Cholesterol profiles and cholesterol-lowering medication in relation to the incidence of atrial fibrillation

BACKGROUND Epidemiological studies have suggested inverse associations between cholesterol levels and the risk of atrial fibrillation (AF). OBJECTIVE To investigate the associations of comprehensive cholesterol profiles, particle numbers, apolipoproteins, and cholesterol-lowering medication with AF incidence. METHODS In 187,680 UK Biobank participants without baseline cardiovascular disease, lipoprotein cholesterol and particle concentrations were quantified by nuclear magnetic resonance spectroscopy. Cox and Fine-Gray competing risk models with restricted cubic spline (RCS) analyses evaluated associations and dose-response relationships. A separate cohort of 394,718 participants was analyzed to assess cholesterol-lowering medication use and AF incidence. RESULTS Most cholesterol measures, including total, LDL-, IDL-, VLDL-, remnant, triglyceride-rich lipoprotein-remnant Cholesterol, were inversely associated with AF, whereas HDL-cholesterol showed a positive association. Small HDL-C was associated with lower AF risk, while large and very large HDL-C showed opposite. RCS models suggested generally linear associations. Particle number analyses yielded consistent, size-dependent patterns, with small HDL particles showing inverse and large HDL particles showing positive associations. Adjustment for apolipoproteins revealed distinct cholesterol cargo conditional effects: LDL- and IDL-C associations were attenuated or reversed, while HDL-related associations persisted. LCAT correlated with higher small HDL-C versus lower large HDL-C, in line with their respective associations with AF. Use of cholesterol-lowering medication, mainly representing statins, was modestly associated with a higher incidence of AF. CONCLUSION Cholesterol and lipoprotein subfractions were heterogeneously associated with AF risk, potentially reflecting biological effects of distribution of different lipoprotein carriers and their cholesterol cargo, while cholesterol-lowering medication was linked to higher AF incidence.