Inflammation dominance over senescence is a conserved feature across heart diseases

Cellular senescence and chronic inflammation are core drivers of heart disease, but whether these two processes act synergistically or exhibit a decoupled pattern across different diseases and cell types remains unclear. Here, we integrated three independent human heart snRNA‑seq datasets from patients with acute myocardial infarction (MI), dilated cardiomyopathy (DCM), and heart failure (HF). Cellular senescence was quantified using the human universal senescence index (hUSI) and the SenMayo gene set (SAUL_SEN_MAYO; MSigDB). Inflammation was assessed using both a curated 23‑gene core signaling signature and unbiased Hallmark pathway analyses; the latter revealed consistent activation of inflammation‑associated pathways (e.g., TNF‑α/NF‑κB) across all three diseases. Compared with controls, the senescence score was significantly decreased in all three diseases, whereas the inflammation score was increased, revealing a consistent decoupled pattern (inflammation elevation with senescence reduction) across heart diseases. To quantify this deviation, the Inflammation‑Senescence Deviation Index (ISDI) was defined as the inflammation Z‑score minus the senescence Z‑score, with positive values indicating relative predominance of inflammation over senescence. Endothelial cells were identified as the only major cell type showing a robust and consistent shift toward inflammation dominance in all three datasets. Mechanistically, the TNF‑alpha signaling via NF‑κB pathway was activated while the p53 pathway was suppressed in disease endothelial cells. A 10‑gene down‑regulated signature derived from DCM endothelial cells showed consistent down‑regulation across the three snRNA‑seq datasets. In a clinical association analysis of LVAD therapy for end‑stage heart failure, NF‑κB pathway activity significantly distinguished non‑responders from responders, whereas senescence scores showed no difference and the inflammation score showed only a non‑significant trend. This signature was validated in six independent external cohorts, and the decoupled pattern itself was confirmed in an independent pediatric DCM snRNA‑seq dataset. These findings challenge the traditional synergistic model of senescence and inflammation in heart disease and highlight inflammation dominance as a conserved feature. The specific association of NF‑κB pathway activity with clinical outcome suggests that targeting inflammatory pathways (e.g., NF‑κB signaling) may have higher therapeutic priority than modulating senescence programs. Integration of three human heart snRNA‑seq datasets (MI, DCM, HF) reveals a decoupled pattern: inflammation increases while senescence decreases across diseases. Endothelial cells are the most consistently affected cell type in all three datasets. In endothelial cells, p53 pathway suppression is consistently observed across all three diseases, while NF‑κB pathway activation is present in DCM and HF but shows heterogeneous regulation in MI. NF‑κB pathway activity, but not senescence, distinguishes LVAD responders from non‑responders, and the decoupled pattern is validated in external cohorts.