Moderate but not severe hypothermia causes pro-arrhythmic changes in cardiac electrophysiology

Abstract

Aims Treatment of arrhythmias evoked by hypothermia/rewarming remains challenging, and the underlying mechanisms are unclear. This in vitro experimental study assessed cardiac electrophysiology in isolated rabbit hearts at temperatures occurring in therapeutic and accidental hypothermia. Methods and results Detailed ECG, surface electrogram, and panoramic optical mapping were performed in isolated rabbit hearts cooled to moderate (31°C) and severe (17°C) hypothermia. Ventricular activation was unchanged at 31°C while action potential duration (APD) was significantly prolonged (176.9 ± 4.2 ms vs. 241.0 ± 2.9 ms, P < 0.05), as was ventricular repolarization. At 17°C, there were proportionally similar delays in both activation and repolarization. These changes were reflected in the QRS and QT intervals of ECG recordings. Ventricular fibrillation threshold was significantly reduced at 31°C (16.3 ± 3.1 vs. 35 ± 3.5 mA, P < 0.05) but increased at 17°C (64.2 ± 9.9, P < 0.05). At 31°C, transverse conduction was relatively unchanged by cooling compared to longitudinal conduction, but at 17°C both transverse and longitudinal conduction were proportionately reduced to a similar extent. The gap junction uncoupler heptanol had a larger relative effect on transverse than longitudinal conduction and was able to restore the transverse/longitudinal conduction ratio, returning ventricular fibrillation threshold to baseline values (16.3 ± 3.1 vs. 36.3 ± 4.3 mA, P < 0.05) at 31°C. Rewarming to 37°C restored the majority of the electrophysiological parameters. Conclusions Moderate hypothermia does not significantly change ventricular conduction time but prolongs repolarization and is pro-arrhythmic. Further cooling to severe hypothermia causes parallel changes in ventricular activation and repolarization, changes which are anti-arrhythmic. Therefore, relative changes in QRS and QT intervals (QR/QTc) emerge as an ECG-biomarker of pro-arrhythmic activity. Risk for ventricular fibrillation appears to be linked to the relatively low temperature sensitivity of ventricular transmural conduction, a conclusion supported by the anti-arrhythmic effect of heptanol at 31°C.

Resistance to ventricular fibrillation predicted by the QRS/QTc - ratio in an intact rat model of hypothermia/rewarming

“…An underlying depolarisation-repolarisation mismatch is apparent in rabbit hearts, a species with similar cardiac electrophysiology to humans. This mismatch was prominent at 31 °C and was associated with a doubled risk for inducing ventricular brillation (VF) [7]. Further temperature reduction, towards 20 °C and below, appears anti-arrhythmic in these experiments [4,6,7].…”

“…However, recent efforts with translational research into this topic have given possible groundbreaking results [6]. In rabbit, both increased ventricular divergence [9] and heterogenic effect of hypothermia on transmural and longitudinal conduction [7] has been documented at 30 °C, with increased risk for developing VF. Cooling to 30 °C also enhanced epicardial APD dispersion, wavebreaks and re-entry, associated with increased vulnerability to pacing-induced VF [8].…”

“…In a series of recent preclinical experiments, we have investigated the pathophysiology of hypothermiainduced VF and cardiac arrest (HCA) [4,6,7]. Our ndings show that moderate hypothermia (32 − 28 °C)…”

“…is pro-arrhythmic [4,6,7]. An underlying depolarisation-repolarisation mismatch is apparent in rabbit hearts, a species with similar cardiac electrophysiology to humans.…”

“…In contrast to rabbits that have cardiac electrophysiology resembling humans and are at risk for developing hypothermia-induced VF [4,[7][8][9], rats do not regularly develop VF, even during several hours of exposure to core temperatures between 15 − 13 °C [10][11][12]. Therefore, in the present study we decided to investigate cardiac electrophysiology using our well-established rat model of severe hypothermia Anesthesia: Anesthesia was introduced intraperitoneally by 55 mg/kg pentobarbital sodium and 50 µg/kg fentanyl, followed by a continuous infusion of 7.5 mg/kg/hour pentobarbital sodium and 50 µg/kg/hour fentanyl through an intravenous line in the right jugular vein, extended to the right auricle.…”