Immune cell signature in non-ischemic heart failure indicates chronic systemic immune activation with features of immunosenescence

Heart failure (HF) is characterized by systemic inflammation and adverse myocardial remodeling involving immune cell activation. Nonetheless, effective immunomodulatory therapies remain lacking. We aimed to characterize the composition and effector function of immune cells in patients with non-ischemic HF. Peripheral blood mononuclear cells were isolated from patients with non-ischemic HF (n = 19) and controls without HF (n = 19). Using multiparametric flow cytometry, immune cell populations—including monocyte subsets, dendritic cells (DCs), and T-cell subsets—were characterized alongside expression of pattern recognition receptors and immune checkpoint molecules. Monocyte effector functions were assessed via intracellular cytokine staining after lipopolysaccharide (LPS) stimulation. In HF patients, circulating monocytes were increased, whereas the proportion of non-classical (CD14⁻CD16⁺) monocytes was reduced. Monocytes showed higher PD-L1 expression, and intermediate/non-classical subsets had increased TLR4. Following LPS stimulation, monocyte cytokine production (IL-1β, IL-6, TNF-α) was unchanged. Lower frequencies of non-classical monocytes correlated with reduced left ventricular ejection fraction but not with NT-proBNP. Circulating DCs were elevated. T-cell analysis revealed increased CD4⁺ effector Th and IL-17-producing (Th17) cells and fewer regulatory T-cells. To explore whether systemic immune alterations are reflected in cardiac infiltration, myocardial tissue from a subset of HF patients (n = 7) and non-failing controls (n = 4) was analyzed by immunohistochemistry. Despite the systemic immune alterations, large myocardial immune cell infiltrates were not readily apparent in end-stage HF tissue. Non-ischemic end-stage HF is associated with systemic immune alterations indicative of chronic activation with features suggestive of immunosenescence. Without overt corresponding myocardial immune cell infiltrates, these findings emphasize the relevance of systemic immune alterations in non-ischemic end-stage HF.