Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Coronary microvascular obstruction and dysfunction in patients with acute myocardial infarction

Nature Reviews Cardiology volume 21, pages 283–298 (2024)Cite this article

Subjects

An Author Correction to this article was published on 05 December 2023

This article has been updated

Abstract

Despite prompt epicardial recanalization in patients presenting with ST-segment elevation myocardial infarction (STEMI), coronary microvascular obstruction and dysfunction (CMVO) is still fairly common and is associated with poor prognosis. Various pharmacological and mechanical strategies to treat CMVO have been proposed, but the positive results reported in preclinical and small proof-of-concept studies have not translated into benefits in large clinical trials conducted in the modern treatment setting of patients with STEMI. Therefore, the optimal management of these patients remains a topic of debate. In this Review, we appraise the pathophysiological mechanisms of CMVO, explore the evidence and provide future perspectives on strategies to be implemented to reduce the incidence of CMVO and improve prognosis in patients with STEMI.

Key points

  • Coronary microvascular obstruction and dysfunction (CMVO) is fairly common in patients with ST-segment elevation myocardial infarction (STEMI) and is associated with poor prognosis.

  • Prompt epicardial recanalization by timely primary percutaneous coronary intervention (PPCI) is the most effective strategy for the treatment and prevention of CMVO but is also a relevant confounding factor in the assessment of additional strategies to reduce CMVO in the modern management of patients with STEMI.

  • The optimal strategies to reduce CMVO in clinical practice remain debated, given that promising results from preclinical and small proof-of-concept studies have often not translated into similarly positive results in large-scale clinical trials.

  • The increasing understanding of the underlying mechanisms and the availability of more advanced tools for the prompt and precise identification of patients at high risk of CMVO will be important in the design of future randomized controlled trials in this field.

  • The prevention, precise and timely identification, and multi-pathway treatment (simultaneously targeting several pathophysiological mechanisms) of CVMO is a promising approach to improve outcomes in patients with STEMI.

  • Further studies are warranted to identify safe and effective pharmacological or mechanical strategies to reduce CMVO in patients with STEMI undergoing PPCI.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mechanisms of coronary no-reflow.
Fig. 2: Assessment of coronary microvascular obstruction and dysfunction.

Similar content being viewed by others

Change history

References

  1. Roth, G. A. et al. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 Study. J. Am. Coll. Cardiol. 76, 2982–3021 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Eeckhout, E. & Kern, M. J. The coronary no-reflow phenomenon: a review of mechanisms and therapies. Eur. Heart J. 22, 729–739 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Heusch, G. The coronary circulation as a target of cardioprotection. Circ. Res. 118, 1643–1658 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Heusch, G. Coronary microvascular obstruction: the new frontier in cardioprotection. Basic. Res. Cardiol. 114, 45 (2019).

    Article  PubMed  Google Scholar 

  5. Niccoli, G. et al. Concordance of angiographic and electrocardiographic indexes of microvascular obstruction: myocardial haemorrhage role. J. Cardiovasc. Med. 17, 382–391 (2016).

    Article  Google Scholar 

  6. de Waha, S. et al. Relationship between microvascular obstruction and adverse events following primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: an individual patient data pooled analysis from seven randomized trials. Eur. Heart J. 38, 3502–3510 (2017).

    Article  PubMed  Google Scholar 

  7. Niccoli, G., Scalone, G., Lerman, A. & Crea, F. Coronary microvascular obstruction in acute myocardial infarction. Eur. Heart J. 37, 1024–1033 (2016).

    Article  PubMed  Google Scholar 

  8. Niccoli, G. et al. Optimized treatment of ST-elevation myocardial infarction. Circ. Res. 125, 245–258 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Heusch, G. & Gersh, B. J. The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur. Heart J. 38, 774–784 (2017).

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  11. Reffelmann, T. & Kloner, R. A. The no-reflow phenomenon: a basic mechanism of myocardial ischemia and reperfusion. Basic. Res. Cardiol. 101, 359–372 (2006).

    Article  PubMed  Google Scholar 

  12. 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 

  13. Scarabelli, T. et al. Apoptosis of endothelial cells precedes myocyte cell apoptosis in ischemia/reperfusion injury. Circulation 104, 253–256 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Kleinbongard, P. & Heusch, G. A fresh look at coronary microembolization. Nat. Rev. Cardiol. 19, 265–280 (2022).

    Article  PubMed  Google Scholar 

  15. Bekkers, S. C., Yazdani, S. K., Virmani, R. & Waltenberger, J. Microvascular obstruction: underlying pathophysiology and clinical diagnosis. J. Am. Coll. Cardiol. 55, 1649–1660 (2010).

    Article  PubMed  Google Scholar 

  16. Kleinbongard, P. et al. Vasoconstrictor potential of coronary aspirate from patients undergoing stenting of saphenous vein aortocoronary bypass grafts and its pharmacological attenuation. Circ. Res. 108, 344–352 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Heusch, G. et al. Coronary microembolization: from bedside to bench and back to bedside. Circulation 120, 1822–1836 (2009).

    Article  PubMed  Google Scholar 

  18. Stakos, D. A. et al. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur. Heart J. 36, 1405–1414 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gick, M. et al. Randomized evaluation of the effects of filter-based distal protection on myocardial perfusion and infarct size after primary percutaneous catheter intervention in myocardial infarction with and without ST-segment elevation. Circulation 112, 1462–1469 (2005).

    Article  PubMed  Google Scholar 

  20. Yoshino, S. et al. Single nucleotide polymorphisms associated with abnormal coronary microvascular function. Coron. Artery Dis. 25, 281–289 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Heusch, G., Bøtker, H. E., Ferdinandy, P. & Schulz, R. Primordial non-responsiveness: a neglected obstacle to cardioprotection. Eur. Heart J. 44, 1687–1689 (2023).

    Article  PubMed  Google Scholar 

  22. Niccoli, G. et al. Protective effect of pre-infarction angina on microvascular obstruction after primary percutaneous coronary intervention is blunted in humans by cardiovascular risk factors. Circ. J. 78, 1935–1941 (2014).

    Article  PubMed  Google Scholar 

  23. Niccoli, G. et al. Ethanol abolishes ischemic preconditioning in humans. J. Am. Coll. Cardiol. 51, 271–275 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Ferdinandy, P. et al. Interaction of cardiovascular nonmodifiable risk factors, comorbidities and comedications with ischemia/reperfusion injury and cardioprotection by pharmacological treatments and ischemic conditioning. Pharmacol. Rev. 75, 159–216 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gibson, C. M. et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 101, 125–130 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Iwakura, K. et al. Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction. J. Am. Coll. Cardiol. 41, 1–7 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Lind, L. et al. The impairment in endothelial function induced by non-esterified fatty acids can be reversed by insulin. Clin. Sci. 99, 169–174 (2000).

    Article  CAS  Google Scholar 

  28. Gresele, P. et al. Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus. J. Am. Coll. Cardiol. 41, 1013–1020 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Hayakawa, H. & Raij, L. Relationship between hypercholesterolaemia, endothelial dysfunction and hypertension. J. Hypertens. 17, 611–619 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Stapleton, P. A., Goodwill, A. G., James, M. E., D’Audiffret, A. C. & Frisbee, J. C. Differential impact of familial hypercholesterolemia and combined hyperlipidemia on vascular wall and network remodeling in mice. Microcirculation 17, 47–58 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kirma, C. et al. Clinical and procedural predictors of no-reflow phenomenon after primary percutaneous coronary interventions: experience at a single center. Circ. J. 72, 716–721 (2008).

    Article  PubMed  Google Scholar 

  32. Ito, H. et al. Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty in patients with acute anterior wall myocardial infarction. Circulation 93, 1993–1999 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Iwakura, K. et al. Predictive factors for development of the no-reflow phenomenon in patients with reperfused anterior wall acute myocardial infarction. J. Am. Coll. Cardiol. 38, 472–477 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Eitel, I. et al. Endothelin-1 release in acute myocardial infarction as a predictor of long-term prognosis and no-reflow assessed by contrast-enhanced magnetic resonance imaging. Am. Heart J. 159, 882–890 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Tarantini, G. et al. Duration of ischemia is a major determinant of transmurality and severe microvascular obstruction after primary angioplasty: a study performed with contrast-enhanced magnetic resonance. J. Am. Coll. Cardiol. 46, 1229–1235 (2005).

    Article  PubMed  Google Scholar 

  36. Durante, A. et al. Identification of high-risk patients after ST-segment-elevation myocardial infarction: comparison between angiographic and magnetic resonance parameters. Circ. Cardiovasc. Imaging 10, e005841 (2017).

    Article  PubMed  Google Scholar 

  37. van ‘t Hof, A. W. et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle Myocardial Infarction Study Group. Circulation 97, 2302–2306 (1998).

    Article  PubMed  Google Scholar 

  38. Vergallo, R. et al. Pre-stenting residual thrombotic volume assessed by dual quantitative coronary angiography predicts microvascular obstruction in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Minerva Cardiol. Angiol. 71, 421–430 (2023).

    Article  PubMed  Google Scholar 

  39. Porto, I. et al. Plaque volume and occurrence and location of periprocedural myocardial necrosis after percutaneous coronary intervention: insights from delayed-enhancement magnetic resonance imaging, thrombolysis in myocardial infarction myocardial perfusion grade analysis, and intravascular ultrasound. Circulation 114, 662–669 (2006).

    Article  PubMed  Google Scholar 

  40. Soeda, T. et al. Morphological predictors for no reflow phenomenon after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction caused by plaque rupture. Eur. Heart J. Cardiovasc. Imaging 18, 103–110 (2017).

    Article  PubMed  Google Scholar 

  41. Satogami, K. et al. Impact of plaque rupture detected by optical coherence tomography on transmural extent of infarction after successful stenting in ST-segment elevation acute myocardial infarction. JACC Cardiovasc. Interv. 10, 1025–1033 (2017).

    Article  PubMed  Google Scholar 

  42. Husser, O. et al. Predictors of cardiovascular magnetic resonance-derived microvascular obstruction on patient admission in STEMI. Int. J. Cardiol. 166, 77–84 (2013).

    Article  PubMed  Google Scholar 

  43. van Kranenburg, M. et al. Prognostic value of microvascular obstruction and infarct size, as measured by CMR in STEMI patients. JACC Cardiovasc. Imaging 7, 930–939 (2014).

    Article  PubMed  Google Scholar 

  44. Regenfus, M. et al. Six-year prognostic value of microvascular obstruction after reperfused ST-elevation myocardial infarction as assessed by contrast-enhanced cardiovascular magnetic resonance. Am. J. Cardiol. 116, 1022–1027 (2015).

    Article  PubMed  Google Scholar 

  45. Bulluck, H. et al. Invasive assessment of the coronary microcirculation in reperfused ST-segment-elevation myocardial infarction patients: where do we stand? Circ. Cardiovasc. Interv. 10, e004373 (2017).

    Article  PubMed  Google Scholar 

  46. Bulluck, H., Dharmakumar, R., Arai, A. E., Berry, C. & Hausenloy, D. J. Cardiovascular magnetic resonance in acute ST-segment-elevation myocardial infarction: recent advances, controversies, and future directions. Circulation 137, 1949–1964 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Carrick, D. et al. Myocardial hemorrhage after acute reperfused ST-segment-elevation myocardial infarction: relation to microvascular obstruction and prognostic significance. Circ. Cardiovasc. Imaging 9, e004148 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ibanez, B. et al. Cardiac MRI endpoints in myocardial infarction experimental and clinical trials: JACC scientific expert panel. J. Am. Coll. Cardiol. 74, 238–256 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Maznyczka, A. M., Oldroyd, K. G., McCartney, P., McEntegart, M. & Berry, C. The potential use of the index of microcirculatory resistance to guide stratification of patients for adjunctive therapy in acute myocardial infarction. JACC Cardiovasc. Interv. 12, 951–966 (2019).

    Article  PubMed  Google Scholar 

  50. McGeoch, R. et al. The index of microcirculatory resistance measured acutely predicts the extent and severity of myocardial infarction in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc. Interv. 3, 715–722 (2010).

    Article  PubMed  Google Scholar 

  51. Bulluck, H. et al. Index of microvascular resistance and microvascular obstruction in patients with acute myocardial infarction. JACC Cardiovasc. Interv. 9, 2172–2174 (2016).

    Article  PubMed  Google Scholar 

  52. Fearon, W. F. et al. Prognostic value of the index of microcirculatory resistance measured after primary percutaneous coronary intervention. Circulation 127, 2436–2441 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  53. De Maria, G. L. et al. Index of microcirculatory resistance as a tool to characterize microvascular obstruction and to predict infarct size regression in patients with STEMI undergoing primary PCI. JACC Cardiovasc. Imaging 12, 837–848 (2019).

    Article  PubMed  Google Scholar 

  54. Scarsini, R. et al. Angiography-derived index of microcirculatory resistance (IMRangio) as a novel pressure-wire-free tool to assess coronary microvascular dysfunction in acute coronary syndromes and stable coronary artery disease. Int. J. Cardiovasc. Imaging 37, 1801–1813 (2021).

    Article  PubMed  Google Scholar 

  55. De Maria, G. L. et al. How does coronary stent implantation impact on the status of the microcirculation during primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction? Eur. Heart J. 36, 3165–3177 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  56. De Maria, G. L. et al. The ATI score (age–thrombus burden–index of microcirculatory resistance) determined during primary percutaneous coronary intervention predicts final infarct size in patients with ST-elevation myocardial infarction: a cardiac magnetic resonance validation study. EuroIntervention 13, 935–943 (2017).

    Article  PubMed  Google Scholar 

  57. Montalto, C. et al. Pre-procedural ATI score (age–thrombus burden–index of microcirculatory resistance) predicts long-term clinical outcomes in patients with ST elevation myocardial infarction treated with primary percutaneous coronary intervention. Int. J. Cardiol. 339, 1–6 (2021).

    Article  PubMed  Google Scholar 

  58. De Maria, G. L. et al. Angiography-derived index of microcirculatory resistance as a novel, pressure-wire-free tool to assess coronary microcirculation in ST elevation myocardial infarction. Int. J. Cardiovasc. Imaging 36, 1395–1406 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kotronias, R. A. et al. Long-term clinical outcomes in patients with an acute ST-segment-elevation myocardial infarction stratified by angiography-derived index of microcirculatory resistance. Front. Cardiovasc. Med. 8, 717114 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Scarsini, R. P. et al. Angiography-derived and sensor-wire methods to assess coronary microvascular dysfunction in patients with acute myocardial infarction. JACC Cardiovasc. Imaging 16, 965–981 (2023).

    Article  PubMed  Google Scholar 

  61. Angiolillo, D. J., Galli, M., Collet, J. P., Kastrati, A. & O’Donoghue, M. L. Antiplatelet therapy after percutaneous coronary intervention. EuroIntervention 17, e1371–e1396 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Ellis, S. G. et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N. Engl. J. Med. 358, 2205–2217 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): randomised trial. Lancet 367, 569–578 (2006).

  64. Galli, M. et al. Early anticoagulation in the current management of NSTE-ACS: evidence, guidelines, practice and perspectives. Int. J. Cardiol. 275, 39–45 (2019).

    Article  PubMed  Google Scholar 

  65. Zijlstra, F. et al. Influence of prehospital administration of aspirin and heparin on initial patency of the infarct-related artery in patients with acute ST elevation myocardial infarction. J. Am. Coll. Cardiol. 39, 1733–1737 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Verheugt, F. W. et al. High dose bolus heparin as initial therapy before primary angioplasty for acute myocardial infarction: results of the Heparin in Early Patency (HEAP) pilot study. J. Am. Coll. Cardiol. 31, 289–293 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Liem, A. et al. High dose heparin as pretreatment for primary angioplasty in acute myocardial infarction: the Heparin in Early Patency (HEAP) randomized trial. J. Am. Coll. Cardiol. 35, 600–604 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Ibanez, B. et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur. Heart J. 39, 119–177 (2018).

    Article  PubMed  Google Scholar 

  69. Yang, X. M. et al. Platelet P2Y12 blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J. Cardiovasc. Pharmacol. Ther. 18, 251–262 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Montalescot, G. et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N. Engl. J. Med. 371, 1016–1027 (2014).

    Article  PubMed  Google Scholar 

  71. Khan, J. N. et al. Infarct size following treatment with second- versus third-generation P2Y12 antagonists in patients with multivessel coronary disease at ST-segment elevation myocardial infarction in the CvLPRIT study. J. Am. Heart Assoc. 5, e003403 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Brener, S. J. et al. Outcomes in patients with ST-segment elevation acute myocardial infarction treated with clopidogrel versus prasugrel (from the INFUSE-AMI trial). Am. J. Cardiol. 113, 1457–1460 (2014).

    Article  PubMed  Google Scholar 

  73. de Waha, S. et al. Association of upstream clopidogrel administration and myocardial reperfusion assessed by cardiac magnetic resonance imaging in patients with ST-elevation myocardial infarction. Eur. Heart J. Acute Cardiovasc. Care 3, 110–117 (2014).

    Article  PubMed  Google Scholar 

  74. Song, Y. B. et al. A high loading dose of clopidogrel reduces myocardial infarct size in patients undergoing primary percutaneous coronary intervention: a magnetic resonance imaging study. Am. Heart J. 163, 500–507 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Jeong, Y. J., Park, K. & Kim, Y.-D. Comparison between ticagrelor and clopidogrel on myocardial blood flow in patients with acute coronary syndrome, using 13N-ammonia positron emission tomography. Am. Heart J. 222, 121–130 (2020).

    Article  CAS  PubMed  Google Scholar 

  76. Xu, J. et al. Impact of ticagrelor versus clopidogrel on coronary microvascular function after non-ST-segment-elevation acute coronary syndrome. Circ. Cardiovasc. Interv. 15, e011419 (2022).

    Article  CAS  PubMed  Google Scholar 

  77. Rollini, F. et al. Crushed prasugrel tablets in patients with STEMI undergoing primary percutaneous coronary intervention: the CRUSH study. J. Am. Coll. Cardiol. 67, 1994–2004 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Parodi, G. et al. Ticagrelor crushed tablets administration in STEMI patients: the MOJITO study. J. Am. Coll. Cardiol. 65, 511–512 (2015).

    Article  PubMed  Google Scholar 

  79. Capodanno, D., Milluzzo, R. P. & Angiolillo, D. J. Intravenous antiplatelet therapies (glycoprotein IIb/IIIa receptor inhibitors and cangrelor) in percutaneous coronary intervention: from pharmacology to indications for clinical use. Ther. Adv. Cardiovasc. Dis. 13, 1753944719893274 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Galli, M. et al. Intracoronary bolus of glycoprotein IIb/IIIa inhibitor as bridging or adjunctive strategy to oral P2Y12 inhibitor load in the modern setting of ST-elevation myocardial infarction. Minerva Cardiol. Angiol. 70, 697–705 (2022).

    PubMed  Google Scholar 

  81. Stone, G. W. et al. Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. JAMA 307, 1817–1826 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Kırma, C. et al. Intracoronary bolus-only compared with intravenous bolus plus infusion of tirofiban application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Catheter. Cardiovasc. Interv. 79, 59–67 (2012).

    Article  PubMed  Google Scholar 

  83. Gargiulo, G. et al. Cangrelor, tirofiban, and chewed or standard prasugrel regimens in patients with ST-segment-elevation myocardial infarction: primary results of the FABOLUS-FASTER trial. Circulation 142, 441–454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Rikken, S. A. O. F. et al. Prepercutaneous coronary intervention zalunfiban dose–response relationship to target vessel blood flow at initial angiogram in ST-elevation myocardial infarction—a post hoc analysis of the CEL-02 phase IIa study. Am. Heart J. 262, 75–82 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Eitel, I. et al. Intracoronary compared with intravenous bolus abciximab application during primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: cardiac magnetic resonance substudy of the AIDA STEMI trial. J. Am. Coll. Cardiol. 61, 1447–1454 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Elbadawi, A. et al. Meta-analysis of randomized trials of intracoronary versus intravenous glycoprotein IIb/IIIa inhibitors in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am. J. Cardiol. 120, 1055–1061 (2017).

    Article  PubMed  Google Scholar 

  87. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04957719 (2023).

  88. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04825743 (2023).

  89. Abtan, J. et al. Efficacy and safety of cangrelor in preventing periprocedural complications in patients with stable angina and acute coronary syndromes undergoing percutaneous coronary intervention: the CHAMPION PHOENIX trial. JACC Cardiovasc. Interv. 9, 1905–1913 (2016).

    Article  PubMed  Google Scholar 

  90. Cavender, M. A. et al. Consistent reduction in periprocedural myocardial infarction with cangrelor as assessed by multiple definitions: findings from CHAMPION PHOENIX (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). Circulation 134, 723–733 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ubaid, S. et al. Cangrelor versus ticagrelor in patients treated with primary percutaneous coronary intervention: impact on platelet activity, myocardial microvascular function and infarct size: a randomized controlled trial. Thromb. Haemost. 119, 1171–1181 (2019).

    Article  PubMed  Google Scholar 

  92. Bulluck, H. et al. Platelet inhibition to target reperfusion injury trial: rationale and study design. Clin. Cardiol. 42, 5–12 (2019).

    Article  PubMed  Google Scholar 

  93. Alyamani, M., Campbell, S., Navarese, E., Welsh, R. C. & Bainey, K. R. Safety and efficacy of intracoronary thrombolysis as adjunctive therapy to primary PCI in STEMI: a systematic review and meta-analysis. Can. J. Cardiol. 37, 339–346 (2021).

    Article  PubMed  Google Scholar 

  94. McCartney, P. J. et al. Effect of low-dose intracoronary alteplase during primary percutaneous coronary intervention on microvascular obstruction in patients with acute myocardial infarction: a randomized clinical trial. JAMA 321, 56–68 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02894138 (2021).

  96. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03998319 (2023).

  97. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03335839 (2023).

  98. Boscarelli, D. et al. Intracoronary thrombolysis in patients with ST-segment elevation myocardial infarction presenting with massive intraluminal thrombus and failed aspiration. Eur. Heart J. Acute Cardiovasc. Care 3, 229–236 (2014).

    Article  PubMed  Google Scholar 

  99. Gregorini, L. et al. α-Adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation 99, 482–490 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Heusch, G. et al. α-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 101, 689–694 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Kleinbongard, P. et al. Aspirate from human stented native coronary arteries vs. saphenous vein grafts: more endothelin but less particulate debris. Am. J. Physiol. Heart Circ. Physiol. 305, H1222–H1229 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Leineweber, K. et al. Intense vasoconstriction in response to aspirate from stented saphenous vein aortocoronary bypass grafts. J. Am. Coll. Cardiol. 47, 981–986 (2006).

    Article  PubMed  Google Scholar 

  103. Niccoli, G., Burzotta, F., Galiuto, L. & Crea, F. Myocardial no-reflow in humans. J. Am. Coll. Cardiol. 54, 281–292 (2009).

    Article  PubMed  Google Scholar 

  104. Yellon, D. M. & Hausenloy, D. J. Myocardial reperfusion injury. N. Engl. J. Med. 357, 1121–1135 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Zhao, Z. Q., Sato, H., Williams, M. W., Fernandez, A. Z. & Vinten-Johansen, J. Adenosine A2-receptor activation inhibits neutrophil-mediated injury to coronary endothelium. Am. J. Physiol. 271, H1456–H1464 (1996).

    CAS  PubMed  Google Scholar 

  106. Heusch, G. Adenosine and maximum coronary vasodilation in humans: myth and misconceptions in the assessment of coronary reserve. Basic. Res. Cardiol. 105, 1–5 (2010).

    Article  PubMed  Google Scholar 

  107. Cohen, M. V. & Downey, J. M. Adenosine: trigger and mediator of cardioprotection. Basic. Res. Cardiol. 103, 203–215 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Haskó, G., Linden, J., Cronstein, B. & Pacher, P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat. Rev. Drug. Discov. 7, 759–770 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Vijayalakshmi, K. et al. Prospective, randomised, controlled trial to study the effect of intracoronary injection of verapamil and adenosine on coronary blood flow during percutaneous coronary intervention in patients with acute coronary syndromes. Heart 92, 1278–1284 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Marzilli, M., Orsini, E., Marraccini, P. & Testa, R. Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction. Circulation 101, 2154–2159 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Fokkema, M. L. et al. Effect of high-dose intracoronary adenosine administration during primary percutaneous coronary intervention in acute myocardial infarction: a randomized controlled trial. Circ. Cardiovasc. Interv. 2, 323–329 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Mahaffey, K. W. et al. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial. J. Am. Coll. Cardiol. 34, 1711–1720 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Ross, A. M., Gibbons, R. J., Stone, G. W., Kloner, R. A. & Alexander, R. W. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J. Am. Coll. Cardiol. 45, 1775–1780 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Kloner, R. A. et al. Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial. Eur. Heart J. 27, 2400–2405 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Niccoli, G. et al. Open-label, randomized, placebo-controlled evaluation of intracoronary adenosine or nitroprusside after thrombus aspiration during primary percutaneous coronary intervention for the prevention of microvascular obstruction in acute myocardial infarction: the REOPEN-AMI study (Intracoronary Nitroprusside Versus Adenosine in Acute Myocardial Infarction). JACC Cardiovasc. Interv. 6, 580–589 (2013).

    Article  PubMed  Google Scholar 

  116. Niccoli, G., Spaziani, C. & Crea, F. Left ventricular remodeling and 1-year clinical follow-up of the REOPEN-AMI trial. J. Am. Coll. Cardiol. 63, 1454–1455 (2014).

    Article  PubMed  Google Scholar 

  117. Nazir, S. A. et al. Strategies to attenuate micro-vascular obstruction during P-PCI: the randomized reperfusion facilitated by local adjunctive therapy in ST-elevation myocardial infarction trial. Eur. Heart J. 37, 1910–1919 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Bulluck, H., Sirker, A., Loke, Y. K., Garcia-Dorado, D. & Hausenloy, D. J. Clinical benefit of adenosine as an adjunct to reperfusion in ST-elevation myocardial infarction patients: an updated meta-analysis of randomized controlled trials. Int. J. Cardiol. 202, 228–237 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Laborante, R. et al. Adenosine as adjunctive therapy in acute coronary syndrome: a meta-analysis of randomized controlled trials. Eur. Heart J. Cardiovasc. Pharmacother. 9, 173–182 (2023).

    Article  PubMed  Google Scholar 

  120. Amit, G. et al. Intracoronary nitroprusside for the prevention of the no-reflow phenomenon after primary percutaneous coronary intervention in acute myocardial infarction. A randomized, double-blind, placebo-controlled clinical trial. Am. Heart J. 152, 887.e9–e14 (2006).

    Article  PubMed  Google Scholar 

  121. Kobara, M., Amano, T., Toba, H. & Nakata, T. Nicorandil suppresses ischemia-induced norepinephrine release and ventricular arrhythmias in hypertrophic hearts. Cardiovasc. Drugs Ther. 37, 53–62 (2023).

    Article  CAS  PubMed  Google Scholar 

  122. Ito, H. et al. Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. J. Am. Coll. Cardiol. 33, 654–660 (1999).

    Article  CAS  PubMed  Google Scholar 

  123. Lee, H. C. et al. Effect of intra-coronary nicorandil administration prior to reperfusion in acute ST segment elevation myocardial infarction. Circ. J. 72, 1425–1429 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Ishii, H. et al. Impact of a single intravenous administration of nicorandil before reperfusion in patients with ST-segment-elevation myocardial infarction. Circulation 112, 1284–1288 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Qian, G. et al. Effects of nicorandil administration on infarct size in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: the CHANGE trial. J. Am. Heart Assoc. 11, e026232 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kitakaze, M. et al. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet 370, 1483–1493 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Xu, L. et al. Nicorandil prior to primary percutaneous coronary intervention improves clinical outcomes in patients with acute myocardial infarction: a meta-analysis of randomized controlled trials. Drug. Des. Dev. Ther. 13, 1389–1400 (2019).

    Article  CAS  Google Scholar 

  128. Antman, E. M., Stone, P. H., Muller, J. E. & Braunwald, E. Calcium channel blocking agents in the treatment of cardiovascular disorders. Part I: basic and clinical electrophysiologic effects. Ann. Intern. Med. 93, 875–885 (1980).

    Article  CAS  PubMed  Google Scholar 

  129. Taniyama, Y. et al. Beneficial effect of intracoronary verapamil on microvascular and myocardial salvage in patients with acute myocardial infarction. J. Am. Coll. Cardiol. 30, 1193–1199 (1997).

    Article  CAS  PubMed  Google Scholar 

  130. Abdelaziz, H. K., Elkilany, W., Khalid, S., Sabet, S. & Saad, M. Efficacy and safety of intracoronary verapamil versus sodium nitroprusside for the prevention of microvascular obstruction during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Coron. Artery Dis. 28, 11–16 (2017).

    Article  PubMed  Google Scholar 

  131. Huang, D. et al. REstoration of COronary flow in patients with no-reflow after primary coronary interVEntion of acute myocaRdial infarction (RECOVER). Am. Heart J. 164, 394–401 (2012).

    Article  PubMed  Google Scholar 

  132. Huang, R. I. et al. Efficacy of intracoronary nicardipine in the treatment of no-reflow during percutaneous coronary intervention. Catheter. Cardiovasc. Interv. 68, 671–676 (2006).

    Article  PubMed  Google Scholar 

  133. Navarese, E. P. et al. Efficacy and safety of intracoronary epinephrine versus conventional treatments alone in STEMI patients with refractory coronary no-reflow during primary PCI: the RESTORE observational study. Catheter. Cardiovasc. Interv. 97, 602–611 (2021).

    Article  PubMed  Google Scholar 

  134. Khan, K. A. et al. Comparison of intracoronary epinephrine and adenosine for no-reflow in normotensive patients with acute coronary syndrome (COAR Trial). Circ. Cardiovasc. Interv. 15, e011408 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Schwartz, R. S. et al. Microemboli and microvascular obstruction in acute coronary thrombosis and sudden coronary death: relation to epicardial plaque histopathology. J. Am. Coll. Cardiol. 54, 2167–2173 (2009).

    Article  PubMed  Google Scholar 

  136. Costantini, C. O. et al. Frequency, correlates, and clinical implications of myocardial perfusion after primary angioplasty and stenting, with and without glycoprotein IIb/IIIa inhibition, in acute myocardial infarction. J. Am. Coll. Cardiol. 44, 305–312 (2004).

    Article  PubMed  Google Scholar 

  137. Schomig, A. et al. A randomized trial of coronary stenting versus balloon angioplasty as a rescue intervention after failed thrombolysis in patients with acute myocardial infarction. J. Am. Coll. Cardiol. 44, 2073–2079 (2004).

    Article  PubMed  Google Scholar 

  138. Kaluski, E., Tsai, S. & Klapholz, M. Coronary stenting with MGuard: from conception to human trials. Cardiovasc. Revasc Med. 9, 88–94 (2008).

    Article  PubMed  Google Scholar 

  139. Kaluski, E. et al. Coronary stenting with MGuard: first-in-man trial. J. Invasive Cardiol. 20, 511–515 (2008).

    PubMed  Google Scholar 

  140. Maia, F. et al. Preliminary results of the INSPIRE trial with the novel MGuard stent system containing a protection net to prevent distal embolization. Catheter. Cardiovasc. Interv. 76, 86–92 (2010).

    Article  PubMed  Google Scholar 

  141. Piscione, F. et al. Multicentre experience with MGuard net protective stent in ST-elevation myocardial infarction: safety, feasibility, and impact on myocardial reperfusion. Catheter. Cardiovasc. Interv. 75, 715–721 (2010).

    Article  PubMed  Google Scholar 

  142. Stone, G. W. et al. Prospective, randomized, multicenter evaluation of a polyethylene terephthalate micronet mesh-covered stent (MGuard) in ST-segment elevation myocardial infarction: the MASTER trial. J. Am. Coll. Cardiol. 60, 1975–1984 (2012).

    Article  PubMed  Google Scholar 

  143. Dudek, D. et al. Mesh-covered embolic protection stent implantation in ST-segment-elevation myocardial infarction: final 1-year clinical and angiographic results from the MGUARD for acute ST elevation reperfusion trial. Circ. Cardiovasc. Interv. 8, e001484 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. Amoroso, G. et al. Assessment of the safety and performance of the STENTYS self-expanding coronary stent in acute myocardial infarction: results from the APPOSITION I study. EuroIntervention 7, 428–436 (2011).

    Article  PubMed  Google Scholar 

  145. van Geuns, R. J. et al. Self-expanding versus balloon-expandable stents in acute myocardial infarction: results from the APPOSITION II study: self-expanding stents in ST-segment elevation myocardial infarction. JACC Cardiovasc. Interv. 5, 1209–1219 (2012).

    Article  PubMed  Google Scholar 

  146. Koch, K. T. et al. One-year clinical outcomes of the STENTYS self-apposing coronary stent in patients presenting with ST-segment elevation myocardial infarction: results from the APPOSITION III registry. EuroIntervention 11, 264–271 (2015).

    Article  PubMed  Google Scholar 

  147. Ismail, M. D., Han, C. K. & Loch, A. Dislodgement of the MGuard prime micronet during primary PCI. Cardiovasc. Interv. Radiol. 39, 785–787 (2016).

    Article  Google Scholar 

  148. Brugaletta, S. et al. 10-Year follow-up of patients with everolimus-eluting versus bare-metal stents after ST-segment elevation myocardial infarction. J. Am. Coll. Cardiol. 77, 1165–1178 (2021).

    Article  CAS  PubMed  Google Scholar 

  149. Carrick, D. et al. A randomized trial of deferred stenting versus immediate stenting to prevent no- or slow-reflow in acute ST-segment elevation myocardial infarction (DEFER-STEMI). J. Am. Coll. Cardiol. 63, 2088–2098 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Madsen, J. M. et al. Clinical outcomes of no stenting in patients with ST-segment elevation myocardial infarction undergoing deferred primary percutaneous coronary intervention. EuroIntervention 18, 482–491 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Loubeyre, C. et al. A randomized comparison of direct stenting with conventional stent implantation in selected patients with acute myocardial infarction. J. Am. Coll. Cardiol. 39, 15–21 (2002).

    Article  PubMed  Google Scholar 

  152. Saad, M. et al. Impact of direct stenting on myocardial injury assessed by cardiac magnetic resonance imaging and prognosis in ST-elevation myocardial infarction. Int. J. Cardiol. 283, 88–92 (2019).

    Article  PubMed  Google Scholar 

  153. Khalil, M., Atkinson, T. & Latif, F. How to prevent and treat no reflow using evidence-based measures. Society for Cardiovascular Angiography & Interventions https://scai.org/how-prevent-and-treat-no-reflow-using-evidence-based-measures (2021).

  154. Burzotta, F. et al. Adjunctive devices in primary or rescue PCI: a meta-analysis of randomized trials. Int. J. Cardiol. 123, 313–321 (2008).

    Article  PubMed  Google Scholar 

  155. Burzotta, F. et al. Clinical impact of thrombectomy in acute ST-elevation myocardial infarction: an individual patient-data pooled analysis of 11 trials. Eur. Heart J. 30, 2193–2203 (2009).

    Article  PubMed  Google Scholar 

  156. Lagerqvist, B. et al. Outcomes 1 year after thrombus aspiration for myocardial infarction. N. Engl. J. Med. 371, 1111–1120 (2014).

    Article  CAS  PubMed  Google Scholar 

  157. Jolly, S. S. et al. Randomized trial of primary PCI with or without routine manual thrombectomy. N. Engl. J. Med. 372, 1389–1398 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Jolly, S. S. et al. Thrombus aspiration in ST-segment-elevation myocardial infarction: an individual patient meta-analysis: thrombectomy trialists collaboration. Circulation 135, 143–152 (2017).

    Article  PubMed  Google Scholar 

  159. Feistritzer, H. J. et al. Long-term outcome after thrombus aspiration in non-ST-elevation myocardial infarction: results from the TATORT-NSTEMI trial: thrombus aspiration in acute myocardial infarction. Clin. Res. Cardiol. 109, 1223–1231 (2020).

    Article  PubMed  Google Scholar 

  160. Vlaar, P. J. et al. Operator dependence of outcome after primary percutaneous coronary intervention. EuroIntervention 6, 760–767 (2011).

    Article  PubMed  Google Scholar 

  161. Kotronias, R. A. et al. Rationale and design of a randomized controlled pilot trial to assess stent retriever thrombectomy for thrombus burden reduction in patients with acute myocardial infarction: the RETRIEVE-AMI study. Cardiovasc. Revasc Med. 52, 75–85 (2023).

    Article  PubMed  Google Scholar 

  162. Topaz, O. et al. Excimer laser angioplasty in acute myocardial infarction (the CARMEL multicenter trial). Am. J. Cardiol. 93, 694–701 (2004).

    Article  PubMed  Google Scholar 

  163. Nishino, M. et al. Indications and outcomes of excimer laser coronary atherectomy: efficacy and safety for thrombotic lesions—the ULTRAMAN registry. J. Cardiol. 69, 314–319 (2017).

    Article  PubMed  Google Scholar 

  164. Karacsonyi, J. et al. Contemporary use of laser during percutaneous coronary interventions: insights from the laser veterans affairs (LAVA) multicenter registry. J. Invasive Cardiol. 30, 195–201 (2018).

    PubMed  Google Scholar 

  165. De Maria, G. L. et al. Novel device-based therapies to improve outcome in ST-segment elevation myocardial infarction. Eur. Heart J. Acute Cardiovasc. Care 10, 687–697 (2021).

    Article  PubMed  Google Scholar 

  166. Van de Hoef, T. P. et al. Intracoronary hemodynamic effects of pressure-controlled intermittent coronary sinus occlusion (PICSO): results from the First-In-Man Prepare PICSO Study. J. Interv. Cardiol. 25, 549–556 (2012).

    Article  PubMed  Google Scholar 

  167. van de Hoef, T. P. et al. Pressure-controlled intermittent coronary sinus occlusion (PICSO) in acute ST-segment elevation myocardial infarction: results of the Prepare RAMSES safety and feasibility study. EuroIntervention 11, 37–44 (2015).

    Article  PubMed  Google Scholar 

  168. De Maria, G. L. et al. Index of microcirculatory resistance-guided therapy with pressure-controlled intermittent coronary sinus occlusion improves coronary microvascular function and reduces infarct size in patients with ST-elevation myocardial infarction: the Oxford Acute Myocardial Infarction–Pressure-controlled Intermittent Coronary Sinus Occlusion study (OxAMI-PICSO study). EuroIntervention 14, e352–e359 (2018).

    Article  PubMed  Google Scholar 

  169. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03625869 (2023).

  170. Heusch, G. & Rassaf, T. Left ventricular unloading in myocardial infarction: gentle reperfusion through the backdoor? J. Am. Coll. Cardiol. 76, 700–702 (2020).

    Article  PubMed  Google Scholar 

  171. Patel, M. R. et al. Intra-aortic balloon counterpulsation and infarct size in patients with acute anterior myocardial infarction without shock: the CRISP AMI randomized trial. JAMA 306, 1329–1337 (2011).

    Article  CAS  PubMed  Google Scholar 

  172. Kapur, N. K. et al. Unloading the left ventricle before reperfusion in patients with anterior ST-segment-elevation myocardial infarction. Circulation 139, 337–346 (2019).

    Article  PubMed  Google Scholar 

  173. Kapur, N. K. et al. Primary left ventricular unloading with delayed reperfusion in patients with anterior ST-elevation myocardial infarction: rationale and design of the STEMI-DTU randomized pivotal trial. Am. Heart J. 254, 122–132 (2022).

    Article  CAS  PubMed  Google Scholar 

  174. Sánchez-Hernández, C. D., Torres-Alarcón, L. A., González-Cortés, A. & Peón, A. N. Ischemia/reperfusion injury: pathophysiology, current clinical management, and potential preventive approaches. Mediators Inflamm. 2020, 8405370 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Srinivasan, M., Rihal, C., Holmes, D. R. & Prasad, A. Adjunctive thrombectomy and distal protection in primary percutaneous coronary intervention: impact on microvascular perfusion and outcomes. Circulation 119, 1311–1319 (2009).

    Article  PubMed  Google Scholar 

  176. Heusch, G. Treatment of myocardial ischemia/reperfusion injury by ischemic and pharmacological postconditioning. Compr. Physiol. 5, 1123–1145 (2015).

    Article  PubMed  Google Scholar 

  177. Heusch, G. et al. STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ. Res. 110, 111–115 (2012).

    Article  CAS  PubMed  Google Scholar 

  178. Chi, H. J. et al. Progress in therapies for myocardial ischemia reperfusion injury. Curr. Drug. targets 18, 1712–1721 (2017).

    Article  CAS  PubMed  Google Scholar 

  179. Garcia-Dorado, D., Rodríguez-Sinovas, A., Ruiz-Meana, M. & Inserte, J. Protection against myocardial ischemia–reperfusion injury in clinical practice. Rev. Esp. Cardiol. 67, 394–404 (2014).

    Article  PubMed  Google Scholar 

  180. Limalanathan, S. et al. Effect of ischemic postconditioning on infarct size in patients with ST-elevation myocardial infarction treated by primary PCI results of the POSTEMI (POstconditioning in ST-Elevation Myocardial Infarction) randomized trial. J. Am. Heart Assoc. 3, e000679 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Lønborg, J. et al. Cardioprotective effects of ischemic postconditioning in patients treated with primary percutaneous coronary intervention, evaluated by magnetic resonance. Circ. Cardiovasc. Interv. 3, 34–41 (2010).

    Article  PubMed  Google Scholar 

  182. Zhao, Z. Q. et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am. J. Physiol. Heart Circ. Physiol. 285, H579–H588 (2003).

    Article  CAS  PubMed  Google Scholar 

  183. Staat, P. et al. Postconditioning the human heart. Circulation 112, 2143–2148 (2005).

    Article  PubMed  Google Scholar 

  184. Zhou, C. et al. Stenting technique, gender, and age are associated with cardioprotection by ischaemic postconditioning in primary coronary intervention: a systematic review of 10 randomized trials. Eur. Heart J. 33, 3070–3077 (2012).

    Article  PubMed  Google Scholar 

  185. Heusch, G. Reduction of infarct size by ischaemic post-conditioning in humans: fact or fiction? Eur. Heart J. 33, 13–15 (2012).

    Article  PubMed  Google Scholar 

  186. Engstrøm, T. et al. Effect of ischemic postconditioning during primary percutaneous coronary intervention for patients with ST-segment elevation myocardial infarction: a randomized clinical trial. JAMA Cardiol. 2, 490–497 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Madsen, J. M. et al. Comparison of effect of ischemic postconditioning on cardiovascular mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention with versus without thrombectomy. Am. J. Cardiol. 166, 18–24 (2022).

    Article  PubMed  Google Scholar 

  188. Lou, B., Cui, Y., Gao, H. & Chen, M. Meta-analysis of the effects of ischemic postconditioning on structural pathology in ST-segment elevation acute myocardial infarction. Oncotarget 9, 8089–8099 (2018).

    Article  PubMed  Google Scholar 

  189. Skyschally, A. et al. Across-species transfer of protection by remote ischemic preconditioning with species-specific myocardial signal transduction by reperfusion injury salvage kinase and survival activating factor enhancement pathways. Circ. Res. 117, 279–288 (2015).

    Article  CAS  PubMed  Google Scholar 

  190. Heusch, G., Bøtker, H. E., Przyklenk, K., Redington, A. & Yellon, D. Remote ischemic conditioning. J. Am. Coll. Cardiol. 65, 177–195 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Hausenloy, D. J. 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 394, 1415–1424 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Bøtker, H. E. et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375, 727–734 (2010).

    Article  PubMed  Google Scholar 

  193. Gaspar, A. et al. Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI). Basic. Res. Cardiol. 113, 14 (2018).

    Article  PubMed  Google Scholar 

  194. Eitel, I. et al. Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial. Eur. Heart J. 36, 3049–3057 (2015).

    Article  PubMed  Google Scholar 

  195. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04813159 (2023).

  196. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04844931 (2023).

  197. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03155022 (2023).

  198. Kim, J. S. et al. Efficacy of high-dose atorvastatin loading before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: the STATIN STEMI trial. JACC Cardiovasc. Interv. 3, 332–339 (2010).

    Article  PubMed  Google Scholar 

  199. Iwakura, K. et al. Chronic pre-treatment of statins is associated with the reduction of the no-reflow phenomenon in the patients with reperfused acute myocardial infarction. Eur. Heart J. 27, 534–539 (2006).

    Article  CAS  PubMed  Google Scholar 

  200. Oesterle, A., Laufs, U. & Liao, J. K. Pleiotropic effects of statins on the cardiovascular system. Circ. Res. 120, 229–243 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Mewton, N. et al. Effect of colchicine on myocardial injury in acute myocardial infarction. Circulation 144, 859–869 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Broch, K. et al. Randomized trial of interleukin-6 receptor inhibition in patients with acute ST-segment elevation myocardial infarction. J. Am. Coll. Cardiol. 77, 1845–1855 (2021).

    Article  CAS  PubMed  Google Scholar 

  203. Ibanez, B. et al. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial. Circulation 128, 1495–1503 (2013).

    Article  CAS  PubMed  Google Scholar 

  204. Roolvink, V. et al. Early intravenous β-blockers in patients with ST-segment elevation myocardial infarction before primary percutaneous coronary intervention. J. Am. Coll. Cardiol. 67, 2705–2715 (2016).

    Article  CAS  PubMed  Google Scholar 

  205. Clemente-Moragón, A. et al. Metoprolol exerts a non-class effect against ischaemia–reperfusion injury by abrogating exacerbated inflammation. Eur. Heart J. 41, 4425–4440 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Lieder, H. R. et al. Cardioprotection by post-conditioning with exogenous triiodothyronine in isolated perfused rat hearts and isolated adult rat cardiomyocytes. Basic. Res. Cardiol. 116, 27 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Hausenloy, D. J. & Yellon, D. M. Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection. Heart Fail. Rev. 12, 217–234 (2007).

    Article  CAS  PubMed  Google Scholar 

  208. Yan, H. J., Qi, G. Q. & Ma, Y. Effect of propofol on myocardial ischemia–reperfusion injury through MAPK/ERK pathway. Eur. Rev. Med. Pharmacol. Sci. 23, 11051–11061 (2019).

    PubMed  Google Scholar 

  209. Zhang, J., Jiang, H., Liu, D. H. & Wang, G. N. Effects of dexmedetomidine on myocardial ischemia–reperfusion injury through PI3K–Akt–mTOR signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 23, 6736–6743 (2019).

    CAS  PubMed  Google Scholar 

  210. Lecour, S. Activation of the protective survivor activating factor enhancement (SAFE) pathway against reperfusion injury: does it go beyond the RISK pathway? J. Mol. Cell Cardiol. 47, 32–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  211. Ottani, F. et al. Cyclosporine A in reperfused myocardial infarction: the multicenter, controlled, open-label CYCLE trial. J. Am. Coll. Cardiol. 67, 365–374 (2016).

    Article  CAS  PubMed  Google Scholar 

  212. Cung, T. T. et al. Cyclosporine before PCI in patients with acute myocardial infarction. N. Engl. J. Med. 373, 1021–1031 (2015).

    Article  CAS  PubMed  Google Scholar 

  213. Erlinge, D. et al. Rapid endovascular catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. The CHILL-MI trial: a randomized controlled study of the use of central venous catheter core cooling combined with cold saline as an adjunct to percutaneous coronary intervention for the treatment of acute myocardial infarction. J. Am. Coll. Cardiol. 63, 1857–1865 (2014).

    Article  PubMed  Google Scholar 

  214. Noc, M. et al. COOL AMI EU pilot trial: a multicentre, prospective, randomised controlled trial to assess cooling as an adjunctive therapy to percutaneous intervention in patients with acute myocardial infarction. EuroIntervention 13, e531–e539 (2017).

    Article  PubMed  Google Scholar 

  215. Nichol, G. et al. Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with ST-segment- elevation myocardial infarction. Circ. Cardiovasc. Interv. 8, e001965 (2015).

    Article  PubMed  Google Scholar 

  216. El Farissi, M. et al. Selective intracoronary hypothermia in patients with ST-elevation myocardial infarction. Rationale and design of the EURO-ICE trial. EuroIntervention 16, 1444–1446 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Davidson, S. M. et al. Multitarget strategies to reduce myocardial ischemia/reperfusion injury: JACC review topic of the week. J. Am. Coll. Cardiol. 73, 89–99 (2019).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiology, Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy

    Mattia Galli

  2. Department of Cardiology, University of Parma, Parma, Italy

    Giampaolo Niccoli & Giulia Magnani

  3. Oxford Heart Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    Gianluigi De Maria & Stefano Benenati

  4. Institut Clinic Cardiovascular, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain

    Salvatore Brugaletta

  5. Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

    Rocco A. Montone & Francesco Burzotta

  6. Department of Internal Medicine, University of Genoa, Genoa, Italy

    Rocco Vergallo & Italo Porto

  7. Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, Genova, Italy

    Rocco Vergallo, Stefano Benenati & Italo Porto

  8. Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy

    Domenico D’Amario

  9. Division of Cardiology, Azienda Ospedaliero Universitaria ‘Maggiore Della Carita’, Novara, Italy

    Domenico D’Amario

  10. Department of Cardiovascular Sciencies, Catholic University of the Sacred Heart, Rome, Italy

    Francesco Burzotta & Filippo Crea

  11. Robert M. Berne Cardiovascular Research Center, Division of Cardiology — Heart and Vascular Center, University of Virginia, Charlottesville, VA, USA

    Antonio Abbate

  12. Division of Cardiology, University of Florida College of Medicine — Jacksonville, Jacksonville, FL, USA

    Dominick J. Angiolillo

Authors
  1. Mattia Galli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giampaolo Niccoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gianluigi De Maria
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Salvatore Brugaletta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rocco A. Montone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rocco Vergallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefano Benenati
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giulia Magnani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Domenico D’Amario
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Italo Porto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Francesco Burzotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Antonio Abbate
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Dominick J. Angiolillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Filippo Crea
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.G., S.B., R.A.M., R.V., S.B., G.M., D.D. and F.B. researched data for the article. M.G., D.J.A. and F.C. discussed the content of the article. M.G., S.B., R.A.M., R.V., S.B., G.M., D.D., F.B., D.J.A. and F.C. wrote the manuscript. All of the authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Dominick J. Angiolillo.

Ethics declarations

Competing interests

M.G. has received speaker fees from Terumo. G.D.M. has received research grants from Medtronic, Opsens, Philips and Terumo. I.P. has received consultant or speaker fees from Abbott, Amgen, AstraZeneca, Bayer, Daiichi-Sankyo, Medtronic, Philips, PIAM, Sanofi and Terumo. F.B. has received speaker fees from Abbott, Abiomed, Medtronic and Terumo. A.A. has received consulting fees or honoraria from Implicit Biosciences, Kiniksa, Novo Nordisk, Olatec and Serpin Pharma. D.J.A. has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi and Vectura. D.J.A.’s institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis and the Scott R. MacKenzie Foundation. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cardiology thanks John Beltrame, who co-reviewed with Olivia Girolamo, and Gerd Heusch for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Galli, M., Niccoli, G., De Maria, G. et al. Coronary microvascular obstruction and dysfunction in patients with acute myocardial infarction. Nat Rev Cardiol 21, 283–298 (2024). https://doi.org/10.1038/s41569-023-00953-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-023-00953-4

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing