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

McGlynn, Karen Patricia (2017) The effect of hypothermia and rewarming on cardiac electrophysiology and mechanical function. PhD thesis, University of Glasgow.

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Abstract

Hypothermia is defined as a core body temperature of 35°C or less and can be induced (i.e. therapeutic) or accidental. It is well established that hypothermia leads to a positive inotropic response which causes an increase in the magnitude of cardiac contraction, however rewarming from hypothermia is associated with a negative inotropic response, and the underlying mechanisms of this remain unclear. Accidental hypothermia is further complicated by risk of ventricular arrhythmias and cardiac arrest. This contributes to high mortality rates among these patients. Although hypothermia is used extensively as a therapeutic intervention and survival is possible after extreme exposure, treatment of arrhythmias during rewarming is still challenging. In order to develop targeted anti-arrhythmic strategies in this very specific situation, we first need to understand the basis for pro-arrhythmia during cooling and rewarming. This study aimed to examine the effect of hypothermia and rewarming on aspects of cardiac inotropy and excitability. An in vitro model of hypothermia and rewarming using isolated rat ventricular cardiomyocytes showed that following 3 hours of hypothermia there was a significant reduction in shortening upon rewarming. This was not accompanied by a change in intracellular Ca2+, suggesting a rewarming induced decrease in myofilament sensitivity to Ca2+. In separate experiments, animals underwent an in vivo hypothermia/rewarming procedure and displayed evidence of rewarming induced contractile dysfunction. Epicardial action potential (AP) measurements on these hearts showed a shortened AP duration (APD) when compared to normothermic control animals, which suggests that a sustained electrophysiological effect that could manifest as a shortened QT interval. In contrast to this, a period of transient hypothermia had alternative detrimental effects on the cardiac APD when compared to prolonged hypothermia, an effect that could predispose to the induction of long QT related arrhythmias and ventricular 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 severe hypothermia all ECG parameters were prolonged. Ventricular activation times were unaffected at 31°C whilst action potential duration (APD90) was significantly prolonged. At 17°C there were significant and proportionally similar delays in both activation and repolarisation. Ventricular fibrillation (VF) threshold was significantly reduced at 31°C (pro-arrhythmic), but at 17°C VF threshold was >2x baseline (37°C) (anti-arrhythmic). At 31°C, transverse conduction (CVt) was relatively insensitive to cooling versus longitudinal conduction (CVl) but at 17°C both CVt and CVl were proportionately reduced to a similar extent. The gap junction uncoupler heptanol had a larger relative effect on CVt than CVl, and at 31°C was able to restore the CVt/CVl ratio, returning VF threshold to baseline values. This suggests that moderate hypothermia creates repolarisation abnormalities and is pro-arrhythmic. These divergent effects appear to be linked to a lower temperature sensitivity of gap junctions, a conclusion supported by the anti-arrhythmic effect of heptanol at 31°C.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Hypothermia, cardiac, electrophysiology.
Subjects: Q Science > QP Physiology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Funder's Name: UNSPECIFIED
Supervisor's Name: Smith, Professor Godfrey
Date of Award: 2017
Depositing User: Karen McGlynn
Unique ID: glathesis:2017-8169
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 18 May 2017 13:32
Last Modified: 10 Jun 2017 11:31
URI: http://theses.gla.ac.uk/id/eprint/8169

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