Female hormones prevent sepsis-induced cardiac dysfunction: an experimental randomized study

Abstract

Although epidemiologic research has demonstrated significant differences in incidence and outcomes of sepsis according to sex, their underlying biological mechanisms are poorly understood. Here, we studied the influence of hormonal status by comparing in vivo cardiac performances measured by MRI in non-ovariectomized and ovariectomized septic female rats. Control and ovariectomized rats were randomly allocated to the following groups: sham, sepsis and sepsis plus landiolol. Sepsis was induced by caecum ligation and punction (CLP). Landiolol, a short-acting selective β1-adrenergic blocker improving the in vivo cardiac performance of septic male rats was perfused continuously after sepsis induction. Cardiac MRI was carried out 18 h after induction of sepsis to assess in vivo cardiac function. Capillary permeability was evaluated by Evans Blue administration and measurement of its tissue extravasation. Variation in myocardial gene and protein expression was also assessed by qPCR and western-blot in the left ventricular tissue. Sepsis reduced indexed stroke volume, cardiac index and indexed end-diastolic volume compared to sham group in ovariectomized females whereas it had no effect in control females. This was associated with an overexpression of JAK2 expression and STAT3 phosphorylation on Ser727 site, and an inhibition of the adrenergic pathways in OVR females. Landiolol increased the indexed stroke volume by reversing the indexed end-diastolic volume reduction after sepsis in ovariectomized females, while it decreased indexed stroke volume and cardiac index in control. This was supported by an overexpression of genes involved in calcium influx in OVR females while an inactivation of the β-adrenergic and a calcium efflux pathway was observed in control females. Sepsis decreased in vivo cardiac performances in ovariectomized females but not in control females, presumably associated with a more pronounced inflammation, inhibition of the adrenergic pathway and calcium efflux defects. Administration of landiolol prevents this cardiac dysfunction in ovariectomized females with a probable activation of calcium influx, while it has deleterious effects in control females in which calcium efflux pathways were down-regulated.

Sex or gender differences in treatment outcomes of sepsis and septic shock

“…They also showed a survival advantage of female sex hormones against subsequent septic challenge [ 24 ]. In addition, less pronounced cardiac dysfunction was seen in female mice than in male mice in a cecal ligation and puncture (CLP) sepsis model [ 25 ]. In that study, female mice showed decreased production of TNF-α, IL-6, and inducible nitric oxide synthase.…”

“…Such effects were assumed to be due to overexpression of genes involved in calcium influx. In contrast, inactivation of the β-adrenergic and a calcium efflux pathway was seen in control females [ 25 ]. The protective effect of estrogen against liver damage in sepsis has also been observed in a lipopolysaccharide (LPS)-induced sepsis model.…”

Interactions between Gender and Sepsis—Implications for the Future

“…Conversely, administration of landiolol increased calcium entry into the cardiomyocytes of ovariectomized female rats. Landiolol restored JAK2 expression and overexpressed genes responsible for calcium influx in ovariectomized septic females, whereas it did the opposite in control females [ 33 ]. This may explain why cardiac performance improves only in ovariectomized septic females (i.e., less exposure to female hormones during sepsis).…”

The Regulation of Neutrophil Migration in Patients with Sepsis: The Complexity of the Molecular Mechanisms and Their Modulation in Sepsis and the Heterogeneity of Sepsis Patients

“…Targeting of single proinflammatory mediators . The targeting of TNFα [ 215 ], IL1, IFNγ [ 125 , 126 , 127 , 136 , 137 ], proteases ( Section 5 [ 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 ]), and female sex hormones [ 413 , 415 , 445 ] has been tried and/or suggested by animal studies, but the results so far have not been convincing, even though IL1 inhibition and immunostimulation seemed to improve survival for subsets of sepsis patients in two of these studies [ 446 , 447 , 448 , 449 , 450 ].…”