Carbon Monoxide Induces Cardiac Arrhythmia via Induction of the Late Na⁺ Current

Abstract

Rationale: Clinical reports describe life-threatening cardiac arrhythmias after environmental exposure to carbon monoxide (CO) or accidental CO poisoning. Numerous case studies describe disruption of repolarization and prolongation of the QT interval, yet the mechanisms underlying CO-induced arrhythmias are unknown. Objectives: To understand the cellular basis of CO-induced arrhythmias and to indentify an effective therapeutic approach. Methods: Patch-clamp electrophysiology and confocal Ca 21 and nitric oxide (NO) imaging in isolated ventricular myocytes was performed together with protein S-nitrosylation to investigate the effects of CO at the cellular and molecular levels, whereas telemetry was used to investigate effects of CO on electrocardiogram recordings in vivo. Measurements and Main Results: CO increased the sustained (late) component of the inward Na 1 current, resulting in prolongation of the action potential and the associated intracellular Ca 21 transient. In more than 50% of myocytes these changes progressed to early after-depolarization-like arrhythmias. CO elevated NO levels in myocytes and caused S-nitrosylation of the Na 1 channel, Na v 1.5. All proarrhythmic effects of CO were abolished by the NO synthase inhibitor L-NAME, and reversed by ranolazine, an inhibitor of the late Na 1 current. Ranolazine also corrected QT variability and arrhythmias induced by CO in vivo, as monitored by telemetry. Conclusions: Our data indicate that the proarrhythmic effects of CO arise from activation of NO synthase, leading to NO-mediated nitrosylation of Na V 1.5 and to induction of the late Na 1 current. We also show that the antianginal drug ranolazine can abolish CO-induced early after-depolarizations, highlighting a novel approach to the treatment of CO-induced arrhythmias.

Carbon monoxide inhibits inward rectifier potassium channels in cardiomyocytes

“…1). This is consistent to the previous report 14 . According to our results, the ratio, which represents the contribution of Na v 1.5 and Kir in the prolonged APs is approximately 3:4.…”

“…The possible candidate ion channels contribute to this prolonged AP include inward rectified K þ currents (Kir2.0) and the sustained (late) component of the inward Na þ current (late I Na ) (Na v 1.5) 14 . Ranolazine (Rano) is a common blocker for Na v 1.5 (ref.…”

A modern literature review of carbon monoxide poisoning theories, therapies, and potential targets for therapy advancement.

“…If CO poisoning were a simple reduction in available tissue oxygen and secondary tissue/organ hypoxia, then the relationship between the HbCO level and symptom severity should be nearly linear, but this is not the case. Furthermore, a simple hypoxic injury does not explain the strange cardiac dysrhythmias that often develop in the face of CO poisoning (Dallas et al, 2012;Gandini et al, 2001;Kalay et al, 2007). Likewise, it fails to explain the cognitive dysfunction that patients often develop, not immediately, but typically between 27 and 270 days post-injury (Choi, 1983;Piantadosi et al, 1997;Qingsong et al, 2013;Thom et al, 2004a).…”

Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload

“…Cellular arrhythmias were induced upon addition of H 2 O 2 (200 μmol/L). It is generally accepted that after-contractions and after-transients were defined as cellular proarrhythmogenic events, in which early after-transients/contractions (EATs/ EACs) may correspond to EADs and delayed after-transients/ contractions (DATs/DACs) may correspond to DADs [7,[20][21][22][23] . Therefore, EATs/EACs and DATs/DACs can be used as proximal direct indices of EADs-like and DADs-like arrhythmias, respectively.…”