Metabolic Vulnerability Index and Atherosclerosis Incident: A Prospective Cohort Study From the UK Biobank

Background Atherosclerosis underlies most cardiovascular disease, but traditional factors incompletely explain risk. This study examined whether a novel Metabolic Vulnerability Index (MVX), integrating inflammatory and metabolic biomarkers, predicts incident atherosclerosis independently of traditional and genetic risks. Methods We analyzed data from 171 600 participants in the UK Biobank without baseline atherosclerotic disease (median follow‐up, 13.6 years). MVX was derived from nuclear magnetic resonance metabolomics and comprised 2 components: the Inflammatory Vulnerability Index (including glycoprotein acetyls and small high‐density lipoprotein particle concentration) and the Metabolic Malnutrition Index (including branched‐chain amino acids and citrate). Associations with incident atherosclerosis (ascertained via hospitalizations and death) were analyzed using Cox models adjusted for demographics and clinical and lifestyle factors. Secondary analyses evaluated MVX components independently and examined potential effect modification by genetic risk using low‐density lipoprotein cholesterol polygenic risk scores. Results Higher MVX predicted significantly increased atherosclerosis risk (hazard ratio [HR] per SD: 1.22 [95% CI, 1.19–1.25]). The highest MVX quartile had 59% greater risk compared with the lowest (HR, 1.59 [95% CI, 1.49–1.69]). This association persisted after adjustment for traditional cardiovascular risk factors. The Inflammatory Vulnerability Index demonstrated robust positive associations with atherosclerosis (adjusted HR per SD, 1.18 [95% CI, 1.15–1.21]). MVX–atherosclerosis associations remained consistent across different genetic risk strata and demographic subgroups. Conclusions The MVX, particularly its inflammatory component, independently predicts atherosclerosis risk beyond traditional risk factors. This supports comprehensive metabolic profiling for refined risk assessment and underscores inflammation’s central role in atherosclerosis progression, highlighting potential novel intervention targets.