There is increasing evidence in the literature that gender, and particularly female hormones, affects the response to sepsis (2, 4, 14). However, the mechanisms of this phenomenon remained to be demonstrated. To our knowledge, we provide the first study comparing cardiac performances in OVR and control female septic rats. A major point of our approach is the assessment of cardiac function using MRI, thereby providing an in vivo evaluation of cardiac function that includes heart-vessels interactions. Our results highlight disparities between control and OVR female rats. No impairment of cardiac performances after sepsis was observed in control females whereas in OVR females, sepsis decreased SVi and CI related to an EDVi diminution.
Different mechanisms may explain this effect. The alteration in cardiac performance (decrease in SVi and CI) in septic OVR females was associated with a decrease in EDVi without effect on LVEF, DBP and MBP. This suggests a left ventricular diastolic dysfunction with a defect of filling during the diastole, while the venous return and the myocardial contractility were preserved. In our previous study (8), we showed that this effect was obtained in males, at variance with females.
Other experimental models have found improved survival in female mice after CLP compared to males (10, 14). This is in accordance with our present data in control females: in OVR septic females, the hemodynamic profile seemed to be close to that of septic males.
This suggests a protective effect of female hormones in sepsis, especially at the cardiovascular level. Female hormones have a protective effect on cardiac functions and cardiovascular response during major inflammation (4). Experimental administration of 17-β-œstradiol improved functional recovery after ischemia-reperfusion in rats (9). In an endotoxin-induced sepsis model, administration of 17-β-œstradiol mitigated septic cardiac dysfunction (15). Different mechanisms could explain the protective effect of female hormones in sepsis; an immunomodulatory effect of oestrogens has been reported in various models (16).
Short acting β-blocker treatment may be a promising therapeutic approach in sepsis. Its efficacy has been shown in male rats septic models (8, 17). Our study confirms these findings in OVR females, since landiolol administration during sepsis improved SVi and CI with an increase in EDVi. The present report suggests that the lack of effect of landiolol in females was mediated by female hormones. Thus, landiolol improved cardiac performance in conditions suggesting a reduced exposure to female hormones during sepsis.
In the second part of our study, we looked for the underlying mechanism of changes in hemodynamic profiles. We previously identified, in a transcriptomic study, major differences in sepsis-induced deregulation of gene expression in male and female rats and confirmed the benefit of landiolol intake on cardiac function in male (13). Our current results highlight a similar gene expression profile in OVR females to that found in males. Thus, genes involved in cardiac contraction, adrenergic signalling pathway and apoptosis were more deregulated in OVR females and partially restored with landiolol administration. No benefit of landiolol was found in control females. These results are in line with findings on the human cardiopathy during sepsis (18). In septic rat, dysregulation of genes involved in α-adrenergic, β-adrenergic and calcium cycling pathway was associated with reduced survival (19). These transcriptomic regulations reduce the L-type calcium current (20) and increase the cytosolic calcium that lead to failure of diastolic relaxation, and decrease the calcium concentration in the sarcoplasmic reticulum, which affect systolic contraction as previously described in septic cardiomyopathy (21). Our MRI findings on cardiac performances and data on transcripts regulation are consistent with these studies.
In contrast to previous studies (8, 22), we did not show any significant decrease in HR during treatment with landiolol, regardless of hormonal status. This lack of difference may be explained by a relatively low number of analysed rats, which probably was a drawback for statistical correlations. Another possible explanation could be a sub-optimal dosage of landiolol. This, however, seems unlikely since we used the same dosage as that previously used to obtain a decrease in HR (8).
During sepsis, there are structural and functional changes in the endothelium responsible for endothelial dysfunction and microcirculation disorders (23, 24), resulting in higher permeability and oedema. Estradiol administration in male rats and in OVR females has been shown to improve intestinal microcirculation during sepsis (25). However, we found no significant differences in EB lung tissue concentration between the various groups, although there was a trend toward an increased permeability in OVR females. Further investigations are needed to define the effects of female hormones on pulmonary endothelium and microcirculation during sepsis.
Our study has several limitations. Our experimental model of sepsis, CLP, is considered as the reference method (26), but the main drawback of this method is its lack of reproducibility (27, 28). We attempted to reproduce the experimental conditions obtained in our previous study. However, we reduced the vascular filling performed during the 18 hours after CLP, to better mimic the initial phase of human septic shock. This resulted in an increased mortality in our septic animals. Nevertheless, we found deleterious consequences and more impaired cardiac performance in the rats assessed in the group with the highest mortality (sepsis plus landiolol females). Another limitation was that our study did not assess the baseline response to landiolol. Landiolol is hydrolysed to an inactivate metabolite by esterases, which activities are higher in female rats than in male rats (29). Whether this activity can be affected by OVR is unknown. Response to general anesthesia may also be sex-mediated (30), and therefore affected by OVR. Finally, the plasma concentrations of female sex hormones are likely to vary depending on oestrus cycle in females, and this cycle was not considered during sepsis.