The Interplay of Oxidative Stress and T Cell Function for Immune Dysregulation in Dilated Cardiomyopathy

The significance of the immune system in the pathogenesis and progression of cardiovascular diseases e.g. dilated cardiomyopathy (DCM) is increasingly recognized, highlighting its potential as a therapeutic target. 

 

The proportion of CD69/IFNγ expressing T cells significantly decreases with advancing NYHA classes in dilated cardiomyopathy patients, indicating a decline in immune function as heart failure progresses. Additionally, DCM patients exhibited significantly higher numbers of leukocytes and granulocytes compared to healthy controls, denoting chronic inflammation. Notably, IFNγ emerged as a highly sensitive prognostic marker for two-year follow-up, with DCM patients having IFNγ levels above 4.04 % experiencing significantly extended progression-free survival (n=34, p=0.03).

Lipid peroxides, markers of oxidative stress, differed significantly between the control and DCM group and increased with NYHA class, particularly in patients with low IFNγ levels (<2%). This suggests that oxidative stress may contribute to immunosuppression by inhibiting T cell function, as indicated by the decreased proportion of CD69/IFNγ expressing cells in advanced stages of DCM.

 

To analyze these immune cell changes, we developed "MorphoMapping," an advanced analytical framework that enhances the accuracy of single-cell analysis by employing dimensionality reduction algorithms and unsupervised clustering to interpret intricate datasets acquired by Imaging Flow Cytometry. This method enabled us to identify nuanced morphological features and functional states of immune cells, providing deeper insights into the immune dysregulation in DCM.

MorphoMapping indicated distinct differences in T cell profiles between healthy subjects and DCM patients in both unstimulated and stimulated groups, although cell-cell contact patterns overlapped – a phenotype known in oxidative stress conditions (n=5 patients per NYHA class). Quantitative analysis of mature synapse count revealed a significant increase from control to NYHA class 3 within the SEB stimulated group (ANOVA, p=0.015), along with a trend towards stronger polarization of leukocytes in the DCM group. 

 

In summary, this study highlights the significant interplay between immune dysregulation and cardiological deterioration in DCM patients. The reduction in CD69/IFNγ expressing T cells and the role of oxidative stress in promoting immunosuppression underscore the potential of IFNγ as a prognostic marker and the importance of addressing oxidative stress in therapeutic strategies. These insights provide a deeper understanding of DCM pathophysiology and may inform future interventions to improve patient outcomes.