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1.  MicroRNA-133a Regulates Insulin-like Growth Factor-1 Receptor Expression and Vascular Smooth Muscle Cell Proliferation in Murine Atherosclerosis 
Atherosclerosis  2013;232(1):171-179.
MicroRNA-133a (miR-133a) and insulin-like growth factor-1 (IGF-1) are two different molecules known to regulate cardiovascular cell proliferation. This study tested whether miR-133a affects expression of IGF-1 receptor (IGF-1R) and proliferation of IGF-1-stimulated vascular smooth muscle cells (VSMC) in a murine model of atherosclerosis.
Methods and Results
Expression of IGF-1R was analyzed by immuno-fluorescence and immuno-blotting, and miR-133a by qRT-PCR in the aortas of wild-type C57BL/6J (WT) and apolipoprotein-E deficient (ApoE−/−) mice. Compared to those in WT aortas, the IGF-1R and miR-133a levels were lower in ApoE−/− aortas. ApoE−/− VSMC grew slower than WT cells in the cultures with IGF-1-containing medium. MiR-133a-specific inhibitor decreased miR-133a, IGF-1R expression, IGF-1-stimulated VSMC growth in lipoprotein-deficient media. By contrast, miR-133a precursor increased IGF-1R levels and promoted IGF-1-induced VSMC proliferation. In the luciferase-IGF-1R 3’UTR reporter system, the reporter luciferase activity was not inhibited in VSMC with miR-133a overexpression. IGF-1R mRNA half-life in ApoE−/− VSMC was shorter than that in WT VSMC. MiR-133a inhibitor reduced but precursor increased the mRNA half-life, although the effects appeared less striking in ApoE−/− VSMC than in WT cells.
MiR-133a serves as a stimulatory factor for IGF-1R expression through prolonging IGF-1R mRNA half-life. In atherosclerosis induced by ApoE deficiency, reduced miR-133a expression is associated with lower IGF-1R levels and suppressive VSMC growth. Administration of miR-133a precursor may potentiate IGF-1 stimulated VSMC survival and growth.
PMCID: PMC4334121  PMID: 24401233
MicroRNA; Insulin-like growth factor; Artery; Smooth muscle cell; Atherosclerosis
2.  Errors in the estimation of wall shear stress by maximum Doppler velocity 
Atherosclerosis  2013;227(2):259-266.
Wall shear stress (WSS) is an important parameter with links to vascular (dys)function. Difficult to measure directly, WSS is often inferred from maximum spectral Doppler velocity (Vmax) by assuming fully-developed flow, which is valid only if the vessel is long and straight. Motivated by evidence that even slight/local curvatures in the nominally straight common carotid artery (CCA) prevent flow from fully developing, we investigated the effects of velocity profile skewing on Vmax-derived WSS.
Velocity profiles, representing different degrees of skewing, were extracted from the CCA of image-based computational fluid dynamics (CFD) simulations carried out as part of the VALIDATE study. Maximum velocities were calculated from idealized sample volumes and used to estimate WSS via fully-developed (Poiseuille or Womersley) velocity profiles, for comparison with the actual (i.e. CFD-derived) WSS.
For cycle-averaged WSS, mild velocity profile skewing caused ±25% errors by assuming Poiseuille or Womersley profiles, while severe skewing caused a median error of 30% (maximum 55%). Peak systolic WSS was underestimated by ~50% irrespective of skewing with Poiseuille; using a Womersley profile removed this bias, but ±30% errors remained. Errors were greatest in late systole, when skewing was most pronounced. Skewing also introduced large circumferential WSS variations: ±60%, and up to ±100%, of the circumferentially averaged value.
Vmax-derived WSS may be prone to substantial variable errors related to velocity profile skewing, and cannot detect possibly large circumferential WSS variations. Caution should be exercised when making assumptions about velocity profile shape to calculate WSS, even in vessels usually considered long and straight.
PMCID: PMC4329978  PMID: 23398945
Doppler ultrasound; wall shear stress; atherosclerosis; computational fluid dynamics; common carotid artery; brachial artery; femoral artery
3.  [No title available] 
PMCID: PMC3905249  PMID: 24468139
4.  [No title available] 
PMCID: PMC4039032  PMID: 24468151
5.  Reduced CD14 expression on classical monocytes and vascular endothelial adhesion markers independently associate with carotid artery intima media thickness in chronically HIV-1 infected adults on virologically suppressive anti-retroviral therapy 
Atherosclerosis  2013;232(1):52-58.
HIV infection causes systemic immune inflammation, and increases the risk for cardiovascular (CVD) disease even among those on virologically suppressive anti-retroviral treatment (ART). We performed a biostatistical analysis and screen of candidate cellular and plasma biomarkers for association with carotid artery intima-media thickness (CIMT), independent of traditional CVD risk factors such as age, gender, systolic blood pressure (SBP), lipid levels, smoking and diabetes. We conducted a multi-stage analysis based on a cross-sectional study of CVD risk in HIV-infected subjects age >45 years on ART for >6 months. The goal of this analysis was to identify candidate cellular and plasma biomarkers of CIMT in HIV-1 infected adults. We further sought to determine if these candidate biomarkers were independent of traditional CVD risk factors previously identified in HIV negative adults. High-resolution B-mode ultrasound images of the right common carotid common artery (CCA) were obtained. Plasma soluble inflammatory mediators, cytokines and chemokines were detected. Monocytes were defined by CD14/CD16 expression, and CD8+ T-cell activation by CD38/HLA-DR expression. Subjects were a median of 49.5 years old, 87% male, had a CIMT of 0.73 mm, FRS of 6%, a median viral load of 48 copies/mL, and CD4+ T cell count of 479 cells/μL. Soluble VCAM-1, and expansion of CD14dimCD16− monocytes each associated with higher CIMT independently of age and SBP. These factors are distinct components of a shared atherogenic process; 1) vascular endothelial molecular expression and 2) vascular monocytes that enter into the vascular endothelium and promote atherosclerotic plaque.
PMCID: PMC3919042  PMID: 24401216
HIV; Carotid intima-media; CIMT; Cardiovascular disease; Framingham risk score; Biomarker; Screen; Regression; CD14; Monocytes; VCAM-1; Cytokines
6.  Association between anthropometric measures of obesity and subclinical atherosclerosis in Bangladesh 
Atherosclerosis  2013;232(1):234-241.
Anthropometric measures such as waist-hip-ratio (WHR), waist-height-ratio (WHtR), waist circumference, Mid-upper arm circumference (MUAC), and upper thigh circumference, have been linked to the risk of cardiovascular disease (CVD). However, their relationships with subclinical atherosclerosis are unclear. Studies in normal-weight populations, especially in Asian countries where leanness is prevalent, are lacking.
We conducted a cross-sectional study to assess the associations of WHR, WHtR, waist circumference, hip circumference, body mass index (BMI), MUAC and upper thigh circumference with carotid intima-media thickness (cIMT) among 562 middle-aged participants free of CVD in rural Bangladesh.
After adjusting for age and sex, WHR and waist circumference but not BMI showed a positive significant association with cIMT. In multivariate analysis, each standard deviation (SD) increase of WHR (0.08) or WHtR (0.07) was associated with an 8.96 μm (95% CI, 1.12–16.81) or 11.45 μm (95%CI, 0.86–22.04) difference in cIMT, respectively, after controlling for age, sex, BMI, smoking status, education level, and systolic blood pressure (SBP). The associations of WHR and WHtR with cIMT were independent of the influence of other anthropometric measures. The associations of other anthropometric measures and cIMT were not apparent.
In our relatively lean, healthy Asian population, WHR and WHtR appear to be better predictors of early atherosclerosis than other common surrogates of adiposity.
PMCID: PMC3888510  PMID: 24401245
7.  HDL anti-oxidant function associates with LDL level in young adults 
Atherosclerosis  2013;232(1):165-170.
The primary objective was to evaluate predictors of HDL anti-oxidant function in young adults.
High-density lipoprotein (HDL) cholesterol is considered a protective factor for cardiovascular disease (CVD). However, increased levels are not always associated with decreased cardiovascular risk. A better understanding of the importance of HDL functionality and how it affects CVD risk is needed.
Fifty non-Hispanic white subjects from the Testing Responses on Youth (TROY) study were randomly selected to investigate whether differences in HDL anti-oxidant function are associated with traditional cardiovascular risk factors, including carotid intima media thickness (CIMT), arterial stiffness and other inflammatory/metabolic parameters. HDL anti-oxidant capacity was evaluated by assessing its ability to inhibit low-density lipoprotein (LDL) cholesterol oxidation by air using a DCF-based fluorescent assay and expressed as a HDL oxidant index (HOI). The associations between HOI and other variables were assessed using both linear and logistic regression.
Eleven subjects (25%) had an HOI ≥ 1, indicating a pro-oxidant HDL. Age, LDL, high sensitivity C-reactive protein (hsCRP), and paraoxonase activity (PON1), but not HDL, were all associated with HOI level in univariate linear regression models. In multivariate models that mutually adjusted for these variables, LDL remained the strongest predictor of HOI (0.13 increase in HOI per 1 SD increase in LDL, 95% CI 0.04, 0.22).
Atherogenic index of plasma, pulse pressure, homocysteine, glucose, insulin, CIMT and measurements of arterial stiffness were not associated with HOI in this population.
These results suggest LDL, hsCRP and DBP might predict HDL anti-oxidant function at an early age.
PMCID: PMC4039385  PMID: 24401232
high density lipoprotein; antioxidant; paraoxonase; atherosclerosis
8.  Novel coronary heart disease risk factors at 60–64 years and life course socioeconomic position: The 1946 British birth cohort 
Atherosclerosis  2015;238(1):70-76.
Social disadvantage across the life course is associated with a greater risk of coronary heart disease (CHD) and with established CHD risk factors, but less is known about whether novel CHD risk factors show the same patterns. The Medical Research Council National Survey of Health and Development was used to investigate associations between occupational socioeconomic position during childhood, early adulthood and middle age and markers of inflammation (C-reactive protein, interleukin-6), endothelial function (E-selectin, tissue-plasminogen activator), adipocyte function (leptin, adiponectin) and pancreatic beta cell function (proinsulin) measured at 60–64 years. Life course models representing sensitive periods, accumulation of risk and social mobility were compared with a saturated model to ascertain the nature of the relationship between social class across the life course and each of these novel CHD risk factors. For interleukin-6 and leptin, low childhood socioeconomic position alone was associated with high risk factor levels at 60–64 years, while for C-reactive protein and proinsulin, cumulative effects of low socioeconomic position in both childhood and early adulthood were associated with higher (adverse) risk factor levels at 60–64 years. No associations were observed between socioeconomic position at any life period with either endothelial marker or adiponectin. Associations for C-reactive protein, interleukin-6, leptin and proinsulin were reduced considerably by adjustment for body mass index and, to a lesser extent, cigarette smoking. In conclusion, socioeconomic position in early life is an important determinant of several novel CHD risk factors. Body mass index may be an important mediator of these relationships.
•We examine associations of life course socioeconomic position (SEP) with novel coronary heart disease risk markers using novel methods to compare different life course models.•SEP during childhood was important for IL-6 and leptin, while SEP during both childhood and early adulthood was important for CRP and proinsulin.•BMI (but not smoking) explained a large part of these relationships.
PMCID: PMC4286122  PMID: 25437893
Socioeconomic position; Life course; Inflammation; Endothelial; Adipocyte; Proinsulin; Birth cohort
9.  Statins use and coronary artery plaque composition: Results from the International Multicenter CONFIRM Registry 
Atherosclerosis  2012;225(1):148-153.
The effect of statins on coronary artery plaque features beyond stenosis severity is not known. Coronary CT angiography (CCTA) is a novel non-invasive method that permits direct visualization of coronary atherosclerotic features, including plaque composition. We evaluated the association of statin use to coronary plaque composition type in patients without known coronary artery disease (CAD) undergoing CCTA.
From consecutive individuals, we identified 6673 individuals (2413 on statin therapy and 4260 not on statin therapy) with no known CAD and available statin use status. We studied the relationship between statin use and the presence and extent of specific plaque composition types, which was graded as non-calcified (NCP), mixed (MP), or calcified (CP) plaque.
The mean age was 59 ± 11 (55% male). Compared to the individuals not taking statins, those taking statins had higher prevalence of risk factors and obstructive CAD. In multivariable analyses, statin use was associated with increased the presence of MP [odds ratio (OR) 1.46, 95% confidence interval (CI) 1.27–1.68), p < 0.001] and CP (OR 1.54, 95% CI 1.36–1.74, p < 0.001), but not NCP (OR 1.11, 95% CI 0.96–1.29, p = 0.1). Further, in multivariable analyses, statin use was associated with increasing numbers of coronary segments possessing MP (OR 1.52, 95% CI 1.34–1.73, p < 0.001) and CP (OR 1.52, 95% CI 1.36–1.70, p < 0.001), but not coronary segments with NCP (OR 1.09, 95% CI 0.94–1.25, p = 0.2).
Statin use is associated with an increased prevalence and extent of coronary plaques possessing calcium. The longitudinal effect of statins on coronary plaque composition warrants further investigation.
PMCID: PMC4277888  PMID: 22981406
Statin; Plaque composition; Coronary CTA; Coronary artery disease; Lipid profile
10.  Bone mineral density and atherosclerosis: The Multi-Ethnic Study of Atherosclerosis, Abdominal Aortic Calcium Study 
Atherosclerosis  2009;209(1):283-289.
Molecular and cell biology studies have demonstrated an association between bone and arterial wall disease, but the significance of a population-level association is less clear and potentially confounded by inability to account for shared risk factors.
To test population-level associations between atherosclerosis types and bone integrity.
Main Outcome Measures
Volumetric trabecular lumbar bone mineral density (vBMD), ankle-brachial index (ABI), intima-media thickness of the common carotid (CCA-IMT) and internal carotid (ICA-IMT) arteries, and carotid plaque echogenicity.
Design, Setting and Participants
A random subset of participants from the Multi-Ethnic Study of Atherosclerosis (MESA) assessed between 2002 and 2005.
904 post-menopausal female (62.4 years; 62% non-white; 12% ABI<1; 17% CCA-IMT>1mm; 33% ICA-IMT>1mm) and 929 male (61.4 years; 58% non-white; 6% ABI<1; 25% CCA-IMT>1mm; 40% ICA-IMT>1mm) were included. In serial, sex-specific regression models adjusting for age, ethnicity, body mass index, dyslipidemia, hypertension, smoking, alcohol consumption, diabetes, homocysteine, interleukin-6, sex hormones, and renal function, lower vBMD was associated with lower ABI in men (p for trend <0.01) and greater ICA-IMT in men (p for trend <0.02). CCA-IMT was not associated with vBMD in men or women. Carotid plaque echogenicity was independently associated with lower vBMD in both men (trend p=0.01) and women (trend p<0.04). In all models, adjustment did not materially affect results.
Lower vBMD is independently associated with structural and functional measures of atherosclerosis in men and with more advanced and calcified carotid atherosclerotic plaques in both sexes.
PMCID: PMC4254856  PMID: 19819456
11.  Impact of Inflammatory Biomarkers on Relation of High Density Lipoprotein-Cholesterol with Incident Coronary Heart Disease: Cardiovascular Health Study 
Atherosclerosis  2013;231(2):10.1016/j.atherosclerosis.2013.08.036.
Inflammatory factors and low HDL-C relate to CHD risk, but whether inflammation attenuates any protective association of high HDL-C is unknown.
Investigate inflammatory markers' individual and collective impact on the association of HDL-C with incident coronary heart disease (CHD).
In 3,888 older adults without known cardiovascular disease (CVD), we examined if the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and lipoprotein-associated phospholipase A2 (Lp-PLA2) modify the relation of HDL-C with CHD. HDL-C, CRP, IL-6, and Lp-PLA2 values were grouped as using gender-specific tertiles. Also, an inflammation index of z-score sums for CRP, IL-6, and Lp-PLA2 was categorized into tertiles. We calculated CHD incidence for each HDL-C/inflammation group and performed Cox regression, adjusted for standard CVD risk factors and triglycerides to examine the relationship of combined HDL-C-inflammation groups with incident events.
CHD incidence (per 1,000 person years) was higher for higher levels of CRP, IL-6, and the index, and lower for higher levels of HDL-C. Compared to high HDL-C/low-inflammation categories (referent), adjusted HRs for incident CHD were increased for those with high HDL-C and high CRP (HR=1.50, p<0.01) or highest IL-6 tertile (HR=1.40, p<0.05), but not with highest Lp-PLA2 tertile. Higher CHD incidence was similarly seen for those with intermediate or low HDL-C accompanied by high CRP, high IL-6, or a high inflammatory index.
The protective relation of high HDL-C for incident CHD appears to be attenuated by greater inflammation.
PMCID: PMC3858257  PMID: 24267235
High Density Lipoprotein; Inflammation; C-Reactive Protein; Coronary Heart Disease
12.  Obstructive Sleep Apnea and Intermittent Hypoxia Increase Expression of Dual Specificity Phosphatase 1 
Atherosclerosis  2013;231(2):10.1016/j.atherosclerosis.2013.09.033.
Dual specificity phosphatase 1 (DUSP1) inhibits mitogen activated protein kinase activity, and is activated by several stimuli such as sustained hypoxia, oxidative stress, and hormones. However, the effect of intermittent hypoxia is not known. The aim of this study was to evaluate the role of intermittent hypoxia on DUSP1 expression, and to validate its role in a human model of intermittent hypoxia, as seen in obstructive sleep apnea (OSA). OSA is characterized by recurrent episodes of hypoxemia/reoxygenation and is a known risk factor for cardiovascular morbidity.
In-vitro studies using human coronary artery endothelial cells (HCAEC) and ex-vivo studies using white blood cells isolated from healthy and OSA subjects.
Intermittent hypoxia induced DUSP1 expression in human coronary artery endothelial cells (HCAEC), and in granulocytes isolated from healthy human subjects. Functionally, DUSP1 increased the expression and activity of manganese superoxide dismutase (MnSOD) in HCAEC. Further, significant increases in DUSP1 mRNA from total blood, and in DUSP1 protein in mononuclear cells and granulocytes isolated from OSA subjects, was observed in the early morning hours after one night of intermittent hypoxemia due to untreated OSA. This early-morning OSA-induced augmentation of DUSP1 gene expression was attenuated by continuous positive airway pressure (CPAP) treatment of OSA.
Intermittent hypoxia increases MnSOD activity via increased DUSP1 expression in HCAEC. Similarly, overnight intermittent hypoxemia in patients with OSA induces expression of DUSP1, which may mediate increases of MnSOD expression and activity. This may contribute significantly to neutralizing the effects of reactive oxygen species, a consequence of the intermittent hypoxemia/reperfusion elicited by OSA.
PMCID: PMC3865929  PMID: 24267255
Dual specificity phosphatase 1; intermittent hypoxia; Obstructive sleep apnea; reactive oxygen species
13.  Nitric Oxide Improves Molecular Imaging of Inflammatory Atheroma using Targeted Echogenic Immunoliposomes 
Atherosclerosis  2013;231(2):10.1016/j.atherosclerosis.2013.09.026.
This study aimed to demonstrate whether pretreatment with nitric oxide (NO) loaded into echogenic immunoliposomes (ELIP) plus ultrasound, applied before injection of molecularly targeted ELIP can promote penetration of the targeted contrast agent and improve visualization of atheroma components.
ELIP were prepared using the pressurization-freeze method. Atherosclerosis was induced in Yucatan miniswine by balloon denudation and a hyperlipidemic diet. The animals were randomized to receive anti-intercellular adhesion molecule-1 (ICAM-1) ELIP or immunoglobulin (IgG)-ELIP, and were subdivided to receive pretreatment with standard ELIP plus ultrasound, NO-loaded ELIP, or NO-loaded ELIP plus ultrasound. Intravascular ultrasound (IVUS) data were collected before and after treatment.
Pretreatment with standard ELIP plus ultrasound or NO-loaded ELIP without ultrasound resulted in 9.2 ± 0.7% and 9.2 ± 0.8% increase in mean gray scale values, respectively, compared to baseline (p<0.001 vs. control). Pretreatment with NO-loaded ELIP plus ultrasound activation resulted in a further increase in highlighting with a change in mean gray scale value to 14.7 ± 1.0% compared to baseline (p<0.001 vs. control). These differences were best appreciated when acoustic backscatter data values (RF signal) were used [22.7 ± 2.0% and 22.4 ± 2.2% increase in RF signals for pretreatment with standard ELIP plus ultrasound and NO-loaded ELIP without ultrasound respectively (p<0.001 vs. control), and 40.0 ± 2.9% increase in RF signal for pretreatment with NO-loaded ELIP plus ultrasound (p<0.001 vs. control)].
NO-loaded ELIP plus ultrasound activation can facilitate anti-ICAM-1 conjugated ELIP delivery to inflammatory components in the arterial wall. This NO pretreatment strategy has potential to improve targeted molecular imaging of atheroma for eventual true tailored and personalized management of cardiovascular diseases.
PMCID: PMC3871611  PMID: 24267236
Molecular Imaging; Atherosclerosis; Contrast Agent; Nitric Oxide; Ultrasound
14.  Oxidized LDL and AGE-LDL in Circulating Immune Complexes Strongly Predict Progression of Carotid Artery IMT in Type 1 Diabetes 
Atherosclerosis  2013;231(2):315-322.
Over 90% of modified LDL in circulation is associated to specific antibodies circulating as part of immune complexes (IC); however, few studies have examined their relationship with cardiovascular disease.
We report the relationship between circulating concentrations of IC of oxidized LDL (oxLDL-IC), malondialdehyde-LDL (MDA-LDL-IC) and advanced glycation end products-LDL (AGE-LDL-IC) and progression of atherosclerosis over a 12 year period in 467 individuals with type 1 diabetes who participated in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study. OxLDL-IC, AGE-LDL-IC and MDA-LDL-IC levels were measured at DCCT closeout. Internal carotid intima-medial thickness (IMT) was measured at EDIC follow-up years 1, 6 and 12.
OxLDL-IC, AGE-LDL-IC and MDA-LDL-IC levels were significantly correlated with age, lipid levels, blood pressure levels and albumin excretion rates. Levels of oxLDL, AGE-LDL and MDA-LDL in isolated LDL-IC were highly inter-correlated (r=0.66 to 0.84, p<0.0001). After adjusting for cardiovascular risk factors individuals in the upper quartile of oxLDL-IC had a 2.98fold increased odds (CI: 1.34, 6.62) of having IMT ≥ 1.00 mm and had a 5.13-fold increased odds (CI: 1.98, 13.3) of having significant IMT progression, relative to those in the lowest quartile. Parallel odds ratios for AGE-LDL-IC were 2.95 (CI: 1.37, 6.34) and 3.50 (CI: 1.38, 8.86), while results for MDA-LDL-IC were 1.76 (0.87, 3.56) and 2.86 (1.20, 6.81).
Our study indicates that high levels of oxLDL-IC and AGE-LDL-IC are important predictors of carotid intima-medial thickening in patients with type 1 diabetes.
PMCID: PMC3924569  PMID: 24267245
modified LDL; subclinical atherosclerosis; carotid artery intima-media thickness; type 1 diabetes
15.  Small high-density lipoprotein is associated with monocyte subsets in stable coronary artery disease 
Atherosclerosis  2014;237(2):589-596.
Objective: High-density lipoprotein (HDL) particles are heterogeneous in structure and function and the role of HDL subfractions in atherogenesis is not well understood. It has been suggested that small HDL may be dysfunctional in patients with coronary artery disease (CAD). Monocytes are considered to play a key role in atherosclerotic diseases. Circulating monocytes can be divided into three subtypes according to their surface expression of CD14 and CD16. Our aim was to examine whether monocyte subsets are associated with HDL subfractions in patients with atherosclerosis. Methods: We included 90 patients with angiographically stable CAD. Monocyte subsets were defined as classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). HDL subfractions were measured by electrophoresis on polyacrylamide gel. Results: Serum levels of small HDL correlated with circulating pro-inflammatory NCM and showed an inverse relationship to circulating CM independently from other lipid parameters, risk factors, inflammatory parameters or statin treatment regime, respectively. IM were not associated with small HDL. In particular, patients with small HDL levels in the highest tertile showed dramatically increased levels of NCM (14.7 ± 7% vs. 10.7 ± 5% and 10.8 ± 5%; p = 0.006) and a decreased proportion of CM (79.3 ± 7% vs. 83.7 ± 6% and 83.9 ± 6%; p = 0.004) compared to patients in the two lower tertiles. In contrast, intermediate HDL, large HDL and total HDL were not associated with monocyte subset distribution. Conclusion: Small HDL levels are associated with pro-inflammatory NCM and inversely correlated with CM. This may suggest that small HDL could have dysfunctional anti-inflammatory properties in patients with established CAD.
•Small HDL levels are associated with non-classical monocytes in stable CAD.•Classical monocytes are inversely associated with small HDL levels.•Associations are independent of other lipid parameters, risk factors, inflammatory parameters or statin treatment regime.•Inflammatory markers do not vary according to small HDL levels.
PMCID: PMC4270455  PMID: 25463093
HDL; Small HDL; Atherosclerosis; Monocytes; Monocyte subsets; Inflammation
16.  Effects of menopause and hormone replacement therapy on the associations of hyperuricemia with mortality 
Atherosclerosis  2012;226(1):220-227.
Serum uric acid (SUA) levels have been associated with cardiovascular and all-cause mortality. It remains unclear whether these associations differ by gender, menopausal status and hormone replacement therapy (HRT) and whether they persist after adjustment for known cardiovascular risk factors.
We determined the associations between fasting SUA level and death certificate-based mortality among 5856 participants of the third US National Health and Nutrition Examination Survey aged ≥20 years recruited between 1988–1994 and followed for mortality until December 2006 (mean follow-up: 13.5 years; maximum follow-up: 18 years). Cox proportional hazards regression analysis was used to adjust for demographic characteristics, cardiovascular risk factors and other variables potentially associated with SUA levels.
Among women, SUA level was associated with all-cause and cardiovascular mortality (adjusted hazard ratio [AHR] 1.17, 95% CI 1.03–1.32 and AHR 1.23 (1.01–1.51) respectively per unit increase in SUA. These associations persisted among postmenopausal but not premenopausal women. Furthermore, among postmenopausal women, significant associations were identified between SUA and all-cause (AHR 1.30 [1.11–1.51]) or cardiovascular (AHR 1.61 [1.33–1.94]) mortality only among women not taking HRT, but not among women on HRT.
We did not identify associations between SUA levels and all-cause or cardiovascular mortality in men, either under or over 51 years of age, in unadjusted or adjusted analyses.
SUA level predicts cardiovascular and all-cause mortality independently of major predictors and risk factors in postmenopausal women not taking HRT but not in premenopausal women, postmenopausal women on HRT, or men.
PMCID: PMC4240945  PMID: 23141471
serum uric acid; mortality; cardiovascular mortality; cohort study; population-based
18.  Menopause, Complement, and Hemostatic Markers in Women at Midlife: The Study of Women’s Health Across the Nation 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.08.039.
To evaluate whether higher circulating levels of complement proteins C3 and C4 are associated with menopausal status and with hemostatic/thrombus formation markers (circulating factor VII (factor VIIc), fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator antigen (tPA-ag)) in a sample of midlife women.
Methods and Results
A total of 100 women (50 late peri-/postmenopausal and 50 pre-/early peri menopausal women) from the Study of Women’s Health Across the Nation (SWAN) Pittsburgh site were included in the present analysis. Factor VIIc and PAI-1 were log transformed. Linear regression was used for analysis. The mean age of the study participants was 50.5±2.6 years with 73% were Caucasian and 27% were African American. C3 but not C4 was significantly higher in postmenopausal women compared to premenopausal women (P value=0.03), adjusting for age, race and BMI. In final model (adjusting for age, race, BMI and menopausal status), C3 was associated with higher levels of log PAI-1 (P value=0.0009) and tPA-ag (P value=0.0003), while C4 was associated with higher levels of log factor VIIc (P value=0.04) and fibrinogen (P value=0.005).
These data suggest that C3 and C4 may be related to blood clots via their associations with hemostatic markers and that C3 is related to menopausal status. Complement proteins C3 and C4 could be possible pathways by which postmenopausal women are at higher risk of atherosclerosis and cardiovascular related events. It is important to replicate these findings in a larger sample size.
PMCID: PMC3844281  PMID: 24125410
Epidemiology, Risk Factors; Coagulation, Fibrinolysis; Menopause
19.  Fibroblast Growth Factor 23, Left Ventricular Mass, and Left Ventricular Hypertrophy in Community-Dwelling Older Adults 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.09.002.
In chronic kidney disease (CKD), high FGF23 concentrations are associated with left ventricular hypertrophy (LVH), cardiovascular events, and death. The associations of FGF23 with left ventricular mass (LVM) and LVH in the general population and the influence of CKD remains uncertain.
C-terminal plasma FGF23 concentrations were measured, and LVM and LVH evaluated by echocardiogram among 2255 individuals ≥65 years in the Cardiovascular Health Study. Linear regression analysis adjusting for demographics, cardiovascular, and kidney related risk factors examined the associations of FGF23 concentrations with LVM. Analyses were stratified by CKD status and adjusted linear and logistic regression analysis explored the associations of FGF23 with LVM and LVH.
Among the entire cohort, higher FGF23 concentrations were associated with greater LVM in adjusted analyses (β=6.71 [95% CI 4.35–9.01] g per doubling of FGF23). 32% (n=624) had CKD (eGFR <60 mL/min/1.73m2 and/or urine albumin-to-creatinine ratio >30 mg/g). Associations were stronger among participants with CKD (p interaction = 0.006): LVM β=9.71 [95% CI 5.86–13.56] g per doubling of FGF23 compared to those without CKD (β=3.44 [95% CI 0.77, 6.11] g per doubling of FGF23). While there was no significant interaction between FGF23 and CKD for LVH (p interaction = 0.25), the OR (1.46 95% CI [1.20–1.77]) in the CKD group was statistically significant and of larger magnitude than the OR for in the no CKD group (1.12 [95% CI 0.97–1.48]).
In a large cohort of older community-dwelling adults, higher FGF23 concentrations were associated with greater LVM and LVH with stronger relationships in participants with CKD.
PMCID: PMC3840534  PMID: 24125420
Left ventricular mass; left ventricular hypertrophy; chronic kidney disease; fibroblast growth factor 23; older adults; cardiovascular disease
20.  Subclinical Atherosclerotic Calcification and Cognitive Functioning in Middle-Aged Adults: The CARDIA Study 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.08.038.
Cardiovascular risk factors in middle-age are associated with cognitive impairment and dementia in older age. Less is known about the burden of calcified subclinical atherosclerosis and cognition, especially in midlife. We examined the association of coronary artery and abdominal aortic calcified plaque (CAC and AAC, respectively) with cognitive functioning in middle-aged adults.
This cross-sectional study included 2,510 black and white adults (age: 43–55 years) without heart disease or stroke who completed a year 25 follow-up exam (2010–11) as part of the Coronary Artery Risk Development in Young Adults Study. CAC and AAC were measured with non-contrast computed tomography. Cognition was assessed with the Digit Symbol Substitution Test (DSST) (psychomotor speed), Stroop Test (executive function), and Rey Auditory Verbal Learning Test (RAVLT) (verbal memory).
A greater amount of CAC and AAC was associated with worse performance on each test of cognitive function after adjustment for age, sex, race, education, and study center. Associations were attenuated, but remained significant for the DSST and RAVLT following additional adjustment for vascular risk factors, including adiposity, smoking, alcohol use, dyslipidemia, hypertension, and diabetes. Compared to participants without CAC or AAC, those with both CAC and AAC, but not CAC or AAC alone was associated with lower DSST scores (p<0.05).
In this community-based sample, greater subclinical atherosclerotic calcification was associated with worse psychomotor speed and memory in midlife. These findings underscore the importance of a life course approach to the study of cognitive impairment with aging.
PMCID: PMC3828555  PMID: 24125414
atherosclerosis; heart disease; calcium score; cognition; subclinical disease; risk factors
21.  Perivascular Adipose Tissue of the Descending Thoracic Aorta is Associated with Systemic Lupus Erythematosus and Vascular Calcification in Women 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.09.004.
Women with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular disease (CVD). Traditional CVD and SLE-disease related risk factors do not fully account for this increased risk. Perivascular adipose tissue (PVAT) is a visceral adipose depot in close proximity to blood vessels possibly influencing CVD. We hypothesized that women with SLE have an increased volume of descending thoracic aortic PVAT (aPVAT) associated with increased vascular calcification.
Using electron beam computed tomography, we quantified the aPVAT in clinically CVD-free SLE women (n=135) and age-/race-matched healthy controls (HC, n=152). Coronary artery calcification (CAC) and aortic calcification (AC) were quantified using Agatston scores and the aPVAT was quantified using standard Hounsfield Units (HU) for adipose tissue.
Women with SLE had greater median aPVAT (32.2 cm3 vs. HC aPVAT 28.6 cm3, p=0.0071) and greater median AC (26.0 vs HC AC 6.0, p=0.0013) than the healthy control women. Total aPVAT (per 25 cm3) remained significantly associated with SLE after adjusting for CVD risk factors (Odds Ratio 1.74 [95% Confidence Interval: 1.04-2.9], p=0.034), but was attenuated when adjusting for circulating inflammatory markers (p=0.34). In a logistic regression analysis, SLE aPVAT (per 25 cm3) was associated with AC (6.78 [2.0-23], p=0.0019), which remained significant after adjusting for circulating inflammatory markers (p=0.0074), and CAC (2.66 [1.4-5.0], p=0.0028).
Total aPVAT is greater in clinically CVD-free SLE women than in age-/race-matched controls and is associated with calcification in different vascular beds.
PMCID: PMC3831349  PMID: 24125423
atherosclerosis; adipose; systemic lupus erythematosus; calcification
22.  Genetic Epidemiology and Genome-Wide Linkage Analysis of Carotid Artery Ultrasound Traits in Multigenerational African Ancestry Families 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.09.005.
Intima-media thickness, adventitial diameter and lumen diameter are indicators of cardiovascular disease risk. The influence of genetic factors on these measures in African ancestry populations is not well defined. Therefore, we estimated heritability and performed genome-wide linkage analysis of carotid ultrasound traits in 7 multigenerational families of African ancestry.
A total of 395 individuals (7 pedigrees; mean family size = 56; 2,392 relative pairs) aged ≥18 years had a common carotid artery ultrasound scan. Statistical analyses were conducted using pedigree-based maximum likelihood methods.
Significant covariates included age, sex, body mass index or height and waist, and systolic blood pressure. Residual heritabilities ranged from 0.35±0.10 to 0.64±0.12 (P<0.0001). We identified a novel quantitative trait locus for adventitial and lumen diameters on chromosome 11 (max LOD=4.09, 133cM).
Further fine mapping of this region may identify specific mutations predisposing to subclinical vascular disease among African ancestry individuals.
PMCID: PMC3837479  PMID: 24125421
carotid ultrasound; intima-media thickness; arterial diameter; genome-wide linkage; African ancestry
23.  A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease 
Atherosclerosis  2014;237(1):5-12.
Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD).
Methods and results
We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test.
In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification.
In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.
•We examined evidence for an interaction between APOE genotype, smoking and risk of coronary heart disease.•This was conducted in the largest meta-analysis of published and unpublished data sets to date (>130,000 individuals).•Our analysis did not identify evidence of interaction.•These findings bring into question presence of a clinically meaningful interaction between APOE genotype and smoking.
PMCID: PMC4232362  PMID: 25173947
APOE genotype; Smoking; Coronary heart disease; Gene–environment interaction
24.  The emergence of proton nuclear magnetic resonance metabolomics in the cardiovascular arena as viewed from a clinical perspective 
Atherosclerosis  2014;237(1):287-300.
The ability to phenotype metabolic profiles in serum has increased substantially in recent years with the advent of metabolomics. Metabolomics is the study of the metabolome, defined as those molecules with an atomic mass less than 1.5 kDa. There are two main metabolomics methods: mass spectrometry (MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy, each with its respective benefits and limitations. MS has greater sensitivity and so can detect many more metabolites. However, its cost (especially when heavy labelled internal standards are required for absolute quantitation) and quality control is sub-optimal for large cohorts. 1H NMR is less sensitive but sample preparation is generally faster and analysis times shorter, resulting in markedly lower analysis costs. 1H NMR is robust, reproducible and can provide absolute quantitation of many metabolites. Of particular relevance to cardio-metabolic disease is the ability of 1H NMR to provide detailed quantitative data on amino acids, fatty acids and other metabolites as well as lipoprotein subparticle concentrations and size. Early epidemiological studies suggest promise, however, this is an emerging field and more data is required before we can determine the clinical utility of these measures to improve disease prediction and treatment.
This review describes the theoretical basis of 1H NMR; compares MS and 1H NMR and provides a tabular overview of recent 1H NMR-based research findings in the atherosclerosis field, describing the design and scope of studies conducted to date. 1H NMR metabolomics-CVD related research is emerging, however further large, robustly conducted prospective, genetic and intervention studies are needed to advance research on CVD risk prediction and to identify causal pathways amenable to intervention.
•1H NMR metabolomics is being increasingly applied to large cohort studies.•Studies have identified potentially novel lipoprotein and metabolite predictors for CVD.•Potential exists for the use of metabolomics in cardiovascular clinical practice.•Current findings are too preliminary to translate into clinical recommendations.•Further large scale studies are now needed to advance the field in a robust manner.
PMCID: PMC4232363  PMID: 25299963
Nuclear magnetic resonance (1H NMR); Metabolomics; Cardiovascular disease (CVD); Lipoprotein; Mass spectrometry (MS); Biomarkers; Advanced lipoprotein testing (ALP)
25.  Low Vasa Vasorum Densities Correlate with Inflammation and Subintimal Thickening – Potential Role in Location-Determination of Atherogenesis 
Atherosclerosis  2009;206(2):362-368.
To assess the role of coronary vasa vasorum (VV) spatial distribution in determining the location of early atherosclerotic lesion development.
Methods and Results
Six, 3-month old, female, crossbred swine were fed 2% high-cholesterol (HC) diet for 3 months prior to euthanasia. Six other pigs were fed normal diet (N) for the entire 6 months. Right coronary arteries were harvested and scanned intact with micro-CT (20μm cubic-voxel-size). After scanning, randomly selected cross-sectional histological sections were stained for nuclear-factor kappaB (NF-κB), hypoxia-inducible factor-1alpha (HIF-1α), macrophages, von-Willebrand-factor, dihydroethidium (DHE), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). The number of positive stained cells, as well as intima-to-media ratio, were compared with VV density (#/mm2) obtained from micro-CT images (which closely matched the location of the histological sections) in each of four equal quadrants of the coronary vessel wall. In normal, as well as HC pigs, the number of NF-κB (r=0.73 and 0.70), HIF-1α (r=0.74 and 0.77), TNF-α (r=0.58 and 0.72) and IL-6 (r=0.70 and 0.72) positive cells as well as the expression of DHE (Kendall tau coefficient −0.64 and −0.63) inversely correlated with VV density. In HC the VV density also inversely correlated with intima/media ratios (r=0.65).
Our data suggest that low-VV-density-territories within the coronary vessel wall are susceptible to hypoxia, oxidative stress and microinflammation and may therefore be starting points of early atherogenesis.
PMCID: PMC4208719  PMID: 19368925
Atherogenesis; Hypoxia; Microinflammation; Micro-CT; Vasa Vasorum

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