Introduction
The complex pathophysiology of heart failure (HF) limits the efficacy of current treatments and calls for novel mechanism-based approaches. Conventional HF therapies primarily target neurohormonal pathways, while direct modulation of the contractile machinery remains underexplored. The interplay between sarcomeric activation, myocardial metabolism, and contraction kinetics is still poorly characterized, partly because most experimental systems fail to reproduce the metabolic demands and dynamic contraction–relaxation cycles of living human myocardium. While living cardiac slices have been shown to detect arrhythmogenic drug effects, it remains unknown whether they can also be used to characterize relevant changes in metabolism and contraction kinetics. Here, we evaluated the human 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 procured from the explanted heart after transplantation. The use of human tissues was approved by institutional ethics committees of the institutions and hospitals at the University of Erlangen, Bad Oeynhausen and the Heart Centre Leipzig, following declaration of Helsinki princples. All patients or their legal guardians gave their written informed consent. Left-ventricular tissue from healthy minipigs was obtained after lethal pentobarbital injection performed in deep narcosis, following national and institutional animal welfare regulations. We prepared slices of 300µm thickness and cultured them for 6d with constant pacing and force recordings at 30 bpm. Slices were treated with either vehicle as control, danicamtiv (3µM), omecamtiv (3µM) or mavacamten (1µM). The culture medium was analyzed to quantify glucose utilization, lactate production and metabolic rate.
Results
Myosin activators increased contraction force in minipig and failing human myocardium (relative changes vs CTRL: danicamtiv: m=3.84±1.245; omecamtiv: m=2.29±0,367, n=4/2), while myosin inhibitors decreased contraction force (mavacamten m=0.277±0.245, n/N=4/2). Danicamtiv affected contraction kinetics only slightly, but a substantial effect of omecamtiv on contractile kinetics was found, where contraction duration and time to relaxation were significantly increased when compared with CTRL (danicamtiv m=0.982±0.245, n=4/2; omecamtiv 1.987±0.245, n=4/2). Mavacamten, in contrast, slightly reduced contraction duration (0.79±0.014).
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 (CTRL 2.81±0.05 µmol/24h; danicamtiv 3.18±0.13 µmol/24h; omecamtiv 3.58±0.51 µmol/24h; mavacamten 1.88±0.32 µmol/24h). These metabolic parameters were paralleled in pig cardiac slices (CTRL: m=1.514±0.052; Dani: m=1.777±0.45; OMe: m=3.577±0.4205; Mava: m=1.077±0.145, p<0.05).
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 favourable diastolic/relaxation profile than omecamtiv. These results suggest myocardial slice culture as a translational ex vivo platform for cardiac drug development and mechanistic testing.
