Cardio-Kidney-Metabolic Phenotypes and Adverse Clinical Outcomes in Patients With Atrial Fibrillation

The prognostic impact of distinct cardio-kidney-metabolic (CKM) phenotypes on outcomes in atrial fibrillation (AF) remains unclear.

The study sought to characterize CKM phenotypes and burden in AF and evaluate associations with clinical outcomes, exploring body mass index (BMI)-related heterogeneity.

This retrospective cohort study included 48,810 adults with AF (2014-2022). Patients were classified by CKM burden and phenotypes. Multivariable Cox and Fine-Gray models were used for heart failure hospitalization (HHF), transient ischemic attack/ischemic stroke, major adverse kidney events (MAKE), major adverse cardiovascular events (MACE), and all-cause mortality.

The median follow-up duration was 3.14 years (Q1-Q3: 1.04-6.10 years). The kidney-only phenotype carried the highest risks of all-cause mortality (adjusted HR [aHR]: 2.04; 95% CI: 1.95-2.14; P < 0.001) and MAKE (aHR: 2.07; 95% CI: 1.99-2.16; P < 0.001). The cardio-kidney phenotype also conferred prominent risks for all-cause mortality (aHR: 1.56; 95% CI: 1.44-1.70; P < 0.001) and MAKE (aHR: 1.74; 95% CI: 1.61-1.88; P < 0.001). For MACE, cardiovascular-only (aHR: 1.61; 95% CI: 1.45-1.79; P < 0.001) and cardiometabolic (aHR: 1.57; 95% CI: 1.42-1.74; P < 0.001) phenotypes showed strongest associations. For HHF, kidney-metabolic (subdistribution HR [sHR]: 1.29; 95% CI: 1.13-1.47; P < 0.001) and metabolic-only (sHR: 1.26; 95% CI: 1.15-1.37; P < 0.001) phenotypes showed largest increases. Underweight (BMI <18.5 kg/m²) predicted all-cause mortality (aHR: 1.97; 95% CI: 1.89-2.06; P < 0.001) and MAKE (aHR: 1.77; 95% CI: 1.70-1.84; P < 0.001), whereas obesity increased HHF risk (sHR: 1.42; 95% CI: 1.29-1.56; P < 0.001).

CKM phenotypes stratify multisystem risks in AF. Kidney domain involvement identifies patients at highest risk for mortality and MAKE, while metabolic phenotypes are strongly associated with HHF. BMI further differentiates risk, with underweight status driving mortality and renal adverse events.