Discussion

Heart disease is a leading cause of global death and disability. Although directly suppressing cardiac muscle cell death is a logical therapeutic strategy, no clinical counter-measures target the relevant myocyte signalling pathways, and progress is hampered by insufficient validation in a human context. Here, we report a novel target, Mitogen-activated Protein Kinase Kinase Kinase Kinase-4 (MAP4K4) is activated in failing human hearts, mouse models of heart disease, and cultured cardiomyocytes subjected to death signals. Mice mimicking this increase are sensitized to ventricular muscle cell death and dysfunction induced by otherwise sub-lethal provocations (pressure-overload; Myh6-Gnaq). Conversely, human stem cell-derived cardiomyocytes (hiPSC-CMs) are protected by MAP4K4 short hairpin RNA or by a novel, selective small-molecule inhibitor developed through 3D field-point modelling and screening in silico. These experiments implicate MAP4K4 as a well-posed target in suppressing human cardiac muscle cell death and highlight the utility of hiPSC-CMs in cardiac drug development.