Cardioprotection
2016; Lippincott Williams & Wilkins; Volume: 134; Issue: 8 Linguagem: Inglês
10.1161/circulationaha.116.022829
ISSN1524-4539
AutoresXavier Rosselló, Derek M. Yellon,
Tópico(s)Acute Myocardial Infarction Research
ResumoHomeCirculationVol. 134, No. 8Cardioprotection Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCardioprotectionThe Disconnect Between Bench and Bedside Xavier Rossello, MD and Derek M. Yellon, PhD, DSc, FRCP Xavier RosselloXavier Rossello From Hatter Cardiovascular Institute, University College London, London, UK (X.R., D.M.Y.); and NIHR UCLH Biomedical Research Centre, University College London Hospital, London, UK (D.M.Y.). and Derek M. YellonDerek M. Yellon From Hatter Cardiovascular Institute, University College London, London, UK (X.R., D.M.Y.); and NIHR UCLH Biomedical Research Centre, University College London Hospital, London, UK (D.M.Y.). Originally published23 Aug 2016https://doi.org/10.1161/CIRCULATIONAHA.116.022829Circulation. 2016;134:574–575IntroductionEarly reperfusion by primary percutaneous intervention in patients with ST-segment–elevation myocardial infarction limits infarct size and preserves left ventricular systolic function, thereby improving prognosis. Despite this process of restoring blood flow to salvage the myocardium, further myocardial damage can occur as a consequence of reperfusion. This is known as myocardial ischemia/reperfusion injury (IRI).Many cardioprotective therapies aimed at reducing IRI have been successfully examined in the preclinical setting. Despite attenuating IRI at the bench, not all have subsequently demonstrated a reduction in infarct size at the bedside, and none have demonstrated clinical benefits.The failure to translate cardioprotective therapies into the clinical setting can be attributed to many factors, from inadequate animal models of infarction to poor clinical study designs. Overall, it seems that hopes are fading that any cardioprotective intervention will ever materialize. However, after thoroughly dissecting the issues, we have come to a relevant diagnosis that we call a disconnection paradigm. This condition refers to the complete disconnect between preclinical and clinical studies in cardioprotection.ST-segment–elevation myocardial infarction is linked to multiple cardiovascular risk factors and comorbidities, and it is intensively treated both short and long term. These concomitant comorbidities and medications induce alterations in myocardial cellular signaling cascades, thereby affecting both the sensitivity to IRI and the response to any cardioprotective intervention. Many examples can illustrate the problem with comorbidities.1 Diabetes mellitus makes the heart more susceptible to IRI and makes conditioning therapies less effective, and aging changes both the pharmacokinetics and pharmacodynamics of cardiovascular drugs and affects the susceptibility to be protected. There has been only a mild response to address this issue, using old and diabetic animals.2 Less attention has been paid to concomitant medications despite the fact that most patients with ST-segment–elevation myocardial infarction receive immediate treatment with aspirin, P2Y12 inhibitors, statins, opioids, β-blockers, and anticoagulation agents (according to the management guidelines3), with many of the above being shown to have a cardioprotective effect.Despite this complex clinical picture, it is surprising how all these factors are systematically ignored in the preclinical setting, where concomitant medications are never assessed. This disconnection between preclinical study designs and clinical reality may justify our failure to translate cardioprotective therapies into clinical practice.As a treatment for this disconnect disorder, we propose a counterintuitive step: Cardioprotection needs to go backward before it can move forward. There is a need to fill this translational gap between bench reductionist models and the increasingly complex reality. We suggest adding an extra step in our current translational approach to approximate bench conditions to the clinical setting (Figure). Currently, placebo-controlled clinical trials test interventions on a background of guideline-recommended therapies that include current standard of care. Why not follow the same example in the laboratory?Download figureDownload PowerPointFigure. A sequential approach to translational studies in cardioprotection. 1, The initial reductionist view gives major insight into mechanisms. 2, More clinically relevant animal studies provide less mechanistic insight and some translational value. 3, Proof-of-concept studies provide limited mechanistic insight but some translational value. 4, Clinical outcomes studies provide no mechanistic value but significant translational importance.Models in young and healthy animals are good for generating hypotheses, identifying mechanistic pathways, and acting as a general screening for cardioprotection, although their conclusions may not be extrapolated in the context of concomitant comorbidities and medications, which are ultimately unavoidable barriers. It is time to go beyond and establish a second step in the research process using animal models on a background of these factors, considering either patient comorbidities or clinical interventions, or even both simultaneously, before going ahead to costly clinical trials.According to work by Downey's group reported by Yang et al,4 an increasing body of evidence confers P2Y12 receptor inhibitors cardioprotective properties independently of their antithrombotic actions. Whereas neither ischemic preconditioning nor postconditioning has been shown to add further protection when applied in the context of a P2Y12 inhibitor,5 the combination of 2 other strategies (hypothermia and cariporide) with P2Y12 inhibitors magnified the degree of protection,4 suggesting that there is room not only for incremental protection but also for further translation.The above discussion tackles only half the issue, that is, the basic science component. It could equally be argued that clinicians need to establish appropriate selection criteria in their trials to optimize the ability to investigate cardioprotective procedures. While clinicians are addressing this point, we encourage all translational researchers in this field to reflect on using models that more closely resemble the clinical setting, applying concomitantly the contemporary state-of-the-art therapy to obtain solid results before further clinical study attempts.Sources of FundingThis work was supported by a proportion of funding from the Department of Health's NIHR Biomedical Research Centre's funding scheme, for which Dr Yellon is a senior investigator. Dr Rossello has received support from the Fundacion Alfonso Martin Escudero fellowship grant.DisclosuresNone.FootnotesCirculation is available at http://circ.ahajournals.org.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Derek M. Yellon, PhD, DSc, FRCP, Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX 2, UK. E-mail [email protected]References1. Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning.Pharmacol Rev. 2007; 59:418–458. doi: 10.1124/pr.107.06002.CrossrefMedlineGoogle Scholar2. Whittington HJ, Harding I, Stephenson CI, Bell R, Hausenloy DJ, Mocanu MM, Yellon DM. Cardioprotection in the aging, diabetic heart: the loss of protective Akt signalling.Cardiovasc Res. 2013; 99:694–704. doi: 10.1093/cvr/cvt140.CrossrefMedlineGoogle Scholar3. O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.Circulation. 2013; 127:e362–e425. doi: 10.1161/CIR.0b013e3182742cf6.LinkGoogle Scholar4. Yang XM, Cui L, Alhammouri A, Downey JM, Cohen MV. Triple therapy greatly increases myocardial salvage during ischemia/reperfusion in the in situ rat heart.Cardiovasc Drugs Ther. 2013; 27:403–412. doi: 10.1007/s10557-013-6474-9.CrossrefMedlineGoogle Scholar5. Yang XM, Liu Y, Cui L, Yang X, Liu Y, Tandon N, Kambayashi J, Downey JM, Cohen MV. Platelet P2Y12 blockers confer direct postconditioning-like protection in reperfused rabbit hearts.J Cardiovasc Pharmacol Ther. 2013; 18:251–262. doi: 10.1177/1074248412467692.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Cho Y, Jung D, Nam K, Bae J, Lee S and Jeon Y (2022) Effects of transcutaneous electrical nerve stimulation on myocardial protection in patients undergoing aortic valve replacement: a randomized clinical trial, BMC Anesthesiology, 10.1186/s12871-022-01611-x, 22:1, Online publication date: 1-Dec-2022. Xu C, Liu Y, Yang J, Zhai M, Fan Z, Qiao R, Jin P and Yang L (2022) Effects of berbamine against myocardial ischemia/reperfusion injury: Activation of the 5' adenosine monophosphate‐activated protein kinase/nuclear factor erythroid 2‐related factor pathway and changes in the mitochondrial state , BioFactors, 10.1002/biof.1820, 48:3, (651-664), Online publication date: 1-May-2022. Ye R, Jneid H, Alam M, Uretsky B, Atar D, Kitakaze M, Davidson S, Yellon D and Birnbaum Y (2022) Do We Really Need Aspirin Loading for STEMI?, Cardiovascular Drugs and Therapy, 10.1007/s10557-022-07327-x Francis R, Chong J, Ramlall M, Bucciarelli-Ducci C, Clayton T, Dodd M, Engstrøm T, Evans R, Ferreira V, Fontana M, Greenwood J, Kharbanda R, Kim W, Kotecha T, Lønborg J, Mathur A, Møller U, Moon J, Perkins A, Rakhit R, Yellon D, Bøtker H, Bulluck H and Hausenloy D (2021) Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy, Basic Research in Cardiology, 10.1007/s00395-021-00896-2, 116:1, Online publication date: 1-Dec-2021. Díaz-Vesga M, Zúñiga-Cuevas Ú, Ramírez-Reyes A, Herrera-Zelada N, Palomo I, Bravo-Sagua R and Riquelme J (2021) Potential Therapies to Protect the Aging Heart Against Ischemia/Reperfusion Injury, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2021.770421, 8 Nernpermpisooth N, Sarre C, Barrere C, Contreras R, Luz-Crawford P, Tejedor G, Vincent A, Piot C, Kumphune S, Nargeot J, Jorgensen C, Barrère-Lemaire S and Djouad F (2021) PPARβ/δ Is Required for Mesenchymal Stem Cell Cardioprotective Effects Independently of Their Anti-inflammatory Properties in Myocardial Ischemia-Reperfusion Injury, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2021.681002, 8 Hansen L, Nielsen N, Christoffersen L and Kruuse C (2021) Translational challenges of remote ischemic conditioning in ischemic stroke – a systematic review, Annals of Clinical and Translational Neurology, 10.1002/acn3.51405, 8:8, (1720-1729), Online publication date: 1-Aug-2021. Kuka J, Makrecka-Kuka M, Vilks K, Korzh S, Cirule H, Sevostjanovs E, Grinberga S, Dambrova M, Liepinsh E and Santulli G (2021) Inhibition of Fatty Acid Metabolism Increases EPA and DHA Levels and Protects against Myocardial Ischaemia-Reperfusion Injury in Zucker Rats, Oxidative Medicine and Cellular Longevity, 10.1155/2021/7493190, 2021, (1-13), Online publication date: 28-Jul-2021. Xu C, Wang J, Fan Z, Zhang S, Qiao R, Liu Y, Yang J, Yang L and Wang H (2021) Cardioprotective effects of melatonin against myocardial ischaemia/reperfusion injury: Activation of AMPK/Nrf2 pathway, Journal of Cellular and Molecular Medicine, 10.1111/jcmm.16691, 25:13, (6455-6459), Online publication date: 1-Jul-2021. Lourbopoulos A, Mourouzis I, Xinaris C, Zerva N, Filippakis K, Pavlopoulos A and Pantos C (2021) Translational Block in Stroke: A Constructive and "Out-of-the-Box" Reappraisal, Frontiers in Neuroscience, 10.3389/fnins.2021.652403, 15 Herrera-Zelada N, Zuñiga-Cuevas U, Ramirez-Reyes A, Lavandero S and Riquelme J (2021) Targeting the Endothelium to Achieve Cardioprotection, Frontiers in Pharmacology, 10.3389/fphar.2021.636134, 12 He Z, Davidson S and Yellon D (2020) The importance of clinically relevant background therapy in cardioprotective studies, Basic Research in Cardiology, 10.1007/s00395-020-00830-y, 115:6, Online publication date: 1-Dec-2020. Golforoush P, Yellon D and Davidson S (2020) Mouse models of atherosclerosis and their suitability for the study of myocardial infarction, Basic Research in Cardiology, 10.1007/s00395-020-00829-5, 115:6, Online publication date: 1-Dec-2020. Li J, Zhang W, Yao H and Li T (2020) Therapeutic effects of interleukin-37 and induced cardiosphere on treating myocardial ischemia-reperfusion injury, International Immunopharmacology, 10.1016/j.intimp.2020.106719, 88, (106719), Online publication date: 1-Nov-2020. Rusiecka O, Montgomery J, Morel S, Batista-Almeida D, Van Campenhout R, Vinken M, Girao H and Kwak B (2020) Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection, Biomolecules, 10.3390/biom10091225, 10:9, (1225) Balbi C, Costa A, Barile L and Bollini S (2020) Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation, Cells, 10.3390/cells9030724, 9:3, (724) Dai S, Wu Q, Zhu R, Wan X and Zhou X (2020) Notch1 protects against myocardial ischaemia‐reperfusion injury via regulating mitochondrial fusion and function, Journal of Cellular and Molecular Medicine, 10.1111/jcmm.14992, 24:5, (3183-3191), Online publication date: 1-Mar-2020. Hou F, Geng Q, Zhang F and Li Y (2020) Protective effects of induced cardiosphere on myocardial ischemia-reperfusion injury through secreting interleukin 10, International Immunopharmacology, 10.1016/j.intimp.2020.106207, 80, (106207), Online publication date: 1-Mar-2020. 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 Zhu P, Tong Q, Zhuang Z, Wang Z, Deng L, Zheng G and Wang Y (2019) Ginkgolide B for Myocardial Ischemia/Reperfusion Injury: A Preclinical Systematic Review and Meta-Analysis, Frontiers in Physiology, 10.3389/fphys.2019.01292, 10 Baehr A, Klymiuk N and Kupatt C (2019) Evaluating Novel Targets of Ischemia Reperfusion Injury in Pig Models, International Journal of Molecular Sciences, 10.3390/ijms20194749, 20:19, (4749) 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. Chen T and Vunjak-Novakovic G (2019) Human Tissue-Engineered Model of Myocardial Ischemia–Reperfusion Injury, Tissue Engineering Part A, 10.1089/ten.tea.2018.0212, 25:9-10, (711-724), Online publication date: 1-May-2019. Davidson S, Arjun S, Basalay M, Bell R, Bromage D, Bøtker H, Carr R, Cunningham J, Ghosh A, Heusch G, Ibanez B, Kleinbongard P, Lecour S, Maddock H, Ovize M, Walker M, Wiart M and Yellon D (2018) The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology, Basic Research in Cardiology, 10.1007/s00395-018-0704-z, 113:6, Online publication date: 1-Nov-2018. Mendoza-Torres E, Riquelme J, Vielma A, Sagredo A, Gabrielli L, Bravo-Sagua R, Jalil J, Rothermel B, Sanchez G, Ocaranza M and Lavandero S (2018) Protection of the myocardium against ischemia/reperfusion injury by angiotensin-(1–9) through an AT2R and Akt-dependent mechanism, Pharmacological Research, 10.1016/j.phrs.2018.07.022, 135, (112-121), Online publication date: 1-Sep-2018. Chen T and Vunjak-Novakovic G (2018) In Vitro Models of Ischemia-Reperfusion Injury, Regenerative Engineering and Translational Medicine, 10.1007/s40883-018-0056-0, 4:3, (142-153), Online publication date: 1-Sep-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. Rossello X, He Z and Yellon D (2018) Myocardial Infarct Size Reduction Provided by Local and Remote Ischaemic Preconditioning: References Values from the Hatter Cardiovascular Institute, Cardiovascular Drugs and Therapy, 10.1007/s10557-018-6788-8, 32:2, (127-133), Online publication date: 1-Apr-2018. Minamino T, Higo S, Araki R, Hikoso S, Nakatani D, Suzuki H, Yamada T, Okutsu M, Yamamoto K, Fujio Y, Ishida Y, Ozawa T, Kato K, Toba K, Aizawa Y and Komuro I (2018) Low-Dose Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction (EPO-AMI-II) ― A Randomized Controlled Clinical Trial ―, Circulation Journal, 10.1253/circj.CJ-17-0889, 82:4, (1083-1091), . Vincent A, Covinhes A, Barrère C, Gallot L, Thoumala S, Piot C, Heurteaux C, Lazdunski M, Nargeot J and Barrère-Lemaire S (2017) Acute and long-term cardioprotective effects of the Traditional Chinese Medicine MLC901 against myocardial ischemia-reperfusion injury in mice, Scientific Reports, 10.1038/s41598-017-14822-x, 7:1, Online publication date: 1-Dec-2017. Singh R, Cummings E, Pantos C and Singh J (2017) Protein kinase C and cardiac dysfunction: a review, Heart Failure Reviews, 10.1007/s10741-017-9634-3, 22:6, (843-859), Online publication date: 1-Nov-2017. Rossello X, Riquelme J, He Z, Taferner S, Vanhaesebroeck B, Davidson S and Yellon D (2017) The role of PI3Kα isoform in cardioprotection, Basic Research in Cardiology, 10.1007/s00395-017-0657-7, 112:6, Online publication date: 1-Nov-2017. Feyzizadeh S and Badalzadeh R (2017) Application of ischemic postconditioning's algorithms in tissues protection: response to methodological gaps in preclinical and clinical studies, Journal of Cellular and Molecular Medicine, 10.1111/jcmm.13159, 21:10, (2257-2267), Online publication date: 1-Oct-2017. McLeod S, Iansavichene A and Cheskes S (2017) Remote Ischemic Perconditioning to Reduce Reperfusion Injury During Acute ST‐Segment–Elevation Myocardial Infarction: A Systematic Review and Meta‐Analysis, Journal of the American Heart Association, 6:5, Online publication date: 5-May-2017. Ndrepepa G, Colleran R and Kastrati A (2017) Reperfusion injury in ST-segment elevation myocardial infarction, Coronary Artery Disease, 10.1097/MCA.0000000000000468, 28:3, (253-262), Online publication date: 1-May-2017. Heusch G (2017) Critical Issues for the Translation of Cardioprotection, Circulation Research, 120:9, (1477-1486), Online publication date: 28-Apr-2017.Traverse J (2016) The Misguided Regulation of Cardiac Emergencies, Circulation Research, 119:10, (1063-1066), Online publication date: 28-Oct-2016. August 23, 2016Vol 134, Issue 8 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.022829PMID: 27550967 Originally publishedAugust 23, 2016 Keywordsmyocardial infarctionmyocardial reperfusion injurycytoprotectionPDF download Advertisement SubjectsAnimal Models of Human DiseaseBasic Science ResearchIschemia
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