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 degrees C to 37 degrees C) temperatures, from myocytes isolated from the LV of nonfailing human hearts identified 2 distinct transient currents, I-to,I-fast (I-to,I-f) and I-to,I-slow (I-to,I-s), with significantly (P<0.0001) different rates of recovery from inactivation and pharmacological sensitives: I-to,I-f recovers in approximate to 10 ms, 100x faster than I-to,I-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,I-f, resulted in hyperpolarization or depolarization, respectively, of the notch potential, whereas slowing the rate of I-to,I-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,I-f was reduced and I-to,I-s was increased, notch and plateau potentials were depolarized (P<0.0001) and AP durations were prolonged (P<0.001). CONCLUSIONS: I-to,I-f and I-to,I-s are differentially expressed in nonfailing human LV, contributing to regional heterogeneities in AP waveforms. I-to,I-f regulates notch and plateau potentials and modulates the time course and amplitude of I-Ca. Slowing I-to,I-f inactivation results in dramatic AP shortening. Remodeling of I-to,I-f in failing human LV subepicardial myocytes attenuates transmural differences in AP waveforms.