The role of obesity-related cardiovascular remodelling in mediating incident cardiovascular outcomes: a population-based observational study

AIMS: We examined associations of obesity with incident cardiovascular outcomes and cardiovascular magnetic resonance (CMR) phenotypes, integrating information from body mass index (BMI) and waist-to-hip ratio (WHR). Then, we used multiple mediation to define the role of obesity-related cardiac remodelling in driving obesity-outcome associations, independent of cardiometabolic diseases. METHODS AND RESULTS: In 491 606 UK Biobank participants, using Cox proportional hazard models, greater obesity (higher WHR, higher BMI) was linked to significantly greater risk of incident ischaemic heart disease, atrial fibrillation (AF), heart failure (HF), all-cause mortality, and cardiovascular disease (CVD) mortality. In combined stratification by BMI and WHR thresholds, elevated WHR was associated with greater risk of adverse outcomes at any BMI level. Individuals with overweight BMI but normal WHR had weaker disease associations. In the subset of participants with CMR (n = 31 107), using linear regression, greater obesity was associated with higher left ventricular (LV) mass, greater LV concentricity, poorer LV systolic function, lower myocardial native T1, larger left atrial (LA) volumes, poorer LA function, and lower aortic distensibility. Of note, higher BMI was linked to higher, whilst greater WHR was linked to lower LV end-diastolic volume (LVEDV). In Cox models, greater LVEDV and LV mass (LVM) were linked to increased risk of CVD, most importantly HF and an increased LA maximal volume was the key predictive measure of new-onset AF. In multiple mediation analyses, hypertension and adverse LV remodelling (higher LVM, greater concentricity) were major independent mediators of the obesity–outcome associations. Atrial remodelling and native T1 were additional mediators in the associations of obesity with AF and HF, respectively. CONCLUSIONS: We demonstrate associations of obesity with adverse cardiovascular phenotypes and their significant independent role in mediating obesity–outcome relationships. In addition, our findings support the integrated use of BMI and WHR to evaluate obesity-related cardiovascular risk.