Decreased inward rectifying K+ current and increased ryanodine receptor sensitivity synergistically contribute to sustained focal arrhythmia in the intact rabbit heart. (7th October 2014)

• Record Type: Journal Article
• Authors: Myles, Rachel C.; Wang, Lianguo; Bers, Donald M.; Ripplinger, Crystal M.
• Is Part Of: Journal of physiology. Volume 593:Number 6(2015:Mar.)
• Page Start: 1479
• Page End: 1493
• Publication Date: 2014-10-07
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2014.279638
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract : Key points: Heart failure leads to dramatic electrophysiological remodelling as a result of numerous cellular and tissue‐level changes. Important cellular changes include increased sensitivity of ryanodine receptors (RyRs) to Ca 2+ release and down‐regulation of the inward rectifying K + current ( I K1 ), both of which contribute to triggered action potentials in isolated cells. We studied the role of increased RyR sensitivity and decreased I K1 in contributing to focal arrhythmia in the intact non‐failing rabbit heart using optical mapping and pharmacological manipulation of RyRs and I K1 . Neither increased RyR sensitivity or decreased I K1 alone led to significant increases in arrhythmia following local sympathetic stimulation; however, in combination, these two factors led to a significant increase in premature ventricular complexes and focal ventricular tachycardia. These results suggest synergism between increased RyR sensitivity and decreased I K1 in contributing to focal arrhythmia in the intact heart and may provide important insights into novel anti‐arrhythmic treatments in heart failure. Abstract: Heart failure (HF) results in dramatic electrophysiological remodelling, including increased sensitivity of ryanodine receptors (RyRs) and decreased inward rectifying K + current ( I K1 ), which predisposes HF myocytes to delayed afterdepolarizations and triggered activity. Therefore, we sought to determine the role of increased RyR sensitivity and decreased I K1 in contributing to focal arrhythmia in the intact non‐failing heart. Optical mapping of transmembrane potential and intracellular Ca 2+ was performed in Langendorff‐perfused rabbit hearts ( n = 15). Local β‐adrenergic receptor stimulation with noradrenaline (norepinephrine; NA, 50 μl, 250 μm ) was applied to elicit focal activity (premature ventricular complexes (PVCs) or ventricular tachycardia (VT ≥ 3 beats)). NA was administered under control conditions (CTL) and following pretreatment with 50 μm BaCl2 to reduce I K1, or 200 μm caffeine (Caff) to sensitize RyRs, both alone and in combination. Local NA injection resulted in Ca 2+ ‐driven PVCs arising from the injection site in all hearts studied. No increase in NA‐mediated PVCs was observed following pretreatment with either BaCl2 or Caff alone (CTL: 1.1 ± 0.7, BaCl2 : 1.0 ± 0.7, Caff: 1.3 ± 0.8 PVCs/injection, P not significant). However, pretreatment with the combination of BaCl2 + Caff resulted in a significant increase in PVCs (2.3 ± 2.8 PVCs/injection, P < 0.05 vs . CTL, BaCl2, Caff). Additionally, pretreatment with BaCl2 + Caff led to sustained monomorphic VT arising from the NA application site in all hearts studied, which lasted up to 6 min following a single NA injection. VT was never observed under any other condition suggesting synergism between increased RyR sensitivity and decreased I K1 in contributing to focal activity. These findings may have important implications for the understanding and prevention of focal arrhythmia in HF.