Abstract
Left ventricular (LV) electrical maladaptation to increased heart rate in failing myocardium contributes to morbidity and mortality. Recently, cardiac cholinergic neuron activation reduced loss of contractile function resulting from chronic transverse-ascending aortic constriction (TAC) in rats. We hypothesized that chronic activation of cardiac cholinergic neurons would also reduce TAC-induced derangement of cardiac electrical activity. We investigated electrophysiological rate adaptation in TAC rat hearts with and without daily chemogenetic activation of hypothalamic oxytocin neurons for downstream cardiac cholinergic neuron stimulation. Sprague–Dawley rat hearts were excised, perfused, and optically mapped under dynamic pacing after 16 wk of TAC with or without 12 wk of daily chemogenetic treatment. Action potential duration at 60% repolarization (APD60) and conduction velocity (CV) maps were analyzed for regional rate adaptation to dynamic pacing. At lower pacing rates, untreated TAC induced elevated LV epicardial APD60. Fitted APD60 steady state (APDss) was reduced in treated TAC hearts. At higher pacing rates, treatment heterogeneously reduced APD60, compared with untreated TAC hearts. Variance of conduction loss was reduced in treated hearts compared with untreated hearts during fast pacing. However, CV was markedly reduced in both treated and untreated TAC hearts throughout dynamic pacing. At 150 ms pacing cycle length, APD60 versus diastolic interval dispersion was reduced in treated hearts compared with untreated hearts. Chronic activation of cardiac cholinergic neurons improved electrophysiological adaptation to increases in pacing rate during the development of TAC-induced heart failure. This provides insight into the electrophysiological benefits of cholinergic stimulation as a treatment for patients with heart failure.NEW & NOTEWORTHY Analysis of electrophysiology from optical mapping of failing left ventricular myocardium provided insight into the possible therapeutic outcomes of cholinergic stimulation within the left ventricle. Chronic hypothalamic oxytocin neuron activation for downstream cardiac cholinergic neuron stimulation blunted onset of failing electrophysiology induced by pressure overload-induced heart failure in rats.
Highlights
Despite major medical advances, morbidity and mortality from cardiac arrhythmia remain high in patients with heart failure [5, 8, 22, 35]
transverse-ascending aortic constriction (TAC) hearts had significantly increased global APD60 mean at 250 ms pacing cycle length (PCL) compared with Sham hearts (P = 0.0108), but not when compared with TAC + CNO hearts (P = 0.1842)
At the shorter 150 ms PCL, global APD60 mean converged for all groups (Fig. 3A); TAC and TAC + CNO hearts continued to exhibit APD60 heterogeneity across the left ventricular (LV) (Fig. 2B)
Summary
Morbidity and mortality from cardiac arrhythmia remain high in patients with heart failure [5, 8, 22, 35]. Action potential (AP) prolongation [46], alterations in conduction [26], altered sodium and calcium homeostasis [6], autonomic imbalance [41], and maladaptive signaling create an arrhythmogenic substrate [47]. Both reentrant and focal mechanisms have been reported in the initiation and maintenance of ventricular tachyarrhythmias within failing myocardium [12, 21, 26, 39]. The amount by which the electrical activity of cardiomyocytes adapts to changes in heart rate, quantified by restitution curves, influences arrhythmia maintenance [16, 50].
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