Remote conditioning the heart overview: translatability and mechanism

Conditioning the heart to resist predictable and unpredictable ischaemia-reperfusion (IR) injury is one of the fastest growing areas of bench to bedside research within cardiology. Basic science has provided important insights into signalling pathways and protective mechanisms in the heart, and a growing number of clinical studies have, with important exceptions, shown the potential applicability and beneficial effect of various mechanical conditioning strategies achieved by intermittent short-lasting-induced ischaemia of the heart itself or a remote tissue. Remote ischaemic conditioning (RIC) in particular has been utilized in a number of clinical settings with promising results. However, while many novel 'downstream' mechanisms of RIC have been discovered, translation to pharmacological conditioning has not yet been convincingly demonstrated in clinical studies. One explanation for this apparent failure may be that most pharmacological approaches mimic a single instrument in a complex orchestra activated by mechanical conditioning. Recent studies, however, provide important insights into upstream events occurring in RIC, which may allow for development of drugs activating more complex systems of biological organ protection. With this review, we will systematically examine the first generation of pharmacological cardioprotection studies and then provide a summary of the recent discoveries in basic science that could illuminate the path towards more advanced approaches in the next generation of pharmacological agents that may work by reproducing the diverse effects of RIC, thereby providing protection against IR injury.