The coronary circulation in cardioprotection: more than just one confounder

Cardioprotection, i.e. the reduction in infarct size by pre-, post-, or remote conditioning, has originally been characterized in young and healthy experimental animals. Over the last two decades many signalling steps of cardioprotection have been identified, again in young and healthy animals. Although proof-of-concept studies unequivocally demonstrated the recruitment of all forms of cardioprotection in humans, the translation of cardioprotection to clinical routine has been poor. The apparent lack of translation has been attributed to poor design of clinical trials, but also to the neglect of confounders, such as age, sex, comorbidities, and comedications, in experimental studies. The present opinionated review focuses on the coronary circulation as a major determinant of cardioprotection. Coronary occlusion and the restoration of coronary blood flow are the causes of myocardial ischaemia and reperfusion injury from which protection is sought. On the other hand, brief cycles of coronary occlusion and reperfusion are also the stimulus for protection from myocardial ischaemia/reperfusion injury. The recruitment of collateral blood flow also contributes to protection from infarction. Finally, the coronary microcirculation is also a target of both injury by myocardial ischaemia/reperfusion and protection from it. Different manifestations of coronary artery disease, such as coronary stenosis or coronary microembolization, impact on both injury and protection.