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Telemetry-instrumented rats were administered ABBV-712 with or without atenolol to investigate effects of co-dosing on hemodynamic parameters and cardiac pathology. In vitro studies included cytotoxicity assessment in human-induced pluripotent stem cell-derived cardiomyocytes and relaxation of isolated rat aorta. Off-target pharmacology was evaluated by binding and inhibition screening assays. Finally, TYK2 knockout mice were administered ABBV-712 to evaluate hemodynamics as compared with wild-type animals. ABBV-712 resulted in decreased mean arterial pressure and increased heart rate in rats that was prevented by pre-dosing atenolol. ABBV-712-induced myocardial necrosis was also prevented by atenolol, suggesting a mechanistic link between hemodynamic changes and cardiac pathology. The pathology was unrelated to direct cytotoxicity on cardiomyocytes as demonstrated in vitro and was shown to be a compound-related effect on vascular relaxation mediated by the endothelium. The toxicity was considered an off-target effect, as demonstrated by similar hemodynamic responses between TYK2 knockout and wild-type mice administered ABBV-712, as well as by the lack of hemodynamic alterations in the knockout mouse. Inhibition of identified off-targets was unlikely to be the cause of the hemodynamic changes. In conclusion. a novel TYK2 inhibitor was associated with decreased mean arterial pressure, increased heart rate, and secondary myocardial necrosis in rats. These effects were unrelated to TYK2 inhibition. 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