Reperfusion injury in humans: a review of clinical trials on reperfusion injury inhibitory strategies.
The principal therapy in patients with myocardial infarction to limit infarct size is myocardial reperfusion by mechanical or pharmacological intervention. Reperfusion has been proposed to cause myocardial injury beyond that caused by the preceding ischaemia, termed "reperfusion injury" (RI). While the precise mechanism of RI is still incompletely understood, a large number of clinical studies have been performed over the past decade targeting some of the postulated mechanisms of RI. These clinical studies were based on experimental data demonstrating significant myocardial salvage. Nevertheless, clinical benefits were absent or very limited. The purpose of this review is to provide an overview of the various strategies that inhibit RI and to discuss potential mechanisms that may contribute to the discrepancy between the promising pre-clinical data and the rather disappointing results obtained from prospective clinical trials. There are numerous differences between the experimental models and clinical studies, including the fact that experimental studies typically use abrupt occlusion and reperfusion protocols in animals with previously healthy myocardium that apparently do not predict the therapeutic efficacy of novel cardioprotective agents in a clinical setting with pre-existing progressive coronary disease, intermittent coronary occlusion, and relatively late reperfusion. However, discrepancies also exist between experimental studies. Future experimental studies of reperfusion injury should use models that mimic the clinical situation more closely. Furthermore, future large clinical trials should only be performed in cases where the drug under investigation proved to reduce RI in a series of well-designed (possibly multicenter) experimental studies and in clinical trials with predefined subgroups.
Dirksen
Maurits T
MT
Amsterdam Department of Interventional Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
Laarman
Gerrit J
GJ
Simoons
Maarten L
ML
Duncker
Dirk J G M
DJ
D000241:Adenosine / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003327:Coronary Disease / Q000188:drug therapy; D005544:Forecasting; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
D000975:Antioxidants; D002121:Calcium Channel Blockers; D017923:Sodium-Hydrogen Exchangers; D000241:Adenosine