Inflammatory and extracellular matrix pathways mediate the association between heart failure and lung cancer risk

Background Heart failure (HF) has been associated with an increased risk of incident lung cancer (LC). However, the molecular mechanisms underlying this association beyond shared risk factors remain poorly characterized. Objectives This study aimed to investigate whether plasma protein-derived biological pathway activities mediate the association between HF and incident LC in a large, population-based cohort. Methods We conducted a retrospective analysis of 438,892 participants from the UK Biobank. Using time-varying Cox proportional hazards models, we assessed the association between an HF diagnosis and incident LC. We then performed a sex-stratified multiple mediation analysis, using 2,923 plasma proteins to quantify the activity of biological pathways in each participant's blood to identify potential biological mediators. This specific research project was conducted under UK Biobank application number 58030. Results Over a median follow-up of 13.1 years, HF was significantly associated with an increased risk of LC in both men (HR: 1.32; 95% CI: 1.11–1.56) and women (HR: 1.39; 95% CI: 1.09–1.76). This association was significantly mediated by inflammatory and ECM remodeling pathways, which collectively accounted for 61.4% of the total effect in men and 42.1% in women. Key mediating pathways included collagen degradation and innate immune activation via Toll-like receptors in men, and inflammatory cytokine signaling and neutrophil activation in women. Conclusions HF is associated with a significantly increased risk of developing LC. This association is substantially mediated by systemic inflammatory and ECM remodeling pathways, with notable sex-specific differences. These findings suggest HF confers a systemic pro-tumorigenic state, providing novel mechanistic insights into reverse cardio-oncology.