Zasadny Frederick M, Dyavanapalli Jhansi, Dowling N Maritza, Mendelowitz David, Kay Matthew W
Biomedical Engineering, George Washington University, United States.
Pharmacology and Physiology, George Washington University, United States.
Am J Physiol Heart Circ Physiol. 2020 Oct 2;319(6):H1358-68. doi: 10.1152/ajpheart.00293.2020.
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 trans-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 weeks of TAC with or without 12 weeks of daily chemogenetic treatment. Action potential duration (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 to untreated TAC hearts. Variance of conduction loss was reduced in treated hearts compared to untreated hearts during fast pacing. However, CV was markedly reduced in both treated and untreated TAC hearts throughout dynamic pacing. At 150msec pacing cycle length, APD60 v. diastolic interval (DI) dispersion was reduced in treated hearts compared to untreated hearts.
Chronic activation of cardiac cholinergic neurons improved electrophysiological adaptation to increases in pacing rate during development of TAC-induced heart failure. This provides insight into the electrophysiological benefits of cholinergic stimulation as a treatment for heart failure patients.
在衰竭心肌中，左心室（LV）电活动对心率增加的适应不良会导致发病和死亡。最近，心脏胆碱能神经元激活减少了大鼠慢性经主动脉缩窄（TAC）导致的收缩功能丧失。我们假设心脏胆碱能神经元的慢性激活也会减少TAC诱导的心脏电活动紊乱。
我们研究了TAC大鼠心脏的电生理速率适应性，这些大鼠心脏在有或没有每日对下丘脑催产素神经元进行化学遗传激活以刺激下游心脏胆碱能神经元的情况下。在TAC 16周后，有或没有12周每日化学遗传治疗，切除Sprague Dawley大鼠心脏，进行灌注，并在动态起搏下进行光学标测。分析动作电位持续时间（APD60）和传导速度（CV）图，以了解区域对动态起搏的速率适应性。
在较低起搏速率下，未治疗的TAC导致左心室心外膜APD60升高。治疗后的TAC心脏中拟合的APD60稳态（APDss）降低。在较高起搏速率下，与未治疗的TAC心脏相比，治疗使APD60异质性降低。在快速起搏期间，与未治疗的心脏相比，治疗后心脏的传导损失方差降低。然而，在整个动态起搏过程中，治疗组和未治疗组的TAC心脏的CV均显著降低。在150毫秒起搏周期长度时，与未治疗的心脏相比，治疗后的心脏中APD60与舒张间期（DI）离散度降低。
心脏胆碱能神经元的慢性激活改善了TAC诱导的心力衰竭发展过程中对起搏速率增加的电生理适应性。这为胆碱能刺激作为心力衰竭患者治疗方法的电生理益处提供了见解。
