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Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk.

ABSTRACT: OBJECTIVE:Whereas epidemiological studies show that levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) predict incident cardiovascular disease (CVD), there is limited evidence relating lipoprotein subfractions and composite measures of subfractions to risk for CVD in prospective cohort studies. METHODS AND RESULTS:We tested whether combinations of lipoprotein subfractions independently predict CVD in a prospective cohort of 4594 initially healthy men and women (the Malmö Diet and Cancer Study, mean follow-up 12.2 years, 377 incident cardiovascular events). Plasma lipoproteins and lipoprotein subfractions were measured at baseline with a novel high-resolution ion mobility technique. Principal component analysis (PCA) of subfraction concentrations identified 3 major independent (ie, zero correlation) components of CVD risk, one representing LDL-associated risk, a second representing HDL-associated protection, and the third representing a pattern of decreased large HDL, increased small/medium LDL, and increased triglycerides. The last corresponds to the previously described "atherogenic lipoprotein phenotype." Several genes that may underlie this phenotype-CETP, LIPC, GALNT2, MLXIPL, APOA1/A5, LPL-are suggested by SNPs associated with the combination of small/medium LDL and large HDL. CONCLUSIONS:PCA on lipoprotein subfractions yielded three independent components of CVD risk. Genetic analyses suggest these components represent independent mechanistic pathways for development of CVD.

SUBMITTER: Musunuru K

PROVIDER: S-EPMC2772123 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk.

Musunuru Kiran K Orho-Melander Marju M Caulfield Michael P MP Li Shuguang S Salameh Wael A WA Reitz Richard E RE Berglund Göran G Hedblad Bo B Engström Gunnar G Williams Paul T PT Kathiresan Sekar S Melander Olle O Krauss Ronald M RM

Arteriosclerosis, thrombosis, and vascular biology 20090903 11

<h4>Objective</h4>Whereas epidemiological studies show that levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) predict incident cardiovascular disease (CVD), there is limited evidence relating lipoprotein subfractions and composite measures of subfractions to risk for CVD in prospective cohort studies.<h4>Methods and results</h4>We tested whether combinations of lipoprotein subfractions independently predict CVD in a prospective cohort of 4594 ...[more]

PMID: 19729614

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Project description:Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo.In 11?186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility-measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88-1.21). In contrast, associations with CVD events were observed for baseline non-high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01-1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11-1.48), and ion mobility-measured non-HDL particles (HR, 1.19; 95% CI, 1.05-1.35) and LDL particles (HR, 1.21; 95% CI, 1.07-1.37). Association with CVD events was also observed for several LDL and very-low-density lipoprotein subfractions but not for ion mobility-measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-C, non-HDL cholesterol, and apolipoprotein B; these were also associated with CVD/all-cause death, as were several LDL and very-low-density lipoprotein subfractions, albeit with a pattern of association that differed from the baseline risk.In JUPITER, baseline LDL-C was not associated with CVD events, in contrast with significant associations for non-HDL cholesterol and atherogenic particles: apolipoprotein B and ion mobility-measured non-HDL particles, LDL particles, and select subfractions of very-low-density lipoprotein particles and LDL particles. During high-intensity statin therapy, on-treatment levels of LDL-C and atherogenic particles were associated with residual risk of CVD/all-cause death.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Project description:Background: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of pcsk9 inhibitors (pcsk9i). Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system employing mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (mace). Methods: The odyssey outcomes trial compared the pcsk9i alirocumab with placebo in patients with recent acute coronary syndrome (acs). We compared risk of mace in the placebo group and mace risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by siemens n-latex nephelometric immunoassay (ia-mass, mg/dl), roche tina-quant® turbidimetric immunoassay (ia-molar, nmol/l), and a non-commercial mass spectrometry-based test (ms, nmol/l). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. Results: Among 11,970 trial participants with results from all 3 tests, baseline median (q1, q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dl, 45.0 (13.2, 153.8) nmol/l, and 42.2 (14.3, 143.1) nmol/l for ia-mass, ia-molar, and ms, respectively. The strongest correlation was between ia-molar and ms (r=0.990), with nominally weaker correlations between ia-mass and ms (r=0.967) and ia-mass and ia-molar (r=0.972). Relationships of lipoprotein(a) with mace risk in the placebo group were nearly identical with each test with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for ldl-c (all spline p≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the three tests, with estimated treatment hazard ratios (hrs) differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all three tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. Conclusions: In patients with recent acs, three lipoprotein(a) tests were similarly prognostic for mace in the placebo group and predictive of mace reductions with alirocumab at the cohort level.

Project description:Background Conventional "low-density lipoprotein cholesterol (LDL-C)" assays measure cholesterol content in both low-density lipoprotein and lipoprotein(a) particles. To clarify the consequences of this methodological limitation for clinical care, our study aimed to compare associations of "LDL-C" and corrected LDL-C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline-recommended LDL-C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from "LDL-C" to obtain corrected LDL-C values (LDL-Ccorr30). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual-patient-data meta-analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow-up). When comparing top versus bottom quartiles, the multivariable-adjusted hazard ratio for cardiovascular disease was significant for "LDL-C" (1.17; 95% CI, 1.05-1.31; P=0.005) but not for LDL-Ccorr30 (1.07; 95% CI, 0.93-1.22; P=0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline-recommended LDL-C categories when using LDL-Ccorr30 was assessed. In "LDL-C" categories of 70 to <100, 100 to <130, 130 to <190, and ?190 mg/dL, significant proportions (95% CI) of participants were reassigned to lower LDL-C categories when LDL-Ccorr30 was used: 30.2% (30.0%-30.4%), 35.1% (34.9%-35.4%), 32.9% (32.6%-33.1%), and 41.1% (40.0%-42.2%), respectively. Conclusions "LDL-C" was associated with incident cardiovascular disease only when lipoprotein(a) cholesterol content was included in its measurement. Refinement in techniques to accurately measure LDL-C, particularly in patients with elevated lipoprotein(a) levels, is warranted to assign risk to the responsible lipoproteins.

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Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk.

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Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk.

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