Lipoprotein Particle Profiles, Standard Lipids, and Peripheral Artery Disease Incidence – Prospective Data from the Women’s Health Study [Original Research Article]

Background—Despite strong and consistent prospective associations of elevated low-density lipoprotein-cholesterol (LDL-C) concentration with incident coronary and cerebrovascular disease (CCVD), data for incident peripheral artery disease (PAD) are less robust. Atherogenic dyslipidemia characterized by increased small LDL particle concentration (LDL-P), rather than total LDL cholesterol content, along with elevated triglyceride-rich lipoproteins and low high-density lipoprotein-cholesterol (HDL-C) may be the primary lipid driver of PAD risk.Methods—The study population was a prospective cohort study of 27,888 women ≥45 years old free of cardiovascular disease at baseline and followed for a median of 15.1 years. We tested whether standard lipid concentrations as well as nuclear magnetic resonance (NMR) spectroscopy-derived lipoprotein measures were associated with incident symptomatic PAD (n=110) defined as claudication and/or revascularization.Results—In age-adjusted analyses, while LDL-C was not associated with incident PAD, we found significant associations for increased total and small LDL-P concentrations, triglycerides, and concentrations of very low-density lipoprotein particle subclasses (VLDL-P), increased total cholesterol (TC):HDL-C, low HDL-C, and low HDL particle concentration (HDL-P) (all P for extreme tertile comparisons <0.05). Findings persisted in multivariable-adjusted models comparing extreme tertiles for elevated total LDL-P (HRadj 2.03; 95% CI, 1.14 to 3.59), small LDL-P [HRadj 2.17 (1.10 to 4.27)], very large VLDL-P (HRadj 1.68 (1.06 to 2.66)], medium VLDL-P (HRadj 1.98 (1.15 to 3.41)], and TC:HDL-C [HRadj, 3.11 (1.67 to 5.81)]. HDL was inversely associated with risk; HRadj for extreme tertiles of HDL-C and HDL-P were 0.30 (P-trend <0.0001) and 0.29 (P-trend <0.0001), respectively. These components of atherogenic dyslipidemia, including small LDL-P, medium and very large VLDL-P, TC:HDL-C, HDL-C, and HDL-P, were more strongly associated with incident PAD than incident CCVD. Finally, the addition of LDL-P and HDL-P to TC:HDL-C measures identified women at heightened PAD risk.Conclusions—In this prospective study, NMR-derived measures of LDL particle concentration, but not LDL-C, were associated with incident PAD. Other features of atherogenic dyslipidemia, including elevations in TC:HDL-C, elevations in triglyceride-rich lipoproteins, and low standard and NMR-derived measures of HDL, were significant risk determinants. These data help clarify prior inconsistencies and may elucidate a unique lipoprotein signature for PAD compared to CCVD.Clinical Trial Registration—URL: http://clinicaltrials.gov Unique Identifier: NCT00000479