Myocardial, transient, outward currents, Ito, have been shown to play pivotal roles in action potential (AP) repolarization and remodeling in animal models. The properties and contribution of Ito 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, Ito,fast (Ito,f) and Ito,slow (Ito,s), with significantly (P<0.0001) different rates of recovery from inactivation and pharmacological sensitives: Ito,f recovers in ≈10 ms, 100× faster than Ito,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 Ito,f, resulted in hyperpolarization or depolarization, respectively, of the notch potential, whereas slowing the rate of Ito,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, ICa. In failing LV subepicardial myocytes, Ito,f was reduced and Ito,s was increased, notch and plateau potentials were depolarized (P<0.0001) and AP durations were prolonged (P<0.001).Conclusions:
Ito,f and Ito,s are differentially expressed in nonfailing human LV, contributing to regional heterogeneities in AP waveforms. Ito,f regulates notch and plateau potentials and modulates the time course and amplitude of ICa. Slowing Ito,f inactivation results in dramatic AP shortening. Remodeling of Ito,f in failing human LV subepicardial myocytes attenuates transmural differences in AP waveforms.