Differential Expression and Remodeling of Transient Outward Potassium Currents in Human Left Ventricles

Background: Myocardial, transient, outward currents, I_to, have been shown to play pivotal roles in action potential (AP) repolarization and remodeling in animal models. The properties and contribution of I_to to left ventricular (LV) repolarization in the human heart, however, are poorly defined. Methods and Results: Whole-cell, voltage-clamp recordings, acquired at physiological (35°C to 37°C) temperatures, from myocytes isolated from the LV of nonfailing human hearts identified 2 distinct transient currents, I_to,fast (I_to,f) and I_to,slow (I_to,s), with significantly (P<0.0001) different rates of recovery from inactivation and pharmacological sensitives: I_to,f recovers in ≈10 ms, 100× faster than I_to,s, and is selectively blocked by the Kv4 channel toxin, SNX-482. Current-clamp experiments revealed regional differences in AP waveforms, notably a phase 1 notch in LV subepicardial myocytes. Dynamic clamp-mediated addition/removal of modeled human ventricular I_to,f, resulted in hyperpolarization or depolarization, respectively, of the notch potential, whereas slowing the rate of I_to,f inactivation resulted in AP collapse. AP-clamp experiments demonstrated that changes in notch potentials modified the time course and amplitudes of voltage-gated Ca²⁺ currents, I_Ca. In failing LV subepicardial myocytes, I_to,f was reduced and I_to,s was increased, notch and plateau potentials were depolarized (P<0.0001) and AP durations were prolonged (P<0.001). Conclusions: I_to,f and I_to,s are differentially expressed in nonfailing human LV, contributing to regional heterogeneities in AP waveforms. I_to,f regulates notch and plateau potentials and modulates the time course and amplitude of I_Ca. Slowing I_to,f inactivation results in dramatic AP shortening. Remodeling of I_to,f in failing human LV subepicardial myocytes attenuates transmural differences in AP waveforms.