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Published on: August 16, 2019
Brain Death-Induced Systolic Ventricular Dysfunction and Its Association With NLRP3-Related Inflammatory Signaling in
Lei Huang1,2, Kevin P Zbierski3, Ye Yuan2
1Department of Neurosurgery, Loma Linda University Medical Center, Loma Linda, CA, USA.
Insights
Brain death (BD) causes 100% left ventricular (LV) dysfunction within 60 minutes in mice. This cardiac dysfunction is linked to increased NLRP3 inflammasome signaling and pro-inflammatory cytokines in the heart.
Area of Science:
- Cardiology
- Immunology
- Transplantation Science
Background:
- Brain death (BD) significantly impacts donor heart quality, limiting organ utilization.
- Left ventricular (LV) dysfunction is a critical complication following BD.
- Understanding the mechanisms behind BD-induced cardiac dysfunction is crucial for improving transplant outcomes.
Purpose of the Study:
- To determine the incidence and temporal profile of BD-induced LV dysfunction in a murine model.
- To investigate the association between BD and NLRP3-related inflammatory signaling in the myocardium.
- To evaluate upstream regulators of NLRP3, including P2X7 and PPAR-γ.
Main Methods:
- Utilized a murine model of brain death (BD) with control groups.
- Performed serial echocardiography and hemodynamic measurements to assess LV function.
- Analyzed LV tissue for the expression of NLRP3, IL-1ß, TNF-alpha, IL-6, P2X7, and PPAR-γ.
Main Results:
- 100% of BD mice exhibited significantly reduced left ventricular ejection fraction (LVEF) by 60 minutes post-BD.
- BD led to significant decreases in LVEF, fractional shortening, and stroke volume.
- Increased expression of NLRP3, IL-1ß, TNF-alpha, and IL-6 was observed in the LV tissue of BD mice.
Conclusions:
- Brain death consistently induces significant left ventricular dysfunction in mice.
- NLRP3 inflammasome activation and associated pro-inflammatory cytokines play a role in BD-induced cardiac dysfunction.
- Targeting the NLRP3 inflammatory pathway may offer a therapeutic strategy to preserve myocardial function after brain death.
Abstract:
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.
