Association of organ dysfunction trajectories and major adverse cardiovascular events using clinical obesity in UK Biobank

Objective: Obesity is a major modifiable risk factor for cardiovascular disease. We evaluated whether multi-organ dysfunction trajectories for major adverse cardiovascular events (MACE) using clinically defined obesity classification improves risk discrimination compared with BMI-based categories. Methods: We analyzed 457,675 UK Biobank participants. BMI-based categories were defined using ethnicity-specific thresholds. Clinically defined obesity was classified as no, preclinical (excess adiposity without organ dysfunction), or clinical obesity (excess adiposity with ≥1 obesity-related organ dysfunction). Organ dysfunction trajectories were constructed over consecutive 2-year periods beginning 2 years after baseline: (1) status (no, period 1 only, period 2 only, persistent organ dysfunctions) and (2) change (no, increase, decrease, persistent organ dysfunctions). Incident MACE was defined as a composite of ischemic heart disease, stroke, and fatal cardiovascular disease. Participants were followed until the first occurrence of incident MACE, death, 10 years after the index date, or the end of follow up, whichever came first. Cox models estimated adjusted hazard ratio (aHR). Results: Across status trajectories, MACE risk increased in a graded response from no dysfunction to persistent dysfunction under both obesity definitions. Within trajectories, clinical obesity showed the highest risk under the clinically defined definition (clinical vs no obesity: no dysfunction aHR 2.03, 95% CI 1.96-2.11; persistent dysfunction aHR 1.61, 95% CI 1.30-2.01), whereas underweight showed the highest risk under BMI categories (underweight vs normal: no dysfunction aHR 1.83, 95% CI 1.62-2.07; persistent dysfunction aHR 2.19, 95% CI 1.32-3.63). The 10-year cumulative incidence of MACE within persistent dysfunction increased monotonically across clinically defined categories (~24% in clinical obesity), while BMI-based categories peaked in the overweight (~20%). Conclusions: Multi-organ dysfunction trajectories were strongly associated with incident MACE, having persistent dysfunction as the highest risk. Clinically defined obesity provided more monotonic, graded risk across trajectories than BMI, which were susceptible to reverse causation. Incorporating clinical obesity definitions with longitudinal dysfunction assessment may improve cardiovascular risk stratification.