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 abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="tjp6352-sec-0010" sec-type="section"> <title>Key points</title> <p> <list id="tjp6352-list-0001" list-type="bullet"> <list-item> <p>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<sup>2+</sup> release and down‐regulation of the inward rectifying K<sup>+</sup> current (<italic>I</italic><sub>K1</sub>), both of which contribute to triggered action potentials in isolated cells.</p> </list-item> <list-item> <p>We studied the role of increased RyR sensitivity and decreased <italic>I</italic><sub>K1</sub> in contributing to focal arrhythmia in the intact non‐failing rabbit heart using optical mapping and pharmacological manipulation of RyRs and <italic>I</italic><sub>K1</sub>.</p> </list-item> <list-item> <p>Neither increased RyR sensitivity or decreased <italic>I</italic><sub>K1</sub> 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.</p> </list-item> <list-item> <p>These results suggest synergism between increased RyR sensitivity and decreased <italic>I</italic><sub>K1</sub> in contributing to focal arrhythmia in the intact heart and may provide important insights into novel anti‐arrhythmic treatments in heart failure.</p> </list-item> </list> </p> </sec> <sec id="tjp6352-sec-0020" sec-type="section"> <title>Abstract</title> <p>Heart failure (HF) results in dramatic electrophysiological remodelling, including increased sensitivity of ryanodine receptors (RyRs) and decreased inward rectifying K<sup>+</sup> current (<italic>I</italic><sub>K1</sub>), which predisposes HF myocytes to delayed afterdepolarizations and triggered activity. Therefore, we sought to determine the role of increased RyR sensitivity and decreased <italic>I</italic><sub>K1</sub> in contributing to focal arrhythmia in the intact non‐failing heart. Optical mapping of transmembrane potential and intracellular Ca<sup>2+</sup> was performed in Langendorff‐perfused rabbit hearts (<italic>n</italic> = 15). Local β‐adrenergic receptor stimulation with noradrenaline (norepinephrine; NA, 50 μl, 250 μ<sc>m</sc>) 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 μ<sc>m</sc> BaCl<sub>2</sub> to reduce <italic>I</italic><sub>K1</sub>, or 200 μ<sc>m</sc> caffeine (Caff) to sensitize RyRs, both alone and in combination. Local NA injection resulted in Ca<sup>2+</sup>‐driven PVCs arising from the injection site in all hearts studied. No increase in NA‐mediated PVCs was observed following pretreatment with either BaCl<sub>2</sub> or Caff alone (CTL: 1.1 ± 0.7, BaCl<sub>2</sub>: 1.0 ± 0.7, Caff: 1.3 ± 0.8 PVCs/injection, <italic>P</italic> not significant). However, pretreatment with the combination of BaCl<sub>2</sub> + Caff resulted in a significant increase in PVCs (2.3 ± 2.8 PVCs/injection, <italic>P</italic> < 0.05 <italic>vs</italic>. CTL, BaCl<sub>2</sub>, Caff). Additionally, pretreatment with BaCl<sub>2</sub> + 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 <italic>I</italic><sub>K1</sub> in contributing to focal activity. These findings may have important implications for the understanding and prevention of focal arrhythmia in HF.</p> </sec> </abstract>