Abstract
Objective: Mitochondrial DNA (mtDNA) is one of several pro-inflammatory damage-associated molecular patterns released from necrotic myocytes during myocardial infarction (MI). Based on our recent observation of a ~50-fold rise in circulating mtDNA after brief whole-body ischemia in a porcine model of cardiac arrest without ongoing MI, we hypothesized that ischemia-induced mtDNA release can occur in the absence of necrosis. Accordingly, we measured circulating mtDNA levels before and after localized myocardial ischemia of insufficient duration to produce myocyte necrosis in swine. Methods: Swine (n=6) were subjected to a 10-minute occlusion of the left anterior descending (LAD) coronary artery based on prior evidence that this duration of ischemia elicits myocardial injury without necrosis. Peripheral venous and coronary sinus (CS) blood samples collected at baseline (BL) as well as 1-hour and 24-hours after reperfusion were analyzed via qPCR to quantify mtDNA and nuclear DNA (nucDNA) release. Results were compared to a separate group of swine (n=6) subjected to a 75-minute LAD occlusion to produce MI. Results: Prolonged ischemia led to a significant rise in CS levels of mtDNA (6.2 ± 3.6-fold vs. BL; p<0.05) and nucDNA (5.4 ± 2.0-fold vs. BL; p<0.05) 1 hour after reperfusion, consistent with rapid non-selective DNA release after myocyte necrosis. In contrast, brief ischemia was associated with detectable elevations in CS mtDNA (4.6 ± 1.4-fold vs. BL; p<0.05) but not nucDNA (2.1 ± 0.5-fold vs. BL; p=0.35) at this timepoint. However, the magnitude of DNA release after brief or prolonged ischemia was not sufficient to increase circulating mtDNA or nucDNA, as peripheral venous levels of mtDNA and nucDNA did not differ from BL at 1-hour or 24-hours post-reperfusion in either group. Conclusion: Brief myocardial ischemia is associated with selective release of mtDNA into circulation, providing a potential mechanism by which immune activation may occur after myocardial injury even when myocyte necrosis is absent. The magnitude of mtDNA release after brief myocardial ischemia is ~10-fold lower than that detected in peripheral blood after resuscitation from cardiac arrest, suggesting that mtDNA is released from other organs after brief whole-body ischemia.
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