TLR4 and NLRP3 Caspase 1- IL-1β- Axis are not Involved in Colon Ascendens Stent Peritonitis (Casp)-Associated Heart Disease

Abstract

Hemodynamic collapse and myocardial dysfunction are among the major causes ofdeath in severe sepsis. The purpose of this study was to assess the role played by TLR4and by the NLRP3 inflammasome in the cardiac dysfunction that occurs after highgradepolymicrobial sepsis. We performed the colon ascendens stent peritonitis (CASP)surgery in Tlr4-/-, Nlrp3-/- and caspase-1-/- mice. We also assessed for the first time theelectrical heart function in the CASP model. The QJ interval was increased in wild-typeC57BL/6J mice after CASP when compared to sham controls, a result paralleled by anincrease in the cardiac action potential duration (APD). The decreases in ejectionfraction (EF), left-ventricle end diastolic volume (LVEDV), stroke volume, and cardiacoutput found after CASP were similar among all groups of mice. Similar heart responsewas found when Nlrp3-/- mice were submitted to high-grade CLP. Despite developingcardiac dysfunction similar to wild-types after CASP, Nlrp3-/- mice had reducedcirculating levels of IL-1β, IL-6 and TNF-α. Our results demonstrate that the geneticablation of Tlr4, Nlrp3, and caspase-1 does not prevent the cardiac dysfunction, despitepreventing the increase in pro-inflammatory cytokines, indicating that these are notfeasible targets to therapy in high-grade sepsis.