Proinflammatory TH17 cytokine activation, disease severity and outcomes in peripartum cardiomyopathy
Graphical abstract
Graphic 1: Depiction of naïve CD4 T-cell differentiation pathways. Increased levels of IFN-γ and IL-12 drive differentiation to TH1 T cells which further produce IFN-γ effector cytokines. Increased IL-6 and TGF-β stimulated CD4 T cells to differentiate into TH17 T cells which further produce IL-17 and IL-22 effector cytokine. Increased levels of IL-4 and IL-33 stimulate differentiation to TH2 T cells which then produce IL-4 effector cytokines.
Section snippets
Abbreviations and definitions
Peripartum cardiomyopathy PPCM Investigations in Pregnancy Associated Cardiomyopathy IPAC Interleukin IL Interferon-gamma IFN-γ Tumor necrosis factor-alpha TNF-α New York Heart Association NYHA Left ventricular ejection fraction LVEF Left ventricular assist device LVAD
Cohort
One hundred women with newly diagnosed PPCM were enrolled at 30 centers between December 2009 and September 2012. Women included were at least 18 years of age, were diagnosed with nonischemic cardiomyopathy late in pregnancy or in the early postpartum period, with a left ventricular ejection fraction estimated by clinical testing of ≤45%. Women with significant valvular disease, coronary artery disease (positive functional study or >50% stenosis of major epicardial vessel), bacteremia, active
Results
For the PPCM cohort available for echo and cytokine analysis (n = 98), the mean age was 30 ± 6 years, time postpartum 31 ± 24 days, LVEF at entry 0.35 ± 0.09, NYHA class I/II/III/IV (by percent) 12/46/26/16 with 29% black women and 71% white or other. There was no significant difference between the PPCM cohort and controls in mean age or race (Table 1), however days postpartum was significantly later for control postpartum women (control 49 ± 11 days versus PPCM 31 ± 24 days, p = 0.02). In
Discussion
Our study examined proinflammatory cytokines including IFN-γ, TNF-α and the TH17 pathway cytokines in the IPAC cohort to characterize the dysregulated immune response in PPCM and evaluate the association with disease severity and outcomes. We found increased production of IL-17, IL-22, and sIL2R were associated with more severe NYHA class, need for inotropes and/or mechanical support, and PPCM patients in the highest tertiles of IL-22 and TNF-α levels demonstrated significantly poorer
Conclusion
Our study demonstrated that in a cohort of women with PPCM, proinflammatory cytokines IL-17, IL-22, and sIL2R were associated with more severe NYHA class, and poorer event-free survival. Our study is the first to identify increased IL-17 and IL-22 production in any PPCM subset, and it is also the first to describe an association between cytokines in the TH17 pathway with disease severity and adverse outcomes. Further studies to elicit the mechanisms by which TH17 activation may play a role in
Funding
This investigation was supported by the National Heart, Lung, and Blood Institute through contract HL102429
Acknowledgements
We would like to acknowledge Allison Sedlock for help in the creation of the graphic for this manuscript.
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