We sought to characterize natriuretic peptide levels in a cohort of rigorously characterized subjects with lone atrial fibrillation(AF). Atrial natriuretic peptide(ANP)and brain natriuretic peptide(BNP)are sensitive biomarkers of cardiac contractile dysfunction. Both peptides have been reported to be elevated in cohorts with AF, but previous studies have included subjects with underlying structural heart disease. We studied these hormones in 150 subjects with lone AF. Study subjects had electrocardiographic evidence of at least one episode of AF and a structurally normal heart on echocardiography. Subjects were excluded if they had a history of a myocardial infarction, rheumatic heart disease, cardiomyopathy, significant valvular disease, hyperthyroidism, or hypertension that preceded the onset of AF. Control subjects were obtained from a healthy outpatient primary care population. Plasma pro-ANP and N-terminal pro-BNP(nt-pro-BNP)levels were determined using commercially available immunoassays. A total of 150 serial subjects with lone AF were enrolled and studied, the majority during normal sinus rhythm. Median levels of nt-pro-BNP were significantly elevated in subjects with lone AF as compared with control subjects(166 vs. 133 fmol/ml, p=0.0003). There was no significant difference in pro-ANP levels between subjects with lone AF and control subjects(1,730 vs. 1,625 fmol/ml, p=0.90). Discordant natriuretic peptide levels were observed in this homogeneous population of subjects with lone AF. This biomarker pattern, which is present even in sinus rhythm, may represent an underlying subclinical predisposition to this common arrhythmia.