Integrative Multi-Omics Profiling of Dynamic Body Mass Index–Systolic Blood Pressure Trajectories in Obesity for Precision Risk Stratification of Heart Failure Subtypes

Background: Obesity is an important risk factor for heart failure (HF). The dynamic heterogeneity of HF risk and its interaction with blood pressure changes among individuals with obesity remain unclear. This study aimed to improve risk assessment and support precision medicine by evaluating joint longitudinal trajectories of body mass index (BMI) and systolic blood pressure (SBP). Methods: We included 14,469 participants with BMI ≥ 30 from the UK Biobank. Group-based multi-trajectory modeling identified joint BMI-SBP trajectories. After inverse probability of treatment weighting, associations between trajectory groups and overall HF and its subtypes were evaluated, and potential mechanisms were explored using polygenic risk score (PRS) and plasma proteomic characteristics. Results: Four distinct trajectory patterns were identified: mild obesity with mild hypertension trajectory (MOMH), severe obesity with high-normal blood pressure progression trajectory (SOHN; BMI approximately 37.0 kg/m2, SBP increasing from approximately 131 to 138 mmHg), moderate obesity with high-normal blood pressure progression trajectory (MOHN; BMI approximately 33.0 kg/m2, SBP increasing from approximately 132 to 139 mmHg), and mild obesity with moderate-to-severe hypertension improvement trajectory (MOMSH). The SOHN group exhibited the highest risk of overall HF (HR=3.76). MOMSH and MOMH were associated with higher HFpEF risk (HRs: 2.68–2.70), whereas MOHN showed the lowest HF risk (HR = 1.82). These trajectory-based subtypes displayed heterogeneity in genetic susceptibility and plasma proteomic characteristics. Conclusions: Dynamic trajectory-based phenotyping identifies distinct obesity-BP patterns associated with differential HF risk and distinct nutritional and metabolic profiles, offering a more informative framework than static indicators for risk assessment.