Temporal expression of cytokines and B-cell phenotypes during mechanical circulatory support

Amit Iyengar; Nicholas Wisniewski; Oh Jin Kwon; Martin Cadeiras; Mario Deng; Joanna Schaenman; Yael Korin; Richard Shemin; Elaine Reed; Murray Kwon

doi:10.1016/j.jtcvs.2019.03.061

Temporal expression of cytokines and B-cell phenotypes during mechanical circulatory support

J Thorac Cardiovasc Surg. 2020 Jan;159(1):155-163. doi: 10.1016/j.jtcvs.2019.03.061. Epub 2019 Apr 4.

Authors

Affiliations

¹ Division of Cardiac Surgery, UCLA Medical Center, Los Angeles, Calif.
² Division of Cardiology, UCLA Medical Center, Los Angeles, Calif.
³ Division of Infectious Disease, UCLA Medical Center, Los Angeles, Calif.
⁴ UCLA Pathology and Laboratory Medicine, UCLA Medical Center, Los Angeles, Calif.
⁵ Division of Cardiac Surgery, UCLA Medical Center, Los Angeles, Calif. Electronic address: mkwon@mednet.ucla.edu.

Abstract

Background: Allosensitization during mechanical circulatory support (MCS) is a well-described phenomenon, although its mechanism remains unknown. Although immune-mediated interactions from devices or blood transfusions have been proposed, the role of inflammation in this development is less clear. This study was undertaken to further investigate the temporal association of cytokines and B-cell phenotypes in the MCS population.

Methods: Adult patients who received the Heartmate II (Thoratec, Pleasanton, Calif) at our center between September 2012 and March 2015 were prospectively followed after device implantation. Blood draws for anti-human leukocyte antigen (HLA) antibody, cytokine expression, and B-cell immunophenotyping were performed before implantation and for 3 weeks postoperatively. Time courses for cytokines and B-cell subsets were expressed using visual representations of median levels as heat maps, and mixed modeling analysis was used to model changes with time and patient factors.

Results: Twenty patients who received the Heartmate II (Thoratec) were analyzed during the study period. Four patients showed measureable levels of anti-HLA antibody during the follow-up period, although 3 of these had evidence of antibodies preoperatively. Analysis of cytokine trends revealed early (interleukin [IL]-6, IL-8, and IL-10) and late peaking (IL-3, IL-4, fibroblast growth factor 2, and CD40L) patterns. Upregulation of switched memory, transitional, and plasma blast B cells occurred over time. Right ventricular assist device use and low Interagency Registry for Mechanically Assisted Circulatory Support score were associated with decreased mature naive and increased antibody-secreting cells.

Conclusions: MCS device implantation was associated with increased inflammatory cytokines and maturation of B-cell phenotypes. No patients developed de novo HLA antibodies, whereas several showed increases in anti-HLA antibody levels detected before implantation. This suggests that inflammation and maturation of existing sensitized B cells might play an important role in the pathogenesis of allosensitization in MCS.

Keywords: B-cell maturation; device mediated sensitization; device-mediated inflammation; mechanical circulatory support; ventricular assist device.

Grants and funding

UL1 TR001881/TR/NCATS NIH HHS/United States