REPERFUSION INJURY - CHALLENGES TO REDUCE IT

Abstract

Reperfusion achieved through pharmacological agents or mechanicalangioplasty is associated with reperfusion injury. This implies several eventsassociated with reperfusion, some transitory like reperfusion arrhythmias mostlyventricular arrhythmias and stunning of myocardium and permanent known aslethal reperfusion injury inferring death of myocardium induced by reperfusion.Whereas transitory effects have been accepted and documented, 'lethalreperfusion injury' following reperfusion in STEMI has long been a matter ofdeliberation. This has been essentially due to lack of definitive clinicaldemonstration in spite of convincing experimental evidence. There has been agap between well-defined and controlled experimental models and unclearhuman proofs - clinical models. 'Lethal reperfusion injury' is defined as apotentially preventable death of myocardium that was viable at the time ofreperfusion, which is consequence of events triggered or exaggerated byreperfusion. The fact that preventive maneuvers like post-conditioning limitinfarct size without affecting ischemic injury is the best demonstration of thereality of lethal reperfusion injury.The idea of lethal reperfusion injury has sincewon progressive acceptance on the basis of evidence coming from clinical andbasic science studies.4

Lethal reperfusion injury reduction concept was first tested in 2005 showing that ischemic post-conditioning can reduce infarctsize in STEMI. In this proof-of-concept trial, ischemic post-conditioning was applied within one minute after reflow byinflating/deflating angioplasty balloon (low-pressure, upstream of the stent) in 4 one-minute cycles. This resulted in a 36%reduction of the area under the curve for creatine kinase release, a surrogate marker of infarct size. Though many but not all, ofthe small trials performed showed infarct size reduction in patients undergoing post-conditioning. However, the largestrandomized clinical trial POST (Effects of Postconditioning on Myocardial Reperfusion in Patients With ST-Segment ElevationMyocardial Infarction) of post-conditioning in STEMI was neutral. Remote ischemic conditioning - conditioning performed in adistant organ has been described as another form of myocardial conditioning well described in animal models. In humanscenario remote ischemic pre-conditioning 4 five-minute brachial cuff inflations applied during ongoing STEMI, duringambulance transfer to the PCI center and before PCI reperfusion resulted in increased myocardial salvage compared withregular PCI,with a potential for fewer long-termclinical events.25,26

Over the past decades, important progress has been made in phase II trials evaluating protective interventions against lethalreperfusion injury. The challenge for the future is to design larger trials to evaluate clinical outcomes employing newer therapiesto contain lethal reperfusion injury. It is believed that the advances in the next decade will emerge from refining the current daytherapies rather that identifying new drugs.