Atheroma Burden Research Articles

Fluorescent gold nanoclusters possess multiple actions against atherosclerosis

Atherosclerosis caused major morbidity and mortality worldwide. Molecules possessing lipid-lowering and/or anti-inflammatory properties are potential druggable targets against atherosclerosis. We examined the anti-atherosclerotic effects of fluorescent gold nanoclusters (FANC), which were dihydrolipoic acid (DHLA)-capped 2-nm gold nanoparticles. We evaluated the 8-week effects of FANC in Western-type diet-fed ApoE-deficient mice by either continuous intraperitoneal delivery (20 μM, 50 μl weekly) or via drinking water (300 nM). FANC reduced aortic atheroma burden, serum total cholesterol, and oxidative stress markers malondialdehyde and 4-hydroxynonenal levels. FANC attenuated hepatic lipid deposit, with changed expression of lipid homeostasis-related genes HMGCR, SREBP, PCSK9, and LDLR in a pattern similar to mice treated with ezetimibe. FANC also inhibited intestinal cholesterol absorption, resembling the action of ezetimibe. The lipid-lowering and anti-atherosclerotic effects of FANC reappeared in Western-type diet-fed LDLr-deficient mice. FANC bound insulin receptor β (IRβ) via DHLA, leading to AKT activation. However, unlike insulin, which also bound IRβ to activate AKT to induce HO-1, activation of AKT by FANC was independent of HO-1 expression in human aortic endothelial cells (HAECs). Alternatively, FANC up-regulated NRF2, interfered the binding of KEAP1 to NRF2, and promoted KEAP1 degradation to free NRF2 for nuclear entry to induce HO-1 that suppressed the expression of ICAM-1 and VCAM-1. Consistently, FANC suppressed ox-LDL-induced enhanced attachment of THP-derived macrophages onto HAECs. In macrophages, FANC up-regulated ABCA1, and reversed ox-LDL-induced suppression of cholesterol efflux. FANC effected in vitro at nano moles. In conclusion, our findings showed novel actions and multiple mechanisms of FANC worked coherently against atherosclerosis.

Lesion-level changes induced by low-density lipoprotein cholesterol lowering therapy in patients with acute myocardial infarction: the pre-specified PACMAN-AMI lesion-level analysis

Abstract Background Previous intracoronary imaging studies investigated atherosclerotic changes induced by lipid-lowering therapy in extensive coronary segments, based on anatomical landmarks and irrespective of the baseline atheroma burden. The effects of lipid-lowering therapy focusing on coronary lesions with advanced atherosclerotic features and at presumably higher risk for future events remains largely unknown. Purpose To provide a lesion-level analysis reporting changes in high-risk atherosclerotic features and plaque phenotypes induced by alirocumab versus placebo in addition to high-intensity statin therapy in nonculprit coronary lesions of patients admitted with acute myocardial infarction (AMI). Methods In this pre-specified lesion-level analysis of the PACMAN-AMI trial, coronary lesions were identified as segments with plaque burden ≥40% defined by intravascular ultrasound (IVUS). IVUS, near-infrared spectroscopy (NIRS) and optical coherence tomography (OCT) images at baseline and 52-week follow-up were manually matched and lesion-level imaging outcome measures were calculated by analysts blinded to treatment allocation and patient clinical data. The evolution of high-risk plaque phenotypes as defined by each imaging modality (IVUS-defined plaque burden ≥70%, NIRS-defined maximum LCBI 4 mm ≥400, OCT-defined thin-cap fibroatheroma <65µm) was investigated. Results Overall, 591 lesions with available baseline and follow-up imaging were included. Of these, 287 were identified in 118 patients (214 vessels) in the alirocumab arm, and 304 lesions were identified in 127 patients (239 vessels) in the placebo arm. At lesion-level, mean change in percent atheroma volume (PAV) by IVUS was -4.86% with alirocumab vs -2.78% with placebo (difference, -2.02 [-3.00 to -1.05], p<.001), substantially greater than that at vessel-level (Figure 1). At the minimum lumen area (MLA) site, mean change in PAV was -10.14% with alirocumab vs -6.70% with placebo (difference, -3.36 (-4.98 to -1.75, p<0.001). MLA increased by 0.15 mm2 with alirocumab and decreased by 0.07 mm2 in the placebo arm (difference, +0.21, 0.01 to 0.41, p=0.036), whereas arterial remodeling was similar between arms (-0.73±1.61 in alirocumab vs -0.63±1.31 in placebo group, p=0.482). Among lesions with high-risk plaque phenotypes at baseline, those in the alirocumab arm more frequently showed a more stable and less lipid-rich plaque phenotype at follow-up than those in the placebo arm (Figure 2). Conclusions At lesion-level, intense lipid-lowering therapy with alirocumab in addition to high-intensity statin therapy induced extensive PAV regression, substantially greater than described in previous vessel-level analyses. Compared to statin therapy alone, alirocumab treatment was associated with a greater enlargement of the lesion MLA, similar negative arterial remodeling, and a more frequent transition of high-risk plaque phenotypes into more stable, less lipid-rich plaque phenotypes.Figure 1.Figure 2

Deep learning detection of subclinical cardiovascular dysfunction in type 2 diabetes through retinal photography

Abstract Background Type 2 diabetes (T2D) is associated with excess atherosclerotic coronary disease and heart failure risk, with several cardiac abnormalities described in asymptomatic patients. Routine digital retinal photography performed for screening of diabetic retinopathy (DR) has the potential to identify patients with underlying cardiovascular disease (CVD). We aimed to determine whether features extracted from digital retinal photographs could detect subclinical cardiovascular dysfunction in asymptomatic people with T2D. Methods We prospectively enrolled adults with T2D and no history or symptoms of CVD to undergo extensive phenotyping with multiparametric stress perfusion cardiac MRI and CT coronary artery calcium scoring. Digital retinal photographs acquired for routine diabetic eye screening and performed within one year of cardiac evaluation were interrogated for retinopathy grading and using four deep learning (DL) models (Xception, Inception, EfficientNet, and MobileNet) to capture complex patterns within the retinal vasculature. Each subject had four retinal photographs (two of each eye) for DL analysis. Cardiac image analysis was performed blinded to participant details and independent of retinal images. Subjects with and without DR were compared. Participants were divided into training (80%) and validation datasets (20%) prior to DL analysis. DL models employed to predict from retinal images: presence or absence of coronary artery calcium on non-contrast CT, myocardial perfusion reserve <2.5, left ventricular (LV) global longitudinal strain <16%, absolute stress and rest myocardial blood flood (mL/g/min) used as continuous variables. AUC was used to assess the ability of DL models to discriminate between those without and without subclinical CVD. Results An initial 254 subjects (comprising 1,016 retinal photographs) were included in the analysis: 212 (83%) with no DR, 42 (17%) with grade 1 (mild background) DR. Key cardiac imaging parameters in subjects with and without DR are displayed in Table 1. The groups were well matched for age, sex, body mass index and blood pressure. Overall, those with grade 1 DR had higher atheroma burden, evidence of increased LV filling pressures (E/e’) and poorer systolic function, but no differences in stress and rest myocardial blood flow or myocardial perfusion reserve. However, all four DL models failed to achieve sufficient discrimination of any of the evaluated cardiac imaging parameters, with the majority achieving AUC scores below 50% for all cardiac parameters. Conclusion Asymptomatic adults with grade 1 DR exhibit more subclinical atherosclerosis and cardiovascular dysfunction than those without DR. However, DL transfer models could not discriminate between subjects with and without cardiovascular disease. Further work is needed to better define whether retinal screening may be used to identify those people with T2D most at risk of underlying cardiovascular disease.Subjects demographics

Investigation of the Association between Bilateral Selective Anterograde Cerebral Perfusion and Postoperative Ischemic Stroke in Obese Patients with Emergency Surgery for Acute Type A Aortic Dissection.

Background and objectives: The relationship between cerebral perfusion and new postoperative ischemic stroke in obese patients is not well defined. The aim of this study was to investigate the association between selective bilateral anterograde cerebral perfusion and new postoperative ischemic stroke in obese patients with emergency surgery for acute type A aortic dissection. Materials and methods: A total of 292 patients with emergency surgery for acute type A aortic dissection were included in this study. Patients with hemorrhagic stroke or ischemic stroke with severe neurological dysfunction at admission that were not candidates for surgery; patients who died in the first 48 h after intensive care admission and patients with incomplete medical records were excluded. Results: The mean age was 59.42 ± 10.68 years and the mean Euroscore was 9.12 ± 1.63. Obesity was present in 76.4%, the incidence of new postoperative ischemic stroke was 27.5%, and the postoperative mortality rate was 26.7%. The mean cardiopulmonary bypass time was 206.81 ± 75.48 min, the aortic cross-clamp time was 118.2 ± 46.42 min, and 90% of cases required cerebral perfusion. The mean cerebral perfusion time was 30.8 ± 24.41 min. Obese patients had a higher frequency of in-hospital death (p = 0.009), smoking (p = 0.036), hypertension (p = 0.023), left common carotid artery dissection (p < 0.001), right common carotid artery dissection (p = 0.029), femoral artery cannulation (p = 0.026), aortic root replacement (p = 0.009), aortic valve replacement (p = 0.005) and early reintervention for bleeding (p = 0.004). Using logistic regression, selective bilateral anterograde cerebral perfusion over 40 min in obese patients was independently associated with new postoperative ischemic stroke (OR = 2.35; 95%CI = 1.36-4.86; p = 0.021). Conclusions: A patient-tailored strategy for cerebral perfusion should be considered in obese patients, considering the high atheromatous burden of the supra-aortic vessels in these patients and the potential risk of atheromatous embolization associated with this technique.

Incidence and prediction of periprocedural myocardial infarction in elective PCI: the ALPHEUS-MI sub-study

Abstract Background PCI-related myocardial infarction (MI) or injury are frequent events that have been shown to be associated with long-term ischemic outcomes and mortality. Determinants of these events with the validated definition of PCI-related myocardial infarction (MI) or injury are not well documented in contemporary elective PCI. Methods The ALPHEUS-MI study is a prespecified analysis of the ALPHEUS randomized trial conducted in 49 centers of two European countries which recruited 1910 patients with chronic coronary syndrome undergoing elective PCI. We analyzed the rate and predictors of periprocedural myocardial necrosis using the primary and secondary endpoint of the ALPHEUS trial (3rd and 4th universal definition of MI) and the ARC2/SCAI definitions. Multivariable model including patient’s demographic, angiographic and procedural characteristics were performed for each definition to determine predictors of periprocedural events. Findings : The primary endpoint of the ALPHEUS trial (type 4a MI or major myocardial injury) occurred in 35.85% of the patients (3rd universal definition of MI); the secondary endpoint of the ALPHEUS trial (type 4a MI and any myocardial injury) occurred in 77.21% of the patients (4th universal definition of MI); significant periprocedural myocardial injury occurred in 3.24% of the patients (ARC2/SCAI definition) and periprocedural MI (ARC2/SCAI definition) in 2.02% of the patients. The rate of events followed a stepwise increase according to the number of high-risk features with all definitions (figure). High risk features were characterized by patients’ characteristics, the complexity of the coronary lesion (anatomy and atheroma burden) and the complexity of the PCI procedure itself. The only common predictor of MI or myocardial injury present with the 4 definitions was the total length of stent implanted (&amp;gt;60mm) ; adjOR 3.23 (2.49-4.18) p&amp;lt;0,001 (type 4a MI/major injury 3rd UDMI ) , adjOR 3.82 (2.51-5.8) p&amp;lt;0,001 (type 4a MI/any injury 4th UDMI) , adjOR 2.2 (1.24-3.91) p=0,007 (myocardial injury ARC2/SCAI) and adjOR 6.0 (3.04-11.9) p&amp;lt;0,001 (MI ARC2/SCAI). Conclusion Whatever definition of type 4aMI and myocardial injury, the strongest predictor of myocardial necrosis seems to be the length of stent implanted which reflects both the severity of atheroma burden and the complexity of PCI.

Associations of High-Density Lipoprotein Functionality with Coronary Plaque Characteristics in Diabetic Patients with Coronary Artery Disease: Integrated Backscatter Intravascular Ultrasound Analysis.

High-density lipoprotein (HDL) functionality has been reported to be associated with coronary artery disease (CAD). However, little is known about the impact of HDL functionality on coronary atherosclerosis. Thirty-eight type 2 diabetic patients with CAD who underwent percutaneous coronary intervention were examined. Coronary atheroma burden and plaque composition of the culprit lesions were assessed using conventional gray-scale and integrated backscatter intravascular ultrasound. HDL-mediated cholesterol efflux capacity (HDL-CEC) and HDL antioxidant capacity, estimated as HDL inflammatory index (HII), were examined. The associations between HDL functionality and coronary plaques were analyzed using multivariate data analysis, including principal components analysis and orthogonal partial least squares (OPLS) models. Percent atheroma volume was correlated with HDL-CEC (r = 0.34, p = 0.04) but not with HII (p = 0.65). The OPLS model demonstrated that the percentage lipid volume was significantly associated with HDL functionality [coefficient (95% confidence interval); HDL-CEC: -0.26 (-0.49, -0.04); HII: 0.34 (0.08, 2.60), respectively]. HII exhibited the highest variable importance in projection score, indicating the greatest contribution. HDL functionality was associated with coronary plaque composition, a key component of plaque vulnerability. Our findings highlight the potential importance of HDL functionality for coronary plaque stabilization.

Coronary artery disease grading by cardiac CT for predicting outcome in patients with stable angina

BackgroundThe coronary atheroma burden drives major adverse cardiovascular events (MACE) in patients with suspected coronary heart disease (CHD). However, a consensus on how to grade disease burden for effective risk stratification is lacking. The purpose of this study was to compare the effectiveness of common CHD grading tools to risk stratify symptomatic patients. MethodsWe analyzed the 5-year outcome of 381 prospectively enrolled patients in the CORE320 international, multicenter study using baseline clinical and cardiac computer-tomography (CT) imaging characteristics, including coronary artery calcium score (CACS), percent atheroma volume, “high-risk” plaque, disease severity grading using the CAD-RADS, and two simplified CAD staging systems. We applied Cox proportional hazard models and area under the curve (AUC) analysis to predict MACE or hard MACE, defined as death, myocardial infarction, or stroke. Analyses were stratified by a history of CHD. Additional forward selection analysis was performed to evaluate incremental value of metrics. ResultsClinical characteristics were the strongest predictors of MACE in the overall cohort. In patients without history of CHD, CACS remained the only independent predictor of MACE yielding an AUC of 73 (CI 67–79) vs. 64 (CI 57–70) for clinical characteristics. Noncalcified plaque volume did not add prognostic value. Simple CHD grading schemes yielded similar risk stratification as the CAD-RADS classification. Forward selection analysis confirmed prominent role of CACS and revealed usefulness of functional testing in subgroup with known CHD. ConclusionIn patients referred for invasive angiography, a history of CHD was the strongest predictor of MACE. In patients without history of CHD, a coronary calcium score yielded at least equal risk stratification vs. more complex CHD grading.

The Role of Coronary CT Angiography in the Management of Patients with Coronary Atherosclerotic Diseas

"Coronary CT angiography is a non-invasive method of analyzing the coronary lumen through which the atheromatous bur-den can be evaluated, with the analysis of the type of plaque (soft, calcified, mixed) and the impact on the arterial lumen (stenosis, occlusion). The anatomical evaluation by coronary CT is indicated in symptomatic patients with low and medium risk factors for coronary atherosclerotic disease, in those with inconclusive laboratory and EKG results, patients with un-certain stress test results, in the evaluation of coronary grafts and intrastent stenoses. Depending on the result of the angiography, the severity of the stenosis and the management of the patient are established. In the case of mild and medium stenoses, risk factors management and drug treatment are recommended. For severe stenoses, patients are referred for interventional coronary angiography or functional evaluation. Coronary CT angiography increases the certainty of coronary atherosclerotic disease diagnosis. It has a superior discriminative capacity of plaques with low attenuation, the main predictor of myocardial infarction, with almost five-fold higher risk. Coronary CT angiography increases the adaptation of medication, and the inclusion of statin therapy decreases the risk of fatal and nonfatal myocardial infarction at 5 years and increases the quality of life "

Supra-renal aortic atheroma extent and composition predict acute kidney injury after transcatheter aortic valve replacement: A three-dimensional computed tomography study

ObjectiveAcute kidney injury (AKI) may complicate transcatheter aortic valve replacement (TAVR) and could be linked to atheroembolization associated with catheter manipulation in the supra-renal (SR) aorta.We sought to determine the impact of SR aortic atheroma burden (SR-AAB) and composition, as well as of the aortic valve calcium score (AV-CS), measured at pre-operative multislice computed tomography (PO-MSCT), on AKI-TAVR. MethodsAll TAVR-patients 3 January-2018 to December-2020 were included. A three-dimensional analysis of PO-MSCT was performed, calculating percentage SR-AAB (%SR-AAB) as [(absolute SR-AAB volume)*100/vessel volume]. Types of plaque were defined according to Hounsfield unit (HU) intensity ranges. Calcified plaque was subcategorized into 3 strata: low- (351–700 HU), mid- (701–1000 HU), and high‑calcium (>1000 HU, termed 1 K-plaque). ResultsThe study population included 222 patients [mean age 83.3 ± 5.7 years, 95 (42.8%) males], AKI-TAVR occurred in 67/222 (30.2%). Absolute SR-AAB (41.3 ± 16.4 cm3 vs. 32.5 ± 10.7 cm3,p < 0.001) and %SR-AAB (17.6 ± 5.1% vs. 13.9 ± 4.3%,p < 0.001) were significantly higher in patients developing AKI-TAVR.Patients who developed AKI-TAVR had higher mid‑calcium (6.9 ± 3.8% vs. 4.2 ± 3.5%,p < 0.001) and 1 K-plaque (5.4 ± 3.7% vs. 2.4 ± 2.4%,p < 0.001) with no difference in AV-CS (p = 0.691).Adjusted multivariable logistic regression analysis showed that %SR-AAB [OR (x%increase): 1.12, 95%CI: 1.04–1.22,p = 0.006] and %SR-calcified plaque [OR (x%increase): 5.60, 95%CI: 2.50–13.36,p < 0.001] were associated with AKI-TAVR. Finally, 3-knots spline analyses identified %SR-AAB >15.0% and %SR-calcified plaque >7.0% as optimal thresholds to predict an increased risk of AKI-TAVR. ConclusionsSuprarenal aortic atheroma, when highly calcified, is associated with AKI-TAVR. Perioperative-MSCT assessment of aortic atherosclerosis may help in identification of patients at high-risk for AKI-TAVR, who could benefit from higher peri-operative surveillance.

Abstract P596: Familiar Hypercholesterolemia is Associated With Lower All-Cause Mortality Despite Higher Complexity of Coronary Lesions and Interventions Among Patients Admitted With Acute Myocardial Infarction

Background: Familiar hypercholesterolemia is a genetic disorder affecting lipoprotein metabolism which is strongly associated with early atherosclerosis. Our resolve in this study is to evaluate the severity of coronary lesions ,complexity of acute interventions and clinical outcomes. Hypothesis: Patients with familiar hypercholesterolemia are relatively younger, have high coronary atheroma burden with less comorbidities, thus likely to have complex atherosclerosis but with paradoxical better prognosis. Method: A retrospective cohort study with data from the 2016 to 2018 combined National Inpatient Sample (NIS) database was employed. ICD-10 codes were used to sample all admissions for acute myocardial infarction who were then dichotomized based secondary diagnosis of familiar hypercholesterolemia. Procedure codes of ICD-10 were used to identify patients undergoing coronary revascularizations. We determined relative frequencies of various ischemic injury patterns and complexity of revascularization procedures among the two cohorts. Primary clinical outcome of mortality rate, and secondary outcomes including length of stay and total hospital charge were then assessed. Multivariate linear and logistic regressions were used to adjust for confounders. Results: We identified a total of 4,300,389 adult hospitalizations for acute myocardial infarction including 0.033% with familiar hypercholesterolemia. Patients with familiar hypercholesterolemia were younger (55.8 years vs 58.2 years, adjusted mean difference: -7.87 years, 95%CI: -9.49 years to -6.0 years). Table 1 below shows details of outcomes of our study. Conclusion: Among patients hospitalized with acute myocardial infarction, comorbid familiar hypercholesterolemia was associated with a 62% reduction in odds of in-hospital all-cause mortality despite a 2.25-fold increased odds of STEMI and higher odds for having multivessel percutaneous. revascularization.

PS-BPB01-5: LOX-1 DEFICIENCY INCREASES RUPTURED ABDOMINAL AORTIC ANEURYSM VIA THINNING OF ADVENTITIAL COLLAGEN

Objective: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a key mediator of inflammation and plays an important role in the pathogenesis of atherosclerosis. Both inflammation and atherosclerosis have been proposed as contributors to abdominal aortic aneurysm (AAA) pathogenesis. However, the role of LOX-1 in AAA pathogenesis remains unknown. We aimed to investigate effects of Olr1, which encodes LOX-1, deletion on angiotensin II (Ang II)-induced AAA in apolipoprotein E knockout (ApoE KO) mice to determine whether LOX-1 deficiency mitigates AAA development. Design and method: Either Ang II (1.44 mg/kg/day) or saline (control) was administered continuously through a subcutaneously implanted osmotic pump for 4 weeks in the following 8-week-old male mice: Apoe-/-Olr1+/+ mice (Ang II, n = 40; saline, n = 10), Apoe-/-Olr1+/- mice (Ang II, n = 30; saline, n = 9), and Apoe-/-Olr1-/- mice (Ang II, n = 39; saline, n = 9). Results: Ang II infusion raised systolic blood pressure by tail-cuff methods in all three groups. Serial non-invasive assessment with ultrasound demonstrated that Ang II gradually increased the maximum area of the suprarenal abdominal aortas leading to AAAs. Although the incidence and expansion rate of AAA were comparable among genotypes, Olr1 deletion significantly increased the severity and rupture rate of AAAs (p = 0.01; incidence of type IV and ruptured AAA was 25% in Apoe-/-Olr1-/- mice vs 5% in Apoe-/-Olr1+/+ mice). Since atherosclerosis is considered a major contributor to the development of AAAs, the extent of the atheroma burden localized in aneurysmal lesions was evaluated by Oil Red O staining. Olr1 deletion did not decrease atherosclerosis formation in the aneurysmal wall. Interestingly, further histopathological analysis revealed that aneurysmal lesions in LOX-1-deficient mice had fewer fibroblasts and myofibroblasts, as well as thinner adventitial collagen, although the degree of elastin fragmentation or disruption was similar between LOX-1-deficient and control mice. These in vivo data suggested that adventitial fibroblasts play a pivotal role in the increased severity of AAA in LOX-1-deficient mice. To further determine the effects of Olr1 deletion on fibroblast differentiation, fibroblasts were isolated from the adventitia of abdominal aortas harvested from 8-week-old Apoe-/-Olr1+/+ and Apoe-/-Olr1-/- mice, and then cultured with Ang II stimulation. An in vitro study confirmed that Olr1 deletion completely abolished the Ang II-induced proliferative activity in the aortic adventitial fibroblasts (p = 0.02). Conclusions: Olr1 deletion may not mitigate aneurysm development but rather increase the vulnerability to rupture by suppressing adventitial fibroblast proliferation and collagen.

LOX-1 deficiency increases ruptured abdominal aortic aneurysm via thinning of adventitial collagen.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a key mediator of inflammation and plays an important role in the pathogenesis of atherosclerosis. Conversely, LOX-1 deficiency has been shown to decrease inflammation and atherosclerosis, both of which have been proposed to contribute to abdominal aortic aneurysm (AAA) pathogenesis. However, the role of LOX-1 in AAA pathogenesis remains unknown. Here, we investigated the effects of Olr1 (which encodes LOX-1) deletion on angiotensin II (Ang II)-induced AAA in apolipoprotein E knockout (ApoE KO) mice to determine whether LOX-1 deficiency mitigates AAA development. To accomplish this, we used serial, non-invasive ultrasound assessment, which revealed that the incidence and expansion rate of AAA were similar regardless of Olr1 deletion. However, Olr1 deletion significantly increased severe AAAs, including ruptured AAAs resulting in death. Oil Red O staining of the harvested aortas showed that the extent of atheroma burden localized in aneurysmal lesions did not differ between LOX-1-deficient and control mice, suggesting that Olr1 deletion did not decrease atheroma burden in the aneurysmal wall. Further histopathological analysis revealed that aneurysmal lesions in LOX-1-deficient mice had fewer fibroblasts and myofibroblasts, as well as thinner adventitial collagen, although the degree of elastin fragmentation or disruption was similar between LOX-1-deficient and control mice. An in vitro study confirmed that the proliferation of adventitial fibroblasts collected from LOX-1-deficient mice was significantly attenuated despite Ang II stimulation. In conclusion, Olr1 deletion may not mitigate aneurysm development but rather increases the vulnerability of rupture by suppressing adventitial fibroblast proliferation and collagen synthesis.

Association between plasma desmosine, a marker of elastin degradation, and total atherosclerotic burden measured by whole body magnetic resonance angiography

Abstract Background Elastin degradation has been implicated in the pathophysiology of vulnerable atherosclerotic plaque. Desmosine is the cross-link component in the elastin molecule and is exclusively released from mature elastin breakdown, thus has the potential to be a physiologically relevant biomarker of atherosclerosis. Objectives The aim of the present study was: 1. To investigate whether patients with known cardiovascular disease (CVD) have higher elastin degradation as indicated by plasma desmosine (pDES); 2. to determine the relationship between pDES and total atherosclerotic burden. Methods We measured pDES by a validated stable isotope dilution LC-MS/MS method1 in a total of 146 subjects from the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study2. (62% male, mean age 64±8 (SD) years). This included 62 patients with prior clinical diagnosis of CVD (including coronary artery disease (CAD), cerebrovascular disease and/or lower extremity arterial disease (LEAD)), and 84 patients without a clinical diagnosis of CVD. Total atherosclerotic burden was measured by whole body magnetic resonance angiography (WB-MRA). The WB-MRA data was divided into 31 anatomical arterial segments with each segment scored according to degree of luminal narrowing: 0 = no stenosis, 1 = &amp;lt;50% stenosis, 2 = 51–70% stenosis, 3 = 71–99% stenosis, 4 = vessel occlusion. The segment scores were summed and from this, a standardized atheroma score (SAS) was calculated by summing each individual segment's stenosis score, and divided by the number of diagnostic segments before dividing by 4 which is the maximum potential score. Relationship between SAS and pDES levels was investigated using multiple linear regression models Results pDES levels were significantly greater in patients with established clinical CVD compared to patients with no CVD (CVD patients, 0.56 (0.45–0.67) ng/mL; patients with no CVD, 0.47 (0.41–0.54)ng/mL; p=0.001). Median SAS for the study population was 4 (2–10). Overall pDES levels showed a strong correlation with SAS (r=0.44, p≤0.001). Univariable analysis suggested a significant association between pDES and whole-body atheroma score as measured by SAS. (β 29.31, p&amp;lt;0.001). This association persisted in the multivariable regression model adjusting for traditional cardiovascular risk factors including age, gender, BMI, systolic blood pressure, diabetes, smoking status and LDL. (adjusted β 18.75, p=0.004) Conclusion pDES levels are elevated in patients with clinical CVD when compared to those with no clinical history of CVD. pDES is also strongly associated with global atheroma burden. Overall, these findings support the role of pDES as a potential biomarker for atherosclerosis. Funding Acknowledgement Type of funding sources: None.

Tayside Screening For Cardiac Events (TASCFORCE) study: a prospective cardiovascular risk screening study

PurposeRisk factor-based models struggle to accurately predict the development of cardiovascular disease (CVD) at the level of the individual. Ways of identifying people with low predicted risk who will develop...

Clonal hematopoiesis of indeterminate potential: A cardiovascular risk factor among others

Clonal hematopoiesis of indeterminate potential (CHIP) are defined by the detection of leukemia-associated somatic mutations in leukocytes of healthy subjects. CHIP are associated with increased risk of cardiovascular event (CVE) related to atherothrombosis (myocardial infarction MI, stroke) independently of traditional cardiovascular risk factors (CVRF). We aim to demonstrate that CHIP increase the risk of occurence of CVE related to atherothrombosis and to determine the mecanisms by which CHIP interact with CVRF to lead to these CVE. The french multi-centric 3 C cohort includes thousands of randomly selected subjects over 65 without history of CVE and who have benefited of cardiological monitoring with 12 years follow-up. We selected 289 subjects (142 suffered from CVE and 147 control without CVE during follow-up) for wich we have biological and clinical data and performed next generation sequencing (NGS) to detect presence of CHIP. We then evaluated global cardiovascular risk using AHA life's simple 7 and defined it as favorable if patient had at least 3 optimum items. Finally, we studied association between presence of CHIP, cardiovascular and inflammatory profile at inclusion, and incidence of CVE (MI or angina). CHIP were detected in 41% of subjects and mainly concerned mutations of DNMT3A (46%) and TET2 (30%) genes. Patients with CHIP were older than ones with no CHIP ( P = 0.03) but without increased CRP levels (1.66 vs. 1.75 mg/L respectively). We did not observe any difference between patients with or without CHIP regarding atheroma burden or prevalence of CVRF. However, patients with CHIP had more frequently low cardiovascular risk (68.2% vs. 55.3%, P = 0.042). During follow-up, 79 patients developed a MI and 73 an angina. Presence of CHIP did not impact frequency nor onset time of CVE. Yet, among patients who suffered from CVE, patients with CHIP had more frequently low cardiovascular risk ( P = 0.0013 for angina ± MI, P = 0.01 for MI only). In a population without history of CVE, presence of CHIP is not associated with increased inflammation nor increased atheroma burden. CHIP alone do not induce major increase of atherothrombosis-linked CVE incidence. However, CHIP seem to interact with conventional CVRF to induce CVE, either through synergic effect, or by replacing particular factors.

Abstract 525: Uncovering Mechanisms Between Oligosaccharide Galactose-alpha 1,3-galactose (alpha-gal) Sensitization And Atherosclerosis

Recent work by our group and others have shown individuals with IgE to the oligosaccharide allergen present in mammalian products (α-gal) have increased atheroma burden with increased necrosis and calcification compared to those without α -gal specific IgE. These data suggest α -gal specific IgE increase plaque severity and vulnerability, yet the mechanisms that promote production of IgE to α -gal are unknown. Previous work from our group utilized multi-omics single cell analysis of circulating PBMCs from subjects with coronary angiography at UVA and showed subjects with IgE α -gal sensitization had a higher frequency of CCR6hi switched memory (SWM) B cells and that the CCR6 ligand, CCL20, increased class switching to IgE. To determine mechanisms whereby CCR6 may mediated class switching to IgE, we enriched total B cells from healthy donor peripheral blood mononuclear cells and stimulated with 20ng/ml human IL-4 and 10μg/ml agnostic anti-human CD40 with or without 20ng/ml CCL20 for 3 days. After 3 days of treatment, cells were collected and stained with a 15-color panel and analyzed via flow cytometry. Cells were analyzed for surface expression of CD20 and CD3 to gate total B cells. Gated B cells were further separated into CD27+/IgM-/IgD- to define SWM B cell population. CCL20 treatment did not increase the total percent of SWM B cells; however, there was a 2-3-fold increase in CCR6+ SWM B cells compared to CCR6- SWM B cells. CCL20 treated CCR6+ SWM B cells have an average of 7% increase of phosphorylated mTOR in total SWM B cells compared to nonCCL20 treated CCR6+ SWM B cells. These results suggest CCL20 stimulation induces mTOR phosphorylation and activation. Thus, mTOR activation and downstream mediators may be necessary for α -gal induced B cell class switching. From these preliminary studies, we conclude that CCL20 stimulation increases the percent pmTOR+ SWM B cells. We will continue to investigate downstream mTOR mediators in regard to B cell class switching after CCL20 stimulation and how α-gal sensitization augments B cell IgE class switching and increases atherosclerosis with our novel α -gal-/- Apoe-/- mouse.

Coronary Artery Disease Features and Epicardial Adipose on CT are Predictive Factors for Cardiovascular Events in Type 2 Diabetic Patients at High/Very High Cardiovascular Risk: A Pilot Retrospective Study

Aim: The study aimed to estimate the association between characterizations on coronary computed tomography angiography (CCTA) and cardiovascular events in type 2 diabetic patients at high/very high cardiovascular risk without known coronary artery disease (CAD), to investigate the incremental value of CCTA in these individuals. Methods: 82 type 2 diabetes patients without known CAD were enrolled according to the 2019 European Society of Cardiology (ESC) guidelines of high/ very high cardiovascular risk. The coronary artery calcium score, plaque location and extent and composition, stenosis severity, and epicardial adipose tissue (EAT) volume were evaluated. The cardiovascular events included cardiac death, non-fatal myocardial infarction, coronary revascularization, non-fatal stroke, hospitalization for unstable angina, and hospitalization for congestive heart failure during a mean follow-up period of 4.7±1.5 years. Univariate analysis and multivariate regression were used to obtain independent risk factors for CVEVs in these patients. The increased discriminative value after the addition of CAD features and EATS volume to the established clinical risk factors were estimated using the area under a receiver-operating characteristic curve (AUC). Results: CVEVs occurred in 26.8% of the patients. Independent predictors of CVEVs included hypertension (odds ratio (OR) 3.844, P=0.020), diabetes duration (OR 1.129, P=0.049), creatinine (OR 1.072, P=0.022), ABOS (OR 1.729, P=0.031), SSS (OR 1.213, P=0.021), and EAT volume (OR 1.025, P=0.012) The combination of ABOS, SSS and clinical risk factors improved the identify of CVEVs, with an area under the receiver operating characteristic curve of 0.955 (95% confidence interval 0.885 to 0.989; P=0.004) for the prediction of the endpoints. Conclusion: The extent and severity of overall coronary atheroma burden and EAT volume based on CCTA are associated with long-term CVEVs for type 2 diabetic patients at high/very high cardiovascular risk. CCTA has incremental value in evaluating the heterogeneity of such subclinical patients and beneficial forewarning for these individuals with CVEVs.

Prevalence and extent of coronary artery disease among patients with a zero calcium score

Background and objective: Coronary artery calcium is a specific indicator of and an independent risk factor for atherosclerosis. However, calcium scoring may miss non calcified plaques, which were indicated to be of clinical importance. This study aimed to identify the presence of non calcified plaques in patients with zero coronary artery calcium score who have been examined with computed tomography coronary angiography and find out any association between the presence of non-calcified plaques and risk factors and presenting symptoms in those patients. Methods: In this retrospective study, we analyzed the computed tomography images of 9826 consecutive patients attending the cardiac center in Erbil, Iraq, between January 2016 and September 2020. Of these patients, we included 2805 patients with a zero coronary artery calcium score in the study. Coronary calcium-scoring scans were followed by computed tomography coronary angiography (256 MSCT Philips ICT). The coronary artery calcium scores were calculated, and the presence of non calcified plaques and significant stenosis (&gt;50% of vessel diameter) were evaluated. Results: Of the 2805 patients with a zero coronary artery calcium score, 896 (31.9%) had atherosclerotic plaques; 143 patients (5.1%) had significant coronary stenosis. Among coronary risk factors, diabetes mellitus (OR = 2.1; 95% CI 1.4-3.3), hypertension (OR = 1.3; 95% CI 1.07-1.58)), male sex (OR = 1.9; 95% CI 1.5-2.3) and old age (OR was 3.2 for the age group 35-44 years reaching 27.7 in the age group ≥ 75 years) were significantly correlated with the presence of atherosclerosis and obstructive coronary artery disease. Conclusion: Although coronary artery calcium scoring is a safe and reliable test to exclude obstructive coronary artery disease, the absence of coronary artery calcium does not absolutely exclude the presence of atherosclerosis. Computed tomography coronary angiography is mandatory for determining the atheroma burden from zero coronary artery calcium score plaques.

Plaque-targeted, proteolysis-resistant, activatable and MRI-visible nano-GLP-1 receptor agonist targets smooth muscle cell differentiation in atherosclerosis.

Background: Glucagon-like peptide-1 receptor (GLP-1R) agonists are powerful glycemia-lowering agents, which have systematically been shown to lower cardiovascular events and mortality. These beneficial effects were difficult to pinpoint within atherosclerotic plaque due to lack of particular specificity of such agonists to the vascular cells and an inadequate understanding of the GLP-1R expression in atherosclerosis. Here, we hypothesized that the direct engagement of the GLP-1R in atherosclerosis by targeted agonists will alleviate vascular inflammation and plaque burden, even at a very low dose.Methods: The expression of GLP-1 receptor (GLP-1R, Glp1r mRNA) in human lesions with pathologic intimal thickening, Apoe-/- mouse atheroma and cultured immune/non-immune cells was investigated using genetic lineage tracing, Southern blotting and validated antisera against human GLP-1R. Protease-resistant and “activatable” nanoparticles (NPs) carrying GLP-1R agonist liraglutide (GlpNP) were engineered and synthesized. Inclusion of gadolinium chelates into GlpNP allowed for imaging by MRI. Atherosclerotic Apoe-/- mice were treated intravenously with a single dose (30 µg/kg of liraglutide) or chronically (1 µg/kg, 6 weeks, 2x/week) with GlpNP, liraglutide or control NPs, followed by assessment of metabolic parameters, atheroma burden, inflammation and vascular function.Results: Humal plaque specimens expressed high levels of GLP-1R within the locus of de-differentiated smooth muscle cells that also expressed myeloid marker CD68. However, innate immune cells under a variety of conditions expressed very low levels of Glp1r, as seen in lineage tracing and Southern blotting experiments examining full-length open reading frame mRNA transcripts. Importantly, de-differentiated vascular smooth muscle cells demonstrated significant Glp1r expression levels, suggesting that these could represent the cells with predominant Glp1r-positivity in atherosclerosis. GlpNP resisted proteolysis and demonstrated biological activity including in vivo glycemia lowering at 30 µg/kg and in vitro cholesterol efflux. Activatable properties of GlpNP were confirmed in vitro by imaging cytometry and in vivo using whole organ imaging. GlpNP targeted CD11b+/CD11c+ cells in circulation and smooth muscle cells in aortic plaque in Apoe-/- mice when assessed by MRI and fluorescence imaging. At a very low dose of 1 µg/kg, previously known to have little effect on glycemia and weight loss, GlpNP delivered i.v. for six weeks reduced triglyceride-rich lipoproteins in plasma, plaque burden and plaque cholesterol without significant effects on weight, glycemia and plasma cholesterol levels.Conclusions: GlpNP improves atherosclerosis at weight-neutral doses as low as 1 µg/kg with the effects independent from the pancreas or the central nervous system. Our study underlines the importance of direct actions of GLP-1 analogs on atherosclerosis, involving cholesterol efflux and inflammation. Our findings are the first to suggest the therapeutic modulation of vascular targets by GlpNP, especially in the context of smooth muscle cell inflammation.

579 Pre-operative computed tomography evaluation of suprarenal aortic burden predicts post-procedural acute kidney injury after transcatheter aortic valve replacement: the spread-AKI study

Abstract Aims Acute kidney injury (AKI) is a potential complication of transcatheter aortic valve replacement (TAVR). Athero-embolization linked to catheter manipulation in the supra-renal aorta is a possible pathogenetic mechanism of AKI after TAVR. We sought to determine the impact of supra-renal aortic atheroma burden (AB) on AKI, and the potential role of pre-operative multislice computed tomography (PO-MSCT) in evaluating the supra-renal aortic atherosclerosis and the pre-operative risk of AKI. Methods and results We collected PO-MSCT, as well as baseline, procedural, and post-procedural characteristics of 222 consecutive patients who underwent TAVR from January 2018 to December 2020 at a single, high-volume, Italian centre. PO-MSCT was performed using a dedicated TAVR protocol with an ECG-triggered high-pitch spiral acquisition. The non-contrast aortic valve calcium score (AV-CS) was calculated by a dedicated software. Angiographic data were analysed on a dedicated 3D workstation. Bidimensional measurements, total renal volume (TRV), and presence of significant (≥50%) renal artery stenosis (RAS) were recorded. The supra-renal AB was quantified using a ‘plaque analysis’ module that automatically segments the entire aortic root, from the sino-tubular junction to the renal arteries, by drawing a centreline across the aortic lumen and delineating the inner and outer vessel walls (including the plaque). Manual correction was applied. A set of Hounsfield unit (HU) intensity ranges were defined and mapped to a color overlay to visualize the various elements of atherosclerotic lesion by using the plaque density classification of the Society of Cardiovascular Computed Tomography (necrotic core, fibro-fatty, fibrous, and calcified plaque); calcified plaque were subcategorized on a voxel-level basis into three strata: low- (351–700 HU), mid- (701–1000 HU), and high-calcium (&amp;gt;1000 HU, termed 1K plaque). Post-procedural complications were defined according to Valve Academic Research Consortium (VARC-3) criteria. Mean age was 83.3 ± 5.7 years, and 95 (42.8%) patients were males. AKI occurred in 67/222 (30.2%). Patients who developed AKI had higher supra-renal AB (17.6 ± 5.1% vs. 13.9 ± 4.3%, P &amp;lt; 0.001), TRV indexed for body surface area (TRVBSA; 153.7 ± 43.1 vs. 134.9 ± 38.7, P = 0.002), mid-calcium plaque (2.2 ± 1.5% vs. 1.3 ± 1.1%, P &amp;lt; 0.001), 1K plaque (5.4 ± 3.7% vs. 2.4 ± 2.4%, P &amp;lt; 0.001) and suffered more post-procedural major/life-threatening (severe) bleedings [9/67 (13.4%) vs. 5/155 (3.2%), P = 0.004], whereas there was no difference in AV-CS (P = 0.691) and RAS (P = 0.077). Multivariate logistic regression analysis adjusted for other univariate predictors (male sex, baseline eGFR, baseline ejection fraction, baseline mean aortic gradient, and RAS) showed percent supra-renal AB (HR: 1.15, 95% CI: 1.06–1.26, P = 0.002), mid-to-high calcium plaque (HR: 5.67, 95% CI: 2.49–13.77, P &amp;lt; 0.001), severe bleedings (HR: 4.93, 95% CI: 1.09–24.69, P = 0.043), and TRVBSA (HR: 1.015, 95% CI: 1.01–1.02, P = 0.021) as independent predictors of AKI. Finally, a 3-knots spline curve analysis identified percent of supra-renal AB &amp;gt; 15.0% as the optimal threshold to predict an increased risk of AKI. Conclusions Suprarenal AB is associated with the occurrence of AKI, and this association is strengthened as the percentage of calcified plaque increases. Quantitative and qualitative pre-operative MSCT assessment of aortic atherosclerosis may help in early identification of patients at high-risk for AKI who could benefit from higher peri-operative surveillance.