Association Between Endogenous Ketosis and Risk of Atrial Fibrillation in Intensive Care Versus General Ward Patients: A Retrospective Cohort Study

Background: Metabolic reprogramming in critical illness and the physiological stress of general hospitalization represent fundamentally different states, yet it remains unknown if ketosis acts as a protective shield or a maladaptive metabolic response in the development of atrial fibrillation (AF) across these contexts. We examined urine and serum β-hydroxybutyrate measurements to understand the metabolic association among intensive care unit (ICU) and general hospital populations. Methods: This retrospective cohort study utilized the MIMIC-IV v3.1 database. Patients with preexisting AF or flutter were excluded. Ketosis was defined as urine ketone positivity (≥20 mg/dL) or serum β-hydroxybutyrate (≥1.0 mmol/L). The final analytic cohort included a general ward cohort (n = 13,641) and an ICU cohort (n = 10,251). Multivariable logistic regression, propensity score matching and subgroup analyses were performed. Results: In the ICU cohort, urine ketone positivity and elevated serum β-hydroxybutyrate were associated with lower incidence of AF (5.2% vs. 6.8%, p = 0.001; 3.1% vs. 9.4%, p = 0.034). After adjustment, urine ketone positivity remained independently associated with reduced odds of incident AF (adjusted OR 0.79, 95% CI 0.64–0.98, p = 0.032). Propensity-matched analyses demonstrated protective associations for urine ketones (OR 0.68, 95% CI 0.52–0.88, p = 0.004) and β-hydroxybutyrate (OR 0.24, 95% CI 0.08–0.70, p = 0.003). In contrast, urine ketone positivity in the general ward cohort was associated with higher incident AF (0.9% vs. 0.5%, p = 0.019) and increased adjusted odds (OR 2.62, 95% CI 1.03–6.66, p = 0.044). Urinary ketosis was associated with lower mortality and reduced inflammatory marker profiles across both the ICU and general ward cohorts. Subgroup analyses revealed directionally consistent ketone-AF associations across biological sex with no significant interaction effects. Conclusions: Endogenous ketones demonstrated a context-dependent association with incident AF across clinical acuity levels. These findings highlight ketone metabolism as a potential target for both arrhythmia monitoring and prevention.