Infarct Size Reduction by Targeting Ischemic Injury
2018; Lippincott Williams & Wilkins; Volume: 122; Issue: 8 Linguagem: Inglês
10.1161/circresaha.118.312939
ISSN1524-4571
AutoresXavier Rosselló, Borja Ibáñez,
Tópico(s)Acute Myocardial Infarction Research
ResumoHomeCirculation ResearchVol. 122, No. 8Infarct Size Reduction by Targeting Ischemic Injury Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBInfarct Size Reduction by Targeting Ischemic InjuryBack to Square One Xavier Rossello and Borja Ibanez Xavier RosselloXavier Rossello From the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Translational Laboratory for Cardiovascular Imaging and Therapy, Madrid, Spain (X.R., B.I.); CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain (X.R., B.I.); and Cardiology Department, IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain (B.I.). and Borja IbanezBorja Ibanez Correspondence to Borja Ibáñez, MD, PhD, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain. E-mail E-mail Address: [email protected] From the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Translational Laboratory for Cardiovascular Imaging and Therapy, Madrid, Spain (X.R., B.I.); CIBER de enfermedades CardioVasculares (CIBERCV), Madrid, Spain (X.R., B.I.); and Cardiology Department, IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain (B.I.). Originally published6 Aug 2018https://doi.org/10.1161/CIRCRESAHA.118.312939Circulation Research. 2018;122:1041–1043This article is a commentary on the followingReflection of Cardioprotection by Remote Ischemic Perconditioning in Attenuated ST-Segment Elevation During Ongoing Coronary Occlusion in PigsTimely reperfusion is needed to salvage viable myocardium in patients with ST-segment–elevation myocardial infarction.1 The concept that the fate of the ischemic myocardium depends on subsequent spontaneous or interventional coronary reperfusion was established in experimental large animal models >4 decades ago.2 Further research identified that the process of restoring blood flow to the ischemic myocardium comes at a cost, as induces additional myocardial damage, known as myocardial ischemia/reperfusion injury.2 For a long time, it has been assumed that although ischemic injury can only be reduced by faster blood flow restoration, reperfusion-related myocardial injury can be ameliorated by interventions applied anytime before (or at the latest at) reperfusion. The possibility of reducing infarct size by a strategy applied soon before reperfusion (eg, in the cath lab) is logistically attractive and for this reason has gained lots of interest. Unlike reperfusion itself, whose translation is one of the most successful stories of medicine ever, cardioprotective therapies targeting reperfusion-related injury have not yet been successful and remain one of the top 10 unmet clinical needs in cardiology.1,3Article, see p 1102One of the major determinants of (long-term) mortality and morbidity in patients with ST-segment–elevation myocardial infarction is the extent of myocardial necrosis, known as infarct size, resulting from both ischemic- and reperfusion-related injuries.4,5 Therapies able to reduce infarct size have been historically tested under the hypothesis that smaller infarctions will result in fewer adverse clinical events in the long term.4,6 Among them, ischemic conditioning deserves special attention. In 1986, Murry et al7 published a seminal study demonstrating that several brief (5 minutes) cycles of noninjurious ischemia and reperfusion render the myocardium significantly protection from a subsequent sustained ischemic insult. This phenomenon whereby the myocardium can endogenously be protected from lethal ischemia/reperfusion injury was defined as ischemic preconditioning and has been subsequently replicated in numerous preclinical studies,8 as well as in other organs.9 Brief episodes of ischemia and reperfusion in one organ render remote tissues and organs resistant to ischemia/reperfusion injury, something known as remote ischemic conditioning.9 Interestingly, remote ischemic conditioning has been shown to exert cardioprotection even when it is initiated during ongoing myocardial infarction,10 a maneuver known as remote ischemic perconditioning (perRIC). All different variants of conditioning (pre, per, post, local, or remote) are thought to reduce infarct size by targeting reperfusion-related injury.In this issue of Circulation Research, Kleinbongard et al11 studied the electrocardiographic changes occurring during perRIC in a swine model of myocardial ischemia/reperfusion injury. Isoflurane-anesthetized Göttingen minipigs underwent open-chest temporary (60 minutes) coronary occlusion followed by reperfusion. At minute 20 of ischemia, pigs were randomized to perRIC (4 cycles of 5-minute occlusion/5-minute reperfusion of the hindlimb) or control (no perRIC). ST-segment elevation was analyzed in a V2-like electrocardiography lead at baseline, at 5- and 55-minute coronary occlusion, and at 10-, 30-, 60-, and 120-minute reperfusion. Hundred and eighty minutes after reperfusion, animals were euthanized, and hearts processed for pathology-based infarct size and no-reflow quantifications. perRIC was associated with significantly smaller infarct sizes. There was a nonsignificant trend for smaller areas of no-reflow in the perRIC group. perRIC increased phosphorylation of STAT3 (signal transducer and activator of transcription 3). These results are in agreement with many previous studies and validate the authors' model of perRIC. The main novelty of the article relates to the serial electrocardiographic findings: at 5-minute ischemia (ie, before perRIC was initiated), ST-segment deviations were not different, but ST-segment deviation at 55-minute ischemia significantly recovered in perRIC pigs compared with matched controls. This observation has 2 main clinical implications: (1) ischemic perconditioning has a clear impact on the ischemic bit of the overall ischemia/reperfusion injury and (2) electrocardiography can be used for real-time monitoring of the impact of cardioprotective therapies over myocardial ischemic injury and, maybe, can be used to roughly identify a subset of patients with a high underlying risk of developing large infarcts who can actually benefit from cardioprotective interventions.The study by Kleinbongard et al11 challenges the paradigm that perRIC mostly attenuates reperfusion-related injury because the reduction in ST-segment elevation observed during ongoing ischemia points toward an impact on ischemic injury. The mechanism by which perRIC can ameliorate ischemic damage is unknown and was beyond the scope of this article. Given the virtual absence of residual blood flow into the ischemic region, it seems implausible that a humoral signal released from the distant organ undergoing brief episodes of ischemia/reperfusion is the source of ischemic injury attenuation. It is intuitive to argue that a neural pathway is involved in this protection, but we are far from understanding the actual mechanism. This study is landmark not only from the conditioning perspective but also for the entire cardioprotection field because it places ischemic injury back in the arena of relevant targets for infarct size reduction, something ignored for many years. This study also provides explanation for a finding identified in the CONDI trial (Effect of RIC on Clinical Outcomes in STEMI Patients Undergoing pPCI),10 where perRIC seemed to offer stronger protection when applied long before reperfusion.12 In this line, another strategy that has been shown to reduce infarct size (ie, intravenous metoprolol) exerts stronger cardioprotection when applied long before reperfusion.13 Altogether, these evidences suggest that therapies effectively reducing infarct size exert an important effect on ischemic injury. Beyond the conceptual change of this finding, there is a practical consequence: these therapies should be applied as soon as possible on myocardial infarction diagnosis, and this is many times in the out-of-hospital setting. The identification of the anti-ischemic effect of perRIC and metoprolol (and probably other strategies) does not mean that they do not ameliorate reperfusion-related injury as well. In this sense, recently it has been shown that metoprolol has a direct effect on neutrophils, and this results in a potent effect against reperfusion-related injury.14 In fact, ischemic- and reperfusion-related injuries are indissoluble from each other, and, thus, any therapy reducing ischemic-related injury will also impact reperfusion-related injury.The electrocardiography is a tool routinely used in patients with suspected AMI to establish a diagnosis.1 The identification of ST-segment elevation in ≥2 contiguous leads provides information about the affected location, the need for reperfusion, and even about its prognosis. Taking into account recent disappointing results in randomized clinical trials assessing cardioprotective therapies, there is a need to find early markers that can provide valuable information to identify patients at high risk, who can actually benefit from cardioprotective therapies, as well as patients already protected who cannot benefit at all of them. Despite being used worldwide for >100 years, electrocardiography is still the cornerstone of the diagnosis of AMI and can emerge as a new test to select which patients should and should not be included in randomized clinical trials evaluating cardioprotective interventions.In the past decades, ST-segment, T-wave, and QRS changes have been incorporated into electrocardiography scoring systems to assess the severity and acuteness of ischemia. For instance, Birnbaum et al15 demonstrated that the distortion in the terminal portion of the QRS complex in admission electrocardiography in patients presenting with ST-segment–elevation myocardial infarction was associated with poor prognosis when present in ≥2 contiguous leads. More recently, this electrocardiographic pattern has been independently associated with larger myocardium at risk and infarct size in patients with anterior AMI.16 Therefore, QRS distortion might be used to select those patients with larger myocardial risk, who can greatly benefit from a cardioprotective intervention.There is currently great expectation for the outcome of the combination of 2 large ongoing randomized, controlled, clinical trials, namely, the CONDI2 (NCT01857414) and ERIC-PPCI (Effect of Remote Ischaemic Conditioning on Clinical Outcomes in ST-Segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention; NCT02342522) studies,17 which is a European endeavor (Denmark, Spain, Serbia, and United Kingdom, respectively) involving together >5300 patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention. These trials aim to evaluate the effect of perRIC on long-term clinical outcomes. These trials enroll patients at a wide range of time to reperfusion (ie, some patients are recruited and put on perRIC long before reperfusion [in the ambulance], whereas others are recruited in the cath lab soon before reperfusion). According to the results from Kleinbongard et al motivating this editorial,11 it seems imperative to design a secondary analysis of the trials in which only patients recruited in the out-of-hospital setting are analyzed. If ischemic injury reduction was the main driver of protection on perRIC, applying this intervention soon before reperfusion (ie, in the cath lab or emergency department), when ischemic damage is almost ended, would significantly reduce the infarct-limiting effects of this maneuver.AcknowledgmentsDr Rossello has received support from SEC-CNIC CARDIOJOVEN Program. Dr Ibanez holds grants related to this topic from the Spanish Ministry of Economy and Competitiveness (MINECO) through the Carlos III Institute of Health-Fondo de Investigación Sanitaria (PI16/02110) and the Fondo Europeo de Desarrolo Regional (FEDER, RD: SAF2013-49663-EXP). The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Ministry of Economy, Industry and Competitiveness (MEIC) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Borja Ibáñez, MD, PhD, Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain. E-mail [email protected]esReferences1. 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Effect of remote ischaemic conditioning on clinical outcomes in patients presenting with an ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.Eur Heart J. 2015; 36:1846–1848.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Díaz-Munoz R, Valle-Caballero M, Sanchez-Gonzalez J, Pizarro G, García-Rubira J, Escalera N, Fuster V, Fernández-Jiménez R and Ibanez B (2021) Intravenous metoprolol during ongoing STEMI ameliorates markers of ischemic injury: a METOCARD-CNIC trial electrocardiographic study, Basic Research in Cardiology, 10.1007/s00395-021-00884-6, 116:1, Online publication date: 1-Dec-2021. Mendieta G, Ben-Aicha S, Casani L, Badimon L, Sabate M and Vilahur G (2019) Molecular pathways involved in the cardioprotective effects of intravenous statin administration during ischemia, Basic Research in Cardiology, 10.1007/s00395-019-0760-z, 115:1, Online publication date: 1-Jan-2020. Heusch G (2020) Myocardial ischaemia–reperfusion injury and cardioprotection in perspective, Nature Reviews Cardiology, 10.1038/s41569-020-0403-y, 17:12, (773-789), Online publication date: 1-Dec-2020. Kleinbongard P (2020) Cardioprotection by early metoprolol- attenuation of ischemic vs. reperfusion injury?, Basic Research in Cardiology, 10.1007/s00395-020-0814-2, 115:5, Online publication date: 1-Sep-2020. Lobo-Gonzalez M, Galán-Arriola C, Rossello X, González‐Del‐Hoyo M, Vilchez J, Higuero-Verdejo M, García-Ruiz J, López-Martín G, Sánchez-González J, Oliver E, Pizarro G, Fuster V and Ibanez B (2020) Metoprolol blunts the time-dependent progression of infarct size, Basic Research in Cardiology, 10.1007/s00395-020-0812-4, 115:5, Online publication date: 1-Sep-2020. Rossello X, Lobo-Gonzalez M and Ibanez B (2019) Editor's Choice- Pathophysiology and therapy of myocardial ischaemia/reperfusion syndrome, European Heart Journal: Acute Cardiovascular Care, 10.1177/2048872619845283, 8:5, (443-456), Online publication date: 1-Aug-2019. Rossello X, Rodriguez-Sinovas A, Vilahur G, Crisóstomo V, Jorge I, Zaragoza C, Zamorano J, Bermejo J, Ordoñez A, Boscá L, Vázquez J, Badimón L, Sánchez-Margallo F, Fernández-Avilés F, Garcia-Dorado D and Ibanez B (2019) CIBER-CLAP (CIBERCV Cardioprotection Large Animal Platform): A multicenter preclinical network for testing reproducibility in cardiovascular interventions, Scientific Reports, 10.1038/s41598-019-56613-6, 9:1, Online publication date: 1-Dec-2019. Amanakis G, Kleinbongard P, Heusch G and Skyschally A (2019) Attenuation of ST-segment elevation after ischemic conditioning maneuvers reflects cardioprotection online, Basic Research in Cardiology, 10.1007/s00395-019-0732-3, 114:3, Online publication date: 1-May-2019. Naryzhnaya N, Maslov L and Oeltgen P (2019) Pharmacology of mitochondrial permeability transition pore inhibitors, Drug Development Research, 10.1002/ddr.21593, 80:8, (1013-1030), Online publication date: 1-Dec-2019. van der Weg K, Prinzen F and Gorgels A (2018) Editor's Choice- Reperfusion cardiac arrhythmias and their relation to reperfusion-induced cell death, European Heart Journal: Acute Cardiovascular Care, 10.1177/2048872618812148, 8:2, (142-152), Online publication date: 1-Mar-2019. Bøtker H, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson S, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femminò S, García-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhäuser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schlüter K, Schulz R, Skyschally A, Wilder C, Yellon D, Ferdinandy P and Heusch G (2018) Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection, Basic Research in Cardiology, 10.1007/s00395-018-0696-8, 113:5, Online publication date: 1-Sep-2018. Lobo M and Ibanez B (2018) Take a deep (nitric oxide) breath and follow the reverse translational research pathway, European Heart Journal, 10.1093/eurheartj/ehy355, 39:29, (2726-2729), Online publication date: 1-Aug-2018. Rossello X, Piñero A, Fernández-Jiménez R, Sánchez-González J, Pizarro G, Galán-Arriola C, Lobo-Gonzalez M, Vilchez J, García-Prieto J, García-Ruiz J, García-Álvarez A, Sanz-Rosa D and Ibanez B (2018) Mirabegron, a Clinically Approved β3 Adrenergic Receptor Agonist, Does Not Reduce Infarct Size in a Swine Model of Reperfused Myocardial Infarction, Journal of Cardiovascular Translational Research, 10.1007/s12265-018-9819-8, 11:4, (310-318), Online publication date: 1-Aug-2018. Chaudhry F, Isherwood J, Bawa T, Patel D, Gurdziel K, Lanfear D, Ruden D and Levy P (2019) Single-Cell RNA Sequencing of the Cardiovascular System: New Looks for Old Diseases, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2019.00173, 6 Related articlesReflection of Cardioprotection by Remote Ischemic Perconditioning in Attenuated ST-Segment Elevation During Ongoing Coronary Occlusion in PigsPetra Kleinbongard, et al. Circulation Research. 2018;122:1102-1108 April 13, 2018Vol 122, Issue 8 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.118.312939PMID: 29650626 Originally publishedAugust 6, 2018 KeywordsEditorialsischemiaischemic preconditioningmyocardiumreperfusion injuryPDF download Advertisement
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