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Observational Study
. 2020 Oct 1;27(10):1108-1122.
doi: 10.5551/jat.54130. Epub 2020 Apr 10.

Small Dense Low-Density Lipoprotein Cholesterol and Carotid Intimal Medial Thickness Progression

Hiroaki Ikezaki  1   2 , Norihiro Furusyo  1   2 , Yuya Yokota  2   3 , Masumi Ai  2   4 , Bela F Asztalos  2   5 , Masayuki Murata  1 , Jun Hayashi  1 , Ernst J Schaefer  2   5
Affiliations
Observational Study

Small Dense Low-Density Lipoprotein Cholesterol and Carotid Intimal Medial Thickness Progression

Hiroaki Ikezaki et al. J Atheroscler Thromb. .

Abstract

Aim: The association between small dense low-density lipoprotein cholesterol (sdLDL-C) levels and carotid intimal medial thickness (cIMT) progression has not been evaluated fully. We assessed specialized lipoproteins, including sdLDL-C, with regard to cIMT progression in a prospective observational study in Japan.

Methods: Plasma total cholesterol, direct LDL-C, sdLDL-C, LDL-triglycerides (LDL-TG), high-density lipoprotein cholesterol (HDL-C), HDL2-C, HDL3-C, triglycerides, Lp(a), and adiponectin were measured in 2,030 men and women (median age 59 years, free of cardiovascular disease (CVD) and off cholesterol lowering medication). At both baseline and after a five-year follow-up, cIMT was assessed. Univariate, multivariate regression, and least square analyses were performed to examine the relationships between direct LDL-C, sdLDL-C, and other lipoproteins with cIMT progression.

Results: The median cIMT at baseline was 0.63 mm and five-year progression was 0.18 mm. After adjustment for standard CVD risk factors, including age, gender, systolic blood pressure, total cholesterol, HDL-C, smoking, diabetes, and hypertension treatment, only direct LDL-C, sdLDL-C, and the sdLDL-C/LDL-C ratio were associated with cIMT progression. Even in subjects with direct LDL-C ＜100 mg/dL, who were considered at low CVD risk, elevated sdLDL-C were associated with cIMT progression (P for trend=0.009) in a model with established CVD risk factors, although the sdLDL-C/LDL-C ratio did not. Those correlations did not change by including triglycerides as a controlling factor or excluding premenopausal women from the analyzed population.

Conclusions: Small dense LDL-C has a stronger relationship with cIMT progression than LDL-C does; therefore, measuring sdLDL-C may allow for the formulation of optimal therapy for CVD prevention.

Keywords: Atherosclerosis; Cardiovascular diseases; Carotid intimal medial thickness; Small dense LDL cholesterol.

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Conflict of interest statement

The authors have nothing to declare with regard to conflict of interest.

Figures

Supplementary Fig. 1.
Supplementary Fig. 1.
Correlations between sdLDL-C and other lipoproteins and hsCRP This figure shows scatter plots between sdLDL-C and other lipoproteins and hsCRP. According to Spearman's r values, positive correlations between sdLDL-C were found in order direct LDL-C, triglycerides, non-HDL-C, LDL-TG, large buoyant LDL-C, calculated LDL-C, total cholesterol, and hsCRP. HDL-C, HDL2-C, HDL3-C, adiponectin, and Lp(a) showed negative correlations between sdLDL-C. sdLDL-C, small dense low-density lipoprotein cholesterol; hsCRP, high sensitivity C reactive protein; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-TG, low-density lipoprotein triglycerides; Lp(a), lipoprotein(a).
Supplementary Fig. 1.
Supplementary Fig. 1.
Correlations between sdLDL-C and other lipoproteins and hsCRP This figure shows scatter plots between sdLDL-C and other lipoproteins and hsCRP. According to Spearman's r values, positive correlations between sdLDL-C were found in order direct LDL-C, triglycerides, non-HDL-C, LDL-TG, large buoyant LDL-C, calculated LDL-C, total cholesterol, and hsCRP. HDL-C, HDL2-C, HDL3-C, adiponectin, and Lp(a) showed negative correlations between sdLDL-C. sdLDL-C, small dense low-density lipoprotein cholesterol; hsCRP, high sensitivity C reactive protein; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-TG, low-density lipoprotein triglycerides; Lp(a), lipoprotein(a).
Supplementary Fig. 1.
Supplementary Fig. 1.
Correlations between sdLDL-C and other lipoproteins and hsCRP This figure shows scatter plots between sdLDL-C and other lipoproteins and hsCRP. According to Spearman's r values, positive correlations between sdLDL-C were found in order direct LDL-C, triglycerides, non-HDL-C, LDL-TG, large buoyant LDL-C, calculated LDL-C, total cholesterol, and hsCRP. HDL-C, HDL2-C, HDL3-C, adiponectin, and Lp(a) showed negative correlations between sdLDL-C. sdLDL-C, small dense low-density lipoprotein cholesterol; hsCRP, high sensitivity C reactive protein; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-TG, low-density lipoprotein triglycerides; Lp(a), lipoprotein(a).
Fig. 1.
Fig. 1.
Relationship between cIMT progression and serum sdLDL-C levels This figure shows cIMT progression levels by sdLDL-C quartiles and LDL-C levels. Subjects were divided into a low LDL-C group (LDL-C ≤ 100 mg/dL) and a high LDL-C group (LDL-C > 100 mg/dL); they were then stratified into four groups according to sdLDL-C quartiles. cIMT levels were adjusted for standard CVD risk factors using least square methods. Jonckheere-Terpstra trend tests were performed to assess the associations between mean cIMT progressions and sdLDL-C quartiles. Mean cIMT progressions in both the low and high LDL-C groups significantly increased in accordance with higher sdLDL-C quartiles (P for trend < 0.01 and < 0.001, respectively). Among the low LDL-C group, individuals with the highest sdLDL-C quartile had significantly increased cIMT levels than those with the lowest sdLDL-C quartile (P < 0.05), but this was not the case for those with 2nd and 3rd sdLDL-C quartiles. Among the high LDL-C group, individuals with the highest sdLDL-C quartile had significantly increased cIMT levels than those with all other sdLDL-C quartiles (all P < 0.05). Individuals with the highest sdLDL-C quartile in the high LDL-C group had significantly increased cIMT levels than those with all other groups (all P < 0.05). cIMT, carotid intimal medial thickness; sdLDL-C, small dense low-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; CVD, cardiovascular disease.
Fig. 2.
Fig. 2.
Relationship between cIMT progression and sdLDL-C/LDL-C ratios This figure shows cIMT progression levels by sdLDL-C/LDL-C ratio quartiles and LDL-C levels. Subjects were divided to a low LDL-C group (LDL-C ≤ 100 mg/dL) and a high LDL-C group (LDL-C > 100 mg/dL); they were then stratified into four groups according to sdLDL-C/LDL-C ratio quartiles. cIMT levels were adjusted for standard CVD risk factors using least square methods. Jonckheere-Terpstra trend tests were performed to assess the associations between mean cIMT progressions and sdLDL-C quartiles. Mean cIMT progression significantly increased in accordance with higher sdLDL-C/LDL-C ratio quartiles only in the high LDL-C group (P for trend < 0.001); however, there was no significant association between sdLDL-C/LDL-C ratio and cIMT progression in the low LDL-C group. Individuals with the highest sdLDL-C/LDL-C ratio quartile in the high LDL-C group had significant increased cIMT levels than those with all other groups (all P < 0.05). cIMT, carotid intimal medial thickness; sdLDL-C, small dense low-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; CVD, cardiovascular disease.
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