Cross-sectional and Longitudinal Associations Between Circadian Alignment and Cardiovascular-Kidney-Metabolic Syndrome in US Adults

Abstract Background Cardiovascular-kidney-metabolic (CKM) syndrome is a progressive, multi-systemic condition defined by recent consensus. Circadian rhythm is a critical regulator of metabolic health, but the relationship between circadian alignment and CKM remains unclear. Objective To explore the association between circadian alignment and CKM risk as well as mortality outcomes. Methods NHANES data from 2011-2014 were used. Circadian alignment was evaluated using phasor analysis of light-activity synchronization, including phasor magnitude and acrophase, categorized into quintiles. CKM stages (0-4) were used to reflect disease progression, comparing advanced stages (3 or 4) with non-advanced stages (0, 1, or 2). Outcomes included advanced CKM stages, cardiovascular disease (CVD), diabetes mellitus (DM), chronic kidney disease (CKD), all-cause mortality, cardiovascular mortality, and premature mortality. Advanced CKM stages, CVD, DM, and CKD were analyzed cross-sectionally, while mortality outcomes were assessed longitudinally. Results A total of 7,246 participants, representing approximately 148 million US adults (median follow-up: 81 months), were included. Participants in the lowest quintile of phasor magnitude, indicating the greatest circadian misalignment, had significantly higher risks of advanced CKM stages (aOR 2.25, 95% CI: 1.59 – 3.19), all-cause mortality (aHR 1.75, 95% CI: 1.35–2.26), cardiovascular mortality (SHR 1.89, 95% CI: 1.22–2.93) compared to those in the highest quintile. However, premature mortality was not significantly associated. A linear inverse relationship was observed between phasor magnitude and both advanced CKM stages and mortality outcomes, with similar patterns for CVD, CKD, and DM. No significant associations were found between phasor acrophase and adverse outcomes. Conclusions Greater circadian misalignment, indicated by lower phasor magnitude, is strongly associated with an increased risk of advanced CKM and other adverse outcomes. Improving circadian alignment may offer a promising strategy for mitigating the burden of cardiovascular and metabolic diseases.