The lipidome meets the brain: CERT2, cognitive function, and 10-year mortality risk in in chronic heart failure

Background Ceramides and phosphatidylcholines (PCs) reflect lipid remodeling, inflammation, and metabolic stress. The ceramide-based risk score CERT2 integrates circulating ceramides and PCs and has established prognostic value in atherosclerotic disease. Its determinants and relevance in chronic heart failure (HF), particularly regarding cognition and long-term outcome, remain incompletely defined. Purpose To identify independent predictors of CERT2 and evaluate its association with cognitive performance and 10-year all-cause mortality in chronic HF. Methods This post-hoc analysis included 123 patients from the Cognition.Matters-HF cohort with chronic HF (median age 64 [55–72] years; 10% female; LVEF 44% [38–48]; NT-proBNP 420 pg/mL [360–475]); 56% had mild cognitive impairment (defined as T-score <40 in ≥1 cognitive domain). Plasma ceramides and phosphatidylcholines were quantified using targeted ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) on a validated LC-MS platform (ZORA Biosciences, Espoo, Finland). CERT2 was calculated based on predefined lipid species and ratios. Multivariable linear regression identified independent predictors of CERT2. Associations with cognitive domains were assessed using correlation analyses. Cox proportional hazards models evaluated 10-year all-cause mortality with stepwise adjustment for age, sex, BMI, LVEF, NT-proBNP, renal function, and other clinical covariates. Results Higher NT-proBNP (β=0.261, p=0.003), total cholesterol (β=0.248, p=0.005), C-reactive protein (β=0.281, p=0.002), and reduced 6-minute walk distance (β=−0.189, p=0.030) independently predicted higher CERT2 scores. CERT2 showed weak but significant inverse correlations with visual-verbal memory (ρ=−0.21, p=0.018). Cer(18:1/18:0) correlated with reduced verbal fluency (ρ=−0.20, p=0.029). Other domains were not consistently associated. During 10 years of follow-up, 54 patients (44%) died. Higher CERT2 was associated with increased mortality risk (HR 1.25, 95% CI 1.12–1.40, p<0.001). The association remained independent after adjustment for age, sex, and BMI (HR 1.21, 95% CI 1.08–1.35, p=0.001) and in fully adjusted models including established HF markers (HR 1.20, 95% CI 1.04–1.39, p=0.015). PC(16:0/16:0) also independently predicted mortality (HR 1.21, 95% CI 1.06–1.38, p=0.004). Conclusion In patients with chronic HF, CERT2 is associated with markers of disease severity and independently predicts long-term mortality risk, with modest associations with cognitive performance. These findings support further investigation of lipidomic profiling as a complementary tool for risk stratification in chronic HF.