Intracoronary Poloxamer 188 Prevents Reperfusion Injury in a Porcine Model of ST-Segment Elevation Myocardial Infarction

• STEMI remains a significant cause of in-hospital mortality, and up to 20% of people go on to develop heart failure.
• P188 is a nonionic triblock copolymer believed to prevent cellular injury after ischemia and reperfusion. The CORE trial examined P188 for STEMI patients showing no benefit when it was infused through a peripheral IV catheter approximately 30 min after revascularization with thrombolytic therapy.
• STEMI was induced in pigs using endovascular coronary artery occlusion to compare intracoronary infusion of P188 immediately after revascularization to infusion of P188 through a peripheral IV catheter 30 min after revascularization. Immediate intracoronary infusion of vehicle control and PEG, a rheological control, were also compared.
• Intracoronary infusion of P188 immediately upon reperfusion reduced infarct size by 68% compared with delayed peripheral P188 infusion, which was similar to vehicle control.
• Mitochondrial respiration and calcium stress tolerance were preserved in the ischemic tissue of pigs treated with immediate intracoronary P188 infusion. Mitochondria from pigs with delayed peripheral P188 infusion were no different from control pigs.
• By reducing infarct size and mitochondrial dysfunction, immediate intracoronary infusion of P188 may provide a therapeutic strategy to improve post-STEMI outcomes. The timing and route of delivery were critical to the observed benefit.

SummaryPoloxamer 188 (P188) is a nonionic triblock copolymer believed to prevent cellular injury after ischemia and reperfusion. This study compared intracoronary (IC) infusion of P188 immediately after reperfusion with delayed infusion through a peripheral intravenous catheter in a porcine model of ST-segment elevation myocardial infarction (STEMI). STEMI was induced in 55 pigs using 45 min of endovascular coronary artery occlusion. Pigs were then randomized to 4 groups: control, immediate IC P188, delayed peripheral P188, and polyethylene glycol infusion. Heart tissue was collected after 4 h of reperfusion. Assessment of mitochondrial function or infarct size was performed. Mitochondrial yield improved significantly with IC P188 treatment compared with control animals (0.25% vs. 0.13%), suggesting improved mitochondrial morphology and survival. Mitochondrial respiration and calcium retention were also significantly improved with immediate IC P188 compared with control animals (complex I respiratory control index: 7.4 vs. 3.7; calcium retention: 1,152 nmol vs. 386 nmol). This benefit was only observed with activation of complex I of the mitochondrial respiratory chain, suggesting a specific effect from ischemia and reperfusion on this complex. Infarct size and serum troponin I were significantly reduced by immediate IC P188 infusion (infarct size: 13.9% vs. 41.1%; troponin I: 19.2 μg/l vs. 77.4 μg/l). Delayed P188 and polyethylene glycol infusion did not provide a significant benefit. These results demonstrate that intracoronary infusion of P188 immediately upon reperfusion significantly reduces cellular and mitochondrial injury after ischemia and reperfusion in this clinically relevant porcine model of STEMI. The timing and route of delivery were critical to achieve the benefit.

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