The 4th Window: A Novel, Clinically Relevant Model Of Delayed Ischemic Preconditioning In Conscious, Chronically Instrumented Pigs

Most studies on cardiac ischemic preconditioning (IPC) focused on the 1 st or 2 nd window, where the preconditioning ischemic stimulus was induced briefly and the cardiac protection all occurred within a few hours or days. More recently 3 rd window models have been described with IPC induced over several days. The goal of this investigation was to determine if IPC could be extended for a longer time, making it more clinically relevant. In this new IPC model, which we named the 4 th window, pigs, chronically instrumented with coronary blood flow transducers, hydraulic occluders, and ultrasonic wall thickness crystals implanted in potentially ischemic and non‐ischemic zones, underwent IPC induced by 6 episodes of 90 min coronary stenosis (40% reduction in blood flow but no necrosis) every 12 hours over 3 days. 60 min coronary artery occlusion (CAO) followed by 3 days of coronary reperfusion, induced one week after IPC, resulted in infarct size, as a fraction of the area at risk, of 11±2.5%, less (p<0.05) than in the absence of IPC (42±3.9%). Most genes expressed in this model were novel, compared to prior IPC models, included genes mediating angiogenesis. To confirm angiogenesis, we found increased capillary density adjacent to the infarct in the 4 th window by 154% (p<0.05), and 38% increased, p<0.05, blood flow (measured with microspheres) during the 60min CAO, compared in the same samples with brief CAO before IPC. In summary, this novel model of 4 th window IPC induces angiogenesis and markedly different gene regulation than previous IPC models.