A. Yoniles2, O. Anjorin1, M. Bhaskara2, M. Wang1 1Indiana University School Of Medicine, Cardiothoracic Surgery, Department Of Surgery, Indianapolis, IN, USA 2Indiana University School Of Medicine, Indianapolis, IN, USA
Introduction: Endotoxemia can occur following cardiac surgery. Previous studies have indicated better myocardial responses with preserved cardiac function in female animals compared to males after LPS challenge; however, the mechanisms remain largely unclear. Understanding how male and female myocardium responds to LPS can provide better insights on managing patients after cardiac operation. Our published studies have revealed that TNFa substantially increased in heart tissue and serum following LPS. Females experienced less cardiac dysfunction than males when exposed to equivalent dose of TNFa. Therefore, sex-related disparities in myocardial impairment could be due to an indirect/secondary outcome from LPS-induced inflammatory cytokines, like TNFa. To better understand myocardial reactions between males and females during endotoxemia, we aim to uncover sex differences in LPS-caused direct effects on cardiac function using coronary infusion of LPS.
Methods: Isolated hearts from aged-matched adult male and female mice were subjected to LPS infusion via Langendorff after >20-min equilibration (Eq). Dose responsive study with LPS at 2.5, 5.0, and 7.5 mg/kg of body weight was performed in male hearts. Left ventricular developed pressure (LVDP) was continuously recorded. Significant depression of LVDP (>20% drop) after LPS infusion was considered rapid response to LPS. Female estrous cycle was determined via vaginal smear. Oxidative phosphorylation (Oxphos) pathway involving 5 protein complexes was determined in heart tissue using Western blot Oxphos cocktail. Data was analyzed using t-test, one-way or two-way ANOVA, n = 4-9 mouse hearts/group, p<0.05 = statistical significance.
Results: Male hearts infused with 5.0 and 7.5 mg/kg of LPS demonstrated significant depression of LV function (Fig. A). Males also experienced worse LV function than females following 5.0 mg/kg of LPS infusion (Fig. B). However, there were no significant differences in cardiac function between female groups in different estrous phases. Interestingly, LV function was back to normal after rapid/1st response to LPS and then depressed again following 50’-LPS infusion (Fig. C, D). Protein levels of complex III-UQCRC2 and IV-MTCO1 were significantly reduced in male hearts with 50’-LPS infusion, but not in the hearts collected after 1st response (short-time LPS infusion) (Fig. E, F).
Conclusion:
Our data demonstrates that male hearts exhibit higher sensitivity to LPS-induced rapid cardiac dysfunction compared to females, but estrogen may have little influence on the heart against LPS-induced rapid functional depression. Short-time LPS infusion may induce defense mechanisms to prevent the heart from metabolic dysfunction via maintained Oxphos pathway.
