Abstract 602: Repetitive Coronary Stenosis Induces a Third Window of Ischemic Preconditioning
The mechanisms responsible for the 1st and 2nd window of protection following ischemic preconditioning (IPC) have been studied in detail. We tested the hypothesis that chronic myocardial ischemia (repetitive bouts of coronary stenosis, CS) may induce IPC mediated by different mechanisms. To study this, 6 episodes of 90 min chronic CS (reduction in coronary blood flow, >35% from baseline), followed by reperfusion every 12 hrs were examined in conscious pigs chronically instrumented to measure left ventricular (LV) pressure and regional wall thickness. Infarct size/area at risk (IF/AAR) was assessed in all groups after 60 min of coronary artery occlusion (CAO) followed by 4 days of reperfusion. This resulted in IF/AAR of 42±5% in control pigs without IPC (n=5). Following repetitive CS, IF/AAR was markedly decreased (p<0.05) (4±6%, n=4). The 2nd window of IPC was induced in 5 pigs by two 10 min periods of CAO. 24 hrs later, the 60 min of CAO also resulted in reduced IF/AAR of 16±4%. In 6 pigs, 24 hrs after IPC without 60 min of CAO, the IPC myocardium was found to have significant, p<0.05, 2– 4-fold increases in iNOS, Cox-2, phosphorylated PKC and AMPK. None of these proteins was elevated in myocardium subjected to repetitive CS. Pretreatment with an NO synthase inhibitor, L-NNA, prevented the 2nd window of IPC as expected, since iNOS was elevated, but failed to prevent the ischemic protection following repetitive CS, where iNOS was not elevated. Following repetitive CS, genomic microarray analysis revealed upregulation of cytoprotective genes, e.g., IAP, H11 kinase, αB-crystallin, Akt 1, Bcl-2. These cytoprotective genes were also found to be upregulated in samples from patients with chronic coronary artery disease and hibernating myocardium. Thus, repetitive CS induces powerful protection against lethal myocardial ischemia, with mechanisms radically different from that observed in the 2nd window of IPC, suggesting a novel “third window” of IPC, which could also be involved in the protection inherent to hibernating myocardium.