Biological and mechanistic pathways of cardiometabolic multiple long-term conditions

Cardiometabolic multiple long-term conditions (MLTC) arise from the complex interplay of biological, sociodemographic, environmental, and behavioural factors across the life course. Shared risk factors and mechanisms, including insulin resistance, adiposity, and chronic inflammation, underpin its development. Growing evidence also implicates that even low-level, long-term exposure to fine particulate matter, nitrogen dioxide, and related pollutants can accelerate the trajectory of cardiometabolic MLTC. Early-life exposures, including undernutrition and overnutrition, altered gut microbiome, and endocrine-disrupting chemicals, interact with social determinants of health to aggravate inflammatory and metabolic dysregulation. These mechanisms, together with genetic susceptibility, epigenetic modifications, and multiomics perturbations, shape disease progression, heterogeneity, and the clustering of cardiometabolic MLTC. Yet, fundamental gaps persist, whereby most mechanistic insights are derived from single-disease studies, leaving the temporal hierarchy, causal pathways, and population-level heterogeneity largely unresolved. Addressing these challenges will require life-course research, integrative systems approaches, and translational studies that link mechanistic insights to precision prevention and therapeutic strategies. By bridging discovery with actions, such efforts can enhance care for cardiometabolic MLTC and promote equitable health outcomes globally.