A Meta-Analysis of Resveratrol Protects against Myocardial Ischemia/Reperfusion Injury: Evidence from Small Animal Studies and Insight into Molecular Mechanisms

Abstract

Aims: Myocardial ischemia/reperfusion (I/R) injury is a leading cause of cardiomyocyte loss and subsequent ventricular dysfunction after restoring the coronary blood flow and contributes to considerable increase in morbidity and mortality. Resveratrol has been declared to confer cardioprotection against in vivo and ex vivo myocardial I/R injury. Here, we have sought to investigate the effects of preconditioning with resveratrol on myocardial I/R damage across the small animal studies.

Methods and results: The MEDLINE, Google Scholar, PubMed, and Cochrane databases were searched for preclinical studies investigating resveratrol vs. vehicle published from the inception to July 2018. Eventually, 10 in vivo and 7 ex vivo studies with 261 animals (130 for resveratrol; 131 for vehicle) were included for meta-analysis. Pooled estimates for primary outcomes demonstrated that pretreatment with resveratrol significantly reduced the infarct size after myocardial I/R injury irrespective of in vivo (weighted mean difference (WMD): -13.42, 95% CI: -16.63 to -10.21, P ≤ 0.001) or ex vivo (WMD: -15.05, 95% CI: -18.23 to -11.86, P ≤ 0.001) studies. Consistently, stratified analysis according to the reperfusion duration, route of administration, or timing regimen of pretreatment all showed the infarct-sparing benefit of resveratrol. Metaregression did not indicate any difference in infarct size based on species, sample size, state, route of administration, reperfusion duration, and timing regimen of pretreatment. Meanwhile, sensitivity analysis also identified the cardioprotection of resveratrol with robust results in spite of significant heterogeneity.

Conclusions: Preconditioning with resveratrol appears to prevent the heart from I/R injury in comparison with vehicle, as evidenced by limited infarct size in a preclinical setting. Studies with large animals or randomized controlled trials will add more evidence and provide the rationale for clinical use.

Figure 1

Flow diagram of the study selection process.

Figure 2

Pooled estimates of infarct size for resveratrol vs. vehicle in vivo. Treatment with resveratrol was associated with a smaller infarct size in in vivo studies (WMD: -13.42, 95% CI: -16.63 to -10.21, P ≤ 0.001). Gray squares represent WMDs in studies. The 95% CIs for each studies are denoted by lines and those for the pooled WMDs by open diamonds. Meta-analysis is performed by random effects model.

Figure 3

Funnel plot for assessment of publication bias for the infarct size in vivo (a) and ex vivo (b). Funnel plots were scatter plots (blue points) of the effect sizes of the included studies versus a measure of their precision usually standard error. The funnel plot appeared to have minimal asymmetry in (a); however, it was symmetrical in (b).

Figure 4

Pooled estimates of infarct size for resveratrol vs. vehicle ex vivo. Resveratrol treatment reduced the infarct size in ex vivo studies (WMD: -15.05, 95% CI: -18.23 to -11.86, P ≤ 0.001). Gray squares represent WMDs in studies. The 95% CIs for each studies are denoted by lines and those for the pooled WMDs by open diamonds. Meta-analysis is performed by the random effects model.