/2), while myosin inhibitors decreased contraction force (mavacamten: 0.28±0.25, n/N=4/2). Danicamtiv affected contraction kinetics only slightly, but a substantial effect of omecamtiv on contraction duration and time to relaxation were detected when compared relative to CTRL (danicamtiv 0.98±0.25, omecamtiv 1.99±0.2). Mavacamten, in contrast, slightly reduced contraction duration (0.79±0.014). Analysis of Ca2+ transients revealed a highly increased decay time in omecamtiv, but not in danicamtiv-treated slices. Human cardiac slices treated with myosin activators exhibited increased metabolic rates as compared to vehicle (CTRL: 2.51±0.02 mW/g; danicamtiv: 3.48±0.25 mW/g; omecamtiv 3.28±0.21 mW/g), whereas slices treated with mavacamten showed a decreased metabolic rate (1.38±0.25 mW/g). This resulted from respective alterations in glucose utilization). These metabolic effects were paralleled in pig cardiac slices (CTRL: 1.51±0.05 mW/g, danicamtiv: 1.78±0.45 mW/g; omecamtiv: 3.58±0.42 mW/g; mavacamten: 1.08±0.16 mW/g). Conclusion Living cardiac tissue slices of both humans and animals are sensitive to pharmacological modulation of sarcomeric function, capturing inotropic, lusitropic and metabolic effects. The detected effects of myosin activators and inhibitors confirm the results of previous in-vivo and preclinical studies and support the idea that danicamtiv has a more favorable diastolic/relaxation profile than omecamtiv. These results also underpin myocardial slice culture as a translational ex vivo platform for cardiac drug development and mechanistic testing.
Seidel et al. (Fri,) conducted a other in Heart failure. Danicamtiv, omecamtiv, or mavacamten vs. Vehicle control was evaluated on Contractile force, kinetics, and energy metabolism. Myosin activators increased metabolic rates in human cardiac slices compared to vehicle (danicamtiv: 3.48 mW/g, omecamtiv: 3.28 mW/g vs 2.51 mW/g), whereas mavacamten decreased it (1.38 mW/g).