Abstract 3664: High Dose Folic Acid Pre-treatment Blocks Cardiac Dysfunction During Ischemia Coupled To Improved Synthesis Of High Energy Phosphates
Backgound: The B-vitamin folic acid (FA) is important for mitochondrial function, is an anti-oxidant, and enhances tetrahydrobiopterin bioavailability required for normal nitric oxide synthase function. We have found that high dose FA blunts in vitro ischemia-reperfusion injury. Here we tested if this involves a primary effect during ischemia itself.
Methods: Wistar rats (n=120) pretreated with either FA (10mg/d) or placebo for 1 week underwent left coronary artery ligation (CaL) for 30 min with or without 90 min reperfusion.
Results: Cardiac function was markedly preserved despite 30 min CaL in FA versus placebo pretreated rats (Table⇓). CaL lowered myocardial ATP and ADP by >66%, and both were significantly preserved with FA-pretreatment (ATP: control: 2740±58; CaL: 947±55; CaL+FA: 1332±101 nmol/g, p=0.02; ADP: control: 371±25; CaL:96±17; CaL+FA: 369±46 nmol/g, p=0.002). Total adenine nucleotides were significantly increased with FA pretreatment vs. placebo (p=0.002), whereas catabolites (e.g. xanthine, hypoxanthine) were unchanged. Ischemia-induced O2− (lucigenin) was less in FA rats (3124±280 vs. placebo 5898±474 cpm/mg tissue, p=0.001), whereas myocardial redox-state (ascorbate, GSH/GSSH) and lipid-peroxidation (malondialdehyde) were unaltered. Changes from FA were not due to improved perfusion, as myocardial blood flow (microspheres) at both 5 and 30 min CaL were similarly reduced (−77.7 ± 5.1% vs. placebo: −73.7 ± 6.0%). As a consequence of less ischemia in FA-rats, myocardial necrosis after reperfusion was minimal (infarct size: 3.8±1.2% area at risk vs. placebo: 60.3±4.1%, p<0.002) with less contraction band necrosis and TUNEL-positivity, eNOS remained coupled, and O2− generation was declined.
Conclusion: These data reveal a novel ability of high dose FA-pretreatment to preserve high energy phosphates, blunt cardiac dysfunction during ischemia and improve subsequent ROS-generation, eNOS-uncoupling, and cell death upon reperfusion.