Abstract

Timely revascularization is the cornerstone of limiting ischemic cell death in acute myocardial infarction (MI) (1). However, delayed percutaneous coronary intervention (PCI) paradoxically poses a significant threat to the myocardium, leading to lethal reperfusion injury—a major clinical problem contributing to adverse outcomes despite successful epicardial reperfusion (2). Microvascular injury resulting from delayed reperfusion, first documented in the 1960s, significantly exacerbates myocardial injury (3). The pathogenesis of lethal reperfusion injury is driven by three central paradoxes: the calcium paradox, involving a pathological surge in intracellular calcium; the oxygen paradox, characterized by a burst of reactive oxygen species (ROS); and the pH paradox, marked by the rapid normalization of intracellular pH (4). These converge to induce mitochondrial permeability transition pore (MPTP) opening, resulting in mitochondrial damage and cardiomyocyte death (5). Despite elucidation of these mechanisms in experimental models, translation to clinical cardioprotection has been challenging (6). This review explores the mechanistic pathways of reperfusion injury, discusses the failures and promises of therapeutic strategies, and highlights future translational directions for protecting the myocardium in the context of delayed PCI. Therefore, overcoming translational challenges by developing targeted combination therapies and refining patient selection based on individual pathophysiology is the crucial next step to harness the therapeutic potential of MPTP inhibition and significantly improve outcomes in delayed PCI (7).

Keywords

  • Myocardial Reperfusion Injury
  • Mitochondrial Permeability Transition Pore
  • Percutaneous Coronary Int

References

  1. Ibanez B, et al. Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015;65(14):1454-1471.
  2. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357(11):1121-1135.
  3. Kloner RA, Ganote CE, Jennings RB. The "no-reflow" phenomenon after temporary coronary occlusion in the dog. Am Heart J. 1985;109(2):305-318.
  4. Hausenloy DJ, Yellon DM. The mitochondrial permeability transition pore: its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol. 2003;35(4):339-341.
  5. Halestrap AP, Richardson AP. The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol. 2015;78:129-141.
  6. Hausenloy DJ, et al. Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res. 2013;98(1):7-27.
  7. Ong SB, et al. Inhibiting Mitochondrial Fission Protects the Heart Against Ischemia/Reperfusion Injury. Circulation. 2010;121(18):2012-2022.
  8. O'Gara PT, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol. 2013;61(4):e78-e140.
  9. Terkelsen CJ, et al. System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. JAMA. 2010;304(7):763-771.
  10. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword?. J Clin Invest. 1985;76(5):1713-1719.
  11. Niccoli G, et al. Myocardial no-reflow in humans. J Am Coll Cardiol. 2009;54(4):281-292.
  12. Anderson JL, Morrow DA. Acute Myocardial Infarction. N Engl J Med. 2017;376(21):2053-2064.
  13. Levine GN, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease. J Am Coll Cardiol. 2016;68(10):1082-1115.
  14. Bøtker HE, et al. Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol. 2018;113(5):39.
  15. Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev. 1989;69(4):1049-1169.
  16. Bolli R, Marbán E. Molecular and cellular mechanisms of myocardial stunning. Physiol Rev. 1999;79(2):609-634.
  17. Heusch G. Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol. 2020;17(12):773-789.
  18. García-Dorado D, et al. Calcium-mediated cell death during myocardial reperfusion. Cardiovasc Res. 2012;94(2):168-180.
  19. Zweier JL, Talukder MA. The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res. 2006;70(2):181-190.
  20. Cohen MV, Downey JM. Ischaemic postconditioning: from bench to bedside. Cardiovasc Res. 2008;79(1):3-4.
  21. Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008;88(2):581-609.
  22. Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans. 2006;34(Pt 2):232-237.
  23. Avkiran M, Marber MS. Na(+)/H(+) exchange inhibitors for cardioprotective therapy: progress, problems and prospects. J Am Coll Cardiol. 2002;39(5):747-753.
  24. Gustafsson ÅB, Gottlieb RA. Heart mitochondria: gates of life and death. Cardiovasc Res. 2008;77(2):334-343.
  25. Reffelmann T, Kloner RA. The no-reflow phenomenon: A basic mechanism of myocardial ischemia and reperfusion. Basic Res Cardiol. 2006;101(5):359-372.
  26. Hausenloy DJ, Yellon DM. Ischaemic conditioning and reperfusion injury. Nat Rev Cardiol. 2016;13(4):193-209.
  27. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation. 1977;56(5):786-794.
  28. Braunwald E. The treatment of acute myocardial infarction: the past, the present, and the future. Eur Heart J Acute Cardiovasc Care. 2012;1(1):9-12.
  29. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990;81(4):1161-1172.
  30. Hausenloy DJ, et al. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial. Lancet. 2019;394(10207):1415-1424.
  31. Cung TT, et al. Cyclosporine before PCI in Patients with Acute Myocardial Infarction. N Engl J Med. 2015;373(11):1021-1031.
  32. Lincoff AM, et al. Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Circulation. 2000;102(25):3032-3038.
  33. Eitel I, et al. Prognostic value and determinants of a hypointense infarct core in T2-weighted cardiac magnetic resonance in acute reperfused ST-elevation myocardial infarction. Circ Cardiovasc Imaging. 2011;4(4):354-362.
  34. Ferdinandy P, et al. Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev. 2014;66(4):1142-1174.
  35. Garcia-Dorado D, et al. Novel therapeutic strategies for the management of myocardial ischemia/reperfusion injury: where are we going?. Trends Cardiovasc Med. 2017;27(1):1-7.
  36. Argaud L, et al. Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol. 2005;38(2):367-374.
  37. Elrod JW, Molkentin JD. Physiologic functions of cyclophilin D and the mitochondrial permeability transition pore. Circ J. 2013;77(5):1111-1122.
  38. White SK, et al. Measuring myocardial salvage. Cardiovasc Res. 2012;94(2):266-275.
  39. Heusch G, et al. Cardiovascular remodelling in coronary artery disease and heart failure. Lancet. 2014;383(9932):1933-1943.
  40. Davidson SM, et al. Multitarget Strategies to Reduce Myocardial Ischemia/Reperfusion Injury: JACC Review Topic of the Week. J Am Coll Cardiol. 2019;73(1):89-99.