Mackey RH, Greenland P, Goff DC Jr, Lloyd-Jones D, Sibley CT, Mora S.
J Am Coll Cardiol. 2012 Jun 27. [Epub]

Background

As there is a well-established inverse association of high-density lipoprotein cholesterol (HDL-C) with atherosclerosis and coronary heart disease (CHD), raising levels of HDL-C might be interesting [1]. Quantification of HDL-C, which is carried by HDL particles (HDL-P), may however not fully capture HDL-related risk [1,2]. Drugs raising HDL-C recently failed to reduce CV events [3,4] or atherosclerosis [5], thereby increasing the interest in alternative indices of HDL quantity or quality.

The association of HDL-C with CHD risk is complicated by the inverse association of HDL-C with triglycerides, insulin resistance, obesity, high-sensitivity C-reactive protein (hsCRP), and atherogenic lipoprotein particles [1]. HDL-C associations with carotid intima-media thickness (cIMT) and incident CHD events might partly reflect correlated lipid, apolipoprotein, or lipoprotein concentrations, particularly LDL-P, but HDL-P associations might be less affected by these metabolic risk factors, including HDL-C.  Using data from the MESA (Multi-Ethnic Study of Atherosclerosis) study, a study of 5598 men and women aged 45 to 84 years old without baseline coronary heart disease, the associations were tested between HDL cholesterol and NMR spectroscopy-measured HDL-particle numbers with cIMT and incident MI, coronary heart disease death, and angina. Potential interactions by baseline diabetes, hsCRP, sex, and ethnicity were also evaluated. After a mean six-year follow-up, 227 coronary heart disease events were documented.

Main results

• HDL-particle concentrations were positively correlated with HDL-cholesterol levels
• Both HDL-particle concentrations and HDL-cholesterol levels had an inverse correlation with LDL cholesterol, LDL particle concentrations, and with other metabolic risk factors.
• Adjusted for confounding variables, mean cIMT was lower among patients with higher concentrations of HDL cholesterol and HDL particles.
• One-standard-deviation (SD) increase in the concentrations of HDL cholesterol (15 mg/dL) or HDL particles (6.64 µmol/L) was associated with a 0.026-mm and 0.030-mm reduction in cIMT, respectively. 
• Each SD-increase in HDL cholesterol and HDL-particle concentrations was associated with a significant 26% and 30% lower risk of coronary heart disease events
  

Conclusion

Quantification of HDL cholesterol, which is the cholesterol carried by HDL particles, might not fully capture the HDL-related risk. Quantitative and metabolic interrelationships between lipids and the lipoprotein particles that carry them should be considered when evaluating associations between single parameters.

Editorial comment [6]

In the setting of HDL-directed therapies, a consistent inverse relationship between HDL cholesterol and cardiovascular risk can no longer be assumed. The independent association of HDL particles with coronary heart disease suggests that it might serve as a better marker of risk than HDL cholesterol and might prove more useful to assess HDL-directed pharmacotherapies and that increasing HDL-particle concentrations might prove to be more appropriate than increasing HDL cholesterol for reducing the risk of cardiovascular events. Several important questions need to be addressed in future studies to clarify the role of HDL-particles in clinical practice.

References

1. Vergeer M, Holleboom AG, Kastelein JJ, Kuivenhoven JA. The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis? J Lipid Res 2010;51:2058 –73.
2. deGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Coll Cardiol 2008;51:2199 –211.
3. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109–22.
4. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563–74.
5. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304–16.
6. Degoma EM, Rader DJ. High-Density Lipoprotein Particle Number: A Better Measure to Quantify High-Density Lipoprotein? J Am Coll Cardiol. 2012 Jun 27.

Abstract

Objectives:
The purpose of this study was to evaluate independent associations of high-density lipoprotein cholesterol (HDL-C) and particle (HDL-P) concentrations with carotid intima-media thickness (cIMT) and incident coronary heart disease (CHD).

Background:
HDL-C is inversely related to CHD, and also to triglycerides, low-density lipoprotein particles (LDL-P), and related metabolic risk. HDL-P associations with CHD may be partially independent of these factors.

Methods:
In a multiethnic study of 5,598 men and women ages 45 to 84 years old, without baseline CHD, excluding subjects on lipid-lowering medications, triglycerides >400 mg/dl, or missing values, we evaluated associations of HDL-C and nuclear magnetic resonance spectroscopy-measured HDL-P with cIMT and incident CHD (myocardial infarction, CHD death, and angina, n = 227 events; mean 6.0 years follow-up). All models were adjusted for age, sex, ethnicity, hypertension, and smoking.

Results:
HDL-C and HDL-P correlated with each other (ρ = 0.69) and LDL-P (ρ = -0.38, -0.25, respectively, p < 0.05 for all). For (1 SD) higher HDL-C (15 mg/dl) or HDL-P (6.64 μmol/l), cIMT differences were - 26.1 (95% confidence interval [CI]: -34.7 to -17.4) and -30.1 (95% CI: -38.8 to - 21.4) μm, and CHD hazard ratios were 0.74 (95% CI: 0.63 to 0.88) and 0.70 (95% CI: 0.59 to 0.82), respectively. Adjusted for each other and LDL-P, HDL-C was no longer associated with cIMT (2.3; 95% CI: - 9.5 to 14.2 μm) or CHD (0.97; 95% CI: 0.77 to 1.22), but HDL-P remained independently associated with cIMT (-22.2; 95% CI: - 33.8 to -10.6 μm) and CHD (0.75; 95% CI: 0.61 to 0.93). Interactions by sex, ethnicity, diabetes, and high-sensitivity C-reactive protein were not significant.

Conclusions:
Adjusting for each other and LDL-P substantially attenuated associations of HDL-C, but not HDL-P, with cIMT and CHD. Potential confounding by related lipids or lipoproteins should be carefully considered when evaluating HDL-related risk.