Abstract 16953: Role of the Fast Transient Outward Current Ito,f in Shaping Action Potential Waveforms in Human iPSC-derived Cardiomyocytes
Abnormalities of a key repolarizing cardiac potassium current, the fast transient outward potassium current, Ito,f, are associated with both heart failure and congenital arrhythmia syndromes. However, the precise role of Ito,f in shaping action potential waveforms remains unclear. This study was designed to define the functional role of the fast transient outward potassium current, Ito,f, in shaping action potentials in human iPSC-derived cardiomyocytes (iPSC-CMs). Most iPSC-CMs (29 of 43 cells) demonstrated spontaneous electrical activity, slow upstroke velocity (63±71 V/s), a wide range of action potential durations (APD90 = 860±722 ms) and heterogeneous action potential waveforms. Using dynamic current clamp, a modeled human ventricular inwardly rectifying K+ current, IK1, was introduced into iPSC-CMs, resulting in silencing of spontaneous activity, hyperpolarization of the resting membrane potential (RMP = -90±3 mV), increased peak upstroke velocity (dV/dt = 346±71 V/s) and decreased APD90 (420±211 ms) to values similar to those recorded in isolated adult human ventricular myocytes (RMP = -84±3 mV, dV/dt = 348±101 V/s and APD90 = 468±133 ms, all p>0.05). Importantly, a ventricular-like action potential waveform was observed in 25 of the 26 cells studied following the dynamic clamp addition of IK1. Using these cells as a model of human ventricular myocytes, further dynamic current clamp experiments introduced a modeled human fast transient outward K+ current, Ito,f, and revealed that increasing in the amplitude of Ito,f results in an increase in the phase 1 notch and a progressive shortening of the action potential duration in iPSC-CMs. Together, the experiments here demonstrate that combining human iPSC-CMs with the power of the dynamic current clamp technique to modulate directly and precisely the “expression” of individual ionic currents provides a novel and quantitative approach to defining the roles of specific ionic conductances in regulating the excitability of human cardiomyocytes.
Author Disclosures: S. Marrus: None. S. Springer: None. R. Martinez: None. E. Dranoff: None. R. Mellor: None. A. Zhang: None. E. Kanter: None. K. Yamada: None. J. Nerbonne: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.