Th9-arterial endothelial cell crosstalk promotes psoriatic atherosclerosis.

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death, and understanding its pathogenic drivers is critical for effective prevention and treatment. Inflammation has a critical role in ASCVD, and patients with inflammatory diseases are at increased risk. However, the key inflammatory mediator promoting ASCVD are incompletely understood, a major barrier when targeting inflammation to prevent ASCVD. Here, we found that interleukin-9 (IL-9) producing T helper cells (Th9) were significantly associated with ASCVD in patients with the autoimmune disease psoriasis. Th9 cells were poised to migrate to coronary vessels and were identified in atherosclerotic plaque. In vivo, murine inflammatory atherogenesis was prevented by IL-9 blockade and by IL-9 receptor (IL-9R) deletion in endothelial cells. In human arterial endothelial cells, IL-9R/STAT3 signaling promoted endothelial dysfunction, angiogenesis, and release of leukocyte chemoattractants. These findings suggest that in autoimmune diseases like psoriasis, Th9/IL-9 promote atherosclerosis by directly targeting endothelial cells, and that IL-9R/STAT3 signaling could be a promising therapeutic target for ASCVD.

Background Systemic inflammation (SI) is recognized as a critical driver of atherosclerotic cardiovascular disease (ASCVD), and it is frequently observed in ASCVD patients with comorbid chronic kidney disease (CKD). Elevated C-reactive protein (CRP) levels, a common biomarker for SI, have been associated with poor prognosis in ASCVD and CKD patients, increased risk of major adverse cardiovascular events and renal disease progression, as well as greater mortality. Purpose To estimate the prevalence of SI in patients with ASCVD in Spain overall and by CKD status, and to describe patients’ clinical characteristics. Methods In this population-based observational study, data from THIN Spain, a database of electronic medical records from a large network of general practitioners, were used to identify adult patients with a diagnosis code of ASCVD (atherosclerotic coronary or cerebrovascular event, peripheral arterial disease, or other atherosclerotic vascular event) and ≥1 eligible CRP measurement between January 1st 2014 to July 31st 2023 (latest data available at time of data extraction).[Figure] SI was defined as CRP ≥ 2mg/L. Point prevalence of SI at the end of the study (among patients alive with ≥1 CRP in the prior 18 months) and the proportion of patients with evidence of SI during the study period (2014-2023) were estimated overall and by CKD status (defined as CKD stage 3+, or eGFR <60 mL/min/1.73m², or urinary albumin-to-creatinine ratio ≥30 mg/g). Patients’ comorbidities (defined using primary care diagnoses), and laboratory values were reported by SI status at first CRP measurement during the study period. Results Among 76,423 patients with ASCVD diagnosis, 15,798 patients (20.7%) were included in the study (mean age: 71.1 years; 43% females), of whom 5,111 (34%) had CKD at first eligible CRP (n=975 with unknown CKD status). Mean CRP in ASCVD patients with CKD was 24% higher than in those without CKD (4.36 vs 3.53 mg/L, p<0.001). The proportion of ASCVD patients with SI at first CRP measurement was 58% overall (65% among CKD patients; 55% among patients without CKD; p<0.001). The point prevalence of SI at the end of the study was 56% among ASCVD patients overall (62% among CKD patients; 52% among patients without CKD; p<0.001), while 64% of ASCVD patients had evidence of SI at any time during the study period (72% among CKD patients; 59% among patients without CKD; p<0.001). Compared to ASCVD patients without SI, higher proportion of SI patients were smokers and with comorbidities. Also, ASCVD patients with SI had lower baseline eGFR levels and higher levels of LDL-C and triglycerides than ASCVD patients without SI.[Table] Conclusions SI prevalence is high among patients with ASCVD in Spain, especially among patients with comorbid CKD. Strategies to target SI may have beneficial effects in prevention of cardiovascular events and mortality in ASCVD patients.

Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis

IntroductionClinical atherosclerotic cardiovascular disease (ASCVD) patients are judged to be very-high-risk if they had a history of multiple major ASCVD events, or one major ASCVD event with multiple high-risk conditions. Very-high-risk ASCVD patients are under high risk of adverse clinical events and need more attention in the management of secondary prevention. This real-world study aimed at estimating the prevalence of very-high-risk ASCVD and investigating the occurrence of adverse clinical events and associated risk factors among patients with very-high-risk ASCVD in China.MethodsData were obtained from the Urban Employee Basic Medical Insurance database in Tianjin, China. Very-high-risk ASCVD patients were identified from 2014 to 2015 through the history of ASCVD events and evidence of high-risk conditions, and followed for 24 months. Adverse clinical events were measured by major adverse cardiovascular events (MACE), a composite endpoint of stroke, myocardial infarction (MI) and death. A Cox regression model was used to identify risk factors of MACE, adjusting for potential confounders.ResultsThe percentage of clinical ASCVD patients identified as very-high-risk was 35.2 (N = 41,181), while 34,740 patients with continuous enrollment were included (mean age: 67.1 years; 42.5% female). The percentage of patients who had MACE in the 24-month follow-up period was 27.7, with stroke (22.3%) as the most prevalent event followed by death (6.9%) and MI (1.3%). Male gender, older age, and having MI or ischemic stroke (versus unstable angina) as the index major ASCVD event were risk predictors of MACE.ConclusionsMore than one-third of patients with clinical ASCVD are under very-high-risk in China, and among them 27.7 percent experience MACE during a 24-month follow-up period. Male patients, older patients, and patients who had MI or ischemic stroke are under higher risk of experiencing MACE. Future studies are warranted for comparing the differences in characteristics, pattern of drug use, occurrence of adverse clinical events and medical burden between very-high-risk ASCVD patients and ASCVD patients not at very-high-risk.

Introduction: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are a promising class of lipid lowering therapy. The number of high-risk atherosclerotic cardiovascular disease (ASCVD) patients who may benefit from PCSK9i therapy, and the number of these patients actually initiated on PCSK9i therapy, has not been well characterized. Methods: We used administrative claims from a large, national commercial payer (n=15 million annual covered lives) during years 2015-2016, including inpatient and outpatient facility and provider claims, pharmacy claims, and laboratory results to determine the total number of ASCVD patients ages 18 to 64 years who were adherent to high-intensity statins with persistently high low-density lipoprotein cholesterol (LDL-C), and the fraction of these patients who were subsequently started on a PCSK9i. Secondary objectives were to compare differences in cardiovascular comorbidities, use and adherence to lipid lowering therapies, and baseline LDL-C measurements between patients who were treated and were not treated with PCSK9i. Results: We identified 5,355 ASCVD patients adherent to high-intensity statins of whom 38 (0.7%) were initiated on a PCSK9i. Of the 5,317 patients not receiving PCSK9i, 2,882 (54%) of these patients had LDL-C greater than 70 mg/dL. Among the 264 ASCVD patients started on a PCSK9i, 38 (14%) had persistent statin use in the previous year. Compared to the ASCVD patients not started on a PCSK9i, those initiated on PCSK9i therapy had higher rates of ezetimibe use (34% vs. 9%; p < .001) and bile acid sequestrant use (10% vs. 2%; p < .001) in the previous year. Of ASCVD patients started on a PCSK9 inhibitor, 54 (20%) had LDL-C less than 70 mg/dL prior to initiating therapy. Conclusions: We observed a small number of patients starting PCSK9 inhibitors in years 2015 and 2016, relative to the number of eligible ASCVD patients adherent to high dose statins with suboptimal LDL-C levels. Among ASCVD patients started on a PCSK9 inhibitor, we found low rates of statin use and 1 out of 5 had LDL-C less than 70 prior to initiation. Our findings suggest that differences in clinician practice and prescribing may be contributing to suboptimal patient selection for these therapies.

Atherosclerotic cardiovascular disease (ASCVD) is a group of clinical diseases based on pathology of atherosclerosis that is the leading cause of mortality worldwide. There is a bidirectional interaction between ASCVD and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Alterations in circulating miRNAs levels are involved in the development of ASCVD in patients infected with SARS-CoV-2, however, the correlation between ASCVD co-infection with SARS-CoV-2 and alterations of cardiac-specific miRNAs is not well understood. The circulating miR-146a and miR-27a are involved in bidirectional interactions between ASCVD and SARS-CoV-2 infections. Circulating miR-146a and miR-27a levels were measured in serum and PBMCs deriving from ASCVD patients and controls after SARS-CoV-2 infection by qRT-PCR analysis. The levels of neutralizing antibodies-resistant SARS-CoV-2 in human serum was determined by competitive magnetic particle chemiluminescence method. Interleukin (IL)-6 levels were detected by automatic biochemical analyzer using electrochemiluminescence. Significant downregulation of circulating miR-146a and upregulation of miR-27a in ASCVD patients after infection with SARS-CoV-2 compared with controls were observed, among which the alterations were more evident in ASCVD patients comorbid with hyperlipidemia and diabetes mellitus. Consistently, correlation analysis revealed that serum miR-146a and miR-27a levels were associated with the levels of lipids and glucose, inflammatory response, and immune function in ASCVD patients. Remarkably, SARS-CoV-2 S protein RBD stimulation of PBMCs derived from both ASCVD and controls significantly downregulated miR-146a, upregulated miR-27a expression levels, and promoted IL-6 release in vitro. The circulating miR-146a and miR-27a are involved in metabolism, inflammation, and immune levels in patients with ASCVD after SARS-CoV-2 infection, laying the foundation for the development of strategies to prevent the risk of SARS-CoV-2 infection in ASCVD patients.

P141 Risk Factors of Atherosclerotic Cardiovascular Disease (Ischemic Heart Disease and Cerebrovascular Accident) in Patients With Inflammatory Bowel Disease: a hospital-based cohort

Objective: Peripheral systolic blood pressure (SBP) has been used to predict atherosclerotic cardiovascular disease (ASCVD). However, the assessment of superiority between peripheral SBP and central SBP to predict ASCVD in asymptomatic patients without hypertension (HTN) has not been fully established. Design and method: Nine hundred and eighteen patients (male:female ratio 700:218, mean age 54.7 ± 13.7 years) without HTN were enrolled from subjects who received non-invasively semiautomated radial artery applanation tonometry (using an Omron HEM-9000AI) in the Department of Internal Medicine, St. Vincent's Hospital, from July 2011 to May 2015. Results: Two hundred and eighteen subjects (male:female ratio 149:69, mean age 61.7 ± 11.1 years) were diagnosed as ASCVD according to coronary angiography or coronary CT scan. Interestingly, ASCVD patients had significantly lower pSBP (124 ± 18 mmHg vs 128 ± 17 mmHg) and SBP2 (114 ± 18 mmHg vs 118 ± 18 mmHg) than the patients without ASCVD. However, ASCVD patients had significantly higher pulse pressure (52 ± 13 mmHg vs 50 ± 12 mmHg) than the patients without ASCVD. After multivariate analysis after adjusted for age, gender, body mass index, fasting plasma glucose, diabetes, lipid profiles, antihypertensive medication and lipid-lowering medication, SBP2 (β = 0.231, 95% CI 1.036 to 1.289, p = 0.010) or pSBP (β = 0.887, 95% CI 0.800 to 0.982, p = 0.021) were associated with ASCVD. In addition, AUC of pSBP was significantly greater than that of SBP2 to identify ASCVD (P = 0.035). Conclusions: Central blood pressure is superior to pSBP in identifying ASCVD, although both peripheral and central SBP are associated with ASCVD in patients without hypertension.

Background The proportion of Australian general practice patients not attaining low-density lipoprotein cholesterol (LDL-C) goals is not well described. The SCOPE-GP study evaluated duration of LDL-C exceeding treatment goals, statin use and discontinuation rates in patients with atherosclerotic cardiovascular disease (ASCVD), without ASCVD events but at moderate/high-risk, and familial hypercholesterolemia (FH). Methods This population-based retrospective cohort study used de-identified medical records of adult patients captured in the IQVIA GP-EMR database. Patients were indexed at the earliest date of ASCVD, FH, or hyperlipidemia diagnosis from January 1, 2010 to June 30, 2022, with a variable follow-up period from index to June 30, 2022. Ascertainment of study cohort was based on the 2021 ESC/EAS guidelines and Framingham Risk Equation. LDL-C test result levels were extracted per patient, summarised and analysed. Patients were stratified based on their test results at latest results/closest to censor date. Average time above target levels is the proportion of number of days above LDL-C target levels over total number of follow-up days for each patient. A Poisson distribution was fitted to estimate 95% confidence interval. Lipid lowering therapies (LLT) were stratified by (ASCVD, FH and moderate/high risk of CVD) at last visit/censor date. Combination of LLT were defined as prescriptions for fixed dose combinations or ≥2 separate scripts of LLT from different classes within 180 days from last visit/censor date (look back period). Discontinuation is defined as no statins were prescribed again after the last script for 270 days or more, limited to the first occurrence. Results The average time with LDL-C levels above target was 1077.5 days in ASCVD patients (n=2,688), 938.6 days in moderate-risk ASCVD (n=37,003), 980.9 days in high-risk ASCVD (n=85,199), and 900.8 days in FH (n=279). The proportion of days above target level for all four cohorts is described in Figure 1. Among 107,552 patients with recorded LDL-C levels ≥1.8mmol/L at their last visit/censor date, 30.9% were on statin monotherapy and 1.0% were on statin+ezetimibe. Statin use was highest in ASCVD patients (65.4%), followed by FH (49.5%), high risk (40.0%) and moderate risk subjects (29.5%) (Table 1). Statin discontinuation rates were 60.3%, 76.3, 66.1%, and 65.8% in these groups, respectively. The predominant reason for statin discontinuation was non-specific adverse drug reactions (12.2% ASCVD, 11.7% moderate-risk, 13.2% high-risk and 17.9% FH). The proportion of subjects contraindicated to statins was highest in moderate risk subjects (0.05%). Conclusions Prolonged periods of elevated LDL-C and high statin discontinuation rates were prevalent among at-risk individuals in Australian primary care. This underscores a significant ASCVD burden that could be prevented with more active lipid management.

Neuregulin-1 (NRG-1), a stress-mediated paracrine transmembrane growth factor, plays vital roles in the pathophysiology of atherosclerosis, myocardial infarction, ischemia-reperfusion, heart failure (HF), cardiomyopathy and other cardiovascular diseases. This study aimed to assess plasma NRG-1 levels in atherosclerotic cardiovascular disease (ASCVD) patients and explore the relationship between NRG-1 levels and patient outcomes. Plasma NRG-1, monocyte chemotactic protein-1 (MCP-1), myeloperoxidase (MPO) and vascular cellular adhesion molecule-1 (VCAM-1) concentrations were quantified in 185 ASCVD patients and 185 age- and sex-matched controls. All ASCVD patients were followed up for 14-16 months, and major adverse cardiovascular and cerebrovascular events (MACCEs), including angina pectoris, nonfatal myocardial infarction, nonfatal stroke, new HF symptoms, and CVD-related death, were recorded. ASCVD patients presented notably lower NRG-1 levels (123.45 ± 0.87 pg/ml, vs. 139.76 ± 0.83 pg/ml for controls, P < 0.001) and higher MCP-1, MPO and VCAM-1 levels. Circulating NRG-1 levels were negatively associated with MCP-1 (-0.278, P < 0.001), MPO (-0.171, P = 0.001) `and VCAM-1 (-0.351, P < 0.001) levels. Logistic regression analysis revealed that a high NRG-1 level was a significant protective effect against ASCVD (OR = 0.859, 95% CI = 0.821-0.900; P < 0.001). In the mediation analysis, MCP-1, MPO, and VCAM-1 explained 20.2%, 8.8%, and 30.1%, respectively, of NRG-1's association with ASCVD. After an average follow-up of 13.8 ± 1.7 months, the mean NRG-1 level was lower in patients with MACCEs than in patients without MACCEs (112.04 ± 1.24 pg/ml vs. 125.93 ± 0.90 pg/ml, P < 0.001). Kaplan-Meier survival analysis revealed that patients with plasma NRG-1 concentration <122.5 pg/ml had a lower survival rate than those with higher levels (P < 0.001). According to the adjusted models, NRG-1 was independently associated with a decreased risk of MACCEs [adjusted HR 0.857 (95% CI 0.809-0.908), P < 0.001]. Reduced NRG-1 levels in ASCVD patients increased the risk of MACCEs. NRG-1 levels may serve as useful laboratory markers of ASCVD prognosis.

Interleukin 6 and Haemostasis

Background: Uncertainty exists about the link between omega-3 fatty acid, omega-6 fatty acid, and total polyunsaturated fatty acid (PUFA) intake and mortality in atherosclerotic cardiovascular disease (ASCVD) patients, and no meta-analyses summarize the relationship between these various types of PUFAs and ASCVD. Methods: Web of Science, PubMed, EBSCO and Cochrane Library up to November 30, 2022 were searched for prospective randomized controlled studies investigating the relationships among omega-3, omega-6, and PUFA intake and mortality and cardiovascular events in ASCVD patients. This study has been registered at PROSPERO (No. CRD42023407566). Results: This meta-analysis included 21 publications from 17 studies involving 40 861 participants published between 1965 and 2022. In ASCVD patients, omega-3 may lower all-cause mortality (RR: 0.90, 95% CI [0.83, 0.98], I2 = 8%), CVD mortality (RR: 0.82, 95% CI [0.73, 0.91], I2 = 34%) and CVD events (RR: 0.90, 95% CI [0.86, 0.93], I2 = 79%). Subgroup analyses showed that EPA or EPA ethyl ester supplementation reduced CVD events, while the mixture of EPA and DHA had no significant impact. Long-chain omega-3 consumption of 1.0-4.0 g per d reduced death risk by 3.5% for each 1 g per d increase. Omega-6 and PUFA had no significant effect on mortality or CVD events, with low-quality evidence and significant heterogeneity. Conclusions: omega-3 intake is associated with a reduced risk of all-cause mortality, CVD mortality, and CVD events in ASCVD patients, while omega-6 or total PUFA intake showed no significant association. Increasing the omega-3 intake by 1 g per d resulted in a 3.5% decrease in the risk of death. These findings support the recommendation of supplements with omega-3 fatty acids for the secondary prevention of ASCVD.

Diabetics are at high risk for atherosclerotic cardiovascular disease (ASCVD) and are considered a coronary heart disease risk equivalent. The utility of aspirin in primary prevention of ASCVD in diabetic patients has been widely studied and is still debated. Overall, the current evidence suggests a modest benefit for reduction in ASCVD events with the greatest benefit among those with higher baseline risk, but at the cost of increased risk of gastrointestinal bleeding. Diabetic patients at higher risk (with 10-year ASCVD risk >10%) are generally recommended for aspirin therapy if bleeding risk is felt to be low. A patient-provider discussion is recommended before prescribing aspirin therapy. Novel markers such as coronary artery calcium scores and high-sensitivity C-reactive protein may help refine ASCVD risk prediction and guide utility for aspirin therapy. This article will review the literature for the most up-to-date studies evaluating aspirin therapy for primary prevention of ASCVD in patients with diabetes.

Introduction: Healthcare expenses for atherosclerotic cardiovascular disease (ASCVD) are associated with substantial financial toxicity (FT). Whether certain social determinants of health (SDOH) portend an increased risk of FT in ASCVD is critical to refine care processes that may be most amenable to interventions. Methods: Using National Health Interview Survey (2013-17), we assessed patients with self-reported ASCVD. We identified 35 discrete SDOH items, rated as favorable/unfavorable, across 6 domains: economic stability, education, food access, neighborhood conditions, social context, and health systems. To capture the cumulative effect of SDOH, an aggregate score was computed as their sum, and divided into quartiles, the highest quartile containing the most unfavorable scores. FT included presence of: difficulty paying medical bills/inability to pay them at all, and/or delayed/foregone care due to cost, and/or cost-related medication non-adherence. Results: Of 164,696 surveyed adults, of which 15,758 (weighted: 8%) reported ASCVD. Mean (SE) age-adjusted SDOH risk scores among ASCVD vs non-ASCVD patients were 11.8 (0.12) vs 9.5 (0.03), respectively. Among individuals with ASCVD, age-adjusted prevalence of any FT was directly proportional to SDOH aggregate scores, with step-wise increases noted. Prevalence of ≥ 2 FT factors among SDOH quartiles 1 st vs 4 th was 8% vs 50% among non-elderly (&lt; 65), and 2% vs 35% among elderly adults with ASCVD, respectively (Figure). Further, in adjusted models, patients in the most unfavorable quartile for SDOH had an 8-fold higher likelihood of FT compared to those in the most favorable group. Conclusions: Among ASCVD patients, a higher number of unfavorable SDOH features is strongly associated with the presence of FT, further calling for the development of interventions to alleviate FT among those with unfavorable SDOH profiles.

Background: Data regarding the combined prognostic role of biomarkers and risk scores in relation with the history of atherosclerotic cardiovascular disease (ASCVD) in COVID-19 patients are lacking. Methods: The aim of this observational cohort study was to evaluate the combined prognostic value of N-terminal pro B-type natriuretic peptide (NT-pro BNP), troponin and risk scores in relation with ASCVD history in hospitalized COVID-19 patients. The primary composite endpoint was Intensive Care Unit (ICU) admission and death. Results: From April 2020 to June 2022, 1066 consecutive COVID-19 patients with available biomarkers upon admission were included. During a median follow-up period of 12 days, 176 patients (16.5%) died. Independent predictors of ICU admission and death in patients with ASCVD were NT-pro BNP (HR 2.63; 95% CI, 1.65–4.18) and troponin (HR 1.51; 95% CI, 1.13–2.03). In patients without ASCVD, only NT-pro BNP was predictive for the primary endpoint (HR 1.66; 95% CI, 1.10–2.53). This remained significant after adjustment for other relevant covariates (HR 3.54; 95% CI, 1.98–6.33) in patients with ASCVD and in patients without ASCVD (HR 1.82; 95% CI, 1.02–3.26). Conclusions: These data showed the combined prognostic accuracy of NT-pro BNP and troponin in relation with ASCVD history for ICU admission and death in COVID-19 patients.