Lipoprotein Particle Profiles, Standard Lipids, and Peripheral Artery Disease Incidence

Abstract

Background: Despite strong and consistent prospective associations of elevated low-density lipoprotein (LDL) cholesterol concentration with incident coronary and cerebrovascular disease, data for incident peripheral artery disease (PAD) are less robust. Atherogenic dyslipidemia characterized by increased small LDL particle (LDL-P) concentration, rather than total LDL cholesterol content, along with elevated triglyceride-rich lipoproteins and low high-density lipoprotein (HDL) 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 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 cholesterol was not associated with incident PAD, we found significant associations for increased total and small LDL-P concentrations, triglycerides, and concentrations of very LDL (VLDL) particle (VLDL-P) subclasses, increased total cholesterol (TC):HDL-C, low HDL-C, and low HDL particle (HDL-P) concentration (all P for extreme tertile comparisons <0.05). Findings persisted in multivariable-adjusted models comparing extreme tertiles for elevated total LDL-P (adjusted hazard ratio [HRadj] 2.03; 95% CI, 1.14-3.59), small LDL-P (HRadj 2.17; 95% CI, 1.10-4.27), very large VLDL-P (HRadj 1.68; 95% CI, 1.06-2.66), medium VLDL-P (HRadj 1.98; 95% CI, 1.15-3.41), and TC:HDL-C (HRadj, 3.11; 95% CI, 1.67-5.81). HDL was inversely associated with risk; HRadj for extreme tertiles of HDL-C and HDL-P concentration 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 coronary and cerebrovascular disease. Finally, the addition of LDL-P and HDL-P concentration to TC:HDL-C measures identified women at heightened PAD risk.

Conclusions: In this prospective study, nuclear magnetic resonance-derived measures of LDL-P, but not LDL cholesterol, 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 nuclear magnetic resonance-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 coronary and cerebrovascular disease.

Clinical trial registration: URL: https://www.clinicaltrials.gov/ . Unique Identifier: NCT00000479.

Keywords: coronary artery disease; lipoproteins; magnetic resonance spectroscopy; peripheral artery disease.

Figures

Figure 1.. Risk Associations Between Standard Lipid and Apolipoprotein Measures and Incident PAD

Hazard ratios and 95% CIs for the top versus bottom tertile of standard lipid and apolipoprotein measures. Model 1 adjusted for age and smoking pack-years. Model 2 adjusted for age, smoking pack-years, metabolic syndrome, hypertension, hormonal therapy, high-sensitivity C-reactive protein, lipid lowering therapy, randomized treatment assignment, and body mass index.

Figure 2.. Risk Associations Between NMR Lipoprotein Particle Concentrations and Size and Incident PAD

Hazard ratios and 95% CIs for the top versus bottom tertile of NMR lipoprotein particle concentrations and sizes. Model 1 adjusted for age and smoking pack-years. Model 2 adjusted for age, smoking pack-years, metabolic syndrome, hypertension, hormonal therapy, high-sensitivity C-reactive protein, lipid lowering therapy, randomized treatment assignment, and body mass index.

Figure 3.. Risk Associations Between NMR Lipoprotein Particle Subclasses and Incident PAD

Hazard ratios and 95% CIs for the top versus bottom tertile of NMR lipoprotein particle subclasses. Model 1 adjusted for age and smoking pack-years. Model 2 adjusted for age, smoking pack-years, metabolic syndrome, hypertension, hormonal therapy, high-sensitivity C-reactive protein, lipid lowering therapy, randomized treatment assignment, and body mass index.

Figure 4.. Risk Associations Between NMR Lipoprotein and Standard Lipid Measures with Incident PAD Versus Incident CCVD

Hazard ratios and 95% CIs for the top versus bottom tertile of incident PAD (blue) and CCVD (red), adjusted for age, smoking pack-years, metabolic syndrome, hypertension, hormonal therapy, high-sensitivity C-reactive protein, lipid lowering therapy, randomized treatment assignment, and body mass index. Measures displayed include all standard lipid and apolipoprotein assays as well as NMR-derived measures with a statistically significant association for incident PAD. Horizontal line separates markers of atherogenic dyslipidemia from other measures without statistical significance for incident PAD.

Figure 5.. Joint Effects of NMR Lipoprotein and Standard Lipid Measures with Incident PAD

A, PAD survival curve according to LDL-C and LDL-P particle concentration (above or below population median). B, PAD survival curve according to LDL-P particle concentration and TC:HDL-C (above or below population median). C, PAD survival curve according to HDL-P particle concentration and TC:HDL-C (above or below population median). D, PAD survival curve according to VLDL-P particle concentration and TC:HDL-C (above or below population median).