The Prognostic Impact of Circulating Regulatory T Lymphocytes on Mortality in Patients with Ischemic Heart Failure with Reduced Ejection Fraction

Abstract

Background. Heart failure with reduced ejection fraction (HFrEF) constitutes a global health issue. While proinflammatory cytokines proved to have a pivotal role in the development and progression of HFrEF, less attention has been paid to the cellular immunity. Regulatory T lymphocytes (Tregs) seem to have an important role in the induction and maintenance of immune homeostasis. Therefore, we aimed to investigate the impact of Tregs on the outcome in HFrEF. Methods. We prospectively enrolled 112 patients with HFrEF and performed flow cytometry for cell phenotyping. Individuals were stratified in ischemic (iHFrEF, n=57) and nonischemic etiology (niHFrEF, n=55). Cox regression hazard analysis was used to assess the influence of Tregs on survival. Results. Comparing patients with iHFrEF to niHFrEF, we found a significantly lower fraction of Tregs within lymphocytes in the ischemic subgroup (0.42% vs. 0.56%; p=0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92; p=0.017). A significant inverse association of Tregs and cardiovascular mortality in patients with iHFrEF with an adj. HR per 1-SD of 0.59 (95% CI: 0.36-0.96; p=0.034) has been observed, while this association was not evident in the nonischemic subgroup (adj. HR per 1-SD of 0.62 (95% CI: 0.17-2.31); p=0.486). Conclusion. Our results indicate a potential influence of Tregs in the pathogenesis and progression of iHFrEF, fostering the implication of cellular immunity in iHFrEF pathophysiology and proving Tregs as a predictor for long-term survival among iHFrEF patients. A preview of this study has been presented at a meeting of the European Society of Cardiology earlier this year.

The age-specific prognostic impact of the platelet-to-lymphocyte ratio on long-term outcome after acute coronary syndrome

“… 19 , 20 While ACS causes additional pro-inflammatory activation, reduced availability of this lymphocyte subset is associated with disbalance in inflammatory homeostasis and adverse events in patients with ischaemic heart failure and reduced ejection fraction. 21 Therefore, an age-specific variability needs to be considered when investigating the impact of the PLR on patient outcome. A concomitant decrease of the lymphocyte count was observed with increasing age and rate of STEMI at presentation.…”

Rapid differentiation of regulatory CD4+ T cells in the infarcted myocardium blunts in situ inflammation

“…Previous studies by our group and others demonstrated that CD4 + T-cells, particularly Tregs expressing the transcription factor FOXP3, can foster myocardial healing 3, 5 . Increased T-cell signal was observed in heart-draining lymph nodes of infarcted patients and Tregs are present in cardiac biopsies 7 , suggesting those responses are conserved in humans 8 . Yet chronic T-cell activation has been shown to mediate detrimental remodeling during both pressure overload and aging 2, 9 .…”

Myocardial-Treg Crosstalk: How to Tame a Wolf

“…In addition, PET/CT imaging using a CXCR4 probe, as a readout for T-cell activity, revealed elevated signal in the heart draining lymph nodes of infarcted patients compared to control subjects, suggesting the existence of a similar MedLN-Heart T-cell axis following MI ( 37 , 67 ). A prospective study found that higher blood Treg numbers were associated with better survival for patients with HF with reduced ejection fraction (HFrEF), indicating Tregs may influence HF progression ( 68 ). Similarly, other studies reported that infarcted patients have decreased Treg numbers in their blood and that pro-inflammatory effector T-cell expansion correlated with the occurrence of ischemic heart disease ( 69 , 70 ), though other studies did not find a clear association ( 71 ).…”