Paradoxical Association of Lipoprotein Measures With Incident Atrial Fibrillation

Abstract

Background Low-density-lipoprotein (LDL) cholesterol is a strong risk factor for atherosclerosis but has an inverse association with AF. We aimed to provide insight into the paradoxical association of LDL-cholesterol with atrial fibrillation (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 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 VLDL 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 VLDL particles (0.78, 0.62-0.99, p=0.04). By contrast, the larger cholesterol-rich LDL particles and all HDL 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

Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts

“…The counterintuitive inverse association of total cholesterol and other pro-atherogenic lipoproteins has been reported earlier 41,42. This observation has been explained by membrane stabilizing characteristics of cholesterol, although the exact pathophysiology remains unclear.…”

Development of a Basic Risk Score for Incident Atrial Fibrillation in a Japanese General Population ― The Suita Study ―

“…4 Mora et al conjectures that the association between LDL and AF could be related to the stabilizing effect of cholesterol on cardiomyocyte membranes. 39 It is also generally accepted that there is an association between lower cholesterol and hyperthyroidism, which is a risk factor for incident AF. 42 Lower cholesterol levels may thus be involved with high incident AF.…”

Blood Lipids and the Incidence of Atrial Fibrillation: The Multi‐Ethnic Study of Atherosclerosis and the Framingham Heart Study

“…Prevalence and severity of atherosclerosis have been associated with the risk of AF, but the few published studies exploring the link between blood lipids and AF have yielded inconsistent and paradoxical results. In contrast with the association observed with coronary heart disease, high levels of LDLc and total cholesterol were unexpectedly associated with lower risk of AF in some community‐based studies . With the general aim of clarifying the role of blood lipids as risk factors for AF, we analyzed data from the Multi‐Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study (FHS), 2 community‐based studies in the United States that have collected extensive information on cardiovascular risk factors including blood lipids.…”