Delayed intracardiac remote ischemic preconditioning reduces infarct size in remote myocardium of pigs

Cardioprotection induced by repetitive ischemia/reperfusion (I/R) is not confined to the ischemic region but may extend to distant myocardial territories, a phenomenon termed intracardiac remote ischemic preconditioning (icRIPC). The present study aimed to evaluate the delayed effects of icRIPC on infarct size (IS), left ventricular (LV) function (LVF), and myocardial gene and protein expression. icRIPC was induced in 13 pigs by 3 cycles of 10 min ischemia/10 min reperfusion of the left anterior descending coronary artery (LAD) (conditioning) territory, followed 24 h later by reperfused acute myocardial infarction (AMI) of the left circumflex artery (LCx) (infarcted) territory, induced by 90-min percutaneous balloon occlusion of the mid LCx followed by reperfusion (group icRIPC-AMI). Thirteen additional pigs underwent a sham icRIPC procedure followed by reperfused LCx AMI 24 h later and served as controls (group AMI). Five pigs from each group were euthanized at 3 days, and myocardial expression of nine selected genes was quantified by RT-qPCR in the distal LAD and LCx territories. Protein expression of the two significantly upregulated genes was assessed by Western blot. The remaining eight pigs in each group were followed for 1 month. At 3 days after reperfused AMI, superoxide dismutase-2 (SOD2) protein expression was increased in the infarcted LCx territory of the icRIPC-AMI group, whereas inducible nitric oxide synthase (iNOS/NOS2) protein expression was increased in the distal LAD territory. At 1 month, IS was lower in the icRIPC-AMI than in the AMI group (8.4±3.7% vs. 14.1±1.8% of LV mass, p=0.003), whereas global LVF was marginally improved. However, segmental mean contraction velocity of the infarcted lateral wall was higher in the icRIPC-AMI than in the AMI group (14.8±1.6 vs. 13.3±0.9 mm/s, p=0.026). These findings provide potentially mechanistic evidence for delayed icRIPC, characterized by reduced IS, improved regional myocardial function, and territory-specific changes in cardioprotective protein expression, and may represent an experimental correlate of the clinical phenomenon of pre-infarction angina.