Cross-species functional transcriptomic analysis distinguishes conserved aging-niche remodeling from inflammatory fibroblast heterogeneity in cardiac aging and heart failure.

Cardiac aging is accompanied by inflammatory and extracellular-matrix remodeling, but the extent to which aging-associated fibroblast programs are reproducibly altered in human heart failure remains unclear. We integrated mouse cardiac aging single-cell RNA sequencing, human cardiac aging resources, adult human cardiac fibroblast single-cell data, and two independent human left-ventricular heart-failure cohorts. Mouse fibroblast subclustering identified an old-enriched inflammatory/stress state (Fib0) that expanded from approximately 2.3% of fibroblasts in young mice to 33.4% in old mice. The same discovery-derived signatures were then applied without redefinition to human datasets. A conserved cardiac aging niche score (CCANS) was increased in both heart-failure cohorts and showed a positive random-effects standardized mean difference (Hedges g = 1.04, 95% CI 0.53 to 1.55; P = 6.32 × 10⁻⁵). In contrast, Fib0-marker and inflammatory-fibroblast scores showed marked between-cohort heterogeneity, precluding their interpretation as uniformly reactivated heart-failure states. Adult human heart fibroblast data localized Fib0-like activity to defined fibroblast states, and reanalysis of published IL-1β-stimulated human cardiac fibroblasts supported inducibility of the inflammatory/NF-κB/CEBP core. These findings support conserved remodeling of a cardiac aging niche program across heart failure while identifying context-dependent divergence of individual inflammatory fibroblast signatures.