Background Sex differences in sepsis are underexplored and incompletely understood. Cardiac function in early sepsis is pivotal in determining survival; hyperdynamic left ventricular ejection fraction is associated with higher mortality. Female sex may be cardioprotective, but variable experimental findings have not controlled for hypovolaemia. Sex-specific local cardiac versus peripheral inflammation in causing cardiovascular dysfunction also remain unclear. We therefore examined whether there are sex-specific differences in cardiac function in early sepsis, controlling for volaemic status and sex-specific differences in the peripheral inflammatory response initiated by tumour necrosis factor (TNFα). Methods We used an experimental polymicrobial sepsis (faecal slurry) model titrated to minimise hypovolaemia as a confounding factor. We quantified cardiac function (transthoracic cardiac echocardiography) 1 week before, and 18 h after, sepsis. Cardiac injury (troponin I), inflammation and immune cell infiltration (flow cytometry) were quantified in naïve and septic female and male mice 18 h after sepsis. To evaluate the sex-specific influence of TNFα derived from peripheral leukocytes, we repeated the experiments in iRHOM2−/− mice that are unable to shed TNFα exclusively from circulating leucocytes. Results Serum troponin I increased to 1.39 ± 0.38 ng mL−1 (from undetectable levels in controls) 18 h after onset of normovolaemic sepsis to a similar extent in both sexes. Stroke volume in male mice increased by 8 µL [(3–13); p = 0.004], compared to individualised pre-sepsis values. By contrast, stroke volume remained at baseline levels in females [mean difference: 4 µL (− 1 to 9)]. Messenger RNA levels of markers for cardiac injury/inflammation after sepsis (real-time polymerase-chain reaction) were elevated in male wild-type mice compared to female wild types (n = 10/sex), with higher cardiac mRNA levels of atrial natriuretic peptide, inflammation (TNFα) and oxidative stress (superoxide dismutase-1), although serum troponin I values were similarly elevated. Flow cytometry analysis of cardiac tissue showed doubling of CD4 + leukocyte infiltration in male mice. Sex-specific cardiac physiologic differences were similar in iRHOM2−/− mice that are unable to shed TNFα exclusively from leucocytes. Conclusions In early normovolaemic polymicrobial sepsis, a relative hyperdynamic response develops in male mice. Myocardial stress/injury after early sepsis is limited in females, with less cardiac infiltration of CD4 + leukocytes but independent of shedding of TNFα from peripheral circulating leukocytes.

and relatives of the same sex. Significance in this preliminary analysis was taken as a P-value <0.05 (uncorrected for multiple comparisons).We present preliminary data on the first 54 families analysed out of 122 families that carry the c.7300G>A variant. These data (Fig. 2) show a significantly greater contracture response in probands compared with their relatives for the dynamic halothane test only. Subgroup analyses suggest that sex of the proband may be a confounding factor.Our preliminary analyses suggest that there may be differences in the IVCT responses of probands, especially males, compared with their first-degree relatives. We plan to increase our sample size with this variant and also look at families with other recurrent variants.