Ischemia and reperfusion both contribute to tissue damage after myocardial infarction. Although many drugs have been shown to reduce infarct size when administered before ischemia, few have been shown to be effective when administered at reperfusion. Moreover, although it is generally accepted that a burst of reactive oxygen species (ROS) occurs at the onset of reperfusion and contributes to tissue damage, the source of ROS and the mechanism of injury is unclear. We now report the finding that chloramphenicol administered at reperfusion reduced infarct size by 60% in a Langendorff isolated perfused rat heart model, and that ROS production was also substantially reduced. Chloramphenicol is an inhibitor of mitochondrial protein synthesis and is also an inhibitor of a subset of cytochrome P450 monooxygenases (CYPs). We could not detect any effect on mitochondrial encoded proteins or mitochondrial respiration in chloramphenicol-perfused hearts, and hypothesized that the effect was caused by inhibition of CYPs. We tested additional CYP inhibitors and found that cimetidine and sulfaphenazole, two CYP inhibitors that have no effect on mitochondrial protein synthesis, were also able to reduce creatine kinase release and infarct size in the Langendorff model. We also showed that chloramphenicol reduced infarct size in an open chest rabbit model of regional ischemia. Taken together, these findings implicate CYPs in myocardial ischemia͞reperfusion injury.C urrent treatment of myocardial infarction is directed at the restoration of blood flow to the ischemic region and reduction of myocardial oxygen demand. However, during reperfusion, the heart undergoes further damage due, in large part, to the generation of reactive oxygen species (ROS) (1). It is clear that permanent ischemia results in necrotic cell death. However, it is unclear whether reperfusion itself induces apoptosis or merely permits the manifestation of cell death processes that were initiated and irreversibly committed to during ischemia. Moreover, the relative contributions to tissue injury by the ischemic phase and by reperfusion have been difficult to evaluate. Resolving this question carries important therapeutic implications, as efforts directed toward treating reperfusion injury would have limited value if most cell death were predestined during ischemia.Although we initially hypothesized that the protective effect of chloramphenicol was caused by inhibition of mitochondrial protein synthesis, we did not see down-regulation of mitochondrial-encoded proteins after chloramphenicol infusion. The energy-sparing effects of inhibition of cytosolic protein synthesis have been described (2), and our previously reported observation that mitochondrial elongation factor Tu is phosphorylated during ischemia suggests a similar process may take place in the mitochondria (3). However, because chloramphenicol also inhibits some cytochrome P450 monooxygenases (CYPs), it was important to determine whether that inhibitory effect was relevant to cardioprotection. In this re...

Introduction: Pulmonary vein (PV) isolation may cure paroxysmal atrial fibrillation (PAF); however, identification of PV potentials may be difficult in sinus rhythm. Studies have suggested that atrial pacing may improve the identification of PV potentials. Methods and Results: In 25 consecutive patients who underwent PV isolation for PAF, the results of pacing from the distal PV, distal and proximal coronary sinus, and high right atrium compared to sinus rhythm were analyzed to determine the most effective pacing site for identification of PV potentials. The percentage of confirmed PV potentials and the longest interval between atrial and PV potentials in each PV were compared during differential site pacing and sinus rhythm. PV potentials were confirmed in 63 (82%) of 77 PVs that could be mapped during the complete pacing protocol and during sinus rhythm. Distal PV pacing identified significantly more PV potentials (left upper pulmonary vein [LUPV] 100%, left lower pulmonary vein [LLPV] 84%, right upper pulmonary vein [RUPV] 80%, right lower pulmonary vein [RLPV] 53%) compared to other pacing sites and sinus rhythm. Among atrial pacing sites, those ipsilateral to the PV being mapped were the most effective for identifying PV potentials. The intervals between atrial and PV potentials were significantly longer during distal PV pacing than pacing at other sites (LUPV 81.6 ± 26.2 ms, LLPV 61.4 ± 26.1 ms, RUPV 59.7 ± 33.2 ms, RLPV 39.7 ± 26.7 ms). Conclusion: (1) Distal PV pacing was most effective for identifying PV potentials. (2) The interval between atrial and PV potentials was longest during distal PV pacing. (J Cardiovasc Electrophysiol, Vol. 14, pp. 1311‐1318, December 2003)