LDL particle size and composition and incident cardiovascular disease in a South-European population: The Hortega-Liposcale Follow-up Study
Introduction
Photometrically assessed low-density lipoprotein (LDL) cholesterol is a standard measure for cardiovascular risk stratification and is directly related to the total amount of cholesterol, which is transported by LDL particles [1]. The assessment of LDL particles carrying cholesterol is feasible nowadays using sophisticated techniques of lipidomics including nuclear magnetic resonance (NMR) spectroscopy [2]. The size, lipid content and number of LDL particles can be measured using NMR-based Advanced Lipoprotein Testing (ALT) and subfractionation, and the resulting LDL particle subclasses are commonly divided into large, medium and small particles according to their respective size [3]. Although the determination of lipoprotein by NMR has been performed for some years, both at the level of research and commercial tests, most approaches are limited to lipid peaks and analysis of lipoproteins in one dimension. The 2D-diffusion ordered spectroscopy (DOSY)-NMR Liposcale®, a two dimensional NMR test, is a unique technique able to determine the number of LDL lipoprotein particles from direct size measurements, providing more accurate results than the commercial alternatives [4].
Over the past years, interest has grown in the predictive value of LDL particle number and size, and the determination of LDL particles has been included into the guidelines of the American Association of Clinical Endocrinologists for prevention of atherosclerosis [5]. However, current evidence is mainly based on studies conducted in patients with elevated cardiovascular risk or sub-studies of clinical trials addressing the effect of lipid-lowering treatment, thus, available data on the relationship between NMR-measured LDL particles and cardiovascular events in the general population is scarce [[6], [7], [8], [9], [10]]. Moreover, inconsistent findings have been reported regarding the relationship of LDL subclasses with cardiovascular disease. Small, medium and large LDL particles have been associated with a higher, lower and null risk for cardiovascular endpoints, nonetheless, the comparison of available studies is challenging due to differences in terms of study population, outcome variables of interest, particle assessment method and statistical analysis [[11], [12], [13], [14]]. Furthermore, the potential role of LDL particle subclasses' composition (proportions of large, medium and small LDL particles over their sum expressed as small-LDL %, medium-LDL % and large-LDL %), rather than absolute concentrations, on cardiovascular disease has not been explored before.
The objective of the present study was to evaluate the association of total LDL cholesterol, LDL particle size, concentration and LDL particle composition with incident cardiovascular disease in adult men and women participating in the Hortega Follow-up Study, a cohort study representative of a general population from Spain.
Section snippets
Study population
The Hortega Study is a population-based survey among adults 15–85 years old residing in the conscription area of the Rio Hortega University Hospital in Valladolid (central Spain). The Hortega Study started in 1997 as a mail survey on a random sample of 20% of public health system beneficiaries (Hortega Phase I), followed by a pilot examination of randomly selected individuals who responded to the questionnaire (Hortega Phase II). In 2001–2002 the Hortega study (phase III) examined and
Study population and lipid profile
A total of 1162 subjects (49% male, mean age 49.7 years) was included into the study. Main demographic characteristics are shown in Table 1. In terms of cardiovascular risk factors, the characteristics of the study population followed a distribution as expected in the Spanish general population. Subjects with incident stroke – as compared to subjects with incident CHD - were older, had a higher rate of obesity and dyslipidemia but a lower rate of former or current smoking status, diabetes and
Discussion
In a representative sample of a general population from Spain, NMR-measured LDL particle concentration and composition were associated with cardiovascular disease incidence. For total lipoprotein concentrations, the magnitude of the observed associations was similar comparing the standard and NMR measurements, after adjustment for cardiovascular and lipid risk factors. Among the LDL particle subclasses, medium LDL particles showed the strongest association with cardiovascular events,
Sources of funding
This work was supported by the Strategic Action for Research in Health Sciences [CP12/03080, PI15/00071, PI12/02615, PI16/01402, PI14/00874 and PI11/00726], PROMETEO/2009/029 and ACOMP/2013/039 from the Valencia Government, SAF2014-52875R from the Spanish Ministry of Economy and Competitiveness, GRS/279/A/08 from Castilla-Leon Government, EU-MASCARA, HEALTH.2011.2.4.2-2 and Big Data for Better Hearts (IMI2-116074); CIBER Fisiopatología Obesidad y Nutrición (CIBERobn) [CIBER-02-08-2009, CB06/03
Disclosure
NA is employed by, is a stockholder of, and serves on the board of directors of Biosfer Teslab, a diagnostic laboratory company that performed the lipoprotein subclass analyses described herein. MAPC is employed (Chief Operations Officer) by Biosfer Teslab. The remaining authors report no relationships that could be construed as a conflict of interest.
Author contributions
NA, MTP and JR developed the study concept and design. MTP, GP and ADL performed statistical analyses. GP, MTP and JR drafted the manuscript. All the authors interpreted data, and critically revised and completed the manuscript. JR is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Permissions information
The authors do hereby declare that all illustrations and figures in the manuscript are entirely original and do not require reprint permission.
Acknowledgements
None.
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This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.