Further studies needed to find effective treatment for reperfusion injury

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By Michael Gibson

Numerous studies have tried and failed to find an effective treatment for reperfusion injury after percutaneous coronary intervention (PCI)—for example, the CIRCUS (Cyclosporine and prognosis in acute myocardial infarction patients) study that was recently presented at the European Society of Cardiology Congress (ESC; 29 August–2 September, London, UK). In this commentary, Michael Gibson reviews the various approaches that have been evaluated for reperfusion injury and states why he believes further studies in this area are still needed.


O
ver the past two decades, the widespread application of reperfusion techniques has considerably improved the prognosis of patients with ST-segment elevation myocardial infarction (STEMI). However, 30-day mortality following a STEMI remains high and, approximately, one quarter of patients who survive the event will subsequently develop heart failure. While factors such as arterial territory involved, presence of collateral flow, and time to reperfusion contribute significantly to the extent and severity of the ischaemic myocardial injury, expansion of the initial damage is paradoxically precipitated by reperfusion. Estimates from animal models suggest that reperfusion injury contributes to approximately one third to one half of the final infarct size.


Several hypotheses have been suggested and investigated in the pathophysiology of reperfusion injury. Mechanisms with significant supporting data include cytokine upsurge, metabolic derangements, calcium overload, increase in reactive oxygen species (ROS), and mitochondrial dysfunction—indicating that reperfusion injury may be due to a combination of cellular events that occur after restoring blood flow to an ischaemic myocardium.


Several of these pathophysiological mechanisms have been investigated as targets for the reduction of reperfusion injury, yet most of these therapeutic strategies have met with limited success. Metabolic agents such as glucose–insulin–potassium (GIK) infusions were the first attempt to restore the perceived derangements that occur after ischaemia-reperfusion. Despite several clinical trials, GIK infusions were not associated with a reduction in infarct size. Sodium-hydrogen exchange inhibitors, such as cariporide, as well as calcium-channel blockers, and magnesium that act to limit intracellular calcium overload likewise did not significantly reduce infarct size. Similarly, anti-inflammatory agents such as FX0630, pexelizumab, anti-CD18 antibodies were unsuccessful in limiting myocardial injury.


Particular interest in mitochondrial dysfunction was generated by the identification of the mitochondrial permeability-transition pore (MPTP), a non-specific channel that opens following reperfusion. Opening of the MPTP disrupts the mitochondrial membrane potential leading to an efflux of proapoptotic factors, and eventual myocyte death. The earliest pilot study in humans investigated the use of cyclosporine, an immunosuppressant that also acts as an inhibitor of MPTP opening, and demonstrated a significant reduction in infarct size with cyclosporine compared with placebo. This was followed by larger clinical trials of two mitochondria-targeting agents—TRO40303 (MITOCARE; Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction) and MTP-131 (EMBRACE: Evaluation of myocardial effects of bendavia for reducing reperfusion injury in patients with acute coronary events)—that demonstrated no significant reduction in infarct size despite promising pre-clinical data and more robust methodologies than prior studies. Despite initial data, further investigation of cyclosporine in the phase III CIRCUS trial demonstrated no reduction in the composite of death from any cause, worsening of heart failure during the initial hospitalisation, rehospitalisation for heart failure, or adverse left ventricular remodelling at one year, as well as in myocardial infarct size.


Given limited success of multiple strategies, the clinical relevance of reperfusion injury has been questioned by some. Nonetheless, failure to identify a successful treatment strategy for a given condition does not necessarily disprove its presence. Similar to any other condition, finding adequate therapeutic strategies for reperfusion injury requires identifying a safe and effective agent that is administered at the right dose, to the right patients, at the right time. With these considerations, it is probable that previously investigated treatments have failed to fulfil these requirements rather than disproved the existence of reperfusion injury in humans. Furthermore, given the relatively small size of the studies conducted, it may be possible that certain investigations were underpowered to determine a small reduction in infarct size, or more importantly, an improvement in clinical outcomes.


Further research is required to identify key pathways and therapeutic strategies for reperfusion injury. Recent studies investigating a strategy of post-conditioning (both ischaemic and pharmacologic) have shown promise, but require further validation in larger clinical trials.


Michael Gibson, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
 @CMichaelGibson