Display options
Share it on

Nat Rev Cardiol. 2021 Jul;18(7):522-536. doi: 10.1038/s41569-021-00506-7. Epub 2021 Feb 02.

Myocardial stunning and hibernation revisited.

Nature reviews. Cardiology

Gerd Heusch

Affiliations

  1. Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany. [email protected].

PMID: 33531698 DOI: 10.1038/s41569-021-00506-7

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.

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). - PubMed
  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). - PubMed
  3. Rahimtoola, S. H. Coronary bypass surgery for chronic angina – 1981. Circulation 65, 225–241 (1982). - PubMed
  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). - PubMed
  5. Rahimtoola, S. H. Clinical overview of management of chronic ischemic heart disease. Circulation 84, I81–I84 (1991). - PubMed
  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). - PubMed
  7. Braunwald, E. & Kloner, R. A. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 66, 1146–1149 (1982). - PubMed
  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). - PubMed
  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). - PubMed
  10. Kloner, R. A. & Przyklenk, K. Hibernation and stunning of the myocardium. N. Engl. J. Med. 325, 1877–1879 (1991). - PubMed
  11. Marban, E. Myocardial stunning and hibernation: the physiology behind the colloquialisms. Circulation 83, 681–688 (1991). - PubMed
  12. Bolli, R. Myocardial ‘stunning’ in man. Circulation 86, 1671–1691 (1992). - PubMed
  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). - PubMed
  14. Heusch, G. Hibernating myocardium. Physiol. Rev. 78, 1055–1085 (1998). - PubMed
  15. Wijns, W., Vatner, S. & Camici, P. Hibernating myocardium. N. Engl. J. Med. 339, 173–181 (1998). - PubMed
  16. Heusch, G., Schulz, R. & Rahimtoola, S. H. Myocardial hibernation: a delicate balance. Am. J. Physiol. Heart Circ. Physiol. 288, H984–H999 (2005). - PubMed
  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). - PubMed
  18. Kloner, R. A. Stunned and hibernating myocardium: Where are we nearly 4 decades later? J. Am. Heart Assoc. 9, e015502 (2020). - PubMed
  19. Maron, D. J. et al. Initial invasive or conservative strategy for stable coronary disease. N. Engl. J. Med. 382, 1395–1407 (2020). - PubMed
  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). - PubMed
  21. Al-Lamee, R. et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet 391, 31–40 (2017). - PubMed
  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). - PubMed
  23. Knuuti, J. et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur. Heart J. 41, 407–477 (2020). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  42. Ellis, S. G. et al. Response of reperfusion-salvaged, stunned myocardium to inotropic stimulation. Am. Heart J. 107, 13–19 (1984). - PubMed
  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). - PubMed
  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). - PubMed
  45. Miura, T. et al. Does myocardial stunning contribute to infarct size limitation by ischemic preconditioning? Circulation 84, 2504–2512 (1991). - PubMed
  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). - PubMed
  47. Ovize, M., Przyklenk, K., Hale, S. L. & Kloner, R. A. Preconditioning does not attenuate myocardial stunning. Circulation 85, 2247–2254 (1992). - PubMed
  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). - PubMed
  49. Bolli, R. The late phase of preconditioning. Circ. Res. 87, 972–983 (2000). - PubMed
  50. Heusch, G. Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat. Rev. Cardiol. 17, 773–789 (2020). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  61. Kloner, R. A. et al. Prolonged abnormalities of myocardium salvaged by reperfusion. Am. J. Physiol. 241, H591–H599 (1981). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  69. Bolli, R. Mechanism of myocardial “stunning”. Circulation 82, 723–738 (1990). - PubMed
  70. Bolli, R. & Marbán, E. Molecular and cellular mechanisms of myocardial stunning. Physiol. Rev. 70, 609–634 (1999). - PubMed
  71. McCord, J. M. Oxygen-derived free radicals in postischemic tissue injury. N. Engl. J. Med. 312, 159–163 (1985). - PubMed
  72. Bolli, R. Oxygen-derived free radicals and postischemic myocardial dysfunction (“stunned myocardium”). J. Am. Coll. Cardiol. 12, 239–249 (1988). - PubMed
  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). - PubMed
  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). - PubMed
  75. Tullio, F., Angotti, C., Perrelli, M. G., Penna, C. & Pagliaro, P. Redox balance and cardioprotection. Basic Res. Cardiol. 108, 392 (2013). - PubMed
  76. Abdallah, Y. et al. Interplay between Ca - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  81. Bolli, R. et al. The iron chelator desferrioxamine attenuates postischemic ventricular dysfunction. Am. J. Physiol. 253, H1372–H1380 (1987). - PubMed
  82. Bolli, R. et al. Iron-mediated reactions upon reperfusion contribute to myocardial “stunning”. Am. J. Physiol. 259, H1901–H1911 (1990). - PubMed
  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). - PubMed
  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). - PubMed
  85. Eddy, L. J. et al. Free radical-producing enzyme, xanthine oxidase, is undetectable in human hearts. Am. J. Physiol. 253, H709–H711 (1987). - PubMed
  86. Vandeplassche, G., Hermans, C., Thone, F. & Borgers, M. Stunned myocardium has increased mitochondrial NADH oxidase and ATPase activities. Cardioscience 2, 47–53 (1991). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  93. Bolli, R. et al. Attenuation of dysfunction in the postischemic “stunned” myocardium by dimethylthiourea. Circulation 76, 458–468 (1987). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  98. Inserte, J., Hernando, V. & Garcia-Dorado, D. Contribution of calpains to myocardial ischaemia/reperfusion injury. Cardiovasc. Res. 96, 23–31 (2012). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  104. Hausenloy, D. J. et al. Mitochondrial ion channels as targets for cardioprotection. J. Cell Mol. Med. 24, 7102–7114 (2020). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  108. White, F. C. & Boss, G. Inotropic interventions during myocardial “stunning” in the pig. Am. J. Cardiovasc. Pathol. 3, 225–236 (1990). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  113. Rose, J. & Heusch, G. Attenuation of regional myocardial stunning by felodipine. Cardiovasc. Drugs Ther. 10, 347–349 (1996). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  117. Jalowy, A., Schulz, R., Dörge, H., Behrends, M. & Heusch, G. Infarct size reduction by AT - PubMed
  118. Dörge, H., Behrends, M., Schulz, R., Jalowy, A. & Heusch, G. Attenuation of myocardial stunning by AT - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  124. Jeremy, R. W. et al. Preservation of coronary flow reserve in stunned myocardium. Am. J. Physiol. 256, H1303–H1310 (1989). - PubMed
  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). - PubMed
  126. Bolli, R., Triana, J. F. & Jeroudi, M. O. Prolonged impairment of coronary vasodilation after reversible ischemia. Circ. Res. 67, 332–343 (1990). - PubMed
  127. Ehring, T. et al. Cholinergic and alpha-adrenergic coronary vasomotion with increasing ischemia-reperfusion injury. Am. J. Physiol. 268, H886–H894 (1995). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  136. Uren, N. G. et al. Delayed recovery of coronary resistive vessel function after coronary angioplasty. J. Am. Coll. Cardiol. 21, 612–621 (1993). - PubMed
  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). - PubMed
  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
  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). - PubMed
  140. Maranta, F. et al. Ivabradine reduces myocardial stunning in patients with exercise-inducible ischaemia. Basic Res. Cardiol. 110, 55 (2015). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  145. Bolli, R. Why myocardial stunning is clinically important. Basic Res. Cardiol. 93, 169–172 (1998). - PubMed
  146. Patel, B., Kloner, R. A., Przyklenk, K. & Braunwald, E. Postischemic myocardial “stunning”: a clinically relevant phenomenon. Ann. Intern. Med. 108, 626–628 (1988). - PubMed
  147. Heusch, G. Stunning – great paradigmatic, but little clinical importance. Basic Res. Cardiol. 93, 164–166 (1998). - PubMed
  148. Braunwald, E. & Rutherford, J. D. Reversible ischemic left ventricular dysfunction: evidence for the “hibernating myocardium”. J. Am. Coll. Cardiol. 8, 1467–1470 (1986). - PubMed
  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). - PubMed
  150. Ross, J. Jr Myocardial perfusion-contraction matching. Implications for coronary heart disease and hibernation. Circulation 83, 1076–1083 (1991). - PubMed
  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). - PubMed
  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). - PubMed
  153. Pantely, G. A. et al. Regeneration of myocardial phosphocreatine in pigs despite continued moderate ischemia. Circ. Res. 67, 1481–1493 (1990). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  161. Zhang, J. et al. Myocardial bioenergetics during acute hibernation. Am. J. Physiol. 273, H1452–H1463 (1997). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  166. Stumpe, T. & Schrader, J. Short-term hibernation in adult cardiomyocytes is PO - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  176. Fallavollita, J. A. & Canty, J. M. Differential - PubMed
  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). - PubMed
  178. Martinez-Milla, J. et al. Translational large animal model of hibernating myocardium: characterization by serial multimodal imaging. Basic Res. Cardiol. 115, 33 (2020). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  188. Fallavollita, J. A., Jacob, S., Young, R. F. & Canty, J. M. Regional alterations in SR Ca - PubMed
  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). - PubMed
  190. Depre, C. et al. Program of cell survival underlying human and experimental hibernating myocardium. Circ. Res. 95, 433–440 (2004). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  194. Bito, V. et al. Cellular mechanisms of contractile dysfunction in hibernating myocardium. Cellular remodeling in hibernation. Circ. Res. 94, 794–801 (2004). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  199. Canty, J. M. J. et al. Hibernating myocardium. Chronically adapted to ischemia but vulnerable to sudden death. Circ. Res. 94, 1142–1149 (2004). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  203. Rahimtoola, S. H. The hibernating myocardium. Am. Heart J. 117, 211–221 (1989). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  207. Gewirtz, H. & Dilsizian, V. Myocardial viability: survival mechanisms and molecular imaging targets in acute and chronic ischemia. Circ. Res. 120, 1197–1212 (2017). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed
  214. Bøtker, H. E. et al. Electromechanical mapping for detection of myocardial viability in patients with ischemic cardiomyopathy. Circulation 103, 1631–1637 (2001). - PubMed
  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). - PubMed
  216. Shivalkar, B. et al. Only hibernating myocardium invariably shows early recovery after coronary revascularization. Circulation 94, 308–315 (1996). - PubMed
  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). - PubMed
  218. Maes, A. et al. Histological alterations in chronically hypoperfused myocardium. Correlations with PET findings. Circulation 90, 735–745 (1994). - PubMed
  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
  220. Schwarz, E. R. et al. Myocyte degeneration and cell death in hibernating human myocardium. J. Am. Coll. Cardiol. 27, 1577–1585 (1996). - PubMed
  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). - PubMed
  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). - PubMed
  223. Ausma, J. et al. Dedifferentiated cardiomyocytes from chronic hibernating myocardium are ischemia-tolerant. Mol. Cell Biochem. 186, 159–168 (1998). - PubMed
  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). - PubMed
  225. Velazquez, E. J. et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N. Engl. J. Med. 374, 1511–1520 (2016). - PubMed
  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). - PubMed
  227. Panza, J. A. et al. Myocardial viability and long-term outcomes in ischemic cardiomyopathy. N. Engl. J. Med. 381, 739–748 (2019). - PubMed
  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). - PubMed
  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). - PubMed
  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). - PubMed

Publication Types