Irx5 and transient outward K currents contribute to transmural contractile heterogeneities in the mouse ventricle.

Previous studies have established that transmural gradients of the fast transient outward K current () correlate with regional differences in action potential (AP) profile and excitation-contraction coupling (ECC) with high expression in the epimyocardium (EPI) being associated with short APs and low contractility and vice versa. Herein, we investigated the effects of altering the gradients on transmural contractile properties using mice lacking (Irx5-KO) or lacking (K4.2-KO) or both. Irx5-KO mice exhibited decreased global LV contractility in association with elevated , as well as reduced cell shortening and Ca transient amplitudes in cardiomyocytes isolated from the endomyocardium (ENDO) but not in cardiomyocytes from the EPI. Transcriptional profiling revealed that the primary effect of ablation on ECC-related genes was to increase gene expression (i.e., and ) in the ENDO, but not the EPI. By contrast, K4.2-KO mice showed selective increases in cell shortening and Ca transients in isolated EPI cardiomyocytes, leading to enhanced ventricular contractility and mice lacking both and displayed elevated ventricular contractility, comparable to K4.2-KO mice, demonstrating a dominant role of -dependent modulation of in the regulation of contractility. Our findings show that the transmural electromechanical heterogeneities in the healthy ventricles depend on the -dependent gradients. These observations provide a useful framework for assessing the molecular mechanisms underlying the alterations in contractile heterogeneity seen in the diseased heart. Irx5 is a vital transcription factor that establishes the transmural heterogeneity of ventricular myocyte contractility, thereby ensuring proper contractile function in the healthy heart. Regional differences in excitation-contraction coupling in the ventricular myocardium are primarily mediated through the inverse relationship between Irx5 and the fast transient outward K current () across the ventricular wall.