Remote ischaemic conditioning reduces infarct size in animalin vivomodels of ischaemia-reperfusion injury: a systematic review and meta-analysis

Abstract

AimsThe potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy.Methods and resultsOur primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8–26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1–25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization.ConclusionsRIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.

Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning

“…Myocardial autonomic innervation is known differ according to the species’ size [59]; however, it is not clear whether these differences relate to the species-specific effect of IPC. Finally, with respect to remote ischaemic conditioning, although there appear to be differences in the signalling cascades important for cardioprotection between species [63], a recent meta-analysis revealed no difference in the efficacy of cardioprotection relative to species [12]. …”

Ventilation strategy has a major influence on remote ischaemic preconditioning in mice

“…However, it is important to recognize that although a number of factors have been proposed to influence the efficacy of RIC, few of these have been systematically examined in either the clinical or experimental setting. This fact is highlighted by a recent meta-analysis that demonstrated a strong, consistent beneficial effect of RIC in reducing infarct size in in vivo animal experiments of ischaemia and reperfusion injury, but was unable to identify experimental variables that significantly contributed to the observed large experimental heterogeneity [8]. In this meta-analysis, the variable most strongly related to the degree of protection by RIPC (albeit not reaching significance), was the oxygenation status, that is to say whether animals were ventilated with room air or with high-flow supplemental oxygen [8].…”

“…This fact is highlighted by a recent meta-analysis that demonstrated a strong, consistent beneficial effect of RIC in reducing infarct size in in vivo animal experiments of ischaemia and reperfusion injury, but was unable to identify experimental variables that significantly contributed to the observed large experimental heterogeneity [8]. In this meta-analysis, the variable most strongly related to the degree of protection by RIPC (albeit not reaching significance), was the oxygenation status, that is to say whether animals were ventilated with room air or with high-flow supplemental oxygen [8]. This led us to hypothesize that RIPC in animal experiments might be affected by supplemental oxygen because limb pO 2 takes longer to reach a sufficient hypoxic threshold for cardioprotection, a variable which has not been considered previously in such experiments.…”

Sex is no determinant of cardioprotection by ischemic preconditioning in rats, but ischemic/reperfused tissue mass is for remote ischemic preconditioning

“…A recent meta‐analysis of animal models on RIC supports no relation between duration or number of ischemia/reperfusion cycles or the mass of ischemic/reperfused peripheral tissue with the magnitude of infarct size reduction (Bromage et al. ). In fact, there is only one experimental study in mice with the aim to identify an optimal algorithm of RIC, in which duration and number of ischemia/reperfusion cycles rather than the mass of ischemic/reperfused peripheral tissue determined the magnitude of infarct size reduction (Johnsen et al.…”