Differential Expression and Remodeling of Transient Outward Potassium Currents in Human Left Ventricles. (January 2018)

• Record Type: Journal Article
• Authors: Johnson, Eric K.; Springer, Steven J.; Wang, Wei; Dranoff, Edward J.; Zhang, Yan; Kanter, Evelyn M.; Yamada, Kathryn A.; Nerbonne, Jeanne M.
• Is Part Of: Circulation. Volume 11:Number 1(2018)
• Publication Date: 2018-01
• Subjects: action potentials -- Brugada syndrome -- heart failure -- ion channels -- membrane potentials -- potassium; Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.128
• DOI: 10.1161/CIRCEP.117.005914
• Languages: English
• ISSNs: 1941-3149

Abstract

Abstract : 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. Abstract : Supplemental Digital Content is available in the text.