Advertisement

Basic Research in Cardiology

, 114:45 | Cite as

Coronary microvascular obstruction: the new frontier in cardioprotection

  • Gerd HeuschEmail author
Review

Abstract

Cardioprotection aims at infarct size reduction and improvement of clinical outcome from myocardial infarction. The translation of cardioprotection from preclinical and promising proof-of-concept studies to clinical benefit for patients has been largely disappointing. Almost all of these studies which did not translate into clinical benefit had infarct size reduction as the primary endpoint and used protocols selected to achieve infarct size reduction. The present review puts forward the hypothesis that the coronary circulation is a so far neglected target of cardioprotection. Mechanisms of ischemia–reperfusion injury to the coronary circulation are detailed. Clinical methods and measures to assess coronary microvascular impairment in reperfused acute myocardial infarction are presented. A comparison of magnetic resonance imaging data on infarct size vs. coronary microvascular obstruction is made. Finally, the design of studies which are optimized not only for infarct size reduction but also for salvage of the coronary microcirculation is advocated.

Keywords

Coronary circulation Infarct size Myocardial infarction No-reflow Reperfusion 

Notes

Funding

GH was supported by the German Research Foundation (SFB 1116 B8) and the European Union COST ACTION 16225.

Compliance with ethical standards

Conflict of interest

The author declares that he has no conflict of interest.

References

  1. 1.
    Achilli F, Pontone G, Bassetti B, Squadroni L, Campodonico J, Corrada E, Facchini C, Mircoli L, Esposito G, Scarpa D, Pidello S, Righetti S, Di Gennaro F, Guglielmo M, Muscogiuri G, Baggiano A, Limido A, Lenatti L, Di Tano G, Malafronte C, Soffici F, Ceseri M, Maggiolini S, Colombo GI, Pompilio G (2019) G-CSF for extensive STEMI: results from the STEM–AMI Outcome CMR substudy. Circ Res 125:295–306.  https://doi.org/10.1161/CIRCRESAHA.118.314617 CrossRefPubMedGoogle Scholar
  2. 2.
    Atar D, Arheden H, Berdeaux A, Bonnet JL, Carlsson M, Clemmensen P, Cuvier V, Danchin N, Dubois-Rande JL, Engblom H, Erlinge D, Firat H, Halvorsen S, Hansen HS, Hauke W, Heiberg E, Koul S, Larsen AI, Le CP, Nordrehaug JE, Paganelli F, Pruss RM, Rousseau H, Schaller S, Sonou G, Tuseth V, Veys J, Vicaut E, Jensen SE (2015) Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results. Eur Heart J 36:112–119.  https://doi.org/10.1093/eurheartj/ehu331 CrossRefPubMedGoogle Scholar
  3. 3.
    Baranyai T, Giricz Z, Varga ZV, Koncsos G, Lukovic D, Makkos A, Sarkozy M, Pavo N, Jakab A, Czimbalmos C, Vago H, Ruzsa Z, Toth L, Garamvolgyi R, Merkely B, Schulz R, Gyongyosi M, Ferdinandy P (2017) In vivo MRI and ex vivo histological assessment of the cardioprotection induced by ischemic preconditioning, postconditioning and remote conditioning in a closed-chest porcine model of reperfused acute myocardial infarction: importance of microvasculature. J Transl Med 15:67.  https://doi.org/10.1186/s12967-017-1166-z CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Belle L, Motreff P, Mangin L, Range G, Marcaggi X, Marie A, Ferrier N, Dubreuil O, Zemour G, Souteyrand G, Caussin C, Amabile N, Isaaz K, Dauphin R, Koning R, Robin C, Faurie B, Bonello L, Champin S, Delhaye C, Cuilleret F, Mewton N, Genty C, Viallon M, Bosson JL, Croisille P, Investigators* M (2016) Comparison of immediate with delayed stenting using the minimalist immediate mechanical intervention approach in acute ST-segment-elevation myocardial infarction: the MIMI Study. Circ Cardiovasc Interv 9:e003388.  https://doi.org/10.1161/CIRCINTERVENTIONS.115.003388 CrossRefPubMedGoogle Scholar
  5. 5.
    Bodi V, Ruiz-Nodar JM, Feliu E, Minana G, Nunez J, Husser O, Martinez-Elvira J, Ruiz A, Bonanad C, Monmeneu JV, Lopez-Lereu MP, Forteza MJ, de Dios E, Hervas A, Moratal D, Gomez C, Mainar L, Sanchis J, Mainar V, Valencia J, Diaz A, Noguera I, Chaustre F, Chorro FJ (2014) Effect of ischemic postconditioning on microvascular obstruction in reperfused myocardial infarction. Results of a randomized study in patients and of an experimental model in swine. Int J Cardiol 175:138–146.  https://doi.org/10.1016/j.ijcard.2014.05.003 CrossRefPubMedGoogle Scholar
  6. 6.
    Borlotti A, Jerosch-Herold M, Liu D, Viliani D, Bracco A, Alkhalil M, De Maria GL, Ox AMISI, Channon KM, Banning AP, Choudhury RP, Neubauer S, Kharbanda RK, Dall’Armellina E (2019) Acute microvascular impairment post-reperfused STEMI is reversible and has additional clinical predictive value: a CMR OxAMI Study. J Am Coll Cardiol Cardiovasc Imaging.  https://doi.org/10.1016/j.jcmg.2018.10.028 CrossRefGoogle Scholar
  7. 7.
    Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT (2010) 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.  https://doi.org/10.1016/S0140-6736(09)62001-8 CrossRefPubMedGoogle Scholar
  8. 8.
    Bulluck H, Dharmakumar R, Arai AE, Berry C, Hausenloy DJ (2018) Cardiovascular magnetic resonance in acute ST-segment-elevation myocardial infarction: recent advances, controversies, and future directions. Circulation 137:1949–1964.  https://doi.org/10.1161/CIRCULATIONAHA.117.030693 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bulluck H, Frohlich GM, Nicholas JM, Mohdnazri S, Gamma R, Davies J, Sirker A, Mathur A, Blackman D, Garg P, Moon JC, Greenwood JP, Hausenloy DJ (2019) Mineralocorticoid receptor antagonist pre-treatment and early post-treatment to minimize reperfusion injury after ST-elevation myocardial infarction: the MINIMIZE STEMI trial. Am Heart J 211:60–67.  https://doi.org/10.1016/j.ahj.2019.02.005 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bulluck H, Rosmini S, Abdel-Gadir A, White SK, Bhuva AN, Treibel TA, Fontana M, Ramlall M, Hamarneh A, Sirker A, Herrey AS, Manisty C, Yellon DM, Kellman P, Moon JC, Hausenloy DJ (2016) Residual myocardial iron following intramyocardial hemorrhage during the convalescent phase of reperfused ST-segment-elevation myocardial infarction and adverse left ventricular remodeling. Circ Cardiovasc Imaging 9:e004940.  https://doi.org/10.1161/CIRCIMAGING.116.004940 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Canty JM, Klocke FJ (1985) Reduced regional myocardial perfusion in the presence of pharmacologic vasodilator reserve. Circulation 71:370–377.  https://doi.org/10.1161/01.CIR.71.2.370 CrossRefPubMedGoogle Scholar
  12. 12.
    Carrick D, Haig C, Ahmed N, Carberry J, Yue May VT, McEntegart M, Petrie MC, Eteiba H, Lindsay M, Hood S, Watkins S, Davie A, Mahrous A, Mordi I, Ford I, Radjenovic A, Oldroyd KG, Berry C (2016) Comparative prognostic utility of indexes of microvascular function alone or in combination in patients with an acute ST-segment-elevation myocardial infarction. Circulation 134:1833–1847.  https://doi.org/10.1161/CIRCULATIONAHA.116.022603 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Carrick D, Haig C, Ahmed N, Rauhalammi S, Clerfond G, Carberry J, Mordi I, McEntegart M, Petrie MC, Eteiba H, Hood S, Watkins S, Lindsay MM, Mahrous A, Welsh P, Sattar N, Ford I, Oldroyd KG, Radjenovic A, Berry C (2016) Temporal evolution of myocardial hemorrhage and edema in patients after acute ST-segment elevation myocardial infarction: pathophysiological insights and clinical implications. J Am Heart Assoc 5:e002834.  https://doi.org/10.1161/JAHA.115.002834 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Crimi G, Pica S, Raineri C, Bramucci E, De Ferrari GM, Klersy C, Ferlini M, Marinoni B, Repetto A, Romeo M, Rosti V, Massa M, Raisaro A, Leonardi S, Rubartelli P, Oltrona VL, Ferrario M (2013) Remote ischemic post-conditioning of the lower limb during primary percutaneous coronary intervention safely reduces enzymatic infarct size in anterior myocardial infarction: a randomized controlled trial. J Am Coll Cardiol Cardiovasc Interv 6:1055–1063.  https://doi.org/10.1016/j.jcin.2013.05.011 CrossRefGoogle Scholar
  15. 15.
    Davidson SM, Ferdinandy P, Andreadou I, Bøtker HE, Heusch G, Ibanez B, Ovize M, Schulz R, Yellon DM, Hausenloy DJ, Garcia-Dorado D, Action CC (2019) Multitarget strategies to reduce myocardial ischemia/reperfusion injury: JACC review topic of the Week. J Am Coll Cardiol 73:89–99.  https://doi.org/10.1016/j.jacc.2018.09.086 CrossRefPubMedGoogle Scholar
  16. 16.
    de Waha S, Patel MR, Granger CB, Ohman EM, Maehara A, Eitel I, Ben-Yehuda O, Jenkins P, Thiele H, Stone GW (2017) Relationship between microvascular obstruction and adverse events following primary 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.  https://doi.org/10.1093/eurheartj/ehx414 CrossRefPubMedGoogle Scholar
  17. 17.
    Desch S, Stiermaier T, de Waha S, Lurz P, Gutberlet M, Sandri M, Mangner N, Boudriot E, Woinke M, Erbs S, Schuler G, Fuernau G, Eitel I, Thiele H (2016) Thrombus aspiration in patients with ST-segment elevation myocardial infarction presenting late after symptom onset. J Am Coll Cardiol Cardiovasc Interv 9:113–122.  https://doi.org/10.1016/j.jcin.2015.09.010 CrossRefGoogle Scholar
  18. 18.
    Desmet W, Bogaert J, Dubois C, Sinnaeve P, Adriaenssens T, Pappas C, Ganame J, Dymarkowski S, Janssens S, Belmans A, Van de Werf F (2011) High-dose intracoronary adenosine for myocardial salvage in patients with acute ST-segment elevation myocardial infarction. Eur Heart J 32:867–877.  https://doi.org/10.1093/eurheartj/ehq492 CrossRefPubMedGoogle Scholar
  19. 19.
    Dörge H, Neumann T, Behrends M, Skyschally A, Schulz R, Kasper C, Erbel R, Heusch G (2000) Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation. Am J Physiol Heart Circ Physiol 279:H2587–H2592.  https://doi.org/10.1152/ajpheart.2000.279.6.H2587 CrossRefPubMedGoogle Scholar
  20. 20.
    Driesen RB, Zalewski J, Vanden Driessche N, Vermeulen K, Bogaert J, Sipido KR, Van de Werf F, Claus P (2012) Histological correlate of a cardiac magnetic resonance imaged microvascular obstruction in a porcine model of ischemia-reperfusion. Cardiovasc Pathol 21:129–131.  https://doi.org/10.1016/j.carpath.2011.07.008 CrossRefPubMedGoogle Scholar
  21. 21.
    Dwyer NB, Mikami Y, Hilland D, Aljizeeri A, Friedrich MG, Traboulsi M, Anderson TJ (2013) No cardioprotective benefit of ischemic postconditioning in patients with ST-segment elevation myocardial infarction. J Interv Cardiol 26:482–490.  https://doi.org/10.1111/joic.12064 CrossRefPubMedGoogle Scholar
  22. 22.
    Ehring T, Krajcar M, Baumgart D, Kompa S, Hümmelgen M, Heusch G (1995) Cholinergic and α-adrenergic coronary vasomotion with increasing ischemia-reperfusion injury. Am J Physiol 268:H886–H894CrossRefGoogle Scholar
  23. 23.
    Eitel I, Stiermaier T, Rommel KP, Fuernau G, Sandri M, Mangner N, Linke A, Erbs S, Lurz P, Boudriot E, Mende M, Desch S, Schuler G, Thiele H (2015) 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.  https://doi.org/10.1093/eurheartj/ehv463 CrossRefPubMedGoogle Scholar
  24. 24.
    Ekeloef S, Halladin N, Fonnes S, Jensen SE, Zaremba T, Rosenberg J, Jonsson G, Aaroe J, Gasbjerg LS, Rosenkilde MM, Gogenur I (2017) Effect of intracoronary and intravenous melatonin on myocardial salvage index in patients with ST-elevation myocardial infarction: a randomized placebo controlled trial. J Cardiovasc Transl Res 10:470–479.  https://doi.org/10.1007/s12265-017-9768-7 CrossRefPubMedGoogle Scholar
  25. 25.
    Engstrøm T, Kelbaek H, Helqvist S, Hofsten DE, Klovgaard L, Clemmensen P, Holmvang L, Jorgensen E, Pedersen F, Saunamaki K, Ravkilde J, Tilsted HH, Villadsen A, Aaroe J, Jensen SE, Raungaard B, Bøtker HE, Terkelsen CJ, Maeng M, Kaltoft A, Krusell LR, Jensen LO, Veien KT, Kofoed KF, Torp-Pedersen C, Kyhl K, Nepper-Christensen L, Treiman M, Vejlstrup N, Ahtarovski K, Lonborg J, Kober L, Third Danish Study of Optimal Acute Treatment of Patients With STEMI-IPI (2017) 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.  https://doi.org/10.1001/jamacardio.2017.0022 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Erlinge D, Gotberg M, Lang I, Holzer M, Noc M, Clemmensen P, Jensen U, Metzler B, James S, Bøtker HE, Omerovic E, Engblom H, Carlsson M, Arheden H, Ostlund O, Wallentin L, Harnek J, Olivecrona GK (2014) 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). J Am Coll Cardiol 63:1857–1865.  https://doi.org/10.1016/j.jacc.2013.12.027 CrossRefPubMedGoogle Scholar
  27. 27.
    Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R (2014) Interaction of risk factors, comorbidities and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 66:1142–1174.  https://doi.org/10.1124/pr.113.008300 CrossRefPubMedGoogle Scholar
  28. 28.
    Fernandez-Jimenez R, Galan-Arriola C, Sanchez-Gonzalez J, Aguero J, Lopez-Martin GJ, Gomez-Talavera S, Garcia-Prieto J, Benn A, Molina-Iracheta A, Barreiro-Perez M, Martin-Garcia A, Garcia-Lunar I, Pizarro G, Sanz J, Sanchez PL, Fuster V, Ibanez B (2017) Effect of ischemia duration and protective interventions on the temporal dynamics of tissue composition after myocardial infarction. Circ Res 121:439–450.  https://doi.org/10.1161/CIRCRESAHA.117.310901 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Fernandez-Jimenez R, Garcia-Prieto J, Sanchez-Gonzalez J, Aguero J, Lopez-Martin GJ, Galan-Arriola C, Molina-Iracheta A, Doohan R, Fuster V, Ibanez B (2015) Pathophysiology underlying the bimodal edema phenomenon after myocardial ischemia/reperfusion. J Am Coll Cardiol 66:816–828.  https://doi.org/10.1016/j.jacc.2015.06.023 CrossRefPubMedGoogle Scholar
  30. 30.
    Galea N, Dacquino GM, Ammendola RM, Coco S, Agati L, De Luca L, Carbone I, Fedele F, Catalano C, Francone M (2019) Microvascular obstruction extent predicts major adverse cardiovascular events in patients with acute myocardial infarction and preserved ejection fraction. Eur Radiol 29:2369–2377.  https://doi.org/10.1007/s00330-018-5895-z CrossRefPubMedGoogle Scholar
  31. 31.
    Galiuto L, Garramone B, Scara A, Rebuzzi AG, Crea F, La TG, Funaro S, Madonna M, Fedele F, Agati L (2008) The extent of microvascular damage during myocardial contrast echocardiography is superior to other known indexes of post-infarct reperfusion in predicting left ventricular remodeling: results of the multicenter AMICI study. J Am Coll Cardiol 51:552–559.  https://doi.org/10.1016/j.jacc.2007.09.051 CrossRefPubMedGoogle Scholar
  32. 32.
    Garcia-Dorado D, Andres-Villarreal M, Ruiz-Meana M, Inserte J, Barba I (2012) Myocardial edema: a translational view. J Mol Cell Cardiol 52:931–939.  https://doi.org/10.1016/j.yjmcc.2012.01.010 CrossRefPubMedGoogle Scholar
  33. 33.
    Garcia-Dorado D, Garcia-Del-Blanco B, Otaegui I, Rodriguez-Palomares J, Pineda V, Gimeno F, Ruiz-Salmeron R, Elizaga J, Evangelista A, Fernandez-Aviles F, San-Roman A, Ferreira-Gonzalez I (2014) Intracoronary injection of adenosine before reperfusion in patients with ST-segment elevation myocardial infarction: a randomized controlled clinical trial. Int J Cardiol 177:935–941.  https://doi.org/10.1016/j.ijcard.2014.09.203 CrossRefPubMedGoogle Scholar
  34. 34.
    Garcia-Dorado D, Théroux P, Munoz R, Alonso J, Elizaga J, Fernandez-Avilés F, Botas J, Solares J, Soriano J, Duran JM (1992) Favorable effects of hyperosmotic reperfusion on myocardial edema and infarct size. Am J Physiol 262:H17–H22PubMedGoogle Scholar
  35. 35.
    Garcia-Prieto J, Villena-Gutierrez R, Gomez M, Bernardo E, Pun-Garcia A, Garcia-Lunar I, Crainiciuc G, Fernandez-Jimenez R, Sreeramkumar V, Bourio-Martinez R, Garcia-Ruiz JM, Del Valle AS, Sanz-Rosa D, Pizarro G, Fernandez-Ortiz A, Hidalgo A, Fuster V, Ibanez B (2017) Neutrophil stunning by metoprolol reduces infarct size. Nat Commun 8:14780.  https://doi.org/10.1038/ncomms14780 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Gaspar A, Lourenco AP, Pereira MA, Azevedo P, Roncon-Albuquerque R Jr, Marques J, Leite-Moreira AF (2018) Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI). Basic Res Cardiol 113:14.  https://doi.org/10.1007/s00395-018-0672-3 CrossRefPubMedGoogle Scholar
  37. 37.
    Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B, Marble SJ, McCabe CH, Raymond L, Fortin T, Poole K, Braunwald E, Group TS (1996) TIMI frame count. A quantitative method of assessing coronary artery flow. Circulation 93:879–888.  https://doi.org/10.1161/01.cir.93.5.879 CrossRefPubMedGoogle Scholar
  38. 38.
    Götberg M, Olivecrona GK, Koul S, Carlsson M, Engblom H, Ugander M, van der PJ, Algotsson L, Arheden H, Erlinge D (2010) A pilot study of rapid cooling by cold saline and endovascular cooling before reperfusion in patients with ST-elevation myocardial infarction. Circ Cardiovasc Interv 3:400–407.  https://doi.org/10.1161/circinterventions.110.957902 CrossRefPubMedGoogle Scholar
  39. 39.
    Gregorini L, Marco J, Kozàkovà M, Palombo C, Anguissola GB, Marco I, Bernies M, Cassagneau B, Distante A, Bossi IM, Fajadet J, Heusch G (1999) α-Adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation 99:482–490.  https://doi.org/10.1161/01.cir.99.4.482 CrossRefPubMedGoogle Scholar
  40. 40.
    Gwag HB, Kim EK, Park TK, Lee JM, Yang JH, Song YB, Choi JH, Choi SH, Lee SH, Chang SA, Park SJ, Lee SC, Park SW, Jang WJ, Lee M, Chun WJ, Oh JH, Park YH, Choe YH, Gwon HC, Hahn JY (2017) Cardioprotective effects of intracoronary morphine in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: a prospective, randomized trial. J Am Heart Assoc 6:e005426.  https://doi.org/10.1161/JAHA.116.005426 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hale SL, Herring MJ, Kloner RA (2013) Delayed treatment with hypothermia protects against the no-reflow phenomenon despite failure to reduce infarct size. J Am Heart Assoc 2:e004234.  https://doi.org/10.1161/JAHA.112.004234 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Hausenloy DJ, Chilian W, Crea F, Davidson SM, Ferdinandy P, Garcia-Dorado D, van Royen N, Schulz R, Heusch G (2019) The coronary circulation in acute myocardial ischaemia/reperfusion injury—a target for cardioprotection. Cardiovasc Res 115:1143–1155.  https://doi.org/10.1093/cvr/cvy286 CrossRefPubMedGoogle Scholar
  43. 43.
    Hausenloy DJ, Kharbanda RK, Møller UK, Ramlall M, Aarøe J, Butler R, Bulluck H, Clayton T, Dana A, Dodd M, Engstrom T, Evans R, Flensted Lassen J, Frischknecht Christensen E, Garcia-Ruiz JM, Gorog DA, Hjort J, Houghton RF, Ibanez B, Knight R, Lippert FK, Lønborg JT, Maeng M, Milasinovic D, More R, Nicholas JM, Okkels Jensen L, Perkins A, Radovanovic N, Rakhit RD, Ravkilde J, Ryding AD, Schmidt MR, Skogstad Riddervold I, Toft Sørensen H, Stankovic G, Varma M, Webb I, Juhl Terkelsen C, Greenwood JP, Yellon DM, Bøtker HE (2019) Effect of remote ischemic conditioning on clinical outcomes at 12 months in acute myocardial infarction patients: the CONDI-2/ERIC-PPCI trial. Lancet.  https://doi.org/10.1016/S0140-6736(19)32039-2 (in press) CrossRefPubMedGoogle Scholar
  44. 44.
    Herring N, Tapoulal N, Kalla M, Ye X, Borysova L, Lee R, Dall’Armellina E, Stanley C, Ascione R, Lu CJ, Banning AP, Choudhury RP, Neubauer S, Dora K, Kharbanda RK, Channon KM (2019) Neuropeptide-Y causes coronary microvascular constriction and is associated with reduced ejection fraction following ST-elevation myocardial infarction. Eur Heart J 40:1920–1929.  https://doi.org/10.1093/eurheartj/ehz115 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Heusch G (2013) Cardioprotection: chances and challenges of its translation to the clinic. Lancet 381:166–175.  https://doi.org/10.1016/S0140-6736(12)60916-7 CrossRefPubMedGoogle Scholar
  46. 46.
    Heusch G (2016) The coronary circulation as a target of cardioprotection. Circ Res 118:1643–1658.  https://doi.org/10.1161/CIRCRESAHA.116.308640 CrossRefPubMedGoogle Scholar
  47. 47.
    Heusch G (2017) Critical issues for the translation of cardioprotection. Circ Res 120:1477–1486.  https://doi.org/10.1161/CIRCRESAHA.117.310820 CrossRefPubMedGoogle Scholar
  48. 48.
    Heusch G (2018) 25 years of remote ischemic conditioning: from laboratory curiosity to clinical outcome. Basic Res Cardiol 113:15.  https://doi.org/10.1007/s00395-018-0673-2 CrossRefPubMedGoogle Scholar
  49. 49.
    Heusch G (2018) Cardioprotection research must leave its comfort zone. Eur Heart J 39:3393–3395.  https://doi.org/10.1093/eurheartj/ehy253 CrossRefPubMedGoogle Scholar
  50. 50.
    Heusch G, Baumgart D, Camici P, Chilian W, Gregorini L, Hess O, Indolfi C, Rimoldi O (2000) α-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 101:689–694.  https://doi.org/10.1161/01.cir.101.6.689 CrossRefPubMedGoogle Scholar
  51. 51.
    Heusch G, Bøtker HE, Przyklenk K, Redington A, Yellon D (2015) Remote ischemic conditioning. J Am Coll Cardiol 65:177–195.  https://doi.org/10.1016/j.jacc.2014.10.031 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Heusch G, Deussen A, Thämer V (1985) Cardiac sympathetic nerve activity and progressive vasoconstriction distal to coronary stenoses: feed-back aggravation of myocardial ischemia. J Auton Nerv Syst 13:311–326CrossRefGoogle Scholar
  53. 53.
    Heusch G, Kleinbongard P, Boese D, Levkau B, Haude M, Schulz R, Erbel R (2009) Coronary microembolization: from bedside to bench and back to bedside. Circulation 120:1822–1836.  https://doi.org/10.1161/CIRCULATIONAHA.109.888784 CrossRefPubMedGoogle Scholar
  54. 54.
    Heusch G, Kleinbongard P, Rassaf T (2019) Cardioprotection beyond infarct size reduction. Circ Res 124:679–680.  https://doi.org/10.1161/CIRCRESAHA.119.314679 CrossRefPubMedGoogle Scholar
  55. 55.
    Heusch G, Kleinbongard P, Skyschally A, Levkau B, Schulz R, Erbel R (2012) The coronary circulation in cardioprotection: more than just one confounder. Cardiovasc Res 94:237–245.  https://doi.org/10.1093/cvr/cvr271 CrossRefPubMedGoogle Scholar
  56. 56.
    Heusch G, Rassaf T (2016) Time to give up on cardioprotection? A critical appraisal of clinical studies on ischemic pre-, post-, and remote conditioning. Circ Res 119:676–695.  https://doi.org/10.1161/CIRCRESAHA.116.308736 CrossRefPubMedGoogle Scholar
  57. 57.
    Heusch P, Nensa F, Heusch G (2015) Is MRI really the gold standard for the quantification of salvage from myocardial infarction? Circ Res 117:222–224.  https://doi.org/10.1161/CIRCRESAHA.117.306929 CrossRefPubMedGoogle Scholar
  58. 58.
    Higginson LA, White F, Heggtveit HA, Sanders TM, Bloor CM, Covell JW (1982) Determinants of myocardial hemorrhage after coronary reperfusion in the anesthetized dog. Circulation 65:62–69.  https://doi.org/10.1161/01.cir.65.1.62 CrossRefPubMedGoogle Scholar
  59. 59.
    Hoole SP, Jaworski C, Brown AJ, McCormick LM, Agrawal B, Clarke SC, West NE (2015) Serial assessment of the index of microcirculatory resistance during primary percutaneous coronary intervention comparing manual aspiration catheter thrombectomy with balloon angioplasty (IMPACT study): a randomised controlled pilot study. Open Heart 2:e000238.  https://doi.org/10.1136/openhrt-2015-000238 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ibanez B, Aletras AH, Arai AE, Arheden H, Bax J, Berry C, Bucciarelli-Ducci C, Croisille P, Dall’Armellina E, Dharmakumar R, Eitel I, Fernández-Jiménez R, Friedrich MG, García-Dorado D, Hausenloy DJ, Kim RJ, Kozerke S, Kramer CM, Salerno M, Sánchez-González J, Sanz J, Fuster V (2019) Cardiac MRI endpoints in myocardial infarction experimental and clinical trials. JACC scientific expert panel JACC scientific expert panel. J Am Coll Cardiol 74:238–256.  https://doi.org/10.1016/j.jacc.2019.05.024 CrossRefPubMedGoogle Scholar
  61. 61.
    Ibanez B, Macaya C, Sanchez-Brunete V, Pizarro G, Fernandez-Friera L, Mateos A, Fernandez-Ortiz A, Garcia-Ruiz JM, Garcia-Alvarez A, Iniguez A, Jimenez-Borreguero J, Lopez-Romero P, Fernandez-Jimenez R, Goicolea J, Ruiz-Mateos B, Bastante T, Arias M, Iglesias-Vazquez JA, Rodriguez MD, Escalera N, Acebal C, Cabrera JA, Valenciano J, de Perez PA, Fernandez-Campos MJ, Casado I, Garcia-Rubira JC, Garcia-Prieto J, Sanz-Rosa D, Cuellas C, Hernandez-Antolin R, Albarran A, Fernandez-Vazquez F, dlT-H JM, Pocock S, Sanz G, Fuster V (2013) 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.  https://doi.org/10.1161/CIRCULATIONAHA.113.003653 CrossRefPubMedGoogle Scholar
  62. 62.
    Infusino F, Niccoli G, Fracassi F, Roberto M, Falcioni E, Lanza GA, Crea F (2014) The central role of conventional 12-lead ECG for the assessment of microvascular obstruction after percutaneous myocardial revascularization. J Electrocardiol 47:45–51.  https://doi.org/10.1016/j.jelectrocard.2013.10.002 CrossRefPubMedGoogle Scholar
  63. 63.
    Iwakura K, Ito H, Ikushima M, Kawano S, Okamura A, Asano K, Kuroda T, Tanaka K, Masuyama T, Hori M, Fujii K (2003) Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction. J Am Coll Cardiol 41:1–7.  https://doi.org/10.1016/s0735-1097(02)02626-8 CrossRefPubMedGoogle Scholar
  64. 64.
    Iwakura K, Ito H, Kawano S, Shintani Y, Yamamoto K, Kato A, Ikushima M, Tanaka K, Kitakaze M, Hori M, Higashina Y, Fujii K (2001) 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.  https://doi.org/10.1016/s0735-1097(01)01405-x CrossRefPubMedGoogle Scholar
  65. 65.
    Janssens SP, Bogaert J, Zalewski J, Toth A, Adriaenssens T, Belmans A, Bennett J, Claus P, Desmet W, Dubois C, Goetschalckx K, Sinnaeve P, Vandenberghe K, Vermeersch P, Lux A, Szelid Z, Durak M, Lech P, Zmudka K, Pokreisz P, Vranckx P, Merkely B, Bloch KD, Van de Werf F, investigators N (2018) Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI): a multicentre, double-blind, randomized controlled trial. Eur Heart J 39:2717–2725.  https://doi.org/10.1093/eurheartj/ehy232 CrossRefPubMedGoogle Scholar
  66. 66.
    Jesel L, Morel O, Ohlmann P, Germain P, Faure A, Jahn C, Coulbois PM, Chauvin M, Bareiss P, Roul G (2007) Role of pre-infarction angina and inflammatory status in the extent of microvascular obstruction detected by MRI in myocardial infarction patients treated by PCI. Int J Cardiol 121:139–147.  https://doi.org/10.1016/j.ijcard.2006.10.022 CrossRefPubMedGoogle Scholar
  67. 67.
    Jones DA, Pellaton C, Velmurugan S, Andiapen M, Antoniou S, van Eijl S, Webb AJ, Westwood M, Parmar M, Mathur A, Ahluwalia A (2015) Randomized phase 2 trial of intra-coronary nitrite during acute myocardial infarction. Circ Res 116:437–447.  https://doi.org/10.1161/CIRCRESAHA.116.305082 CrossRefPubMedGoogle Scholar
  68. 68.
    Karlsson JE, El-Saadi W, Ali M, Puskar W, Skogvard P, Engvall JE, Andersson RG, Maret E, Jynge P (2015) Mangafodipir as a cardioprotective adjunct to reperfusion therapy: a feasibility study in patients with ST-segment elevation myocardial infarction. Eur Heart J Cardiovasc Pharmacother 1:39–45.  https://doi.org/10.1093/ehjcvp/pvu021 CrossRefPubMedGoogle Scholar
  69. 69.
    Kasseckert SA, Schafer C, Kluger A, Gligorievski D, Tillmann J, Schluter KD, Noll T, Sauer H, Piper HM, Abdallah Y (2009) Stimulation of cGMP signalling protects coronary endothelium against reperfusion-induced intercellular gap formation. Cardiovasc Res 83:381–387.  https://doi.org/10.1093/cvr/cvp065 CrossRefPubMedGoogle Scholar
  70. 70.
    Keeble TR, Karamasis GV, Noc M, Sredniawa B, Aradi D, Neskovic AN, Arheden H, Erlinge D, Holzer M (2018) Effect of intravascular cooling on microvascular obstruction (MVO) in conscious patients with ST-elevation myocardial infarction undergoing primary PCI: results from the COOL AMI EU pilot study. Cardiovasc Revasc Med.  https://doi.org/10.1016/j.carrev.2018.09.014 CrossRefPubMedGoogle Scholar
  71. 71.
    Kim EK, Hahn JY, Song YB, Lee SC, Choi JH, Choi SH, Lee SH, Choe YH, Gwon HC (2015) Effect of ischemic postconditioning on myocardial salvage in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: cardiac magnetic resonance substudy of the POST randomized trial. Int J Cardiovasc Imaging 31:629–637.  https://doi.org/10.1007/s10554-015-0589-y CrossRefPubMedGoogle Scholar
  72. 72.
    Kirma C, Izgi A, Dundar C, Tanalp AC, Oduncu V, Aung SM, Sonmez K, Mutlu B, Ozdemir N, Erentug V (2008) Clinical and procedural predictors of no-reflow phenomenon after primary percutaneous coronary interventions: experience at a single center. Circ J 72:716–721.  https://doi.org/10.1253/circj.72.716 CrossRefPubMedGoogle Scholar
  73. 73.
    Kleinbongard P, Baars T, Moehlenkamp S, Kahlert P, Erbel R, Heusch G (2013) 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.  https://doi.org/10.1152/ajpheart.00358.2013 CrossRefPubMedGoogle Scholar
  74. 74.
    Kleinbongard P, Boese D, Baars T, Moehlenkamp S, Konorza T, Schoener S, Elter-Schulz M, Eggebrecht H, Degen H, Haude M, Levkau B, Schulz R, Erbel R, Heusch G (2011) Vasoconstrictor potential of coronary aspirate from patients undergoing stenting of saphenous vein aortocoronary bypass grafts and its pharmacological attenuation. Circ Res 108:344–352.  https://doi.org/10.1161/CIRCRESAHA.110.235713 CrossRefPubMedGoogle Scholar
  75. 75.
    Kleinbongard P, Botker HE, Ovize M, Hausenloy DJ, Heusch G (2019) Co-morbidities and co-medications as confounders of cardioprotection—Does it matter in the clinical setting? Br J Pharmacol.  https://doi.org/10.1111/bph.14839 CrossRefPubMedGoogle Scholar
  76. 76.
    Kloner RA, Ganote CE, Jennings RB (1974) The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 54:1496–1508CrossRefGoogle Scholar
  77. 77.
    Krug A, du Mesnil de Rochemont W, Korb G (1966) Blood supply of the myocardium after temporary coronary occlusion. Circ Res 19:57–62.  https://doi.org/10.1161/01.res.19.1.57 CrossRefPubMedGoogle Scholar
  78. 78.
    Kupatt C, Wichels R, Horstkotte J, Krombach F, Habazettl H, Boekstegers P (2002) Molecular mechanisms of platelet-mediated leukocyte recruitment during myocardial reperfusion. J Leukoc Biol 72:455–461.  https://doi.org/10.1189/jlb.72.3.455 CrossRefPubMedGoogle Scholar
  79. 79.
    Liu Z, Zhao L, Hong D, Gao J (2016) Remote ischaemic preconditioning reduces myocardial ischaemic reperfusion injury in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Acta Cardiol 71:596–603.  https://doi.org/10.2143/AC.71.5.3167504 CrossRefPubMedGoogle Scholar
  80. 80.
    Lonborg J, Engstrøm T, Ahtarovski KA, Nepper-Christensen L, Helqvist S, Vejlstrup N, Kyhl K, Schoos MM, Ghotbi A, Goransson C, Bertelsen L, Holmvang L, Pedersen F, Jorgensen E, Saunamaki K, Clemmensen P, De Backer O, Klovgaard L, Hofsten DE, Kober L, Kelbaek H, Investigators D- (2017) Myocardial damage in patients with deferred stenting after STEMI: a DANAMI-3-DEFER substudy. J Am Coll Cardiol 69:2794–2804.  https://doi.org/10.1016/j.jacc.2017.03.601 CrossRefPubMedGoogle Scholar
  81. 81.
    Ludman AJ, Yellon DM, Hasleton J, Ariti C, Babu GG, Boston-Griffiths E, Venugopal V, Walker M, Holdright D, Swanton H, Crake T, Brull D, Moon JC, Puranik R, Mutharangu V, Taylor A, Hausenloy DJ (2011) Effect of erythropoietin as an adjunct to primary percutaneous coronary intervention: a randomised controlled clinical trial. Heart 97:1560–1565.  https://doi.org/10.1136/hrt.2011.223867 CrossRefPubMedGoogle Scholar
  82. 82.
    Manciet LH, Poole DC, McDonagh PF, Copeland JG, Mathieu-Costello O (1994) Microvascular compression during myocardial ischemia: mechanistic basis for no-reflow phenomenon. Am J Physiol 266:H1541–H1550PubMedGoogle Scholar
  83. 83.
    Mangion K, Carrick D, Clerfond G, Rush C, McComb C, Oldroyd KG, Petrie MC, Eteiba H, Lindsay M, McEntegart M, Hood S, Watkins S, Davie A, Auger DA, Zhong X, Epstein FH, Haig CE, Berry C (2019) Predictors of segmental myocardial functional recovery in patients after an acute ST-Elevation myocardial infarction. Eur J Radiol 112:121–129.  https://doi.org/10.1016/j.ejrad.2019.01.010 CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Marenzi G, Cosentino N, Cortinovis S, Milazzo V, Rubino M, Cabiati A, De Metrio M, Moltrasio M, Lauri G, Campodonico J, Pontone G, Andreini D, Bonomi A, Veglia F, Bartorelli A (2015) Myocardial infarct size in patients on long-term statin therapy undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction. Am J Cardiol 116:1791–1797.  https://doi.org/10.1016/j.amjcard.2015.09.016 CrossRefPubMedGoogle Scholar
  85. 85.
    McCartney PJ, Eteiba H, Maznyczka AM, McEntegart M, Greenwood JP, Muir DF, Chowdhary S, Gershlick AH, Appleby C, Cotton JM, Wragg A, Curzen N, Oldroyd KG, Lindsay M, Rocchiccioli JP, Shaukat A, Good R, Watkins S, Robertson K, Malkin C, Martin L, Gillespie L, Ford TJ, Petrie MC, Macfarlane PW, Tait RC, Welsh P, Sattar N, Weir RA, Fox KA, Ford I, McConnachie A, Berry C, Group TT (2019) 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.  https://doi.org/10.1001/jama.2018.19802 CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Mewton N, Thibault H, Roubille F, Lairez O, Rioufol G, Sportouch C, Sanchez I, Bergerot C, Cung TT, Finet G, Angoulvant D, Revel D, Bonnefoy-Cudraz E, Elbaz M, Piot C, Sahraoui I, Croisille P, Ovize M (2013) Postconditioning attenuates no-reflow in STEMI patients. Basic Res Cardiol 108:383.  https://doi.org/10.1007/s00395-013-0383-8 CrossRefPubMedGoogle Scholar
  87. 87.
    Nazir SA, McCann GP, Greenwood JP, Kunadian V, Khan JN, Mahmoud IZ, Blackman DJ, Been M, Abrams KR, Shipley L, Wilcox R, Adgey AA, Gershlick AH (2016) 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.  https://doi.org/10.1093/eurheartj/ehw136 CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Nepper-Christensen L, Høfsten DE, Helqvist S, Lassen JF, Tilsted HH, Holmvang L, Pedersen F, Joshi F, Sørensen R, Bang L, Bøtker HE, Terkelsen CJ, Maeng M, Okkels Jensen L, Aarøe J, Kelbæk H, Køber L, Engstrøm T, Lønborg J (2019) Interaction of ischaemic postconditioning and thrombectomy in patients with ST-elevation myocardial infarction. Heart.  https://doi.org/10.1136/heartjnl-2019-314952 CrossRefPubMedGoogle Scholar
  89. 89.
    Niccoli G, Cosentino N, Spaziani C, Fracassi F, Tarantini G, Crea F (2013) No-reflow: incidence and detection in the cath-lab. Curr Pharm Des 19:4564–4575.  https://doi.org/10.2174/1381612811319250005 CrossRefPubMedGoogle Scholar
  90. 90.
    Niccoli G, Montone R, Ibanez B, Thiele H, Crea F, Heusch G, Bulluck H, Hausenloy D, Berry C, Stiermaier T, Camici P, Eitel I (2019) Optimized treatment of ST-elevation myocardial infarction: the unmet need to target coronary microvascular obstruction as primary treatment goal to further improve prognosis. Circ Res 125:245–258.  https://doi.org/10.1161/CIRCRESAHA.119.315344 CrossRefPubMedGoogle Scholar
  91. 91.
    Niccoli G, Scalone G, Cosentino N, Fabretti A, Mirizzi AM, Gramegna M, Panebianco M, Roberto M, Crea F (2014) Protective effect of pre-infarction angina on microvascular obstruction after primary percutaneous coronary intervention is blunted in humans by cardiovascular risk factors. Circ J 8:1935–1941.  https://doi.org/10.1253/circj.CJ-14-0194 CrossRefGoogle Scholar
  92. 92.
    Nichol G, Strickland W, Shavelle D, Maehara A, Ben-Yehuda O, Genereux P, Dressler O, Parvataneni R, Nichols M, McPherson J, Barbeau G, Laddu A, Elrod JA, Tully GW, Ivanhoe R, Stone GW, Investigators V (2015) Prospective, multicenter, randomized, controlled pilot trial of peritoneal hypothermia in patients with ST-segment- elevation myocardial infarction. Circ Cardiovasc Interv 8:e001965.  https://doi.org/10.1161/CIRCINTERVENTIONS.114.001965 CrossRefPubMedGoogle Scholar
  93. 93.
    O’Farrell FM, Mastitskaya S, Hammond-Haley M, Freitas F, Wah WR, Attwell D (2017) Capillary pericytes mediate coronary no-reflow after myocardial ischaemia. Elife 6:e29280.  https://doi.org/10.7554/eLife.29280 CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Patel MR, Smalling RW, Thiele H, Barnhart HX, Zhou Y, Chandra P, Chew D, Cohen M, French J, Perera D, Ohman EM (2011) 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.  https://doi.org/10.1001/jama.2011.1280 CrossRefPubMedGoogle Scholar
  95. 95.
    Pearson PJ, Schaff HV, Vanhoutte PM (1990) Acute impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries. Circ Res 67:385–393.  https://doi.org/10.1161/01.res.67.2.385 CrossRefPubMedGoogle Scholar
  96. 96.
    Pryds K, Nielsen RR, Jorsal A, Hansen MS, Ringgaard S, Refsgaard J, Kim WY, Petersen AK, Botker HE, Schmidt MR (2017) Effect of long-term remote ischemic conditioning in patients with chronic ischemic heart failure. Basic Res Cardiol 112:67.  https://doi.org/10.1007/s00395-017-0658-6 CrossRefPubMedGoogle Scholar
  97. 97.
    Reinstadler SJ, Stiermaier T, Reindl M, Feistritzer HJ, Fuernau G, Eitel C, Desch S, Klug G, Thiele H, Metzler B, Eitel I (2018) Intramyocardial haemorrhage and prognosis after ST-elevation myocardial infarction. Eur Heart J Cardiovasc Imaging 20:138–146.  https://doi.org/10.1093/ehjci/jey101 CrossRefGoogle Scholar
  98. 98.
    Robbers LF, Eerenberg ES, Teunissen PF, Jansen MF, Hollander MR, Horrevoets AJ, Knaapen P, Nijveldt R, Heymans MW, Levi MM, van Rossum AC, Niessen HW, Marcu CB, Beek AM, van RN (2013) Magnetic resonance imaging-defined areas of microvascular obstruction after acute myocardial infarction represent microvascular destruction and haemorrhage. Eur Heart J 34:2346–2353.  https://doi.org/10.1093/eurheartj/eht100 CrossRefPubMedGoogle Scholar
  99. 99.
    Saad M, Stiermaier T, Fuernau G, Poss J, de Waha-Thiele S, Desch S, Thiele H, Eitel I (2019) 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.  https://doi.org/10.1016/j.ijcard.2018.11.141 CrossRefPubMedGoogle Scholar
  100. 100.
    Sheehan FH, Braunwald E, Canner P, Dodge HT, Gore J, Van Natta P, Passamani ER, Williams DO, Zaret B (1987) The effect of intravenous thrombolytic therapy on left ventricular function: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI Phase I) trial. Circulation 75:817–829.  https://doi.org/10.1161/01.cir.75.4.817 CrossRefPubMedGoogle Scholar
  101. 101.
    Skyschally A, Amanakis G, Neuhauser M, Kleinbongard P, Heusch G (2017) Impact of electrical defibrillation on infarct size and no-reflow in pigs subjected to myocardial ischemia-reperfusion without and with ischemic conditioning. Am J Physiol Heart Circ Physiol 313:H871–H878.  https://doi.org/10.1152/ajpheart.00293.2017 CrossRefPubMedGoogle Scholar
  102. 102.
    Skyschally A, Walter B, Heusch G (2013) Coronary microembolization during early reperfusion—infarct extension, but protection by ischemic postconditioning. Eur Heart J 34:3314–3321.  https://doi.org/10.1093/eurheartj/ehs434 CrossRefPubMedGoogle Scholar
  103. 103.
    Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, Pedersen L, Sorensen HT, Bøtker HE (2014) Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J 35:168–175.  https://doi.org/10.1093/eurheartj/eht369 CrossRefPubMedGoogle Scholar
  104. 104.
    Stempien-Otero A, Karsan A, Cornejo CJ, Xxiang H, Eunson T, Morrison RS, Kay M, Winn R, Harlan J (1999) Mechanisms of hypoxia-induced endothelial cell death. Role of p53 in apoptosis. J Biol Chem 274:8039–8045CrossRefGoogle Scholar
  105. 105.
    Stone GW, Abizaid A, Silber S, Dizon JM, Merkely B, Costa RA, Kornowski R, Abizaid A, Wojdyla R, Maehara A, Dressler O, Brener SJ, Bar E, Dudek D (2012) 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.  https://doi.org/10.1016/j.jacc.2012.09.004 CrossRefPubMedGoogle Scholar
  106. 106.
    Stone GW, Selker HP, Thiele H, Patel MR, Udelson JE, Ohman EM, Maehara A, Eitel I, Granger CB, Jenkins PL, Nichols M, Ben-Yehuda O (2016) Relationship between infarct size and outcomes following primary PCI: patient-level analysis from 10 randomized trials. J Am Coll Cardiol 67:1674–1683.  https://doi.org/10.1016/j.jacc.2016.01.069 CrossRefPubMedGoogle Scholar
  107. 107.
    Thuny F, Lairez O, Roubille F, Mewton N, Rioufol G, Sportouch C, Sanchez I, Bergerot C, Thibault H, Cung TT, Finet G, Argaud L, Revel D, Derumeaux G, Bonnefoy-Cudraz E, Elbaz M, Piot C, Ovize M, Croisille P (2012) Post-conditioning reduces infarct size and edema in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 59:2175–2181.  https://doi.org/10.1016/j.jacc.2012.03.026 CrossRefPubMedGoogle Scholar
  108. 108.
    Traverse JH, Swingen C, Henry TD, Fox J, Wang Y, Chavez I, Lips D, Lesser JR, Pedersen WR, Burke NM, Pai A, Lindberg JL, Garberich RF (2019) NHLBI-sponsored trial of postconditioning during primary percutaneous coronary intervention for ST-elevation myocardial infarction. Circ Res 124:769–778.  https://doi.org/10.1161/CIRCRESAHA.118.314060 CrossRefPubMedGoogle Scholar
  109. 109.
    van’t Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, Zijlstra F (1998) 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.  https://doi.org/10.1161/01.cir.97.23.2302 CrossRefGoogle Scholar
  110. 110.
    van den Berg BM, Vink H, Spaan JAE (2003) The endothelial glycocalyx protects against myocardial edema. Circ Res 92:592–594.  https://doi.org/10.1161/01.RES.0000065917.53950.75 CrossRefPubMedGoogle Scholar
  111. 111.
    van Kranenburg M, Magro M, Thiele H, de Waha S, Eitel I, Cochet A, Cottin Y, Atar D, Buser P, Wu E, Lee D, Bodi V, Klug G, Metzler B, Delewi R, Bernhardt P, Rottbauer W, Boersma E, Zijlstra F, van Geuns RJ (2014) Prognostic value of microvascular obstruction and infarct size, as measured by CMR in STEMI patients. J Am Coll Cardiol Cardiovasc Imaging 7:930–939.  https://doi.org/10.1016/j.jcmg.2014.05.010 CrossRefGoogle Scholar
  112. 112.
    Vanezis AP, Arnold JR, Rodrigo G, Lai FY, Debiec R, Nazir S, Khan JN, Ng LL, Chitkara K, Coghlan JG, Hetherington SL, McCann GP, Samani NJ (2018) Daily remote ischaemic conditioning following acute myocardial infarction: a randomised controlled trial. Heart 104:1955–1962.  https://doi.org/10.1136/heartjnl-2018-313091 CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Wei M, Xin P, Li S, Tao J, Li Y, Li J, Liu M, Li J, Zhu W, Redington AN (2011) Repeated remote ischemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction. Circ Res 108:1220–1225.  https://doi.org/10.1161/CIRCRESAHA.110.236190 CrossRefPubMedGoogle Scholar
  114. 114.
    Weis SM, Cheresh DA (2005) Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437:497–504.  https://doi.org/10.1038/nature03987 CrossRefPubMedGoogle Scholar
  115. 115.
    White SK, Froehlich GM, Sado DM, Maestrini V, Fontana M, Treibel TA, Tehrani S, Flett AS, Meier P, Ariti C, Davies JR, Moon JC, Yellon DM, Hausenloy DJ (2015) Remote ischemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol Cardiovasc Interv 8:178–188.  https://doi.org/10.1016/j.jcin.2014.05.015 CrossRefGoogle Scholar
  116. 116.
    Wu KC, Kim RJ, Bluemke DA, Rochitte CE, Zerhouni EA, Becker LC, Lima JAC (1998) Quantification and time course of microvascular obstruction by contrast-enhanced echocardiography and magnetic resonance imaging following acute myocardial infarction and reperfusion. J Am Coll Cardiol 32:1756–1764CrossRefGoogle Scholar
  117. 117.
    Wu KC, Zerhouni EA, Judd RM, Lugo-Olivieri CH, Barouch LA, Schulman SP, Blumenthal RS, Lima JA (1998) Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 97:765–772.  https://doi.org/10.1161/01.cir.97.8.765 CrossRefPubMedGoogle Scholar
  118. 118.
    Yoon CH, Chung WY, Suh JW, Cho YS, Youn TJ, Chun EJ, Choi SI, Chae IH, Choi DJ (2013) Distal protection device aggravated microvascular obstruction evaluated by cardiac MR after primary percutaneous intervention for ST-elevation myocardial infarction. Int J Cardiol 167:2002–2007.  https://doi.org/10.1016/j.ijcard.2012.05.029 CrossRefPubMedGoogle Scholar
  119. 119.
    Zhao JL, Yang YJ, You SJ, Cui CJ, Gao RL (2007) Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic mini-swines. Microvasc Res 73:137–142.  https://doi.org/10.1016/j.mvr.2006.09.002 CrossRefPubMedGoogle Scholar
  120. 120.
    Zhao Z-Q, Corvera JS, Halkos ME, Kerendi F, Wang N-P, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579–H588.  https://doi.org/10.1152/ajpheart.01069.2002 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute for Pathophysiology, West German Heart and Vascular CenterUniversity of Essen Medical SchoolEssenGermany

Personalised recommendations