Association of Apolipoprotein B and NMR Spectroscopy–Derived LDL Particle Number with Outcomes

Association of Apolipoprotein B and Nuclear Magnetic Resonance Spectroscopy–Derived LDL Particle Number with Outcomes in 25 Clinical Studies              

1. Thomas G. Cole¹,*,                      
2. John H. Contois²,
3. Gyorgy Csako³,
4. Joseph P. McConnell⁴,
5. Alan T. Remaley³,
6. Sridevi Devaraj⁵,
7. Daniel M. Hoefner⁴,
8. Tonya Mallory⁴,
9. Amar A. Sethi⁶ and
10. G. Russell Warnick⁴

                    

Abstract

 

BACKGROUND: The number of circulating LDL particles is a strong indicator of future cardiovascular disease (CVD) events, even superior to the concentration of LDL cholesterol. Atherogenic (primarily LDL) particle number is typically determined either directly by the serum concentration of apolipoprotein B (apo B) or indirectly by nuclear magnetic resonance (NMR) spectroscopy of serum to obtain NMR-derived LDL particle number (LDL-P).

                    

CONTENT: To assess the comparability of apo B and LDL-P, we reviewed 25 clinical studies containing 85 outcomes for which both biomarkers were determined. In 21 of 25 (84.0%) studies, both apo B and LDL-P were significant for at least 1 outcome. Neither was significant for any outcome in only 1 study (4.0%). In 50 of 85 comparisons (58.8%), both apo B and LDL-P had statistically significant associations with the clinical outcome, whereas in 17 comparisons (20.0%) neither was significantly associated with the outcome. In 18 comparisons (21.1%) there was discordance between apo B and LDL-P.

                    

CONCLUSIONS: In most studies, both apo B and LDL-P were comparable in association with clinical outcomes. The biomarkers were nearly equivalent in their ability to assess risk for CVD and both have consistently been shown to be stronger risk factors than LDL-C. We support the adoption of apo B and/or LDL-P as indicators of atherogenic particle numbers into CVD risk screening and treatment guidelines. Currently, in the opinion of this Working Group on Best Practices, apo B appears to be the preferable biomarker for guideline adoption because of its availability, scalability, standardization, and relatively low cost.

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AHA Scientific Statement

Triglycerides and Cardiovascular Disease

A Scientific Statement From the American Heart Association

1. Introduction

A long-standing association exists between elevated triglyceride levels and cardiovascular disease* (CVD).^1,2 However, the extent to which triglycerides directly promote CVD or represent a biomarker of risk has been debated for 3 decades.³ To this end, 2 National Institutes of Health consensus conferences evaluated the evidentiary role of triglycerides in cardiovascular risk assessment and provided therapeutic recommendations for hypertriglyceridemic states.^4,5 Since 1993, additional insights have been made vis-à-vis the atherogenicity of triglyceride-rich lipoproteins (TRLs; ie, chylomicrons and very low-density lipoproteins), genetic and metabolic regulators of triglyceride metabolism, and classification and treatment of hypertriglyceridemia. It is especially disconcerting that in the United States, mean triglyceride levels have risen since 1976, in concert with the growing epidemic of obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM).^6,7 In contrast, mean low-density lipoprotein cholesterol (LDL-C) levels have receded.⁷ Therefore, the purpose of this scientific statement is to update clinicians on the increasingly crucial role of triglycerides in the evaluation and management of CVD risk and highlight approaches aimed at minimizing the adverse public health–related consequences associated with hypertriglyceridemic states. This statement will complement recent American Heart Association scientific statements on childhood and adolescent obesity⁸ and dietary sugar intake⁹ by emphasizing effective lifestyle strategies designed to lower triglyceride levels and improve overall cardiometabolic health. It is not intended to serve as a specific guideline but will be of value to the Adult Treatment Panel IV (ATP IV) of the National Cholesterol Education Program, from which evidence-based guidelines will ensue. Topics to be addressed include epidemiology and CVD risk, ethnic and racial differences, metabolic determinants, genetic and family determinants, risk factor correlates, and effects related to nutrition, physical activity, and lipid medications.

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Genetic studies lay the foundations for anti-inflammatory drugs to prevent heart disease

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies

Original Text

IL6R Genetics Consortium Emerging Risk Factors Collaboration

Summary

Background

Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.

Methods

In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.

Findings

The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4—38·2) and of interleukin 6 by 14·6% (10·7—18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9—9·1) and of fibrinogen by 1·0% (0·7—1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8—5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.

Interpretation

Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.

Funding

British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

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View the article here.
See also this article in theheart.org.