PhD Scientific Days 2021

TT_III_L: Theoretical and Translational Medicine III. Lectures

Lack of efficacy of remote ischemic preconditioning on infarct size in rats: evidence from randomized, blinded studies of myocardial ischemia/reperfusion injury in three different study centers and from a systematic review

Nabil V Sayour1, Gábor B Brenner1, András Makkos1, Bernadett Kiss1, Tamás G Gergely1 Sverre Groever Aurkust1, Cindy Tian1, Kamilla Gömöri2,3, Tamara Szabados2,3, Péter Bencsik2,3, Andre Heinen4, Rainer Schulz5, Gary F Baxter6, Coert J Zuurbier7, Péter Ferdinandy1,2, Zoltán Giricz1

1Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
2Pharmahungary Group, Szeged, Hungary
3Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
4Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
5Institute of Physiology, Justus-Liebig University Giessen, Giessen, Germany
6School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB UK
7Amsterdam UMC, University of Amsterdam, Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands

Text of the abstract

INTRODUCTION: Despite promising results on cardioprotection elicited by remote ischemic preconditioning (RIPC) in preclinical models of myocardial ischemia/reperfusion injury (MIRI), large clinical trials show no clinical benefit. This translational failure can be due to an incomplete understanding of the factors that may determine or confound RIPC efficacy.
AIMS: To identify these factors, here we systematically reviewed publications on RIPC in rats and assessed cardioprotective efficacy of the commonly applied RIPC protocols in rat models of acute MIRI, conducted at three study centers in Hungary and the Netherlands.
METHODS: Systematic review of 348 publications was performed, and factors of design- and reporting quality were scored. Most commonly used methodologies were identified, and animal study was performed accordingly. Healthy, male, 10-12 week old Wistar rats anesthetized with pentobarbital were subjected to 20, 25, 30, or 45 min occlusion followed by 120 min reperfusion of the left anterior descending coronary artery (LAD) with or without preceding RIPC with either 3×5-5 min intermittent occlusion/reperfusion of one femoral artery or 4×5-5 min of one or both femoral arteries. RIPC was induced by either clamping the femoral artery and vein, or by a tourniquet, or by using a pressure cuff. As a positive control, we applied local ischemic preconditioning (IPC) by 3×5-5 min LAD occlusion/reperfusion in two study centers. IS, microvascular obstruction (MVO), and MIRI-induced arrhythmias were measured.
RESULTS: Over 50% of the publications reported less than 40% of reporting- and design quality parameters. While IPC significantly decreased IS, MVO, and occurrence of MIRI-induced arrhythmias, none of the investigated RIPC protocols affected these endpoints at any study sites.
CONCLUSION: Although unanimously reporting efficacy, most preclinical RIPC studies in the literature were either poorly designed or reported, therefore, their reproducibility may be questionable and confounding factors cannot be identified. This is the first demonstration of the neutral effect of RIPC on cardioprotection in rats assessed in individually randomized, blinded acute in-vivo studies in three study centers.
FUNDING: EFOP-3.6.3-VEKOP-16-2017-00009; Richter Gedeon Excellence PhD Scholarship; NVKP-16-1-2016-0017; Higher Education Institutional Excellence Program (FIKP).

University and Doctoral School

Semmelweis University, Doctoral School of Pharmaceutical Sciences