Brain Death–Induced Systolic Ventricular Dysfunction and Its Association With NLRP3-Related Inflammatory Signaling in a Murine Model

BACKGROUND Cardiac dysfunction after brain death limits donor heart utilization. We sought to define the incidence and time course of brain death (BD)-induced left ventricular (LV) dysfunction and its association with NLRP3-related inflammatory signaling in a murine model. Upstream regulators of NLRP3 signaling, including P2X7 and PPAR-γ, were also evaluated. MATERIAL AND METHODS Thirty C57BL/6 mice were studied. In phase I, mice were randomized to control (n=8) and BD (n=10) groups. Echocardiography was performed at baseline, and serially for 3 hours. Hemodynamic data were compared. In phase II, mice were randomized to control (n=6) and BD (n=6) groups. Similar measurements were obtained at baseline and periodically for 60 minutes (T60). Mice were killed, and LV tissue samples collected for biochemical analyses. RESULTS In phase I, all BD animals developed significantly depressed LVEF by T60, with no deaths. Six animals in each group survived to T120, and 4 animals to T180. In phase II, all animals survived to T60. Mean LVEF, fractional shortening, and stroke volume were significantly reduced in the BD group. BD group demonstrated significantly greater expression of NLRP3, IL-1ß, TNF-alpha, and IL-6 in LV tissue. P2X7 expression did not differ between groups, while PPAR-γ expression showed a trend toward increase in BD animals. CONCLUSIONS The incidence of depressed LV function was 100% at T60, with no attrition. BD-induced LV dysfunction was associated with increased expression of NLRP3 and pro-inflammatory cytokines in LV tissue, suggesting involvement of NLRP3-related inflammatory signaling. Targeting this pathway may represent a potential strategy to preserve myocardial function following brain death.