Distinct cardioprotective mechanisms of immediate, early and delayed ischaemic postconditioning

Cardioprotection against ischaemia/reperfusion injury in mice can be achieved by delayed ischaemic postconditioning (IPost) applied as late as 30 min after the onset of reperfusion. We determined the efficacy of delayed IPost in a rat model of myocardial infarction (MI) and investigated potential underlying mechanisms of this phenomenon. Rats were subjected to 20, 30 or 45 min of coronary artery occlusion followed by 120 min of reperfusion (I/R). Immediate and early IPost included six cycles of I/R (10/10 s) applied 10 s or 10 min after reperfusion onset. In the second series of experiments, the rats were subjected to 30 min of coronary occlusion followed by IPost applied 10 s, 10, 30, 45 or 60 min after the onset of reperfusion. Immediate and early IPost (applied 10 s or 10 min of reperfusion) established cardioprotection only when applied after a period of myocardial ischaemia lasting 30 min. Delayed IPost applied after 30 or 45 min of reperfusion reduced infarct sizes by 36 and 41 %, respectively (both P < 0.01). IPost applied 60 min after reperfusion onset was ineffective. Inhibition of RISK pathway (administration of ERK1/2 inhibitor PD-98059 or PI3K inhibitor LY-294002) abolished cardioprotection established by immediate IPost but had no effect on cardioprotection conferred by early IPost. Blockade of SAFE pathway using JAK/STAT inhibitor AG490 had no effect on the immediate or early IPost cardioprotection. Blockade of mitochondrial KATP (mitoKATP) channels (with 5-Hydroxydecanoate) abolished cardioprotection achieved by immediate and early IPost, but had no effect on cardioprotection when IPost was applied 30 or 45 min into the reperfusion period. Immediate IPost increased phosphorylation of PI3K-AKT and ERK1/2. Early or delayed IPost had no effect on phosphorylation of PI3K-AKT, ERK1/2 or STAT3. These data show that in the rat model, delayed IPost confers significant cardioprotection even if applied 45 min after onset of reperfusion. Cardioprotection induced by immediate and early postconditioning involves recruitment of RISK pathway and/or mitoKATP channels, while delayed postconditioning appears to rely on a different mechanism

Postconditioning in ST-elevation myocardial infarction: a systematic review, critical appraisal, and meta-analysis of randomized clinical trials

M Abdelnoor,1,2 I Sandven,1 S Limalanathan,3 J Eritsland3 1Centre of Epidemiology and Biostatistics, 2Centre of Clinical Heart Research, 3Department of Cardiology, Oslo University Hospital, Ullev&aring;l, NorwayObjective: We aimed to summarize the evidence from randomized clinical trials studies examining the efficacy of ischemic postconditioning (IPost) in ST-elevation myocardial infarction. Design: The study was a systematic review and critical appraisal, with meta-analysis of randomized clinical trials. Materials and methods: We searched the literature. A total of 21 randomized clinical trials were identified. Both fixed effect and random effects models were used to synthesize the results of individual studies. Heterogeneity between studies was examined by subgroup and random effects meta-regression analyses, considering ptient-related and study-level variables. Publication bias, or &ldquo;small-study effect&rdquo;, was evaluated. Results: Substantial heterogeneity was present. The random effects model pooled estimate for the outcome infarct size assessed by cardiac magnetic resonance was estimated by the standardized mean difference (SMD) =&minus;0.06, 95% confidence interval (CI): &minus;0.34 to 0.21, ie, no effect of IPost. For the end point infarct size, estimated by biomarkers of myocardial necrosis, an overall pooled effect was SMD =&minus;0.58, 95% CI: &minus;0.96 to &minus;0.19. This effect disappeared in powered and nonbiased studies (SMD =0.03, 95% CI: &minus;0.48 to 0.55). Finally, for the outcome left ventricular ejection fraction, SMD =0.47 95% CI: 0.20 to 0.74. Unfortunately, selection bias (small-study effect) was present. For this outcome, the meta-regression showed that both presence of hypertension and the inclusion of nonbiased studies explained 28.3% of the heterogeneity among the studies. Simulation by the &ldquo;trim and fill&rdquo; method, which controlled for selection bias using random effects model, diluted the effect (SMD =0.17 95% CI: &minus;0.13 to 0.48). No effects by IPost on ST-segment resolution or on the majority of adverse clinical events were observed during follow up, except the incidence of congestive heart failure was found. Conclusion: Evidence from this study suggests no cardioprotection from IPost, on surrogate and the majority of clinical end points. A possible beneficial effect on the incidence of congestive heart failure needs to be replicated by a large clinical trial. Keywords: ischemic postconditioning, acute myocardial infarction, percutaneous coronary interventio