β-adrenergic stimulation augments transmural dispersion of repolarization via modulation of delayed rectifier currents IKs and IKr in the human ventricle

C. Kang, A. Badiceanu, J. A. Brennan, C. Gloschat, Y. Qiao, N. A. Trayanova, I. R. Efimov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Long QT syndrome (LQTS) is an inherited or drug induced condition associated with delayed repolarization and sudden cardiac death. The cardiac potassium channel, IKr, and the adrenergic-sensitive cardiac potassium current, IKs, are two primary contributors to cardiac repolarization. This study aimed to elucidate the role of β-adrenergic (β-AR) stimulation in mediating the contributions of IKr and IKs to repolarizing the human left ventricle (n = 18). Optical mapping was used to measure action potential durations (APDs) in the presence of the IKs blocker JNJ-303 and the IKr blocker E-4031. We found that JNJ-303 alone did not increase APD. However, under isoprenaline (ISO), both the application of JNJ-303 and additional E-4031 significantly increased APD. With JNJ-303, ISO decreased APD significantly more in the epicardium as compared to the endocardium, with subsequent application E-4031 increasing mid- and endocardial APD80 more significantly than in the epicardium. We found that β-AR stimulation significantly augmented the effect of IKs blocker JNJ-303, in contrast to the reduced effect of IKr blocker E-4031. We also observed synergistic augmentation of transmural repolarization gradient by the combination of ISO and E-4031. Our results suggest β-AR-mediated increase of transmural dispersion of repolarization, which could pose arrhythmogenic risk in LQTS patients.

Original languageEnglish (US)
Article number15922
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Funding

The authors wish to gratefully acknowledge Washington Regional Transplant Community, Washington DC and Mid-America Transplant Services, St. Louis, M.O. We are grateful to Dr. Michael Pasque from Washington University School of Medicine, and the families of donors for donating cardiac tissues, which enabled this research program. We gratefully acknowledge funding from the National Institutes of Health grants R01 HL114395 and R01 HL126802 and Leducq Foundation Network of Excellence grant Repolarization HeterogeneitY imaging for personalized Therapy of Heart arrhythmia (RHYTHM).

ASJC Scopus subject areas

  • General

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