Abstract 19495: Cardioprotective Effect of AMP Deaminase Inhibition in Oxygen Deprivation
Studies on the effect of genetic polymorphisms known to affect AMP deaminase (AMPD) activity on progress of heart disease are conflicting: some highlights benefit of decreased AMPD activity in heart failure and ischemic heart disease while the other failed to confirm it. Detailed studies to identify clinical scenario that benefits from decreased AMPD activity are thus needed. We evaluated cardiac effects of decreased AMPD activity during acute oxygen deprivation in clinical and experimental settings. Patients undergoing coronary artery bypass grafting with use of extracorporeal circulation (n=184) were clinically analyzed and genotyped for C34T mutation of AMPD1 that we previously found to decrease cardiac AMPD activity. The effect of new inhibitor of AMPD: 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (AMPDI) was tested in apoA/LDLr knockout mouse exposed for 5 min to 5% oxygen in breathing air. The activity of AMP regulated protein kinase (AMPK) in heart homogenates was measured following co-incubation with purified AMPD. Ejection fraction changed perioperatively by 1.16±2.16% (n=12,±SD) among patients with C34T mutation in patients subgroup reporting angina pain as compared to −1.67±1.03% (n=56) in patients with normal AMPD1 genotype (p<0.01). There were 2 perioperative deaths within 150 patients with normal AMPD1 genotype and none in 34 patients with C34T mutation. In experimental hypoxia in mouse, infusion of 100 mg/kg of AMPDI for 30 min before hypoxia reduced cardiac accumulation of AMPD product inosine monophosphate (IMP) from 0.307±0.047 μmol/g dry wt in controls to 0.102±0.002 (n=6, p<0.05), attenuated STU area of ECG from −362±32 mV/s*105 in controls to −140±28 (p<0.01) and reduced plasma Troponin I concentration from 0.26±0.01 ng/ml in controls to 0.20±0.02 (p<0.05). Activity of AMPK in heart homogenates was reduced to 18%(±7, n=5) when isolated AMPD was added. This effect was prevented by AMPDI. This study highlights that AMPD activity reduction is beneficial under conditions of acute oxygen deprivation. Activation of protective AMPK cascade by increased availability of AMP could be the mechanism involved.
- © 2010 by American Heart Association, Inc.