Integrative Transcriptomics Links Dapagliflozin-Opposed Macrophage Programs to BHLHE40-Associated Regulation and NFKB1-Associated Signaling in HFpEF

Heart failure with preserved ejection fraction (HFpEF) involves interacting immune, vascular, and stromal abnormalities. We asked whether macrophage genes showing opposite diet-associated and dapagliflozin-associated effects could identify regulatory and signaling programs relevant to HFpEF. Genes were ranked in a 2 × 2 × 2 dataset of sorted murine cardiac macrophages, and the locked signatures were evaluated in cardiac single-cell and single-nucleus datasets. Regulon analysis and network-constrained sensitivity testing identified BHLHE40 as the more robust program-level candidate. NFKB1, in turn, was linked to the broadest curated communication network, including TNF-, IL1B-, and PDGFB-related endothelial and fibroblast branches. External evidence varied across datasets and cell compartments. In myocardium from 19 HFpEF and 24 control donors, the CCR2− and cross-subset signatures were higher in macrophages, and the CCR2− signature was also higher in fibroblasts. PDGFB-related fibroblast branches received broader external evidence than the discovery-ranked TNF–TNFRSF1A endothelial branch, whose direction was not retained in human myocardium. These results nominate testable macrophage regulatory and signaling hypotheses for HFpEF but do not establish drug-specific reversal or cross-model conservation.