© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
The hibernators heart
Nature's response to arrhythmogenesis?
Department of Medical Physiology, University Medical Center, PO Box 80043, 3508 TA Utrecht, The Netherlands
* Corresponding author. Tel.: +31-30-253-8900; fax: +31-30-253-9036 t.opthof{at}med.uu.nl
Received 20 March 2000; accepted 23 March 2000
See article by Saitongdee et al. [1] (pages 108–115) in this issue.
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1 Introduction |
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 Top 1 Introduction 2 Conduction at low...3 Hibernators: paradigma of...References |
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In this issue, Saitongdee et al. [1] describe an increase in connexin43, the major constituent of gap junctions in ventricular muscle [2], in hamsters (Mesocricetus auratus) exposed to circumstances that provoke hibernation of the animals. The hamsters were subjected to a temperature of 5°C in combination with 2 h of light per 24 h during a period of 8–10 weeks after a gradual transition from normal conditions to hypothermia. During control conditions the temperature was 20°C with a 8:16-h light/dark circadian photoperiod. Reduction of temperature and light period was 1°C and 30 min per day, respectively. This procedure led to the induction of hibernation in some, but not all animals. The latter were considered cold controls. Interestingly, the area density of connexin43 was 2.5 times as large in hibernators compared with controls (deduced from Fig. 2 in Ref. [1]) with the ‘cold controls’ in between. Both the number and the dimensions of the gap junctions increased. The increase in connexin43 was not only observed in the animals that actually hibernated, but also in the animals that did not, despite the presence of identical environmental stimuli. This suggests that the environmental stimuli and not primarily the body temperature (which was 5°C in hibernating animals and normal in ‘cold controls’) cause the increase in connexin43. Arousal, which is the biological term for full ‘warming-up’ from hibernation after normal temperature and photoperiod have been reinstalled, restores control connexin43 levels within 2 h.
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2 Conduction at low temperature |
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Top1 Introduction2 Conduction at low...3 Hibernators: paradigma of...References |
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Cardiac action potential propagation depends on the combination of action potential upstroke velocity and electrical cell-to-cell communication via gap junctions. Geometrical factors play an additional role. Action potential upstroke velocity strongly depends on the Na+-channel gating kinetics and conductance, which both depend on temperature [3,4]. The information on the effect of hypothermia on cardiac gap junctional conductance is limited. Between isolated neonatal rat heart cell pairs, both overall gap junctional conductance and single gap junction channel conductance are reduced by 65–75% when temperature drops from normal to 0°C [5]. Similar temperature dependent changes in single channel gap junction conductance have been reported for embryonic chicken myocytes, in concert with a reduction in channel open probability [6]. Impaired Na+ channel function and decreased gap junctional conductance, both predict a decrease in conduction velocity at low temperature. Data on conduction velocity in intact ventricle at low temperatures are sparse. Most reports deal with relatively mild hypothermia (25°C) in non-hibernating species compared to the low body temperatures reached during hibernation (<10°C). Thus, in dogs, an acute 12°C drop in body temperature renders the heart more susceptible to ventricular fibrillation in association with a marked prolongation of action potential duration (i.e. QT-interval) and a decrease in conduction velocity [7].
There is, in general, a lack in knowledge with respect to the consequences of changes in gap junction density for conduction velocity [8]. However, redistribution of gap junctions (without changing the total amount of connexin43) from intercalated disks towards the sides of ventricular myocytes resulting from experimentally induced hypertrophy, decreases longitudinal conduction velocity by 25% [9]. It is impossible to predict whether the increase in connexin43 observed in the paper of Saitongdee et al. [1] has any functional consequence at all [8], let alone whether it compensates for (i) decreased conduction velocity, or for (ii) decreased gap junction conductance, or that it (iii) may create supranormal conduction velocity as an anti-arrhythmic defense mechanism at low temperature.
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3 Hibernators: paradigma of adaptation to arrhythmogenesis |
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Top1 Introduction2 Conduction at low...3 Hibernators: paradigma of...References |
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Extirpating a mammalian heart, handling it in cold Tyrode's solution and rewarming it to normal temperature in Langendorff perfusion will inevitably cause ventricular fibrillation. However, the heart of hibernators is an exception to this rule. Neither during the onset of hibernation, which is a gradual process, nor during arousal which only takes hours, ventricular fibrillation occurs despite the fact that the body temperature may increase by over 30°C within 2 h [10]. This in itself makes the hibernator's heart of interest. Hibernators have short QT intervals and their T waves are much steeper than in non-hibernators of comparable size [11,12]. In the hedgehog, the QT interval is only 7% of the cycle length during hibernation, although it is 47% during the summer when the animal is awake. Thus, although heart rate during hibernation may be as low as 2–12 beats/min [11,13], the QT interval is not longer than 330 ms [13]. Short refractoriness in itself is considered a risk for reentrant arrhythmias [14], but hibernators may have handled this problem by creating a minimum in dispersion of the moment of recovery from inexcitability, which can be appreciated from the unusual steep ‘T complex’ [11]. Hearts of hibernators also have a lower maximum driving frequency than hearts of non-hibernators [12]. Comparison of effective refractory periods at the same cycle lengths and temperatures in hibernating (hedgehog) and non-hibernating animals (guinea-pig) of comparable size shows that these values are always shorter in the hibernator [15]. An important difference between hibernating and non-hibernating species appears to be that the hibernator is capable to prevent excessive increase in refractoriness at low temperature and low heart rate. In other words, these animals cannot produce long QT intervals. Given the relatively short QT interval of hibernators, this suggests that these species may have developed postrepolarization refractoriness under normoxic conditions.
Another interesting characteristic of the heart of hibernators is that ‘winterhearts’ behave different from ‘summerhearts’, even if they are considered at the same — normal — temperature. Summerhearts, but not winterhearts of the woodchuck (Marmota monax) develop ventricular fibrillation after warming-up from 0–3°C to 30–45°C [15]. Differences between hearts isolated from hibernating and non-hibernating individuals from the same species assessed at normothermia point to reversible changes.
Restriction of sympathetic innervation to the conduction system and coronary vessels of the heart of hibernators has previously been reported [16] and may present another intrinsic defense mechanism to avoid inhomogeneity. Thus, the working ventricular myocardium of hibernators relies completely on the interaction between systemic catecholamines and receptors with minimal contribution of locally released neurogenic catecholamines. It is of interest that sympathetic stimulation increases dispersion in refractoriness [17,18], whereas systemic administration of catecholamines does not [17,19].
Although the study of Saitongdee et al. [1] in this issue unfortunately does not provide us with functional data, the increase in connexin43 in the hamster ventricle of the hibernating animals may constitute an interesting third dynamic adaptation mechanism. In addition to the steep ‘T-complex’ and the absence of sympathetic innervation of the working ventricular myocardium, the increase in connexin43 may serve as a mechanism to avoid potentially arrhythmogenic low conduction velocity during hibernation.
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References |
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