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

PLoS One. 2015 Nov 18;10(11):e0142021. doi: 10.1371/journal.pone.0142021. eCollection 2015.


Background: Ischemic 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.

Objective: To appraise all preclinical evidence on IPC for myocardial infarction and identify factors hampering translation.

Methods and results: Using 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.

Conclusions: Translation 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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Animals
  • Clinical Trials as Topic
  • Disease Models, Animal
  • Heart / physiopathology*
  • Humans
  • Ischemic Preconditioning, Myocardial*
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control*

Grant support

This work was supported by The Netherlands Organization for Health Research and Development (ZonMW, project #104024065). KEW performed part of this work with support of the Laboratory Animal Science Association and The Company of Biologists Ltd. NPR is supported by a Clinical Fellowship of ZonMW and the Netherlands Heart Foundation (dr. Dekker fellowship). ES’ contribution was funded by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) infrastructure award: ivSyRMAF, the CAMARADES–NC3Rs in vivo systematic review and meta-analysis facility. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.