Elsevier

International Journal of Cardiology

Volume 339, 15 September 2021, Pages 93-98
International Journal of Cardiology

Proinflammatory TH17 cytokine activation, disease severity and outcomes in peripartum cardiomyopathy

https://doi.org/10.1016/j.ijcard.2021.06.022Get rights and content

Highlights

  • Immune dysregulation contributes to the pathogenesis and outcomes in patients with peripartum cardiomyopathy (PPCM).

  • 98 women with PPCM were followed postpartum with LVEF assessment, proinflammatory and immune-regulatory cytokine analysis.

  • Proinflammatory cytokines were associated with adverse outcomes, and immune-regulatory cytokines with myocardial recovery.

Abstract

Background

Immune dysregulation is implicated in the development and clinical outcomes of peripartum cardiomyopathy (PPCM).

Methods and results

98 women with PPCM were enrolled and followed for 1 year postpartum (PP). LVEF was assessed at entry, 6-, and 12-months PP by echocardiography. Serum levels of soluble interleukin (IL)-2 receptor (sIL2R), IL-2, IL-4, IL-17, IL-22, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by ELISA at entry. Cytokine levels were compared between women with PPCM by NYHA class. Outcomes including myocardial recovery and event-free survival were compared by cytokine tertiles. For cytokines found to impact survival outcomes, parameters indicative of disease severity including baseline LVEF, medications, and use of inotropic and mechanical support were analyzed. Levels of proinflammatory cytokines including IL-17, IL-22, and sIL2R, were elevated in higher NYHA classes at baseline. Subjects with higher IL-22 levels were more likely to require inotropic or mechanical support. Higher levels of TNF-α and IL-22 were associated with poorer event-free survival. Higher TNF-α levels were associated with lower mean LVEF at entry and 12 months. In contrast, higher levels of immune-regulatory cytokines such as IL-4 and IL-2 were associated with higher LVEF during follow up.

Conclusion

Proinflammatory cytokines IL-22 and TNF-α were associated with adverse event-free survival. IL-17 and IL-22 were associated with more severe disease. In contrast, higher levels of IL-2 and IL-4 corresponded with higher subsequent LVEF. Increased production of TH17 type cytokines in PPCM correlated with worse disease and outcomes, while an increased immune-regulatory response seems to be protective.

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.

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Section snippets

Abbreviations and definitions

Peripartum cardiomyopathyPPCM
Investigations in Pregnancy Associated CardiomyopathyIPAC
InterleukinIL
Interferon-gammaIFN-γ
Tumor necrosis factor-alphaTNF-α
New York Heart AssociationNYHA
Left ventricular ejection fractionLVEF
Left ventricular assist deviceLVAD

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.

References (17)

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