Alexis Cralley (Denver, CO / US), Ernest E. Moore (Denver, CO / US), Ian LaCroix (Denver, CO / US), Terry J Schaid (Denver, CO / US), Otto Thielen (Denver, CO / US), William Hallas (Denver, CO / US), Sanchayita Mitra (Denver, CO / US), Patrick Hom (Denver, CO / US), Mitchell J Cohen (Denver, CO / US), Christopher Silliman (Denver, CO / US), Kirk Hansen (Denver, CO / US), Angelo D'Alessandro (Denver, CO / US), Angela Sauaia (Denver, CO / US)
Abstract text (incl. references and figure legends)
Introduction: Ischemia-reperfusion injury (IRI) occurs after hemorrhagic shock when blood flow to organs is restored. IRI results in the accumulation of succinate and further oxidative injury. Following reperfusion rapid metabolism of succinate into fumarate leads to reversal of the electron transport chain and generation of reactive oxygen species (Figure 1). The effects of aortic occlusion (AO) on mitochondrial function have not yet been elucidated. We hypothesized in our polytrauma swine model of hemorrhagic shock Zone 1 AO would worsen mitochondrial dysfunction evidenced by succinate accumulation.
Material & Methods: Swine underwent polytrauma with bilateral femur fractures, hemorrhagic shock to base excess -10, and blast head injury. Swine were randomized to 30 minutes of either no AO (n=6), AO at Zone 1 (above celiac artery; n=6), or Zone 3 (below renal arteries; n=4) during the last 30 minutes of shock followed by resuscitation. Plasma samples underwent to mass spectrometry-based metabolomics. Relative metabolic changes were compared using mixed models adjusting for false discovery rate.
Results: The largest metabolite increases were seen in succinate, fumarate, and malate. At 60 minutes into resuscitation Zone 1 group metabolites remained significantly elevated above the others (p<0.05). Regarding succinate, both Zone 1 and No AO groups had significant increases from baseline (p<0.05), with almost 30x increases in succinate levels. Succinate accumulation following Zone 3 AO was not significant, with only a 10x increase.
Conclusions: Zone 1 AO results in prolonged disturbances of mitochondrial metabolism. Zone 3 AO attenuated succinate buildup and compared to Zone 1 avoided accumulation of other mitochondrial metabolites. These findings suggest visceral ischemia is an important driver of IRI and Zone 3 AO may mitigate IRI.
References: Chouchani et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014
Disclosure: Do you have a significant financial interest, consultancy or other relationship with products, manufacturer(s) of products or providers of services related to this abstract? (If not, please enter "No" in the text field.)
This research is funded by the US Department of Defense contract W81XWH2010205, the US National Institute of General Medical Sciences of the National Institute of Health (T32 GM008315) and a US NIH RM1 grant (1RM1GM131968-01).