Skip to main content
SpringerLink
Log in

The Recovery of Hibernating Hearts Lies on a Spectrum: from Bears in Nature to Patients with Coronary Artery Disease

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Clinicians often use the term “hibernating myocardium” in reference to patients with ischemic heart disease and decreased function within viable myocardial regions. Because the term is a descriptor of nature’s process of torpor, we provide a comparison of the adaptations observed in both conditions. In nature, hearts from hibernating animals undergo a shift in substrate preference in favor of fatty acids, while preserving glucose uptake and glycogen. Expression of electron transport chain proteins in mitochondria is decreased while antioxidant proteins including uncoupling protein-2 are increased. Similarly, hibernating hearts from patients have a comparable metabolic signature, with increased glucose uptake and glycogen accumulation and decreased oxygen consumption. In contrast to nature however, patients with hibernating hearts are at increased risk for arrhythmias, and contractility does not fully recover following revascularization. Clearly, additional interventions need to be advanced in patients with coronary artery disease and hibernating myocardium to prevent refractory heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Rahimtoola, S. H. (1989). The hibernating myocardium. American Heart Journal, 117(1), 211–221.

    Article  CAS  PubMed  Google Scholar 

  2. Geiser, F., & Ruf, T. (1995). Hibernation versus daily torpor in mammals and birds: physiological variables and classification of torpor patterns. Physiological Zoology, 68, 935–966.

    Google Scholar 

  3. Harlow, H., Lohuis, T., Anderson-Sprecher, R., & Beck, T. (2004). Body surface temperature profiles of hibernating black bears may be related to periodic muscle activity. Journal of Mammalogy, 85, 414–496.

    Article  Google Scholar 

  4. Nelson, R., Wahner, H., McGill, D., & Code, C. (1973). Metabolism of bears before, during, and after winter sleep. American Journal of Physiology, 224, 491–496.

    CAS  PubMed  Google Scholar 

  5. Laske, T., Harlow, H., Garshelis, D., & Iaizzo, P. (2010). Extreme respiratory sinus arrhythmia enables overwintering black bear survival—physiological insights and applications to human medicine. Journal of Cardiovascular Translational Research, 3, 559–569.

    Article  PubMed  Google Scholar 

  6. Harlow, H., Lohuis, T., Grogam, R., & Beck, T. (2002). Body mass and lipid changes by hibernating reproductive and nonreproductive black bears (Ursus americanus). Journal of Mammology, 85, 414–419.

    Article  Google Scholar 

  7. Lohuis, T., Harlow, H., & Beck, T. (2007). Hibernating black bears (Ursus americanus) experience skeletal muscle protein balance during winter anorexia. Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 147, 20–28.

    Article  CAS  Google Scholar 

  8. Laske, T., Garshelis, D., & Iaizzo, P. (2011). Monitoring the wild black bear’s reaction to human and environmental stressors. BMC Physiology, 11, 1–14.

    Article  Google Scholar 

  9. Laske, T., Garshelis, D., & Iaizzo, P. (2014). BIg data in wildlife research: remote web-based monitoring of hibernating black bears. BMC Physiology, 14, 1–9.

    Article  Google Scholar 

  10. Egorov, Y., Glukhov, A., Efimov, I., & Rosenshtraukh, L. (2012). Hypothermia-induced spatially discordant action potential duration alternans and arrhythmogenesis in nonhibernating versus hibernating mammals. American Journal of Physiology, 303, H1035–H1046.

    CAS  PubMed  Google Scholar 

  11. Kudej, R., & Vatner, S. (2003). Nitric oxide-dependent vasodilation maintains blood flow in true hibernating myocardium. Journal of Molecular and Cellular Cardiology, 35, 931–935.

    Article  CAS  PubMed  Google Scholar 

  12. Yatani, A., Kim, S., Kudej, R., Wang, Q., Depre, C., KIrie, K., et al. (2001). Insights into cardioprotection obtained from study of cellular Ca2+ handling in myocardium of true hibernating mammals. American Journal of Physiology, 286, H2219–H2228.

    Google Scholar 

  13. Brauch, K., Dhruv, N., Hanse, E., & Andrews, M. (2005). Digital transcriptome analysis indicates adaptive mechanisms in the heart of a hibernating mammal. Physiological Genomics, 23, 227–234.

    Article  CAS  PubMed  Google Scholar 

  14. Andrews, M., Russeth, K., Drewes, L., & Henry, P. (2009). Adaptive mechanisms regulate preferred utilization of ketones in the heart and brain of a hibernating mammal during arousal from torpor. American Journal of Physiology, 296, R383–R393.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Packard, M., & Packard, G. (2005). Patterns of variation in glycogen, free glucose and lactate in organs of supercooled hatchling painted turtes (Chrysemys picta). Journal of Experimental Biology, 208, 3169–3176.

    Article  CAS  PubMed  Google Scholar 

  16. Yan, J., Barnes, B., Kohl, F., & Marr, T. (2008). Modulation of gene expression in hibernating arctic ground squirrels. Physiological Genomics, 32, 170–181.

    Article  CAS  PubMed  Google Scholar 

  17. Fedorov, V., Goropashnaya, A., Toien, O., Stewart, N., Chang, C., Wang, H., et al. (2011). Modulation of gene expression in heart and liver of hibernating black bears (Ursus americanus). BMC Genomics, 12, 1–15.

  18. Boss, O., Samec, S., Dulloo, A., Seydoux, J., Muzzin, P., & Glacobino, J. (1997). Tissue-dependent upregulation of rat uncoupling protein-2 expression in response to fasting or cold. FEBS Letters, 412, 111–114.

    Article  PubMed  Google Scholar 

  19. Echtay, K., Roussel, D., St-Pieere, J., Jekabsons, M., Cardenas, S., Stuart, J., et al. (2002). Superoxide activates mitochondrial uncoupling proteins. Nature, 415, 96–99.

    Article  CAS  PubMed  Google Scholar 

  20. McLeod, C., Aziz, A., Hoyt, R., McCoy, P., & Sack, M. (2005). Uncoupling proteins 2 and 3 function in concert to augment tolerance to cardiac ischemia. Journal of Biological Chemistry, 280, 33470–33476.

    Article  CAS  PubMed  Google Scholar 

  21. Teshima, Y., Akao, M., Jones, S., & Marban, E. (2003). Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes. Circulation Research, 93, 192–200.

    Article  CAS  PubMed  Google Scholar 

  22. Cabrera, J. A., Ziemba, E. A., Colbert, R., Kelly, R. F., Kuskowski, M., Arriaga, E. A., et al. (2012). Uncoupling protein-2 expression and effects on mitochondrial membrane potential and oxidant stress in heart tissue. Translational Research, 159(5), 383–390.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Korshunov, S., Skulachev, V., & Starkov, A. (1997). High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Letters, 416, 15–18.

    Article  CAS  PubMed  Google Scholar 

  24. Kowaltowski, A., Castilho, R., & Vercesi, A. (2001). Mitochondrial permeability transition and oxidative stress. FEBS Letters, 495, 12–15.

    Article  CAS  PubMed  Google Scholar 

  25. Vucetic, M., Stancic, A., Otasevic, V., Jankovic, A., Korac, A., Markelic, M., et al. (2013). The impact of cold acclimation and hibernation on antioxidant defenses in the ground squirrel (Spermophilus citellus): an update. Free Radical Biology and Medicine, 65, 916–924.

    Article  CAS  PubMed  Google Scholar 

  26. Li, H., Liu, T., Chen, W., Jain, M., Vatner, D., Vatner, S., et al. (2013). Proteomic mechanisms of cardioprotection during mammalian hibernation in woodchucks, marmaota monax. Journal of Proteome Research, 12, 4221–4229.

    Article  CAS  PubMed  Google Scholar 

  27. Carey, H., Andrews, M., & Martin, S. (2003). Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature. Physiological Reviews, 83, 1153–1181.

    Article  CAS  PubMed  Google Scholar 

  28. Buzadzic, B., Spasic, M., Saicic, Z., & Petrovic, V. (1992). Seasonal dependence of the activity of antioxidant defence enzymes in the ground squirrel (Citellus citellus): the effect of cold. Comparative Biochemistry and Physiology - Part B, 101, 547–551.

    Article  CAS  Google Scholar 

  29. Hong, J., Sigg, D., Coles, J. J., Oeltgen, P., Harlow, H., Soule, C., et al. (2005). Hibernation induction trigger reduces hypoxic damage of swine skeletal muscle. Muscle and Nerve, 32, 200–207.

    Article  PubMed  Google Scholar 

  30. Grabek, K., Karimpour-Fard, A., Epperson, L., Hindle, A., Hunter, L., & Martin, S. (2011). Multistate proteomics analysis reveals novel strategies used by a hibernator to precondition the heart and conserve ATP for winter heterothermy. Physiological Genomics, 43, 1263–1275.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Nelson, B., Ding, X., Boney-Montoya, J., Gerard, R., Kliewer, S., & Andrews, M. (2013). Metabolic hormone FGF21 is induced in ground squirrels during hibernation but its overexpression is not sufficient to cause torpor. PLoS One, 8, 1–13.

    Google Scholar 

  32. Canty, J. M., Jr., & Fallavollita, J. A. (2000). Chronic hibernation and chronic stunning: a continuum. Journal of Nuclear Cardiology, 7(5), 509–527.

    Article  PubMed  Google Scholar 

  33. McFalls, E. O., Baldwin, D., Palmer, B., Marx, D., Jaimes, D., & Ward, H. B. (1997). Regional glucose uptake within hypoperfused swine myocardium as measured by positron emission tomography. American Journal of Physiology, 272(1 Pt 2), H343–H349.

    CAS  PubMed  Google Scholar 

  34. McFalls, E., Kelly, R., Hu, Q., Mansoor, A., Lee, J., Kuskowski, M., et al. (2007). The energetic state within hibernating myocardium is normal during dobutamine despite inhibition of ATP-dependent potassium channel opening with glibenclamide. American Journal of Physiology, 293, H2945–H2951.

    CAS  PubMed  Google Scholar 

  35. Kelly, R. F., Sluiter, W., & McFalls, E. O. (2008). Hibernating myocardium: is the program to survive a pathway to failure? Circulation Research, 102(1), 3–5.

    Article  CAS  PubMed  Google Scholar 

  36. Alderman, E., Fisher, L., Litwin, P., Kaiser, G., Myers, W., Maynard, C., et al. (1983). Results of coronary artery surgery in patients with poor left ventricular function (CASS). Circulation, 68, 785–795.

    Article  CAS  PubMed  Google Scholar 

  37. Tillisch, J., Brunken, R., Marshall, R., Schwaiger, M., Mandelkern, M., Phelps, M., et al. (1986). Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. New England Journal of Medicine, 314, 884–888.

    Article  CAS  PubMed  Google Scholar 

  38. Di Carli, M. F., Davidson, M., Little, R., Khanna, S., Mody, F. V., Brunken, R. C., et al. (1994). Value of metabolic imaging with positron emission tomography for evaluating prognosis in patients with coronary artery disease and left ventricular dysfunction. American Journal of Cardiology, 73(8), 527–533.

    Article  PubMed  Google Scholar 

  39. McFalls, E., Baldwin, D., Kuskowsk, M., Liow, J., Chesler, E., & Ward, H. (2000). Utility of positron emission tomography in predicting improved left ventricular ejection fraction after coronary artery bypss grafting among patients with ischemic cardiomyopathy. Cardiology, 93, 105–112.

    Article  CAS  PubMed  Google Scholar 

  40. Vanoverschelde, J., Depre, C., Gerber, B., Borgers, M., Wijns, W., Robert, A., et al. (2000). Time course of functional recovery after coronary artery bypass graft surger in patients with chronic left ventricular ischemic dysfunction. American Journal of Cardiology, 85, 1432–1439.

    Article  CAS  PubMed  Google Scholar 

  41. Depre, C., Vanoverschelde, J. L., Melin, J. A., Borgers, M., Bol, A., Ausma, J., et al. (1995). Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans. American Journal of Physiology, 268(3 Pt 2), H1265–H1275.

    CAS  PubMed  Google Scholar 

  42. Tamaki, N., Yonekura, Y., Yamashita, K., Saji, H., Magata, Y., Sends, M., et al. (1989). Positron emission tomography using fluorine-18 deoxyglucose in evaluation of coronary artery bypass grafting. American Journal of Cardiology, 64, 860–865.

    Article  CAS  PubMed  Google Scholar 

  43. Page, B., Young, R., Iyer, V., Suzuki, G., Lis, M., Korotchkina, L., et al. (2008). Persistent regional downregulation in mitochondrial enzymes and upregulation of stress proteins in swine with chronic hibernating myocardium. Circulation Research, 102(1), 103–112.

    Article  CAS  PubMed  Google Scholar 

  44. Cabrera, J. A., Butterick, T. A., Long, E. K., Ziemba, E. A., Anderson, L. B., Duffy, C. M., et al. (2013). Reduced expression of mitochondrial electron transport chain proteins from hibernating hearts relative to ischemic preconditioned hearts in the second window of protection. Journal of Molecular and Cellular Cardiology, 60, 90–96.

    Article  CAS  PubMed  Google Scholar 

  45. McFalls, E. O., Sluiter, W., Schoonderwoerd, K., Manintveld, O. C., Lamers, J. M., Bezstarosti, K., et al. (2006). Mitochondrial adaptations within chronically ischemic swine myocardium. Journal of Molecular and Cellular Cardiology, 41(6), 980–988.

    Article  CAS  PubMed  Google Scholar 

  46. Canty, J. M., Jr., & Suzuki, G. (2012). Myocardial perfusion and contraction in acute ischemia and chronic ischemic heart disease. Journal of Molecular and Cellular Cardiology, 52(4), 822–831.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Fallavollita, J. A., Malm, B. J., & Canty, J. M., Jr. (2003). Hibernating myocardium retains metabolic and contractile reserve despite regional reductions in flow, function, and oxygen consumption at rest. Circulation Research, 92(1), 48–55.

    Article  CAS  PubMed  Google Scholar 

  48. Lim, H., Fallavollita, J. A., Hard, R., Kerr, C. W., & Canty, J. M., Jr. (1999). Profound apoptosis-mediated regional myocyte loss and compensatory hypertrophy in pigs with hibernating myocardium. Circulation, 100(23), 2380–2386.

    Article  CAS  PubMed  Google Scholar 

  49. Depre, C., Kim, S. J., John, A. S., Huang, Y., Rimoldi, O. E., Pepper, J. R., et al. (2004). Program of cell survival underlying human and experimental hibernating myocardium. Circulation Research, 95(4), 433–440.

    Article  CAS  PubMed  Google Scholar 

  50. Pizzuto, M., Suzuki, G., Banas, M., Heavey, B., Fallavollita, J., & Canty, J. (2013). Dissociation of hemodynamic and electrocardiographic indexes of myocardial ischemia in pigs with hibernating myocardium and sudden cardiac death. American Journal of Physiology, 304, H1697–H1707.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Fallavollita, J. A., Jacob, S., Young, R. F., & Canty, J. M., Jr. (1999). Regional alterations in SR Ca(2+)-ATPase, phospholamban, and HSP-70 expression in chronic hibernating myocardium. American Journal of Physiology, 277(4 Pt 2), H1418–H1428.

    CAS  PubMed  Google Scholar 

  52. Fernandez, S., Ovchinnikov, V., Canty, J., & Fallavollita, J. (2013). Hibernating myocardium results in partial sympathetic denervation and nerve sprouting. American Journal of Physiology, 304, H318–H327.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Velazquez, E. J., Lee, K. L., Deja, M. A., Jain, A., Sopko, G., Marchenko, A., et al. (2011). Coronary-artery bypass surgery in patients with left ventricular dysfunction. New England Journal of Medicine, 364(17), 1607–1616.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Shah, B., Khattar, R., & Senior, R. (2013). The hibernating myocardium: current concepts, diagnostic dilemmas, and clinical challenges in the post-STICH era. European Heart Journal, 34, 1324–1334.

    Article  Google Scholar 

  55. Kelly, R. F., Cabrera, J. A., Ziemba, E. A., Crampton, M., Anderson, L. B., McFalls, E. O., et al. (2011). Continued depression of maximal oxygen consumption and mitochondrial proteomic expression despite successful coronary artery bypass grafting in a swine model of hibernation. Journal of Thoracic and Cardiovascular Surgery, 141(1), 261–268.

    Article  CAS  PubMed  Google Scholar 

  56. Holley, C., Duffy, C., Butterick, T., Long, E., Lindsey, M., Cabrera, J., et al. (2015). Expression of uncoupling protein-2 remains increased within hibernating myocardium despite successful coronary artery bypass grafting at 4 weeks post-revascularization. Journal of Surgical Research, 193, 15–21.

    Article  CAS  PubMed  Google Scholar 

  57. Holley, C., Long, E., Lindsey, M., McFalls, E., Kelly, R. (2015). Recovery of hibernating myocardium: what is the role of surgical revascularization? Journal of Cardiac Surgery 30(2),224–31.

  58. Moss, A., Zareba, W., Hall, J., Klein, H., Wilber, D., Cannom, D., et al. (2002). Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejetion fraction. The New England Journal of Medicine, 346, 877–883.

    Article  PubMed  Google Scholar 

  59. Liedtke, A., Brenstrom, B., Nellis, S., Hall, J., & Stanley, W. (1995). Mechanical and metabolic functions in pig hearts after 4 days of chronic coronary stenosis. Journal of the American College of Cardiology, 26, 815–825.

    Article  CAS  PubMed  Google Scholar 

  60. Vanoverschelde, J., Wijns, W., Borgers, M., Heyndricks, G., Depre, C., Flameng, W., et al. (1997). Chronic myocardial hibernation in humans: from bedside to bench. Circulation, 95, 1961–1971.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of Interest

There are no potential conflicts of interest with this work.

Funding

The work was supported in part by grants from The Veterans Affairs Merit Review and The Lillehei Foundation (High-Risk High Reward).

Dr. Garcia is a recipient of a career development award (1IK2CX000699-01) from the VA Office of Research and Development.

Compliance with Ethical Standards

• All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

• All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. In addition, all procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

• In studies involving patients, informed consent was obtained from all individual participants included in the study.

Author information

Authors and Affiliations

  1. Cardiology Division, VA Medical Center, University of Minnesota, Minneapolis, MN, USA

    Robert W. Colbert, Selcuk Adabag, Santiago Garcia & Edward O. McFalls

  2. Department of Cardiothoracic Surgery, University of Minnesota, Minneapolis, MN, USA

    Christopher T. Holley, Laura Hocum Stone, Melanie Crampton, Herbert B. Ward & Rosemary F. Kelly

  3. Department of Surgery, University of Minnesota, Minneapolis, MN, USA

    Paul A. Iaizzo

  4. Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA

    Paul A. Iaizzo

  5. The Institute for Engineering in Medicine, University of Minnesota, Minneapolis, MN, USA

    Paul A. Iaizzo

  6. Cardiology (111C), VA Medical Center, 1 Veterans Drive, Minneapolis, MN, 55417, USA

    Edward O. McFalls

Authors
  1. Robert W. Colbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher T. Holley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura Hocum Stone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Melanie Crampton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Selcuk Adabag
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Santiago Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul A. Iaizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Herbert B. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rosemary F. Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Edward O. McFalls
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward O. McFalls.

Additional information

Editor-in-Chief Jennifer L. Hall oversaw the review of this article

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Colbert, R., Holley, C.T., Stone, L.H. et al. The Recovery of Hibernating Hearts Lies on a Spectrum: from Bears in Nature to Patients with Coronary Artery Disease. J. of Cardiovasc. Trans. Res. 8, 244–252 (2015). https://doi.org/10.1007/s12265-015-9625-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-015-9625-5

Keywords

Search

Navigation