β-adrenergic stimulation augments transmural dispersion of repolarization via modulation of delayed rectifier currents IKs and IKr in the human ventricle.
C KangA BadiceanuJ A BrennanC GloschatY QiaoN A TrayanovaIgor R EfimovPublished in: Scientific reports (2017)
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.
Keyphrases
- drug induced
- liver injury
- endothelial cells
- left ventricular
- angiotensin converting enzyme
- end stage renal disease
- high resolution
- pulmonary artery
- induced pluripotent stem cells
- pulmonary hypertension
- newly diagnosed
- chronic kidney disease
- magnetic resonance
- pluripotent stem cells
- heart failure
- peritoneal dialysis
- coronary artery
- congenital heart disease
- patient reported outcomes
- cardiac resynchronization therapy
- risk assessment
- adverse drug