Cardioprotection
Authors: Xavier Rossello, Derek M. Yellon
Journal: Circulation (2016)

arly reperfusion by primary percutaneous intervention in patients with ST-segment-elevation myocardial infarction limits infarct size and preserves left ventricular systolic function, thereby improving prognosis.Despite this process of restoring blood flow to salvage the myocardium, further myocardial damage can occur as a consequence of reperfusion.This is known as myocardial ischemia/ reperfusion injury (IRI).Many cardioprotective therapies aimed at reducing IRI have been successfully examined in the preclinical setting.Despite attenuating IRI at the bench, not all have subsequently demonstrated a reduction in infarct size at the bedside, and none have demonstrated clinical benefits.The failure to translate cardioprotective therapies into the clinical setting can be attributed to many factors, from inadequate animal models of infarction to poor clinical study designs.Overall, it seems that hopes are fading that any cardioprotective intervention will ever materialize.However, after thoroughly dissecting the issues, we have come to a relevant diagnosis that we call a disconnection paradigm.This condition refers to the complete disconnect between preclinical and clinical studies in cardioprotection.ST-segment-elevation myocardial infarction is linked to multiple cardiovascular risk factors and comorbidities, and it is intensively treated both short and long term.These concomitant comorbidities and medications induce alterations in myocardial cellular signaling cascades, thereby affecting both the sensitivity to IRI and the response to any cardioprotective intervention.Many examples can illustrate the problem with comorbidities. 1 Diabetes mellitus makes the heart more susceptible to IRI and makes conditioning therapies less effective, and aging changes both the pharmacokinetics and pharmacodynamics of cardiovascular drugs and affects the susceptibility to be protected.There has been only a mild response to address this issue, using old and diabetic animals. 2 Less attention has been paid to concomitant medications despite the fact that most patients with ST-segment-elevation myocardial infarction receive immediate treatment with aspirin, P2Y 12 inhibitors, statins, opioids, β-blockers, and anticoagulation agents (according to the management guidelines 3 ), with many of the above being shown to have a cardioprotective effect.Despite this complex clinical picture, it is surprising how all these factors are systematically ignored in the preclinical setting, where concomitant medications are never assessed.This disconnection between preclinical study designs and clinical reality may justify our failure to translate cardioprotective therapies into clinical practice.As a treatment for this disconnect disorder, we propose a counterintuitive step: Cardioprotection needs to go backward before it can move forward.There is a need to fill this translational gap between bench reductionist models and the increasingly complex reality.We suggest adding an extra step in our current translational approach to approximate bench conditions to the clinical setting (Figure).Currently, placebo-controlled clinical trials test interventions on a background of guideline- CardioprotectionThe Disconnect Between Bench and Bedside