• Blood Cardioplegia Induction, Perfusion Storage and Graft Dysfunction in Cardiac Xenotransplantation

      Goerlich, Corbin E; Griffith, Bartley; Singh, Avneesh K; Abdullah, Mohamed; Singireddy, Shreya; Kolesnik, Irina; Lewis, Billeta; Sentz, Faith; Tatarov, Ivan; Hershfeld, Alena; et al. (Frontiers Media S.A., 2021-06-09)
      Background: Perioperative cardiac xenograft dysfunction (PCXD) describes a rapidly developing loss of cardiac function after xenotransplantation. PCXD occurs despite genetic modifications to increase compatibility of the heart. We report on the incidence of PCXD using static preservation in ice slush following crystalloid or blood-based cardioplegia versus continuous cold perfusion with XVIVO© heart solution (XHS) based cardioplegia. Methods: Baboons were weight matched to genetically engineered swine heart donors. Cardioplegia volume was 30 cc/kg by donor weight, with del Nido cardioplegia and the addition of 25% by volume of donor whole blood. Continuous perfusion was performed using an XVIVO © Perfusion system with XHS to which baboon RBCs were added. Results: PCXD was observed in 5/8 that were preserved with crystalloid cardioplegia followed by traditional cold, static storage on ice. By comparison, when blood cardioplegia was used followed by cold, static storage, PCXD occurred in 1/3 hearts and only in 1/5 hearts that were induced with XHS blood cardioplegia followed by continuous perfusion. Survival averaged 17 hours in those with traditional preservation and storage, followed by 11.47 days and 15.03 days using blood cardioplegia and XHS+continuous preservation, respectively. Traditional preservation resulted in more inotropic support and higher average peak serum lactate 14.3±1.7 mmol/L compared to blood cardioplegia 3.6±3.0 mmol/L and continuous perfusion 3.5±1.5 mmol/L. Conclusion: Blood cardioplegia induction, alone or followed by XHS perfusion storage, reduced the incidence of PCXD and improved graft function and survival, relative to traditional crystalloid cardioplegia-slush storage alone.
    • Innate immune TLR7 signaling mediates platelet activation and platelet-leukocyte aggregate formation in murine bacterial sepsis

      Williams, Brittney; Zhu, Jing; Zou, Lin; Chao, Wei (Taylor and Francis Inc., 2022-01-01)
      Thrombocytopenia is a common complication in sepsis and is associated with higher mortality. Activated platelets express CD62P, which facilitates platelet-leukocyte aggregate (PLA) formation and contributes to thrombocytopenia in sepsis. We have reported that thrombocytopenia in murine sepsis is partly attributable to TLR7 signaling, but the underlying mechanism is unclear. In the current study, we tested the hypothesis that TLR7 mediates platelet activation and PLA formation during sepsis. In vitro, whole blood from WT mice treated with loxoribine, a TLR7 agonist, exhibited a dose-dependent increase in activated platelets compared to the control (PBS with 0.05% DMSO) or loxoribine-treated TLR7−/− whole blood. In a murine model of sepsis, there was a significant increase in platelet activation and PLA formation 24 hours after cecal ligation and puncture (CLP) as evidenced by double positive expression of CD41+/CD62P+ and CD45+/CD62P+, respectively. The sepsis-induced PLA formation was significantly attenuated in TLR7−/− mice. Finally, in ex-vivo experiments, plasma isolated from septic mice induced WT platelet activation, but such effect was significantly attenuated in platelets deficient of TLR7. These findings demonstrate a pivotal role of TLR7 signaling in platelet activation and PLA formation during bacterial sepsis. © 2022 Taylor & Francis Group, LLC.
    • Porcine Orthotopic Cardiac Xenotransplantation: The Role and Perspective of Anesthesiologists.

      Strauss, Erik R; Odonkor, Patrick N; Williams, Brittney (Elsevier, 2022-04-08)
    • Role of extracellular microRNA-146a-5p in host innate immunity and bacterial sepsis

      Wang, Sheng; Yang, Yang; Suen, Andrew; Zhu, Jing; Williams, Brittney; Hu, Jiang; Chen, Fengqian; Kozar, Rosemary; Shen, Shiqian; Li, Ziyi; et al. (Elsevier Inc., 2021-11-13)
      Extracellular miRNAs (ex-miRNAs) mediate intercellular communication and play a role in diverse physiological and pathological processes. Using small RNA sequencing, we identify that miRNAs are the most abundant RNA species in the plasma and differentially expressed in murine and human sepsis, such as miR-146a-5p. Exogenous miR-146a-5p, but not its duplex precursor, induces a strong immunostimulatory response through a newly identified UU-containing motif and TLR7 activation, and an immunotolerance by rapid IRAK-1 protein degradation via TLR7→MyD88 signaling and proteasome activation, whereas its duplex precursor acts by targeting 3′ UTR of Irak-1 gene via Ago2 binding. miR-146a knockout in mice offers protection against sepsis with attenuated interleukin-6 (IL-6) storm and organ injury, improved cardiac function, and better survival. In septic patients, the plasma miR-146a-5p concentrations are closely associated with the two sepsis outcome predictors, blood lactate and coagulopathy. These data demonstrate the importance of extracellular miR-146a-5p in innate immune regulation and sepsis pathogenesis. © 2021 The Author(s)
    • Thrombopoietin, Soluble CD40 Ligand, and Platelet Count During Veno-arterial Extracorporeal Membrane Oxygenation

      Mazzeffi, Michael; Henderson, Reney; Powell, Elizabeth; Strauss, Erik; Williams, Brittney; Tanaka, Kenichi; Yang, Stephen; Deatrick, Kristopher; Madathil, Ronson (Wolters Kluwer Health, 2022-05-01)