Metabolic obesity phenotypes and degenerative valvular heart disease: A cohort study

Aims We evaluated the association between metabolic obesity phenotypes and degenerative valvular heart disease (VHD) risk, and elucidate underlying molecular pathways via large-scale proteomics. Methods We categorized 487,443 UK Biobank participants into four phenotypes based on Body Mass Index (BMI) and metabolic syndrome criteria: metabolically healthy normal weight (MHNO), metabolically healthy obese (MHO), metabolically unhealthy normal weight (MUNO), and metabolically unhealthy obese (MUO). Multivariable-adjusted Cox models assessed the risk of VHD and its subtypes. We further integrated polygenic risk scores (PRS) and plasma proteomic profiling to explore gene-environment interactions and biological mechanisms. Results Over a median 13.3-year follow-up, 12,793 participants (2.6%) developed degenerative VHD. Compared with MHNO, higher VHD risk was noted in MHO (HR 1.12, 95%CI 1.07-1.17) and MUO (HR 1.30, 95%CI 1.24-1.37) groups, but not MUNO (HR 1.05, 95%CI 0.92-1.19). Associations were most pronounced for aortic stenosis (AS) (MHO: HR 1.42, 95%CI 1.31-1.54; MUO: HR 1.67, 95%CI 1.32-2.11), modest for aortic regurgitation (AR) and insignificant for mitral regurgitation (MR). Individuals with MUO and high genetic risk exhibited the highest AS risk (HR 2.91, 95%CI 2.51-3.36), although no significant interaction was found (P-interaction=0.938). MUO exhibited the most distinct proteomic signatures, characterized by extensive overlap with AS-related proteins and enrichment in immune-inflammation, extracellular matrix remodeling, and MAPK signaling pathways. Conclusion Obesity is persistently associated with increased aortic valve pathology risk, indicating that MHO is not entirely benign. Concomitant metabolic dysfunction further compounds this risk, highlighting the need to integrate weight management with metabolic health optimization for VHD prevention.