Background: Limb remote ischemic conditioning is a series of mechanical interruptions that alters the hydrodynamics of reperfusion of a remote, distal organ or limb rendering a significantly reduced infarct size. Here, we are providing a first, extensive, and technical review of mechanisms involved in remote pre, per, and postconditioning of stroke in preclinical models to facilitate the translation to a clinical protocol.
Methods: Three databases were searched using these terms: “remote,” “condition(ing),” “pre,” “per,” “post,” “ischemic,” “stroke,” “brain,” “cerebral,” “stroke,” “rat(s),” “mouse,” “mice,” and “outcomes.” An extensive analysis of each article’s experimental research protocol design was done to gather both quantitative and qualitative data to compose an exhaustive list of mechanisms involved in remote ischemic conditioning. In addition, recommendations are provided on how to improve the studies to maximize clinical application.
Results: We identified 1,153 articles of which 125 were reviewed in depth to show a decreased infarction size, cerebral edema, and neurologic deficits. Studies showed the following: a range of significantly decreased infarct volume (43 to 26%, p<0.05), reduced cerebral edema (84 to 81%, p<0.05), and most studies included a decreased neurologic deficit test (p<0.05). Of interest, studies revealed the therapeutic window for conditioning can be as late as 3h after reperfusion. The figure depicts systemic and molecular pathways involved.
Conclusion: As an attractive low-cost, low-risk, and easily-operated therapy, the application of remote ischemic conditioning can be applied to cerebral ischemia in the clinical setting. When carrying out experimental studies, such detailed mechanisms of action and potential biomarkers should be integrated into clinical trial designs to ensure proper translation and ultimately therapeutic efficacy.