Determinants of the Efficacy of Cardiac Ischemic Preconditioning: A Systematic Review and Meta-Analysis of Animal Studies.

Thomas B Sterenborg,Niels P Riksen,Merel Ritskes-Hoitinga,Carlijn R Hooijmans,Michiel C Warlé,Emily S Sena,Kimberley E Wever

doi:10.1371/journal.pone.0142021

Abstract

BackgroundIschemic preconditioning (IPC) of the heart is a protective strategy in which a brief ischemic stimulus immediately before a lethal ischemic episode potently limits infarct size. Although very promising in animal models of myocardial infarction, IPC has not yet been successfully translated to benefit for patients.ObjectiveTo appraise all preclinical evidence on IPC for myocardial infarction and identify factors hampering translation.Methods and resultsUsing systematic review and meta-analysis, we identified 503 animal studies reporting infarct size data from 785 comparisons between IPC-treated and control animals. Overall, IPC reduced myocardial infarction by 24.6% [95%CI 23.5, 25.6]. Subgroup analysis showed that IPC efficacy was reduced in comorbid animals and non-rodents. Efficacy was highest in studies using 2–3 IPC cycles applied <45 minutes before myocardial infarction. Local and remote IPC were equally effective. Reporting of study quality indicators was low: randomization, blinding and a sample size calculation were reported in 49%, 11% and 2% of publications, respectively.ConclusionsTranslation of IPC to the clinical setting may be hampered by the observed differences between the animals used in preclinical IPC studies and the patient population, regarding comorbidity, sex and age. Furthermore, the IPC protocols currently used in clinical trials could be optimized in terms of timing and the number of ischemic cycles applied. In order to inform future clinical trials successfully, future preclinical studies on IPC should aim to maximize both internal and external validity, since poor methodological quality may limit the value of the preclinical evidence.

Highlights

Coronary heart disease is projected to remain the leading cause of disability and death worldwide until 2030[1,2]
Translation of Ischemic preconditioning (IPC) to the clinical setting may be hampered by the observed differences between the animals used in preclinical IPC studies and the patient population, regarding comorbidity, sex and age
The IPC protocols currently used in clinical trials could be optimized in terms of timing and the number of ischemic cycles applied

Summary

Introduction

Coronary heart disease is projected to remain the leading cause of disability and death worldwide until 2030[1,2]. Mortality and morbidity in patients with acute coronary syndrome remain significant. This is caused, at least in part, by ‘lethal reperfusion injury’[3]. Over thirty clinical trials have investigated the protective effects of remote IPC (RIPC) in patients undergoing major cardiovascular surgery [4]. Compared to the preceding animal studies, the results have been disappointing: the most extensive meta-analysis of remote ischemic conditioning in cardiovascular surgery indicated that 11 out of 15 trials found no effect of RIPC on peak troponin levels [5]. The promising protective effect of ischemic conditioning in animal studies has not yet been translated to the clinical setting [9]. Very promising in animal models of myocardial infarction, IPC has not yet been successfully translated to benefit for patients

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Discussion

Conclusion