Hibernator Citellus undulatus maintains safe cardiac conduction and is protected against tachyarrhythmias during extreme hypothermia: possible role of Cx43 and Cx45 up-regulation.

BACKGROUND Most mammals experience cardiac arrest during hypothermia. In contrast, hibernators remain in sinus rhythm even at body temperatures of 0 degrees C. OBJECTIVES The purpose of this study was to quantify electrical activity and connexin expression in the heart of hibernating Siberian ground squirrel Citellus undulatus. METHODS Optical imaging and microelectrode recordings were conducted in Langendorff-perfused hearts and isolated papillary muscles of summer active (SA, n = 19), winter hibernating (WH, n = 21), interbout arousal (IBA, n = 12), and winter active (WA, n = 3) ground squirrels and rabbits (n = 14) at temperatures from +37 degrees C to +3 degrees C. RESULTS All studied SA and WH hearts maintained spontaneous sinus rhythm, safe propagation through the entire conduction system, and normal pattern of ventricular excitation at all temperatures. However, three of the seven IBA and all rabbit hearts lost excitability at 10 degrees C +/- 1 degrees C and 12 degrees C +/- 1 degrees C, respectively. In WH, SA, and IBA ground squirrels, temperature reduction from 37 degrees C to 3 degrees C resulted in a 10-fold slowing of ventricular conduction velocity and increased excitation threshold. At any temperature, WH ventricles had faster conduction velocity and lower excitation threshold compared with SA and IBA. Immunolabeling demonstrated that connexin43 (Cx43) was significantly up-regulated in WH and WA compared with SA myocardium: Cx43 area density was 12.4 +/- 1.3, 15.0 +/- 3.0 and 8.6 +/- 1.1 microm(2)/1,000 microm(2), respectively. Moreover, Cx45 was expressed in the WH but not in the SA or WA ventricles. CONCLUSION Hibernator Citellus undulatus has evolved to maintain safe conduction at extreme hypothermia via up-regulation of Cx43 and Cx45 in order to protect the heart against arrhythmia associated with hypothermia.

[1]  J. Bertram,et al.  Cancer prevention by retinoids and carotenoids: independent action on a common target. , 2005, Biochimica et biophysica acta.

[2]  N. F. Ruby,et al.  Hibernation: When Good Clocks Go Cold , 2003, Journal of biological rhythms.

[3]  H. Badeer.  Ventricular fibrillation in hypothermia; a review of factors favoring fibrillation in hypothermia with and without cardiac surgery. , 1958, The Journal of thoracic surgery.

[4]  D. Roden,et al.  Nkx 2-5 mutation causes anatomic hypoplasia of the cardiac conduction system , 2022 .

[5]  J. White.  Cardiac arrest in hypothermia. , 1980, JAMA.

[6]  P. Razeghi,et al.  Clock Genes in the Heart: Characterization and Attenuation With Hypertrophy , 2001, Circulation research.

[7]  B. Johansson.  The hibernator heart--nature's model of resistance to ventricular fibrillation. , 1996, Arctic medical research.

[8]  E. Lakatta,et al.  Adaptive mechanisms of intracellular calcium homeostasis in mammalian hibernators. , 2002, The Journal of experimental biology.

[9]  R. Burlington,et al.  Low-Temperature Performance of Isolated Working Hearts from a Hibernator and a Nonhibernator , 1988, Physiological Zoology.

[10]  Li Li,et al.  Shock-induced arrhythmogenesis is enhanced by 2,3-butanedione monoxime compared with cytochalasin D. , 2004, American journal of physiology. Heart and circulatory physiology.

[11]  M. Andersen,et al.  Mechanisms of ventricular fibrillation during hypothermia. Relative changes in myocardial refractory period and conduction velocity. , 1966, The Journal of thoracic and cardiovascular surgery.

[12]  D. Roden,et al.  Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system. , 2004, The Journal of clinical investigation.

[13]  C. Lillehei,et al.  Coronary resistance changes with hypothermic perfusion , 1966 .

[14]  T. Opthof,et al.  The hibernators heart. Nature's response to arrhythmogenesis? , 2000, Cardiovascular research.

[15]  G. Biorck,et al.  Comparative studies on temperature effects upon the electrocardiogram in some vertebrates. , 1955, Acta physiologica Scandinavica.

[16]  A. Loudon,et al.  Photoperiod-dependent modulation of cardiac excitation contraction coupling in the Siberian hamster. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[17]  G. Burnstock,et al.  Increased connexin43 gap junction protein in hamster cardiomyocytes during cold acclimatization and hibernation. , 2000, Cardiovascular research.

[18]  I R Efimov,et al.  Hypoxia and Hypothermia Enhance Spatial Heterogeneities of Repolarization in Guinea Pig Hearts: , 1998, Journal of cardiovascular electrophysiology.

[19]  A. Kleber,et al.  Flow of “Injury” Current and Patterns of Excitation during Early Ventricular Arrhythmias in Acute Regional Myocardial Ischemia in Isolated Porcine and Canine Hearts: Evidence for Two Different Arrhythmogenic Mechanisms , 1980, Circulation research.

[20]  T. Opthof,et al.  Cardiac gap junction channels: modulation of expression and channel properties. , 2001, Cardiovascular research.

[21]  T. Opthof,et al.  Connexin43 orthologues in vertebrates: phylogeny from fish to man , 2004, Development Genes and Evolution.

[22]  Sandra L Martin,et al.  Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature. , 2003, Physiological reviews.

[23]  F. South,et al.  Effects of temperature on cardiac transmembrane potentials in hibernation. , 1976, The American journal of physiology.

[24]  Bin Liu,et al.  Effect of cold on transmembrane potentials in cardiac cells of the hedgehog , 1987 .

[25]  William J Brady,et al.  Electrocardiographic manifestations of hypothermia. , 2002, The American journal of emergency medicine.

[26]  A. Malan,et al.  Living in the Cold , 1989 .

[27]  D. Caprette,et al.  Isovolumetric performance of isolated ground squirrel and rat hearts at low temperature. , 1984, The American journal of physiology.

[28]  R. Weingart,et al.  Temperature dependence of gap junction properties in neonatal rat heart cells , 1993, Pflügers Archiv.

[29]  H. Jongsma,et al.  Replacement of Connexin40 by Connexin45 in the Mouse: Impact on Cardiac Electrical Conduction , 2004, Circulation research.

[30]  G. Duker,et al.  Monophasic action potentials during induced hypothermia in hedgehog and guinea pig hearts. , 1987, The American journal of physiology.

[31]  Toshihisa Nagatomo,et al.  Temperature dependence of early and late currents in human cardiac wild-type and long Q-T ΔKPQ Na+ channels. , 1998, American journal of physiology. Heart and circulatory physiology.

[32]  A. Moorman,et al.  Downregulation of connexin 45 gene products during mouse heart development. , 1999, Circulation research.

[33]  B. Barnes.  Freeze avoidance in a mammal: body temperatures below 0 degree C in an Arctic hibernator. , 1989, Science.

[34]  Birgit E J Teunissen,et al.  Transcriptional control of myocardial connexins. , 2004, Cardiovascular research.

[35]  D. A. Eagles,et al.  Cardiac arrhythmias during arousal from hibernation in three species of rodents. , 1988, The American journal of physiology.

[36]  C. Owman,et al.  Difference in cardiac adrenergic innervation between hibernators and non-hibernating mammals. , 1968, Acta physiologica Scandinavica. Supplementum.

[37]  R Wilders,et al.  Gap junctions in cardiovascular disease. , 2000, Circulation research.

[38]  T. Rosenquist.  Ultrastructural changes in the plasma membrane and sarcoplasmic reticulum of myocardial cells during hibernation. , 1970, Cryobiology.

[39]  S H Chung,et al.  The temperature dependence of conductance of the sodium channel: implications for mechanisms of ion permeation. , 1995, Receptors & channels.

[40]  K. Storey,et al.  Mitogen-activated protein kinases and selected downstream targets display organ-specific responses in the hibernating ground squirrel. , 2005, The international journal of biochemistry & cell biology.

[41]  M. Zimny,et al.  Ultrastructural modifications of the intercalated disc during hypothermia in the rat and the ground squirrel , 1968 .

[42]  J. Senturia,et al.  Ventricular fibrillation in hibernators and nonhibernators. , 1983, Cryobiology.

[43]  K. Storey,et al.  Metabolic rate depression in animals: transcriptional and translational controls , 2004, Biological reviews of the Cambridge Philosophical Society.

[44]  P. Tchou,et al.  Transmembrane Voltage Changes Produced by Real and Virtual Electrodes During Monophasic Defibrillation Shock Delivered by an Implantable Electrode , 1997, Journal of cardiovascular electrophysiology.

[45]  A. Dawe,et al.  Characteristics of the hibernating heart. , 1955, American heart journal.

[46]  B. Johansson,et al.  Temperature effects on the Na and Ca currents in rat and hedgehog ventricular muscle. , 1991, Cryobiology.

[47]  S. Vatner,et al.  Insights into cardioprotection obtained from study of cellular Ca2+ handling in myocardium of true hibernating mammals. , 2004, American journal of physiology. Heart and circulatory physiology.

[48]  W. Beavers.  Hypothermia: effects of hypertonic solutions on incidence of ventricular fibrillation. , 1959, The American journal of physiology.

[49]  R. Baudinette,et al.  The effect of temperature on isolated perfused hearts of heterothermic marsupials. , 1989, Comparative biochemistry and physiology. A, Comparative physiology.

[50]  G. Salama,et al.  Optical Mapping of Repolarization and Refractoriness From Intact Hearts , 1994, Circulation.