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 Ca 2+ 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.