Association of insomnia and its proteomic signatures with incident heart failure: A European population-based study.

Heart failure is a major public health burden, and insomnia has emerged as a potential risk factor for heart failure development. Although a small amount of clinical evidence supports this association, the underlying molecular mechanisms remain poorly understood. Based on 52,273 participants from the UK Biobank, plasma samples were analyzed for 2911 proteins by using Olink technology. Insomnia was assessed through self-reported questionnaires. Linear regression and LASSO regression revealed that plasma proteins were associated with insomnia. LASSO regression was used to construct proteomic signatures associated with insomnia. Cox regression models were used to assess the relationship between insomnia and insomnia-related proteomic signatures and heart failure; additionally, mediation analyses identified key proteins that potentially mediate the association between insomnia and heart failure. Insomnia (reported "usually") was independently associated with an increased heart failure risk (HR: 1.39; 95% CI: 1.17-1.65). The study identified 118 proteins associated with insomnia that are primarily associated with immune inflammation and metabolism, as well as complement and coagulation cascades. Proteomic signatures constructed by using these 118 proteins were also independently associated with the risk of new heart failure. Mediation analysis revealed 68 proteins potentially mediating the insomnia-heart failure relationship through similar pathways. TNF, CD4, AMBP, SPP1, and ITGAM were identified as central hub proteins in the protein-protein interaction network. This study demonstrates that insomnia significantly increases heart failure risk through multiple molecular pathways, which primarily involve inflammatory responses and complement cascade activation. Sleep quality optimization may provide additional benefits in the prevention of heart failure.