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BACKGROUND AND AIMS: Low-grade chronic inflammation is a pathogenetic factor in atherosclerotic cardiovascular diseases (ASCVD), but the underlying mechanisms are not well understood. We aimed to explore the role of intestinal permeability and ensuing metabolic endotoxemia as risk factors for cardiovascular mortality.METHODS: A random sub-cohort of home-living participants from the Helsinki Businessmen Study (HBS), born between 1919 and 1934 and followed since 1964, was recalled in 2003 (n = 632), 2011 (n = 316) and 2017 (n = 82). Six biomarkers representing intestinal permeability and endotoxemia were measured and the results were combined with extensive data on ASCVD prevalence, conventional risk factors, and mortality.RESULTS: Correlation on the individual levels was observed for zonulin, lipopolysaccharide-binding protein (LBP), and intestinal fatty acid-binding protein (I-FABP) across the entire 15-year follow-up. These biomarkers are highly intercorrelated. Particularly zonulin, a marker of intestinal permeability, correlated with most of the conventional ASCVD risk factors. None of the biomarkers correlated with prevalent ASCVD, but higher levels of zonulin and LBP associated with 10-year risk of death from coronary artery disease (CAD, age-adjusted p < 0.001 and p = 0.006, respectively).CONCLUSIONS: The results support metabolic endotoxemia as a contributing pathogenetic factor in atherosclerotic cardiovascular disease with an adverse outcome. Of the surrogate biomarkers studied, zonulin was the most robust predictor of mortality in CAD. Levels of zonulin, LBP, and I-FABP remained relatively stable in individuals over the 15-year follow up, suggesting a potential role for them as biomarkers for ASCVD risk.