Cardioprotective efficacy of limb remote ischaemic preconditioning in rats: discrepancy between a meta-analysis and a three-centre in vivo study

Abstract Aims Remote ischaemic preconditioning (RIPC) is a robust cardioprotective intervention in preclinical studies. To establish a working and efficacious RIPC protocol in our laboratories, we performed randomized, blinded in vivo studies in three study centres in rats, with various RIPC protoco...

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Published in:	Cardiovascular research Vol. 119; no. 6; pp. 1336 - 1351
Main Authors:	Sayour, Nabil V, Brenner, Gábor B, Makkos, András, Kiss, Bernadett, Kovácsházi, Csenger, Gergely, Tamás G, Aukrust, Sverre Groever, Tian, Huimin, Zenkl, Viktória, Gömöri, Kamilla, Szabados, Tamara, Bencsik, Péter, Heinen, Andre, Schulz, Rainer, Baxter, Gary F, Zuurbier, Coert J, Vokó, Zoltán, Ferdinandy, Péter, Giricz, Zoltán
Format:	Journal Article
Language:	English
Published:	US Oxford University Press 13-06-2023
Subjects:	Animals Ischemic Preconditioning - methods Male Myocardial Reperfusion Injury - prevention & control Original Rats Rats, Wistar Reproducibility of Results Limb remote ischaemic preconditioning Systematic review Myocardial ischaemia/reperfusion injury Three-centre study Meta-analysis
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Summary:	Abstract Aims Remote ischaemic preconditioning (RIPC) is a robust cardioprotective intervention in preclinical studies. To establish a working and efficacious RIPC protocol in our laboratories, we performed randomized, blinded in vivo studies in three study centres in rats, with various RIPC protocols. To verify that our experimental settings are in good alignment with in vivo rat studies showing cardioprotection by limb RIPC, we performed a systematic review and meta-analysis. In addition, we investigated the importance of different study parameters. Methods and results Male Wistar rats were subjected to 20–45 min cardiac ischaemia followed by 120 min reperfusion with or without preceding RIPC by 3 or 4 × 5−5 min occlusion/reperfusion of one or two femoral vessels by clamping, tourniquet, or pressure cuff. RIPC did not reduce infarct size (IS), microvascular obstruction, or arrhythmias at any study centres. Systematic review and meta-analysis focusing on in vivo rat models of myocardial ischaemia/reperfusion injury with limb RIPC showed that RIPC reduces IS by 21.28% on average. In addition, the systematic review showed methodological heterogeneity and insufficient reporting of study parameters in a high proportion of studies. Conclusion We report for the first time the lack of cardioprotection by RIPC in rats, assessed in individually randomized, blinded in vivo studies, involving three study centres, using different RIPC protocols. These results are in discrepancy with the meta-analysis of similar in vivo rat studies; however, no specific methodological reason could be identified by the systematic review, probably due to the overall insufficient reporting of several study parameters that did not improve over the past two decades. These results urge for publication of more well-designed and well-reported studies, irrespective of the outcome, which are required for preclinical reproducibility, and the development of clinically translatable cardioprotective interventions. Graphical Abstract Graphical Abstract We tested the cardioprotective efficacy of various RIPC protocols in three study centres in Hungary and the Netherlands. Neither of the applied methodologies resulted in cardioprotection. To verify that our in vivo methodological settings are in accordance with those reported in the literature, a systematic review and meta-analysis was performed. A discrepancy between meta-analysis and our in vivo results was found, despite that major methodological settings were similar to the publications analysed. Systematic review identifies insufficient and highly heterogeneous reporting of the investigated data items that did not improve over time, which could contribute to the discrepancy. RIPC: remote ischaemic preconditioning; I/R: ischaemia/reperfusion; IPC: in situ ischaemic preconditioning; MI: myocardial infarction; IS: infarct size; IQR: inter-quartile range. The figure was created with BioRender.com.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Undefined-3 Conflict of interest: P.F. is the founder and CEO, Z.G. is involved in the management, and G.F.B is a member of the Advisory Board of Pharmahungary Group. Péter Ferdinandy and Zoltán Giricz contributed equally. Nabil V Sayour and Gábor B Brenner contributed equally.
ISSN:	0008-6363 1755-3245
DOI:	10.1093/cvr/cvad024