CAESAR
2015; Lippincott Williams & Wilkins; Volume: 116; Issue: 4 Linguagem: Espanhol
10.1161/circresaha.115.305841
ISSN1524-4571
AutoresRodrigo Fernández‐Jiménez, Borja Ibáñez,
Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoHomeCirculation ResearchVol. 116, No. 4CAESAR Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCAESAROne Step Beyond in the Construction of a Translational Bridge for Cardioprotection Rodrigo Fernández-Jiménez and Borja Ibanez Rodrigo Fernández-JiménezRodrigo Fernández-Jiménez From the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (R.F.-J., B.I.); and Hospital Universitario Clínico San Carlos, Madrid, Spain (R.F.-J., B.I.). and Borja IbanezBorja Ibanez From the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (R.F.-J., B.I.); and Hospital Universitario Clínico San Carlos, Madrid, Spain (R.F.-J., B.I.). Originally published13 Feb 2015https://doi.org/10.1161/CIRCRESAHA.115.305841Circulation Research. 2015;116:554–556Timely reperfusion is known as the best therapeutic strategy for limiting the extent of myocardial damage during an ST-segment–elevation myocardial infarction (STEMI).1,2 The concept of reperfusion as a means to limit necrosis during an STEMI was established in an experimental large animal (dog) model 4 decades ago.3,4 Noteworthy, the translation of the reperfusion concept in STEMI is one of the most successful stories of therapies ever. This example highlights the critical relevance of using preclinical models similar to humans for efficient translational research. Further research in the field identified that reperfusion is not a free lunch, and it can come at the price of inducing additional damage to the myocardium, a phenomenon known as reperfusion injury.5 The final extent of myocardial necrosis after a STEMI, resulting from both ischemic and reperfusion injuries, is a major determinant of mortality and morbidity after infarction.6 Therefore, huge efforts have been dedicated for exploring cardioprotective therapies that might limit ischemia/reperfusion injury beyond timely reperfusion. Opposed to what occurred with the reperfusion concept, the translation of therapies aiming to ameliorate reperfusion injury has been more disappointing than the former. With the exception of a few therapies succeeding in translating experimental results into positive proof of concept clinical trials demonstrating reduction in infarct size and increase in myocardial salvage,7–11 most promising cardioprotectives agents/interventions have failed to replicate the positive results in experimental models in the clinical arena over the last decades.8,12 It is important to note that failure in translation is not restricted to the cardioprotection field, and similar frustrating findings have been observed in other areas.13,14Article, see p 572What are the reasons responsible for this loss in translation? Inadequate experimental data and overoptimistic erroneous conclusions resulting from methodological flaws in animal studies might be one of the main reasons accounting for this scientific inconsistency.15 Like in any formal clinical trial, animal studies testing the efficacy of a given (cardioprotective) therapy/intervention should be based on a well-designed prespecified protocol paying rigorous attention to design (including expected effect size), conduct, statistical, and reporting-style aspects. Unfortunately, critical methodological elements such as blinding, randomization, or a priori sample size calculation are too frequently neglected in the experimental setting, increasing the chances of biased and hyped positive results.16 In the case of cardioprotective therapies, specific aspects directly related to the ultimate myocardial damage, such as animal species, strain differences, anesthetic agents, duration of ischemia, drug administration, manner and duration of reperfusion, and methodology and timing of end point (myocardial damage/salvage) evaluation,17–19 may be decisive in the outcome of the study as well. Having all these variables as potential sources of variability, it is not so surprising that the replication and reproducibility of experimental results among different laboratories are alarmingly low.20 Several Working Groups of experts have deeply discussed the reasons for the failure to effectively translate potential therapies for protecting the heart from ischemia/reperfusion, making recommendations to try solving this unmet research need.17,19,21 The US initiative further included the creation of a national network of research laboratories with expertise in small and large animal models of ischemia/reperfusion injury to systematically test a particular cardioprotective therapy using a multicenter randomized controlled study approach as a checkpoint before jumping into the clinical setting: the CAESAR (Consortium for preclinicAl assESsment of cARdioprotective therapies) Cardioprotection Consortium22 (http://www.nihcaesar.org/). Recently, the European Society of Cardiology Group in Cellular Biology of the Heart have proposed the establishment of a European network of research centers to test cardioprotective interventions17 in an attempt to mimic the pioneer endeavor of the CAESAR's enterprise.Two highly relevant papers on the topic of translating preclinical results into clinics in the field of cardioprotection during STEMI appear in this issue of the Journal. Jones et al23 report the initial validation of the CAESAR initiative by testing the protection afforded by preconditioning, and Prof Heusch24 presents an outstanding comprehensive review of the mechanisms and signal transduction pathways in ischemic conditioning. The landmark CAESAR validation23 is based on the principles of detailed conduct of experimental protocols, randomization, researcher blinding, a priori sample size calculation and exclusion criteria, appropriate statistical analyses, and assessment of reproducibility. For such proof of concept validation, authors decided to test ischemic (local) preconditioning as the intervention to reduce infarct size in 3 species (mouse, rabbit, and pig) at 3 different centers of the consortium (2 sites/species). Authors wisely chose ischemic preconditioning as a protective intervention because it is probably the most robust and reproducible cardioprotective intervention known to date. The mechanisms of protection during ischemic preconditioning are extensively presented in the review paper appearing in the same issue of the journal.24The CAESAR authors and institutions involved in this work should be congratulated for their innovative and huge effort to achieve a rigorous experimental setting. Overall, this approach should result in a reduction of potential biases and consequently in an increase in the confidence of attributing the differences observed between groups of animals allocated to different interventions to the treatment under investigation rather than to confounding factors or to just random error. However, there are potential shortcomings in the implementation and universalization of the CAESAR methodology. Counterintuitively, the excessive protocol standardization to reduce data variance can come at a negative price in some cases. It has been postulated that highly environmental standardized conditions may reveal restricted conclusions to a concrete experimental setting with little external validity being a cause, rather than a cure, of poor study reproducibility25 something that has been previously referred to as the standardization fallacy.26 External validity of experimental studies can be also affected by inevitable species differences. Therefore, even with rigorous design and conduct of an experimental study, such as the one elegantly presented by CAESAR, the translation of animal results to the clinics may fail because of disparities between the model and the real-world patient. CAESAR tries to overcome this limitation by using >1 laboratory for each species, but in the end 2 laboratories closely associated and following the exact same methodology are virtually a single hyperspecialized unit. The adding of more laboratories, eventually using slight different approaches (eg, different strain of animals, different anesthetics, different methods for outcome assessment, etc.), can serve to further improve the salutary long-term benefits of CAESAR.Even the best animal models are approximations to human physiology/pathophysiology, and it is fair to acknowledge that in most cases they are only partially resembling what is seen in a more complex human diseased system. As an example, aging and multiple comorbid conditions seen in patients included in regular clinical trials are barely present in the experimental setting. Obviously, the intrinsic limitations inherent to animal models do not invalidate the use of laboratory research. We are convinced that animal models are useful tools in biomedical research, but a call for rigor in experimental investigation as presented by CAESAR initiative is necessary to improve translation. In this regard, it is noteworthy that in the paper by Jones et al,23 there seems to be a species-related effect size gradient: infarct size reduction by the applied preconditioning intervention was largest in mice, intermediate in rabbits, and smallest in pigs. This anecdotic findings highlight that the extrapolation of animal results into clinics highly depends on the species evaluated.Another relevant aspect close to the topic here discussed is the positive results publication bias. The report of negative preclinical studies is an extremely hard endeavor, and many times animal studies yielding neutral results are never reported. CAESAR is certainly an endeavor of such relevance that a room for the report of negative preclinical studies should be identified. In this regard, it is noteworthy that Jones et al23 acknowledge in their paper that 2 other agents have been tested by CAESAR, sodium nitrite and sildenafil citrate, and both failed to limit infarct size despite prior experimental studies reporting beneficial effects with these therapies. The best venue for reporting these negative findings in CAESAR is to be decided by the implicated institutions.What is the ultimate translational relevance of the CAESAR initiative? This enterprise will certainly help in the better identification of therapies/interventions with chances to be tested in pilot clinical trials. Early identification of therapies with no (or limited) benefits will be of massive help for the scientific and pharmaceutical communities. The personal and economical costs associated with clinical trials is humongous and the proper early identification of potential failures is capital. There are some interventions that have already shown positive results in pilot clinical trials (for more details, we refer to the accompanying review paper by G. Heusch24). It is noteworthy that these positive experiences were always preceded by thorough preclinical studies.9,11,27Emulating Julius Caesar and his legionaries, who built the first 2 bridges across the Rhine River to defeat Germanic tribes during the Gallic War in 53 BC, the CAESAR initiative23 has built a new bridge that will help the translation expansion in the field of cardioprotection during STEMI.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Borja Ibanez, MD, PhD, Myocardial Pathophysiology Program, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain. E-mail [email protected]References1. Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC)Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation.Eur Heart J. 2012; 33:2569–2619.CrossrefMedlineGoogle Scholar2. American College of Emergency Physicians; Society for Cardiovascular Angiography and InterventionsO'Gara PT, Kushner FG, Ascheim DD, et al. 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.J Am Coll Cardiol. 2013; 61:e78–e140.CrossrefMedlineGoogle Scholar3. Maroko PR, Libby P, Ginks WR, Bloor CM, Shell WE, Sobel BE, Ross J. Coronary artery reperfusion. I. Early effects on local myocardial function and the extent of myocardial necrosis.J Clin Invest. 1972; 51:2710–2716. doi: 10.1172/JCI107090.CrossrefMedlineGoogle Scholar4. Ginks WR, Sybers HD, Maroko PR, Covell JW, Sobel BE, Ross J. Coronary artery reperfusion. II. Reduction of myocardial infarct size at 1 week after the coronary occlusion.J Clin Invest. 1972; 51:2717–2723. doi: 10.1172/JCI107091.CrossrefMedlineGoogle Scholar5. Ibanez B, Fuster V, Jiménez-Borreguero J, Badimon JJ. Lethal myocardial reperfusion injury: a necessary evil?Int J Cardiol. 2011; 151:3–11. doi: 10.1016/j.ijcard.2010.10.056.CrossrefMedlineGoogle Scholar6. Larose E, Rodes-Cabau J, Pibarot P, et al. Predicting late myocardial recovery and outcomes in the early hours of ST-segment elevation myocardial infarction traditional measures compared with microvascular obstruction, salvaged myocardium, and necrosis characteristics by cardiovascular magnetic resonance.J Am Coll Cardiol. 2010; 55:2459–2469.MedlineGoogle Scholar7. Bøtker HE, Kharbanda R, Schmidt MR, 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. 2010; 375:727–734. doi: 10.1016/S0140-6736(09)62001-8.CrossrefMedlineGoogle Scholar8. Heusch G. Cardioprotection: chances and challenges of its translation to the clinic.Lancet. 2013; 381:166–175. doi: 10.1016/S0140-6736(12)60916-7.CrossrefMedlineGoogle Scholar9. Ibanez B, Macaya C, Sanchez-Brunete V, 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. 2013; 128:1495–1503.LinkGoogle Scholar10. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction.N Engl J Med. 2008; 359:473–481.CrossrefMedlineGoogle Scholar11. Pizarro G, Fernandez-Friera L, Fuster V, et al. Long-term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: results from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction).J Am Coll Cardiol. 2014; 63:2356–2362.CrossrefMedlineGoogle Scholar12. Vander Heide RS, Steenbergen C. Cardioprotection and myocardial reperfusion: pitfalls to clinical application.Circ Res. 2013; 113:464–477. doi: 10.1161/CIRCRESAHA.113.300765.LinkGoogle Scholar13. Franco R, Cedazo-Minguez A. Successful therapies for Alzheimer's disease: why so many in animal models and none in humans?Front Pharmacol. 2014; 5:146. doi: 10.3389/fphar.2014.00146.CrossrefMedlineGoogle Scholar14. Sena E, van der Worp HB, Howells D, Macleod M. How can we improve the pre-clinical development of drugs for stroke?Trends Neurosci. 2007; 30:433–439. doi: 10.1016/j.tins.2007.06.009.CrossrefMedlineGoogle Scholar15. van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O'Collins V, Macleod MR. Can animal models of disease reliably inform human studies?PLoS Med. 2010; 7:e1000245. doi: 10.1371/journal.pmed.1000245.CrossrefMedlineGoogle Scholar16. Bebarta V, Luyten D, Heard K. Emergency medicine animal research: does use of randomization and blinding affect the results?Acad Emerg Med. 2003; 10:684–687.CrossrefMedlineGoogle Scholar17. Lecour S, Botker HE, Condorelli G, et al. ESC working group cellular biology of the heart: position paper: improving the preclinical assessment of novel cardioprotective therapies.Cardiovasc Res. 2014; 104:399–411.CrossrefMedlineGoogle Scholar18. Fernandez-Jimenez R, Sanchez-Gonzalez J, Aguero J, et al. Myocardial edema after ischemia/reperfusion is not stable and follows a bimodal pattern: advanced imaging and histological tissue characterization.J Am Coll Cardiol. 2015; 65:315–323doi: 10.1016/j.jacc.2014.11.004.CrossrefMedlineGoogle Scholar19. Bolli R, Becker L, Gross G, Mentzer R, Balshaw D, Lathrop DA; NHLBI Working Group on the Translation of Therapies for Protecting the Heart from Ischemia. Myocardial protection at a crossroads: the need for translation into clinical therapy.Circ Res. 2004; 95:125–134. doi: 10.1161/01.RES.0000137171.97172.d7.LinkGoogle Scholar20. Collins FS, Tabak LA. Policy: NIH plans to enhance reproducibility.Nature. 2014; 505:612–613.CrossrefMedlineGoogle Scholar21. Hausenloy DJ, Baxter G, Bell R, et al. Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations.Basic Res Cardiol. 2010; 105:677–686. doi: 10.1007/s00395-010-0121-4.CrossrefMedlineGoogle Scholar22. Schwartz Longacre L, Kloner RA, Arai AE, et al; National Heart, Lung, and Blood Institute, National Institutes of Health. New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute Workshop.Circulation. 2011; 124:1172–1179.LinkGoogle Scholar23. Jones SP, Tang XL, Guo Y, et al. The NHLBI-Sponsored Consortium for preclinicAl assESsment of cARdioprotective Therapies (CAESAR): a new paradigm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs.Cir Res. 2015; 116:572–586. doi: 10.1161/CIRCRESAHA.116.305462.LinkGoogle Scholar24. Heusch G. The molecular basis of cardioprotection: signal 5 transduction in ischemic pre-, post- and remote conditioning.Cir Res. 2015; 116:587–599.LinkGoogle Scholar25. Richter SH, Garner JP, Würbel H. Environmental standardization: cure or cause of poor reproducibility in animal experiments?Nat Methods. 2009; 6:257–261. doi: 10.1038/nmeth.1312.CrossrefMedlineGoogle Scholar26. Würbel H. Behaviour and the standardization fallacy.Nat Genet. 2000; 26:263. doi: 10.1038/81541.CrossrefMedlineGoogle Scholar27. Ibanez B, Prat-González S, Speidl WS, Vilahur G, Pinero A, Cimmino G, García MJ, Fuster V, Sanz J, Badimon JJ. Early metoprolol administration before coronary reperfusion results in increased myocardial salvage: analysis of ischemic myocardium at risk using cardiac magnetic resonance.Circulation. 2007; 115:2909–2916. doi: 10.1161/CIRCULATIONAHA.106.679639.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Zhang J, Hu Y, Wang H, Hou J, Xiao W, Wen X, Wang T, Long P, Jiang H, Wang Z, Liu H and Chen X (2022) Advances in research on the protective mechanisms of traditional Chinese medicine (TCM) in myocardial ischaemia-reperfusion injury, Pharmaceutical Biology, 10.1080/13880209.2022.2063342, 60:1, (931-948), Online publication date: 31-Dec-2022. Ma H, Hao J, Liu H, Yin J, Qiang M, Liu M, He S, Zeng D, Liu X, Lian C and Gao Y (2021) Peoniflorin Preconditioning Protects Against Myocardial Ischemia/Reperfusion Injury Through Inhibiting Myocardial Apoptosis: RISK Pathway Involved, Applied Biochemistry and Biotechnology, 10.1007/s12010-021-03680-z, 194:3, (1149-1165), Online publication date: 1-Mar-2022. 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, 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. Elgebaly S, Poston R, Todd R, Helmy T, Almaghraby A, Elbayoumi T and Kreutzer D (2019) Cyclocreatine protects against ischemic injury and enhances cardiac recovery during early reperfusion, Expert Review of Cardiovascular Therapy, 10.1080/14779072.2019.1662722, 17:9, (683-697), Online publication date: 2-Sep-2019. Maximilian Buja L (2017) Mitochondria in Ischemic Heart Disease Mitochondrial Dynamics in Cardiovascular Medicine, 10.1007/978-3-319-55330-6_7, (127-140), . García-Ruiz J, Fernández-Jiménez R, García-Alvarez A, Pizarro G, Galán-Arriola C, Fernández-Friera L, Mateos A, Nuno-Ayala M, Aguero J, Sánchez-González J, García-Prieto J, López-Melgar B, Martínez-Tenorio P, López-Martín G, Macías A, Pérez-Asenjo B, Cabrera J, Fernández-Ortiz A, Fuster V and Ibáñez B (2016) Impact of the Timing of Metoprolol Administration During STEMI on Infarct Size and Ventricular Function, Journal of the American College of Cardiology, 10.1016/j.jacc.2016.02.050, 67:18, (2093-2104), Online publication date: 1-May-2016. Ibáñez B, Heusch G, Ovize M and Van de Werf F (2015) Evolving Therapies for Myocardial Ischemia/Reperfusion Injury, Journal of the American College of Cardiology, 10.1016/j.jacc.2015.02.032, 65:14, (1454-1471), Online publication date: 1-Apr-2015. February 13, 2015Vol 116, Issue 4 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.115.305841PMID: 25677511 Originally publishedFebruary 13, 2015 KeywordsinfarctionEditorialsreproducibility of resultsreperfusionischemic preconditioningrandom allocationanimal experimentationPDF download Advertisement SubjectsAnimal Models of Human Disease
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