Abstract
Objective
The objective of this cross-sectional analysis was to investigate the relation between two major high-density lipoprotein cholesterol (HDL-C) subfractions (HDL2-C and HDL3-C) and carotid plaque in a population based cohort.
Methods
We evaluated 988 stroke-free participants (mean age 66±8 years; 40% men; 66% Hispanic and 34% Non-Hispanic) with available data on HDL subfractions using precipitation method and carotid plaque area and thickness assessed by a high-resolution 2D ultrasound. The associations between HDL-C subfractions and plaque measurements were analyzed by quantile regression.
Results
Plaque was present in 56% of the study population. Among those with plaque, the mean±SD plaque area was 19.40±20.46 mm2 and thickness 2.30±4.45 mm. The mean±SD total HDL-C was 46±14 mg/dl, HDL2-C 14±8 mg/dl, and HDL3-C 32±8 mg/dl. After adjusting for demographics and vascular risk factors, there was an inverse association between HDL3-C and plaque area (per mg/dl: beta= −0.26 at the 75th percentile, p=0.001 and beta= −0.32 at the 90th percentile, p=0.02). A positive association was observed between HDL2-C and plaque thickness (per mg/dl; beta= 0.02 at the 90% percentile, p=0.003). HDL-C was associated with plaque area (per mg/dl: beta= −0.18 at the 90th percentile, p=0.01), but only among Hispanics.
Conclusion
In our cohort we observed an inverse association between HDL3-C and plaque area and a positive association between HDL2-C and plaque thickness. HDL-C subfractions may have different contributions to the risk of vascular disease. More studies are needed to fully elucidate HDL-C anti-atherosclerotic functions in order to improve HDL-based treatments in prevention of vascular disease and stroke.
Keywords: high-density lipoprotein, high-density lipoprotein subfractions, carotid plaque
Introduction
Epidemiological studies consistently demonstrate that low levels of high density lipoprotein cholesterol (HDL-C) are associated with increased risk for cardiovascular disease (CVD) and stroke 1, 2. The same inverse association has been demonstrated between HDL-C and carotid atherosclerosis 3, but with less consistency.
However, recent clinical trials have failed to translate the same epidemiological association into evidence that pharmacological raising of HDL-C prevents CVD morbidity and mortality 4–6. Such studies reinforce the need to focus on heterogeneity and functionality of HDL-C subclasses, rather than on measurements of total HDL-C, in order to better explain its pleiotropic effects.
Based on its density, HDL-C has two major subfractions, more dense and smaller HDL3-C and less dense and larger HDL2-C cholesterol. High-density lipoprotein subfractions differ in their biochemical properties, vascular metabolism, and biological activity, and their distribution represents a dynamic process that can be altered by the presence of chronic diseases, drug therapies, and lifestyle changes. Decreased risk of CVD has been linked to higher levels of HDL2-C cholesterol, but not consistently, and uncertainty over the value of HDL-C subfractions in vascular risk remains 7, 8.
Atherosclerosis is a disease involving a series of inflammatory events. Carotid plaque, as a focal manifestation of atherosclerosis, represents a validated subclinical ultrasonographic marker of cardiovascular disease and stroke 9. Similar to the association with CVD, the severity and progression of atherosclerosis has been predominantly linked to lower levels of the HDL2-C subfraction. 10–12. However, the benefits of HDL3-C subfraction have also been well documented in the pathogenesis of atherosclerosis 13–15. The aim of this study was to investigate the relationship between the HDL2-C and HLD3-C subfractions and carotid plaque in a large and predominantly Hispanic cohort comprised of stroke-free individuals.
Material and Methods
Study Participants
We included 988 stroke-free participants from the Northern Manhattan Study (NOMAS), an ongoing, prospective, population-based study of stroke incidence and vascular risk factors, who had data available on HDL-C, measured by precipitation, subfractions and carotid plaque measured by high-resolution B-mode ultrasound. Details on the subject ascertainment, extensive assessments, and methods used in NOMAS are described elsewhere 16. Briefly, eligible subjects: a) had never been diagnosed with ischemic stroke; b) were >40 years old; and c) resided in Northern Manhattan for ≥ 3 months, in a household with a telephone. Subjects were identified by random-digit dialing. The telephone response rate was 91%. Subjects were recruited from the telephone sample to have an in-person baseline interview and assessment. The enrollment response rate was 75%, the overall participation rate was 69%, and a total of 3298 subjects were enrolled. Of the total of 3298 subjects, 54% of subjects had data on the HDL subfractions (n=1793) and carotid ultrasound measurements (n=1788). These two subcohorts overlapped resulting in 30% of the study participants (n=988) having both HDL subfractions and carotid plaque measurements. NOMAS was approved by the Institutional Review Boards of Columbia University Medical Center and the University of Miami, and all participants gave written informed consent.
Baseline Evaluation
Data were collected through interviews with trained research assistants in English or Spanish. Physical and neurological examinations were conducted by study neurologists. Race-ethnicity was based upon self-identification through a series of questions modeled after the US census and conforming to standard definitions outlined by Directive 15 17. Standardized questions were adapted from the Behavioral Risk Factor Surveillance System by the Centers for Disease Control regarding hypertension, diabetes, smoking, and cardiac conditions 18. Blood pressure (BP) was measured with mercury sphygmomanometers and appropriately-sized cuffs. Hypertension was defined as a BP ≥140/90 mmHg (based on the average of two measurements during one sitting), the patient’s self-reported hypertension, or use of anti-hypertensive medications. Diabetes mellitus was defined by fasting glucose ≥126 mg/dl, the patient’s self-reported diabetes, or use of insulin or oral anti-diabetic medication. Body mass index (BMI) was calculated in kg/m2. Smoking was categorized as never smoking, former smoking, and current (within the past year) smoking. Mild-moderate alcohol use was defined as current drinking of >1 drink per month and ≤2 drinks per day. Physical activity was defined as the frequency and duration of 14 different recreational activities during the 2-week period before the interview, as described previously 16.
HDL-C, HDL2-C and HDL3-C Measurements
Blood samples were drawn after an overnight fast. Plasma levels of cholesterol and triglycerides (TGs) were measured using standardized enzymatic procedures with a Hitachi 705 automated spectrophotometer (Boehringer Mannheim, Mannheim, Germany). HDL-C was measured after precipitation of plasma apo B-containing lipoproteins with phosphotungstic acid. The inter-assay coefficient of variation in our laboratory was 3% for HDL-C. Two major HDL subfractions were determined in plasma by sequential precipitation using heparin-manganese and dextran sulfate 19. In this procedure, apo B-containing lipoproteins are precipitated in the first precipitation reaction using heparin-manganese chloride at final concentrations of 1.26 mg/ml and 0.091 M, respectively. The supernatant (total HDL-C) is removed, an aliquot is saved for analysis, and dextran sulphate (mol wt 15,000; Genzyme, Cambridge, MA) is added to precipitate HDL2-C, which was estimated by subtracting HDL3-C from HDL-C. Following centrifugation, the supernatant (HDL3-C) is removed and analyzed for cholesterol content. The inter-assay coefficients of variation for HDL2-C and HDL3-C assays are 8% and 7%, respectively, at levels of 28 mg/dl (HDL2-C) and 32 mg/dl (HDL3-C).
Carotid Ultrasound
High-resolution B-mode ultrasound (GE LogIQ 700, 9/13-MHz linear-array transducer) was performed by trained and certified sonographers using standardized and validated scanning and reading protocols as described previously 20. Plaque is defined as a focal wall thickening or protrusion in the lumen more than 50% greater than the surrounding thickness. Carotid plaque area (mm2) and thickness (mm) were measured using an automated computerized edge tracking software M’Ath (Paris, France) 21. Total plaque area (TPA) was a sum of area measured in all plaques within an individual. Maximum plaque thickness was measured for each plaque in an individual at the highest plaque prominence between the lumen-intima and media-adventitia boundaries. The maximum value of maximal thickness measured in all plaques within an individual was used in the analyses 22.
Statistical Analysis
The primary independent variables of interest were HDL2-C, HDL3-C, and total HDL-C, all assessed as continuous measurements in mg/dl. The HDL-C variables were examined in relation to the demographics, anthropometrics, and lifestyle and vascular risk factors, among 988 NOMAS participants. We calculated the means and standard deviations. Due to the non-normal distribution of plaque area and thickness, with 44% of the study population without plaque, we used quantile regression to examine these plaque phenotypes as continuous outcomes. For individuals without plaque a value of 0 was assigned for each of these plaque phenotypes. For plaque area and thickness we chose the 75th and 90th percentiles as our outcomes of interest. Because a large portion of the study population did not have plaque present, we chose the 75th percentile of plaque thickness and area to represent a middle value of these variables among those that had plaque. The 90th percentile was chosen to represent a value at the high end of our phenotype spectrum. The association between HDL-C variables and plaque presence was examined using logistic regression models.
The associations of total HDL-C, HDL2-C and HDL3-C with all plaque measurements were examined and adjusted for age, sex, race/ethnicity, low density lipoprotein cholesterol (LDL-C), TGs, smoking, body mass index (BMI), diabetes, hypertension, mild-moderate alcohol use, and physical activity. Finally, a stratified analysis by Hispanic ethnicity was performed as well as an analysis of HDL-C subfractions stratified by the levels of total HDL-C (cut-offs: men < 40 mg/dl and women < 50 mg/dl), both as exploratory analyses. SAS version 9.1 (SAS institute, Cary, NC) was used for statistical analyses and p<0.05 was considered significant.
Results
The mean age among the 988 study participants was 66±8 years and 60% were women. Other demographic characteristics and vascular risk factors in relation to HDL variables are presented in Table 1. The mean±SD levels of total HDL-C, HDL2-C and HDL3-C were as follows 46±14 mg/dl, 14±8 mg/dl, and 32±8 mg/dl, respectively. The mean total HDL-C was similar in the NOMAS participants with carotid plaque measurements but without available HDL subfractions (n= 806; 47 mg/dl), suggesting unbiased selection of our sub-cohort sample.
Table 1.
Clinical characteristics of study participants
| Demographics | N (988) | HDL-C (mg/dl) Mean (SD) |
HDL2-C (mg/dl) Mean (SD) |
HDL3-C (mg/dl) Mean (SD) |
|---|---|---|---|---|
| Race/ethnicity | ||||
| Hispanic | 655 | 43 (12)* | 13 (7)* | 30 (7)* |
| Non-Hispanic | 333 | 48 (15) | 16 (9) | 33 (9) |
| Age | ||||
| 40–59 | 283 | 44 (13)* | 13 (7)* | 31 (8) |
| 60–69 | 407 | 45 (14) | 14 (8) | 31 (7) |
| 70–79 | 230 | 47 (15) | 15 (9) | 32 (9) |
| 80+ | 68 | 48 (13) | 16 (8) | 32 (7) |
| Sex | ||||
| Male | 397 | 41 (13)* | 12 (7)* | 29 (7)* |
| Female | 591 | 48 (14) | 15 (8) | 33 (8) |
| BMI | ||||
| Normal | 240 | 50 (16)* | 16 (9)* | 33 (8)* |
| Overweight | 457 | 45 (14) | 14 (8) | 31 (8) |
| Obese | 288 | 44 (12) | 13 (7) | 31 (7) |
| Smoking | ||||
| Current | 152 | 44 (13) | 13 (8) | 30 (8) |
| Former | 366 | 45 (14) | 14 (9) | 31 (8) |
| Never | 470 | 46 (13) | 14 (8) | 32 (8) |
| Mild-moderate alcohol use | ||||
| Yes | 381 | 47 (15)* | 14 (8) | 32 (8)* |
| No | 607 | 45 (13) | 14 (8) | 31 (8) |
| Moderate-heavy physical activity | ||||
| Yes | 95 | 49 (15)* | 16 (9)* | 33 (9)* |
| No | 890 | 45 (14) | 14 (8) | 31 (8) |
| Cholesterol lowering medications | ||||
| Yes | 150 | 47 (14) | 14 (7) | 33 (8) |
| No | 838 | 45 (14) | 14 (8) | 31 (8) |
| Hypertension | ||||
| Yes | 716 | 45 (14) | 14 (8) | 31 (8) |
| No | 272 | 47 (14) | 15 (9) | 32 (8) |
| Diabetes | ||||
| Yes | 203 | 43 (13)* | 13 (8)* | 30 (7)* |
| No | 785 | 46 (14) | 14 (8) | 32 (8) |
| LDL-C (mg/dl) | ||||
| >160 | 818 | 46 (14)* | 14 (8)* | 32 (8) |
| ≤160 | 166 | 44 (11) | 12 (6) | 32 (7) |
| TGs (mg/dl) | ||||
| >150 | 276 | 39(10)* | 11(6)* | 28(7)* |
| ≤150 | 711 | 48(14) | 15 (8) | 33(8) |
ANOVA or t-test p<0.05 (categories of covariates were compared for the HDL variables as continuous measures).
HDL-C, high-density lipoprotein cholesterol; BMI, body mass index; LDL-C, low-density lipoprotein cholesterol; TGs, triglycerides
A strong positive correlation was observed between total HDL-C and each of the HDL-C subfractions (HDL-C:HDL2-C; r=.81, p<0.0001 and HDL-C:HDL3-C; r=.75, p<0.0001, respectively), as expected. Conversely, a weak positive correlation was observed between HDL2-C and HDL3-C subfractions (r=.34, p<0.0001).
Plaque was present in 56% of the study population and among them, the mean plaque area was 19.40±20.46 mm2 and the mean maximum plaque thickness was 2.30±4.45 mm. For the analyses of the association between HDL-C variables and plaque measurements we excluded 150 participants (15% of the study population) that were on lipid-lowering medications, the majority of them (n=128) being on statins. Table 2 shows the association between the HDL variables and plaque thickness, area and presence in the fully adjusted model. Total HDL-C was not associated with any of the plaque measurements. HDL3-C subfraction showed an inverse association with the 75th and 90th percentiles of plaque area. The association of HDL3-C with the 75% percentile of plaque area was stronger among the individuals with low HDL-C as compared to those with higher HDL-C levels (per mg/dl; beta= −0.38 mm, p=0.02 vs. beta=−0.17, p=0.19, respectively). Similar to the 75th percentile, an inverse association between HDL3-C and the 90th percentile of plaque area was more pronounced among participants with low HDL-C as compared to the individuals with higher HDL-C levels (per mg/dl; beta= −0.38 mm, p=0.12 vs. beta=−0.20, p=0.43, respectively). HDL2-C was positively associated with the 90th percentile of plaque thickness, while no association was observed between HDL2-C and plaque area. Among the individuals with and without plaque presence, the levels (all in mg/dl) were similar for total HDL-C (mean±SD; 46±14 vs. 46±14, respectively, p=0.71), HDL3-C (mean±SD; 31±8 vs. 32±8, respectively, p=0.21), and HDL2-C (mean±SD; 14±8 vs. 14±8, respectively, p=0.93). None of the HDL-C variables were associated with plaque presence.
Table 2.
The association of HDL variables with plaque thickness (PT) and plaque area (PA) percentiles and plaque presence
| Per mg/dl | PT (mm) (effects, p values) | PA (mm2) (effects, p values) | Plaque presence OR (95% CI) |
||
|---|---|---|---|---|---|
|
| |||||
| 75% | 90% | 75% | 90% | ||
| HDL-C | 0.002 | 0.01 | −0.09 | −0.08 | 1.00 |
| mg/dl | 0.71 | 0.08 | 0.12 | 0.35 | (0.99–1.01) |
| HDL2-C | 0.02 | 0.02 | 0.06 | 0.13 | 1.00 |
| mg/dl | 0.29 | 0.003 | 0.61 | 0.40 | (0.98–1.02) |
| HDL3-C | −0.01 | −0.01 | −0.26 | −0.32 | 0.99 |
| mg/dl | 0.15 | 0.35 | 0.001 | 0.02 | (0.97–1.02) |
Quantile regression: adjusted for age, sex, race/ethnicity, LDL-C, and TGs, cholesterol-lowering medication use, smoking, BMI, diabetes, hypertension, mild-moderate alcohol use, physical activity. HDL-C, high-density lipoprotein cholesterol
Stratified analyses of all HDL-C variables in relation to plaque thickness and area by Hispanic ethnicity are shown in Table 3. Only among Hispanics HDL3-C was inversely associated with the 90th percentile of plaque thickness and both total HDL-C and HDL3-C were inversely associated with the 90th percentile of plaque area. We did not observe an association between HDL2-C and any of the plaque measurements in this stratified analysis. There was some suggestion of potential effect modification by ethnicity for the relationships between total HDL-C and HDL3-C with the 90th percentile of plaque thickness. However, the limited statistical power of the tests for interaction as well as the main effects in the exploratory stratified analyses is important to note, and therefore these results should be interpreted with caution.
Table 3.
HDL variables and plaque thickness (PT) and plaque area (PA) stratified by ethnicity
| Per mg/dl | Non-Hispanic (n=279) (effects, p values) | Hispanic (n=552) (effects, p values) | Interaction p-value |
|---|---|---|---|
| PT mm 75th percentile | |||
| HDL-C | 0.01, 0.12 | −0.001, 0.81 | 0.17 |
| HDL2-C | 0.02, 0.16 | 0.01, 0.57 | 0.46 |
| HDL3-C | −0.01, 0.56 | −0.01, 0.17 | 0.54 |
| PT mm 90th percentile | |||
| HDL-C | 0.01, 0.15 | −0.01, 0.34 | 0.02 |
| HDL2-C | 0.02, 0.37 | 0.004, 0.74 | 0.19 |
| HDL3-C | 0.003, 0.81 | −0.02, 0.03 | 0.09 |
| PA mm2 75th percentile | |||
| HDL-C | 0.01, 0.92 | −0.08, 0.17 | 0.46 |
| HDL2-C | 0.27, 0.24 | −0.06, 0.64 | 0.13 |
| HDL3-C | −0.37, 0.06 | −0.09, 0.35 | 0.31 |
| PA mm2 90th percentile | |||
| HDL-C | 0.23, 0.28 | −0.18, 0.01 | 0.36 |
| HDL2-C | 0.57, 0.28 | 0.02, 0.91 | 0.89 |
| HDL3-C | −0.25, 0.50 | −0.39, 0.01 | 0.52 |
Quantile regression: adjusted for age, sex, LDL-C, TGs, cholesterol-lowering medication use, smoking, BMI, diabetes, hypertension, mild-moderate alcohol use, physical activity. HDL-C, high-density lipoprotein cholesterol.
Discussion
In the present study we report an association between increased levels of HDL3-C with smaller plaque area. In contrast, we observed a positive association between HDL2-C and plaque thickness. In addition to HDL3-C, elevated levels of total HDL-C were associated with reduced plaque thickness, but only among Hispanics. The same association was stronger for HDL3-C than for total HDL-C. Our study was mostly comprised of Caribbean Hispanics and therefore further studies are needed to confirm the race-ethnic effect modification of HDL3-C and total HDL-C relationship with plaque burden among other diverse populations.
An inverse association between total HDL-C and the risk of CVD has been shown in multiple epidemiological studies 23–25. However, total HDL-C concentration measurement does not offer insight into the variable composition of different HDL-C subfractions responsible for complex functions and atheroprotective mechanisms associated with cardiometabolic outcomes 26. The complexity of HDL-C subclass proportions and activities can be altered from “functional” to “dysfunctional” under a variety of metabolic abnormalities and pharmacological and non-pharmacological treatments. More importantly, their heterogeneous properties are frequently unrelated to the overall HDL-C concentration and remain undetected by measurement of total HDL-C 27.
Several studies have examined differential effects of HDL-C and HDL subfractions on markers of atherosclerosis with controversial results. However, there are currently several methods using different approaches in analyzing physical and chemical properties of HDL 28. Therefore, it is challenging to compare data obtained with different methodology in order to evaluate the relationship of HDL subfractions and their functions with CVD risk. Three studies reported similar findings by using different laboratory methods. Total HDL-C and HDL2-C subfractions quantified by ultracentrifugation, have been correlated inversely with the coronary artery disease score in 105 male survivors of myocardial infarction under the age 45 11. However, the association was only significant for HDL2-C subfraction, indicating its protective effect on the progression of coronary atheromatosis. Another study, using the gradient gel electrophoresis method,10 examining the effect between five major HDL subclasses and coronary atherosclerosis, has reported similar findings. According to that study, the protective effects of total HDL-C for coronary heart disease or coronary atherosclerosis may be accounted by larger HDL2b-C particles rather than smaller HDL3-C particles. Similarly, Xu et al 12 have reported that HDL2-C and HDL3-C subfractions, determined by two dimensional gel electrophoresis, are highly correlated with coronary stenosis, but with HDL3a-C and HDL3b-C exhibiting positive and HDL2b-C negative correlation.
However, a more recent study 15 reported that HDL3-C, compared to total HDL-C, had a stronger inverse association with plaque lipid-rich necrotic core, a high-risk feature of atherosclerotic risk. Our study, using a precipitation method, supports these results, suggesting that HDL3-C is more strongly inversely associated with carotid plaque burden than HDL2-C and total HDL-C.
The benefits of HDL3-C subfraction have been well documented in the pathogenesis of atherosclerosis. Small and dense HDL3-C subfraction is less prone to oxidation due to greater paraoxonase 1 activity 13 and it appears to inhibit LDL oxidation to a greater extent than HDL2-C 14. In addition, HDL3-C has been more effective than HDL2-C in inhibiting vascular cell adhesion molecule expression in endothelial cells 29, involved in mediating the process of early atherosclerosis. The benefits of HDL3-C have also been recently extended to increased longevity 30, as well as reduced risk of cancer in men 31. Also, smaller and more dense HDL3-C subfraction represents the major subfraction in newborns, thus providing a greater protection against infection in early life 32.
Despite longstanding evidence from epidemiological studies for the inverse relationship between total HDL-C and CVD risk, the most recent pharmacological strategies to raise HDL-C have failed to yield positive results. The clinical trials with torcetrabip, a cholesteryl ester transfer protein (CETP) inhibitor, aimed at raising total HDL-C, concomitant with reduction in low-density lipoprotein cholesterol, did not translate into reduced CVD morbidity and mortality 4, 33, 34. A more recent study reported that the same CETP inhibitor, combined with atorvastatin, enhanced the capacity of postprandial HDL2a-C and HDL2b-C to mediate cellular free cholesterol efflux. The same mechanism was superior for larger HDL2-C than HDL3-C subspecies 35. Thus, the association between total HDL-C and subclinical and clinical CVD seems complex. A better understanding of HDL-C subfractions may be important for more effective prevention and treatment of CVD.
Lastly, carotid plaque as a distinct phenotype of atherosclerosis is more influenced by environmental and less by genetic factors 21. Furthermore, plaque grows longitudinally along the carotid axis of flow more than two times faster than thickness 36. In our analysis HDL3-C, with its potent anti-oxidative and anti-inflammatory properties, was more inversely associated with plaque area, as a more sensitive measure of atherosclerotic burden than thickness 37. In regard to ethnic differences in non-invasive measures of atherosclerosis, several studies have shown the significant association between the presence of carotid plaque and the risk of vascular events but predominantly in white populations. In our current analysis, the association between total HDL-C and the 90th percentile of plaque area, as well as the associations between HDL3-C and the 90th percentiles of plaque thickness and area were present only among Hispanics, though statistically significant interactions with Hispanic ethnicity were not found in these power-limited analyses. We have previously shown that even though Hispanics had lower amount of plaque thickness, compared to whites and blacks, they were more susceptible to vascular events. More specifically, Hispanics with carotid plaque had a three- to fourfold increased risk of vascular events in comparison to a one- to two-fold increased risk among Non-Hispanics 22.
Strengths of the current study include a large population with extensive information obtained on vascular risk factors. We used a dual-step precipitation method for HDL-C isolation. This method has a greater precision than the electrophoresis method (the coefficient of variance of the within-run analysis; 4.8% vs. 10.7%, respectively) 38 used in some of the previous studies examining the association between HDL-C subfractions and carotid plaque atherosclerotic characteristics 10, 12. Our research also contributes to greater understanding of the association between total HDL-C and its subfractions with atherosclerotic plaque development. One of the potential limitations of our study is its cross-sectional design. We could not assess the changes in the levels of HDL subfractions and whether they affected progression of atherosclerosis over time. Finally, we assessed the plasma levels of two major HDL subfractions without studying their subclasses and the biological activity responsible for diverse atheroprotective properties.
In summary, our study shows that the HDL3-C subfraction, unlike HDL2-C and total HDL-C, is inversely associated with plaque area as a marker of subclinical atherosclerosis among stroke-free individuals. These novel findings support the role of HDL-C subfractions in atherosclerosis and emphasize the overall complexity of HDL-C functions. Future studies are needed to fully elucidate HDL-C anti-atherosclerotic functions, and their role among different ethnic groups, in order to improve HDL-based treatments in prevention of CVD and stroke.
Highlights.
Recent trials have challenged the HDL-Cholesterol anti-atherosclerotic hypothesis
HDL3 is inversely associated with plaque area and plaque thickness
HDL-C subfractions may have different contributions to the risk of vascular disease
Investigate HDL “quality” and not only HDL “quantity”
Acknowledgments
Sources of funding: This work was supported by the National Institute of Neurological Disorders and Stroke [R37 NS 29993]; NIH [K24 to T.R., K02 to C.W., and RO1 013094 to M.D]; and Evelyn McKnight Brain Institute
Footnotes
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Contributor Information
Eduard Tiozzo, Email: etiozzo@med.miami.edu.
Hannah Gardener, Email: hgardener@med.miami.edu.
Barry I. Hudson, Email: bhudson@med.miami.edu.
Chuanhui Dong, Email: cdong@med.miami.edu.
David Della-Morte, Email: ddellamorte@stroke.med.miami.edu.
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