Beneficial Electrophysiological Effects of Rotigaptide Are Unable to Suppress Therapeutic Hypothermia-Provoked Ventricular Fibrillation in Failing Rabbit Hearts With Acute Ischemia-Reperfusion Injury.

Hui-Ling Lee,Hung-Ta Wo,Hao-Tien Liu,Chung-Chuan Chou,Po-Cheng Chang,Ming-Shien Wen

doi:10.3389/fphys.2021.726389

Hui-Ling Lee, Hung-Ta Wo + Show 4 more

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https://doi.org/10.3389/fphys.2021.726389

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Abstract

Aims: Whether therapeutic hypothermia (TH) is proarrhythmic in preexisting failing hearts with acute ischemia–reperfusion (IR) injury is unknown. Additionally, the effectiveness of rotigaptide on improving conduction slowing in hearts with IR injury is ambiguous. We investigated the electrophysiological effects of TH and rotigaptide in failing rabbit hearts with acute IR injury and determined the underlying molecular mechanisms.Methods and Results: Heart failure was induced by right ventricular pacing (320 beats/min, 4 weeks). Rabbits with pacing-induced heart failure were randomly divided into TH (n = 14) and non-TH (n = 7) groups. The IR rabbit model was created by ligating the coronary artery for 60 min, followed by reperfusion for 15 min in vivo. Then, the hearts were excised quickly and Langendorff-perfused for simultaneous voltage and intracellular Ca2+ (Cai) optical mapping. Electrophysiological studies were conducted, and vulnerability to ventricular fibrillation (VF) was evaluated using pacing protocols. TH (33°C) was instituted after baseline studies, and electrophysiological studies were repeated. Rotigaptide (300 nM) was infused for 20 min, and electrophysiological studies were repeated under TH. Cardiac tissues were sampled for Western blotting. TH increased the dispersion and beat-to-beat variability of action potential duration (APD), aggravated conduction slowing, and prolonged Cai decay to facilitate spatially discordant alternans (SDA) and VF induction. Rotigaptide reduced the dispersion and beat-to-beat variability of APD and improved slowed conduction to defer the onset of arrhythmogenic SDA by dynamic pacing and elevate the pacing threshold of VF during TH. However, the effect of rotigaptide on TH-enhanced VF inducibility was statistically insignificant. TH attenuated IR-induced dysregulation of protein expression, but its functional role remained uncertain.Conclusion: Therapeutic hypothermia is proarrhythmic in failing hearts with acute IR injury. Rotigaptide improves TH-induced APD dispersion and beat-to-beat variability and conduction disturbance to defer the onset of arrhythmogenic SDA and elevate the VF threshold by dynamic pacing, but these beneficial electrophysiological effects are unable to suppress TH-enhanced VF inducibility significantly.

Highlights

Cardiac ischemia–reperfusion (IR) injury-induced downregulation of voltage-gated sodium current (INa) (Chang et al, 2018a) and alterations of gap junction uncoupling (De Groot and Coronel, 2004) are associated with conduction slowing and repolarization heterogeneities
We previously reported that conduction velocity (CV) in the IR zone (CVIR) is significantly slower than CV in the non-IR zone (CVnon−IR), which is associated with the upregulation of non-phosphorylated Cx43 (NP-Cx43) in the IR zone in failing rabbit hearts (Chou et al, 2020b)
We investigated the effects of Therapeutic hypothermia (TH) and rotigaptide administration on cardiac electrophysiological parameters and vulnerability to ventricular fibrillation (VF) by performing electrophysiological examinations and optical mapping studies

Summary

Introduction

Cardiac ischemia–reperfusion (IR) injury-induced downregulation of voltage-gated sodium current (INa) (Chang et al, 2018a) and alterations of gap junction uncoupling (De Groot and Coronel, 2004) are associated with conduction slowing and repolarization heterogeneities. Perturbations in electrophysiological properties during TH, including slow conduction velocity (CV), heterogeneous ventricular activations, and occurrence of spatially discordant alternans (SDA) (Hsieh et al, 2016), together might contribute to the proarrhythmic myocardial substrate and predispose hearts with acute IR injury to reentrant arrhythmias. The incidence of ventricular arrhythmia with hemodynamic instability was around 2.2% in patients with cardiac arrest due to ventricular fibrillation (VF) post-resuscitation undergoing TH (Hypothermia after Cardiac Arrest Study Group, 2002). Previous studies showed that heart failure enhances susceptibility to SDA, which markedly increases repolarization gradients and is associated with an increased incidence of inducible VF (Wilson et al, 2009). It is possible that TH enhances ventricular arrhythmias in failing hearts with acute IR injury

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