## 4 Discussion  
In this study, we showed that sevoflurane AP induces changes in cytokine dynamics in rats, and that AP administered 24 h before or immediately before induction of I/R was associated with reduced myocardial apoptosis, increased infiltration of endothelial progenitor cells and reduced fibrotic scars. This has important implications for clinical practice, as volatile anesthetics represent an attractive preconditioning stimulus that benefits from extensive clinical experience and involves fewer risks while being associated with a more predictable cardioprotective response than IP [26]. Clinical trials have involved only the early preconditioning phase [27]. Taking into account the present results, the beneficial effects of late preconditioning in the clinical context are also worth exploring. Figure 8: Optical microscopy, cross section through the heart at the level of the left ventricle. Histological appearance of the infarction area (blue color) at 14 days, atypical aspect of hematoxylin-eosin and methyl blue staining, in the CG (**A**), EAFG (**B**) and LAPG (**C**) using \(\times\)10 magnification. Figure 9: Graphical representation of the degree of fibrosis in the three groups, with a reduced fibrotic area for the preconditioned groups when compared to the control group. CG in blue, EAPG in green, LAPG in purple. * marks statistically significant results. The phenomenon of AP is an attractive concept in medical practice because perioperative ischemia and myocardial infarction are a major cause of mortality and morbidity, especially following high-risk interventions. Therefore, the fact that the protective effect of volatile anesthesia extends long after surgery is of real clinical interest. There are data that provide a connection between AP and another interesting topic, namely bone marrow stem cells, with its subpopulation of endothelial progenitor cells [11]. [PERSON] et al. reported in 2009 that one of the cardioprotective mechanisms of late remote ischemic preconditioning is increased MSC mobilization and recruitment; they also demonstrated that this behavior of the MSC is closely correlated with the increase in the plasma level of some cytokines involved in the dynamics of the respective cells. An interventional study was performed which showed that by blocking the SDF-1\(\alpha\)-CXCR4 axis (CXCR4 is a surface receptor for SDF-1 \(\alpha\)) both the mobilization of the BMSC and their related protection are abolished [6]. Sevoflurane AP led to significantly increased levels of VEGF at 3 h and of G-CSF and IL-6 at 6 h. Both VEGF [28] and IL-6 [19] are involved in pro-survival signaling. VEGF is the ligand for flk-1 [29], the marker of endothelial progenitor cells. It plays important roles in angiogenesis and vasculogenesis [29], and has previously been implicated in IP [30]. IL-6 deficient mice are resistant to IP [19]. In humans, CD34+ endothelial progenitor cell mobilization induced by acute myocardial infarction was associated with a rise in G-CSF [31]. Moreover, it is unlikely that the observed changes in cytokine dynamics are attributable to a pro-inflammatory status, as rats suffered minimal manipulation prior to intubation and ventilation and were not subjected to a surgical intervention. At 24 h following AP, treated rats exhibited decreased numbers of cardiac apoptotic bodies and increased numbers of c-kit\({}^{+}\) endothelial progenitor cells. This is highly interesting, as c-kit\({}^{+}\)cells have been shown to be critical for the late window of ischemic preconditioning [6]. We acknowledge that our study did not allow us to distinguish between resident cardiac versus bone marrow-derived MSCs. Fibrotic scar extension represents a clinical prognostic factor in patients recovering after an acute myocardial infarction [32; 33]. In our study, the fibrotic area at 14 days was significantly reduced in preconditioned rats, and these findings were consistent for both the early and the late windows of AP, with a more pronounced reduction for the late preconditioned group.