Natural and Built Environments and Heart Failure Risk: An Exposome-Wide Analysis in the UK Biobank.

Natural and built environments are closely linked to cardiovascular health, yet the environmental determinants of heart failure (HF) risk remain poorly understood. In a prospective cohort of 377,694 UK Biobank participants without HF at baseline, we analyzed the associations between 241 environmental exposures and the risk of incident HF using an exposome-wide approach. Our analysis included exposome-wide association study (ExWAS) analyses via Cox regression, identification of key exposures using regularized Cox regression and LightGBM models, and pattern recognition with self-organizing maps and k-means clustering to assess cumulative effects. After adjusting for confounders and multiple testing, 54 exposures were significantly associated with HF risk in the ExWAS. Combining results from the regularization model and LightGBM, we identified protective factors like greater natural space and lower air pollution, and risk factors such as proximity to industrial facilities and high traffic density. Seven environmental patterns were identified, with the lowest HF risk linked to high natural environments and robust infrastructure. BMI was found to mediate these environmental links to HF. Our findings demonstrate that natural and built environments are strongly associated with HF risk, and targeted strategies to reduce environmental pollution and optimize community design may offer promising ways for mitigating HF burden.