Neglect of the coronary circulation: some critical remarks on problems in the translation of cardioprotection

Acute myocardial infarction remains a significant health problem throughout the world, and for those patients surviving the immediate event, infarct size is the main determinant of further prognosis.1–3 Timely reperfusion, as originally reported in dogs by John Ross Jr over 30 years ago,4–6 is still the only way to reduce ultimate infarct size but comes also at a price and induces injury in itself.7,8 Ischaemic preconditioning and ischaemic postconditioning, again originally both reported in dogs,9,10 reduce infarct size—provided there is also reperfusion!—in all species tested so far, including man.11–15 Although the phenomena of ischaemic pre- and postconditioning have stimulated research on the pathobiology of myocardial ischaemia and reperfusion in general, and notably on endogenous protective signalling mechanisms,12,16 their value has thus far remained mostly paradigmatic. The translation of experimental findings to patients with acute myocardial infarction has remained somewhat inferential for ischaemic preconditioning11 and has been limited to small-scale proof-of-concept studies in highly selected patients17,18 or retrospective analyses19 for ischaemic postconditioning, but has not yet been successful as a therapeutic reality. Obvious problems in the translation of cardioprotection from the experiment to the clinic have been critically reviewed before,13–15,20 including the choice of species and model to mimic the human situation, the choice of the potentially cardioprotective molecule/drug, the design of the clinical trial with respect to dose and time of treatment, and the selection of patients with respect to size, site and collateralization of their infarcting myocardium, their age,21 co-morbidities, and co-treatments.22