Exploring the Underlying Mechanisms Linking Adiposity and Cardiovascular Disease: A Prospective Cohort Study of 404,332 UK Biobank Participants

Obesity is causally associated with multiple cardiovascular outcomes but effective population mea-sure to control obesity is limited. This study aims to decipher to which extent excess atherosclerotic cardio-vascular diseases (ASCVD) and heart failure (HF) risk due to obesity can be explained by conventional risk factors. This is a prospective cohort study of 404,332 White UK Biobank participants. Participants with prior CVDs or other chronic diseases at baseline, or body mass index <18.5 kg/m2 were excluded. Data were collected at the baseline assessment between 2006 and 2010. Linkage to death registrations and hospital admission records was used to ascertain ASCVD and HF outcomes up to late 2021. Obesity was defined as body mass index >30 kg/m2. Candidate mediators included lipids, blood pressure (BP), glycated hemo-globin (HbA1c), and liver and kidney function markers, which were chosen based on clinical trials and Mendelian randomization studies. Cox propor-tional hazard models were used to estimate hazard ratios (HR) and their 95% confidence intervals (CIs). Mediation analysis based on g-formula was used to separately estimate the relative importance of media-tors for ASCVD and HF. Compared with people with-out obesity, obese people had an increased risk of ASCVD (HR 1.30, 95% CI, 1.26-1.35) and HF (HR 2.04, 95% CI, 1.96-2.13) after adjusting for sociodemo-graphic and lifestyle factors and medications for cho-lesterol, BP and insulin. The strongest mediators for ASCVD were renal function (eGFR: mediation pro-portion: 44.6%), BP (SBP: 24.4%; DBP: 31.1%), tri-glycerides (19.6%), and hyperglycemia (HbA1c 18.9%). These mediators collectively explained more excess risk of ASCVD than that of HF. Interventions that help obese individuals to maintain healthy lipid concentrations, BP, glycemic control, and kidney func-tion could potentially alleviate a sizable proportion of the ASCVD burden. However, HF burden could not be meaningfully reduced without weight management. (Curr Probl Cardiol 2023;48:101715.)