Warm ischemia provokes inflammation and regional hypercoagulability within the heart during off-pump coronary artery bypass: a possible target for serine protease inhibition

Objective: Accumulating evidence suggests that a hypercoagulable state influences early graft failure after off-pump coronary artery bypass (OPCAB). We hypothesized that regional myocardial ischemia caused by obligatory periods of coronary occlusion during OPCAB is an important trigger for this prothrombotic state. Methods: Using a series of biomarkers, 60 consecutive patients undergoing OPCAB were monitored for myocardial injury (myoglobin), inflammation (TNF-a, IL-8) and thrombosis (thrombin generation-F1.2, contact activation pathway-FXII-a, platelet derived microparticles-via flow cytometry). The transcardiac gradients of these markers were determined by assaying both arterial and coronary sinus blood just after protamine administration. Intramyocardial pH was monitored continuously during coronary occlusion in a subset (N = 30 grafts, 11 patients). The influence of management strategies affecting hemostasis (e.g. antiplatelet therapy, anti-fibrinolytics, peak activated clotting time (ACT) during heparinization) was analyzed. Results: Ischemic injury, depicted by the transcardiac myoglobin gradient, significantlycorrelatedwithintramyocardialacidosisduringcoronaryocclusion(R = 0.96,p < 0.0001)andpredictedthetranscardiacgradientsof TNF-a (R = 0.83, p < 0.001) and F1.2 (R = 0.72, p < 0.0001). Transcardiac F1.2 strongly correlated with TNF-a (R = 0.73, p = 0.01) and IL-8 (R = 0.51, p = 0.02). Patients receiving aprotinin (N = 20) showed significantly lower transcardiac gradients for myoglobin (4.1 7.5% vs 72.9 108.8% change, p = 0.002), F1.2 (31 37% vs 89 149%, p = 0.03), FXII-a (2.6 4.1% vs 19.2 34%, p = 0.04) and microparticles (7 3.9% vs 12.9 8%, p = 0.01). Conclusions: Strong correlations between myocardial ischemia and the transcardiac gradients of markers for inflammation and thrombosis suggest that even brief episodes of coronary occlusion in the beating heart may have pathophysiologic consequences. Aprotinin, but not other factors that influence the coagulation system, appears to mitigate this process during OPCAB.