Peripheral Blood Transcriptomic Stratification of Chronic Heart Failure Reveals Heterogeneous Immune States

Background/Objectives: Immune alterations in chronic heart failure (CHF) have been characterized mainly at the group level, leaving heterogeneity between patients undefined. We asked whether peripheral blood transcriptomes resolve distinct immune states within CHF, and how the same transcripts behave in tumors relevant to cardio-oncology. Methods: Features were selected from publicly available peripheral blood transcriptomes (CHF = 944, normal = 11) by multiple network analyses and machine learning algorithms, and consensus clustering was applied within the CHF cohort. Clusters were characterized by enrichment analyses and by estimated immune cell composition and immune-related functional signatures. The coordinates separating the clusters were fixed and applied to an independent CHF cohort of 197 patients with measured blood count differentials. Immunohistochemical and overall survival data from public tumor cohorts were examined. Results: Five weakly correlated transcripts (CASP6, CAPNS1, BAK1, CASP4 and BAD) separated the 944 patients with CHF into four clusters placed on two nearly independent coordinates, the dominant one being the balance between lymphoid and myeloid programs. Patients at opposite ends of that axis differed in almost every immune measure and in opposite directions, from a lymphoid-enriched, effector-engaged state to a myeloid-skewed, lymphoid-depleted state. Cluster 1, the largest at 39.5%, lay near the cohort average. Enriched terms were largely shared, so the separation was carried by immune cell composition rather than pathway level divergence. In the independent cohort, the coordinates kept the same relation to measured lymphocyte, neutrophil and monocyte counts. In exploratory tumor analyses, the five transcripts did not keep a single direction outside blood, and their associations with overall survival differed between tumor types. Conclusions: Peripheral blood transcriptomes place patients with CHF along a continuous lymphoid-to-myeloid axis, carried mainly by circulating immune cell composition, on which the four clusters mark positions rather than separate states and which holds in an independent cohort. Immune status in CHF is a property of the individual patient rather than of the population.