Genesis of remote conditioning: action at a distance - 'hypotheses non fingo'?

Remote ischemic preconditioning is the phenomenon whereby brief episodes of ischemia-reperfusion applied in a distant organ or tissue render the myocardium resistant to infarction. The discovery of remote conditioning was not a serendipitous finding, but, rather, was predicted by mathematical modeling. In the current review, we describe how the hypothesis for remote conditioning was formulated and tested, how the paradigm has expanded to encompass a spectrum of remote triggers, and summarize the progress that has been made in elucidating the mechanisms responsible for this intriguing form of cardioprotection.