540 Paradox effects of MMP2 and MMP9 are beneficial in viral induced experimental myocarditis

During acute myocardial infarction (AMI), ischemia leads to necrotic areas, that are surrounded by borderzones of reversibly damaged cardiomyocytes, in which membrane flip-flop is induced. Reperfusion of ischemic myocardium results in binding of inflammatory mediators on these reversibly damaged cells, inducing additional cardiomyocyte death and thereby infarct size expansion. sPLA2-IIA is an important and early inflammatory mediator in this process of ischemia/reperfusion-injury, that induces cell-toxicity and facilitates binding of other inflammatory mediators on the reversibly damaged cardiomyocytes in-vitro. Therefore, it was hypothesized that sPLA2-IIA inhibition would reduce infarct size. The therapeutic effect of sPLA2-IIA inhibition in AMI was investigated in a rat-AMI model. Rats were divided into 3 groups: the sham-operated group (n=4), the control group (n=13), and a treatment group (n=17) receiving the sPLA2-IIA inhibitor PX-18. Treatment was given intravenously, for three days post AMI. After 4 weeks, heart function was analyzed using echocardiography, and infarct size was calculated using QPRODIT analysis. The sPLA2-IIA inhibitor PX-18 significantly reduced infarct size with an infarct reduction of 73±9% (P<0.05), compared to the vehicle-treated group. Also mortality was significantly reduced in the PX-18 treated group, namely there was no mortality in the PX-18 treated group, compared to 23% mortality in the control group (P<0.05). Also, a trend towards improved cardiac output and stroke volume in the PX-18 treated group was found, when compared to the control. Importantly, no cardiac rupture or other adverse effects were found after therapy, suggesting that normal wound healing was not impaired. Taken it together, our results suggest that sPLA2-IIA inhibition is an effective therapy for decreasing myocardial infarct size after AMI.