SUMMARY

1. The hibernating mammals inherited a stable cardio-vascular function as a result of adaptation to extreme externaland internal environments during hibernation.

2. The cardiovascular function of a hibernator is character-ized by three distinct features: (i) tolerance of hypothermia; (ii)resistance to dysrhythmia; and (iii) endurance of hypoxia. Allthese have clinical relevance in cardiovascular disorders inhumans.

3. We suggest that the hibernating mammal can serve as a useful animal model for research into the cardiovascularsystem.

Key words: adaptation, cardiovascular research, dysrhyth-mia, hibernation, hypothermia, hypoxia.

INTRODUCTION

Cardiovascular diseases are stubborn foes of human health. Greatefforts have been made worldwide to combat them. However, millions of people still die of circulation problems. Innovative findings to combat cardiovascular diseases and to improve cardio-vascular function remain a challenging task.

Mammalian hibernation is an adaptation to cold weather andfood shortage. The body temperature (Tb) of a hibernator, usuallykept endothermically, as in other mammals, can be down-regulatedto a few degrees in winter and can also be restored in tens of min-utes by rapid heat production during arousal.1 The sustained deephypothermia during hibernation, steep Tb shift, strong sympatheticstimulation and over-driving state during arousal demand a verystable cardiovascular function.

Based on evidence from our laboratory and in the literature, wepostulated that the maintained stability of cardiovascular functionin hibernating mammals is of notable clinical significance.

EVIDENCE

So far, many investigations on hibernating mammals have suggested the stability of cardiovascular function in hibernatingmammals. From a clinical point of view, at least three aspects aremost important.

Tolerance of hypothermia

Tolerance of hypothermia is a fundamental property of hibernators.Most non-hibernating mammals, including humans, are not able tomaintain circulation under deep hypothermia. The dog dies fromcardiac arrest or severe ventricular fibrillation during hypothermianear 20°C Tb,2 whereas all hibernating mammals can shift their Tb

between 38°C and freezing point without endangering their lives,keeping a normal blood pressure of 90/30 mmHg with a main-tained autoregulation of coronary flow, even when Tb is near freez-ing point during hibernation.1

Hibernators show resistance to hypothermia at a cellular level.Cellular K+ in aortic strips from ground squirrels has been shown tofall from 147 to 138 mmol/L after 48 h exposure to 7°C, while inrats it falls from 151 to 14 mmol/L.3 Membrane potentials andexcitability are more stable in cardiac cells of hibernators.4 Actionpotentials of 60 mV have been recorded in ground squirrel myo-cardium super-cooled to –5°C.5 Cardiac myocytes from hibernatorsmaintain constant levels of intracellular free calcium6 and forcefulcontractility1,7 at 10°C or lower, in contrast with calcium overload6

and a loss of contractility1,7 below 25°C in non-hibernators.Tolerance of hypothermia changes with seasonal regulation of

hibernation cycle. Decrease of temperature down to 12°C causesless decay of the cardiac resting potential and action potential inhibernating hamsters than in non-hibernating individuals.8 Hypo-thermic contractility is also improved in the hibernating season,1

partially based on the enhanced function of the sarcoplasmic reticulum to regulate intracellular calcium.7,9,10

Resistance to dysrhythmia

During hibernation, the Tb of hibernators has to pass a critical bandat approximately 20°C, where non-hibernating mammals developsevere ventricular fibrillation,2 but fibrillation is never seen inhibernators during the entrance and arousal of hibernation. Evenslight dysrhythmia, such as intermittent periods of asystole andbradycardia, has been shown to result from strong sympatheticstimulation.11

Proceedings of the Second Scientific Symposium of Cardiovascular Science Across the Strait

MEDICAL SIGNIFICANCE OF CARDIOVASCULAR FUNCTION INHIBERNATING MAMMALS

Shi-Qiang Wang and Zeng-Quan Zhou

College of Life Sciences, Peking University, Beijing, China

Correspondence: Zeng-Quan Zhou, College of Life Sciences, PekingUniversity, Beijing 100871, China. E-mail: zhouzq@lsc.pku.edu.cn

Presented at the Second Scientific Symposium of CardiovascularScience Across the Strait, Dalian, China, April 1998.

Received 23 April 1999; accepted 10 May 1999.

Clinical and Experimental Pharmacology and Physiology (1999) 26, 837–839

838 S-Q Wang and Z-Q Zhou

More importantly, even at normal Tb, hibernators resist thedevelopment of dysrhythmia. Local application of aconitine,administration of CaCl2, K+-free perfusion, procaine injection afteradrenaline administration and ligation of the left descending coronary artery all failed to induce fibrillation in hibernators.12

Although electrical stimulation during a vulnerable period couldproduce ventricular fibrillation in a few hedgehogs, a higher stimulus strength was needed.12

Hibernators also show dysrhythmia resistance in some patho-logical conditions. During the ischaemia–reperfusion procedure,the heart of the ground squirrel, a hibernator, has been shown tosuffer less ventricular fibrillation and tachycardia than the heart ofthe rat, a non-hibernator.13

Resistance to dysrhythmia also exhibits seasonal variation. Theheart of the winter-hibernating woodchuck is completely free fromfibrillation during cooling, warming, puncture and administrationof noradrenaline, but this is not the case in summer-active indi-viduals.14 At the cellular level, after-depolarization often occursbetween 15 and 20°C in the myocardium of active ground squirrels, but never in hibernating ground squirrels (unpublishedobservations) and chipmunks, even after application of a cardio-tonic agent.15

Endurance of hypoxia

Hibernating hedgehogs were found to survive inhalation of purenitrogen, cyanide or carbon monoxide for 2 h before an initial riseof heart rate and a prolongation of the QRS duration.16 More con-vincing evidence of hypoxia endurance in hibernators is the factthat 100% non-hibernating ground squirrels survived 1 h of 4.5%O2, while 80% of rats died.17

The heart of the hibernator is also resistant to ischaemic injury.Significantly less injury of heart tissue was observed in activeground squirrels than in rats during ischaemia–reperfusion.13

Again, hearts from hibernating individuals in winter suffered evenless injury than those in summer, suggesting a seasonal variation.

DISCUSSION

Hibernation involves multiple extreme factors and heavy stress.During the evolutionary counteraction between animals and theenvironment, nature has designed a perfectly adapted cardiac func-tion that enables hibernators to survive the factors or stresses thata non-hibernator dies from. This means that hibernators may beresistant against some cardiovascular problems that humansencounter in some pathological conditions. For example, ventricu-lar fibrillation is a fatal heart disorder. The aetiology of many cardiovascular diseases involves local or whole-tissue ischaemia.The recovery of cardiac function from hypothermic anaesthesia is a key problem in thoracic surgery. The preservation of a living heart under low temperatures is a fundamental question in transplantation. Now that the hibernators are characterized bytheir resistance against hypothermia, dysrhythmia and hypoxia/ischaemia, a better understanding of their adaptive mechanismsshould help solve these problems.

Most notably, the above three features are enhanced duringhibernating seasons. Although hibernating hibernators were foundto have a more powerful calcium homeostatic system6,9,10 and afatty acid-based metabolic system,1 the most important mechanismis the neural and humoral regulation behind these changes.

Because both hibernators and non-hibernators are mammals andshare major biological principles of signalling and regulation, it is possible that certain mechanisms involved in hibernators may be effective in regulating human function. Thus, exploring the regulatory mechanisms of hibernation will provide new insights inthe clinical management of some diseases. In this sense, the hiber-nating mammal may be a useful animal model for medicalresearch.

As a successful example, Chien et al. found that hibernation-inducing trigger (HIT) obtained from hibernating woodchucks pro-longed the survival time of a canine autoperfused multi-organpreparation, including working heart, lung, kidney etc., from anaverage of 16 to 43 h.17 This study produced one of the longestaverage survival times for organ preservation.

It should be pointed out that the medical significance of hiber-nating mammals is not restricted to the cardiovascular system. Forexample, circannual rhythm in the immune system18 and otherfunctions1 have been reported. With modern biology, especiallymolecular biology as a theoretical and technological tool, more andmore mechanisms involved in the adaptation of hibernation can beinvestigated indepth and applied to improve human health. Thus,hibernation, a pure zoological topic in the past, will be of increas-ing medical value in the future.

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