Effects of different dosages esketamine on cardiac conduction and heterogeneity of Cx43: the epicardial mapping in guinea pigs

Ying Cao; Yingnan Song; Zijun Wang; Jian Tang; Jing Yi; Yanqiu Liu; Li An; Zhijun Pan; Hong Gao

doi:10.21037/atm-22-2614

Effects of different dosages esketamine on cardiac conduction and heterogeneity of Cx43: the epicardial mapping in guinea pigs

Ann Transl Med. 2022 Jul;10(14):772. doi: 10.21037/atm-22-2614.

Authors

Ying Cao^#^{1

2}, Yingnan Song^#³, Zijun Wang², Jian Tang⁴, Jing Yi^{1

5}, Yanqiu Liu⁶, Li An^{1

5}, Zhijun Pan^{1

2}, Hong Gao⁵

Affiliations

¹ School of Clinical Medicine, Guizhou Medical University, Guiyang, China.
² Department of Anesthesiology, The Affiliated Jinyang Hospital of Guizhou Medical University, The Second People's Hospital of Guiyang, Guiyang, China.
³ Translational Medicine Research Center of Guizhou Medical University, Guiyang, China.
⁴ Department of Anesthesiology, The First People's Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China.
⁵ Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
⁶ Department of Anesthesiology, The Fourth People's Hospital of Guiyang, Guiyang, China.

^# Contributed equally.

Abstract

Background: Esketamine is favored in clinical settings. Relative to other anesthetics it preserves protective airway reflexes, maintains spontaneous respiration, stabilizes hemodynamics, and alleviates neuropathic pain. This study sought to evaluate the cardiac safety of esketamine at 3 sub-anesthetic gradient concentrations.

Methods: We examined the cardiac electrophysiological effects of esketamine with infusion rates of 0.125, 0.25, and 0.5 mg·kg^-1·h^-1. Short-term studies were performed in ventricular myocytes using patch-clamp techniques and optically mapped Langendorff-perfused guinea-pig hearts. Long-term studies were performed using Langendorff-perfused guinea-pig hearts and electrically mapping the receipt of the infusion for 3 hours.

Results: Esketamine changed the action potential (AP) morphology of cardiomyocytes. Notably, it increased the resting membrane potential (RMP), attenuated the amplitude of action potential (APA), reduced the maximum upstroke velocity (Vmax), and shortened the action potential duration (APD) at 30% to 70%, which led to relatively prolonged monophasic action potentials (MAP) triangulation in G_0.25 and G_0.5. All the effects were partially eluted. Optical mapping demonstrated almost equal and heterogeneous conduction. G_0.125 resulted in an increased heart rate (HR) accompanied by a shortened APD. No detectable arrhythmia was observed at the cycle lengths (CLs) used. Long-term electrical mapping demonstrated the dose-dependent deceleration of the Vmax and APA, but only prolonged the AP parameters in G_0.5. Left-ventricular isochronal conduction maps revealed the conduction heterogeneities at G_0.5, and conduction velocity (CV) was increased in G_0.125 and G_0.25. None of these effects were reversed on drug washout. Electrocardiogram (ECG) traces revealed an accelerated HR with the associated curtailment of QT intervals in G_0.125; HRs were decreased in G_0.25 and G_0.5; the PR intervals and QRS duration differed between G_0.125 and G_0.25, G_0.5, which elicited electrical alternans. Connexin43 (Cx43) expression were significantly decreased in G_0.125, G_0.25 and G_0.5.

Conclusions: These data provide a basic electrophysiology for esketamine. Specifically, we found that (I) various methods of esketamine infusion had different effects on cardiac conduction at different dosages; (II) the heterogeneous expression of Cx43 is associated with spatially dispersed conduction; and (III) potential cardiac risks should be considered for high-risk patients receiving continuous esketamine infusions of high dosages.

Keywords: Connexin43 (Cx43); Esketamine; cardiac safety; electrical mapping; optical mapping.