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.
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.
Adiponectin; High-molecular-weight adiponectin; Coronary artery plaque; Coronary low-attenuation plaque
Adiponectin has insulin-sensitizing and anti-atherosclerotic effects, partly mediated through its action on monocytes. We aimed to determine adiponectin levels and expression of its receptors (AdipoR1 and AdipoR2) in peripheral monocytes from overweight and obese patients with coronary artery disease (CAD).
Fifty-five overweight/obese patients, suspected for CAD, underwent coronary angiography: 31 were classified as CAD patients (stenosis ≥ 50% in at least one main vessel) and 24 as nonCAD. Quantitative RT-PCR and flow cytometry were used for determining mRNA and protein surface expression of adiponectin receptors in peripheral monocytes. A high sensitivity multiplex assay (xMAP technology) was used for the determination of plasma adiponectin and interleukin-10 (IL-10) secreted levels.
Plasma adiponectin levels were decreased in CAD compared to nonCAD patients (10.9 ± 3.1 vs. 13.8 ± 5.8 μg/ml respectively, p = 0.033). In multivariable analysis, Matsuda index was the sole independent determinant of adiponectin levels. AdipoR1 and AdipoR2 protein levels were decreased in monocytes from CAD compared to nonCAD patients (59.5 ± 24.9 vs. 80 ± 46 and 70.7 ± 39 vs. 95.6 ± 47.8 Mean Fluorescence Intensity Arbitrary Units respectively, p < 0.05). No significant differences were observed concerning the mRNA levels of the adiponectin receptors between CAD and nonCAD patients. AdipoR2 protein levels were positively correlated with plasma adiponectin and Matsuda index (r = 0.36 and 0.31 respectively, p < 0.05 for both). Furthermore, basal as well as adiponectin-induced IL-10 release was reduced in monocyte-derived macrophages from CAD compared to nonCAD subjects.
Overweight patients with CAD compared to those without CAD, had decreased plasma adiponectin levels, as well as decreased surface expression of adiponectin receptors in peripheral monocytes. This fact together with the reduced adiponectin-induced IL-10 secretion from CAD macrophages could explain to a certain extent, an impaired atheroprotective action of adiponectin.
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.
Biomarkers; Atherosclerosis; Cardiac CT; Imaging; Coronary artery disease
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.
Computed tomography coronary angiography; Coronary artery plaque; Plaque characterization; Contrast material; Lumen enhancement
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.
atherosclerosis; computed tomography; coronary artery disease; risk factors; progression
Adiponectin is an adipose tissue secreted protein known for its insulin sensitising and anti-atherogenic actions. To this date two adiponectin receptors have been discovered, adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2). The aim of this study was to investigate the association of ADIPOR2 gene variations with coronary artery disease (CAD).
Eight common single nucleotide polymorphisms (SNPs) spanning the entire ADIPOR2 locus were chosen to perform association studies with anthropometric and metabolic parameters in a Greek population. They were classified as either CAD (stenosis >50% in at least one main vessel) or non-CAD individuals in accordance with coronary angiography data.
Genotyping was performed using a microsphere-based suspension array and the Allele Specific Primer Extension (ASPE) method. Expression of ADIPOR2 protein and mRNA in circulating CD14+ monocytes were determined using flow cytometry and real time Polymerase Chain Reaction assays respectively.
There was a significant difference in the distribution of genotypes of polymorphism rs767870 of ADIPOR2 between CAD and non-CAD individuals (p = 0.017). Furthermore, heterozygotes of the rs767870 polymorphism had significantly lower Flow Mediated Dilatation (FMD) values, higher values of Intima-Media Thickness (IMT) and increased ADIPOR2 protein levels in peripheral monocytes, compared to homozygotes of the minor allele after adjustment for age, sex, waist to hip ratio and HOMA.
Our findings suggest that variants of ADIPOR2 could be a determinant for atherosclerosis independent of insulin resistance status, possibly by affecting ADIPOR2 protein levels.
Disorders of endocrine substances in epicardial adipose tissue are known causes of coronary artery disease (CAD). Adiponectin is associated with cardiovascular disease. However, expression of adiponectin in epicardial adipose tissue and its function in CAD pathogenesis is unclear. This study investigates adiponectin expression in epicardial adipose tissue in CAD patients.
Vessels or adipose tissue samples collected from CAD patients and non-CAD controls were examined after immunochemical staining. Adiponectin, cytokines of interleukin-6 (IL-6) and necrosis factor-α (TNF-α) and toll-like receptor 4 (TLR4) expression level in adipose tissue were measured using real-time quantitative RT-PCR. Adiponectin concentrations in peripheral and coronary sinus vein plasma were measured with enzyme-linked immunosorbent assay. Peripheral vein plasma biochemistries were performed with routine laboratory techniques. Monocytes were collected from blood using lymphocyte separation medium. Expression level of cytokines and transcription factor NF-κB were measured to learn the effect of adiponectin on stearic acid-stimulated monocytes. Percentage of TLR4 positive monocytes was analyzed using flow cytometry.
Histological examination revealed increased macrophage infiltration into epicardial adipose tissue of CAD patients. Decreased adiponectin displayed by real-time quantitative RT-PCR was associated with enhanced cytokines of IL-6 and TNF-α or TLR4 expression level in epicardial adipose tissue, suggesting decreased circulating adiponectin may be useful as a more sensitive predictor for coronary atherosclerosis than routine laboratory examinations. Adiponectin suppressed secretion of IL-6 and TNF-α in stimulated monocytes and TLR4 was expressed on cell surfaces.
Endocrine disorders in epicardial adipose tissue are strongly linked to CAD, and adiponectin has a protective effect by inhibiting macrophage-mediated inflammation.
Adiponectin is a circulating hormone that is produced exclusively by adipocytes and has anti-inflammatory and anti-atherogenic properties. The hypothesis that there are differences in adiponectin levels between stable and unstable coronary-artery disease patients remains controversial. Furthermore, the potential relationships between the plasma adiponectin level and the inflammatory and non-inflammatory markers (oxidized low density lipoprotein and nitric oxide) in patients with stable and unstable coronary-artery disease relative to normal subjects have not been assessed.
To assess whether plasma adiponectin levels differ among patients with stable and unstable coronary-artery disease and among control subjects, and to correlate plasma adiponectin level with inflammatory and clinical risk factors (such as oxidized-LDL and nitric oxide) in these patients.
This study included 50 control subjects, 50 stable angina patients and 50 unstable angina patients with angiographically documented coronary-artery disease. Plasma adiponectin and oxidized-LDL levels were determined using an enzyme immunoassay. Plasma nitric oxide, high sensitivity C-reactive protein and lipid profile levels were also measured.
Plasma adiponectin levels were lower in the unstable angina patients (4.9±1.30 µg/mL) than in the stable angina patients (6.34±1.0 µg/mL) or in the controls (9.25±1.8 µg/mL); these levels were also significantly lower in stable angina patients versus controls (p<0.001). Plasma adiponectin levels were negatively correlated with oxidized-LDL, high sensitivity C-reactive protein, lipid profile and other clinical risk factors but positively correlated with nitric oxide.
Plasma adiponectin levels were found to be lower in both stable and unstable angina patients relative to control subjects, and the correlation between plasma adiponectin and cardiovascular markers is weakened in these patients.
Adiponectin; Nitric oxide; Ox-LDL; Stable; Unstable
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.
Vitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE−/− model of atherosclerosis.
A total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE−/− mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K1 (VK1, 1.5 mg/g) or vitamin K1 and warfarin (VK1&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.
VKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE−/− mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle.
Objective: To investigate whether concentrations of plasma adiponectin constitute a significant coronary risk factor, with particular focus on the relation between plasma concentrations of adiponectin and the development of acute coronary syndrome (ACS).
Subjects and methods: Plasma concentrations of adiponectin were measured in 123 patients with coronary artery disease (CAD) and in 17 control participants. Patients were divided into three groups according to condition type: acute myocardial infarction (AMI) group (n = 59), unstable angina pectoris (UAP) group (n = 28), and stable angina pectoris (SAP) group (n = 36).
Results: Plasma concentrations of adiponectin correlated negatively with body mass index (r = −0.18, p < 0.05), serum triglyceride (r = −0.25, p < 0.01), and fasting glucose concentrations (r = −0.21, p < 0.05), but correlated positively with age (r = 0.26, p < 0.01), high density lipoprotein cholesterol concentrations (r = 0.35, p < 0.01), and low density lipoprotein particle size (r = 0.37, p < 0.01). Plasma concentrations of adiponectin in patients with ACS, in both the AMI and UAP groups, were significantly lower than those in patients with SAP and in the control group (ACS, 6.5 (3.0) μg/ml; SAP, 11.3 (5.9) μg/ml; control 12.8 (4.3) μg/ml; p < 0.01). Additionally, plasma concentrations of adiponectin in patients with CAD (7.9 (4.6) μg/ml, p < 0.01) were significantly lower than in the control group. There were, however, no significant differences between patients with SAP and the control group (p = 0.36). Multiple logistic regression analysis showed that smoking, fasting glucose concentration, and low log adiponectin concentration correlated independently with the development of an ACS.
Conclusions: The findings suggest that measurement of plasma concentrations of adiponectin may be of use for assessing the risk of CAD and may be related to the development of ACS.
adiponectin; LDL particle size; acute coronary syndrome; coronary artery disease; coronary risk factor
Background and Objectives
Non-invasive detection and characterization of plaque composition may constitute an important step in risk stratification and monitoring of the progression of coronary atherosclerosis. Multislice computed tomography (MSCT) allows for accurate, non-invasive detection and characterization of atherosclerotic plaques, as well as determination of coronary artery stenosis. The aim of this study was to determine the usefulness of MSCT for characterizing non-calcified coronary plaques previously classified by intravascular ultrasound (IVUS).
Subjects and Methods
Seventy-one plaques were evaluated in 42 patients undergoing MSCT and IVUS. Coronary plaques were classified as hypoechoic or hyperechoic based on IVUS echogenicity. On MSCT, CT attenuation was measured using circular regions of interest (ROI) and represented as Hounsfield units (HU).
MSCT attenuation in hypoechoic plaques was significantly lower than it was in hyperechoic plaques (52.9±24.6 HU vs. 98.6±34.9 HU, respectively, p<0.001). When comparing CT attenuation between hypoechoic and hyperechoic plaques, 60.2 HU was the cut-off value for differentiating between the two, with a 90.7% sensitivity and a 78.6% specificity.
MSCT might be a useful tool for non-invasively evaluating the characteristics of coronary artery plaques.
Atherosclerosis; Coronary arteries; X-ray computed tomography
AIM: To investigate whether nonalcoholic fatty liver disease (NAFLD) affects coronary artery disease (CAD) and identify candidate mediators.
METHODS: Patients who underwent coronary angiography were consecutively recruited. The patients were classified into four groups by coronary artery stenosis: A, insignificant; B, one-vessel disease; C, two-vessel disease; and D, three-vessel disease. Abdominal ultrasonography was performed to determine the presence of a fatty liver and categorize by grade: 0, no evidence; 1, mild; 2, moderate; and 3, severe. We measured not only known CAD risk factors, but also serum insulin, HOMA-index, adiponectin, interleukin-6, tumor necrosis factor-α and high-sensitivity C-reactive protein levels.
RESULTS: Of the 134 patients who met the inclusion criteria, 82 (61.2%) had ultrasonographically diagnosed NAFLD. Among the 46 patients with CAD, 37 (80.4%) had evidence of a fatty liver. The two groups (A vs B-D) were significantly different in terms of age, total cholesterol, triglycerides, low-density lipoprotein levels and fatty liver. Coronary artery stenosis was strongly associated with fatty liver in a grade-dependent manner (P = 0.025). In binary logistic regression, NAFLD was a significant independent predictor of CAD (P = 0.03, OR = 1.685; 95%CI: 1.051-2.702). Among the candidate mediators, the serum adiponectin level showed a trend toward lowering based on CAD progression (P = 0.071).
CONCLUSION: NAFLD is an independent risk factor for CAD in a grade-dependent manner. Moreover, adiponectin might be related to the pathogenesis of NAFLD.
Nonalcoholic fatty liver disease; Coronary artery disease; Coronary angiography; Adiponectin; Insulin resistance
Leptin and adiponectin are two adipose tissue hormones and their association with the incidence of cardiovascular diseases is under evaluation. The aim of this study was to determine the relationship of leptin and adiponectin with coronary artery diseases.
One hundred and seventy patients with angina pectoris and indications of coronary angiography underwent angiography. Serum levels of blood lipids, leptin, and adiponectin were measured. The gathered data was evaluated using SPSS15 software, by multivariate variance analysis.
Analysis of the data demonstrated that 45.1% of the patients had positive angiographic findings. The serum levels of leptin and adiponectin were significantly lower than the minimum levels specified by the kit. However, the two groups, i.e., patients with positive angiographic findings and those with negative findings were not significantly different according to the serum levels of the hormones. Moreover, no significant correlation between the serum levels of the hormones and serum lipids was observed.
Various studies have demonstrated that high serum level of leptin and the incidence of coronary artery diseases are correlated. On the other hand, they have reported that adiponectin has cardioprotective role. Confirmation of these findings requires more detailed studies.
Leptin; Adiponectin; Coronary artery disease
It is still unknown whether increased cardiac adiposity is related to the risk factors of coronary artery disease (CAD). We measured epicaridal adopose tissue (EAT) and mediastinal adipose tissue (MAT) using echocardiography and examined their correlations with CAD and serum adiponectin.
One hundred fifty three patients who underwent elective coronary angiography for chest pain were measured cardiac adiposity by transthoracic echocardiography. The correlations of cardiac adipose tissue with the presence and severity of CAD and the serum adiponectin level were examined.
EAT was thicker in patients with CAD (1.8±1.4 vs. 3.8±1.9 mm, p<0.001), but MAT was not different according to the presence of CAD (2.9±2.8 vs. 3.5±2.5 mm, p=0.121). EAT showed a significant positive correlation with age (r=0.225, p=0.005), homocystein (r=0.289, p=0.001), fasting glucose (r=0.167, p=0.042), and fibrinogen (r=0.218, p=0.009), and a significant negative correlation with serum adiponectin (r=-0.194, p=0.016). EAT thickness (OR 11.53, 95% CI; 3.61-36.84, p<0.001) and low serum adiponectin (OR 2.88, 95% CI; 1.02-8.15, p=0.046) were independent predictors of obstructive CAD. However, MAT thickness was not associated with CAD.
EAT was associated with the severity and risk factors of CAD and correlated with serum adiponectin level. In contrast with EAT, MAT was not associated with CAD and adiponectin.
Epicardium; Adiponectin; Coronary artery disease; Echocardiography
Coronary artery disease has an important impact on the morbidity and mortality statistics and health economics worldwide. Diagnosis of coronary artery disease is important in risk stratification and guides further management. Invasive coronary angiography is the traditional method of imaging the coronary arteries and remains the gold standard. It detects luminal stenosis but provides little information about the vessel wall or plaques. Besides, not all anatomical lesions are functionally significant. This has lent itself to a wide variety of imaging techniques to identify and assess a flow-limiting stenosis. The approach to diagnosis of coronary artery disease is broadly based on anatomical and functional imaging. Coronary CT and MRI of coronary arteries provide an anatomical assessment of coronary stenosis. Coronary calcium score and coronary CT assess subclinical atherosclerosis by assessing the atherosclerotic plaque burden. The haemodynamic significance of a coronary artery stenosis can be assessed by stress radioisotope studies, stress echocardiography and stress MRI. The more recent literature also focuses on plaque assessment and identification of plaques that are likely to give rise to an acute coronary syndrome. There is an explosion of literature on the merits and limitations of the different imaging modalities. This review article will provide an overview of all the imaging modalities in the diagnosis of coronary artery disease.
New tomographic cardiovascular imaging tests, such as intravascular ultrasonography (IVUS), coronary computed tomography (CT) angiography and magnetic resonance imaging (MRI), can be used to assess atherosclerotic plaques for the characterization and early staging of coronary artery disease (CAD). Although IVUS images have very high resolution capable of revealing very early preclinical CAD, it is an invasive technique used clinically only in conjunction with a coronary intervention. Multiple-slice coronary CT angiography, which is noninvasive, shows promise as a diagnostic method for CAD. New 64-slice cardiac CT technology has high accuracy for the detection of lesions obstructing more than 50% of the lumen, with sensitivity, specificity, and positive and negative predictive values all better than 90% in patients without known CAD. Cardiac MRI is also improving accuracy in coronary plaque detection and offers a better opportunity for plaque characterization. With further advances in tomographic imaging of coronary atheromas, the goal will be to detect plaques earlier in the development of CAD and to characterize the plaques most likely to generate a clinical event.
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.
Aortic valve calcification; coronary artery disease; multi-detector computed tomography; calcified plaque; non-calcified plaque; mixed plaque
Matrix metalloproteinases (MMPs) and Tissue Inhibitor of Matrix Metalloproteinases (TIMPs) may be associated with atherogenesis and plaque rupture. We evaluated the relationship between MMP-1, MMP-9, TIMP-1 and IL-6 levels and risk factors, presentation, extent and severity of atherosclerotic coronary artery disease (CAD).
Consecutive patients who underwent coronary angiography were randomly included. The serum concentrations of MMP-1, MMP-9, TIMP-1 and IL-6 were analyzed with ELISA method in 134 patients. Participants were divided into 5 groups; stable angina pectoris (SAP; n= 34), unstable angina pectoris (USAP; n=29), non-ST elevation myocardial infarction (NSTEMI; n=16), acute ST elevation myocardial infarction (STEMI; n=25) and controls (n=30). Coronary angiographic Gensini score was calculated.
MMP-1 levels were higher in STEMI and NSTEMI groups compared with USAP, SAP and control groups (STEMI vs USAP p=0.005; STEMI vs SAP p=0.001; STEMI vs control p<0.001; NSTEMI vs USAP p=0.02; NSTEMI vs SAP p=0.027; NSTEMI vs control p<0.001). In STEMI group, MMP-9 levels were higher than USAP and control groups (p=0.002; p<0,001). TIMP-1 levels were not significantly different within all 5 groups. MMP-1 levels were found to be elevated in diabetic patients (p=0.020); whereas MMP-9 levels were higher in smokers (p=0.043). Higher MMP-1, MMP-9 and IL-6 levels were correlated with severe Left Anterior Descending artery (LAD) stenosis and higher angiographic Gensini Score (for severe LAD stenosis; r = 0.671, 0.363, 0.509 p<0.001; for Gensini score; r = 0.717, 0.371, 0.578 p<0.001).
Serum levels of MMP-1, MMP-9, and IL-6 are elevated in patients with CAD; more so in acute coronary syndromes. MMP-1, MMP-9 and IL-6 are associated with more extensive and severe CAD (as represented by Gensini score).
Matrix metalloproteinase; Interleukin-6; coronary artery disease; Gensini score.
Objectives. We hypothesized that adiponectin gene SNP+45 (rs2241766) and SNP+276 (rs1501299) would be associated with atherosclerotic peripheral arterial disease (PAD). Furthermore, the association between circulating adiponectin levels, fetuin-A, and tumoral necrosis factor-alpha (TNF-α) in patients with atherosclerotic peripheral arterial disease was investigated. Method. Several blood parameters (such as adiponectin, fetuin-A, and TNF-α) were measured in 346 patients, 226 with atherosclerotic peripheral arterial disease (PAD) and 120 without symptomatic PAD (non-PAD). Two common SNPs of the ADIPOQ gene represented by +45T/G 2 and +276G/T were also investigated. Results. Adiponectin concentrations showed lower circulating levels in the PAD patients compared to non-PAD patients (P < 0.001). Decreasing adiponectin concentration was associated with increasing serum levels of fetuin-A in the PAD patients. None of the investigated adiponectin SNPs proved to be associated with the subjects' susceptibility to PAD (P > 0.05). Conclusion. The results of our study demonstrated that neither adiponectin SNP+45 nor SNP+276 is associated with the risk of PAD.
Reduced circulating adiponectin levels contribute to the etiology of insulin-resistance. Adiponectin circulates in three different isoforms: high (HMW), medium (MMW), and low (LMW) molecular weight. The genetics of adiponectin isoforms is mostly unknown. Our aim was to investigate whether and to which extent circulating adiponectin isoforms are heritable and whether they share common genetic backgrounds with insulin resistance-related traits.
In a family based sample of 640 non diabetic White Caucasians from Italy, serum adiponectin isoforms concentrations were measured by ELISA. Three SNPs in the ADIPOQ gene previously reported to affect total adiponectin levels (rs17300539, rs1501299 and rs677395) were genotyped. The heritability of adiponectin isoform levels was assessed by variance component analysis. A linear mixed effects model was used to test association between SNPs and adiponectin isoforms. Bivariate analyses were conducted to study genetic correlations between adiponectin isoforms levels and other insulin resistance-related traits.
All isoforms were highly heritable (h2=0.60−0.80, p=1×10−13–1×10−23). SNPs rs17300539, rs1501299 and rs6773957 explained a significant proportion of HMW variance (2–9%, p=1×10−3–1×10−5). In a multiple-SNP model, only rs17300539 and rs1501299 remained associated with HMW adiponectin (p=3×10−4 and 2.0×10−2). Significant genetic correlations (p=1×10−2–1×10−5) were observed between HMW adiponectin and fasting insulin, HOMAIR, HDL-cholesterol and the metabolic syndrome score. Only rs1501299 partly accounted for these genetic correlations.
Circulating levels of adiponectin isoforms are highly heritable. The genetic control of HMW adiponectin is shared in part with insulin resistance-related traits and involves, but is not limited to the ADIPOQ locus.
ADIPOQ gene; Adiponectin isoforms; insulin resistance
Cardiovascular disease is the leading cause of death worldwide, with high medical costs and rates of disability. It is therefore important to evaluate the use of cardiovascular biomarkers in the early diagnosis of coronary artery disease (CAD). We have screened a variety of recently identified bioactive peptides candidates in anticipation that they would allow detection of atherosclerotic CAD. Especially, we have focused on novel anti-atherogenic peptides as indicators and negative risk factors for CAD. In vitro, in vivo and clinical studies indicated that human adiponectin, heregulin-β1, glucagon-like peptide-1 (GLP-1), and salusin-α, peptides of 244, 71, 30, and 28 amino acids, respectively, attenuate the development and progression of atherosclerotic lesions by suppressing macrophage foam cell formation via down-regulation of acyl-coenzyme A: cholesterol acyltransferase-1. Circulating levels of these peptides in the blood are significantly decreased in patients with CAD compared to patients without CAD. Receiver operating characteristic analyses showed that salusin-α is a more useful biomarker, with better sensitivity and specificity, compared with the others for detecting CAD. Therefore, salusin-α, heregulin-β1, adiponectin, and/or GLP-1, alone or in various combinations, may be useful as biomarkers for atherosclerotic CAD.
acyl-coenzyme A: cholesterol acyltransferase-1; adiponectin; atherosclerosis; biomarker; coronary artery disease; glucagon-like peptide-1; heregulin-β1; macrophage, salusin-α
USF1 regulates the transcription of more than 40 cardiovascular related genes and is well established as a gene associated with familial combined hyperlipidemia, a condition increasing the risk for coronary heart disease. No detailed data, however, exists on the impact of this gene to the critical outcome at the tissue level: different types of atherosclerotic lesions.
Methods and Results
We analyzed the USF1 in 2 autopsy series of altogether 700 middle-aged men (the Helsinki Sudden Death Study) with quantitative morphometric measurements of coronary atherosclerosis. SNP rs2516839, tagging common USF1 haplotypes, associated with the presence of several types of atherosclerotic lesions, particularly with the proportion of advanced atherosclerotic plaques (P=0.02) and area of calcified lesions (P<0.001) of the coronary arteries. Importantly, carriers of risk alleles of rs2516839 also showed a 2-fold risk for sudden cardiac death (genotype TT versus CC; OR 2.10, 95% CI 1.17 to 3.75, P=0.04). The risk effect of rs2516839 was present also in aorta samples of the men.
Our findings in this unique study sample suggest that USF1 contributes to atherosclerosis, the pathological arterial wall phenotype resulting in coronary heart disease and in its most dramatic consequence—sudden cardiac death.
atherosclerosis; coronary; genes; genetics; death; sudden
We explored whether the presence of 3 known features of plaque vulnerability on coronary CT angiography (CCTA) – low attenuation plaque content (LAP), positive remodeling (PR), and spotty calcification (SC) – identifies plaques associated with greater inducible myocardial hypoperfusion measured by myocardial perfusion imaging (MPI).
We analyzed 49 patients free of cardiac disease who underwent CCTA and MPI within a 6-month period and were found on CCTA to have focal 70–99% stenosis from predominantly non-calcified plaque in the proximal or mid segment of 1 major coronary artery. Presence of LAP (≤30 Hounsfield Units), PR (outer wall diameter exceeds proximal reference by ≥5%), and SC (≤3mm long and occupies ≤90° of cross-sectional artery circumference) were determined. On MPI, reversible hypoperfusion in the myocardial territory corresponding to the diseased artery was quantified both as percentage of total myocardium (RevTPDART) by an automatic algorithm and as summed difference score (SDSART) by two experienced readers. RevTPDART≥3% and SDSART≥3 defined significant inducible hypoperfusion in the territory of the diseased artery.
Plaques in patients with RevTPDART≥3% more frequently exhibited LAP (70% vs. 14%, p<0.001) and PR (70% vs. 24%, p=0.001) but not SC (55% vs. 34%, p=0.154). RevTPDART increased from 1.3±1.2% in arteries with LAP−/PR− plaques to 3.2±4.3% with LAP+/PR− or LAP−/PR+ plaques to 8.3±2.4% with LAP+/PR+ plaques (p<0.001); SDSART showed a similar increase: 0.3±0.7 to 2.3±2.8 to 6.0±3.8 (p<0.001). Using the same LAP/PR categorization, there was a marked increase in the frequency of significant hypoperfusion as determined by both RevTPDART≥3% (1/19 to 10/21 to 9/9, p<0.001) and SDSART≥3 (1/19 to 8/21 to 8/9, p<0.001). LAP and PR, but not SC, were strong predictors of RevTPDART and SDSART in regression models adjusting for potential confounders.
Presence of low attenuation plaque and positive remodeling in severely stenotic plaques on CCTA is strongly predictive of myocardial hypoperfusion and may be useful in assessing the hemodynamic significance of such lesions.
coronary artery stenosis; low attenuation plaque; positive remodeling; spotty calcification; myocardial perfusion