Adverse Remodeling of the Electrophysiological Response to Ischemia–Reperfusion in Human Heart Failure Is Associated With Remodeling of Metabolic Gene Expression

Abstract

Background Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia-reperfusion (I-R), although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute I-R in heart failure, and its potential causes, including the remodeling of metabolic gene expression. Methods and Results We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D). Preparations were subjected to 30 minutes of global ischemia, followed by 30 minutes of reperfusion. Failing hearts had exaggerated electrophysiological responses to I-R, with greater action potential duration (APD) shortening (p<0.001 at 8 minutes ischemia; p=0.001 at 12 minutes ischemia) and greater conduction slowing during ischemia, delayed recovery of electrical excitability following reperfusion (F 4.8±1.8 vs. D 1.0±0 mins, p<0.05), and incomplete restoration of APD and conduction velocity early after reperfusion. Expression of 46 metabolic genes were probed using custom-designed TaqMan arrays, using extracted RNA from 15 failing and 9 donor hearts. Ten genes important in cardiac metabolism were downregulated in heart failure, with SLC27A4 and KCNJ11 significantly downregulated at a false discovery rate of 0%. Conclusions We demonstrate, for the first time in human hearts, that the electrophysiological response to I-R in heart failure is accelerated during ischemia with slower recovery following reperfusion. This can enhance spatial conduction and repolarization gradients across the ischemic border and increase arrhythmia susceptibility. This adverse response was associated with downregulation of expression of cardiac metabolic genes.

Letter by Ng and Efimov Regarding Article, “Electrophysiological Effects of Selective Atrial Coronary Artery Occlusion in Humans”

“…We previously studied the electrophysiological effects of acute myocardial ischemia in explanted human hearts using high-resolution optical mapping, 2,3 and reported progressive slowing of local conduction velocities with ischemia, consistent with the slowing of intra-atrial conduction observed in this study. Furthermore, we also mapped repolarization changes and confirmed the progressive shortening of action potential durations with ischemia in human.…”

“…Both intraoperative recordings performed during acute ischemia, 4,5 and our work on explanted human hearts, 2,3 point towards the rapid onset of ischemia-induced electrophysiological changes in humans, with changes in conduction and repolarization firmly established approximately 10 minutes after onset of ischemia. Does the time course of electrophysiological changes in human atria mirror that of the ventricles?…”

Transmural electrophysiological heterogeneity, the T-wave and ventricular arrhythmias

“…In the presence of disease uncoupling may occur, as in heart failure, and M cell behavior might become apparent. However, Ng et al did not find M cell behavior in wedge preparations from human end-stage failing hearts (Ng et al, 2014).…”

“…Other studies using optical and electrical mapping have demonstrated that the transmural repolarization gradient is small and cannot entirely account for the duration of the T-wave (Anyukhovsky et al, 1999;Boukens et al, 2015;Janse et al, 2011;Meijborg et al, 2014;Rodriguez-Sinovas et al, 1997). Furthermore, recent studies in human left ventricular wedge preparations did not show a subpopulation of M-cells Glukhov et al, 2012;Glukhov et al, 2010;Ng et al, 2014). Lou et al did observe a small island of myocytes in the midmyocardium with longer action potential than the adjacent subendocardial or subepicardial myocytes in 3 out of 5 preparations (Lou et al, 2011).…”

Kcnj11 Ablation Is Associated With Increased Nitro-Oxidative Stress During Ischemia-Reperfusion Injury

“…While KCNJ11 transcript levels in patients with heart failure have been reported, the patient population in the study was not specifically ICM, but rather a group with mixed etiologies of heart failure. 33 The current study specifically compared known ICM patient samples to control patient samples thereby, definitively establishing that KCNJ11 transcript level is decreased in ICM. Prior work has suggested K ATP channel expression and function is decreased with age in animal models 34, 35 , however, this was predominantly due to a decrease in SUR2A gene expression.…”