Small and medium sized HDL particles are protectively associated with coronary calcification in a cross-sectional population-based sample
Introduction
The notion that HDL cholesterol (HDL-C) is protective against coronary heart disease (CHD) has, together with the dominant LDL cholesterol hypothesis, served as a key paradigm governing CHD causation and prevention over the past five decades. However, drug trials with niacin and CETP inhibitors that substantially increased HDL-C failed to reduce the risk of CHD [1] and a Mendelian randomization study did not support a causal role for HDL-C [2]. Consequently, serious doubt has been raised as to a causal link between HDL-C and CHD [3]. Nevertheless, the key role of HDL in reverse cholesterol transport is not in question [4]. As HDL is a complex and molecularly heterogeneous collection of different-size particles that carry out multiple functions, it seems unlikely that a single measure, i.e. the cholesterol carried in HDL, can capture its full functionality. Recent evidence suggests that small, dense, protein-rich HDL particles display more potent atheroprotective properties than large, buoyant cholesterol-rich particles [5], [6], [7]. Thus, drugs that successfully increased levels of HDL-C by increasing the relative amounts of larger-size particles, might not necessarily have affected attributes that confer protective properties to HDL.
Advances in the separation of lipoproteins [8], [9], [10], [11] by size, density, charge, chemical composition and functionality permit their further characterization. With the availability of newer HDL measures, and fueled by the disappointing results of HDL-C targeted treatment trials, research has intensified to identify HDL measures that may be causal risk factors as well as better markers and predictors of CHD than the traditional HDL-C. Whereas earlier studies which measured the cholesterol content of HDL subclasses using density gradient ultracentrifugation (classified as small dense (HDL3) and large buoyant (HDL2)) suggested the large HDL2 subclass to be a better predictor of CHD [12], [13], more recent studies using the same separation technique have identified the smaller HDL3 subclass in this role [7], [14], [15], [16], [17]. Using Nuclear Magnetic Resonance (NMR) spectroscopy, an inverse association with CHD has been reported for HDL particle concentration (HDL-P), which measures the total number of particles into which HDL cholesterol is packaged [18], [19], [20], [21], and it has been suggested that HDL-P might replace HDL-C in prediction of CHD [4], though not unanimously so [22]. Also, cholesterol overloaded HDL particles (as reflected by a higher HDL-C/HDL-P ratio) have been shown to be positively associated with CHD [23].
Whether the newer findings for the HDL2 and HDL3-subclasses and HDL-P persist across different populations, laboratory methods and outcome measures remains unanswered. To further explore this, we investigated the associations of NMR measures of HDL parameters: HDL-P, HDL-P subclasses, and average HDL-P size with coronary artery calcification (CAC), a reflection of the burden of coronary atherosclerosis [24], in a population-based sample of Israelis and Palestinians residing in Jerusalem.
Section snippets
Materials and methods
The methods of sampling and data collection in this cross-sectional study have been reported [25], [26]. An age-sex stratified random sample of 2000 Israelis and 2000 Palestinians between ages 25–74 years was drawn from the Israel National Population Registry. Between 2004 and 2008, 70.5% of Palestinians and 74.8% of Israelis were successfully located. Institutionalized, housebound or pregnant individuals, those with a serious health disorder (such as metastatic cancer or end stage renal
Baseline characteristics
Of the 504 study participants, 297 (58.9%) had evidence of any CAC and 135 (26.8%) had a CAC score ≥100. Men (age-adjusted OR 2.02, 95% CI 1.28–3.17 vs. women), older examinees and participants with diabetes and hypertension were more likely to have a CAC score ≥100. SBP showed a stronger association with CAC ≥100 than DBP (Table 1). BMI, smoking, lipid-lowering medication and population group were not significantly associated with CAC status. Over 75% of the participants had a BMI >25 kg/m2.
Baseline lipid and NMR measures
Discussion
Statistically significant multivariable-adjusted inverse associations of MS-HDL-P and HDL-P with CAC scores ≥100 were evident in a sample of Arabs and Jews residing in Jerusalem. Adjustment for HDL-C did not affect the magnitude of the observed associations. Large HDL-P and average HDL particle size were not associated with CAC. A protective association of HDL-C with CAC was evident only in men. Although HDL-C is an indisputable risk marker for CHD [4], these findings indicate that HDL-P and
Conflict of interest
The authors declared that they do not have anything to disclose regarding conflict of interest with respect to this manuscript.
Financial support
This study was supported by research grants from the USAID Middle Eastern Regional Cooperation (MERC) Program (grant no TA-MOU-01-M21-002) and from D-CURE-Diabetes Care in Israel to JDK.
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