Paradoxical Association of Lipoprotein Measures With Incident Atrial Fibrillation

BACKGROUND: Low-density lipoprotein (LDL) cholesterol is a strong risk factor for atherosclerosis but has an inverse association with atrial fibrillation (AF). We aimed to provide insight into the paradoxical association of LDL cholesterol with AF by evaluating the relationship of various lipoprotein measures and incident AF. METHODS AND RESULTS: We prospectively evaluated lipoprotein measures among 23 738 healthy middle-aged and older women (median follow-up 16.4 years; N=795 incident AF events). Baseline LDL cholesterol was directly measured, lipoprotein particle concentrations and size were measured by nuclear magnetic resonance spectroscopy, and apolipoproteins were measured by immunoassay. Cox regression models were adjusted for age, AF risk factors, inflammatory, and dysglycemic biomarkers. After multivariable adjustment, inverse associations with AF were observed (hazard ratio, 95% confidence interval for top versus bottom quintile, P value) for LDL cholesterol (0.72, 0.56-0.92, P=0.009), the total number of LDL particles (0.77, 0.60-0.99, P=0.045), and very-low-density lipoprotein particles (0.78, 0.61-0.99, P=0.04), which was driven by the number of cholesterol-poor small LDL (0.78, 0.61-1.00, P=0.05) and small very-low-density lipoprotein particles (0.78, 0.62-0.99, P=0.04). By contrast, the larger cholesterol-rich LDL particles and all high-density lipoprotein measures were not associated with AF in multivariable models. Adjustment for inflammatory and dysglycemic biomarkers had minimal impact on these associations. CONCLUSIONS: In this prospective study, the inverse association between LDL cholesterol and AF extended to several other atherogenic lipoproteins, and these associations are unlikely to be mediated by direct cholesterol effects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Unique Identifier: NCT00000479.