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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]