Atrium-Specific Kir3.x Determines Inducibility, Dynamics, and Termination of Fibrillation by Regulating Restitution-Driven Alternans

Abstract

Background— Atrial fibrillation is the most common cardiac arrhythmia. Ventricular proarrhythmia hinders pharmacological atrial fibrillation treatment. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current ( I K,ACh-c ) after atrial remodeling, might circumvent this problem. However, it is unknown whether and how I K,ACh-c contributes to atrial fibrillation induction, dynamics, and termination. Therefore, we investigated the effects of I K,ACh-c blockade and Kir3.x downregulation on atrial fibrillation. Methods and Results— Neonatal rat atrial cardiomyocyte cultures and intact atria were burst paced to induce reentry. To study the effects of Kir3.x on action potential characteristics and propagation patterns, cultures were treated with tertiapin or transduced with lentiviral vectors encoding Kcnj3 - or Kcnj5 -specific shRNAs. Kir3.1 and Kir3.4 were expressed in atrial but not in ventricular cardiomyocyte cultures. Tertiapin prolonged action potential duration (APD; 54.7±24.0 to 128.8±16.9 milliseconds; P <0.0001) in atrial cultures during reentry, indicating the presence of I K,ACh-c . Furthermore, tertiapin decreased rotor frequency (14.4±7.4 to 6.6±2.0 Hz; P <0.05) and complexity (6.6±7.7 to 0.6±0.8 phase singularities; P <0.0001). Knockdown of Kcnj3 or Kcnj5 gave similar results. Blockade of I K,ACh-c prevented/terminated reentry by prolonging APD and changing APD and conduction velocity restitution slopes, thereby altering the probability of APD alternans and rotor destabilization. Whole-heart mapping experiments confirmed key findings (eg, >50% reduction in atrial fibrillation inducibility after I K,ACh-c blockade). Conclusions— Atrium-specific Kir3.x controls the induction, dynamics, and termination of fibrillation by modulating APD and APD/conduction velocity restitution slopes in atrial tissue with I K,ACh-c . This study provides new molecular and mechanistic insights into atrial tachyarrhythmias and identifies Kir3.x as a promising atrium-specific target for antiarrhythmic strategies.

Action potential shortening rescues atrial calcium alternans

“…), acetylcholine‐activated (Bingen et al . ) and ultra‐rapid rectifier (Ravens & Wettwer, ) K + channels are predominantly expressed in the atria. In addition, mutations in Kv7.1 (Chen et al .…”

Mechanisms of arrhythmogenesis related to calcium-driven alternans in a model of human atrial fibrillation

“…However, the mechanisms underlying alternans may differ, since calcium handling is altered between paroxysmal and chronic AF20. In paroxysmal AF, evidence suggests that SK channels40, acetylcholine-activated K + current41, and late Na + current42 may play a more prominent role in alternans propensity and arrhythmogenesis. Given the arrhythmogenic implications of APD alternans presented in this and other studies, these differences in the fundamental mechanisms underlying APD alternans in paroxysmal versus chronic AF underscore the need for further research on the diversity of AF mechanisms2, in order to develop better targeted, patient-specific therapies.…”

Potassium channels related to primary aldosteronism: Expression similarities and differences between human and rat adrenals

“…The role of KCNJ5 in mice has been previously studied in the heart (Liang et al, 2014; Mesirca et al, 2013) and in a mouse cardiac muscle cell line (Nobles et al, 2010). In rats, KCNJ5 has also been studied in cardiac tissue (Atkinson et al, 2013; Bingen et al, 2013), and in kidney tissue of obese rats (Kang et al, 2013). However, to date, no studies have investigated the role of KCNJ5 in the adrenal cortex or in aldosterone regulation in rodents.…”