The effect of hypothermia and rewarming on cardiac electrophysiology and mechanical function

[摘要] Hypothermia is defined as a core body temperature of 35°C or less and can beinduced (i.e. therapeutic) or accidental. It is well established that hypothermialeads to a positive inotropic response which causes an increase in the magnitudeof cardiac contraction, however rewarming from hypothermia is associated witha negative inotropic response, and the underlying mechanisms of this remainunclear. Accidental hypothermia is further complicated by risk of ventriculararrhythmias and cardiac arrest. This contributes to high mortality rates amongthese patients. Although hypothermia is used extensively as a therapeuticintervention and survival is possible after extreme exposure, treatment ofarrhythmias during rewarming is still challenging. In order to develop targetedanti-arrhythmic strategies in this very specific situation, we first need tounderstand the basis for pro-arrhythmia during cooling and rewarming. Thisstudy aimed to examine the effect of hypothermia and rewarming on aspects ofcardiac inotropy and excitability.An in vitro model of hypothermia and rewarming using isolated rat ventricularcardiomyocytes showed that following 3 hours of hypothermia there was asignificant reduction in shortening upon rewarming. This was not accompaniedby a change in intracellular Ca2+, suggesting a rewarming induced decrease inmyofilament sensitivity to Ca2+. In separate experiments, animals underwent anin vivo hypothermia/rewarming procedure and displayed evidence of rewarminginduced contractile dysfunction. Epicardial action potential (AP) measurementson these hearts showed a shortened AP duration (APD) when compared tonormothermic control animals, which suggests that a sustainedelectrophysiological effect that could manifest as a shortened QT interval. Incontrast to this, a period of transient hypothermia had alternative detrimentaleffects on the cardiac APD when compared to prolonged hypothermia, an effectthat could predispose to the induction of long QT related arrhythmias andventricular tachycardia.Separate experiments assessed the effect of moderate (31˚C) and severe (17˚C)hypothermia on cardiac excitability in Langendorff perfused rabbit hearts.Moderate hypothermia prolonged PR and QT intervals whilst in severehypothermia all ECG parameters were prolonged. Ventricular activation timeswere unaffected at 31°C whilst action potential duration (APD90) wassignificantly prolonged. At 17°C there were significant and proportionally similardelays in both activation and repolarisation. Ventricular fibrillation (VF)threshold was significantly reduced at 31°C (pro-arrhythmic), but at 17°C VFthreshold was >2x baseline (37°C) (anti-arrhythmic). At 31°C, transverseconduction (CVt) was relatively insensitive to cooling versus longitudinalconduction (CVl) but at 17°C both CVt and CVl were proportionately reduced to asimilar extent. The gap junction uncoupler heptanol had a larger relative effecton CVt than CVl, and at 31°C was able to restore the CVt/CVl ratio, returning VFthreshold to baseline values. This suggests that moderate hypothermia createsrepolarisation abnormalities and is pro-arrhythmic. These divergent effectsappear to be linked to a lower temperature sensitivity of gap junctions, aconclusion supported by the anti-arrhythmic effect of heptanol at 31°C.

[发布机构] University:University of Glasgow;Department:Institute of Cardiovascular and Medical Sciences

[关键词] Hypothermia, cardiac, electrophysiology.