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Apoprotein B, Small‐Dense LDL and Impaired HDL Remodeling Is Associated With Larger Plaque Burden and More Noncalcified Plaque as Assessed by Coronary CT Angiography and Intravascular Ultrasound With Radiofrequency Backscatter: Results From the ATLANTA I Study

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Szilard Voros
Szilard Voros
Szilard Voros
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Parag H Joshi at University of Texas Southwestern Medical Center
Parag H Joshi
Zhen Qian at United Imaging Healthcare
Zhen Qian
Sarah Rinehart
Sarah Rinehart
Sarah Rinehart
  • This person is not on ResearchGate, or hasn't claimed this research yet.
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Abstract and Figures

Apoprotein B-containing lipoproteins are atherogenic, but atheroprotective functions of apoprotein A-containing high-density lipoprotein (HDL) particles are poorly understood. The association between lipoproteins and plaque components by coronary computed tomography angiography (CTA) and intravascular ultrasound with radiofrequency backscatter (IVUS/VH) has not been evaluated. Quantitative, 3-dimensional plaque measurements were performed in 60 patients with CTA and IVUS/VH. Apoproteins, lipids, and HDL subpopulations were measured with 2-dimensional (2D) gel electrophoresis, and correlation was assessed with univariate and multivariable models. ApoB particles were associated with a higher proportion of noncalcified plaque (NCP) and a lower proportion of calcified plaque (small, dense low-density lipoprotein cholesterol and high-density NCP: r=0.3, P=0.03; triglycerides and low-density NCP: r=0.34, P=0.01). Smaller, dense, lipid-poor HDL particles were associated with a shift from calcified plaque to NCP on CTA (α3-HDL% and low-density NCP: r=0.32, P=0.02) and with larger plaque volume on IVUS/VH (α4-HDL%: r=0.41, P=0.01; α3-HDL%: r=0.37, P=0.03), because of larger dense calcium (α4-HDL%: r=0.37, P=0.03), larger fibrous tissue (α4-HDL%: r=0.34, P=0.04), and larger necrotic core (α4-HDL%: r=0.46, P<0.01; α3-HDL%: r=0.37, P=0.03). Larger lipid-rich HDL particles were associated with less low-density NCP on CTA (α2-HDL%: r=-0.34, P=0.02; α1-HDL%: r=-0.28, P=0.05), with smaller plaque volume on IVUS/VH (pre-α2-HDL: r=-0.33, P=0.05; α1-HDL%: r=-0.41, P=0.01; pre-α2-HDL: r=-0.33, P=0.05) and with less necrotic core (α1-HDL: r=-0.42, P<0.01; pre-α2-HDL: r=-0.38, P=0.02; α2-HDL: r=-0.35, P=0.03; pre-α1-HDL: r=-0.34, P=0.04). Pre-β2-HDL was associated with less calcification and less stenosis by both modalities. ApoB and small HDL particles are associated with larger plaque burden and more noncalcified plaque, whereas larger HDL and pre-β2-HDL particles are associated with plaque burden and less noncalcified plaque by both CTA and IVUS/VH.
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Apoprotein B, Small‐Dense LDL and Impaired HDL Remodeling Is Associated With Larger Plaque Burden and More Noncalcified Plaque as Assessed by Coronary CT Angiography and Intravascular Ultrasound With Radiofrequency Backscatter: Results From the ATLANTA I Stu
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... 12,13 Lipoprotein subclasses are also associated with CVD risk 11,13 and, more recently, have been shown to be related to coronary plaque composition as measured by multiple different imaging modalities. [20][21][22] In the ATLANTA (Assessment of Tissue Characteristics, Lesion Morphology, and Hemodynamics by Angiography With Fractional Flow Reserve, Intravascular Ultrasound and Virtual Histology, and Noninvasive Computed Tomography in Atherosclerotic Plaques) study of 60 individuals without oCAD presenting with chest pain, small, dense LDL and small HDL are associated with HRP features (namely, larger plaque volume, more noncalcified plaque, and higher volume of necrotic core) on coronary CTA and intravascular ultrasound, whereas larger HDL particles are associated with lower plaque volume and lower volume of necrotic core. 21 Supportive of the role of impaired reverse cholesterol transport, in a separate study using carotid magnetic resonance imaging assessment to detect HRP, the Chicago Healthy Aging Study found that HDL efflux capacity correlates with large and medium HDL subclasses; however, after multivariable adjustment, neither efflux capacity nor subclasses associate with HRP. ...
... [20][21][22] In the ATLANTA (Assessment of Tissue Characteristics, Lesion Morphology, and Hemodynamics by Angiography With Fractional Flow Reserve, Intravascular Ultrasound and Virtual Histology, and Noninvasive Computed Tomography in Atherosclerotic Plaques) study of 60 individuals without oCAD presenting with chest pain, small, dense LDL and small HDL are associated with HRP features (namely, larger plaque volume, more noncalcified plaque, and higher volume of necrotic core) on coronary CTA and intravascular ultrasound, whereas larger HDL particles are associated with lower plaque volume and lower volume of necrotic core. 21 Supportive of the role of impaired reverse cholesterol transport, in a separate study using carotid magnetic resonance imaging assessment to detect HRP, the Chicago Healthy Aging Study found that HDL efflux capacity correlates with large and medium HDL subclasses; however, after multivariable adjustment, neither efflux capacity nor subclasses associate with HRP. 23 In another study of statin-treated patients with diabetes, the triglyceride/HDL-C ratio was significantly associated with HRP features detected by frequency-domain optical coherence tomography. ...
... Our major findings center around NMR-derived HDL particle subclasses. It is possible that other methods to measure HDL subclasses might determine different associations with HRP; however, given that our study is consistent with one that demonstrated similar associations of large HDL particles measured by gel electrophoresis with HRP, 21 we believe this is unlikely. We also note that the associations of HDL subclasses with HRP were attenuated when including HDL-C in our multivariable regression models. ...
Lipoprotein Subclasses Associated With High-Risk Coronary Atherosclerotic Plaque: Insights From the PROMISE Clinical Trial
Article
Full-text available
  • Dec 2022
BACKGROUND More than half of major adverse cardiovascular events (MACE) occur in the absence of obstructive coronary artery disease and are often attributed to the rupture of high‐risk coronary atherosclerotic plaque (HRP). Blood‐based biomarkers that associate with imaging‐defined HRP and predict MACE are lacking. METHODS AND RESULTS Nuclear magnetic resonance–based lipoprotein particle profiling was performed in the biomarker substudy of the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial (N=4019) in participants who had stable symptoms suspicious for coronary artery disease. Principal components analysis was used to reduce the number of correlated lipoproteins into uncorrelated lipoprotein factors. The association of lipoprotein factors and individual lipoproteins of significantly associated factors with core laboratory determined coronary computed tomographic angiography features of HRP was determined using logistic regression models. The association of HRP‐associated lipoproteins with MACE was assessed in the PROMISE trial and validated in an independent coronary angiography biorepository (CATHGEN [Catheterization Genetics]) using Cox proportional hazards models. Lipoprotein factors composed of high‐density lipoprotein (HDL) subclasses were associated with HRP. In these factors, large HDL (odds ratio [OR], 0.70 [95% CI, 0.56–0.85]; P <0.001) and medium HDL (OR, 0.84 [95% CI, 0.72–0.98]; P =0.028) and HDL size (OR, 0.82 [95% CI, 0.69–0.96]; P =0.018) were associated with HRP in multivariable models. Medium HDL was associated with MACE in PROMISE (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), which was validated in the CATHGEN biorepository (HR, 0.91 [95% CI, 0.88–0.94]; P <0.001). CONCLUSIONS Large and medium HDL subclasses and HDL size inversely associate with HRP features, and medium HDL subclasses inversely associate with MACE in PROMISE trial participants. These findings may aid in the risk stratification of individuals with chest pain and provide insight into the pathobiology of HRP. REGISTRATION URL: https://clinicaltrials.gov ; Unique identifier: NCT01174550
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... In contrast, those lipoproteins associated with reverse cholesterol transport are able to clean out excess cholesterol from macrophages in atherosclerotic lesions, thus offering an atheroprotective effect. The lipoprotein particles consist of lipid components, including cholesterol, cholesterylester, phospholipids, and triglycerides, and protein components like Apo A, B, C, and E. The critical mechanism of the atherogenic dyslipidemia paradigm is that the lipoprotein particles contained by Apo B are atherogenic due to the physical binding of Apo B to proteoglycans in the arterial wall while the HDL particles contained in Apo A are atheroprotective through removing cholesterol from macrophages in the arterial wall and preventing LDL oxidation and maladaptive inflammation [27]. Apo A is mainly synthesized by the liver and intestines and secreted into blood circulation. ...
... Apo A is mainly synthesized by the liver and intestines and secreted into blood circulation. In the circulation, Apo A undergoes some remodeling processes facilitated by some enzymes including plasma lipid transfer protein, lecithin-cholesterol acyltransferase, and cholesterol ester transfer protein and finally matures to more lipid-rich and larger HDL particles before performing its atheroprotective function [27]. This theory explains our findings that the epicardial fat volume is negatively correlated with HDL or Apo A but positively correlated with Apo B/ Apo A. TG is positively correlated with Apo B but negatively correlated with HDL, and thus, TG may indirectly affect the epicardial fat and consequently the prevalence of three-vessel coronary lesions through affecting Apo B and HDL. ...
Epicardial fat volume evaluated with multidetector computed tomography and other risk factors for prevalence of three-vessel coronary lesions
Article
Full-text available
  • Dec 2022
Purpose To retrospectively investigate the epicardial fat volume with multidetector computed tomography (MDCT) and other risk factors for the prevalence of three-vessel coronary lesion. Materials and methods MDCT was performed on 424 subjects with or without three-vessel coronary lesion. Blood was tested for triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), apolipoprotein A (ApoA), apolipoprotein B (ApoB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipoprotein a, and fasting blood glucose. Results Among all the subjects, a significant ( P < 0.05) negative linear correlation existed between age and ALT or ALT/AST. The epicardial fat had a significant ( P < 0.05) negative linear correlation with HDL and Apo A but a positive correlation with age and ApoB/ApoA. The epicardial fat volume and the fasting blood glucose were significantly ( P = 0.001) greater in the patients than in the control group, whereas HDL and Apo A were both significantly ( P < 0.0001) smaller in the patients than in the control groups. A significant prediction value ( P < 0.05) existed in age increase, male gender, epicardial fat increase, low HDL, high LDL, and elevated fasting blood glucose. Conclusion Three-vessel coronary lesions are more prevalent in subjects with greater volume of epicardial fat and in male gender.
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... Moreover, HDL dialyzed with calcium inhibited closely by 80% the oxidation of low-density lipoprotein (LDL) [21]. Interestingly, results from the ATLANTA I study, using intravascular ultrasound (IVUS) and coronary tomography observed some HDL subpopulation can be associated to more cholesterol plaque content and less calcified lesions [22]. ...
Vascular Calcification, Insight in Its Pathophysiological Pathways, Genetics and Clinical Aspects
Chapter
Full-text available
  • Oct 2023
The pathophysiology and genetic regulation of this process are both evaluated in this chapter along with the key mechanisms at play. Vascular calcification is highly associated with cardiovascular disease mortality, particularly in high risk patients with diabetes and chronic kidney diseases (CKD). In blood vessels, intimal calcification is associated with atherosclerosis, whereas medial calcification is a non-occlusive process which leads to increased vascular stiffness and reduced vascular compliance. In the valves, calcification of the leaflets can change the mechanical properties of the tissue and result in stenosis. For many decades, vascular calcification has been noted as a consequence of aging. Recent research suggests that arterial calcification is an independent cardiovascular risk factor (CRF) for morbidity and mortality. New studies have pointed out the existence of complex physiopathological mechanisms that flocks inflammation, oxidation, the release of chemical mediators, and genetic factors that promote the osteochondrogenic differentiation of vascular smooth muscle cells (VSMC).
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... Interestingly, results from the ATLANTA I study, analyzing the relationship between lipoproteins and plaque components by computed tomography angiography (CTA) and intravascular ultrasound (IVUS), showed that apoB-containing lipoproteins, as well as HDL-P, were involved [40]. Indeed, apoB particles were associated with a higher proportion of non-calcified plaque and a lower proportion of calcified plaques. ...
Atherosclerosis Calcification: Focus on Lipoproteins
Article
Full-text available
  • Mar 2023
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the vessel wall, leading to the formation of an atheroma and eventually to the development of vascular calcification (VC). Lipoproteins play a central role in the development of atherosclerosis and VC. Both low- and very low-density lipoproteins (LDL and VLDL) and lipoprotein (a) (Lp(a)) stimulate, while high-density lipoproteins (HDL) reduce VC. Apolipoproteins, the protein component of lipoproteins, influence the development of VC in multiple ways. Apolipoprotein AI (apoAI), the main protein component of HDL, has anti-calcific properties, while apoB and apoCIII, the main protein components of LDL and VLDL, respectively, promote VC. The role of lipoproteins in VC is also related to their metabolism and modifications. Oxidized LDL (OxLDL) are more pro-calcific than native LDL. Oxidation also converts HDL from anti- to pro-calcific. Additionally, enzymes such as autotaxin (ATX) and proprotein convertase subtilisin/kexin type 9 (PCSK9), involved in lipoprotein metabolism, have a stimulatory role in VC. In summary, a better understanding of the mechanisms by which lipoproteins and apolipoproteins contribute to VC will be crucial in the development of effective preventive and therapeutic strategies for VC and its associated cardiovascular disease.
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... A significant increase in LDL particle size was observed with Omega-3 compared with Control at week 8 (p = 0.0040). We consider the increase in LDL particle size to be beneficial for patients with dyslipidemia as sdLDL is associated with larger plaque burden and more noncalcified plaque in patients receiving coronary computed tomography angiography and intravascular ultrasound with radiofrequency backscatter [20]. In the sdLDL fraction, a significant decrease was observed with Omega-3 compared with Control at week 8 in the concentration of cholesterol (p = 0.0004) and phospholipid (p = 0.0047); however, no significant decrease in the concentration of TG, free cholesterol and TG/cholesterol ratio was observed. ...
Omega-3 fatty acid ethyl esters improve low-density lipoprotein subclasses without increasing low-density lipoprotein-cholesterol levels: A phase 4, randomized study
Article
  • Nov 2019
  • Atherosclerosis
Background and aims: We aimed to investigate blood lipid and lipoprotein profiles in patients with dyslipidemia receiving hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) after 8 weeks of omega-3 fatty acid ethyl esters (Omega-3) treatment, using high-performance liquid chromatography with highly-sensitive gel filtration columns. Methods: In this phase 4, randomized, open-label study, patients with dyslipidemia receiving statins were randomized 1:1 to Omega-3 treatment (oral Omega-3 2 g twice daily) or Control (no Omega-3). Primary endpoint was change in mean particle size of low-density lipoprotein (LDL) and small dense LDL (cholesterol monitoring) in the specific 20-lipoprotein fraction assay. Secondary endpoints included changes in lipids, apolipoproteins, and lipoprotein concentrations in fasting blood. Changes were compared between treatments using analysis of covariance, adjusted by baseline fasting triglycerides and age. Results: Fifty-three patients were randomized (Omega-3, n = 24; Control, n = 29). The difference in LDL particle size between Omega-3 and Control groups was significant at week 8 (p = 0.0040). Differences in least squares mean change in concentration from baseline to week 8 between Omega-3 and Control groups were significant for total cholesterol (p = 0.0009), LDL-C (p = 0.0442), non-high-density lipoprotein cholesterol (p = 0.0009), and remnant lipoprotein-cholesterol (p = 0.0396). Differences were significant for apolipoproteins AI, AII, B, B-48, B-100, CII, CIII, and CII/III, but not apolipoprotein E. Conclusions: Significant increases in LDL particle sizes and significant decreases in blood lipid, lipoprotein and apolipoprotein concentrations were observed with Omega-3 compared with Control. Omega-3 may improve blood lipid profile and increase LDL particle size, resulting in an anti-atherogenic profile.
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Role of the tripartite motif-containing (TRIM) family of proteins in insulin resistance and related disorders
Article
  • Sep 2023
  • DIABETES OBES METAB
Emerging evidence suggests that the ubiquitin-mediated degradation of insulin-signalling-related proteins may be involved in the development of insulin resistance and its related disorders. Tripartite motif-containing (TRIM) proteins, a superfamily belonging to the E3 ubiquitin ligases, are capable of controlling protein levels and function by ubiquitination, which is essential for the modulation of insulin sensitivity. Recent research has indicated that some of these TRIMs act as key regulatory factors of metabolic disorders such as type 2 diabetes mellitus, obesity, nonalcoholic fatty liver disease, and atherosclerosis. This review provides a comprehensive overview of the latest evidence linking TRIMs to the regulation of insulin resistance and its related disorders, their roles in regulating multiple signalling pathways or cellular processes, such as insulin signalling pathways, peroxisome proliferator-activated receptor signalling pathways, glucose and lipid metabolism, the inflammatory response, and cell cycle control, as well as recent advances in the development of TRIM-targeted drugs.
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Plasma ApoB/AI: An effective indicator for intracranial vascular positive remodeling
Article
  • Mar 2022
  • J NEUROL SCI
Objectives Both vascular positive remodeling and apolipoprotein B/apolipoprotein AI (apoB/AI) are important risk factors for ischemic stroke. However, it is unclear whether apoB/AI level plays a role in vascular positive remodeling. This study aimed to investigate the association between apoB/AI and intracranial vascular positive remodeling. Materials and methods Symptomatic patients with intracranial artery 30–99% stenosis were recruited and underwent high-resolution magnetic resonance (MR) imaging. The levels of apolipoprotein B (apoB), apolipoprotein AI (apoAI) and apoB/AI were tested. Intracranial vascular remodeling index (RI) defined as the wall area ratio between maximal luminal narrowing and reference site was evaluated on MR images. Positive remodeling was defined as RI ≥1.05. The association between apoB/AI level and positive remodeling was respectively determined in anterior and posterior circulation. Results Of 65 recruited patients (mean age: 58.5 ± 10.6 years; 36 males), 25 (38.5%) had positive remodeling, of which 24 (36.9%) were in the posterior circulation group. Patients with positive remodeling had significantly higher apoB (1.0 ± 0.3 g/L vs. 0.8 ± 0.3 g/L, P = 0.003) and apoB/AI (1.0 ± 0.3 vs. 0.8 ± 0.2, P = 0.008) than those without. Univariate logistic regression showed that apoB/AI (OR: 2.302, 95%CI: 1.229–4.321, P = 0.009) was significantly associated with positive remodeling. After adjusted for confounders, the association of apoB/AI (OR: 2.935, 95%CI: 1.061–8.123, P = 0.038) with positive remodeling remained significant. ApoB/AI (OR: 76.110, 95%CI: 1.169–4953.287, P = 0.042) was significantly associated with positive remodeling in posterior circulation but not in anterior circulation. Conclusion ApoB/AI is a potential indicator for intracranial vulnerable atherosclerosis characterized by positive remodeling, especially in posterior circulation.
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Effect of a late afternoon/early evening bout of aerobic exercise on postprandial lipid and lipoprotein particle responses to a high-sugar meal breakfast the following day in postmenopausal women: a randomized cross-over study
Article
  • Sep 2021
High-sugar consumption is related to dyslipidemia. How acute exercise affects postprandial lipid and lipoprotein particle responses to a high-sugar meal (HSM) in postmenopausal women is unclear. We examined the effects of a late afternoon/early evening bout of aerobic exercise on postprandial lipid and lipoprotein particle responses to a HSM breakfast the following day in 22 postmenopausal women. Subjects underwent exercise (EX) and no exercise (NE) conditions in the evening 13–16 h before the HSM breakfast consumption, in a random order. During the EX condition, subjects performed supervised aerobic exercise for 60 min at 75% of age-predicted maximum heart rate. The HSM (75.6% carbohydrate and 33% energy needs) was consumed after a 12-h fast. Serum lipids and lipoproteins were assessed at baseline and postprandially (60, 120, 180 min). Repeated measures analysis showed significantly lower area under the curve (geometric means [95% CI]) for triglycerides (TG) (2.96[2.43, 3.61] vs. 3.24[2.70, 3.88] mmol/L*hr; p = 0.049) and very low density lipoprotein particles (VLDLP) (114.6[88.2, 148.9] vs. 134.3[108.1, 166.9] nmol/L*hr; p = 0.02) during the EX versus NE condition. There were no condition effects for other variables. In conclusion, the EX versus NE condition lowered postprandial AUC for TG and VLDLP following HSM consumption in postmenopausal women. Trial Registration: ClinicalTrials.gov Identifier: NCT02919488
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Associations of HDL metrics with coronary artery calcium score and density among women traversing menopause
Article
Full-text available
  • Jul 2021
  • J LIPID RES
The cardioprotective association of high-density lipoprotein cholesterol (HDL-C) may vary by menopause stage or estradiol level. We tested whether associations of comprehensive HDL metrics [HDL subclasses, phospholipid and triglyceride content and HDL cholesterol efflux capacity (HDL-CEC)] with coronary artery calcium (CAC) score and density vary by menopause stage or estradiol level in women transitioning through menopause. Participants [N=294; mean age(SD): 51.3 (2.9)] had data on HDL metrics and CAC measures at one or two time points during the menopause transition. Generalized estimating equations were used for analyses. Effect modifications by menopause stage or estradiol level were tested in multivariable models. In adjusted models, menopause stage modified the associations of specific HDL metrics with CAC measures. Higher small HDL particles (HDL-P) concentrations (p-interaction=0.008) and smaller HDL size (p-interaction=0.02) were associated with greater odds of CAC presence in late perimenopause than in pre/early perimenopause stage. Women in the highest estradiol tertile, but not the lower tertiles, showed a protective association of small HDL-P with CAC presence (p-interaction=0.007). Lower large HDL-P concentrations (p-interaction=0.03) and smaller HDL size (p-interaction=0.03) were associated with lower CAC density in late perimenopause than in postmenopause stage. Associations of HDL phospholipid and triglyceride content and HDL-CEC with CAC measures did not vary by menopause stage or estradiol level. We concluded that HDL subclasses may impact the likelihood of CAC presence and the stability of coronary plaque differently over the menopause transition. Endogenous estradiol levels may contribute to this observation.
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Effects of Pitavastatin on Lipoprotein Subfractions and Oxidized Low-density Lipoprotein in Patients with Atherosclerosis
Article
  • Oct 2020
It has been demonstrated that pitavastatin can significantly reduce low-density lipoprotein (LDL) cholesterol (LDL-C), but its impact on lipoprotein subfractions and oxidized low-density lipoprotein (oxLDL) has not been determined. The aim of the present study was to investigate the potential effects of pitavastatin on subfractions of LDL and high-density lipoprotein (HDL) as well as oxLDL in untreated patients with coronary atherosclerosis (AS). Thirty-six subjects were enrolled in this study. Of them, 18 patients with AS were administered pitavastatin 2 mg/day for 8 weeks and 18 healthy subjects without therapy served as controls. The plasma lipid profile, lipoprotein subfractions and circulating oxLDL were determined at baseline and 8 weeks respectively. The results showed that pitavastatin treatment indeed not only decreased LDL-C, total cholesterol (TC), triglycerides (TG) and apolipoprotein B (ApoB) levels, and increased HDL cholesterol (HDL-C), but also reduced the cholesterol concentration of all of the LDL subfractions and the percentage of intermediate and small LDL subfractions. Meanwhile, pitavastatin could decrease plasma oxLDL levels. Furthermore, a more close correlation was found between oxLDL and LDL-C as well as LDL subfractions after pitavastatin treatment. We concluded that a moderate dose of pitavastatin therapy not only decreases LDL-C and oxLDL concentrations but also improves LDL subfractions in patients with AS.
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A Prospective Natural-History Study of Coronary Atherosclerosis
Article
Full-text available
  • Jan 2011
  • NEW ENGL J MED
Atherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis. Lesion-related risk factors for such events are poorly understood. In a prospective study, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicated to be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The median follow-up period was 3.4 years. The 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline (mean [±SD] diameter stenosis, 32.3±20.6%). However, on multivariate analysis, nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm(2) or less (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P=0.001) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI, 1.77 to 6.36; P<0.001). In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics, as determined by gray-scale and radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano; ClinicalTrials.gov number, NCT00180466.).
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Wilensky RL, Mohler ER, Rothblat GH, Rader DJ. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis
Article
Full-text available
  • Jan 2011
  • NEW ENGL J MED
High-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden. We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima-media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B-depleted serum from the study participants. The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima-media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P=0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P=0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins. Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.).
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Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis
Article
  • Jul 2011
  • J VASC SURG
We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima–media thickness, 442 patients with angiograph ically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B–depleted serum from the study participants. Results The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima–media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P = 0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P = 0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins. Conclusions Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima–media thickness and the likeli hood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.)
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Coronary Atherosclerosis Imaging by Coronary CT Angiography Current Status, Correlation With Intravascular Interrogation and Meta-Analysis
Article
  • May 2011
Coronary computed tomography angiography (CTA) allows coronary artery visualization and the detection of coronary stenoses. In addition; it has been suggested as a novel, noninvasive modality for coronary atherosclerotic plaque detection, characterization, and quantification. Emerging data show that coronary CTA-based semiquantitative plaque characterization and quantification are sufficiently reproducible for clinical purposes, and fully quantitative approaches may be appropriate for use in clinical trials. Furthermore, several lines of investigation have validated plaque imaging by coronary CTA against other imaging modalities such as intravascular ultrasound/"virtual histology" and optical coherence tomography, and there are emerging data using biochemical modalities such as near-infrared spectroscopy. Finally, clinical validation in patients with acute coronary syndrome and in the outpatient setting has shown incremental value of CTA-based plaque characterization for the prediction of major cardiovascular events. With recent developments in image acquisition and reconstruction technologies, coronary CTA can be performed with relatively low radiation exposure. With further technological innovation and clinical research, coronary CTA may become an important tool in the quest to identify vulnerable plaques and the at-risk patient.
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Prospective Validation of Standardized, 3-Dimensional, Quantitative Coronary Computed Tomographic Plaque Measurements Using Radiofrequency Backscatter Intravascular Ultrasound as Reference Standard in Intermediate Coronary Arterial Lesions
Article
  • Feb 2011
This study sought to determine the accuracy of 3-dimensional, quantitative measurements of coronary plaque by computed tomography angiography (CTA) against intravascular ultrasound with radiofrequency backscatter analysis (IVUS/VH). Quantitative, 3-dimensional coronary CTA plaque measurements have not been validated against IVUS/VH. Sixty patients in a prospective study underwent coronary X-ray angiography, IVUS/VH, and coronary CTA. Plaque geometry and composition was quantified after spatial coregistration on segmental and slice-by-slice bases. Correlation, mean difference, and limits of agreement were determined. There was significant correlation for all pre-specified parameters by segmental and slice-by-slice analyses (r = 0.41 to 0.84; all p < 0.001). On a segmental basis, CTA underestimated minimal lumen diameter by 21% and overestimated diameter stenosis by 39%. Minimal lumen area was overestimated on CTA by 27% but area stenosis was only underestimated by 5%. Mean difference in noncalcified plaque volume and percent and calcified plaque volume and percent were 38%, -22%, 104%, and 64%. On a slice-by-slice basis, lumen, vessel, noncalcified-, and calcified-plaque areas were overestimated on CTA by 22%, 19%, 44%, and 88%. There was significant correlation for percentage of atheroma volume (0.52 vs. 0.54; r = 0.51; p < 0.001). Compositional analysis suggested that high-density noncalcified plaque on CTA best correlated with fibrous tissue and low-density noncalcified plaque correlated with necrotic core plus fibrofatty tissue by IVUS/VH. This is the first validation that standardized, 3-dimensional, quantitative measurements of coronary plaque correlate with IVUS/VH. Mean differences are small, whereas limits of agreement are wide. Low-density noncalcified plaque correlates with necrotic core plus fibrofatty tissue on IVUS/VH.
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Quantitative measurements of coronary arterial stenosis, plaque geometry, and composition are highly reproducible with a standardized coronary arterial computed tomographic approach in high-quality CT datasets
Article
  • Feb 2011
Computed tomographic (CT) coronary angiography provides a noninvasive method for coronary plaque detection and quantification, but data are limited on reproducibility of a quantitative evaluation. Intrarater and interrater reliability of a semiquantitative and highly standardized, fully quantitative approach was evaluated in 480 coronary segments in 30 patients. Quantitative vessel-wall and plaque geometrical parameters (minimal lumen diameter [MLD], minimal lumen area [MLA], percentage of atheroma volume [PAV], and remodeling index [RI]) and compositional parameters (calcified plaque volume [CAP] and % of CAP [%CAP], noncalcified plaque [NCP] and % of NCP [%NCP], high-density NCP volume [HD-NCP] and % of HD-NCP [%HD-NCP] and low-density NCP volume [LD-NCP] and % of LD-NCP [%LD-NCP]) were measured. Semiquantitative agreement was evaluated by weighted κ; quantitative agreement was evaluated by concordance correlation coefficient (CCC) and Bland-Altman analysis. Intraobserver agreement for MLD, MLA, and RI was excellent (CCC: 0.96, 0.96, and 0.84, respectively). Intraobserver agreement for %CAP, %HD-NCP, and %LD-NCP was also excellent (CCC: 0.99, 0.98,and 0.96, respectively). Interobserver agreement for MLD, MLA, PAV and RI was excellent (CCC: 0.98, 0.99, 0.96,and 0.86, respectively). Interobserver agreement for %CAP, % NCP, %HD-NCP, and %LD-NCP was also excellent (CCC: 0.99, 0.99, 0.98,and 0.90, respectively), and mean differences were small. Quantitative analysis showed statistically significant differences in both geometrical and compositional parameters between normal segments and those with plaque. Standardized, quantitative analysis of coronary CTA datasets is reproducible for the measurement of plaque geometrical and compositional parameters and can quantify differences between normal and abnormal segments in high-quality datasets.
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Significance of Serum High-Density Lipoprotein Cholesterol Levels for Diagnosis of Coronary Stenosis as Determined by MDCT in Patients with Suspected Coronary Artery Disease
Article
  • May 2010
  • J Atherosclerosis Thromb
Since we previously reported that lower levels of HDL-C may be most useful for predicting coronary artery disease (CAD) as assessed by multi-detector row computed tomography (MDCT), we sought to confirm, among the levels of LDL-C, HDL-C, non-HDL-C (total cholesterol minus HDL-C) and the ratio of LDL-C to HDL-C (LDL-C/HDL-C), which is most closely related to the presence of CAD. The subjects consisted of 506 consecutive patients with suspected CAD who underwent MDCT with (+) or without (-) statin treatment. The levels of LDL-C in the statin (-) group were similar in categories I, II and III according to the Japan Atherosclerosis Society (JAS) Guidelines 2007, whereas the levels of HDL-C significantly decreased and LDL-C/HDL-C significantly increased as the category number increased. In the statin (-) group, the prevalence of CAD in categories I, II and III was 0, 16 and 33%, respectively (p=0.0018 for trend), in patients with good control of LDL-C levels according to the Guidelines. Multivariate logistic regression analysis was per-formed to examine the association between the presence of CAD and 11 possible factors. Age and HDL-C in the statin (-) group, and HDL-C in the statin (+) group were identified as significant independent variables that correlated with the presence of CAD. Receiver-operating characteristic curve analysis in the statin (-) and statin (+) groups showed a higher area under the curve for HDL-C than for LDL-C, non-HDL-C or LDL-C/HDL-C. In particular, the cut-off levels of HDL-C with the greatest sensitivity and specificity for the diagnosis of CAD in the statin (+) group were 55 mg/dL (sensitivity 0.816, specificity 0.510). HDL-C levels are most closely associated with the presence of CAD. In particular, we need to perform coronary CT for suspected CAD patients with lower HDL-C levels under statin treatment.
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Low-Density Lipoprotein and Noncalcified Coronary Plaque Composition in Patients With Newly Diagnosed Coronary Artery Disease on Computed Tomographic Angiography
Article
  • Mar 2010
We sought to determine significant relations between atherogenic lipoproteins and the contribution of calcified plaque (CP), mixed plaque (MP), and noncalcified plaque (NCP) to the total plaque (TP) burden in patients without previous coronary artery disease. From 823 adult patients without previously established coronary artery disease (52% receiving statin therapy, 34% asymptomatic) but with visible coronary plaque on coronary computed tomographic angiography, we obtained segmental CP, MP, NCP, and TP counts from contrast-enhanced, electrocardiographic-gated computed tomography. Multivariate linear regression analysis was used to determine the associations of clinical factors and lipoprotein levels to CP, MP, and NCP counts and CP/TP, MP/TP, and NCP/TP count ratios. Age, male gender, diabetes, smoking, and statin therapy were significantly associated with the CP count (p <0.001, p <0.001, p = 0.049, p = 0.016, and p = 0.003, respectively). Low-density lipoprotein (LDL) cholesterol was significantly associated with MP and NCP counts (all p values </=0.002). LDL cholesterol was also the only variable to demonstrate significant concurrent relations with CP/TP, MP/TP, and NCP/TP ratios, including an inverse association with CP/TP (p = 0.008) and a positive association with MP/TP (p = 0.032). Analyses using non-high-density lipoprotein cholesterol in place of LDL cholesterol yielded similar results. In conclusion, among the traditional clinical factors used to estimate cardiovascular event risk, LDL cholesterol is associated with an increased MP and NCP burden and is the sole variable that independently predicted relative predominance of CP, MP, and NCP, suggesting a potentially important role for lipoprotein levels in modulating the type of detectable coronary arterial plaque.
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Feasibility of Noninvasive Assessment of Thin-Cap Fibroatheroma by Multidetector Computed Tomography
Article
  • Dec 2009
The purpose of this study was to investigate whether multidetector computed tomography (MDCT) can noninvasively help assess thin-cap fibroatheroma (TCFA). Plaque rupture and thrombus formation play key roles in the onset of acute coronary syndrome. TCFA is recognized as a precursor lesion for plaque rupture, and MDCT angiography can potentially help identify plaques prone to rupture. We enrolled 105 patients with coronary artery disease (acute coronary syndromes, n = 31; stable angina pectoris, n = 74). Culprit lesions were assessed by both MDCT and optical coherence tomography (OCT). Patients were divided into a TCFA and a non-TCFA group according to OCT findings; clinical and MDCT observations were compared for 2 groups. There were no differences in patients' characteristics between the 2 groups. OCT revealed 25 TCFAs at the culprit site in 105 patients. Acute coronary syndrome was more frequent in the TCFA group than in the non-TCFA group (52% vs. 23%, p = 0.01). High-sensitive C-reactive protein was higher in the TCFA group (0.32 +/- 0.32 mg/dl vs. 0.17 +/- 0.16 mg/dl, p < 0.001). Positive remodeling identified by MDCT was observed more frequently in the TCFA group than in the non-TCFA group (76% vs. 31%, p < 0.001). Computed tomography attenuation value of the culprit plaque in the TCFA group was lower than that in the non-TCFA group (35.1 +/- 32.3 HU vs. 62.0 +/- 33.6 HU, p < 0.001). The frequency of ring-like enhancement in the TCFA group was higher than in the non-TCFA group (44% vs. 4%, p < 0.0001). The sensitivity, specificity, positive predictive value, and negative predictive value of ring-like enhancement for detecting TCFA are 44%, 96%, 79%, and 85%, respectively. By stepwise regression, the ring-like enhancement, high-sensitive C-reactive protein, and diagnosis of acute events were associated with the presence of TCFA at the culprit site. MDCT can identify differences in plaque morphologies between TCFA and non-TCFA. From our results, MDCT may provide for the noninvasive assessment of vulnerable plaque.
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