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 ofI 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 ) andI 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 thanI 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 ventricularI to,f , resulted in hyperpolarization or depolarization, respectively, of the notch potential, whereas slowing the rate ofI 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 andI 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 andI 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 ofI Ca . SlowingI to,f inactivation results in dramatic AP shortening. Remodeling ofI to,f in failing human LV subepicardial myocytes attenuates transmural differences in AP waveforms.