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1.  Lower ratio of high-molecular-weight adiponectin level to total may be associated with coronary high-risk plaque 
BMC Research Notes  2013;6:83.
Although high-molecular-weight (HMW) adiponectin is believed to protect against atherosclerosis, the association between HMW adiponectin and the composition of coronary plaques is unknown. We evaluated whether the HMW to total adiponectin ratio was associated with the presence of coronary plaque and its composition using multi-slice computed tomography coronary angiography (MSCTCA).
Serum total and HMW adiponectin levels were measured in 53 consecutive patients (age, 71) with >50% coronary artery stenosis detected by MSCTCA. A low-attenuation coronary plaque was defined as a plaque with a mean CT density <50 Hounsfield units. Multivariate logistic regression analyses were performed to evaluate the predictors of the presence of low-attenuation coronary plaques, which is thought to be high risk, on CT.
Decreased serum levels of total as well as HMW adiponectin were significantly associated with the presence of at least one calcified or non-calcified coronary artery plaque (total adiponectin level: odds ratio 0.76, 95% CI 0.58–0.99, P = 0.048; HMW adiponectin level: odds ratio 0.65, 95% CI 0.42–0.99, P = 0.047). A low ratio of HMW to total adiponectin was significantly associated with the presence of low-attenuation coronary plaques (4.55, 1.94–21.90, P = 0.049). However, neither the total adiponectin nor the HMW adiponectin level was associated with the presence of low-attenuation coronary plaques.
Lower total or HMW adiponectin levels are associated with the presence of calcified and non-calcified coronary plaques, whereas a lower ratio of HMW to total adiponectin associated with the presence of low-attenuation coronary plaques (thought to be high risk). Measurement of total and HMW adiponectin levels and the HMW to total adiponectin ratio may be useful for risk stratification of coronary artery plaques.
PMCID: PMC3599310  PMID: 23497474
Adiponectin; High-molecular-weight adiponectin; Coronary artery plaque; Coronary low-attenuation plaque
2.  MMP-1 serum levels predict coronary atherosclerosis in humans 
Myocardial infarction results as a consequence of atherosclerotic plaque rupture, with plaque stability largely depending on the lesion forming extracellular matrix components. Lipid enriched non-calcified lesions are considered more instable and rupture prone than calcified lesions. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes with plaque destabilisating characteristics which have been implicated in atherogenesis. We therefore hypothesised MMP-1 and MMP-9 serum levels to be associated with non-calcified lesions as determined by CT-angiography in patients with coronary artery disease.
260 patients with typical or atypical chest pain underwent dual-source multi-slice CT-angiography (0.6-mm collimation, 330-ms gantry rotation time) to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified.
In multivariable regession analysis, MMP-1 serum levels were associated with total plaque burden (OR: 1.37 (CI: 1.02-1.85); p < 0.05) in a model adjusted for age, sex, BMI, classical cardiovascular risk factors, hsCRP, adiponectin, pericardial fat volume and medication. Specification of plaque morphology revealed significant association of MMP-1 serum levels with non-calcified plaques (OR: 1.16 (CI: 1.0-1.34); p = 0.05) and calcified plaques (OR: 1.22 (CI: 1,03-1.45); p < 0.05) while association with mixed plaques was lost in the fully adjusted model. No associations were found between MMP9 serum levels and total plaque burden or plaque morphology.
MMP-1 serum levels are associated with total plaque burden but do not allow a specification of plaque morphology.
PMCID: PMC2754422  PMID: 19751510
3.  Differential associations between blood biomarkers of inflammation, oxidation, and lipid metabolism with varying forms of coronary atherosclerotic plaque as quantified by coronary CT angiography 
Although epidemiologic data link biomarkers of cardiovascular risk with incident and prevalent coronary artery disease, exact anatomic relationships between biomarkers and coronary atherosclerosis as measured by coronary CT angiography remain unclear. Patients with acute chest pain who ultimately had no evidence of acute coronary syndrome underwent contrast-enhanced 64-slice coronary CT angiography to determine presence, extent and composition of coronary atherosclerotic plaque. We determined the differences in levels of blood biomarkers measured at the time of the CT scan between different CT-based atherosclerotic plaque groups. Among 313 patients (mean age: 51.6 ± 11 years, 62% male) high-sensitivity C-reactive protein (hs-CRP) and matrix metalloproteinase-2 were associated with the extent of calcified plaque (P = 0.03 and P<0.001), while hs-CRP and apolipoprotein A1 were associated with the extent of non-calcified plaque (P = 0.03 and P = 0.004; respectively). Despite a generally lower risk profile, subjects with exclusively non-calcified plaque had significantly higher levels of hs-CRP and oxidized low-density lipoprotein (P = 0.01 and P = 0.03; respectively) and lower levels of adiponectin (P = 0.03) when compared to subjects with calcified plaque (n = 130, 42%). Biomarkers reflecting inflammation, vascular remodeling, oxidation, and lipoprotein metabolism maybe associated with different patterns of coronary atherosclerosis as quantified by coronary CT angiography.
PMCID: PMC3099253  PMID: 21222039
Biomarkers; Atherosclerosis; Cardiac CT; Imaging; Coronary artery disease
4.  Assessment of Coronary Plaque Progression in Coronary CT Angiography Using a Semi-Quantitative Score 
JACC. Cardiovascular imaging  2009;2(11):1262-1270.
To describe progression of coronary atherosclerotic plaque over time by computed tomography (CT) angiography stratified by plaque composition and its association with cardiovascular risk profiles.
Data on the progression of atherosclerosis stratified by plaque composition using non-invasive assessment by CT are limited and hampered by high measurement variability.
This analysis included patients who presented with acute chest pain to the emergency room but had initially no evidence for acute coronary syndrome. All patients underwent contrast enhanced 64-slice CT at baseline and after 2-years using a similar protocol. CT datasets were co-registered and assessed for presence of calcified and non-calcified plaque at 1mm cross-sections of the proximal 40mm of each major coronary artery. Plaque progression over time and its association to risk factors were determined. Measurement reproducibility and correlation to plaque volume was performed in a subset of patients.
We included 69 patients (mean age 55±12years, 59% male) and compared 8,311 co-registered cross-sections at baseline and follow-up. At baseline, any plaque, calcified plaque, and non-calcified were detected in 12.5%, 10.1%, and 2.4% of cross-sections per patient. There was significant progression in the mean number of cross-sections containing any plaque (16.5±25.3 versus 18.6±25.5, p=0.01) and non-calcified plaque (3.1±5.8 versus 4.4±7.0, p=0.04), but not calcified plaque (13.3±23.1 versus 14.2±22.0, p=0.2). In longitudinal regression analysis, the presence of baseline plaque, number of cardiovascular risk factors and smoking were independently associated with plaque progression after adjustment for age, gender and follow-up time interval. The semi-quantitative score based on cross-sections correlated close with plaque volume progression (r=0.75, p<0.0001) and demonstrated an excellent intra- and inter-observer agreement (κ=0.95 and κ=0.93, retrospectively).
Coronary plaque burden of patients with acute chest pain significantly increases over two years. Progression over time is dependent on plaque composition and cardiovascular risk profile. Larger studies are needed to confirm these results and to determine the effect of medical treatment on progression.
PMCID: PMC2796339  PMID: 19909929
atherosclerosis; computed tomography; coronary artery disease; risk factors; progression
5.  Neutrophil/Lymphocyte Ratio Is Associated with Non-Calcified Plaque Burden in Patients with Coronary Artery Disease 
PLoS ONE  2014;9(9):e108183.
Elevations in soluble markers of inflammation and changes in leukocyte subset distribution are frequently reported in patients with coronary artery disease (CAD). Lately, the neutrophil/lymphocyte ratio has emerged as a potential marker of both CAD severity and cardiovascular prognosis.
The aim of the study was to investigate whether neutrophil/lymphocyte ratio and other immune-inflammatory markers were related to plaque burden, as assessed by coronary computed tomography angiography (CCTA), in patients with CAD.
Twenty patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and 30 patients with stable angina (SA) underwent CCTA at two occasions, immediately prior to coronary angiography and after three months. Atherosclerotic plaques were classified as calcified, mixed and non-calcified. Blood samples were drawn at both occasions. Leukocyte subsets were analyzed by white blood cell differential counts and flow cytometry. Levels of C-reactive protein (CRP) and interleukin(IL)-6 were measured in plasma. Blood analyses were also performed in 37 healthy controls.
Plaque variables did not change over 3 months, total plaque burden being similar in NSTE-ACS and SA. However, non-calcified/total plaque ratio was higher in NSTE-ACS, 0.25(0.09–0.44) vs 0.11(0.00–0.25), p<0.05. At admission, levels of monocytes, neutrophils, neutrophil/lymphocyte ratios, CD4+ T cells, CRP and IL-6 were significantly elevated, while levels of NK cells were reduced, in both patient groups as compared to controls. After 3 months, levels of monocytes, neutrophils, neutrophil/lymphocyte ratios and CD4+ T cells remained elevated in patients. Neutrophil/lymphocyte ratios and neutrophil counts correlated significantly with numbers of non-calcified plaques and also with non-calcified/total plaque ratio (r = 0.403, p = 0.010 and r = 0.382, p = 0.024, respectively), but not with total plaque burden.
Among immune-inflammatory markers in NSTE-ACS and SA patients, neutrophil counts and neutrophil/lymphocyte ratios were significantly correlated with non-calcified plaques. Data suggest that these easily measured biomarkers reflect the burden of vulnerable plaques in CAD.
PMCID: PMC4182451  PMID: 25268632
6.  Association of Aortic Valve Calcification to the Presence, Extent, and Composition of Coronary Artery Plaque Burden: ROMICAT Study 
American heart journal  2009;158(4):562-568.
Aortic valve calcification (AVC) is associated with cardiovascular risk factors and coronary artery calcification. We sought to determine whether AVC is associated with the presence and extent of overall plaque burden, as well as to plaque composition (calcified, mixed, and non-calcified).
We examined 357 subjects (mean age: 53 ± 12 years, 61% male) who underwent contrast-enhanced ECG-gated 64-slice multi-detector computed tomography from the ROMICAT trial for the assessment of presence and extent of coronary plaque burden according to the 17-coronary segment model and presence of AVC.
Patients with AVC (n=37, 10%) were more likely than those without AVC (n=320, 90%) to have coexisting presence of any coronary plaque (89% vs. 46%, p<0.001) and had a greater extent of coronary plaque burden (6.4 segments vs. 1.8 segments, p<0.001). Those with AVC had over 3-fold increase odds of having any plaque (adjusted odds ratio [OR] 3.6, p=0.047) and an increase of 2.5 segments of plaque (p<0.001) as compared to those without AVC. When stratified by plaque composition, AVC was associated most with calcified plaque (OR 5.2, p=0.004), then mixed plaque (OR 3.2, p=0.02), but not with non-calcified plaque (p=0.96).
AVC is associated with the presence and greater extent of coronary artery plaque burden and may be part of the later stages of the atherosclerosis process, as its relation is strongest with calcified plaque, less with mixed plaque, and nonsignificant with non-calcified plaque. If AVC is present, consideration for aggressive medical therapy may be warranted.
PMCID: PMC2764241  PMID: 19781415
Aortic valve calcification; coronary artery disease; multi-detector computed tomography; calcified plaque; non-calcified plaque; mixed plaque
7.  HMGB1 Is Associated with Atherosclerotic Plaque Composition and Burden in Patients with Stable Coronary Artery Disease 
PLoS ONE  2012;7(12):e52081.
The role of inflammation in atherosclerosis is widely appreciated. High mobility group box 1 (HMGB1), an injury-associated molecular pattern molecule acting as a mediator of inflammation, has recently been implicated in the development of atherosclerosis. In this study, we sought to investigate the association of plasma HMGB1 with coronary plaque composition in patients with suspected or known coronary artery disease (CAD).
HMGB1, high sensitive troponin T (hsTnT) and high sensitive C-reactive protein (hsCRP) were determined in 152 consecutive patients with suspected or known stable CAD who underwent clinically indicated 256-slice coronary computed tomography angiography (CCTA). Using CCTA, we assessed 1) coronary calcification, 2) non-calcified plaque burden and 3) the presence of vascular remodeling in areas of non-calcified plaques.
Using univariate analysis, hsCRP, hsTnT and HMGB1 as well as age, and atherogenic risk factors were associated with non-calcified plaque burden (r = 0.21, p = 0.009; r = 0.48, p<0.001 and r = 0.34, p<0.001, respectively). By multivariate analysis, hsTnT and HMGB1 remained independent predictors of the non-calcified plaque burden (r = 0.48, p<0.01 and r = 0.34, p<0.001, respectively), whereas a non-significant trend was noticed for hs-CRP (r = 0.21, p = 0.07). By combining hsTnT and HMGB1, a high positive predictive value for the presence of non-calcified and remodeled plaque (96% and 77%, respectively) was noted in patients within the upper tertiles for both biomarkers, which surpassed the positive predictive value of each marker separately.
In addition to hs-TnT, a well-established cardiovascular risk marker, HMGB1 is independently associated with non-calcified plaque burden in patients with stable CAD, while the predictive value of hs-CRP is lower. Complementary value was observed for hs-TnT and HMGB1 for the prediction of complex coronary plaque.
PMCID: PMC3524090  PMID: 23284878
8.  Procoagulant activity of circulating microparticles is associated with the presence of moderate calcified plaque burden detected by multislice computed tomography 
Circulating microparticles (MPs) have been reported to be associated with coronary artery disease (CAD). In this study, we explored the relationship between MPs procoagulant activity and characteristics of atherosclerotic plaque detected by 64-slice computed tomography angiography (CTA).
In 127 consecutive patients with CAD but without acute coronary syndrome and who underwent 64-slice CTA, MPs procoagulant activity in plasma (by a thrombin generation test), soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) and N(epsilon)-(carboxymethyl) lysine (CML) circulating levels (by ELISA) were measured. A quantitative volumetric analysis of the lumen and plaque burden of the vessel wall (soft and calcific components), for the three major coronary vessels, was performed. The patients were classified in three groups according to the presence of calcium volume: non-calcified plaque (NCP) group (calcium volume (%) = 0), moderate calcified plaque (MCP) group (0 < calcium volume (%) < 1), and calcified plaque (CP) group (calcium volume (%) ≥ 1).
MPs procoagulant activity and CML levels were higher in MCP group than in CP or NCP group (P = 0.009 and P = 0.027, respectively). MPs procoagulant activity was positively associated with CML (r = 0.317, P < 0.0001) and sLOX-1 levels (r = 0.216, P = 0.0025).
MPs procoagulant activity was higher in the MCP patient group and correlated positively with sLOX-1 and CML levels, suggesting that it may characterize a state of blood vulnerability that may locally precipitate plaque instability and increase the risk of subsequent major cardiovascular events.
PMCID: PMC3981978  PMID: 24748876
Computed tomography; Microparticles; Low density lipoprotein; Lysine; Coronary artery disease
9.  Lower Adiponectin is Associated with Subclinical Cardiovascular Disease among HIV-infected Men 
AIDS (London, England)  2014;28(6):901-909.
To examine if altered levels of adipokines, adipose-derived peptides associated with myocardial infarction in the general population, may contribute to subclinical coronary atherosclerosis in HIV-infected persons.
Nested cohort study.
We studied HIV-infected(HIV+) and HIV-uninfected(HIV−) men in the Multicenter AIDS Cohort Study with noncontrast CT to measure coronary artery calcium and regional adiposity; 75% additionally underwent coronary CT angiography to measure plaque composition and stenosis. Adiponectin and leptin levels were assessed. Multiple regression models were used to assess associations between adipokine levels and HIV disease parameters, regional adiposity, and plaque adjusted for age, race, HIV serostatus and CVD risk factors (RFs).
Significant findings were limited to adiponectin. HIV+ men (n=493) had lower adiponectin levels than HIV− men (n=250) after adjusting for CVD RFs (p<0.0001), which became non-significant after adjustment for abdominal visceral and thigh subcutaneous adipose tissue. Among HIV+ men, lower adiponectin levels were associated with higher CD4+ T cell counts (p= 0.004), longer duration of antiretroviral therapy (p= 0.006) and undetectable HIV RNA levels (p = 0.04) after adjusting for age, race and CVD RFs; only CD4+ cell count remained significant after further adjustment for adipose tissue. In both groups, lower adiponectin levels were associated with increased odds of coronary stenosis > 50% (p <0.007). Lower adiponectin levels were associated with increased extent of plaque in HIV+ and of mixed plaque in HIV− men.
Adiponectin levels were lower in HIV-infected men and related to the severity of subclinical atherosclerosis, independent of traditional CVD risk factors.
PMCID: PMC3967406  PMID: 24401646
Adipokines; adiponectin; leptin; heart; subclinical coronary atherosclerosis; metabolic side effects of HIV infection; coronary CT angiography; cardiac CT
10.  Associations between HIV Infection and Subclinical Coronary Atherosclerosis: The Multicenter AIDS Cohort Study (MACS) 
Annals of internal medicine  2014;160(7):458-467.
Coronary artery disease (CAD) has been associated with HIV infection; however data are not consistent.
We performed cardiac CT to determine whether HIV-infected men have more coronary atherosclerosis than uninfected men.
Cross-sectional study within the Multicenter AIDS Cohort Study(MACS).
HIV-infected (n=618) and –uninfected (n=383) men who have sex with men (MSM) had non-contrast and contrast enhanced cardiac CT if they were between 40–70 years, weighed <300 pounds, and had no history of coronary revascularization.
Presence and extent, for those with plaque, of coronary artery calcium (CAC) on non-contrast CT, and of any plaque, non-calcified, mixed or calcified plaque and stenosis on CT angiography.
1001 men underwent non-contrast CT of whom 759 had coronary CT angiography. After adjusting for age, race, center, and cohort, HIV-infected men had a greater prevalence of CAC [Prevalence ratio(PR)=1.21, 95% confidence interval (CI) 1.08–1.35, p=0.001], and any plaque [PR=1.14(1.05–1.24),p=0.001], including non-calcified plaque [PR=1.28(1.13–1.45),p<0.001) and mixed plaque [PR=1.35(1.10–1.65),p=0.004] than HIV-uninfected men. Associations between HIV-infection and any plaque and non-calcified plaque remained significant (p<0.005) after CAD risk factor adjustment. HIV-infected men also had a greater extent of non-calcified plaque after CAD risk factor adjustment (p=0.026). HIV-infected men had a greater prevalence of coronary artery stenosis>50% than HIV-uninfected men [PR=1.48(1.06–2.07),p=0.020), but not after CAD risk factor adjustment. Longer duration of highly active antiretroviral therapy [PR=1.09(1.02–1.17), p=0.007,per year] and lower nadir CD4+ T-cell count [PR=0.80(0.69–0.94),p=0.005, per 100 cells] were associated with coronary stenosis>50%.
Coronary artery plaque, especially non-calcified plaque, is more prevalent and extensive in HIV-infected men, independent of CAD risk factors.
Cross-sectional observational study design and inclusion of only men.
Primary Funding Source
PMCID: PMC4143766  PMID: 24687069
11.  Influence of Pericoronary Adipose Tissue on Local Coronary Atherosclerosis as Assessed by a Novel MDCT Volumetric Method 
Atherosclerosis  2011;219(1):151-157.
Pericoronary adipose tissue (PCAT) may create a pro-inflammatory state, contributing to the development of coronary artery disease (CAD). We sought to evaluate the feasibility of avolumetric PCAT quantification method using a novel threshold based computed tomography approach. In addition we determined the relation between PCAT volumes and CAD.
In 51 patients (49.5±5.1 years, 64.8% male) who underwent 64-slice MDCT, we measured threshold-based PCAT volumes using distance and anatomic-based methods. Using the most reproducible method, we performed the proximal 40-mm distance measurement in three groups as stratified by coronary plaque and high-sensitivity C-reactive protein (hs-CRP) levels: Group 1 (presence of coronary plaque, hs-CRP >2.0 mg/L); an intermediate group (Group 2, no plaque, hs-CRP >2.0 mg/L); and Group 3 (no plaque, hs-CRP<1.0 mg/L). We compared PCAT volumes to the presence of coronary plaque on a patient (n=51) and vessel (n=153) basis. On a subsegment basis (n=1224), we compared PCAT volume to the presence of plaque as well as plaque morphology.
Distance-based PCAT volume measurements yielded excellent reproducibility with intra-observer intraclass correlation (ICC) of 0.997 and inter-observer ICC of 0.951. On a both a per-patient and per-vessel analysis, adjusted PCAT volume was greater in patients with plaque (Group 1) than without plaque (Group 2 and 3, p<0.001). No difference in PCAT volume was seen between high and low hs-CRP groups without plaque (p=0.51). Adjusted PCAT volumes were higher in subsegments with plaque as compared without (p<0.001). Additionally, adjusted PCAT volume was greatest in subsegments with mixed plaque followed by non-calcified plaque, calcified plaque, and the lowest volume in segments with no plaque (p<0.001).
In this proof-of-concept study, threshold based PCAT volume assessment is feasible and highly reproducible. PCAT volume is increased in patients and vessels with coronary plaques. Surrounding vessel subsegments with coronary plaque, particularly mixed plaques, have greatest PCAT volume and highlight the effect of local PCAT in the development of coronary atherosclerosis.
PMCID: PMC3203345  PMID: 21782176
Coronary artery disease; pericoronary fat; epicardial fat; adipose tissue; inflammation; computed tomography
12.  Segmental heterogeneity of vasa vasorum neovascularization in human coronary atherosclerosis and role of intraplaque hemorrhage in plaque calcification 
JACC. Cardiovascular imaging  2010;3(1):32-40.
To investigate the role of coronary vasa vasorum (VV) neovascularization in the progression and complications of human coronary atherosclerotic plaques.
Accumulating evidence supports an important role of VV neovascularization in atherogenesis and lesion location determination in coronary artery disease. VV neovascularization can lead to intraplaque hemorrhage, which has been identified as a promoter of plaque progression and complications like plaque rupture. We hypothesized that distinctive patterns of VV neovascularization and associated plaque complications can be found in different stages of human coronary atherosclerosis.
Hearts from 15 patients (age 52±5, mean±SEM) were obtained at autopsy, perfused with Microfil™ and subsequently scanned with micro-computed tomography (micro-CT). Two-cm-segments (n=50) were histologically classified as either normal (n=12), nonstenotic plaque (<50% stenosis, n=18), or calcified (n=10) or non-calcified (n=10) stenotic plaque. Micro-CT images were analyzed for VV density (#/mm2), VV vascular area fraction (mm2/mm2) and VV endothelial surface fraction (mm2/mm3). Histological sections were stained for Mallory’s (iron), von Kossa (calcium) and glycophorin-A (erythrocyte fragments) as well as endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α).
VV density was higher in segments with non-stenotic and non-calcified stenotic plaques as compared to normals (3.36±0.45, 3.72±1.03 vs. 1.16±0.21, P<0.01). In calcified stenotic plaques VV spatial density was lowest (0.95±0.21, P<0.05 vs. non-stenotic and non-calcified stenotic plaque). The amount of iron and glycophorin A was significantly higher in non-stenotic and stenotic plaques as compared to normals, and correlated with VV density (Kendall-Tau correlation-coefficient 0.65 and 0.58 respectively, P<0.01). Moreover, relatively high amounts of iron and glycophorin A were found in calcified plaques. Further immunohistochemical characterization of VV revealed positive staining for eNOS and TNF-α but not VEGF.
Our results support a possible role of VV neovascularization, VV rupture and intraplaque hemorrhage in the progression and complications of human coronary atherosclerosis.
PMCID: PMC2872563  PMID: 20129528
vasa vasorum; human coronary atherosclerosis; micro-CT; calcification; intraplaque hemorrhage
13.  Aortic Distensibility and its Relationship to Coronary and Thoracic Atherosclerosis Plaque and Morphology by MDCT: Insights from the ROMICAT Trial 
International journal of cardiology  2012;167(4):1616-1621.
Multi-detector cardiac computed tomography (CT) allows for simultaneous assessment of aortic distensibility (AD), coronary atherosclerosis, and thoracic aortic atherosclerosis.
We sought to determine the relationship of AD to the presence and morphological features in coronary and thoracic atherosclerosis.
In 293 patients (53±12 years, 63% male), retrospectively-gated MDCT were performed. We measured intraluminal aortic areas across 10 phases of the cardiac cycle (multiphase reformation 10% increments) at pre-defined locations to calculate the ascending, descending, and local AD (at locations of thoracic plaque). AD was calculated as maximum change in area/(minimum area × pulse pressure). Coronary and thoracic plaques were categorized as calcified, mixed, or non-calcified.
Ascending and descending AD were lower in patients with any coronary plaque, calcified or mixed plaque than those without (all p<0.0001) but not with non-calcified coronary plaque (p≥0.46). Per 1 mmHg−110−3 increase in ascending and descending AD, there was an 18–29% adjusted risk reduction for having any coronary, calcified plaque, or mixed coronary plaque (ascending AD only) (all p≤0.04). AD was not associated with non-calcified coronary plaque or when age was added to the models (all p>0.39). Local AD was lower at locations of calcified and mixed thoracic plaque when compared to non-calcified thoracic atherosclerosis (p<0.04).
A stiffer, less distensible aorta is associated with coronary and thoracic atherosclerosis, particularly in the presence of calcified and mixed plaques, suggesting that the mechanism of atherosclerosis in small and large vessels is similar and influenced by advancing age.
PMCID: PMC3419779  PMID: 22578738
aortic distensibility; coronary atherosclerosis; thoracic atherosclerosis; peripheral vascular disease; computed tomography; cardiovascular aging
14.  Non-invasive evaluation of atherosclerosis with contrast enhanced 16 slice spiral computed tomography: results of ex vivo investigations 
Heart  2004;90(12):1471-1475.
Objective: To evaluate the diagnostic accuracy of 16 slice computed tomography (CT) in determining plaque morphology and composition in an experimental setting. The results were compared with histopathological analysis as the reference standard.
Methods: Nine human popliteal arteries derived from amputations because of atherosclerotic disease were investigated with multislice spiral CT (MSCT). Atherosclerotic lesions were morphologically classified (completely or partially occlusive, concentric, eccentric), and tissue densities were determined within these plaques. In addition, vessel dimensions were quantitatively measured.
Results: The results were compared with histological analysis. The concordance index κ for morphological classification was 0.88. Plaque density (n  =  51 lesions) was significantly different (p < 0.0001) between lipid rich, fibrotic, and calcified lesions (Stary stage III: n  =  2, 58 (8) Hounsfield units (HU); Stary V: n  =  11, 50 (21) HU; Stary VI: n  =  14, 96 (42) HU; Stary VII: n  =  6, 858 (263) HU; Stary VIII: n  =  18, 126 (99) HU). The concordance index κ for the classification of plaques based on density was 0.51. Vessel dimensions had a good correlation (r  =  0.98).
Conclusions: 16 slice CT was found to be a reliable non-invasive imaging technique for assessing atherosclerotic plaque morphology and composition. Although calcified lesions can be differentiated from non-calcified lesions, the diagnostic accuracy in further subclassifying non-calcified plaques as lipid rich and fibrotic is low, even under experimental conditions.
PMCID: PMC1768560  PMID: 15547032
atherosclerosis; coronary artery disease; multislice spiral computed tomography; non-calcified plaques
15.  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
16.  Mechanism of lumen enlargement with direct stenting versus predilatation stenting: influence of remodelling and plaque characteristics assessed by volumetric intracoronary ultrasound 
Heart  2003;89(1):84-90.
Objective: To compare the effects of arterial remodelling and plaque characteristics on the mechanisms of direct stenting and predilatation stenting. Direct stenting has become routine in some laboratories and differs technically from predilatation stenting.
Methods: Pre- and post-interventional volumetric intravascular ultrasound (IVUS) was undertaken in 30 patients with direct stenting and in 30 with predilatation stenting of non-calcified native coronary lesions, using the same stent design and stent length. Lumen, vessel (external elastic membrane (EEM)), and plaque (plaque + media) volumes were calculated. Remodelling was determined by comparing the EEM area at the centre of the lesion with the EEM areas at proximal and distal reference sites. Plaque eccentricity was defined as the thinnest plaque diameter to the thickest plaque diameter ratio. Plaque composition was characterised as soft, mixed, or dense.
Results: All volumetric IVUS changes were similar in the two groups. Pre-intervention remodelling remained uninfluenced after direct stenting, but was neutralised after predilatation stenting. Eccentric lesions responded to intervention by a greater luminal gain owing to greater vessel expansion in direct stenting. Plaque composition influenced luminal gain in direct stenting, the gain being greatest in the softest plaques; in predilatation stenting, luminal gain was equivalent but vessel expansion was greater for “dense” plaque and plaque reduction greater for “soft” plaque.
Conclusions: In non-calcified lesions, the mechanisms of lumen enlargement after direct or predilatation stenting are significantly influenced by atherosclerotic remodelling, plaque eccentricity, and plaque composition.
PMCID: PMC1767502  PMID: 12482801
stents; intravascular ultrasound; angioplasty; remodelling
17.  Relationship among coronary plaque compliance, coronary risk factors and tissue characteristics evaluated by integrated backscatter intravascular ultrasound 
The purpose of the present study was to evaluate the mechanical properties of coronary plaques and plaque behavior, and to elucidate the relationship among tissue characteristics of coronary plaques, mechanical properties and coronary risk factors using integrated backscatter intravascular ultrasound (IB-IVUS).
Non-targeted plaques with moderate stenosis (plaque burden at the minimal lumen site: 50-70%) located proximal to the site of the percutaneous coronary intervention target lesions were evaluated by IB-IVUS. Thirty-six plaques (less calcified group: an arc of calcification ≤10°) in 36 patients and 22 plaques (moderately calcified group: 10° < an arc of calcification ≤60°) in 22 patients were evaluated. External elastic membrane volume (EEMV) compliance, lumen volume (LV) compliance, plaque volume (PV) response (difference between PV in systole and diastole), EEM area stiffness index were measured at the minimal lumen site. Relative lipid volume (lipid volume/internal elastic membrane volume) was calculated by IB-IVUS.
In the less calcified group, there was a significant correlation between EEMV compliance and the relative lipid volume (r = 0.456, p = 0.005). There was a significant inverse correlation between EEM area stiffness index and the relative lipid volume (p = 0.032, r = −0.358). The LV compliance and EEM area stiffness index were significantly different in the diabetes mellitus (DM) group than in the non-DM group (1.32 ± 1.49 vs. 2.47 ± 1.79%/10 mmHg, p =0.014 and 28.3 ± 26.0 vs. 15.7 ± 17.2, p =0.020). The EEMV compliance and EEM area stiffness index were significantly different in the hypertension (HTN) group than in the non-HTN group (0.77 ± 0.68 vs. 1.57 ± 0.95%/10 mmHg, p =0.012 and 26.5 ± 24.3 vs. 13.0 ± 16.7, p =0.020). These relationships were not seen in the moderately calcified group.
The present study provided new findings that there was a significant correlation between mechanical properties and tissue characteristics of coronary arteries. In addition, our results suggested that the EEMV compliance and the LV compliance were independent and the compliance was significantly impaired in the patients with DM and/or HTN. Assessment of coronary mechanical properties during PCI may provide us with useful information regarding the risk stratification of patients with coronary heart disease.
PMCID: PMC3489794  PMID: 22846428
Coronary artery disease; Intravascular ultrasound; Plaque; Stiffness; Tissue
18.  Characteristics of coronary artery disease in symptomatic type 2 diabetic patients: evaluation with CT angiography 
Coronary artery disease (CAD) is a common and severe complication of type 2 diabetes mellitus (DM). The aim of this study is to identify the features of CAD in diabetic patients using coronary CT angiography (CTA).
From 1 July 2009 to 20 March 2010, 113 consecutive patients (70 men, 43 women; mean age, 68 ± 10 years) with type 2 DM were found to have coronary plaques on coronary CTA. Their CTA data were reviewed, and extent, distribution and types of plaques and luminal narrowing were evaluated and compared between different sexes.
In total, 287 coronary vessels (2.5 ± 1.1 per patient) and 470 segments (4.2 ± 2.8 per patient) were found to have plaques, respectively. Multi-vessel disease was more common than single vessel disease (p < 0.001), and the left anterior descending (LAD) artery (35.8%) and its proximal segment (19.1%) were most frequently involved (all p < 0.001). Calcified plaques (48.8%) were the most common type (p < 0.001) followed by mixed plaques (38.1%). Regarding the different degrees of stenosis, mild narrowing (36.9%) was most common (p < 0.001); however, a significant difference was not observed between non-obstructive and obstructive stenosis (50.4% vs. 49.6%, p = 0.855). Extent of CAD, types of plaques and luminal narrowing were not significantly different between male and female diabetic patients.
Coronary CTA depicted a high plaque burden in patients with type 2 DM. Plaques, which were mainly calcified, were more frequently detected in the proximal segment of the LAD artery, and increased attention should be paid to the significant prevalence of obstructive stenosis. In addition, DM reduced the sex differential in CT findings of CAD.
PMCID: PMC2992482  PMID: 21067585
19.  The diagnostic and prognostic value of coronary CT angiography in asymptomatic high-risk patients: a cohort study 
Open Heart  2014;1(1):e000096.
To prospectively assess the value of coronary CT angiography (CTA) in asymptomatic patients with high ‘a priori’ risk of coronary artery disease (CAD).
711 consecutive asymptomatic patients (61.8 years; 40.1% female) with high ‘a priori’ risk of CAD were prospectively examined with a coronary calcium score (CCS) and CTA. Coronary arteries were evaluated for atherosclerotic plaque (non-calcified and calcified) and stenosis (mild <50%, intermediate 50–70% or high-grade >70%). Coronary Segment Involvement Score (SIS, total number of segments with plaque) and nc (non-calcified) SIS were calculated. Primary end points were major adverse cardiac events (ST-elevation MI, non-ST-elevation MI and cardiac death); secondary end points were coronary revascularisation and >50% stenosis by invasive angiography.
Of 711 patients, 28.3% were negative for CAD and 71.7% positive (CAD+) by CTA (15.6% had plaques without stenosis, 23.9% mild, 10.7% intermediate and 21.5% high-grade stenosis). CCS zero prevalence was 306 (43%), out of those 100 (32.7%) had non-calcified plaque only. Mean follow-up period was 2.65 years. MACE rate was 0% in CAD negative and higher (1.2%) in CAD positive by CTA. Coronary revascularisation rate was 5.5%. Patients with SIS ≥5 had an HR of 6.5 (95% CI 1.6 to 25.8, p<0.013) for MACE, patients with ncSIS ≥1 had an HR of 2.4 (95% CI 1.2 to 4.6, p<0.01) for secondary end point. The sensitivity of CTA for stenosis >50% compared with invasive angiography was 92.9% (95% CI 83.0% to 98.1%). Negative predictive value of CTA was 99.4% (95% CI 98.3% to 99.8%) for combined end points.
CAD prevalence by CTA in asymptomatic high-risk patients is high. CCS zero does not exclude CAD. CTA is highly accurate to exclude CAD. Total coronary plaque burden and nc plaques, even if only one segment is involved, are associated with an increased risk of adverse outcome.
PMCID: PMC4189305  PMID: 25332810
20.  Noninvasive assessment of the carotid and cerebrovascular atherosclerotic plaques by multidetector CT in type-2 diabetes mellitus patients with transient ischemic attack or stroke 
The cerebrovasuclar artery disease as a common complication of type-2 diabetes mellitus (T2DM) caused huge economic burden and lives threatening to patients. We evaluated the prevalence and morphology of carotid and cerebrovascular atherosclerotic plaques in T2DM patients with transient ischemic attack (TIA) or stroke using multidetector CT (MDCT).
64-MDCT and dual-source CT (DSCT) angiographies were performed in 195 T2DM patients with TIA or stroke (mean age 65.7+/-12.8 years; 118 men) between January 2009 to August 2011. During the process, plaque type, its distribution, extensive and obstructive natures were determined for each segment derived from the patients.
Atherosclerotic plaques were detected in 183 (93.8%) patients. A total of 1056 segments with plaque were identified, of which 450 (42.6%) were non-calcified, 192 (18.2%) were mixed and 414 (39.2%) calcified ones. Among them, 562 (53.2%) resulted in mild stenosis, 291 (27.6%) moderate stenosis, 170 (16.1%) severe stenosis and 33 (3.1%) occlusion. Non-calcified plaques contributed 91.8% to non-obstructive lumen narrowing, while mixed and calcified plaques contributed 89.0% and 65.0% respectively.
MDCT angiography detected a high prevalence of plaques in T2DM patients with TIA or stroke. A relatively high proportion of plaques were non-calcified, as well as with non-obstructive stenosis. MDCT angiography might further enhance the detection and management of carotid and cerebrovascular atherosclerosis in T2DM patients with TIA and stroke
PMCID: PMC3598273  PMID: 23443053
21.  Identification of Noncalcified Plaque in Young Persons with Diabetes 
Academic radiology  2012;19(7):889-893.
Coronary computed tomographic angiography (CTA) is a valuable tool for assessing coronary artery disease (CAD). Although statin use is widely recommended for persons with diabetes older than age 40, little is known about the presence and severity of CAD in younger patients with diabetes mellitus (DM). We evaluated coronary artery calcium (CAC) and coronary CTA in young persons with both DM1 and DM2 in an attempt to detect the earliest objective evidence of arteriosclerosis eligible for primary prevention.
Methods and Materials
We prospectively enrolled 40 persons with DM (25 type 1 and 15 type 2) between the ages of 19 and 35 presenting with diabetes for 5 years or longer. All patients underwent coronary CTA and CAC scans to evaluate for early atherosclerotic disease. Each plaque in the coronary artery was classified as noncalcified or calcified-mixed. We also evaluated all segments with stenosis, dividing them into mild (<50%), moderate (50–70%), and severe (>70%).
The average age of the DM1 subjects were 26 ± 4 (SD) years and 30 ± 4 years for DM2 patients (P < .01), with duration of diabetes of 8 ± 5 years and average HbA1c% of 8.7 ± 1.6 (norm = 4.6–6.2). Abnormal scans were present in 57.5%, noncalcified in 35% and calcified-mixed plaque in 22.5%. Persons with DM2 had a higher prevalence of positive coronary CTA scans than DM1: 80% versus 44% (P < .03) and more positive CAC scores 53% versus 4%, (P < .01). The total segment score of 2.1 ± 3.4 (P < .01) and total plaque score 1.9 ± 2.8 (P < .01) were highly correlated to each other. Plaque was almost uniformly absent below age 25, and became increasingly common in individuals over the age of 25 years for both groups. The average radiation exposure was 2.5 ± 1.3 mSv.
Our study verifies that early CAD can be diagnosed with coronary CTA and minimal radiation exposure in young adults with DM. A negative CAC score was not sufficient to exclude early CAD as we observed a preponderance of noncalcified plaque in this cohort. Coronary CTA in young DM patients older than age 25 may provide earlier identification of disease than does a CAC because only non-calcified plaque is frequently present. Coronary CTA provides an opportunity to consider initiation of earlier primary CAD prevention rather than waiting for the age of 40 as currently recommended by the American Diabetes Association guidelines.
PMCID: PMC4277701  PMID: 22542200
Atherosclerosis; diabetes mellitus; cardiac computed tomography; coronary calcium
22.  Diagnostic accuracy of dual-source CT angiography and coronary risk stratification 
The aim of this study was to evaluate the diagnostic accuracy of dual-source computed tomography (DSCT) in coronary artery disease, and to test the possibility of using this technique for coronary risk stratification.
With the advent of DSCT, it is possible to image coronary plaque noninvasively. However, the accuracy of this method in terms of sensitivity and specificity has not been determined. Furthermore, noninvasive determination of plaque composition and plaque burden may be important for improving coronary risk stratification.
Forty-six patients with known coronary artery disease underwent DSCT quantitative coronary angiography (QCA), and intravascular ultrasound (IVUS) were included in the study. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of DSCT was calculated against QCA and IVUS. Plaque analysis software in a DSCT workstation was used to detect plaque characteristics associated with the Hounsfield unit (Hu) value compared with IVUS. Coronary artery plaques were classified into three types of lesions based on DSCT, and the relationship between different coronary lesions and clinical diagnosis was determined.
DSCT angiography was performed in 46 patients, and a diagnostic-quality CT image was obtained in 44 patients. Coronary angiography was performed in 138 vessels and IVUS in 102 vessels of all 46 patients. Sensitivity, specificity, PPV, and NPV of DSCT compared with QCA was 100%, 98%, 92%, and 100%, respectively. The same corresponding index of DSCT compared with IVUS was 100%, 99%, 95%, and 100%, respectively. Quantitative coronary stenosis analysis revealed a good correlation between DSCT and QCA (r = 0.85, P < 0.05, 95% confidence interval [CI] 0.60–0.87). There was also a good correlation between DSCT and IVUS (r = 0.81, P < 0.05, 95% CI 0.56–0.82). In comparison with IVUS, DSCT predicted plaque characteristics more accurately. The coefficient correlation (r) of luminal cross-sectional area and external elastic membrane cross-sectional area between DSCT and IVUS was 0.82 (P < 0.01, CI 0.67–0.89) and 0.78 (P < 0.01, CI 0.67–0.86), respectively. Three different types of plaque were identified on IVUS. Fatty plaque had a 45 ± 14 Hu value, fibrous plaque 90 ± 20, and calcified plaque 530 ± 185, respectively, on DSCT. The relationship between clinical diagnosis and coronary plaque on DSCT indicated that lesions in patients with unstable angina pectoris or ST elevation myocardial infarction were mainly discrete soft plaques, but there was no significant difference in the distributive characteristics of the lesions in patients with non-ST elevation myocardial infarction and stable angina pectoris patients.
DSCT is a noninvasive tool that allows accurate evaluation of plaque characteristics, diagnosis of coronary artery disease, and stratification of coronary risk according to different coronary plaque type.
PMCID: PMC2964946  PMID: 21057578
dual-source computed tomography; quantitative coronary angiography; intravascular ultrasound; risk stratification
23.  Plaque imaging with CT coronary angiography: Effect of intra-vascular attenuation on plaque type classification 
World Journal of Radiology  2012;4(6):265-272.
AIM: To assess the attenuation of non-calcified atherosclerotic coronary artery plaques with computed tomography coronary angiography (CTCA).
METHODS: Four hundred consecutive patients underwent CTCA (Group 1: 200 patients, Sensation 64 Cardiac, Siemens; Group 2: 200 patients, VCT GE Healthcare, with either Iomeprol 400 or Iodixanol 320, respectively) for suspected coronary artery disease (CAD). CTCA was performed using standard protocols. Image quality (score 0-3), plaque (within the accessible non-calcified component of each non-calcified/mixed plaque) and coronary lumen attenuation were measured. Data were compared on a per-segment/per-plaque basis. Plaques were classified as fibrous vs lipid rich based on different attenuation thresholds. A P < 0.05 was considered significant.
RESULTS: In 468 atherosclerotic plaques in Group 1 and 644 in Group 2, average image quality was 2.96 ± 0.19 in Group 1 and 2.93 ± 0.25 in Group 2 (P ≥ 0.05). Coronary lumen attenuation was 367 ± 85 Hounsfield units (HU) in Group 1 and 327 ± 73 HU in Group 2 (P < 0.05); non-calcified plaque attenuation was 48 ± 23 HU in Group 1 and 39 ± 21 HU in Group 2 (P < 0.05). Overall signal to noise ratio was 15.6 ± 4.7 in Group 1 and 21.2 ± 7.7 in Group 2 (P < 0.01).
CONCLUSION: Higher intra-vascular attenuation modifies significantly the attenuation of non-calcified coronary plaques. This results in a more difficult characterization between lipid rich vs fibrous type.
PMCID: PMC3391672  PMID: 22778879
Computed tomography coronary angiography; Coronary artery plaque; Plaque characterization; Contrast material; Lumen enhancement
24.  Effect of age and plaque morphology on diagnostic accuracy of dual source multidetector computed tomography coronary angiography 
Multidetector computed tomography (MDCT) coronary angiography represents one of the most exciting technological revolutions in cardiac imaging and it has been increasingly used in the diagnosis of coronary artery disease. The purpose of this study is to investigate the effect of age and coronary plaque calcification on diagnostic accuracy of MDCT.
The patients were examined by using dual-source MDCT and conventional coronary angiography. MDCT results were analyzed with regard to the severity (> 50% stenosis) and morphology (non-calcified, mixed, or calcified) of coronary atherosclerotic plaques evaluated in a 16-segment model.
In total, 181 patients (94 men and 87 women) with 2,687 coronary artery segments were examined with MDCT. Ninety three patients were older than 65 years of age (group A, 42 men) and 88 were younger (group B, 52 men). Two-hundred nine coronary artery segments (7.2%) were excluded because of small distal coronary vessel segments and/or motion artifacts. The overall number of segments with non-diagnostic image quality was similar in both groups of patients. Of the 2,687 evaluated segments, 157 (5.8%) were significantly diseased, and 144 of them were correctly detected by MDCT. Diagnostic evaluation showed that the sensitivity, positive predictive value, specificity, and negative predictive value were 89.5%, 62.5%, 96.0%, and 99.2%, respectively in group A, and 95.2%, 64.8%, 97.5%, and 99.8% in group B, respectively. In addition, detailed segment-based analyses in coronary segments with non-calcified, mixed and calcified plaques in both groups were similar diagnostic accuracy.
Very high diagnostic accuracy observed in this study suggests that MDCT coronary angiography could be a suitable diagnostic tool for not only younger patients but also for older patients.
PMCID: PMC4076449  PMID: 25009559
Age; Calcification; Coronary artery disease; Computed tomography
25.  Coronary Plaque Type and Burden By Computed Tomography Angiography Without Association to C-Reactive Protein 
Contrast-enhanced computed tomography angiography (CTA) of the coronaries allows identification of plaques. Limited data exists on the relationship between C-reactive protein (CRP) and the plaque type or plaque burden detected by CTA.
We studied relationship between CRP and coronary atherosclerosis.
Materials and Methods:
92 patients without history of coronary disease underwent coronary CTA for chest pain. Coronary arteries were evaluated with each detected plaque labeled as calcified, noncalcified or mixed. Logarithmic transformation was done on CRP values for statistical analysis.
1380 coronary segments were evaluated. The average age was 57 years (SE 1.0) and basal metabolic index (BMI) 28.9 kg/m2 (SE 0.5). Median CRP level was 2.75 mg/L (range 0.17-16.98). No association was found between CRP quartiles and plaque type. In stepwise multivariate analysis, only diabetes was associated with noncalcified plaque (P < 0.001). When calcified and mixed plaques were added to the model, age (P < 0.001), diabetes (P < 0.02), and statin use (P < 0.05) were associated with an increased number of plaques per subject. No association was found between log-CRP for any type of plaque.
There was no association between CRP and plaque type by CTA. Lack of association is likely due to limited spatial resolution and underestimation of noncalcified plaque burden by CTA.
PMCID: PMC4083526  PMID: 25006560
Atherosclerosis; Computed tomography angiography; Coronary calcium; CRP; CTA; Imaging

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