Mild hypothermia decreases arrhythmia susceptibility in a canine model of global myocardial ischemia*

Abstract

Objectives: Although the majority of sudden cardiac arrests occur in patients with ischemic heart disease, the effect of therapeutic hypothermia on arrhythmia susceptibility during acute global ischemia is not well understood. While both ischemia and severe hypothermia are arrhythmogenic, patients undergoing therapeutic hypothermia do not have an increase in arrhythmias, despite the fact that most sudden cardiac arrest occur in the setting of ischemia. We hypothesized that mild hypothermia induced prior to myocardial ischemia and reperfusion will have a beneficial effect on ischemia-related arrhythmia substrates.

Design: We developed a model of global ischemia and reperfusion in the canine wedge preparation to study the transmural electrophysiologic effects of ischemia at different temperatures.

Setting: Animal study.

Subjects: Male mongrel dogs.

Interventions: Canine left ventricle wedge preparations at 1) control (36°C) or 2) mild hypothermia, to simulate temperatures used in therapeutic hypothermia (32°C), were subjected to 15 mins of no-flow ischemia and subsequently reperfused.

Measurements and main results: Optical action potentials were recorded spanning the transmural wall of left ventricle. Action potential duration for epicardial, mid-myocardial, and epicardial cells was measured. Transmural dispersion of repolarization and conduction velocity were measured at baseline, during ischemia, and during reperfusion. No difference was seen at baseline for conduction velocity or dispersion of repolarization between groups. Conduction velocity decreased from 0.46 ± 0.02 m/sec to 0.23 ± 0.07 m/sec, and dispersion of repolarization increased from 30 ± 5 msecs to 57 ± 4 msecs in the control group at 15 mins of ischemia. Mild hypothermia attenuated both the ischemia-induced conduction velocity slowing (decreasing from 0.44 ± 0.02 m/sec to 0.35 ± 0.03 m/sec; p = .019) and the ischemia-induced increase in dispersion of repolarization (25 ± 3 msecs to 37 ± 7 msecs; p = .037). Epicardial conduction block was observed in six of seven preparations of the control group, but no preparations in the mild hypothermia group developed conduction block (0/6).

Conclusions: Mild hypothermia attenuated ischemia-induced increase in dispersion of repolarization, conduction slowing, and block, which are known mechanisms of arrhythmogenesis in ischemia. These data suggest that therapeutic hypothermia may decrease arrhythmogenesis during myocardial ischemia.

Figure 1. Mild hypothermia attenuates ischemia-induced derangements in action potential duration, conduction time and repolarization gradients

Panel A. Representative action potentials from each cell type during ischemia and reperfusion from the control group are shown. ECG is also shown. Left. Action potentials at baseline demonstrate a baseline dispersion of 20 ms. Middle. During ischemia, marked prolongation of dispersion is observed, secondary to significant epicardial action potential duration shortening. Right. After 10 min reperfusion, dispersion and action potential duration returns toward baseline. Panel B. Representative action potentials during ischemia and reperfusion from the mild hypothermia group are shown. ECG is also shown. Left. Action potentials at baseline. Middle. During ischemia epicardial shortening is attenuated. Right. After 10 min reperfusion, dispersion returns to baseline.

Figure 1. Mild hypothermia attenuates ischemia-induced derangements in action potential duration, conduction time and repolarization gradients

Panel A. Representative action potentials from each cell type during ischemia and reperfusion from the control group are shown. ECG is also shown. Left. Action potentials at baseline demonstrate a baseline dispersion of 20 ms. Middle. During ischemia, marked prolongation of dispersion is observed, secondary to significant epicardial action potential duration shortening. Right. After 10 min reperfusion, dispersion and action potential duration returns toward baseline. Panel B. Representative action potentials during ischemia and reperfusion from the mild hypothermia group are shown. ECG is also shown. Left. Action potentials at baseline. Middle. During ischemia epicardial shortening is attenuated. Right. After 10 min reperfusion, dispersion returns to baseline.

Figure 2. Mild hypothermia attenuates ischemia-induced dispersion of repolarization

Summary data is shown in mild hypothermia and control groups during ischemia and reperfusion. No difference in transmural dispersion of repolarization was observed at baseline. Significant increase is observed at 15 min ischemia in the control group compared to therapeutic hypothermia group (denoted by *). Overall group by time difference was significant (p=.007)

Figure 3. Mild hypothermia attenuates ischemia- induced transmural conduction slowing

Activation maps of the transmural surface of the canine wedge preparation for conduction time are shown at baseline, 15 min ischemia, and 10 min reperfusion for control and therapeutic hypothermia groups Top. Control group. Ischemia increased conduction time and produced epicardial conduction block; both returned to baseline upon reperfusion. Bottom. Mild Hypothermia Group. Conduction slowing is attenuated during ischemia compared to the control group and returns to baseline upon reperfusion. No epicardial block is observed.

Figure 4. Mild hypothermia attenuates conduction slowing

Summary data is shown for mild hypothermia and control groups during ischemia and reperfusion. No difference in conduction velocity was seen at baseline. Significant increase is seen at 15 min ischemia in the control group compared to mild hypothermia group (denoted by *). Overall group by time difference was significant (p=.027)

Figure 5. Arrhythmia secondary to conduction block during ischemia

Panel A. ECG and action potentials during programmed electrical stimulation are shown. Three endocardial paced beats (S1, S2, S3) are followed by induction of ventricular tachycardia. Panel B. Activation mapping before ischemia compared to 15 minutes of ischemia (S1 beat). Note that ischemia induces significant conduction slowing (crowding of isochrones). During ischemia, conduction fails in the epicardium (area with dashed line). Conduction block occurs during the S3 beat (block symbol in panel A ,red line in panel B) followed by the initiation of ventricular tachycardia, with the first beat reentering through the more electrically preserved subepicardium.