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  • Review Article
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Myocardial stunning and hibernation revisited

Nature Reviews Cardiology volume 18, pages 522–536 (2021)Cite this article

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Abstract

Unlike acute myocardial infarction with reperfusion, in which infarct size is the end point reflecting irreversible injury, myocardial stunning and hibernation result from reversible myocardial ischaemia–reperfusion injury, and contractile dysfunction is the obvious end point. Stunned myocardium is characterized by a disproportionately long-lasting, yet fully reversible, contractile dysfunction that follows brief bouts of myocardial ischaemia. Reperfusion precipitates a burst of reactive oxygen species formation and alterations in excitation–contraction coupling, which interact and cause the contractile dysfunction. Hibernating myocardium is characterized by reduced regional contractile function and blood flow, which both recover after reperfusion or revascularization. Short-term myocardial hibernation is an adaptation of contractile function to the reduced blood flow such that energy and substrate metabolism recover during the ongoing ischaemia. Chronic myocardial hibernation is characterized by severe morphological alterations and altered expression of metabolic and pro-survival proteins. Myocardial stunning is observed clinically and must be recognized but is rarely haemodynamically compromising and does not require treatment. Myocardial hibernation is clinically identified with the use of imaging techniques, and the myocardium recovers after revascularization. Several trials in the past two decades have challenged the superiority of revascularization over medical therapy for symptomatic relief and prognosis in patients with chronic coronary syndromes. A better understanding of the pathophysiology of myocardial stunning and hibernation is important for a more precise indication of revascularization and its consequences. Therefore, this Review summarizes the current knowledge of the pathophysiology of these characteristic reperfusion phenomena and highlights their clinical implications.

Key points

  • Myocardial stunning is the reversible, but only slowly recovering, contractile dysfunction that follows brief periods of myocardial ischaemia.

  • Myocardial stunning reflects genuine reperfusion injury as a consequence of increased formation of reactive oxygen species and reduced calcium responsiveness.

  • Myocardial stunning occurs in patients after percutaneous coronary interventions or exercise-induced myocardial ischaemia, but is not haemodynamically compromising.

  • Short-term myocardial hibernation is characterized by matched moderate reductions in blood flow and contractile function, metabolic recovery and maintenance of myocardial viability.

  • With limited coronary flow reserve, repetitive myocardial stunning induced by stress-related myocardial ischaemia transitions to a situation of matched reductions in contractile function and blood flow.

  • In patients with chronic coronary syndrome and contractile dysfunction, improvement in contractile function after revascularization provides evidence for the existence of myocardial hibernation.

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Fig. 1: Blood flow and contractile function in myocardial stunning and hibernation.
Fig. 2: Myocardial stunning follows coronary occlusion.
Fig. 3: Mechanisms of myocardial stunning.
Fig. 4: Features of short-term myocardial hibernation.
Fig. 5: PET imaging of hibernating myocardium in patients with coronary artery disease and left ventricular dysfunction.
Fig. 6: Ultrastructure of normal and hibernating human myocardium.

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References

  1. Maroko, P. R. et al. Coronary artery reperfusion. I. Early effects on local myocardial function and the extent of myocardial necrosis. J. Clin. Invest. 51, 2710–2716 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ibanez, B., Heusch, G., Ovize, M. & Van de Werf, F. Evolving therapies for myocardial ischemia/reperfusion injury. J. Am. Coll. Cardiol. 65, 1454–1471 (2015).

    Article  PubMed  Google Scholar 

  3. Rahimtoola, S. H. Coronary bypass surgery for chronic angina – 1981. Circulation 65, 225–241 (1982).

    Article  CAS  PubMed  Google Scholar 

  4. Rahimtoola, S. H. A perspective on the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. Circulation 72, V123–V135 (1985).

    CAS  PubMed  Google Scholar 

  5. Rahimtoola, S. H. Clinical overview of management of chronic ischemic heart disease. Circulation 84, I81–I84 (1991).

    CAS  PubMed  Google Scholar 

  6. Heyndrickx, G. R., Millard, R. W., McRitchie, R. J., Maroko, P. R. & Vatner, S. F. Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J. Clin. Invest. 56, 978–985 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Braunwald, E. & Kloner, R. A. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 66, 1146–1149 (1982).

    Article  CAS  PubMed  Google Scholar 

  8. Diamond, G. A., Forrester, J. S., de Luz, P. L., Wyatt, H. L. & Swan, H. J. C. Postextrasystolic potentiation of ischemic myocardium by atrial stimulation. Am. Heart J. 95, 204–209 (1978).

    Article  CAS  PubMed  Google Scholar 

  9. Heusch, G. The relationship between regional blood flow and contractile function in normal, ischemic, and reperfused myocardium. Basic Res. Cardiol. 86, 197–218 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Kloner, R. A. & Przyklenk, K. Hibernation and stunning of the myocardium. N. Engl. J. Med. 325, 1877–1879 (1991).

    Article  CAS  PubMed  Google Scholar 

  11. Marban, E. Myocardial stunning and hibernation: the physiology behind the colloquialisms. Circulation 83, 681–688 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Bolli, R. Myocardial ‘stunning’ in man. Circulation 86, 1671–1691 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Dilsizian, V. & Bonow, R. O. Current diagnostic techniques of assessing myocardial viability in patients with hibernating and stunned myocardium. Circulation 87, 1–20 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Heusch, G. Hibernating myocardium. Physiol. Rev. 78, 1055–1085 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Wijns, W., Vatner, S. & Camici, P. Hibernating myocardium. N. Engl. J. Med. 339, 173–181 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Heusch, G., Schulz, R. & Rahimtoola, S. H. Myocardial hibernation: a delicate balance. Am. J. Physiol. Heart Circ. Physiol. 288, H984–H999 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Canty, J. M. Jr. & Suzuki, G. Myocardial perfusion and contraction in acute ischemia and chronic ischemic heart disease. J. Mol. Cell Cardiol. 52, 822–831 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Kloner, R. A. Stunned and hibernating myocardium: Where are we nearly 4 decades later? J. Am. Heart Assoc. 9, e015502 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Maron, D. J. et al. Initial invasive or conservative strategy for stable coronary disease. N. Engl. J. Med. 382, 1395–1407 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Boden, W. E. et al. Optimal medical therapy with or without PCI for stable coronary disease. N. Engl. J. Med. 356, 1503–1516 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Al-Lamee, R. et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet 391, 31–40 (2017).

    Article  PubMed  Google Scholar 

  22. Bangalore, S., Maron, D. J., Stone, G. W. & Hochman, J. S. Routine revascularization versus initial medical therapy for stable ischemic heart disease: a systematic review and meta-analysis of randomized trials. Circulation 142, 841–857 (2020).

    Article  PubMed  Google Scholar 

  23. Knuuti, J. et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur. Heart J. 41, 407–477 (2020).

    Article  PubMed  Google Scholar 

  24. Heyndrickx, G. R. et al. Depression of regional blood flow and wall thickening after brief coronary occlusions. Am. J. Physiol. Heart Circ. Physiol. 234, H653–H659 (1978).

    Article  CAS  Google Scholar 

  25. Weiner, J. M., Apstein, C. S., Arthur, J. H., Pirzada, F. A. & Hood, W. B. Jr. Persistence of myocardial injury following brief periods of coronary occlusion. Cardiovasc. Res. 10, 678–686 (1976).

    Article  CAS  PubMed  Google Scholar 

  26. Preuss, K. C., Gross, G. J., Brooks, H. L. & Warltier, D. C. Time course of recovery of “stunned” myocardium following variable periods of ischemia in conscious and anesthetized dogs. Am. Heart J. 114, 696–703 (1987).

    Article  CAS  PubMed  Google Scholar 

  27. Triana, J. F., Li, X.-Y., Jamaluddin, U., Thornby, J. I. & Bolli, R. Postischemic myocardial “stunning”: identification of major differences between the open-chest and the conscious dog and evaluation of the oxygen radical hypothesis in the conscious dog. Circ. Res. 69, 731–747 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Lange, R., Ware, J. & Kloner, R. A. Absence of a cumulative deterioration of regional function during three repeated 5 or 15 minute coronary occlusions. Circulation 69, 400–408 (1984).

    Article  CAS  PubMed  Google Scholar 

  29. Nicklas, J. M., Becker, L. C. & Bulkley, B. H. Effects of repeated brief coronary occlusion on regional left ventricular function and dimension in dogs. Am. J. Cardiol. 56, 473–478 (1985).

    Article  CAS  PubMed  Google Scholar 

  30. Cohen, M. V. & Downey, J. M. Myocardial stunning in dogs: preconditioning effect and influence of coronary collateral flow. Am. Heart J. 120, 282–291 (1990).

    Article  CAS  PubMed  Google Scholar 

  31. Hoffmeister, H. M., Mauser, M. & Schaper, W. Repeated short periods of regional myocardial ischemia: effect on local function and high energy phosphate levels. Basic Res. Cardiol. 81, 361–372 (1986).

    Article  CAS  PubMed  Google Scholar 

  32. Matsuzaki, M., Gallagher, K. P., Kemper, W. S., White, F. & Ross, J. Jr. Sustained regional dysfunction produced by prolonged coronary stenosis: gradual recovery after reperfusion. Circulation 68, 170–182 (1983).

    Article  CAS  PubMed  Google Scholar 

  33. Matsuzaki, M. et al. Effects of a calcium-entry blocker (diltiazem) on regional myocardial flow and function during exercise in conscious dogs. Circulation 69, 801–814 (1984).

    Article  CAS  PubMed  Google Scholar 

  34. Homans, D. C., Sublett, E., Dai, X.-Z. & Bache, R. J. Persistence of regional left ventricular dysfunction after exercise-induced myocardial ischemia. J. Clin. Invest. 77, 66–73 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Thaulow, E. et al. Characteristics of regional myocardial stunning after exercise in dogs with chronic coronary stenosis. Am. J. Physiol. Heart Circ. Physiol. 257, H113–H119 (1989).

    Article  CAS  Google Scholar 

  36. Homans, D. C., Laxon, D. D., Sublett, E., Lindstrom, P. & Bache, R. J. Cumulative deterioration of myocardial function after repeated episodes of exercise-induced ischemia. Am. J. Physiol. 256, H1462–H1471 (1989).

    CAS  PubMed  Google Scholar 

  37. Ellis, S. G. et al. Time course of functional and biochemical recovery of myocardium salvaged by reperfusion. J. Am. Coll. Cardiol. 1, 1047–1055 (1983).

    Article  CAS  PubMed  Google Scholar 

  38. Lavallee, M., Cox, D., Patrick, T. A. & Vatner, S. F. Salvage of myocardial function by coronary artery reperfusion 1, 2 and 3 hours after occlusion in conscious dogs. Circ. Res. 53, 235–247 (1983).

    Article  CAS  PubMed  Google Scholar 

  39. Brown, M. A., Norris, R. M., Takayama, M. & White, H. D. Post-systolic shortening: a marker of potential for early recovery of acutely ischemic myocardium in the dog. Cardiovasc. Res. 21, 703–716 (1987).

    Article  CAS  PubMed  Google Scholar 

  40. Takayama, M. et al. Postsystolic shortening of acutely ischemic canine myocardium predicts early and late recovery of function after coronary artery reperfusion. Circulation 78, 994–1007 (1988).

    Article  CAS  PubMed  Google Scholar 

  41. Rose, J., Schulz, R., Martin, C. & Heusch, G. Post-ejection wall thickening as a marker of successful short term hibernation. Cardiovasc. Res. 27, 1306–1311 (1993).

    Article  CAS  PubMed  Google Scholar 

  42. Ellis, S. G. et al. Response of reperfusion-salvaged, stunned myocardium to inotropic stimulation. Am. Heart J. 107, 13–19 (1984).

    Article  CAS  PubMed  Google Scholar 

  43. Arnold, J. M. O., Braunwald, E., Sandor, T. & Kloner, R. A. Inotropic stimulation of reperfused myocardium with dopamine: effects on infarct size and myocardial function. J. Am. Coll. Cardiol. 6, 1036–1044 (1985).

    Article  Google Scholar 

  44. Ito, B. R., Tate, H., Kobayashi, M. & Schaper, W. Reversibly injured, postischemic canine myocardium retains normal contractile reserve. Circ. Res. 61, 834–846 (1987).

    Article  CAS  PubMed  Google Scholar 

  45. Miura, T. et al. Does myocardial stunning contribute to infarct size limitation by ischemic preconditioning? Circulation 84, 2504–2512 (1991).

    Article  CAS  PubMed  Google Scholar 

  46. Murry, C. E., Richard, V. J., Jennings, R. B. & Reimer, K. A. Myocardial protection is lost before contractile function recovers from ischemic preconditioning. Am. J. Physiol. Heart Circ. Physiol. 260, H796–H804 (1991).

    Article  CAS  Google Scholar 

  47. Ovize, M., Przyklenk, K., Hale, S. L. & Kloner, R. A. Preconditioning does not attenuate myocardial stunning. Circulation 85, 2247–2254 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Sun, J.-Z. et al. Late preconditioning against myocardial stunning. An endogenous protective mechanism that confers resistance to postischemic dysfunction 24 h after brief ischemia in conscious pigs. J. Clin. Invest. 95, 388–403 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bolli, R. The late phase of preconditioning. Circ. Res. 87, 972–983 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Heusch, G. Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat. Rev. Cardiol. 17, 773–789 (2020).

    Article  PubMed  Google Scholar 

  51. Taegtmeyer, H., Roberts, A. F. C. & Raine, A. E. G. Energy metabolism in reperfused heart muscle: metabolic correlates to return of function. J. Am. Coll. Cardiol. 6, 864–870 (1985).

    Article  CAS  PubMed  Google Scholar 

  52. Du Toit, E. F. & Opie, L. H. Role for the Na+/H+ exchanger in reperfusion stunning in isolated perfused rat heart. J. Cardiovasc. Pharmacol. 22, 877–883 (1993).

    Article  PubMed  Google Scholar 

  53. Gao, W. D., Atar, D., Backx, P. H. & Marban, E. Relationship between intracellular calcium and contractile force in stunned myocardium direct evidence for decreased myofilament Ca2+ responsiveness and altered diastolic function in intact ventricular muscle. Circ. Res. 76, 1036–1048 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Ambrosio, G., Jacobus, W. E., Bergmann, C. A., Weisman, H. F. & Becker, L. C. Preserved high energy phosphate metabolic reserve in globally stunned hearts despite reduction of basal ATP content and contractility. J. Mol. Cell Cardiol. 19, 953–964 (1987).

    Article  CAS  PubMed  Google Scholar 

  55. Zweier, J. L., Rayburn, B. K., Flaherty, J. T. & Weisfeldt, M. L. Recombinant superoxide dismutase reduces oxygen free radical concentrations in reperfused myocardium. J. Clin. Invest. 80, 1728–1734 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Flameng, W., Andres, J., Ferdinande, P., Mattheussen, M. & van Belle, H. Mitochondrial function in myocardial stunning. J. Mol. Cell Cardiol. 23, 1–11 (1991).

    Article  CAS  PubMed  Google Scholar 

  57. Kusuoka, H., Porterfield, J. K., Weisman, H. F., Weisfeldt, M. L. & Marban, E. Pathophysiology and pathogenesis of stunned myocardium: depressed Ca2+ activation of contraction as a consequence of reperfusion-induced cellular calcium overload in ferret hearts. J. Clin. Invest. 79, 950–961 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kitakaze, M., Weisfeldt, M. L. & Marban, E. Acidosis during early reperfusion prevents myocardial stunning in perfused ferret hearts. J. Clin. Invest. 82, 920–927 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kusuoka, H., de Hurtado, M. C. C. & Marban, E. Role of sodium/calcium exchange in the mechanism of myocardial stunning: protective effect of reperfusion with high sodium solution. J. Am. Coll. Cardiol. 21, 240–248 (1993).

    Article  CAS  PubMed  Google Scholar 

  60. DeBoer, L. W. V., Ingwall, J. S., Kloner, R. A. & Braunwald, E. Prolonged derangements of canine myocardial purine metabolism after a brief coronary artery occlusion not associated with anatomic evidence of necrosis. Proc. Natl Acad. Sci. USA 77, 5471–5475 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kloner, R. A. et al. Prolonged abnormalities of myocardium salvaged by reperfusion. Am. J. Physiol. 241, H591–H599 (1981).

    CAS  PubMed  Google Scholar 

  62. Swain, J. L., Sabina, R. L., McHale, P. A., Greenfield, J. C. & Holmes, E. W. Prolonged myocardial nucleotide depletion after brief ischemia in the open-chest dog. Am. J. Physiol. 242, H818–H826 (1982).

    CAS  PubMed  Google Scholar 

  63. Guth, B. D., Martin, J. F., Heusch, G. & Ross, J. Jr. Regional myocardial blood flow, function and metabolism using phosphorus-31 nuclear magnetic resonance spectroscopy during ischemia and reperfusion. J. Am. Coll. Cardiol. 10, 673–681 (1987).

    Article  CAS  PubMed  Google Scholar 

  64. Henrichs, K. J., Matsuoka, H. & Schaper, J. Influence of repetitive coronary occlusions on myocardial adenine nucleotides, high energy phosphates and ultrastructure. Basic Res. Cardiol. 82, 557–565 (1987).

    Article  CAS  PubMed  Google Scholar 

  65. Hoffmeister, H. M., Mauser, M. & Schaper, W. Effect of adenosine and AICAR on ATP content and regional contractile function in reperfused canine myocardium. Basic Res. Cardiol. 80, 445–458 (1985).

    Article  CAS  PubMed  Google Scholar 

  66. Ambrosio, G., Jacobus, W. E., Mitchell, M. C., Litt, M. R. & Becker, L. C. Effects of ATP precursors on ATP and free ADP content and functional recovery of postischemic hearts. Am. J. Physiol. 256, H560–H566 (1989).

    CAS  PubMed  Google Scholar 

  67. Zhao, M. et al. Profound structural alterations of the extracellular collagen matrix in postischemic dysfunctional (“stunned”) but viable myocardium. J. Am. Coll. Cardiol. 10, 1322–1334 (1987).

    Article  CAS  PubMed  Google Scholar 

  68. Weil, B. R. et al. Brief myocardial ischemia produces cardiac troponin I release and focal myocyte apoptosis in the absence of pathological infarction in swine. J. Am. Coll. Cardiol. Basic Transl. Sci. 2, 105–114 (2017).

    Google Scholar 

  69. Bolli, R. Mechanism of myocardial “stunning”. Circulation 82, 723–738 (1990).

    Article  CAS  PubMed  Google Scholar 

  70. Bolli, R. & Marbán, E. Molecular and cellular mechanisms of myocardial stunning. Physiol. Rev. 70, 609–634 (1999).

    Article  Google Scholar 

  71. McCord, J. M. Oxygen-derived free radicals in postischemic tissue injury. N. Engl. J. Med. 312, 159–163 (1985).

    Article  CAS  PubMed  Google Scholar 

  72. Bolli, R. Oxygen-derived free radicals and postischemic myocardial dysfunction (“stunned myocardium”). J. Am. Coll. Cardiol. 12, 239–249 (1988).

    Article  CAS  PubMed  Google Scholar 

  73. Zweier, J. L., Flaherty, J. T. & Weisfeldt, M. L. Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc. Natl Acad. Sci. USA 84, 1404–1407 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bolli, R., Patel, B. S., Jeroudi, M. O., Lai, E. K. & McCay, P. B. Demonstration of free radical generation in “stunned” myocardium of intact dogs with the use of the spin trap a-phenyl N-tert-butyl nitrone. J. Clin. Invest. 82, 476–485 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tullio, F., Angotti, C., Perrelli, M. G., Penna, C. & Pagliaro, P. Redox balance and cardioprotection. Basic Res. Cardiol. 108, 392 (2013).

    Article  PubMed  Google Scholar 

  76. Abdallah, Y. et al. Interplay between Ca2+ cycling and mitochondrial permeability transition pores promotes reperfusion-induced injury of cardiac myocytes. J. Cell Mol. Med. 15, 2478–2485 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kinugawa, S. et al. Coronary microvascular endothelial stunning after acute pressure overload in the conscious dog is caused by oxidant processes. The role of angiotensin II type 1 receptor and NAD(P)H oxidase. Circulation 108, 2934–2940 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Engler, R. L. & Covell, J. W. Granulocytes cause reperfusion ventricular dysfunction after 15 minute ischemia in the dog. Circ. Res. 61, 20–28 (1987).

    Article  CAS  PubMed  Google Scholar 

  79. Baxter, G. F. The neutrophil as a mediator of myocardial ischemia-reperfusion injury: time to move on. Basic Res. Cardiol. 97, 268–275 (2002).

    Article  PubMed  Google Scholar 

  80. Zorov, D. B., Juhaszova, M. & Sollott, S. J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 94, 909–950 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bolli, R. et al. The iron chelator desferrioxamine attenuates postischemic ventricular dysfunction. Am. J. Physiol. 253, H1372–H1380 (1987).

    CAS  PubMed  Google Scholar 

  82. Bolli, R. et al. Iron-mediated reactions upon reperfusion contribute to myocardial “stunning”. Am. J. Physiol. 259, H1901–H1911 (1990).

    CAS  PubMed  Google Scholar 

  83. Xia, Y. & Zweier, J. L. Substrate control of free radical generation from xanthine oxidase in the postischemic heart. J. Biol. Chem. 270, 18797–18803 (1995).

    Article  CAS  PubMed  Google Scholar 

  84. Charlat, M. I. et al. Evidence for a pathogenetic role of xanthine oxidase in the “stunned” myocardium. Am. J. Physiol. 252, H566–H577 (1987).

    CAS  PubMed  Google Scholar 

  85. Eddy, L. J. et al. Free radical-producing enzyme, xanthine oxidase, is undetectable in human hearts. Am. J. Physiol. 253, H709–H711 (1987).

    CAS  PubMed  Google Scholar 

  86. Vandeplassche, G., Hermans, C., Thone, F. & Borgers, M. Stunned myocardium has increased mitochondrial NADH oxidase and ATPase activities. Cardioscience 2, 47–53 (1991).

    CAS  PubMed  Google Scholar 

  87. Talukder, M. A. et al. Cardiomyocyte-specific overexpression of an active form of Rac predisposes the heart to increased myocardial stunning and ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 304, H294–H302 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Rowe, G. T., Manson, N. H., Caplan, M. & Hess, M. L. Hydrogen peroxide and hydroxyl radical mediation of activated leukocyte depression of cardiac sarcoplasmic reticulum. Participation of the cyclooxygenase pathway. Circ. Res. 53, 584–591 (1983).

    Article  CAS  PubMed  Google Scholar 

  89. Canton, M., Neverova, I., Menabó, R., Van Eyk, J. & Di Lisa, F. Evidence of myofibrillar protein oxidation induced by postischemic reperfusion in isolated rat hearts. Am. J. Physiol. Heart Circ. Physiol. 286, H870–H877 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Przyklenk, K. & Kloner, R. A. Superoxide dismutase plus catalase improve contractile function in the canine model of the “stunned myocardium”. Circ. Res. 58, 148–156 (1986).

    Article  CAS  PubMed  Google Scholar 

  91. Jeroudi, M. O., Triana, F. J., Patel, B. S. & Bolli, R. Effects of superoxide dismutase and catalase, given separately, on myocardial stunning. Am. J. Physiol. 259, H889–H901 (1990).

    CAS  PubMed  Google Scholar 

  92. Myers, M. L., Bolli, R., Lekich, R. F., Hartley, C. J. & Roberts, R. N-2-mercaptopropionylglycine improves recovery of myocardial function after reversible regional ischemia. J. Am. Coll. Cardiol. 8, 1161–1168 (1986).

    Article  CAS  PubMed  Google Scholar 

  93. Bolli, R. et al. Attenuation of dysfunction in the postischemic “stunned” myocardium by dimethylthiourea. Circulation 76, 458–468 (1987).

    Article  CAS  PubMed  Google Scholar 

  94. Tani, M. & Neely, J. R. Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Circ. Res. 65, 1045–1056 (1989).

    Article  CAS  PubMed  Google Scholar 

  95. Ladilov, Y. V., Siegmund, B. & Piper, H. M. Protection of reoxygenated cardiomyocytes against hypercontracture by inhibition of Na+/H+ exchange. Am. J. Physiol. 268, H1531–H1539 (1995).

    CAS  PubMed  Google Scholar 

  96. Atar, D., Gao, W. D. & Marban, E. Alterations of excitation-contraction coupling in stunned myocardium and in failing myocardium. J. Mol. Cell Cardiol. 27, 783–791 (1995).

    Article  CAS  PubMed  Google Scholar 

  97. Heusch, G., Rose, J., Skyschally, A., Post, H. & Schulz, R. Calcium responsiveness in regional myocardial short-term hibernation and stunning in the in situ porcine heart – inotropic responses to postextrasystolic potentiation and intracoronary calcium. Circulation 93, 1556–1566 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Inserte, J., Hernando, V. & Garcia-Dorado, D. Contribution of calpains to myocardial ischaemia/reperfusion injury. Cardiovasc. Res. 96, 23–31 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. van Eyk, J. E. & Murphy, A. M. The role of troponin abnormalities as a cause for stunned myocardium. Coron. Artery Dis. 12, 343–347 (2001).

    Article  PubMed  Google Scholar 

  100. Kögler, H., Soergel, D. G., Murphy, A. M. & Marban, E. Maintained contractile reserve in a transgenic mouse model of myocrdial stunning. Am. J. Physiol. Heart Circ. Physiol. 280, H2623–H2630 (2001).

    Article  PubMed  Google Scholar 

  101. Thomas, S. A., Fallavollita, J. A., Lee, T.-C., Feng, J. & Canty, J. M. Absence of troponin I degradation or altered sarcoplasmic reticulum uptake protein expression after reversible ischemia in swine. Circ. Res. 85, 446–456 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Feng, J., Schaus, B. J., Fallavollita, J. A., Lee, T.-C. & Canty, J. M. Preload induces troponin I degradation independently of myocardial ischemia. Circulation 103, 2035–2037 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Weil, B. R., Suzuki, G., Young, R. F., Iyer, V. & Canty, J. M. Jr. Troponin release and reversible left ventricular dysfunction after transient pressure overload. J. Am. Coll. Cardiol. 71, 2906–2916 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hausenloy, D. J. et al. Mitochondrial ion channels as targets for cardioprotection. J. Cell Mol. Med. 24, 7102–7114 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Wang, X. et al. Quantitative proteomic and phosphoproteomic profiling of ischemic myocardial stunning in swine. Am. J. Physiol. Heart Circ. Physiol. 318, H1256–H1271 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Becker, L. C., Levine, J. H., DiPaula, A. F., Guarnieri, T. & Aversano, T. Reversal of dysfunction in postischemic stunned myocardium by epinephrine and postextrasystolic potentiation. J. Am. Coll. Cardiol. 7, 580–589 (1986).

    Article  CAS  PubMed  Google Scholar 

  107. Heusch, G., Schäfer, S. & Kröger, K. Recruitment of inotropic reserve in “stunned” myocardium by the cardiotonic agent AR-L 57. Basic Res. Cardiol. 83, 602–610 (1988).

    Article  CAS  PubMed  Google Scholar 

  108. White, F. C. & Boss, G. Inotropic interventions during myocardial “stunning” in the pig. Am. J. Cardiovasc. Pathol. 3, 225–236 (1990).

    CAS  PubMed  Google Scholar 

  109. Przyklenk, K. & Kloner, R. A. Effect of verapamil on postischemic “stunned” myocardium: importance of the timing of treatment. J. Am. Coll. Cardiol. 11, 614–623 (1988).

    Article  CAS  PubMed  Google Scholar 

  110. Farber, N. E. & Gross, G. J. Cardioprotective effects of a new vascular intracellular calcium antagonist, KT-362, in the stunned myocardium. J. Pharmacol. Exp. Ther. 248, 39–43 (1989).

    CAS  PubMed  Google Scholar 

  111. Przyklenk, K., Ghafari, G. B., Eitzman, D. T. & Kloner, R. A. Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic “stunned” myocardium. J. Am. Coll. Cardiol. 13, 1176–1183 (1989).

    Article  CAS  PubMed  Google Scholar 

  112. Ehring, T., Böhm, M. & Heusch, G. The calcium antagonist nisoldipine improves the functional recovery of reperfused myocardium only when given before ischemia. J. Cardiovasc. Pharmacol. 20, 63–74 (1992).

    CAS  PubMed  Google Scholar 

  113. Rose, J. & Heusch, G. Attenuation of regional myocardial stunning by felodipine. Cardiovasc. Drugs Ther. 10, 347–349 (1996).

    CAS  PubMed  Google Scholar 

  114. Hale, S. L. & Kloner, R. A. Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit. J. Cardiovasc. Pharmacol. Ther. 11, 249–255 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Ehring, T. et al. Attenuation of myocardial stunning by the ACE-inhibitor ramiprilat through a signal cascade of bradykinin and prostaglandins, but not nitric oxide. Circulation 90, 1368–1385 (1994).

    Article  CAS  PubMed  Google Scholar 

  116. Przyklenk, K. & Kloner, R. A. Angiotensin converting enzyme inhibitors improve contractile function of stunned myocardium by different mechanisms of action. Am. Heart J. 121, 1319–1330 (1991).

    Article  CAS  PubMed  Google Scholar 

  117. Jalowy, A., Schulz, R., Dörge, H., Behrends, M. & Heusch, G. Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs. J. Am. Coll. Cardiol. 32, 1787–1796 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Dörge, H., Behrends, M., Schulz, R., Jalowy, A. & Heusch, G. Attenuation of myocardial stunning by AT1 receptor antagonist candesartan. Basic Res. Cardiol. 94, 208–214 (1999).

    Article  PubMed  Google Scholar 

  119. Auchampach, J. A., Maruyama, M., Cavero, I. & Gross, G. J. Pharmacological evidence for a role of ATP-dependent potassium channels in myocardial stunning. Circulation 86, 311–319 (1992).

    Article  CAS  PubMed  Google Scholar 

  120. Heusch, G., Frehen, D., Kröger, K., Schulz, R. & Thämer, V. Integrity of sympathetic neurotransmission in stunned myocardium. J. Appl. Cardiol. 3, 259–272 (1988).

    Google Scholar 

  121. Gutterman, D. D., Morgan, D. A. & Miller, F. J. Effect of brief myocardial ischemia on sympathetic coronary vasoconstriction. Circ. Res. 71, 960–969 (1992).

    Article  CAS  PubMed  Google Scholar 

  122. Miura, H., Morgan, D. A. & Gutterman, D. D. Oxygen-derived free radicals contribute to neural stunning in the canine heart. Am. J. Physiol. 273, H1596–H1575 (1997).

    Google Scholar 

  123. Abe, T., Morgan, D. A. & Gutterman, D. D. Role of adenosine receptor subtypes in neural stunning of sympathetic coronary innervation. Am. J. Physiol. 41, H25–H34 (1997).

    Google Scholar 

  124. Jeremy, R. W. et al. Preservation of coronary flow reserve in stunned myocardium. Am. J. Physiol. 256, H1303–H1310 (1989).

    CAS  PubMed  Google Scholar 

  125. Triana, J. F. & Bolli, R. Decreased flow reserve in “stunned” myocardium after a 10-min coronary occlusion. Am. J. Physiol. 261, H793–H804 (1991).

    CAS  PubMed  Google Scholar 

  126. Bolli, R., Triana, J. F. & Jeroudi, M. O. Prolonged impairment of coronary vasodilation after reversible ischemia. Circ. Res. 67, 332–343 (1990).

    Article  CAS  PubMed  Google Scholar 

  127. Ehring, T. et al. Cholinergic and alpha-adrenergic coronary vasomotion with increasing ischemia-reperfusion injury. Am. J. Physiol. 268, H886–H894 (1995).

    CAS  PubMed  Google Scholar 

  128. McFalls, E. O., Duncker, D. J., Ward, H. & Fashingbauer, P. Impaired endothelium-dependent vasodilation of coronary resistance vessels in severely stunned porcine myocardium. Basic Res. Cardiol. 90, 498–509 (1995).

    Article  CAS  PubMed  Google Scholar 

  129. Schulz, R., Guth, B. D. & Heusch, G. No effect of coronary perfusion on regional myocardial function within the autoregulatory range in pigs: evidence against the Gregg phenomenon. Circulation 83, 1390–1403 (1991).

    Article  CAS  PubMed  Google Scholar 

  130. Stahl, L. D., Aversano, T. R. & Becker, L. C. Selective enhancement of function of stunned myocardium by increased flow. Circulation 74, 843–851 (1986).

    Article  CAS  PubMed  Google Scholar 

  131. Schulz, R., Janssen, F., Guth, B. D. & Heusch, G. Effect of coronary hyperperfusion on regional myocardial function and oxygen consumption of stunned myocardium in pigs. Basic Res. Cardiol. 86, 534–543 (1991).

    Article  CAS  PubMed  Google Scholar 

  132. Nienaber, C. A. et al. Metabolic and functional recovery of ischemic human myocardium after coronary angioplasty. J. Am. Coll. Cardiol. 18, 966–978 (1991).

    Article  CAS  PubMed  Google Scholar 

  133. Sheiban, I., Tonni, S., Benussi, P., Martini, A. & Trevi, G. P. Left ventricular dysfunction following transient ischaemia induced by transluminal coronary angioplasty. Beneficial effects of calcium antagonists against post-ischaemic myocardial stunning. Eur. Heart J. 14, 14–21 (1993).

    Article  PubMed  Google Scholar 

  134. Hoole, S. P. et al. Stunning and cumulative left ventricular dysfunction occurs late after coronary balloon occlusion in humans: insights from simultaneous coronary and left ventricular hemodynamic assessment. JACC Cardiovasc. Interv. 3, 412–418 (2010).

    Article  PubMed  Google Scholar 

  135. McCormick, L. M. et al. Pre-treatment with glucagon-like peptide-1 protects against ischemic left ventricular dysfunction and stunning without a detected difference in myocardial substrate utilization. J. Am. Coll. Cardiol. Cardiovasc. Interv. 8, 292–301 (2015).

    Article  Google Scholar 

  136. Uren, N. G. et al. Delayed recovery of coronary resistive vessel function after coronary angioplasty. J. Am. Coll. Cardiol. 21, 612–621 (1993).

    Article  CAS  PubMed  Google Scholar 

  137. Fragasso, G. et al. Symptom-limited exercise testing causes sustained diastolic dysfunction in patients with coronary disease and low effort tolerance. J. Am. Coll. Cardiol. 17, 1251–1255 (1991).

    Article  CAS  PubMed  Google Scholar 

  138. Scognamiglio, R., Ponchia, A., Fasoli, G., Miraglia, G. & Dalla-Volta, S. Exercise-induced left ventricular dysfunction in coronary heart disease. A model for studying the stunned myocardium in man. Eur. Heart J. 12, 16–19 (1991).

    PubMed  Google Scholar 

  139. Ambrosio, G. et al. Prolonged impairment of regional contractile function after resolution of exercise-induced angina. Evidence of myocardial stunning in patients with coronary artery disease. Circulation 94, 2455–2464 (1996).

    Article  CAS  PubMed  Google Scholar 

  140. Maranta, F. et al. Ivabradine reduces myocardial stunning in patients with exercise-inducible ischaemia. Basic Res. Cardiol. 110, 55 (2015).

    Article  CAS  PubMed  Google Scholar 

  141. Jeroudi, M. O., Cheirif, J., Habib, G. & Bolli, R. Prolonged wall motion abnormalities after chest pain at rest in patients with unstable angina: a possible manifestation of myocardial stunning. Am. Heart J. 127, 1241–1250 (1994).

    Article  CAS  PubMed  Google Scholar 

  142. Topol, E. J. et al. Regional wall motion improvement after coronary thrombolysis with recombinant tissue plasminogen activator: importance of coronary angioplasty. J. Am. Coll. Cardiol. 6, 426–433 (1985).

    Article  CAS  PubMed  Google Scholar 

  143. Sharif, D., Matanis, W., Sharif-Rasslan, A. & Rosenschein, U. Doppler echocardiographic myocardial stunning index predicts recovery of left ventricular systolic function after primary percutaneous coronary intervention. Echocardiography 33, 1465–1471 (2016).

    Article  PubMed  Google Scholar 

  144. Calabretta, R. et al. Prediction of functional recovery after primary PCI using the estimate of myocardial salvage in gated SPECT early after acute myocardial infarction. Eur. J. Nucl. Med. Mol. Imaging 45, 530–537 (2018).

    Article  PubMed  Google Scholar 

  145. Bolli, R. Why myocardial stunning is clinically important. Basic Res. Cardiol. 93, 169–172 (1998).

    Article  CAS  PubMed  Google Scholar 

  146. Patel, B., Kloner, R. A., Przyklenk, K. & Braunwald, E. Postischemic myocardial “stunning”: a clinically relevant phenomenon. Ann. Intern. Med. 108, 626–628 (1988).

    Article  CAS  PubMed  Google Scholar 

  147. Heusch, G. Stunning – great paradigmatic, but little clinical importance. Basic Res. Cardiol. 93, 164–166 (1998).

    Article  CAS  PubMed  Google Scholar 

  148. Braunwald, E. & Rutherford, J. D. Reversible ischemic left ventricular dysfunction: evidence for the “hibernating myocardium”. J. Am. Coll. Cardiol. 8, 1467–1470 (1986).

    Article  CAS  PubMed  Google Scholar 

  149. Bristow, J. D., Arai, A. E., Anselone, C. G. & Pantely, G. A. Response to myocardial ischemia as a regulated process. Circulation 84, 2580–2587 (1991).

    Article  CAS  PubMed  Google Scholar 

  150. Ross, J. Jr Myocardial perfusion-contraction matching. Implications for coronary heart disease and hibernation. Circulation 83, 1076–1083 (1991).

    Article  PubMed  Google Scholar 

  151. Shen, Y.-T. & Vatner, S. F. Mechanism of impaired myocardial function during progressive coronary stenosis in conscious pigs. Hibernation versus stunning. Circ. Res. 76, 479–488 (1995).

    Article  CAS  PubMed  Google Scholar 

  152. Fedele, F. A., Gewirtz, H., Capone, R. J., Sharaf, B. & Most, A. S. Metabolic response to prolonged reduction of myocardial blood flow distal to a severe coronary artery stenosis. Circulation 78, 729–735 (1988).

    Article  CAS  PubMed  Google Scholar 

  153. Pantely, G. A. et al. Regeneration of myocardial phosphocreatine in pigs despite continued moderate ischemia. Circ. Res. 67, 1481–1493 (1990).

    Article  CAS  PubMed  Google Scholar 

  154. Arai, A. E., Pantely, G. A., Anselone, C. G., Bristow, J. & Bristow, J. D. Active downregulation of myocardial energy requirements during prolonged moderate ischemia in swine. Circ. Res. 69, 1458–1469 (1991).

    Article  CAS  PubMed  Google Scholar 

  155. Schulz, R., Guth, B. D., Pieper, K., Martin, C. & Heusch, G. Recruitment of an inotropic reserve in moderately ischemic myocardium at the expense of metabolic recovery: a model of short-term hibernation. Circ. Res. 70, 1282–1295 (1992).

    Article  CAS  PubMed  Google Scholar 

  156. Offstad, J., Kirkeboen, K. A., Lande, K. & Ilebekk, A. Cardiac adaptation to one hour of mild regional low flow ischemia in the pig. Cardiovasc. Res. 27, 2248–2253 (1993).

    Article  CAS  PubMed  Google Scholar 

  157. Schulz, R., Rose, J., Martin, C., Brodde, O. E. & Heusch, G. Development of short-term myocardial hibernation: its limitation by the severity of ischemia and inotropic stimulation. Circulation 88, 684–695 (1993).

    Article  CAS  PubMed  Google Scholar 

  158. Arai, A. E., Grauer, S. E., Anselone, C. G., Pantely, G. A. & Bristow, J. D. Metabolic adaptation to a gradual reduction in myocardial blood flow. Circulation 92, 244–252 (1995).

    Article  CAS  PubMed  Google Scholar 

  159. Martin, C., Schulz, R., Rose, J. & Heusch, G. Inorganic phosphate content and free energy change of ATP hydrolysis in regional short-term hibernating myocardium. Cardiovasc. Res. 39, 318–326 (1998).

    Article  CAS  PubMed  Google Scholar 

  160. Przyklenk, K., Bauer, B. & Kloner, R. A. Reperfusion of hibernating myocardium: contractile function, high-energy phosphate content, and myocyte injury after 3 hours of sublethal ischemia and 3 hours of reperfusion in the canine model. Am. Heart J. 123, 575–588 (1992).

    Article  CAS  PubMed  Google Scholar 

  161. Zhang, J. et al. Myocardial bioenergetics during acute hibernation. Am. J. Physiol. 273, H1452–H1463 (1997).

    CAS  PubMed  Google Scholar 

  162. Schulz, R. et al. Progressive loss of perfusion-contraction matching during sustained moderate ischemia in pigs. Am. J. Physiol. Heart Circ. Physiol. 280, H1945–H1953 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Schulz, R., Rose, J., Post, H., Skyschally, A. & Heusch, G. Less afterload sensitivity in short-term hibernating than in acutely ischemic and stunned myocardium. Am. J. Physiol. Heart Circ. Physiol. 279, H1106–H1110 (2000).

    Article  CAS  PubMed  Google Scholar 

  164. Heusch, G., Post, H., Michel, M. C., Kelm, M. & Schulz, R. Endogenous nitric oxide and myocardial adaptation to ischemia. Circ. Res. 87, 146–152 (2000).

    Article  CAS  PubMed  Google Scholar 

  165. Schulz, R., Kappeler, C., Coenen, H. H., Bockisch, A. & Heusch, G. Positron emission tomography analysis of (1-11C) acetate kinetics in short-term hibernating myocardium. Circulation 97, 1009–1016 (1998).

    Article  CAS  PubMed  Google Scholar 

  166. Stumpe, T. & Schrader, J. Short-term hibernation in adult cardiomyocytes is PO2 dependent Ca2+ mediated. Am. J. Physiol. Heart Circ. Physiol. 280, H42–H50 (2001).

    Article  CAS  PubMed  Google Scholar 

  167. Kitakaze, M. & Marban, E. Cellular mechanism of the modulation of contractile function by coronary perfusion pressure in ferret hearts. J. Physiol. 414, 455–472 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Schaefer, S., Carr, L. J., Kreutzer, U. & Jue, T. Myocardial adaptation during acute hibernation: mechanisms of phosphocreatine recovery. Cardiovasc. Res. 27, 2044–2051 (1993).

    Article  CAS  PubMed  Google Scholar 

  169. Schulz, R., Rose, J., Post, H. & Heusch, G. Regional short-term hibernation in swine does not involve endogenous adenosine or KATP channels. Am. J. Physiol. 268, H2294–H2301 (1995).

    CAS  PubMed  Google Scholar 

  170. Schulz, R., Gres, P. & Heusch, G. Role of endogenous opioids in ischemic preconditioning but not in short-term hibernation in pigs. Am. J. Physiol. Heart Circ. Physiol. 280, H2175–H2181 (2001).

    Article  CAS  PubMed  Google Scholar 

  171. Kudej, R. K. et al. Nitric oxide, an important regulator of perfusion-contraction matching in conscious pigs. Am. J. Physiol. Heart Circ. Physiol. 279, H451–H456 (2000).

    Article  CAS  PubMed  Google Scholar 

  172. Canty, J. M. & Klocke, F. J. Reductions in regional myocardial function at rest in conscious dogs with chronically reduced regional coronary artery pressure. Circ. Res. 61, 107–116 (1987).

    Article  Google Scholar 

  173. Shen, Y.-T., Kudej, R. K., Bishop, S. P. & Vatner, S. F. Inotropic reserve and histological appearance of hibernating myocardium in conscious pigs with ameroid-induced coronary stenosis. Basic Res. Cardiol. 91, 479–485 (1996).

    Article  CAS  PubMed  Google Scholar 

  174. Kudej, R. K. et al. Ineffective perfusion-contraction matching in conscious, chronically instrumented pigs with an extended period of coronary stenosis. Circ. Res. 82, 1199–1205 (1998).

    Article  CAS  PubMed  Google Scholar 

  175. Thomas, S., Fallavollita, J., Borgers, M. & Canty, J. Dissociation of regional adaptations to ischemia and global myolysis in an accelerated swine model of chronic hibernating myocardium. Circ. Res. 91, 970–977 (2002).

    Article  CAS  PubMed  Google Scholar 

  176. Fallavollita, J. A. & Canty, J. M. Differential 18F-2-deoxyglucose uptake in viable dysfunctional myocardium with normal resting perfusion. Circulation 99, 2798–2805 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  178. Martinez-Milla, J. et al. Translational large animal model of hibernating myocardium: characterization by serial multimodal imaging. Basic Res. Cardiol. 115, 33 (2020).

    Article  CAS  PubMed  Google Scholar 

  179. Kelly, R. F. et al. Continued depression of maximal oxygen consumption and mitochondrial proteomic expression despite successful coronary artery bypass grafting in a swine model of hibernation. J. Thorac. Cardiovasc. Surg. 141, 261–268 (2011).

    Article  CAS  PubMed  Google Scholar 

  180. Page, B. J. et al. Revascularization of chronic hibernating myocardium stimulates myocyte proliferation and partially reverses chronic adaptations to ischemia. J. Am. Coll. Cardiol. 65, 684–697 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Fallavollita, J. A., Logue, M. & Canty, J. M. Stability of hibernating myocardium in pigs with a chronic left anterior descending coronary artery stenosis: absence of progressive fibrosis in the setting of stable reductions in flow, function and coronary flow reserve. J. Am. Coll. Cardiol. 37, 1989–1995 (2001).

    Article  CAS  PubMed  Google Scholar 

  182. Liedtke, A. J., Renstrom, B., Nellis, S. H., Hall, J. L. & Stanley, W. C. Mechanical and metabolic functions in pig hearts after 4 days of chronic coronary stenosis. J. Am. Coll. Cardiol. 26, 815–828 (1995).

    Article  CAS  PubMed  Google Scholar 

  183. McFalls, E. O. et al. Regional glucose uptake within hypoperfused swine myocardium as measured by positron emission tomography. Am. J. Physiol. Heart Circ. Physiol. 41, H343–H349 (1997).

    Article  Google Scholar 

  184. Hu, Q. et al. Reductions in mitochondrial O2 consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium. Am. J. Physiol. Heart Circ. Physiol. 297, H223–H232 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Fallavollita, J. A., Lim, H. & Canty, J. M. Jr. Myocyte apoptosis and reduced SR gene expression precede the transition from chronically stunned to hibernating myocardium. J. Mol. Cell Cardiol. 33, 1937–1944 (2001).

    Article  CAS  PubMed  Google Scholar 

  186. Thijssen, V. L. J. L. Temporal and spatial variations in structural protein expression during the progression from stunned to hibernating myocardium. Circulation 110, 3313–3321 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  188. Fallavollita, J. A., Jacob, S., Young, R. F. & Canty, J. M. Regional alterations in SR Ca2+-ATPase, phospholamban, and HSP-70 expression in chronic hibernating myocardium. Am. J. Physiol. 277, H1418–H1428 (1999).

    CAS  PubMed  Google Scholar 

  189. Fallavollita, J. A. & Canty, J. M. J. Ischemic cardiomyopathy in pigs with two-vessel occlusion and viable, chronically dysfunctional myocardium. Am. J. Physiol. Cell Physiol. 282, H1370–H1379 (2002).

    Article  CAS  Google Scholar 

  190. Depre, C. et al. Program of cell survival underlying human and experimental hibernating myocardium. Circ. Res. 95, 433–440 (2004).

    Article  CAS  PubMed  Google Scholar 

  191. Page, B. et al. Persistent regional downregulation in mitochondrial enzymes and upregulation of stress proteins in swine with chronic hibernating myocardium. Circ. Res. 102, 103–112 (2008).

    Article  CAS  PubMed  Google Scholar 

  192. Page, B. J., Young, R. F., Suzuki, G., Fallavollita, J. A. & Canty, J. M. Jr The physiological significance of a coronary stenosis differentially affects contractility and mitochondrial function in viable chronically dysfunctional myocardium. Basic Res. Cardiol. 108, 354 (2013).

    Article  PubMed  Google Scholar 

  193. Qu, J. et al. Reproducible ion-current-based approach for 24-plex comparison of the tissue proteomes of hibernating versus normal myocardium in swine models. J. Proteome Res. 13, 2571–2584 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Bito, V. et al. Cellular mechanisms of contractile dysfunction in hibernating myocardium. Cellular remodeling in hibernation. Circ. Res. 94, 794–801 (2004).

    Article  CAS  PubMed  Google Scholar 

  195. Weil, B. R., Suzuki, G., Leiker, M. M., Fallavollita, J. A. & Canty, J. M. Jr. Comparative efficacy of intracoronary allogeneic mesenchymal stem cells and cardiosphere-derived cells in swine with hibernating myocardium. Circ. Res. 117, 634–644 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Suzuki, G., Iyer, V., Cimato, T. & Canty, J. M. Jr. Pravastatin improves function in hibernating myocardium by mobilizing CD133+ and cKit+ bone marrow progenitor cells and promoting myocytes to reenter the growth phase of the cardiac cell cycle. Circ. Res. 104, 255–264 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Kupatt, C. et al. Endothelial nitric oxide synthase overexpression provides a functionally relevant angiogenic switch in hibernating pig myocardium. J. Am. Coll. Cardiol. 49, 1575–1584 (2007).

    Article  CAS  PubMed  Google Scholar 

  198. Luisi, A. J. J., Fallavollita, J. A., Suzuki, G. & Canty, J. M. J. Spatial inhomogeneity of sympathetic nerve function in hibernating myocardium. Circulation 106, 779–781 (2002).

    Article  PubMed  Google Scholar 

  199. Canty, J. M. J. et al. Hibernating myocardium. Chronically adapted to ischemia but vulnerable to sudden death. Circ. Res. 94, 1142–1149 (2004).

    Article  CAS  PubMed  Google Scholar 

  200. Mills, I. et al. Adaptive responses of coronary circulation and myocardium to chronic reduction in perfusion pressure and flow. Am. J. Physiol. Heart Circ. Physiol. 266, H447–H457 (1994).

    Article  CAS  Google Scholar 

  201. Schömig, A. et al. Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset. A randomized controlled trial. J. Am. Med. Assoc. 293, 2865–2872 (2005).

    Article  Google Scholar 

  202. Ndrepepa, G., Kastrati, A., Mehilli, J., Antoniucci, D. & Schomig, A. Mechanical reperfusion and long-term mortality in patients with acute myocardial infarction presenting 12 to 48 hours from onset of symptoms. J. Am. Med. Assoc. 301, 487–488 (2009).

    Article  CAS  Google Scholar 

  203. Rahimtoola, S. H. The hibernating myocardium. Am. Heart J. 117, 211–221 (1989).

    Article  CAS  PubMed  Google Scholar 

  204. Vanoverschelde, J.-L. J. et al. Mechanisms of chronic regional postischemic dysfunction in humans. New insights from the study of noninfarcted collateral-dependent myocardium. Circulation 87, 1513–1523 (1993).

    Article  CAS  PubMed  Google Scholar 

  205. Zhang, X. et al. Blood flow, flow reserve, and glucose utilization in viable and nonviable myocardium in patients with ischemic cardiomyopathy. Eur. J. Nucl. Med. Mol. Imaging 40, 532–541 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Anavekar, N. S., Chareonthaitawee, P., Narula, J. & Gersh, B. J. Revascularization in patients with severe left ventricular dysfunction: is the assessment of viability still viable? J. Am. Coll. Cardiol. 67, 2874–2887 (2016).

    Article  PubMed  Google Scholar 

  207. Gewirtz, H. & Dilsizian, V. Myocardial viability: survival mechanisms and molecular imaging targets in acute and chronic ischemia. Circ. Res. 120, 1197–1212 (2017).

    Article  CAS  PubMed  Google Scholar 

  208. Bonow, R. O., Dilsizian, V., Cuocolo, A. & Bacharach, S. L. Identification of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction. Circulation 83, 26–37 (1991).

    Article  CAS  PubMed  Google Scholar 

  209. Beanlands, R. S. et al. F-18-Fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2). J. Am. Coll. Cardiol. 50, 2002–2012 (2007).

    Article  PubMed  Google Scholar 

  210. Gerber, B. L. et al. Myocardial blood flow, glucose uptake, and recruitment of inotropic reserve in chronic left ventricular ischemic dysfunction. Implications for the pathophysiology of chronic myocardial hibernation. Circulation 94, 651–659 (1996).

    Article  CAS  PubMed  Google Scholar 

  211. Glaveckaite, S. et al. Prediction of long-term segmental and global functional recovery of hibernating myocardium after revascularisation based on low dose dobutamine and late gadolinium enhancement cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 16, 83 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Indolfi, C. et al. Inotropic stimulation by dobutamine increases left ventricular regional function at the expense of metabolism in hibernating myocardium. Am. Heart J. 132, 542–549 (1996).

    Article  CAS  PubMed  Google Scholar 

  213. Wiggers, H. et al. Energy stores and metabolites in chronic reversibly and irreversibly dysfunctional myocardium in humans. J. Am. Coll. Cardiol. 37, 100–108 (2001).

    Article  CAS  PubMed  Google Scholar 

  214. Bøtker, H. E. et al. Electromechanical mapping for detection of myocardial viability in patients with ischemic cardiomyopathy. Circulation 103, 1631–1637 (2001).

    Article  PubMed  Google Scholar 

  215. Wiggers, H. et al. Electromechanical mapping versus positron emission tomography and single photon emission computed tomography for the detection of myocardial viability in patients with ischemic cardiomyopathy. J. Am. Coll. Cardiol. 41, 843–848 (2003).

    Article  PubMed  Google Scholar 

  216. Shivalkar, B. et al. Only hibernating myocardium invariably shows early recovery after coronary revascularization. Circulation 94, 308–315 (1996).

    Article  CAS  PubMed  Google Scholar 

  217. Vanoverschelde, J.-L. et al. Time course of functional recovery after coronary artery bypass graft surgery in patients with chronic left ventricular ischemic dysfunction. Am. J. Cardiol. 85, 1432–1439 (2000).

    Article  CAS  PubMed  Google Scholar 

  218. Maes, A. et al. Histological alterations in chronically hypoperfused myocardium. Correlations with PET findings. Circulation 90, 735–745 (1994).

    Article  CAS  PubMed  Google Scholar 

  219. Depré, C. et al. Structural and metabolic correlates of the reversibility of chronic left ventricular ischemic dysfunction in humans. Am. J. Physiol. 268, H1265–H1275 (1995).

    PubMed  Google Scholar 

  220. Schwarz, E. R. et al. Myocyte degeneration and cell death in hibernating human myocardium. J. Am. Coll. Cardiol. 27, 1577–1585 (1996).

    Article  CAS  PubMed  Google Scholar 

  221. Frangogiannis, N. G. et al. Active interstitial remodeling: an important process in the hibernating human myocardium. J. Am. Coll. Cardiol. 39, 1468–1474 (2002).

    Article  PubMed  Google Scholar 

  222. Ausma, J. et al. Molecular changes of titin in left ventricular dysfunction as a result of chronic hibernation. J. Mol. Cell Cardiol. 27, 1203–1212 (1995).

    Article  CAS  PubMed  Google Scholar 

  223. Ausma, J. et al. Dedifferentiated cardiomyocytes from chronic hibernating myocardium are ischemia-tolerant. Mol. Cell Biochem. 186, 159–168 (1998).

    Article  CAS  PubMed  Google Scholar 

  224. Flameng, W. et al. Ultrastructural correlates of left ventricular contraction abnormalities in patients with chronic ischemic heart disease: determinants of reversible segmental asynergy post revascularization surgery. Am. Heart J. 102, 846–857 (1981).

    Article  CAS  PubMed  Google Scholar 

  225. Velazquez, E. J. et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N. Engl. J. Med. 374, 1511–1520 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Howlett, J. G. et al. CABG improves outcomes in patients with ischemic cardiomyopathy: 10-year follow-up of the STICH trial. J. Am. Coll. Cardiol. Heart Fail. 7, 878–887 (2019).

    Google Scholar 

  227. Panza, J. A. et al. Myocardial viability and long-term outcomes in ischemic cardiomyopathy. N. Engl. J. Med. 381, 739–748 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Canty, J. M. Jr. Editorial commentary: Is it still important to evaluate patients with ischemic cardiomyopathy for viable dysfunctional myocardium prior to myocardial revascularization? Trends Cardiovasc. Med. 28, 38–40 (2018).

    Article  PubMed  Google Scholar 

  229. Spertus, J. A. et al. Health-status outcomes with invasive or conservative care in coronary disease. N. Engl. J. Med. 382, 1408–1419 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  230. Lopes, R. D. et al. Initial invasive versus conservative management of stable ischemic heart disease patients with a history of heart failure or left ventricular dysfunction: insights from the ISCHEMIA trial. Circulation 142, 1725–1735 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

G.H. receives support from the German Research Foundation (SFB 1116 B8) and the European Union COST ACTION (CA 16225).

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  1. Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg–Essen, Essen, Germany

    Gerd Heusch

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Nature Reviews Cardiology thanks H.E. Bøtker, J.M. Canty, P. Pagliaro and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Post-extrasystolic potentiation

Increase in cardiac contractile force following an extrasystole (premature ventricular contraction).

Reactive hyperaemia

Transient overshoot of blood flow above baseline following a period of blood flow reduction below baseline.

Dyskinesia

Inappropriate cardiac contraction with outward wall motion (‘bulging’) rather than inward wall motion during systole.

Post-ejection wall excursion

Shortening of cardiac muscle fibres after aortic valve closure.

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Heusch, G. Myocardial stunning and hibernation revisited. Nat Rev Cardiol 18, 522–536 (2021). https://doi.org/10.1038/s41569-021-00506-7

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