Abstract 4599: Controlled Low Flow Reperfusion Improves Post Ischemic Myocardial Function through a Reactive Oxygen Species (ROS) Mediated Mechanism
Cardioprotection following myocardial ischemia has been demonstrated using stuttered start-stop reperfusion. Although this type of reperfusion control is not possible in clinical cardiac arrest, we hypothesize that a low level of coronary flow following ischemia, such as may occur with CPR, confers similar cardioprotection through a reactive oxygen species (ROS) mediated mechanism. To test this hypothesis, male Sprague Dawley rat hearts were isolated and perfused at 85 mm Hg with temperature controlled (37.4° C) modified Krebs Henseleit buffer. Hearts were infused with dihydrofluorescein, an intracellular probe converted to fluorescein by ROS, and amplex red, a vascular probe converted to resorufin by hydrogen peroxide. Fluorescein and resorufin epifluorescence were measured at the left ventricular (LV) wall. Hearts (n=4/group) were subjected to either
20 min of global ischemia (No Flow);
6 min of global ischemia followed by 14 min of low flow at 10% of baseline coronary flow (Low Flow);
No Flow with the NADPH oxidase inhibitor apocynin during full flow reperfusion or
Low Flow with apocynin during low and full flow reperfusion.
Beginning at 20 minutes all hearts received full flow reperfusion at 85 mm Hg for 15 minutes. Fluorescence (F/F0) and rate pressure product (RPP) were calculated as a fraction of baseline and analyzed with ANOVA. At reperfusion, in the Low Flow group fluorescein F/F0 was decreased (0.577 ± 0.039 vs. 1.081 ± 0.060, p<0.001) and resorufin F/F 0 was increased (1.375 ± 0.012 vs. 1.115 ± 0.014, p<0.001) compared to the No Flow group. RPP, at the end of reperfusion, was improved in Low Flow hearts compared to No Flow (0.75 ± 0.07 vs. 0.87± 0.02, p=0.1). In the presence of apocynin, resorufin F/F0 at reperfusion was decreased in both groups (p<0.001) and RPP was significantly improved in the low flow group (p<0.01). Low coronary flow prior to full reperfusion mediates a compartment specific ROS response which is associated with improved recovery of LV function. NADPH oxidase inhibition attenuates the low flow induced amplification of vascular ROS, further improving recovery of LV function. This suggests the CPR low flow period may afford a treatment window for targeted antioxidant therapy.
This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).