Abstract
Aim: Experimental studies report that intermediate-density lipoprotein (IDL), the precursor of low-density lipoprotein, promotes atherosclerotic plaque formation. However, whether IDL is involved in the development of atherosclerosis in humans is still unclear. The aim of this community-based study is to examine the association between IDL particle (IDL-P) concentrations and the 5-year progression of carotid atherosclerosis.
Methods: Baseline IDL-P concentrations were measured using nuclear magnetic resonance spectroscopy in 927 participants aged 45–74 years with no history of cardiovascular disease (CVD) at baseline. To estimate the association between baseline IDL-P concentrations and 5-year progression of carotid atherosclerosis, indicated by atherosclerotic plaque progression and changes in total plaque area (TPA), multivariable-adjusted regression was employed.
Results: During the 5-year follow-up period, 45.8% of participants developed new plaques. Baseline IDL-P concentrations were significantly associated with the progression of carotid atherosclerosis. Participants in the highest quartile of IDL-P concentrations exhibited 1.36-fold (95% confidence interval [CI]: 1.09–1.68) increased progression of carotid plaque and 1.67-fold (95% CI: 1.04–2.69) higher TPA than those in the lowest quartile. These relationships were independent of baseline concentrations of low-density lipoprotein particles and very-low-density lipoprotein particles and their subclasses.
Conclusions: Elevated IDL-P concentrations were independently associated with the progression of carotid atherosclerosis, suggesting that IDL-P is a novel risk factor for the development of atherosclerosis.
Introduction
Increasing evidence has demonstrated that elevated low-density lipoprotein cholesterol (LDL-C) is a critical causal risk factor for atherosclerotic cardiovascular disease1). Even after lipid-control therapies, the residual risk of atherosclerotic cardiovascular disease remains2-4). Therefore, to estimate, and mitigate these residual risks in specific patients, new approaches are required. The identification of novel lipid and lipoprotein targets that predict the residual risk of atherosclerotic cardiovascular disease and thus reduce the disease burden is urgently needed.
Intermediate-density lipoprotein (IDL), one of the major groups of lipoproteins, represents the intermediate step in the process through which very low-density lipoproteins (VLDLs) are degraded by hepatic lipase to low-density lipoproteins (LDLs)5). The contribution of IDL to the pathogenesis of atherosclerosis has attracted attention. Recent cohort studies have demonstrated that IDL-related parameters are significantly associated with the incidence of ischemic heart disease or ischemic stroke6, 7) and that the magnitude of the myocardial infarction risk associated with IDL cholesterol was even higher than that associated with LDL-C or VLDL cholesterol (VLDL-C)7). These findings suggest that IDL might be a stronger atherogenic lipoprotein. However, the exact mechanisms underlying the increased risk of cardiovascular disease mediated by IDL are still unclear. Previous experimental studies have shown that IDL particles (IDL-P) enhance foam cell and plaque formation by entering and retaining within the vessel wall, undergoing phagocytosis by macrophages, and releasing lipolysis components, hence inducing inflammation8-14). Furthermore, the number of lipoprotein particles instead of the amount of cholesterol carried by the particles is suggested to assess lipoprotein function and influence the initiation and progression of atherosclerosis15, 16). Therefore, the exact impact of IDL-P on the development of atherosclerosis in humans should be clarified. Previous studies have shown that IDL-P concentrations are not associated with changes in carotid intima-media thickness (IMT) in patients with type 1 diabetes17). However, changes in IMT may not be an appropriate indicator for atherosclerosis development18), as they do not reflect the progression of atherosclerosis or the incidence of atherosclerotic plaque. Therefore, data on the relationship between IDL-P and the development of atherosclerotic plaque are lacking.
Aim
In the present study, lipoprotein particle concentrations were measured using nuclear magnetic resonance (NMR) spectroscopy in middle-aged and elderly participants with no history of cardiovascular diseases. This community-based cohort study aimed to examine the association of NMR-measured IDL-P concentrations over a 5-year progression of carotid atherosclerotic plaque and total plaque area (TPA) changes in new-onset plaque.
Methods
Study Participants
The Chinese Multi-Provincial Cohort Study (CMCS)-Beijing Project was launched in 1992. The design and selection criteria of the CMCS have been detailed previously19). The present cohort study enrolled 1,324 participants aged 45–74 years who received a standardized questionnaire on cardiovascular risk factors and physical and carotid ultrasound examinations at baseline in 2002. After excluding participants who suffered from cardiovascular diseases or who were lacking baseline blood samples, 1,256 participants were invited to undergo a repeated assessment of cardiovascular risk factors and carotid ultrasound examination in 2007. In total, 927 participants with complete information at both time points were eligible for the current study (Supplemental Fig.1). All the participants provided written informed consent. The Ethics Committee of Beijing An Zhen Hospital, Capital Medical University approved the protocol.
Cardiovascular Risk Factor Survey
The standardized questionnaire modified by the World Health Organization Multinational Monitoring of Trends and Determinants of Cardiovascular Disease protocol was administered to all participants to obtain information on demographic characteristics, personal history, and medical treatment. During the physical examination, height, weight, and blood pressure were measured. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Physical activity was defined as engaging in high-intensity exercise more than 3 days a week for ≥ 30 min each time20). Information regarding lipid-lowering treatment, antihypertensive therapy, and physical activity was self-reported. Details of the investigation methods and definitions of risk factors have been described previously19).
Laboratory Measurements
Overnight fasting blood samples collected from participants were used for laboratory measurements. On the survey day, fresh blood samples were collected to assess blood glucose, creatinine, and traditional blood lipid profiles, including measurements of total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Fasting blood glucose, TC, and TGs were determined using enzymatic methods, and LDL-C and HDL-C were determined using homogeneous methods. Serum creatinine levels were determined by Jaffe’s assay. VLDL-C was calculated by subtracting LDL-C and HDL-C from TC. The remaining samples were stored at −80℃ without repeated freezing and thawing. In 2013, the concentrations of lipoprotein particles were measured using an NMR assay at Liposcience (Raleigh, NC)19). Diameter range estimates for the subclasses were as follows21): total VLDL particles (VLDL-P) (＞27.0 nm), IDL-P (23.1–27.0 nm), LDL particles (LDL-P) (18.1–23.0 nm), and high-density lipoprotein particles (HDL-P) (7.3–13.0 nm). The VLDL subclasses encompassed large VLDL-P and chylomicrons (＞60.0 nm), medium VLDL-P (35.1–60.0 nm), and small VLDL-P (27.1–35.0 nm). The LDL subclasses encompassed both large LDL-P (21.3–23.0 nm) and small LDL-P (18.1–21.2 nm).
Carotid Ultrasound Examination
High-resolution B-mode ultrasonography was conducted at baseline and follow-up examinations. The method and the measurement validation have been previously reported19). Briefly, the presence of a plaque was defined as a focal region with IMT ≥ 1.5 mm or a focal structure that encroached into the arterial lumen measuring at least 0.5 mm or more than 50% of the surrounding IMT22). The progression of carotid plaque was defined as the appearance of at least new one plaque at re-examination in any previously nonplaque artery segment (far and near walls of the bilateral common carotid arteries, bifurcations, and internal carotid arteries) at baseline. The incidence of new-onset carotid plaque was defined as the appearance of new plaques at re-examination following the absence of plaque in all segments at baseline. Moreover, the TPA at re-examination was measured by a Vascular Research Tools 6 carotid analyzer (Medical Imaging Applications, Coralville, IA) to determine the burden of carotid atherosclerosis among participants with new-onset plaque. Regarding the presence of plaque, the kappa values for intraobserver and interobserver agreement ranged from 0.83 to 1.00 for both baseline and re-examination. Additionally, the kappa value of interobserver agreement was 0.79 (p＜0.001) between the two examinations. Regarding the TPA, the average intraclass correlation coefficient for interobserver agreement was 0.97 (95% confidence interval [CI]: 0.92−0.99)19).
Study Power Estimation
Thus far, no studies have investigated the association between baseline IDL-P concentrations and carotid plaque progression. A study investigating the association between IDL-P concentrations and the incidence of ischemic stroke found that participants in the highest quartile of IDL-P concentrations had a 1.46-fold (95% CI: 1.04–2.04) higher risk than those in the lowest quartile23). In the present study, the 5-year progression rate of carotid plaque was 45.8%. The R2 of the IDL-P concentrations with other covariates was 0.47. The estimated necessary sample size was 557 participants using an alpha (probability of type I error) of 0.05 and beta (probability of type II error) of 0.10. As this study enrolled 927 eligible participants, it had sufficient statistical power to detect the relationships of interest.
Statistical Analysis
Continuous variables with normal distributions are presented as the mean±standard deviation. Continuous variables with skewed distributions are expressed as the median (interquartile range). Categorical variables are expressed as numbers (percentages). The p values for trend were determined by linear or logistic regression of IDL-P concentration quartiles with the baseline characteristics. Baseline characteristics were compared between eligible and unavailable for re-examination participants using Student’s t-test (normal distributions) and the Mann–Whitney U test (skewed distributions) for continuous variables and Pearson’s chi-square test for categorical variables. Spearman partial correlation coefficients were calculated to estimate the correlations between IDL-P concentrations and other baseline characteristics after adjusting for age and sex.
Relative risks (RRs) and 95% CIs for the association between the progression of carotid plaque and baseline IDL-P concentration quartiles (cut-off values: ＜129, 129–198, 199–273, and ≥ 274 nmol/L) were calculated using a modified Poisson regression model, the lowest quartile of IDL-P concentrations was used as a reference. The regression model was adjusted for conventional risk factors (age, sex, current smoking, BMI, systolic blood pressure, diabetes, lipid-lowering treatment, and physical activity), as well as lipid- and lipoprotein-related parameters, including LDL-P, VLDL-P, HDL-C, and TGs, whereas considering their collinearity with IDL-P. The p values for trend were calculated by entering the median value of each quartile of IDL-P concentrations as a continuous variable in the models.
Multivariable-adjusted restricted cubic splines were conducted to examine the relationship between IDL-P concentrations and the progression of carotid plaque on a continuous scale with three knots (according to Akaike’s information criteria). The reference value of IDL-P concentration was set at 10 nmol/L to allow estimations of risk with increased IDL-P concentrations over the entire concentration range. Among participants with no plaque at baseline, ordinal logistic regression analysis was used to calculate the odds ratio (OR) to explore the association of IDL-P concentration quartiles with the burden of new-onset carotid plaque. The burden of new-onset carotid plaque was represented by TPA at re-examination, which was divided into no plaque (TPA=0), TPA below the median and TPA above the median (TPA median =15.52 mm2). The reference group was defined as the no plaque group. The parallel regression assumption was evaluated, and no major violations were observed. Discrimination and reclassification were used to evaluate the predictive capabilities of IDL-P on plaque progression. The discriminatory power of a model was assessed by area under the receiver operating characteristic curve (AUC), which was compared between the traditional model (age, sex, current smoking, BMI, systolic blood pressure, diabetes, lipid-lowering treatment, and physical activity, LDL-P, HDL-C, and TG), and traditional model plus IDL-P quartile using receiver operating characteristic curve (ROC) analysis. We also tested the ability of the IDL quartile to reclassify the risk of plaque progression by calculating the continuous net reclassification index (NRI).
Sensitivity analyses were conducted after excluding participants who received lipid-lowering treatment (n=111) or those with diabetes at baseline (n=84). Additionally, given the difference in IDL-P concentrations between males and females, analyzing the relation between sex-specific quartiles of IDL-P and plaque progression was conducted to validate the robustness of the main results (cut-off values of IDL-P concentrations for males: ＜109, 109–187, 188–260, and ≥ 261 nmol/L, those for females: ＜139, 139–209, 210–287, and ≥ 288 nmol/L). The association between baseline IDL-P concentration quartiles and progression of carotid plaque was also adjusted for VLDL-P and LDL-P and their subclasses. Additional adjustment was also conducted for serum creatinine as a confounding factor, considering chronic kidney disease as a well-known risk factor for the development of cardiovascular disease.
All analyses were conducted using R version 4.1.2 (R Project for Statistical Computing, Vienna, Austria). A two-tailed p＜0.05 was considered statistically significant.
Results
Baseline Characteristics
Among the 927 participants, the mean age was 58.9±7.9 years, and 54.7% were females. The median (interquartile range) concentration of IDL-P was 199 (129, 274) nmol/L, which is higher than that of VLDL-P but lower than that of LDL-P (Supplemental Table 1). Baseline IDL-P concentrations had a right-skewed distribution. IDL-P concentrations were lower in males than in females, with median (interquartile range) values of 188 (109, 260) nmol/L in males and 210 (139, 287) nmol/L in females (p＜0.001) (Fig.1). Table 1 shows the baseline characteristics stratified by IDL-P quartile. Concentrations of cholesterol, large LDL-P, and total VLDL-P as well as its medium and small subclasses were higher, whereas TG, large VLDL-P, and small LDL-P concentrations were lower in participants with higher IDL-P concentrations. Participants with higher IDL-P concentrations were less likely to have hypertension and receive lipid-lowering treatment than those with lower IDL-P concentrations.
Supplemental Table 1.Baseline characteristics of the study participants who were eligible and unavailable for re-examination
| Baseline characteristics |
All (n= 1256)
|
Eligible (n= 927)
|
Participants unavailable for re-examination (n= 329)
|
p value
|
| Age, years |
59.1±7.9 |
58.9±7.9 |
59.4±7.7 |
0.351 |
| Female, n (%)
|
674 (53.7) |
507 (54.7) |
167 (50.8) |
0.244 |
| Current smoking, n (%)
|
120 (9.6) |
91 (9.8) |
29 (8.8) |
0.673 |
| Body mass index, kg/m2
|
24.9±3.2 |
25.0±3.2 |
24.9±3.3 |
0.598 |
| Systolic blood pressure, mmHg |
129.2±18.5 |
129.7±18.3 |
128.0±19.2 |
0.169 |
| Diastolic blood pressure, mmHg |
80.8±10.1 |
80.8±10.1 |
80.7±10.2 |
0.864 |
| Hypertension, n (%)
|
602 (47.9) |
447 (48.2) |
155 (47.1) |
0.779 |
| Fasting blood glucose, mg/dL |
88.8±20.4 |
88.2±18.0 |
90.6±26.0 |
0.074 |
| Diabetes, n (%)
|
116 (9.2) |
85 (9.2) |
31 (9.4) |
0.980 |
| Lipid-lowering treatment, n (%)
|
150 (11.9) |
111 (12.0) |
39 (11.9) |
0.999 |
| Physical activity, n (%)
|
220 (17.5) |
164 (17.7) |
56 (17.0) |
0.849 |
| Creatinine, mg/dL |
1.02 (0.89, 1.16) |
1.02 (0.88, 1.16) |
1.03 (0.91, 1.18) |
0.249 |
| Conventional lipids-related parameters |
|
|
|
|
| Total cholesterol, mg/dL |
214.9±39.6 |
215.1±39.4 |
214.0±40.2 |
0.662 |
| LDL cholesterol, mg/dL |
129.4±32.2 |
129.2±32.0 |
130.0±32.9 |
0.707 |
| HDL cholesterol, mg/dL |
53.6±11.9 |
53.8±12.0 |
53.0±11.6 |
0.315 |
| VLDL cholesterol, mg/dL |
27 (20, 39) |
27 (20, 39) |
27 (19, 40) |
0.608 |
| Triglyceride, mg/dL |
116.0 (84, 167) |
115 (84, 166) |
117 (86, 173) |
0.836 |
| NMR measured lipoprotein particle concentration |
|
|
|
|
| IDL, nmol/L |
199 (127, 277) |
199 (129, 274) |
199 (122, 282) |
0.897 |
| VLDL, nmol/L |
55.5 (44.1, 68.4) |
55.8 (44.3, 68.6) |
54.8 (43.5, 67.7) |
0.567 |
| Large VLDL |
2.4 (1.2, 4.2) |
2.4 (1.2, 4.1) |
2.5 (1.2, 4.3) |
0.547 |
| Medium VLDL |
13.4 (7.3, 19.7) |
13.2 (7.5, 19.7) |
13.6 (6.8, 19.7) |
0.946 |
| Small VLDL |
38.7 (30.0, 48.0) |
39.0 (30.1, 48.2) |
38.1 (29.4, 47.3) |
0.295 |
| LDL, nmol/L |
866 (708, 1027) |
865 (700, 1027) |
869 (727, 1019) |
0.693 |
| Large LDL |
257 (124, 370) |
251 (126, 368) |
264 (107, 378) |
0.630 |
| Small LDL |
586 (411, 816) |
586 (414, 809) |
586 (405, 822) |
0.944 |
| HDL, μmol/L |
29.9 (26.7, 33.1) |
29.9 (26.9, 33.4) |
29.9 (26.3, 32.4) |
0.059 |
Abbreviation: HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; NMR, nuclear magnetic resonance spectroscopy; VLDL, very low-density lipoprotein.
Table 1. Baseline characteristics of participants stratified by the quartiles of IDL particle concentrations
| Baseline characteristics |
Quartiles of IDL particle concentrations (nmol/L) |
| Quartile 1 |
Quartile 2 |
Quartile 3 |
Quartile 4 |
p for trend
|
| (＜129) |
(129-198) |
(199-273) |
(≥ 274) |
| (n= 230)
|
(n= 233)
|
(n= 232)
|
(n= 232)
|
| Age, years |
59.3±8.0 |
58.4±8.2 |
58.4±7.8 |
59.6±7.5 |
0.701 |
| Female, n (%)
|
104 (45.2) |
130 (55.8) |
129 (55.6) |
144 (62.1) |
＜0.001 |
| Current smoker, n (%)
|
24 (10.4) |
20 (8.6) |
27 (11.6) |
20 (8.6) |
0.786 |
| BMI, kg/m2
|
25.1±3.3 |
25.1±3.2 |
24.9±3.3 |
24.7±3.2 |
0.152 |
| Physical activity, n (%)
|
39 (17.0) |
30 (12.9) |
42 (18.1) |
53 (22.8) |
0.041 |
| SBP, mmHg |
131.9±20.0 |
129.2±17.8 |
129.4±17.8 |
128.3±17.5 |
0.050 |
| DBP, mmHg |
81.7±10.2 |
80.9±9.7 |
81.0±10.4 |
79.7 ±10.0 |
0.039 |
| Hypertension, n (%)
|
122 (53.0) |
116 (49.8) |
116 (50.0) |
93 (40.1) |
＜0.001 |
| FBG, mg/dL |
88.1±15.8 |
86.3±14.4 |
90.0±22.1 |
88.6±18.8 |
0.341 |
| Diabetes, n (%)
|
26 (11.3) |
18 (7.7) |
18 (7.8) |
23 (9.9) |
0.630 |
| Lipid-lowering treatment, n (%)
|
42 (18.3) |
23 (9.9) |
20 (8.6) |
26 (11.2) |
0.020 |
| Creatinine, mg/dL |
1.04 (0.88, 1.16) |
1.01 (0.87, 1.15) |
1.03 (0.91, 1.19) |
1.00 (0.87, 1.13) |
0.686 |
| Conventional lipids-related parameters |
|
|
|
|
|
| Total cholesterol, mg/dL |
190.4±38.2 |
206.4±32.2 |
218.6±29.4 |
245.0±35.5 |
＜0.001 |
| LDL cholesterol, mg/dL |
104.7±25.4 |
122.5±25.5 |
135.5±23.8 |
154.0±30.8 |
＜0.001 |
| HDL cholesterol, mg/dL |
47.7±11.0 |
54.3±12.0 |
54.3±10.9 |
58.7±11.7 |
＜0.001 |
| VLDL cholesterol, mg/dL |
31 (19, 49) |
25 (19, 35) |
26 (20, 34) |
30 (23, 41) |
0.004 |
| Triglyceride, mg/dL |
142 (90, 226) |
116 (76, 171) |
112 (84, 149) |
109 (85, 149) |
＜0.001 |
| NMR measured lipoprotein particle concentrations |
|
|
|
|
|
| IDL, nmol/L |
84 (52, 108) |
165 (146, 183) |
233 (216, 254) |
339 (304, 385) |
＜0.001 |
| Total VLDL, nmol/L |
50.3 (40.7, 62.2) |
53.3 (42.3, 66.0) |
57.5 (47.1, 70.1) |
62.3 (48.0, 75.2) |
＜0.001 |
| Large VLDL |
2.8 (1.6, 4.7) |
2.4 (1.0, 4.2) |
2.1 (1.2, 3.8) |
2.2 (1.2, 3.4) |
＜0.001 |
| Medium VLDL |
10.9 (5.5, 16.2) |
12.6 (6.7, 18.1) |
14.8 (8.2, 20.7) |
16.0 (9.7, 22.9) |
＜0.001 |
| Small VLDL |
34.6 (27.6, 44.1) |
38.2 (29.0, 46.7) |
40.0 (32.1, 48.3) |
43.1 (32.2, 51.8) |
＜0.001 |
| LDL, nmol/L |
857 (691, 1054) |
859 (668, 1017) |
866 (731, 1009) |
893 (715, 1044) |
0.174 |
| Large LDL |
138 (40, 288) |
251 (132, 361) |
262 (162, 369) |
298 (200, 415) |
＜0.001 |
| Small LDL |
660 (470, 913) |
573 (399, 799) |
548 (413, 749) |
553 (377, 757) |
＜0.001 |
| HDL, μmol/L |
29.8 (26.2, 33.7) |
30.0 (26.9, 33.2) |
29.5 (26.9, 33.0) |
30.5 (27.9, 33.7) |
0.132 |
Abbreviation: BMI, body mass index; DBP, diastolic blood pressure; FBG, fasting blood glucose; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; NMR, nuclear magnetic resonance spectroscopy; SBP, systolic blood pressure; VLDL, very low-density lipoprotein.
Data were shown in mean±standard deviation, median (interquartile range), or n (%).
IDL-P concentrations correlated with most lipid parameters, except for LDL-P, HDL-P, and VLDL-C concentrations, after adjusting for age and sex. Briefly, the IDL-P concentrations were positively correlated with LDL-C (r=0.59), HDL-C (r=0.32), large LDL-P (r=0.31), medium VLDL-P (r=0.24), total VLDL-P (r=0.23), and small VLDL-P concentrations (r=0.18) and negatively correlated with TG (r=−0.15), small LDL-P (r=−0.13), and large VLDL-P concentrations (r=−0.11). However, regarding other lipoprotein particles closer to the size of IDL-P, large LDL-P concentrations were negatively correlated with VLDL-C concentrations (r=−0.50), yet small VLDL-P concentrations were positively correlated with TG concentrations (r=0.16). There was no significant correlation between IDL-P concentrations and BMI, systolic blood pressure, or fasting blood glucose (Fig.2).
Association between Baseline IDL-P Concentrations and the 5-Year Progression of Carotid Atherosclerosis
Among the 927 participants, 45.8% had carotid plaque progression in any previously nonplaque artery segment during the 5-year follow-up. Baseline IDL-P concentrations were independently and significantly related to plaque progression (Table 2, Fig.3, Supplemental Table 2, and Supplemental Fig.2). The multivariable-adjusted RR for progression among participants in the highest quartile of IDL-P concentrations was 1.36 (95% CI: 1.09–1.68) compared with that among those in the lowest quartile of IDL-P concentrations.
Table 2. The association between baseline IDL particle concentrations quartiles and progression of carotid atherosclerosis
|
Plaque progression |
Incidence of new-onset plaque |
TPA of new-onset plaque |
|
RR (95% CI) |
RR (95% CI) |
OR (95% CI) |
| Quartiles of IDL particle (nmol/L) |
|
|
|
| ＜129 |
reference |
reference |
reference |
| 129-198 |
1.12 (0.90-1.38) |
1.13 (0.89-1.43) |
1.17 (0.76-1.81) |
| 199-273 |
1.20 (0.97-1.48) |
1.19 (0.94-1.52) |
1.36 (0.87-2.14) |
| ≥ 274 |
1.36 (1.09-1.68) |
1.32 (1.03-1.70) |
1.67 (1.04-2.69) |
| p for trend
|
0.004 |
0.026 |
0.027 |
| Age, 1 year |
1.03 (1.02-1.04) |
1.03 (1.02-1.04) |
1.04 (1.02-1.07) |
| Male |
1.04 (0.89-1.21) |
1.01 (0.84-1.22) |
1.13 (0.80-1.58) |
| Current smoking |
1.22 (0.99-1.51) |
1.31 (1.03-1.67) |
1.60 (0.93-2.74) |
| BMI, 1 kg/m2
|
1.02 (1.00-1.04) |
1.02 (0.99-1.04) |
1.02 (0.98-1.08) |
| SBP, 1 mmHg |
1.01 (1.00-1.01) |
1.01 (1.00-1.01) |
1.01 (1.01-1.02) |
| Diabetes |
1.09 (0.87-1.35) |
0.99 (0.75-1.31) |
0.94 (0.55-1.58) |
| Lipid-lowering treatment |
0.90 (0.73-1.10) |
0.85 (0.66-1.10) |
0.79 (0.47-1.29) |
| Physical activity |
0.90 (0.75-1.08) |
0.92 (0.74-1.14) |
0.88 (0.58-1.32) |
| HDL-C, 1 mg/dL |
0.99 (0.98-1.00) |
0.99 (0.98-1.00) |
0.97 (0.96-0.99) |
| TG, 1 mg/dL |
1.00 (1.00-1.00) |
1.00 (1.00-1.00) |
1.00 (0.99-1.00) |
| LDL particle, 50 nmol/L |
1.03 (1.01-1.05) |
1.04 (1.02-1.06) |
1.09 (1.05-1.13) |
| VLDL particle, 10 nmol/L |
1.01 (0.97-1.06) |
1.03 (0.98-1.09) |
1.05 (0.95-1.16) |
Abbreviations: BMI, body mass index; CI, confidence interval; HDL-C, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; OR, odd ratio; RR, risk ratio; SBP, systolic blood pressure; TG, triglyceride; TPA, total plaque area; VLDL, very low- density lipoprotein.
RRs were calculated by modified Poisson regression, ORs were calculated by ordinal logistic regression.
Supplemental Table 2. Relative risks (RRs) and 95% confidence intervals (CI) of risk of carotid plaque progression with baseline IDL particle concentrations quartiles
| Variables |
Adjusted model 1 |
Adjusted model 2 |
Adjusted model 3 |
Adjusted model 4 |
Adjusted model 5 |
Adjusted model 6 |
|
RR (95% CI) |
RR (95% CI) |
RR (95% CI) |
RR (95% CI) |
RR (95% CI) |
RR (95% CI) |
| Quartiles of IDL particle concentrations, nmol/L |
|
|
|
|
|
|
| ≤ 128 |
reference |
reference |
reference |
reference |
reference |
reference |
| 129-198 |
1.12 (0.90-1.38) |
1.13 (0.92-1.40) |
1.14 (0.92-1.40) |
1.13 (0.92-1.40) |
1.14 (0.92-1.40) |
1.12 (0.91-1.37) |
| 199-273 |
1.20 (0.97-1.48) |
1.20 (0.98-1.49) |
1.23 (0.99-1.51) |
1.23 (1.00-1.51) |
1.24 (1.00-1.53) |
1.20 (0.98-1.47) |
| ≥ 274 |
1.36 (1.09-1.68) |
1.38 (1.11-1.71) |
1.41 (1.14-1.75) |
1.39 (1.13-1.72) |
1.42 (1.12-1.78) |
1.36 (1.11-1.68) |
| Age, 1 year |
1.03 (1.02-1.04) |
1.03 (1.02-1.04) |
1.03 (1.02-1.04) |
1.03 (1.02-1.04) |
1.03 (1.02-1.04) |
1.03 (1.02-1.04) |
| Male |
1.04 (0.89-1.21) |
0.98 (0.83-1.14) |
1.04 (0.88-1.22) |
1.04 (0.89-1.21) |
1.04 (0.89-1.21) |
1.04 (0.89-1.22) |
| Current smoking |
1.22 (0.99-1.51) |
1.26 (1.02-1.54) |
1.26 (1.03-1.55) |
1.22 (0.99-1.51) |
1.22 (0.99-1.51) |
1.22 (0.99-1.51) |
| BMI, 1 kg/m2
|
1.02 (1.00-1.04) |
1.02 (1.00-1.05) |
1.02 (1.00-1.05) |
1.02 (1.00-1.05) |
1.02 (1.00-1.04) |
1.02 (1.00-1.05) |
| SBP, 1 mmHg |
1.01 (1.00-1.01) |
1.01 (1.00-1.01) |
1.01 (1.00-1.01) |
1.01 (1.00-1.01) |
1.01 (1.00-1.01) |
1.01 (1.00-1.01) |
| Diabetes |
1.09 (0.87-1.35) |
1.08 (0.87-1.35) |
1.11 (0.89-1.38) |
1.08 (0.87-1.35) |
1.09 (0.87-1.35) |
1.10 (0.88-1.36) |
| Lipid-lowering treatment |
0.90 (0.73-1.10) |
0.91 (0.74-1.11) |
0.92 (0.75-1.12) |
0.89 (0.73-1.09) |
0.89 (0.72-1.09) |
0.90 (0.73-1.10) |
| Physical activity |
0.90 (0.75-1.08) |
0.92 (0.77-1.10) |
0.90 (0.75-1.08) |
0.90 (0.75-1.07) |
0.90 (0.75-1.08) |
0.90 (0.75-1.07) |
| HDL-C, 1 mg/dl |
0.99 (0.98-1.00) |
0.98 (0.98-0.99) |
0.99 (0.98-1.00) |
0.99 (0.98-1.00) |
0.99 (0.98-1.00) |
0.99 (0.98-1.00) |
| TG, 1 mg/dl |
1.00 (1.00-1.00) |
1.00 (1.00-1.00) |
1.00 (1.00-1.00) |
1.00 (1.00-1.00) |
1.00 (1.00-1.00) |
1.00 (1.00-1.00) |
| LDL particle, 50 nmol/L |
1.03 (1.01-1.05) |
|
|
1.03 (1.02-1.05) |
1.03 (1.01-1.05) |
1.03 (1.01-1.05) |
| Large LDL particle, 50 nmol/L |
|
1.04 (1.01-1.07) |
|
|
|
|
| Small LDL particle, 50 nmol/L |
|
|
1.01 (1.00-1.03) |
|
|
|
| VLDL particle, 10 nmol/L |
1.01 (0.97-1.06) |
1.03 (0.99-1.07) |
1.02 (0.98-1.07) |
|
|
|
| Large VLDL particle, 10 nmol/L |
|
|
|
0.80 (0.51-1.25) |
|
|
| Medium VLDL particle, 10 nmol/L |
|
|
|
|
0.97 (0.88-1.07) |
|
| Small VLDL particle, 10 nmol/L |
|
|
|
|
|
1.03 (0.98-1.09) |
Abbreviations: BMI, body mass index; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; RR, risk ratio; SBP, systolic blood pressure; TG, triglyceride; VLDL, very low-density lipoprotein.
Adjusted model 2 was replaced total LDL particle with large LDL particle.
Adjusted model 3 was replaced total LDL particle with small LDL particle.
Adjusted model 4 was replaced total VLDL particle with large VLDL particle.
Adjusted model 5 was replaced total VLDL particle with medium VLDL particle.
Adjusted model 6 was replaced total VLDL particle with small VLDL particle.
A total of 746 participants had no plaque at baseline. In these participants, baseline IDL-P concentrations were associated with the incidence of new-onset carotid plaque. Furthermore, the association between baseline IDL-P concentrations and changes in TPA was examined. Participants in the highest quartile of IDL-P concentrations had a 1.67-fold (95% CI: 1.04–2.69) higher TPA than those in the lowest quartile.
The significant association between baseline IDL-P concentrations and the progression of carotid atherosclerosis was preserved using sex-specific grouping methods, and after further adjustment for baseline VLDL-P, LDL-P, their subclasses, and serum creatinine as well as after excluding participants who received lipid-lowering therapy or who had diabetes at baseline (Supplemental Tables 3, 4, 5, 6). ROC analysis indicated that adding the IDL-P quartile to the traditional model had an AUC of 0.703 (95% CI: 0.669–0.736) but did not significantly improve the discriminative power of the traditional model with an AUC of 0.696 (95% CI: 0.662–0.729). However, the addition of the IDL-P quartile significantly improved reclassification with a continuous NRI of 0.145 (95% CI: 0.016–0.273, p=0.028).
Supplemental Table 3. The association between baseline IDL particle concentrations quartiles and progression of carotid atherosclerosis in sensitivity analysis
| Quartiles of IDL particle |
Total participants using sex-specific quartiles of IDL particle |
Participants without diabetes |
Participants without lipid-lowering treatment |
| Progression rate % (n/N) |
RR (95% CI) |
Progression rate % (n/N) |
RR (95% CI) |
Progression rate % (n/N) |
RR (95% CI) |
| Quartile 1 |
40.8% (93/228) |
reference |
39.7% (81/204) |
reference |
39.9% (75/188) |
reference |
| Quartile 2 |
44.2% (102/231) |
1.15 (0.93-1.42) |
41.9% (90/215) |
1.12 (0.89-1.41) |
41.9% (88/210) |
1.09 (0.87-1.37) |
| Quartile 3 |
44.0% (103/234) |
1.17 (0.94-1.45) |
48.6% (104/214) |
1.30 (1.04-1.63) |
46.2% (98/212) |
1.18 (0.94-1.47) |
| Quartile 4 |
54.3% (127/234) |
1.38 (1.11-1.71) |
50.7% (106/209) |
1.40 (1.10-1.78) |
52.9% (109/206) |
1.33 (1.06-1.67) |
Abbreviations: CI, confidence interval; IDL, intermediate-density lipoprotein; n, events number; N, number of participants in each quartile; RR, risk ratio. RRs were calculated by modified Poisson regression after adjustment for age, sex, current smoking, body mass index, systolic blood pressure, diabetes, lipid-lowering treatment, physical activity and low-density lipoprotein particles, very low-density lipoprotein particles, high-density lipoprotein cholesterol, triglyceride. Sex specific quartiles of IDL particle concentration were analyzed as males: ＜109, 109-187, 188-260, ≥ 261 nmol/L; and females: ＜139, 139-209, 210-287, ≥ 288 nmol/L. The adjusted variables were specified according to the characteristics of excluded participants.
Supplemental Table 4. The association between baseline IDL particle concentrations quartiles and incidence of new-onset carotid plaque in sensitivity analysis
| Quartiles of IDL particle |
Total participants using sex-specific quartiles of IDL particle |
Participants without diabetes |
Participants without lipid-lowering treatment |
| Incidence rate % (n/ N) |
RR (95% CI) |
Incidence rate % (n/ N) |
RR (95% CI) |
Incidence rate % (n/ N) |
RR (95% CI) |
| Quartile 1 |
37.4% (67/179) |
reference |
37.3% (60/161) |
reference |
38.6% (59/153) |
reference |
| Quartile 2 |
43.0% (86/200) |
1.15 (0.90-1.47) |
41.6% (74/178) |
1.15 (0.89-1.48) |
40.6% (71/175) |
1.11 (0.86-1.44) |
| Quartile 3 |
43.2% (80/185) |
1.21 (0.95-1.55) |
46.9% (83/177) |
1.28 (0.99-1.65) |
44.6% (79/177) |
1.20 (0.93-1.55) |
| Quartile 4 |
51.6% (94/182) |
1.34 (1.04-1.71) |
49.1% (81/165) |
1.35 (1.03-1.78) |
50.3% (82/163) |
1.34 (1.03-1.75) |
Abbreviations: CI, confidence interval; IDL, intermediate-density lipoprotein; n, events number; N, number of participants in each quartile; RR, risk ratio. RRs were calculated by modified Poisson regression after adjustment for age, sex, current smoking, body mass index, systolic blood pressure, diabetes, physical activity and low-density lipoprotein particles, very low-density lipoprotein particles, high-density lipoprotein cholesterol, triglyceride. Sex specific quartiles of IDL particle concentration were analyzed as males: ＜109, 109-187, 188-260, ≥ 261 nmol/L; and females: ＜139, 139-209, 210-287, ≥ 288 nmol/L. The adjusted variables were specified according to the characteristics of excluded participants.
Supplemental Table 5. The association between baseline IDL particle concentrations quartiles and total plaque area changes of new-onset carotid plaque in sensitivity analysis
|
Total participants using sex-specific quartiles of IDL particle |
Participants without diabetes |
Participants without lipid-lowering treatment |
| Quartiles of IDL particle |
OR (95% CI) |
OR (95% CI) |
OR (95% CI) |
| Quartile 1 |
reference |
Reference |
reference |
| Quartile 2 |
1.23 (0.80-1.90) |
1.23 (0.78-1.94) |
1.10 (0.70-1.77) |
| Quartile 3 |
1.41 (0.90-2.23) |
1.59 (1.00-2.56) |
1.39 (0.87-2.23) |
| Quartile 4 |
1.81 (1.14-2.90) |
1.88 (1.14-3.13) |
1.88 (1.14-3.10) |
Abbreviations: CI, confidence interval; IDL, intermediate-density lipoprotein; OR, odd ratio. Ordinal logistic regression analysis was used to calculate ORs for exploring the association of IDL particle quartiles with total plaque area changes of new-onset carotid plaque, which was divide into no plaque (TPA = 0), TPA below median and TPA above median (TPA median = 15.52 mm2), after adjustment for age (categorized by 65 years), sex, current smoking, body mass index, systolic blood pressure, diabetes, lipid-lowering treatment, physical activity and low-density lipoprotein particles, very low-density lipoprotein particles, high-density lipoprotein cholesterol, triglyceride. Sex specific quartiles of IDL particle concentration were analyzed as males: ＜109, 109-187, 188-260, ≥ 261 nmol/L; and females: ＜139, 139-209, 210-287, ≥ 288 nmol/L. The adjusted variables were specified according to the characteristics of excluded participants.
Supplemental Table 6. The association between baseline IDL particle concentrations quartiles and progression of carotid atherosclerosis after additional adjustment for serum creatinine at baseline
|
Plaque progression |
Incidence of new-onset plaque |
TPA of new-onset plaque |
| Quartiles of IDL particle (nmol/L) |
RR (95% CI) |
RR (95% CI) |
OR (95% CI) |
| ＜129 |
reference |
reference |
reference |
| 129-198 |
1.12 (0.90-1.38) |
1.13 (0.89-1.44) |
1.18 (0.77-1.83) |
| 199-273 |
1.19 (0.96-1.47) |
1.19 (0.93-1.51) |
1.36 (0.87-2.13) |
| ≥ 274 |
1.35 (1.09-1.68) |
1.32 (1.03-1.69) |
1.67 (1.04-2.68) |
| p for trend
|
0.005 |
0.029 |
0.030 |
Abbreviations: CI, confidence interval; IDL, intermediate-density lipoprotein; OR, odd ratio; RR, risk ratio; TPA, total plaque area. RRs were calculated by modified Poisson regression, ORs were calculated by ordinal logistic regression.
All models were adjusted for age, sex, current smoker, body mass index, systolic blood pressure, diabetes, lipid-lowering treatment, physical activity, and low-density lipoprotein particles, very low-density lipoprotein particles, high-density lipoprotein cholesterol, triglyceride, serum creatinine.
Discussion
In this prospective community-based cohort study, baseline IDL-P concentrations were substantially variable in middle-aged and elderly adults who were free of cardiovascular diseases. Furthermore, for the first time, we reported that higher IDL-P concentrations were associated with an increased risk of 5-year carotid atherosclerosis progression and the burden of new-onset carotid plaque.
Although previous studies have explored the association between IDL cholesterol and subclinical atherosclerosis24), growing evidence demonstrated the discrepancy between the amount of particle and the amount of contained cholesterol in each lipoprotein. As the downstream lipoprotein of IDL, LDL can be classified into multiple distinct particles of differing size, density, and composition, and their atherogenicity seems to vary accordingly. Several studies showed that small dense LDL with high particle concentration but low contained cholesterol was associated with the atherogenic risk, which was stronger than other LDL subclasses25-27). Therefore, lipoprotein particle number is a better indicator to reflect the atherogenic effect of lipoprotein and identify individuals with residual risk of atherosclerotic cardiovascular disease19, 28-30). Data on the prospective relationship between NMR-measured IDL-P concentrations and carotid atherosclerosis are limited. To date, one prospective study, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study, has investigated the relationship between IDL-P concentrations and 12-year change in carotid IMT in 455 patients aged 13–39 years with type 1 diabetes mellitus; this study found no significant relationship17). However, that study examined only patients with diabetes and thus cannot be extrapolated to the general population, which may be due to the following aspects. First, patients with type 1 diabetes mellitus usually exhibit abnormal lipid metabolism, mainly manifesting as increased VLDL secretion and reduced hepatic clearance of TG-rich lipoproteins31), such as VLDL, and IDL. Second, the use of hypoglycemic agents may influence the change of carotid IMT. Unlike this study, the Multi-Ethnic Study of Atherosclerosis (MESA) explored the cross-sectional association between IDL-P concentrations and carotid IMT in 5,388 community-based participants aged 45–84 years, that study reported that NMR spectroscopy-measured IDL-P concentrations were significantly associated with carotid IMT32). However, the association between IDL-P concentrations and the development of subclinical atherosclerosis in the general population was unclear. Additionally, IMT may not be the best indicator to estimate early vascular risk due to the lack of methodological standardization and its lack of added value in predicting future cardiovascular disease events. The 2021 European Society of Cardiology cardiovascular disease prevention guidelines in clinical practice recommend the use of ultrasound-measured carotid plaque, to assess the risk of cardiovascular diseases, which is superior to IMT18). Thus, the present study used a prospective community-based cohort to investigate the impact of IDL-P concentrations on plaque progression. We observed that elevated IDL-P concentrations were associated with the occurrence of new-onset carotid plaque and a larger burden of TPA in all carotid segments, providing new evidence of the involvement of IDL-P in the development of atherosclerosis in humans.
Notably, hypertriglyceridemia is one of the most common features of dyslipidemia, particularly in China, with a prevalence of 13.8%, which is higher than that of hypercholesterolemia33). Recent studies have demonstrated that TG-rich lipoprotein is an important risk factor for atherosclerotic cardiovascular disease, most of these studies have focused on the relationship of small VLDL-P concentrations with cardiovascular disease events6, 34). The present study found that IDL-P concentrations were independently related to the development of carotid atherosclerosis even after adjusting for small VLDL-P concentrations. Consistent with the present findings, the MESA also showed that IDL-P concentrations were significantly related to IMT after adjusting for small VLDL-P concentrations32). However, a recent Mendelian randomization study that investigated the contributions of specific lipoproteins to the risk of peripheral artery disease and coronary artery disease reported that IDL-P concentrations are not significantly associated with peripheral artery disease and coronary artery disease; a significant causal relationship was reported between large LDL-P concentrations and coronary artery disease35). Although NMR spectroscopy was used to measure lipoprotein subclasses in both studies, the categorization criteria for lipoprotein subclasses differed between this Mendelian randomization study and our present study. The average diameter of large LDL-P was 25.5 nm in the Mendelian randomization study, which overlapped with the diameter range of IDL-P (23–27 nm) in the present study, suggesting that lipoprotein particles with a diameter range of 23–27 nm may be causally related to the risk of coronary artery disease and implying that IDL-P plays an important role in atherosclerosis.
The association between elevated IDL-P concentrations and an increased risk of carotid atherosclerosis progression could be explained by several mechanisms. First, IDL is an apolipoprotein B (apoB)-containing lipoprotein with a diameter of less than 70 nm. Although a strong correlation between IDL-P and LDL-C was found in the present study, it may be due more to the differences in testing methods. LDL-C determined by the homogeneous method may contain the cholesterol carried by LDL-P and IDL-P, whereas NMR can separate IDL and LDL according to the diameter of lipoproteins. Actually, IDL-P contains four-fold more cholesterol per particle than LDL-P5). In the pathophysiological process of atherosclerosis, only lipoprotein particles with a diameter less than 70 nm, such as IDL-P, and LDL-P, can enter the arterial wall, accumulate under the endothelium, and promote the formation of foam cells10, 12, 16, 36). Second, IDL-P is less likely to efflux under the intima and more likely to adhere to extracellular matrix proteoglycans, despite being larger than LDL-P10, 11, 37, 38). Furthermore, IDL-P is generated from the lipolysis of VLDL-P. During this process, the TG component carried by VLDL-P is decomposed into free fatty acids, monoacylglycerols, and other molecules, which can cause local injury and inflammation38, 39), leading to endothelial cell damage. Higher IDL-P concentrations might generate from more active VLDL lipolysis, along with elevated concentrations of free fatty acids and monoacylglycerols, which would promote the development of atherosclerosis. Nevertheless, the actual mechanisms by which IDL-P influences the pathogenesis of atherosclerosis remain unclear and must be studied further.
The present study carefully examined the relationship between IDL-P and carotid atherosclerosis progression based on reliable lipoprotein measurements using NMR spectroscopy and a recommended indicator of subclinical atherosclerosis, carotid artery plaque repeatedly measured through ultrasound, to evaluate atherosclerosis development, and progression. We reported, for the first time, that elevated IDL-P concentration was independently associated with the progression of atherosclerotic plaque. Despite these clear strengths, our study has several possible study limitations. First, the blood samples assessed via NMR spectroscopy were collected in 2002 and stored for nearly 10 years at −80℃ without freezing and thawing until measurement. This long-term storage may have caused measurement errors. However, previous studies have shown that long-term storage without freezing and thawing has little effect on NMR spectroscopy detection of lipoprotein21). Second, although we adjusted for all other classic risk factors of cardiovascular disease in the model, potential confounding factors from excluding lipoprotein due to collinearity in the adjusted model and unmeasured residual confounding factors, such as the type of lipid-lowering treatment, could not be avoided. Therefore, further studies should verify the role of IDL-P in subclinical atherosclerosis risk. Third, the large sample size allowed us to parse out the impact of specific lipoproteins on atherosclerosis. However, the included participants in the final analysis were only a subset of the original cohort. Although there were no significant differences in the baseline characteristics between study participants who were eligible and unavailable for re-examination, the present results using a larger sample size should be validated further.
Conclusion
In this community-based cohort study, elevated circulating IDL-P concentrations were independently associated with greater progression of carotid atherosclerosis among asymptomatic individuals. More importantly, the atherogenic impact of IDL-P was independent of concentrations of LDL-P and VLDL-P and their subclasses. These findings show that IDL-P may be a new lipoprotein-related risk factor for the development of atherosclerosis; it could thus facilitate the early identification of high cardiovascular risk and treatment of atherosclerotic cardiovascular disease.
Conflict of Interest
The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this work.
Notice of Grant Support
This study was supported by the Beijing Natural Science Foundation (No. 7212006), the National Natural Science Foundation of China (grant numbers 82073635 and 81570409), Beijing municipal medical research institutes pilot reform project (grant number 2021-07), the National Key Research and Development Program of China (grant number 2016YFC0900902), and the National Science and Technology Pillar Program (grant numbers 2011BAI09B01, 2011BAI11B03, 2006BAI01A01 and 2006BAI01A02).
Acknowledgements
We gratefully acknowledge the contribution of all the investigators from participating centers in the CMCS study for data collection.
Author Contributions
TL analysed data and drafted the manuscript. YQ contributed to initial concepts and study design. All authors contributed to acquisition or interpretation of data. YQ and JS contributed to laboratory measurements. YQ, JL and DZ contributed to manuscript revision and supervision. All authors approved the final version of the manuscript.
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