Cardiac Autonomic Neuropathy is Associated with the Incidence and Progression of Cardiovascular–Kidney–Metabolic Syndrome

AIMS: To investigate the role of cardiac autonomic neuropathy (CAN) in the development and progression of cardiovascular-kidney-metabolic (CKM) syndrome. METHODS: A three-stage analytical framework was applied. Cross-sectional associations between CAN (assessed by cardiovascular autonomic reflex tests) and CKM stages were examined in a discovery cohort and validated in the UK Biobank cohort. Longitudinal analyses evaluated the association between CAN and incident CKM syndrome in the UK Biobank. Multi-state models were used to assess the influence of CAN on CKM progression. RESULTS: The prevalence of CAN increased progressively across CKM stages (P for trend < 0.001). After adjustment for confounders, CAN was independently associated with advanced CKM stages in the discovery cohort (OR 1.90, 95% CI 1.14-2.60) and validated in the UK Biobank cohort (OR 1.20, 95% CI 1.13-1.27). Prospectively, CAN was associated with a higher incidence of CKM syndrome (HR 1.24, 95% CI 1.18-1.31) and earlier occurrence of its individual components, with coronary heart disease and diabetes occurring 4.0 and 3.1 years earlier, respectively. Multi-state analyses further showed that individuals with CAN had 34% and 39% higher risks of transition from stages 0-1 to stage 2 and from stage 2 to stage 4, respectively. These associations were particularly pronounced among individuals with excess adiposity, highlighting a potentially vulnerable subgroup for targeted intervention. CONCLUSION: CAN was associated with the development and progression of CKM syndrome and may have potential utility in CKM risk assessment and early intervention.