Chronotype, Life's Essential 8, and risk of cardiovascular disease: a prospective cohort study in UK Biobank.

Introduction: Individuals with an evening chronotype often experience circadian misalignment, which may disrupt health behaviors and circadian regulation of cardiometabolic functions such as blood pressure. However, the associations of chronotype with modifiable cardiovascular disease (CVD) risk factors and incident CVD are not fully understood. Methods: We conducted a prospective study in 322,777 UK Biobank participants aged 39-74 years who were free of known CVD (2006-2010). Chronotype was self-reported using a single representative question from the Morningness-Eveningness Questionnaire. The Life's Essential 8 (LE8) score was calculated based on 8 modifiable CVD risk factors, and ranged from 0 to 100 with higher scores indicating better cardiovascular health. Incident CVD was defined as first myocardial infarction (MI) or stroke leading to hospitalization or death, identified via validated algorithms. Cox proportional hazards models estimated the association between chronotype and CVD risk, adjusted for socio-demographics, shift work, and family history of CVD. Under the causal mediation framework, we evaluated the role of LE8 in the association between chronotype and CVD risk by decomposing the total effect into natural direct effect (i.e., independent of LE8) and natural indirect effect (i.e., mediated by LE8; NIE). Results: Participants (mean age: 57) with a "definite evening" chronotype (8% of the total sample) were 79% more likely to have an overall poor LE8 score (<50 points) compared to "intermediate" type (prevalence ratio 95% CI: 1.72 - 1.85). Over a median of 13.2 years of follow-up, there were 17,584 incident CVD events (11,091 MI; 7,214 stroke). The hazard ratio (HR) for total CVD was 1.03 (0.99 - 1.07) for the "definite morning" and 1.16 (1.10 - 1.22) for "definite evening" compared with "intermediate" chronotype (P-trend: 0.10). LE8 explained 74% of the association between evening chronotype and CVD (NIE comparing "definite evening" to "intermediate: 1.11; 95% CI: 1.09, 1.13). Findings were similar when MI and stroke were examined individually. Conclusions: Compared to intermediate chronotype, evening chronotype was associated with modestly higher CVD risk, which was mainly explained by overall poorer cardiovascular health. These results suggest that individuals with evening chronotype may particularly benefit from interventions targeting CVD risk factors.