Lifelong non-cardiac comorbidity burden and mortality risk in adults with lower-complex congenital heart disease: a population-based cohort study from the UK Biobank

Background and aims As adults with lower-complex congenital heart disease (CHD) age and are often considered clinically stable, non-cardiac comorbidities have emerged as an under-recognized prevention challenge. We aimed to quantify system-specific incidence, relative and absolute lifetime risks of non-cardiac comorbidities and to evaluate their impact on long-term mortality in this understudied population. Methods A stepwise classification algorithm was used to define 3,307 lower-complex CHD and 492,232 non-CHD individuals in the UK Biobank. Primary outcome was first occurrence of nine system-specific non-cardiac comorbidities (pulmonary, neurological, mental, genitourinary, digestive, musculoskeletal, endocrine, skin, and blood-related), with lifetime risk assessed using life-table method and multivariable Cox regression models. Secondary outcome was all-cause mortality among individuals with lower-complexity CHD, assessed according to baseline and incident comorbidity status using time-varying Cox regression models. Median follow-up was approximately 13 years. Results Compared to individuals without CHD, adults with lower-complexity CHD had significantly higher cumulative incidence of non-cardiac comorbidities across nine organ systems. Hazard ratios (HRs), adjusted for major demographic and lifestyle factors, ranged from 1.25 (skin disease) to 2.48 (blood disease). Excess incidence was evident from midlife and widened substantially with ageing. Absolute lifetime risks ranged from 17.1% (skin disease) to 46.0% (digestive disease), which were significantly higher in lower-complex CHD patients than in non-CHD individuals across eight systems. The largest excess risks were observed in endocrine (18.5%), digestive (16.0%), and pulmonary (12.7%) systems. Among individuals with CHD, incident non-cardiac comorbidities were independently associated with increased subsequent all-cause mortality, with pulmonary disease conferring the strongest risk (HR, 3.32). Conclusions Lower-complex CHD is not a benign condition in adulthood. Substantial and early-onset multi-system non-cardiac comorbidities significantly contribute to long-term mortality. These findings support a paradigm shift from cardiac-centered follow-up to integrated, prevention-oriented, life-course management.