Sacubitril valsartan modulates CD4+/CD8 + ratio and correlates with alleviated heart failure progression

Heart failure (HF) remains a global health challenge with complex pathophysiology. The CD4+/CD8 + T-cell ratio represents a potential immune marker. While sacubitril/valsartan (SV) has demonstrated clinical benefits in HF treatment, its modulatory effects are not fully elucidated. This clinical study enrolled 20 HF patients who were randomly assigned to receive either standard guideline‑directed therapy with β‑blockers plus aldosterone receptor antagonists (BB + ARA) or BB + ARA plus SV (BB + ARA+SV group) for three months. Cardiac function, biomarkers, and T-cell subsets were assessed to evaluate the effects of SV on HF progression. CD8⁺ T-cell proportions in peripheral blood were measured by flow cytometry. A doxorubicin (DOX) induced HF mouse model was established with three groups (Control, DOX, DOX + SV). Cardiac function was evaluated by echocardiography. Histopathological changes were analyzed via hematoxylin-eosin and Masson staining. CD4 expression was detected by immunohistochemistry, and TGF-β1 expression was assessed by immunofluorescence. mRNA and protein expression levels were measured by RT-qPCR and western blot. Bioinformatics analysis (identification of differentially expressed genes and enriched pathways from public HF datasets) was performed to explore potential causal links between modifications in the pathway and the protective effects of SV. SV significantly improved left ventricular ejection fraction, reduced left ventricular end-diastolic diameter, brain natriuretic peptide, N-terminal pro-B-type natriuretic peptide, and decreased the CD4+/CD8 + ratio compared with both baseline and the BB + ARA control group. In DOX-induced mice, SV improved cardiac function, reduced fibrosis, inflammatory infiltration, CD4 + T-cell accumulation, and significantly suppressed TGF-β1 expression in myocardial tissues. Bioinformatic analysis highlighted extracellular matrix (ECM)-receptor interaction as a key pathway, and in vivo, SV downregulated matrix metalloproteinase (MMP)2 and MMP9, while upregulating tissue inhibitor of metalloproteinase-1. SV treatment is associated with a reduced CD4+/CD8 + T-cell ratio and suppressed pathological ECM remodeling via the ECM-receptor interaction pathway, suggesting a potential immunomodulatory contribution to its therapeutic effects in HF.