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
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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