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dc.contributor.authorWalker, SLMen_US
dc.contributor.authorMuthoo, Cen_US
dc.contributor.authorSanchez, Jen_US
dc.contributor.authorDel Arroyo, AGen_US
dc.contributor.authorAckland, GLen_US
dc.description.abstractBACKGROUND: 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.en_US
dc.format.extent27 - ?en_US
dc.relation.ispartofIntensive Care Med Expen_US
dc.rightsCreative Commons
dc.rightsAttribution 3.0 United States*
dc.subjectCardiac dysfunctionen_US
dc.titleSex-specific differences in cardiac function, inflammation and injury during early polymicrobial sepsis.en_US
dc.rights.holder© The Author(s) 2022.
pubs.notesNot knownen_US
pubs.publication-statusPublished onlineen_US
rioxxterms.funderDefault funderen_US
rioxxterms.identifier.projectDefault projecten_US
qmul.funderUnderstanding vagal control of the left ventricle::British Heart Foundation Programme Granten_US

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