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The prognostic impact of nonobstructive coronary artery disease (CAD), as opposed to normal coronary arteries, on long-term outcomes of patients with myocardial infarction with no obstructive coronary arteries (MINOCA) is unclear. We aimed to address the association between nonobstructive-CAD and major adverse events (MAE) following MINOCA. We conducted a retrospective cohort study of consecutive MINOCA patients admitted to a large referral medical center between 2005 and 2018. Patients were classified according to coronary angiography as having either normal-coronaries or nonobstructive-CAD. The primary outcome was MAE, defined as the composite of all-cause mortality and recurrent acute coronary syndrome (ACS). Of the 1544 MINOCA patients, 651 (42%) had normal coronaries, and 893 (58%) had CAD. The mean age was 61.2 ± 12.6 years, and 710 (46%) were females. Nonobstructive-CAD patients were older and less likely to be females, with higher rates of diabetes, hypertension, dyslipidemia, atrial fibrillation, and chronic renal-failure (p < 0.05). At a median follow-up of 7 years, MAE occurred in 203 (23%) patients and 67 (10%) patients in the nonobstructive-CAD and normal-coronaries groups, respectively (p < 0.01). In multivariable models, nonobstructive -CAD was significantly associated with long-term MAE [adjusted-hazard-ratio (aHR):1.67, 95% confidence-interval (95%CI):1.25–2.23; p < 0.001]. Other factors associated with a higher MAE-risk were older-age (aHR:1.05,95%CI:1.03–1.06; p < 0.001) and left ventricular ejection-fraction<40% (aHR:3.04,95%CI:2.03–4.57; p < 0.001), while female-sex (aHR:0.72, 95%CI: 0.56–0.94; p= 0.014) and sinus rhythm at presentation (aHR:0.66, 95%CI: 0.44–0.98; p= 0.041) were associated with lower MAE-risk. In MINOCA, nonobstructive-CAD is independently associated with a higher MAE-risk than normal-coronaries. This finding may promote risk-stratification of patients with nonobstructive-CAD-MINOCA who require tighter medical follow-up and treatment optimization. [Display omitted] • Myocardial infarction with no obstructive coronary arteries (MINOCA) carries a considerable long-term risk for death and recurrent acute coronary syndrome (re-ACS). • In MINOCA, the presence of nonobstructive CAD carries higher risk for death or re-ACS. • Reduced LVEF and older age are associated with increased risk for death and re-ACS. • Sinus rhythm and female sex are associated with lower risk for death and re-ACS. [ABSTRACT FROM AUTHOR]

Skin autofluorescence (AF), a measure of tissue accumulation of advanced glycation end products (AGEs), has been associated with diabetes and cardiovascular disease. However, the association of skin AF with subclinical coronary atherosclerosis in the general population is largely unknown. Our study aimed to examine the associations between skin AF and subclinical atherosclerosis in coronary and carotid arteries in a middle-aged population. Skin AF and subclinical atherosclerosis were measured in 4416 subjects (aged 50–64 years) from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Skin AF was measured non-invasively using an autofluorescence reader. Subclinical atherosclerosis was assessed by ultrasonography of carotid arteries for evaluation of carotid plaques and computed tomography for the evaluation of the coronary artery calcium score (CACS). A total of 615 (13.9%) individuals had CACS >100 and 1340 (30.3%) subjects had bilateral carotid plaques (median total plaque area: 8 mm2). After controlling for confounding factors, there were significant associations between skin AF (per 1 standard deviation (SD) increase) and CACS >100: odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.06–1.29, p = 0.001. Total carotid plaque area and occurrence of bilateral carotid plaques (OR per 1 SD increase: 1.10, 95%CI: 1.01–1.19, p = 0.02) were similarly associated with skin AF after multivariable adjustments. Elevated skin AF was significantly associated with subclinical atherosclerosis in coronary and carotid arteries independently of conventional risk factors. Skin AF, a measure of accumulation of AGEs, could be a marker for the identification of middle-aged subjects with elevated atherosclerotic risk. [Display omitted] • Elevated skin autofluorescence was independently associated with coronary calcification in this population-based study. • Skin autofluorescence associated with occurrence of carotid plaque and carotid total plaque areas. • Skin autofluorescence could be a useful tool for identifying subjects with increased subclinical atherosclerotic burden in coronary and carotid arteries. [ABSTRACT FROM AUTHOR]

Coronary artery calcium (CAC) may encourage patients to adhere to primary prevention recommendations. This study sought to evaluate the benefit of a CAC-guided risk-management protocol in those with a family history of premature coronary artery disease (FHCAD). In this Australian multi-centre, randomized controlled trial (Coronary Artery Calcium score: Use to Guide management of Hereditary Coronary Artery Disease, CAUGHT-CAD), asymptomatic, statin-native participants at low-intermediate cardiovascular risk with FHCAD underwent CAC assessment. Those with CAC between 1 and 400 were randomized (1:1) to disclosing the CAC result to both patient and physician and commencing atorvastatin (intervention) or blinding the CAC result with risk factor education only (control). The primary endpoint of this sub-study was change in Pooled Cohort Equation (PCE) at 12 months. Of 1088 participants who were scanned, 450 were randomised and 214 in both groups completed 1-year follow-up. At 1 year, PCE-risk decreased by 1.0% (95% CI 0.13 to 1.81) in the CAC-disclosed group and increased by 0.43% (95%CI 0.11–0.75) in the CAC-blinded group. LDL-C decreased in the CAC-disclosed group in both those who continued (1.5 mmol/L; 95% CI 1.36 to 1.74) and discontinued statins (0.62 mmol/L; 95% CI 0.32 to 0.92) but was unchanged in the CAC-blinded group. Participants unblinded to their CAC showed reductions in LDL irrespective of statin continuation when compared to controls at 12 months. Improvements in individual risk factors and PCE risk were also noted. CAC assessment may positively influence patients and physicians to improve risk factor control. • The role of coronary artery calcium (CAC) imaging to improve adherence to primary prevention interventions is controversial. • Intermediate risk patients were randomised to seeing their CAC image and statin treatment or remained blinded without treatment. • At 1-year, CAC visualization predicted lower on- or off-statin treatment LDL-C, SBP and cardiovascular risk. [ABSTRACT FROM AUTHOR]

The potential impact of coronary atherosclerosis, as detected by coronary artery calcium, on clinical outcomes in COVID-19 patients remains unsettled. We aimed to evaluate the prognostic impact of clinical and subclinical coronary artery disease (CAD), as assessed by coronary artery calcium score (CAC), in a large, unselected population of hospitalized COVID-19 patients undergoing non-gated chest computed tomography (CT) for clinical practice. SARS-CoV 2 positive patients from the multicenter (16 Italian hospitals), retrospective observational SCORE COVID-19 (calcium s core for CO VID-19 R isk E valuation) registry were stratified in three groups: (a) "clinical CAD" (prior revascularization history), (b) "subclinical CAD" (CAC >0), (c) "No CAD" (CAC = 0). Primary endpoint was in-hospital mortality and the secondary endpoint was a composite of myocardial infarction and cerebrovascular accident (MI/CVA). Amongst 1625 patients (male 67.2%, median age 69 [interquartile range 58–77] years), 31%, 57.8% and 11.1% had no, subclinical and clinical CAD, respectively. Increasing rates of in-hospital mortality (11.3% vs. 27.3% vs. 39.8%, p < 0.001) and MI/CVA events (2.3% vs. 3.8% vs. 11.9%, p < 0.001) were observed for patients with no CAD vs. subclinical CAD vs clinical CAD, respectively. The association with in-hospital mortality was independent of in-study outcome predictors (age, peripheral artery disease, active cancer, hemoglobin, C-reactive protein, LDH, aerated lung volume): subclinical CAD vs. No CAD: adjusted hazard ratio (adj-HR) 2.86 (95% confidence interval [CI] 1.14–7.17, p= 0.025); clinical CAD vs. No CAD: adj-HR 3.74 (95% CI 1.21–11.60, p= 0.022). Among patients with subclinical CAD, increasing CAC burden was associated with higher rates of in-hospital mortality (20.5% vs. 27.9% vs. 38.7% for patients with CAC score thresholds≤100, 101–400 and > 400, respectively, p < 0.001). The adj-HR per 50 points increase in CAC score 1.007 (95%CI 1.001–1.013, p= 0.016). Cardiovascular risk factors were not independent predictors of in-hospital mortality when CAD presence and extent were taken into account. The presence and extent of CAD are associated with in-hospital mortality and MI/CVA among hospitalized patients with COVID-19 disease and they appear to be a better prognostic gauge as compared to a clinical cardiovascular risk assessment. [Display omitted] • The potential impact of coronary atherosclerosis, as detected by coronary artery calcium, on clinical outcomes in COVID-19 remains unsettled. • If coronary artery calcium, a marker of atherosclerotic burden, may be a better gauge of COVID-19 outcomes than clinical profile is unsettled. • Clinical and subclinical coronary artery disease assessed by coronary artery calcium score is associated with in-hospital mortality. • Cardiovascular risk factors are not independently associated with in-hospital mortality when coronary atherosclerosis is considered. [ABSTRACT FROM AUTHOR]

We aimed to characterize the spatial proximity of plaque destabilizing features local endothelial shear stress (ESS), minimal luminal area (MLA), plaque burden (PB), and near-infrared spectroscopy (NIRS) lipid signal in high- vs. low-risk plaques. Coronary arteries imaged with angiography and NIRS-intravascular ultrasound (IVUS) underwent 3D reconstruction and computational fluid dynamics calculations of local ESS. ESS, PB, MLA, and lipid core burden index (LCBI), for each 3-mm arterial segment were obtained in arteries with large lipid-rich plaque (LRP) vs. arteries with smaller LRP. The locations of the MLA, minimum ESS (minESS), maximum ESS (maxESS), maximum PB (maxPB), and maximum LCBI in a 4-mm segment (maxLCBI 4mm) were determined along the length of each plaque. The spatial distributions of minESS, maxESS, maxPB, and maxLCBI 4mm , in reference to the MLA, were significantly heterogeneous within and between each variable. The location of maxLCBI 4mm was spatially discordant from sites of the MLA (p< 0.0001), minESS (p = 0.003), and maxESS (p = 0.003) in arteries with large LRP (maxLCBI 4mm ≥ 400) and non-large LRP. Large LRP arteries had higher maxESS (9.31 ± 4.78 vs. 6.32 ± 5.54 Pa; p = 0.023), lower minESS (0.41 ± 0.16 vs. 0.61 ± 0.26 Pa; p = 0.007), smaller MLA (3.54 ± 1.22 vs. 5.14 ± 2.65 mm2; p = 0.002), and larger maxPB (70.64 ± 9.95% vs. 56.70 ± 13.34%, p<0.001) compared with non-large LRP arteries. There is significant spatial heterogeneity of destabilizing plaque features along the course of both large and non-large LRPs. Large LRPs exhibit significantly more abnormal destabilizing plaque features than non-large LRPs. Prospective, longitudinal studies are required to determine which patterns of heterogeneous destabilizing features act synergistically to cause plaque destabilization. Image 1 • The spatial relationship between plaque features of local endothelial shear stress (ESS), minimal luminal area (MLA), plaque burden (PB), and near-infrared spectroscopy (NIRS) lipid signal is unknown. • Coronary arteries imaged with angiography and NIRS-intravascular ultrasound (IVUS) underwent 3D reconstruction and computational fluid dynamics calculations of local flow patterns. • The spatial distributions of minESS, maxESS, maxPB, and maxLCBI 4mm , in reference to the MLA, were significantly heterogeneous within and between each variable. • The location of maxLCBI 4mm was spatially discordant from sites of MLA, minESS, and maxESS in most arteries, but not discordant with the site of maxPB. • There is significant heterogeneity between hemodynamic, anatomic, and biochemical coronary plaque features. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) and pre-diabetes are associated with an increased risk of cardiovascular disease (CVD). We aimed to investigate vulnerable plaque composition in relation to IR and pre-diabetes in asymptomatic non-diabetic men. All participants underwent a contrast-enhanced coronary computed tomography angiography (CCTA) to evaluate coronary artery plaque burden and plaque composition (necrotic core, dense calcium, fibrotic and fibrous-fatty volume). Homeostasis model assessment of IR (HOMA-IR) was used, and participants were stratified into tertiles. Participants underwent a standard oral glucose tolerance test (OGTT) and were categorized into 2 groups (normal glucose tolerance (NGT) or pre-diabetes). A multivariable linear regression model was used to evaluate the association between vulnerable plaque composition and IR or glycemic group. Four-hundred-and-fifty non-diabetic men without known CAD were included. The mean age was 70 ± 3 years. Participants in the higher HOMA-IR tertile (H-IR) had higher median necrotic plaque volume compared to the lower HOMA-IR tertile (L-IR) (18.2 vs. 11.0 mm3, p = 0.02). H-IR tertile (β 0.37 [95% CI 0.10–0.65], p = 0.008), pack-years (β 0.07 [95% CI 0.007–0.14], p = 0.03) and total atheroma volume (TAV) (β 0.47 [95% CI 0.36–0.57], p < 0.001) remained associated with necrotic plaque volume in the multivariable linear regression model. IR was associated with necrotic plaque volume in asymptomatic men without diabetes. Thus, even in asymptomatic men without diabetes, IR seems to have an incremental effect on necrotic plaque volume and vulnerable plaque composition. [Display omitted] • Insulin resistance seems to increase necrotic plaque volume in coronary arteries in asymptomatic elderly men without manifest diabetes. • Hyperglycemia assessed by oral glucose tolerance test seems not to increase the necrotic plaque volume. • The extent of coronary atherosclerosis assessed as total atheroma volume was associated with increased necrotic plaque volume. • Smoking exposure increased necrotic plaque volume. [ABSTRACT FROM AUTHOR]

Heterozygous familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease. Semi-automated plaque characterization (SAPC) by coronary computed tomographic angiography (CTA) provides information regarding coronary plaque burden and plaque characterization. Our aim was to quantify and characterize the coronary plaque burden of patients with FH using SAPC analysis and to identify which factors are related to plaque burden and plaque characteristics. A second aim was to analyse the prognostic implications of these parameters. Two hundred and fifty-nine asymptomatic individuals with molecularly determined FH were enrolled in this follow-up cohort study and underwent a coronary CTA analysed with SAPC. Mean follow-up time after coronary CTA was 3.9 ± 2 years. Mean age was 46.9 (10.7) years (130 women, 50.2%). Median plaque burden was 25.0% (19.0–29.0), non-calcified plaque burden 22.83% (17.94–26.88), calcified plaque-burden 1.12% (0.31–2.86) and CCS 8.9 (0–93). Five-year risk was independently related to plaque burden, non-calcified plaque burden, calcified plaque burden and coronary calcium score (B:3.75, 95%CI:2.92–4.58; p < 0.001, B:2.9, 95%CI:2.15–3.66; p < 0.001, B:0.75, 95%CI 0.4–1.1; p < 0.001 and B:82.2, 95%CI:49.28–115.16; p < 0.001 respectively). During follow-up, there were 15 (5.81%) nonfatal events and 1 (0.4%) fatal event. Plaque burden was significantly related to event-free survival during follow-up (HR:1.11; 95%CI:1.05–1.18; p < 0.001). Coronary atherosclerosis and its qualitative components may be quantified by means of SAPC in patients with FH. Plaque burden, calcified plaque burden and non-calcified plaque burden were independently related to the estimated cardiovascular risk. Plaque burden was also related to prognosis. Image 1 • Coronary atherosclerosis burden may be quantified and plaque characteristics analysed in the coronary artery tree using coronary CTA in patients with familial hypercholesterolemia (FH). • Coronary atherosclerosis, beyond coronary calcium, is highly prevalent in asymptomatic patients with FH. • By means of coronary CTA, we can study every component of the coronary atherosclerotic plaque. • Plaque burden, calcified plaque burden and non-calcified plaque burden are independently related to the cardiovascular risk and cardiovascular prognosis. • This new diagnostic approach might improve the risk re-stratification and management optimization, allowing more personalized lipid lowering treatment, such us the use of PCSK9 inhibitors. [ABSTRACT FROM AUTHOR]

Although coronary artery calcium (CAC) density has been associated with plaque stability, pathological evidence is lacking. We investigated the relationship between coronary computed tomography (CCT)-derived CAC density and multiple calcified and high-risk plaque (HRP) characteristics using optical coherence tomography (OCT). We analyzed 83 plaques from 33 stable angina patients who underwent both CCT and OCT. CAC density was measured at calcium plaques with ≥90 Hounsfield units (HU) and ≥130 HU using custom CT software. The correlation between median CAC density and OCT-derived calcium size (thickness and area) was assessed. To investigate whether median CAC densities measured at the 90 HU threshold were associated with plaque vulnerability, OCT-derived plaque characteristics and HRP characteristics were compared between the low (90–129 HU), intermediate (130–199 HU) and high (≥200 HU) CAC HU groups. Median CAC densities at 130 HU were moderately associated with calcium thickness (R = 0.573, p < 0.001) and area (R = 0.560, p < 0.001). Similar results were observed at 90 HU (thickness, R = 0.615, p < 0.001; area, R = 0.612, p < 0.001). Among groups with low, intermediate and high HU levels, calcium thickness (0.42 ± 0.14 mm, 0.60 ± 0.17 mm and 0.77 ± 0.19 mm, respectively; p < 0.001) and area (0.55 ± 0.29 mm2, 1.20 ± 0.58 mm2 and 1.78 ± 0.87 mm2, respectively; p < 0.001) were significantly greater in the high HU group. HRP characteristics, however, did not differ among the three groups. OCT-derived calcium size, but not HRP characteristics, were associated with CAC density, suggesting that CAC density is driven mainly by calcified plaque size but not local plaque vulnerability. Image 1 • CAC density was positively associated with OCT-derived calcified plaque size. • CAC density was not associated with OCT-derived high-risk plaque features. • CAC density at 90 Hounsfield Units was also associated with OCT-derived calcified plaque size. [ABSTRACT FROM AUTHOR]

Coronary computed tomography (CT) allows calculating coronary artery calcium score (CACS). However, other CT features might be more strongly related to plaque vulnerability and risk of future coronary events. This study investigated the association of plaque calcification pattern and attenuation with plaque instability features, coronary artery disease (CAD) grade and CACS. One-hundred patients with coronary stenosis associated with calcified plaques were considered for this analysis. CACS, CAD grade, calcification pattern and attenuation, features of plaque instability, and epicardial adipose tissue (EAT) thickness and attenuation were assessed with non-contrast and contrast-enhanced CT angiography. Of 373 calcified plaques, 131 were responsible for the highest degree of coronary stenosis (1.31 ± 0.53 per patient). Participants were stratified according to the features of the highest-grade lesion(s) into patients with large (35%), spotty (52%) or mixed (13%) calcification pattern and tertiles of plaque calcification attenuation (using the mean value for multiple lesions). Patients with large calcification pattern or higher plaque calcification attenuation had higher stenosis and CACS grade (and EAT attenuation), but lower plaque instability score, whereas those with spotty calcification pattern or lower plaque calcification attenuation had lower stenosis and CACS grade (and EAT attenuation), but higher plaque instability score. Among the instability features, low attenuation and napkin-ring sign, but not positive remodeling, were associated with a spotty pattern and a lower calcification attenuation. Both the pattern and attenuation of calcification should be considered, in addition to CACS, for risk stratification of heavily calcified high-risk patients with non-critical coronary stenosis. Image 1 • Spotty calcification is associated with a lower stenosis and calcification grade. • Large calcification is associated with a higher stenosis and calcification grade. • Plaques with spotty calcification are more unstable and less densely calcified. • Plaques with large calcification are more stable and more densely calcified. • Calcification pattern and attenuation should be considered for risk stratification. [ABSTRACT FROM AUTHOR]

Coronary artery calcification (CAC) is one of the most sensitive and specific markers of coronary atherosclerosis and believed to be heritable. We hypothesized that functionally relevant single-nucleotide polymorphisms (SNPs) in the G-protein signal pathway, which have been previously related to coronary artery disease, are associated with CAC progression. 3108 participants from the Heinz Nixdorf Recall study with CAC measurements at both baseline (CACb) and 5-year follow-up (CAC5y) were included. We genotyped SNPs rs1042714 (ADRB2), rs6026584 and rs12481583 (GNAS), and rs5443 (GNB3) and defined a priori risk alleles derived from literature data. Regression analyses were applied to measures of 5-year CAC progression, unadjusted, adjusted for age, sex, and adjusted for age, sex, log(CACb+1) as well as for cardiovascular risk factors. The presence of one or more risk alleles was associated with a 26.9% (95% CI 5.5–52.4) increase in 5-year CAC progression (p = 0.011) and a 29.2% (95% CI 5.9–57.6) accelerated increase of CAC over the 5-year period compared to what was expected with respect to the baseline CAC percentile value (p = 0.012). Each of those risk alleles increased the 5-year CAC progression by 4.4% (95% CI 1.3–7.6, p = 0.006) and resulted in a 4.9% accelerated increase of CAC over the 5-year period (95% CI 1.6–8.4, p = 0.004). These unadjusted data did not change after adjustment. Genetic variations in the G-protein signal pathway are associated with CAC progression in a cumulative fashion, indicating the importance of the pathway for genetic heritability in CAC progression and coronary artery disease. Image 1 • Coronary artery calcification (CAC) is believed to be partly heritable. • Genetic variations in the G-protein signal pathways influence CAC progression. • Presence of one or more risk allele: nearly 30% increase in CAC progression. • G-protein pathway is important for genetics in CAC progression and coronary artery disease. [ABSTRACT FROM AUTHOR]

The Agatston coronary artery calcium score (CACS) may fail to identify small or less dense coronary calcification that can be detected on coronary CT angiography (CCTA). We investigated the prevalence and prognostic importance of subtle calcified plaques on CCTA among individuals with CACS 0. From the prospective multicenter CONFIRM registry, we evaluated patients without known CAD who underwent CAC scan and CCTA. CACS was categorized as 0, 1–10, 11–100, 101–400, and >400. Patients with CACS 0 were stratified according to the visual presence of coronary plaques on CCTA. Plaque composition was categorized as non-calcified (NCP), mixed (MP) and calcified (CP). The primary outcome was a major adverse cardiac event (MACE) which was defined as death and myocardial infarction. Of 4049 patients, 1741 (43%) had a CACS 0. NCP and plaques that contained calcium (MP or CP) were detected by CCTA in 110 patients (6% of CACS 0) and 64 patients (4% of CACS 0), respectively. During a 5.6 years median follow-up (IQR 5.1–6.2 years), 413 MACE events occurred (13%). Patients with CACS 0 and MP/CP detected by CCTA had similar MACE risk compared to patients with CACS 1–10 (p = 0.868). In patients with CACS 0, after adjustment for risk factors and symptom, MP/CP was associated with an increased MACE risk compared to those with entirely normal CCTA (HR 2.39, 95% CI [1.09–5.24], p = 0.030). A small but non-negligible proportion of patients with CACS 0 had identifiable coronary calcification, which was associated with increased MACE risk. Modifying CAC image acquisition and/or scoring methods could improve the detection of subtle coronary calcification. Image 1 • The Agatston coronary artery calcium score (CACS) method may fail to detect very small or less dense calcified plaques. • 4% of patients with CACS 0 had evidence of coronary calcification (mixed plaque [MP] or calcified plaque [CP]) on CCTA. • In patients with CACS 0, MP/CP was associated with an increased risk of MACE compared to those with no plaque by CCTA. • Modification of CAC scan acquisition and/or scoring methods are needed in order to improve plaque detection sensitivity. [ABSTRACT FROM AUTHOR]

Epicardial adipose tissue (EAT) is a visceral AT, surrounding myocardium and coronary arteries. Its volume is higher in Type 2 diabetic (DM2) patients, associated with cardiovascular disease risk. Lipoprotein lipase (LPL) hydrolyses triglycerides (TG) from circulating lipoproteins, supplying fatty acids to AT, contributing to its expansion. We aimed to evaluate LPL expression and activity in EAT from DM2 and no DM2 patients, and its regulators ANGPTL4, GPIHBP1 and PPARγ levels, together with VLDLR expression and EAT LPL association with VLDL characteristics. We studied patients undergoing coronary by-pass graft (CABG) divided into CABG-DM2 (n = 21) and CABG-noDM2 (n = 29), and patients without CABG (No CABG, n = 30). During surgery, EAT and subcutaneous AT (SAT) were obtained, in which LPL activity, gene and protein expression, its regulators and VLDLR protein levels were determined. Isolated circulating VLDLs were characterized. EAT LPL activity was higher in CABG-DM2 compared to CABG-noDM2 and No CABG (p= 0.002 and p< 0.001) and in CABG-noDM2 compared to No CABG (p= 0.02), without differences in its expression. ANGPTL4 levels were higher in EAT from No CABG compared to CABG-DM2 and CABG-noDM2 (p< 0.001). GPIHBP1 levels were higher in EAT from CABG-DM2 and CABG-noDM2 compared to No CABG (p= 0.04). EAT from CABG-DM2 presented higher PPARγ levels than CABG-noDM2 and No CABG (p= 0.02 and p= 0.03). No differences were observed in VLDL composition between groups, although EAT LPL activity was inversely associated with VLDL-TG and TG/protein index (p< 0.05). EAT LPL regulation would be mainly post-translational. The higher LPL activity in DM2 could be partly responsible for the increase in EAT volume. Image 1 • LPL activity was increased in EAT from DM2 patients. • In DM2, increased GPIHBP1 and decreased ANGPTL4 EAT expression modulated LPL activity. • Higher EAT LPL activity was responsible for TG-VLDL catabolism and fatty acids release. • EAT VLDL receptor was inversely associated with circulating VLDL mass and TG-VLDL. • The higher EAT LPL activity in DM2 could be responsible for the increased EAT volume. [ABSTRACT FROM AUTHOR]

Diffuse idiopathic skeletal hyperostosis (DISH) is a common incidental finding on medical imaging and often thought to be benign. Our objective was to investigate whether DISH is associated with coronary artery disease as measured with the coronary artery calcification (CAC) score in a large cohort of current and former smokers. In a subset of subjects from the COPDGene study, DISH was scored by a minimum of two independent readers if there were four adjacent levels of flowing osteophytes and a third reader adjudicated discrepancies. CAC was calculated using a modified Agatston method. Associations of DISH with the presence and extent of CAC were analyzed with and without adjustment for COPD and known atherosclerotic risk factors, including age, sex, race, diabetes, hypertension, high cholesterol, body mass index and smoking. DISH was present in 361 subjects (13.2%) from a total group of 2728. Median (interquartile range) Agatston was 81 (0–329) in DISH subjects compared to 0 (0–94 in subjects without DISH (p < 0.001). DISH prevalence was 8.8% in CAC = 0, 12.8% in CAC1-100, 20.0% in CAC100-400 and 24.7% in CAC.400. Subjects with DISH had a significantly higher risk of having coronary artery calcifications; OR [CI95%] 1.37[1.05–1.78] (p= 0.019) after correction for age, gender, race, COPD and atherosclerotic risk factors. Subjects with DISH, a common musculoskeletal disorder involving bone formation anterior to the spine, have an increased burden of coronary artery disease, and therefore DISH may be a more relevant incidental finding than commonly thought. • Diffuse idiopathic skeletal hyperostosis (DISH) is a common incidental finding on medical imaging and often thought to be benign. • Subjects with DISH have more CAC as a reflection of coronary atherosclerosis. • DISH is usually observed as an incidental finding on imaging and may be an important finding to stimulate assessment of occult cardiovascular disease. [ABSTRACT FROM AUTHOR]

A recently identified locus for coronary artery disease (CAD) tagged by rs8042271 is in a region of tight linkage disequilibrium (LD) between 2 genes (MFGE8, ABHD2) previously linked to atherosclerosis. Here we have explored the regulatory framework of this region to identify its functional relationship to CAD. The CAD Associated Region between MFGE8 and ABHD2 (CARMA) was investigated by bioinformatic approaches and transcriptional reporter assays to prioritize target genes and identify putative causal variants. Findings were integrated with publicly available gene expression datasets. MFGE8 silencing was performed in cell models relevant to CAD. The regulatory potential of CARMA is disseminated sparsely over the entire region. CARMA contains multiple eQTL that regulate MFGE8 in coronary artery and coronary artery smooth muscle cell (CoSMC). SNPs that predict the expression of MFGE8 in artery are concordantly associated with higher risk of CAD (p val = 0.0014). Targeting CARMA by CRISPR/Cas9 in a cellular model increased MFGE8 expression. MFGE8 silencing was found to reduce CoSMC and monocyte (THP-1) but not endothelial cell proliferation. These findings support a mechanistic link between a GWAS identified CAD risk locus and atherosclerosis. The intergenic locus CARMA regulates MFGE8 in a haplotype dependent manner. Individuals genetically susceptible to increased MFGE8 expression exhibit greater CAD risk. Suppressing MFGE8 expression reduced SMC and THP-1 proliferation. These data support an atherogenic contribution of CARMA/ MFGE8 that may be linked to cell proliferation and/or improved survival of CAD relevant cell types. Image 1 • A chromosome region associated with heart disease influences expression of neighboring genes. • The region is located in a gene desert and consists of multiple variants in tight linkage. • MFGE8 is identified as a likely intermediate bridging the variants to heart disease. [ABSTRACT FROM AUTHOR]

Density may indicate some tissue characteristics and help reveal the role of epicardial adipose tissue (EAT) in coronary artery disease (CAD). Therefore, we assessed the association of EAT density with the coronary artery plaque burden in patients presenting with chest pain. This retrospective cohort study comprised 614 patients (mean age 61 ± 9 years, 61% males) with a high cardiovascular disease risk, who underwent cardiac computed tomography angiography. Density was reflected as attenuation. EAT attenuation was significantly associated with EAT volume with a negative Pearson's correlation coefficient and gradually increased across coronary artery calcium (CAC) scores of 0, 1–100, 101–400 and > 400. EAT attenuation was tightly associated with CAD risk factors, including age, sex, BMI, total cholesterol, neutrophil to lymphocyte ratios and CAC score. The association between EAT attenuation and CAC score was strengthened after adjusting for multivariable indices (OR 1.21, 95% CI 1.05–1.40, p = 0.01) and further adjusting for EAT volume (OR 1.26 95% CI 1.06–1.51, p <0.01). However, EAT attenuation was associated only with CAD presence (OR 1.32, 95% CI 1.02–1.69, p <0.05), CAC presence (OR 1.28, 95% CI 1.02–1.60, p <0.05), segment involvement score (OR 1.19, 95% CI 1.01–1.40, p <0.05) and segment stenosis score (OR 1.19, 95% CI 1.01–1.40, p <0.05) in the EAT volume- and multivariable-adjusted model. Additionally, EAT attenuation was not associated with significant coronary artery lesions and triple-vessel plaques. Higher EAT attenuation is associated with a higher risk of CAD. Image 1 • Epicardial adipose tissue (EAT) attenuation and volume significantly correlated, but this relationship gradually diminished with increasing CAC scores • EAT attenuation was associated with CAD risk factors and the presence of CAD and CAC. • EAT attenuation was not associated with the presence of significant coronary lesions and triple-vessel plaques. • EAT attenuation was associated with CAC score, SIS and SSS. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Serum paraoxonase 1 (PON1) and myeloperoxidase (MPO) are HDL-associated enzymes that contribute significantly to the formation of dysfunctional HDL. The present study thus seeks to comparatively analyze the predictive role of PON1, MPO and the MPO/PON1 ratio and to also evaluate which one has a stronger predictive role in their combined utility as an MPO/PON1 ratio in coronary artery disease (CAD). Methods PON1 activity and MPO concentrations were determined in patients with established CAD and those without significant CAD. Receiver operating characteristic (ROC) curves were drawn by plotting true positivity versus false positivity. Results The ROC curve analyses showed that PON1 (AUC = 61%, p = 0.003) and MPO/PON1 (AUC = 60%, p = 0.01) have a better diagnostic performance than MPO (AUC = 50%, p = 0.42) in detecting patients with CAD. PON1 and MPO/PON1 were found to have a significantly stronger discriminatory power for the age range ≥52 and < 60 years (AUC = 69%, p = 0.008 for PON1; AUC = 66%, p = 0.022 for MPO/PON1). The multivariate analysis revealed PON1 as an independent variable that was significantly associated with the multi-vessel disease [odds ratio (OR) = 0.98; p = 0.017]. At the cutoff point of 30 μmol/mL/min for PON1 and 1.85 for MPO/PON1, specificities were 97% and 73% and sensitivities 30% and 54% for discriminating patients with single-vessel disease from non-CAD subjects. Conclusions The diagnostic performance of PON1 alone was comparable to that of the MPO/PON1 ratio for CAD risk assessment; however, MPO may increase the true positive rate. A larger number of blocked vessels seems to be associated with an increased predictive power for both PON1 and MPO/PON1. Recent data support the fact that PON1 and MPO may potentially be appropriate therapeutic targets for preventing CAD. Graphical abstract Image 1 Highlights • The diagnostic performance of serum paraoxonase 1 (PON1) alone was comparable to that of the myeloperoxidase (MPO)/PON1 ratio. • MPO may increase the true positive rate in the MPO/PON1 ratio for CAD risk assessment. • PON1 and MPO/PON1 had a stronger discriminatory power in the age range of ≥52 and < 60 years. • A larger number of blocked vessels is associated with an increased predictive power for both PON1 and MPO/PON1. • Recent data support the fact that PON1 and MPO may be appropriate therapeutic targets for preventing CVD. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Familial combined hyperlipidemia (FCHL) is a complex dyslipidemia associated with premature cardiovascular disease (CVD). The present study was conducted to 1) determine the incidence of CVD in FCHL in this era of protocolled, primary prevention; and 2) examine whether cardiovascular risk estimation based on the Systemic Coronary Risk Estimation (SCORE) chart, as proposed in the 2016 ESC/EAS guidelines for the management of dyslipidemia, is justified in FCHL. Methods FCHL patients, their normolipidemic (NL) relatives and spouses originally included in our baseline cohort in 1998–2005 (n = 596) were invited for a follow-up visit to determine the incidence of CVD, defined as (non-)fatal coronary artery disease, ischemic stroke and peripheral artery disease requiring invasive treatment. Results Follow-up data (median: 15 years) was acquired for 85% of the original cohort. The cumulative incidence of CVD was significantly higher in FCHL patients than in spouses (23.6% versus 4.7%; hazard ratio (HR): 5.4, 95%CI: 2.0–14.6; HR after adjustment for risk factors included in SCORE: 4.7, 95%CI: 1.6–13.8), but not in NL relatives compared to spouses (5.8% versus 4.7%). The SCORE chart tended to overestimate CVD risk in the spouses (observed [O]/expected [E] ratio:0.2, p = 0.01), but not in FCHL patients (O/E:1.3, p = 0.50). Conclusions Risk of primary CVD is still substantially increased in FCHL patients, despite preventive measures. The overestimation of CVD risk by the SCORE chart – a nowadays frequently observed phenomenon thanks to improved primary prevention – was not seen in FCHL. These results suggest that more aggressive treatment is justified to avoid excessive CVD in FCHL. Graphical abstract Image 1 Highlights • Three quarters of familial combined hyperlipidemia (FCHL) patients receive lipid lowering treatment. • The 15-year incidence of cardiovascular disease is still very high in FCHL. • The SCORE risk factors do not fully account for the increased risk in FCHL. [ABSTRACT FROM AUTHOR]

Objective Coronary collaterals play a crucial role during an acute ischemic attack. Angiogenesis has an important role in the formation of coronary collateral vessels. Previously, it was shown that apelin is a potential angiogenetic factor. Thus, we aimed to investigate relationship between plasma apelin levels and coronary collateral circulation in patients with stable coronary artery disease. Methods Among patients who underwent coronary angiography with stable angina pectoris, patients with a stenosis of ≥90% were included in our study. Collateral degree was graded according to Rentrop-Cohen classification. Patients with grade 2 or 3 collateral degree were included in good collateral group and patients with grade 0 or 1 collateral degree were included in poor collateral group. Results Plasma apelin level was significantly higher in good collateral group (0.69 ± 0.2 vs 0.59 ± 0.2 ng/dl, p < 0.001). Serum nitric oxide levels were similar between two groups. In multivariate regression analysis apelin [6.95 (1.46-33.15), p = 0.015] and presence of total occlusion [4.40 (1.04-18.62), p = 0.044] remained as independent predictors for good coronary collateral development. Conclusions Higher plasma apelin level was related to better coronary collateral development. Demonstration of favorable affects of apelin on good collateral development may lead to consider apelin in antiischemic treatment strategies in order to increase collateral development. [ABSTRACT FROM AUTHOR]

Abstract: Background: Few studies have examined plaque characteristics among multiple arterial beds in vivo. The purpose of this study was to compare the plaque morphology and arterial remodeling between coronary and peripheral arteries using gray-scale and radiofrequency intravascular ultrasound (IVUS) at clinical presentation. Methods and results: IVUS imaging was performed in 68 patients with coronary and 93 with peripheral artery lesions (29 carotid, 50 renal, and 14 iliac arteries). Plaques were classified as fibroatheroma (VH-FA) (further subclassified as thin-capped [VH-TCFA] and thick-capped [VH-ThCFA]), fibrocalcific plaque (VH-FC) and pathological intimal thickening (VH-PIT). Plaque rupture (13% of coronary, 7% of carotid, 6% of renal, and 7% of iliac arteries; P = NS) and VH-TCFA (37% of coronary, 24% of carotid, 16% of renal, and 7% of iliac arteries; P = 0.02) were observed in all arteries. Compared with coronary arteries, VH-FA was less frequently observed in renal (P < 0.001) and iliac arteries (P < 0.006). Lesions with positive remodeling demonstrated more characteristics of VH-FA in coronary (84% vs. 25%, P < 0.001), carotid (72% vs. 20%, P = 0.001), and renal arteries (42% vs. 4%, P = 0.001) compared with those with intermediate/negative remodeling. There was positive relationship between remodeling index and percent necrotic area in all four arteries. Conclusions: Atherosclerotic plaque phenotypes were heterogeneous among four different arteries; renal and iliac arteries had more stable phenotypes compared with coronary artery. In contrast, the associations of remodeling pattern with plaque phenotype and composition were similar among the various arterial beds. [Copyright &y& Elsevier]

Abstract: To elucidate the associations between Lp(a) levels and coronary and aortic atherosclerosis, we performed aortic MRI in 143 patients undergoing coronary angiography. Severity of aortic atherosclerosis was represented as plaque scores. Of the 143 patients, 104 had coronary artery disease (CAD). Thoracic and abdominal aortic plaques were found in 89 and 131 patients. Lp(a) levels increased stepwise with the number of stenotic coronary vessels: 15.7 (CAD(−)), 21.2 (1-vessel), 21.4 (2-vessel), and 22.9mg/dl (3-vessel) (P <0.05). For aortic atherosclerosis, 143 patients were divided into quartiles by plaque scores. Lp(a) did not differ among quartiles of thoracic plaques: 17.1, 19.0, 23.5, and 21.2mg/dl (P =NS), whereas Lp(a) increased stepwise with quartiles of abdominal plaques: 17.1, 19.2, 19.1, and 24.0mg/dl (P <0.05). Lp(a) was an independent factor for CAD and abdominal aortic plaques, but not thoracic plaques. Thus, Lp(a) levels were associated with aortic atherosclerosis, especially in abdominal aorta, as well as coronary atherosclerosis. [Copyright &y& Elsevier]

Abstract: Background: Regional differences in shear stress have been identified as reason for early plaque formation in vessel bifurcations. We aimed to investigate regional plaque morphology and composition using intravascular ultrasound (IVUS) and virtual histology (IVUS–VH) in coronary artery bifurcations. Methods: We performed IVUS and IVUS–VH studies at coronary bifurcations to analyze segmental plaque burden and composition of different segments in relation to their orientation to the bifurcation. Results: A total of 236 patients with a mean age of 59±11 years (69% male) were analyzed. Plaque burden was higher at the contralateral vessel wall facing the bifurcation compared to the ipsilateral vessel wall and this difference was true for proximal and distal segments (proximal: 37±12% and 45±15% for segments at the ipsilateral and contralateral vessel wall, respectively, p <0.001; distal: 37±10% and 47±15% for segments at the ipsilateral and contralateral vessel wall, respectively, p <0.001). In addition, these segments exhibited a higher proportion of dense calcium and a lower proportion of fibrous tissue and fibro fatty tissue. Conclusions: Segments on the contralateral wall of the bifurcation which have previously been identified as regions with low shear stress not only exhibited a higher plaque burden, but also a higher degree of calcification. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We aimed to determine, whether the amount of local pericoronary fat volume is associated with the presence of plaque burden in the underlying coronary artery segment. Methods: We assessed 311 coronary segments from ECG-gated contrast-enhanced dual-source computed tomography for presence of plaque as well as segmental pericoronary fat volume. For pericoronary fat evaluation, regions of interest were manually traced containing any fat surrounding a coronary artery segment, with the myocardial wall, the pericardial sac and other coronary segments as outer border. Results: Per each doubling of pericoronary fat volume, we observed an 2.5-fold increase in the presence of plaque in the underlying coronary segment in unadjusted models (95% confidence interval [CI] 1.87–3.27, p <0.001), which remained after adjustment for traditional cardiovascular risk factors (odds ratio [OR] 3.07 [2.16–4.35], p <0.001) and when additionally accounting for overall pericardial fat volume (OR 2.68 [1.90–3.79], p <0.001). Associations were similar in all coronary artery segments and not related to the type of plaque (calcified or non-calcified, p <0.01 for all). Conclusion: Pericoronary fat is associated with atherosclerosis in the coronary arteries. Our results support the hypothesis that perivascular fat depots may function as a local endocrine risk factor in atherosclerosis development. [Copyright &y& Elsevier]

Abstract: Objective: Adiponectin has anti-atherogenic properties and low circulating adiponectin has been linked to coronary atherosclerosis. Yet, there is considerable evidence that the high-molecular weight (HMW) complex of adiponectin is the major active form of this adipokine. We therefore investigated whether HMW adiponectin is associated with the extent of coronary artery disease (CAD) in men. Research design and methods: Associations among CAD, HMW adiponectin and the HMW/total-adiponectin ratio were assessed in 240 male patients undergoing elective coronary angiography. Total adiponectin and HMW adiponectin was measured by enzyme-linked immunosorbent assay and serum levels were correlated with defined coronary scores and established cardiovascular risk factors. Results: We found significant inverse correlations between angiographic scores and HMW adiponectin [Extent Score (ES): r =−0.39; Gensini Score (GS): r =−0.35; and Severity Score (SS): r =−0.40, all P <0.001], and the HMW/total-adiponectin ratio (ES: r =−0.49; GS: r =−0.46; SS: r =−0.46; all P <0.001). Multivariable regression analyses revealed that HMW adiponectin and the HMW/total-adiponectin ratio were significantly associated with the extent of CAD (both P <0.001). ROC analyses demonstrated that the predictive value of HMW adiponectin and the HMW/total-adiponectin ratio for the extent of coronary atherosclerosis significantly exceeded that of total adiponectin (P <0.001, P =0.010, respectively). Conclusions: HMW adiponectin and the HMW/total-adiponectin ratio inversely correlate with the extent of CAD. HMW adiponectin in particular seems to be a better marker for CAD extent than total adiponectin. [Copyright &y& Elsevier]

Abstract: Objective: Natural killer (NK) cells, key elements in initiation and modulation of immune responses, were recently found to be reduced in coronary artery disease (CAD). To clarify mechanisms behind this reduction, we here investigated NK cell apoptosis in CAD patients. Since oxidative stress has been linked to NK cell apoptosis, we related the findings to oxidative stress in vivo and evaluated the ex vivo susceptibility of NK cells to oxidized lipids. Methods and results: The number of apoptotic NK cells in peripheral blood was significantly increased in CAD patients compared to controls. Purified NK cells from CAD patients also showed a higher rate of spontaneous apoptosis ex vivo. Dose- and time-dependent effects of oxidized LDL and 7β-hydroxycholesterol (7βOH) on apoptosis and ROS production were determined in NK cells from blood donors. Thereafter, purified NK cells from CAD patients and healthy controls were exposed to the oxidized lipids in a paired design. NK cells from patients were more susceptible to apoptosis induced by oxidized LDL, in particular 7βOH, compared to cells from controls. Plasma measurements of LDL protein oxidation and lipid peroxidation did not show any differences between patients and controls. On the other hand, plasma carotenoids were significantly decreased in patients and inversely correlated to NK cell apoptosis rate. Conclusion: The rate of spontaneous NK cell apoptosis was increased in CAD patients. Although NK cells in CAD patients were more sensitive to oxidized lipids ex vivo, indicating a mechanism contributing to the reduced NK cell activity in CAD, the data could not verify an obvious link between NK cell apoptosis and increased oxidative stress in vivo. [Copyright &y& Elsevier]

Abstract: Objective: While renal failure greatly increases coronary risk, mild renal impairment is not usually considered a major risk factor. To explore this we assessed relations between measures of mild impairment of renal function and coronary artery disease (CAD) together with other risk factors. Methods and results: In 408 consecutive patients aged 75 years or less with angiographically defined normal or obstructed coronary arteries and an estimated glomerular filtration rate (eGFR) >45mL/min per 1.73m2, we assessed relations between severity of CAD and levels of plasma cystatin C, creatinine, eGFR, lipid profile, C-reactive protein (CRP), homocysteine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). With univariate ANOVA, the severity of CAD was significantly associated with all indices of renal function: increased plasma cystatin C (p =0.003) and creatinine (p =0.004) and decreased eGFR (p =0.008). An elevated plasma cystatin C was associated with increases in ADMA, SDMA, CRP, homocysteine and age. ADMA, SDMA, CRP and homocysteine levels were not associated with CAD severity. eGFR was negatively associated only with SDMA and homocysteine. In multivariate analysis, increased plasma cystatin C predicted both the occurrence and the severity of CAD more strongly than other measures of renal function. Conclusions: We conclude that mild renal impairment detected by elevated cystatin C is associated with both the occurrence and the severity of CAD, independent of the other risk factors we measured and that mild renal impairment results in increased plasma levels of homocysteine, ADMA and SDMA. Our findings suggest a possible mechanistic link between CAD and mild renal impairment in which cystatin C may serve as an early marker for CAD and may also participate directly in atherogenesis. [Copyright &y& Elsevier]

Abstract: Monocytes have been shown to take an important role in collateral growth in animal studies. The aim of the study was to investigate the relation of circulating monocyte count with collateral development in patients with severely stenotic CAD. Patients who had ≥95% stenosis in at least one major coronary artery were included in the study. Coronary angiograms of 210 eligible patients from our database were analyzed again and 103 of them had good and 107 had poor collateral development according to Cohen-Rentrop method. Only the monocyte count was found to be significantly different between two groups (671±218mm−3 versus 522±195mm−3, p <0.001) when multivariate analysis was performed and an increased monocyte count was observed in the good collateral group (Odds ration [OR], 2.918; 95% confidence interval [CI], 1.281–6.648, p =0.011). This study in which the relationship between monocyte count in blood and collateral development was disclosed has a potential importance in clinical and basic cardiovascular medicine. [Copyright &y& Elsevier]

Abstract: Background: Hypertension, hypercholesterolemia, obesity and smoking are highly prevalent among patients with familial premature coronary artery disease (FP-CAD). Whether these risk factors equally affect other family members remains unknown. Methods: We examined 222 FP-CAD patients, 158 unaffected sibs, 197 offspring and 94 spouses in 108 FP-CAD families (≥2 sibs having survived CAD diagnosed before age 51 (M)/56 (F)), and compared them to population controls. Results: Unaffected sibs had a higher prevalence of hypertension (49% versus 24%, p <0.001), hypercholesterolemia (47% versus 34%, p =0.002), abdominal obesity (35% versus 24%, p =0.006) and smoking (39% versus 24%, p =0.001) than population controls. Offspring had a higher prevalence of hypertension (females), hypercholesterolemia and abdominal obesity than population controls. No difference was observed between spouses and controls. Compared to unaffected sibs, FP-CAD affected sibs had a similar risk factor profile, except for smoking, which was more prevalent (76% versus 39%, p =0.008). Conclusions: Hypertension, obesity and hypercholesterolemia are highly prevalent among first-degree relatives, but not spouses, of patients with FP-CAD. These persons deserve special medical attention due to their familial/genetic susceptibility to atherogenic metabolic abnormalities. In these families, smoking may be the trigger for FP-CAD. [Copyright &y& Elsevier]

Abstract: Objectives: To evaluate the feasibility of an assay for urinary levels of matrix metalloproteinases (MMPs) and the potential usefulness of urinary MMPs as a marker of coronary atherosclerosis or acute coronary syndromes (ACS). Methods and results: We measured urine and plasma MMP-9, MMP-2 and urine tissue inhibitor of metalloproteinase (TIMP-1) in patients with ACS (n =27), patients with coronary artery disease (CAD), but no clinical instability (n =47) and a group of healthy volunteers (n =15) who were <35 years of age, had no risk factors for CAD and did not undergo angiography. Compared with volunteers, patients with ACS and CAD had higher urine MMP-9, urine TIMP-1, plasma MMP-9 and plasma MMP-2 levels, but these did not differ between those with CAD and ACS. Using the volunteers to roughly establish an upper limit of normal, 84% of the urine TIMP-1 values and 95% of the urine MMP-9 values were abnormally elevated among those with CAD and ACS. Conclusions: Urine MMP-9 and TIMP-1 levels are elevated in patients with CAD and ACS compared with healthy volunteers. A high percent of patients with CAD or ACS had elevated urine values of MMP-9 and TIMP-1 suggesting these variables might be a useful marker of atherosclerotic disease. [Copyright &y& Elsevier]

Abstract: The nitric oxide produced by endothelial nitric oxide synthase (eNOS) plays a pivotal role in protecting the arterial wall from damages and atherosclerosis. The T–786C, the 27-bp repeat in intron 4, and the E298D eNOS gene polymorphisms were studied in 715 Brazilian patients (447 Caucasian- and 268 African-Brazilians) who underwent coronary angiography. The −786C frequency was increased in coronary artery disease (CAD) cases with significant lesions (≥50% luminal obstruction) when compared with lesion-free controls; this difference was detected in smokers but not in nonsmokers, both in Caucasian- (p =0.011) and African-Brazilians (p =0.005). The interaction between −786C carriers and smoking was an independent CAD predictor (OR: 2.9, 95% CI: 1.4–5.9; p =0.003) in multiple logistic regression. The 298D mutation frequency was also higher among CAD cases (p =0.036) in African-Brazilian smokers, but this effect was not independent from other variables in the regression model. Though not associated with CAD, the 4-repeat allele combined with different T–786C alleles showed protective and susceptible effects in Caucasian-Brazilian smokers. The −786C/4-repeat/298E haplotype frequency was higher (p =0.020), whereas −786T/4-repeat/298E was lower (p =0.023) in these cases. These results showed a smoking-dependent effect of the T–786C eNOS polymorphism on CAD in both Caucasian- and African-Brazilians. Additionally, the haplotype analysis revealed different eNOS haplotypes associated with protection and susceptibility to the disease. [Copyright &y& Elsevier]

Abstract: Relative changes in lumen size during progression and regression of coronary atherosclerosis remain largely unknown. We assessed these changes using serial intravascular ultrasound (IVUS). From the baseline IVUS interrogations of the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, 210 focal coronary lesions with <50% angiographic stenosis were identified. Lesions were matched to the follow-up IVUS, performed after 18 months of treatment with atorvastatin 80mg/day or pravastatin 40mg/day. Changes in external elastic membrane (EEM) and lumen areas of lesions demonstrating progression and regression (i.e. increased and decreased atheroma area) were examined. In progressors (n =128), there was 1.34mm2 increase in EEM area for every 1mm2 increase in atheroma area (r =0.72, p <0.0001). This resulted in 0.34mm2 increase in lumen area for every 1mm2 increase in atheroma area (r =0.25, p =0.004). In contrast, there was no significant change in lumen area with regression of disease (n =82, r =−0.06, p =0.59). Progression of coronary atherosclerosis can be associated with a paradoxical increase in lumen cross-sectional area, whereas regression is not associated with any change in lumen area. Measurement of changes in lumen size may not be an accurate method to study progression and regression of atherosclerotic lesions with <50% stenosis. [Copyright &y& Elsevier]

Abstract: Autosomal recessive hypercholesterolemia (ARH) is a rare disorder, due to complete loss of function of an adaptor protein (ARH protein) required for receptor-mediated hepatic uptake of LDL. ARH is a phenocopy of homozygous familial hypercholesterolemia (HoFH) due to mutations in LDL receptor (LDLR) gene; however, previous studies suggested that ARH phenotype is less severe than that of HoFH. To test this hypothesis we compared 42 HoFH and 42 ARH patients. LDLR and ARH genes were analysed by Southern blotting and sequencing. LDLR activity was measured in cultured fibroblasts. In ARH plasma LDL cholestrol (LDL-C) level (14.25±2.29mmol/L) was lower than in receptor-negative HoFH (21.38±3.56mmol/L) but similar to that found in receptor-defective HoFH (15.52±2.39mmol/L). The risk of coronary artery disease (CAD) was 9-fold lower in ARH patients. No ARH patients ≤20 years of age were found to have CAD as opposed to 43% of HoFH. The CAD prevalence was or tended to be lower in ARH also in the 21–40 (45% versus 86%) and 41–60 (78% versus 100%) age groups. Heterozygous ARH carriers showed higher level of LDL-C (+17%) than non-carrier family members. In conclusion the clinical phenotype of ARH is milder than that of receptor-negative HoFH and resembles that observed in receptor-defective HoFH. [Copyright &y& Elsevier]

Abstract: We utilized coronary artery calcium scores (CACS) to assess differences in atherosclerosis burden between asymptomatic White populations living in continents with different cardiovascular disease rates. The similarities in the genetic pool between Brazilian and Portuguese Caucasian subjects offered an opportunity to assess the influence of environmnetal factors on the development of atherosclerosis. We reviewed CACS data from 17,563 individuals (12,378 men and 5169 women) collected in the USA (74% of the subjects), Brazil (15% of the subjects) and Portugal (11% of the subjects). CACS was absent in 80 and 88% of Portuguese men and women, compared with 46 and 62% and 33 and 59% of Brazilian and US counterparts (p <0.0001). Although the US subjects showed the lowest prevalence of risk factors they had a higher median (interquartile range) CACS than the Brazilian and the Portuguese cohorts: 4 (0;87), 1 (0;68) and 0 (0;0), respectively (p <0.0001). After adjusting for differences in age and cardiovascular risk factors, US men showed higher relative risk ratios of having any CACS than either Brazilian or Portuguese men. Brazilian and US women did not differ as far as risk of CACS although they demonstrated a greater risk than Portuguese women. In this study, significant differences in CACS were detected among three nations in different continents. The CACS differences paralleled the respective cardiovascular mortality rates. [Copyright &y& Elsevier]

Abstract: Objectives: We studied whether the amount of heparin-released extracellular superoxide dismutase (EC-SOD), which is an antioxidative enzyme, is associated with coronary artery disease (CAD). Methods and results: EC-SOD was measured in plasma at basal and at post-heparin injection in 315 patients. Heparin-released EC-SOD was calculated as the difference between the two values. After exclusion of a mutant EC-SOD group (n =27:8.6%), 288 patients were divided into three groups by angiographic findings; those with normal coronary (the normal group; n =63), those with atherosclerosis without significant stenosis (the mild atherosclerosis group; n =36), and those with significant stenosis (the atherosclerosis group; n =189). Although the basal values were similar among the three groups, heparin-released EC-SOD levels were significantly lower in the atherosclerosis group (131.0±42.8ng/ml, p =0.0003) than in the normal group (156.9±66.2ng/ml). Moreover, logistic analysis revealed that heparin-released EC-SOD independently contributed to CAD. The coronary score showed a significant correlation with heparin-released EC-SOD. As for factors affecting the level of heparin-released EC-SOD, the level of high-density lipoprotein cholesterol and age showed a positive correlation. Conclusions: The results suggest that heparin-released EC-SOD is significantly reduced in CAD and that the tissue-bound location of this enzyme might be important for antioxidative function. [Copyright &y& Elsevier]

Abstract: Eotaxin (CCL11) is an eosinophil-specific chemoattractant which has been found to be highly expressed at sites of vascular pathology. In the present study, we aimed to evaluate the association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease (CAD). Three hundred and fifty six consecutive patients attending for elective coronary angiography were investigated. Compared with 111 patients without CAD, 245 with CAD showed higher eotaxin concentrations [median (interquartile range): 76.0 (56.3–103.0)pg/ml versus 116.0 (80.5–162.0)pg/ml, respectively; P <0.001]. Importantly, a significant Spearman correlation was found between eotaxin levels and the extent score of coronary artery stenosis (r =0.449, P <0.001). A stepwise increase in plasma levels of eotaxin was also found depending on the number of >50% coronary stenosis: median value 76.0pg/ml in CAD(−) subjects, 96.0pg/ml in 1-vessel disease, 128.0pg/ml in 2-vessel disease, and 129.0pg/ml in 3-vessel disease (P <0.001 for trend). After confounding variables were controlled for, multiple stepwise regression analysis demonstrated that plasma eotaxin was an independent predictor of angiographic extent of CAD (β =0.426, P <0.001). Our data suggest that increased eotaxin levels are associated with the presence of CAD and that circulating levels of this chemokine may reflect the extent of coronary atherosclerosis. [Copyright &y& Elsevier]

Abstract: Elevation in plasma triglycerides (TG) has been widely accepted as a coronary artery disease (CAD) risk predictor. Recently, a new apolipoprotein playing an important role in TG metabolism named apolipoprotein AV (apoAV) was discovered, which is encoded by the APOA5 gene. Several single nucleotide polymorphisms (SNPs) of APOA5 associated with increased TG concentrations have been identified. We here report that a recently identified genetic variant, c.553G>T in the APOA5 gene which causes a substitution of a cysteine for a glycine residue at amino acid residue 185(G185C) is also associated with increased TG levels. To investigate the association between this genetic variation and the risk of CAD, a case-control study comprising 232 patients with CAD and 302 controls from the same area of China was performed. The minor allele frequencies of c.553G>T for the CAD and control groups were 7.76 and 3.97%, respectively (P =0.008). In both the CAD and control groups, the T allele carriers had higher serum TG levels than homozygous carriers of the major G allele (CAD group: 2.67±1.48mmol/l versus 1.95±1.02mmol/l, P =0.021; controls: 2.31±1.20mmol/l versus 1.68±0.95mmol/l, P =0.002). After adjustment for age, gender, body mass index, smoking status, glucose and presence of hypertension, the odds ratio (OR) for CAD in the T allele carriers was 2.089 (95% CI=1.140–3.830, P =0.017), in comparison to the individuals without the T allele. These results suggest that the APOA5 c.553G>T polymorphism is an important predictor for hypertriglyceridemia and CAD. [Copyright &y& Elsevier]

Abstract: We measured 381 genomewide markers and performed genetic linkage analyses in search of loci influencing coronary artery calcification (CAC), a measure of atherosclerosis determined by electron beam computed tomography, in 948 non-Hispanic white siblings (mean age [±standard deviation]=59.6±9.9 years; 73.7% hypertensive). Measured risk factors for atherosclerosis included body mass index, pulse pressure, and high-density lipoprotein (HDL)-cholesterol. After adjustment for sex and age, the logarithm transformed measure of CAC was heritable (0.40±0.08, P <0.0001) and genetically correlated with body mass index (0.28, P <0.001), pulse pressure (0.36, P <0.001), and HDL-cholesterol (−0.19, P <0.001). Univariate linkage analysis demonstrated evidence of linkage for CAC, defined by maximum LOD scores (MLS)≥1.30, on chromosomes 1p, 4p, 5q, 7p, 13q, and 14q. Bivariate linkage analyses of CAC with each risk factor provided evidence of two regions with pleiotropic effects on CAC and HDL-cholesterol on chromosomes 4p16 (MLS=3.03, P =0.00084) and 9q12 (MLS=3.21, P =0.00056), and of a region with pleiotropic effects on CAC and body mass index on chromosome 17p11 (MLS=3.04, P =0.00082). Inasmuch as the chromosome 9 and 17 regions were not detected in the univariate linkage analysis for CAC, multivariate linkage analyses of CAC and genetically correlated risk factors may help localize genes for coronary atherosclerosis. [Copyright &y& Elsevier]

Abstract: Objective: Transesophageal echocardiography (TEE) has been used to visualize aortic arch plaques. TEE is moderately invasive. We employed a new non-invasive method for visualization of the aortic arch to assess the correlation of the extent of plaque in the aortic arch as visualized by non-invasive ultrasound with the prevalence of coronary artery disease (CAD). Methods: The aortic arch was examined with B-mode sonography using a right supraclavicular approach in 517 consecutive patients referred for carotid duplex sonography. CAD was defined as previous myocardial infarction, previous coronary revascularization or typical angina pectoris requiring treatment. Cardiovascular risk factors were documented. Results: The aortic arch could be visualized to measure intima–media thickness (IMT) in 97% of the 517 patients. The IMT was a strong predictor for the presence of CAD. Only 14% (37 out of 256) of patients with an IMT of <1.1mm had overt CAD. The prevalence increased consistently with increase of IMT to 86% among the patients with IMT over 5mm (χ 2, p <0.0000001) (R =0.97, p <0.001). The average IMT increased also with age, diabetes mellitus, arterial hypertension, hypercholesterolemia and tobacco smoking. Conclusions: Aortic arch IMT can be measured in the majority of patients using the right supraclavicular window. The method is non-invasive, allowing sequential examinations applicable to prospective studies of the risk of CAD. [Copyright &y& Elsevier]

Abstract: The molecular causes of severe high-density lipoprotein cholesterol (HDL-C) deficiency was examined in a group of 54 unrelated French Canadian subjects. The lecithin:cholesterol acyl transferase (LCAT) and apolipoprotein (apo) A-I gene were analyzed in all probands by direct DNA sequencing. While no LCAT mutation was detected, a novel nonsense apoA-I mutation (E136X) was found in 3/54 probands. Genetic analysis of two kindreds showed a stong co-segregation of the apoA-I locus with the low HDL-C trait. The E136X mutation was detected in families by MaeI restriction digestion. E136X carriers (n =17) had marked HDL-C deficiency; among the nine carriers ≥35 years old, five men had developed premature coronary artery disease (CAD). A peptide of apparent molecular weight of 14kDa was identified in fresh plasma, the HDL fractions and lipoprotein deficient plasma from the three probands but not in normal controls (n =3), suggesting that the mutant apoA-I peptide is secreted and binds lipids. The mutation was not observed in an additional 210 chromosomes from unrelated subjects of French Canadian descent, <60 years of age, with CAD and low HDL-C levels. We conclude that apoA-I (E136X) is a cause of HDL-C deficiency in the French Canadian population and is associated with premature CAD. [Copyright &y& Elsevier]

Abstract: Introduction: The association between plasma C-reactive protein (CRP) and the extent of coronary artery disease (CAD) in patients with stable angina remains controversial. Obesity is strongly associated with elevated CRP levels, potentially confounding the relationship between CRP and CAD severity. Methods and results: We studied 830 subjects without CAD and 218 patients with CAD undergoing elective coronary angiography. Geometric means of CRP were computed in a two-way analysis of covariance model in which study participants were stratified into nine groups according to CAD status (no CAD, single-vessel disease or multivessel disease) and tertiles of BMI. There was a significant interaction between CAD and categories of BMI with regard to CRP level (P =0.002). In the lower tertile of BMI, patients with CAD had markedly higher CRP concentration compared to control subjects (1.16, 1.80 and 2.82mg/L in subjects without CAD, patients with single-vessel disease and patients with multivessel disease, respectively; P =0.003). However, the relationship between CRP and CAD became weaker for patients in the second BMI tertile (P =0.15), whereas no significant relationship was observed for patients in the third BMI tertile (P =0.75). In patients undergoing coronary angioplasty (n =195), BMI was independently related to the magnitude of the angioplasty-induced CRP elevations (P =0.002). Conclusion: The level of obesity is essential to the interpretation of the relationship between CRP and severity of CAD. The production of inflammatory mediators with increasing levels of obesity becomes the dominant determinant of plasma CRP levels and masks the vascular contribution due to CAD. [Copyright &y& Elsevier]

Abstract: Background: Elevated plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide production, are reported to be associated with coronary artery disease (CAD). Methods: We measured plasma levels of ADMA and related compounds, nitrate+nitrite (NO x ), total homocysteine (tHCY) and assessed renal function and lipid profiles in 145 patients—75 with triple vessel coronary disease and 70 with no detectable coronary disease. Results: Levels of ADMA, l-arginine, l-arginine/ADMA and plasma NO x were not different in the two groups but smokers with triple vessel disease had higher ADMA and lower NO x levels than the non-smokers, relationships also present for all smokers and non-smokers in the two groups combined. In all 145 patients ADMA, symmetric dimethylarginine (SDMA) and tHCY levels were significantly higher in patients with glomerular filtration rate (GFR) <81mL/min/1.73m2 than in patients with GFR≥81mL/min/1.73m2. There was a modest positive correlation between tHCY and ADMA and both were strongly correlated with SDMA which is excreted by the kidney. ADMA, SDMA and tHCY were negatively correlated with GFR. Conclusions: We suggest that the reported ADMA increases in CAD patients are due to an associated reduction in renal function and to smoking habit. [Copyright &y& Elsevier]

Abstract: Oxidative stress may play a role in the development of atherosclerosis. The purpose of the present study was to explore the relationship between 8-isoprostaglandin F2α (8-iso-PGF2α) levels and the presence of coronary artery disease (CAD) and to also clarify whether 8-iso-PGF2α might add independently to measures of CAD extent. The study group consisted of 241 consecutive patients who were undergoing coronary angiography for suspected CAD. 8-iso-PGF2α levels were recorded for all participants. The analysis revealed a significant difference in 8-iso-PGF2α levels in patients with and without hypertension (P <0.001), in patients with diabetes relative to nondiabetic patients (P <0.05), and in males respect to females (P <0.001). A significant positive correlation was found between age and 8-iso-PGF2α levels (P <0.001). 8-iso-PGF2α levels correlated with the number of cardiovascular risk factors (P <0.001). 8-iso-PGF2α levels were higher in the CAD(+) respect to the CAD(−) groups (337.7±80.2 and 263.8±74.2pg/ml and P <0.001). A stepwise elevation in the 8-iso-PGF2α levels was found depending on the number of affected vessels (P <0.001). The 8-iso-PGF2α levels showed a significant positive correlation with the numbers of >50 and >25% stenotic segments (P <0.001) and the extent score of coronary stenosis (P <0.001). The multivariate logistic regression analysis indicated 8-iso-PGF2α as an independent factor associated with CAD (odds ratio, 2.47 and P =0.001). The results suggested that 8-iso-PGF2α is associated with the presence of CAD in patients undergoing coronary angiography and is also related to the extent of coronary stenosis in Chinese population. [Copyright &y& Elsevier]

Abstract: Background: Ascending aortic blood pressure-derived indices were shown to be related to coronary atherosclerosis. Unfortunately, most studies published so far included patients with preserved left ventricular function. Therefore, the aim of the present study was to investigate the relation between ascending aortic blood pressure-derived indices and the extent of coronary atherosclerosis in patients with impaired left ventricular function. Methods: The study group consisted of 375 patients (302 men and 73 women; mean age: 59.0±10.1 years) with angiographically confirmed coronary artery disease and ejection fraction ≤55%. Invasive ascending aortic blood pressure during catheterization and conventional sphygmomanometer measurements were taken. Results: None of the brachial or aortic blood pressure-derived indices differed between patients with one-, two- and three-vessel coronary artery disease. They were not independently related to the risk of having three-vessel coronary artery disease in none of the constructed models in logistic regression analysis. Moreover, none of the studied indices was correlated with Gensini or severity scores. We also did not find any significant correlation between blood pressure-derived indices and extent of coronary atherosclerosis in patients with ejection fraction ≤25%, 25–40% or >40%. Conclusion: Ascending aortic blood pressure-derived indices are not correlated with the severity of coronary atherosclerosis in patients with coronary artery disease and impaired left ventricular function. [Copyright &y& Elsevier]

Abstract: Mast cells may participate actively in the inflammatory process of atherosclerotic plaques by releasing proteolytic enzymes and various other pro-inflammsatory substances. We hypothesized that increased levels of mast cell tryptase, could be an important biomarker in patients with stable coronary artery disease (CAD). We measured tryptase in 102 patients without acute coronary syndromes undergoing cardiac catheterization. Patients with significant CAD [≥50% stenosis in ≥1 artery (n=66)] had significantly higher serum tryptase than patients with normal angiography (n=13) or non-significant CAD [<50% stenosis (n=23)]. The median, 25th and 75th percentiles for tryptase in these two groups were 8.38 (6.4 and 10.7)μg/L versus 6.78 (5.61 and 9.72)μg/L, p=0.014. Patients in the highest quartile of tryptase levels had a 4.3-fold risk for CAD [Odds ratio (OR): 4.3; 95% confidence interval (CI): 1.08–17.19; p=0.04]. In a multivariate regression analysis, tryptase remained an independent predictor for CAD along with age (OR: 1.178; 95% CI: 1.021–1.359, p=0.025). High circulating tryptase levels may be a result of chronic low-grade inflammatory activity present in atherosclerotic plaques. Tryptase measurements may emerge as a novel way of identifying asymptomatic patients with CAD, and represent a new biomarker of therapeutic efficacy in patients with CAD. [Copyright &y& Elsevier]

Abstract: Because the mechanisms of the biological effects of statin and angiotensin converting enzyme inhibitor therapies differ, we studied the vascular responses to these therapies in hypercholesterolemic patients with coronary artery disease. We administered simvastatin 20mg and placebo or ramipril 10mg daily during 2 months with washout 2 months to 32 hypercholesterolemic patients with coronary artery disease. This study was randomized, double-blind, placebo-controlled, crossover in design. Simvastatin alone or combined with ramipril significantly changed lipoproteins, and improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements by 33 ± 6% and by 50 ± 14%, respectively (both P < 0.001) and reduced plasma levels of nitrate relative to baseline measurements (P = 0.413 and 0.037, respectively), the plasma MDA levels relative to baseline measurements by 8 ± 8% and by 18 ± 9% (P = 0.039 and P < 0.001, respectively) and MCP-1 relative to baseline measurements by 7 ± 4% and by 13 ± 3%, respectively (P = 0.019 and P < 0.001, respectively), and CRP from 0.22 to 0.14mg/dl and from 0.22 to 0.15mg/dl, respectively (P = 0.124 and 0.002, respectively), and PAI-1 antigen relative to baseline measurements (P = 0.690 and 0.018, respectively). However, simvastatin combined with ramipril changed to greater but statistically insignificant extent the percent flow-mediated dilator response to hyperemia and plasma levels of nitrate, MDA, MCP-1, and PAI-1 antigen than simvastatin alone. Simvastatin alone or combined with ramipril showed significant beneficial effects on endothelial function in hypercholesterolemic patients with coronary artery disease. However, simvastatin combined with ramipril did not significantly change, compared with simvastatin alone. [Copyright &y& Elsevier]