Measures Of Subclinical Atherosclerosis Research Articles

Abstract P530: Thoracic Aorta and Coronary Artery Calcification and Atherosclerotic Cardiovascular Disease Risk in South Asian Americans

Background: South Asian populations have a high risk of atherosclerotic cardiovascular disease (ASCVD). Subclinical atherosclerosis measures, including thoracic aortic calcification (TAC) and coronary artery calcification (CAC), are associated with ASCVD events, and TAC is a stronger predictor in women than men. However, no prior studies have investigated TAC in South Asians. Methods: We examined data from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study from 2015-2018. TAC and CAC were measured from computerized tomography scans using the Agatston method, and scores were categorized as 0, 1-99, and 100 or greater. Ten-year ASCVD risk was calculated using the 2013 pooled cohort equations, categorized as low, intermediate, or high risk. We determined associations of traditional risk factors with TAC and CAC and used multivariable ordinal logistic regression to examine associations between TAC and CAC with ASCVD risk in stepwise models. Results: Of 958 participants, 30% had TAC scores between 1-99 and 24% had TAC ≥100. TAC and CAC were modestly correlated (r = 0.30). There was a graded prevalence of TAC and CAC scores with levels of ASCVD risk (Figure). Both TAC and CAC were associated with several traditional risk factors; however, only CAC was associated with current smoking, HDL-cholesterol, triglycerides, and diastolic blood pressure. After adjusting for age, gender, and these four additional risk factors, only TAC ≥100 remained associated with ASCVD risk (OR 3.29, 95% CI 1.86 - 2.23), while CAC and TAC <100 were not. The association between TAC and ASCVD risk was stronger for women than men (p-for-interaction <0.001). Conclusion: Though TAC and CAC are associated with traditional risk factors, high TAC levels were independently associated with ASCVD risk, especially among women. Further study is needed to determine whether high TAC scores may be predictive of ASCVD events in South Asian populations.

Ankle-Brachial Index and Risk of Sudden Cardiac Death in the Community: The ARIC Study.

Sudden cardiac death (SCD) is a significant global public health problem accounting for 15% to 20% of all deaths. A great majority of SCD is associated with coronary heart disease, which may first be detected at autopsy. The ankle-brachial index (ABI) is a simple, noninvasive measure of subclinical atherosclerosis. The purpose of this study was to examine the relationship between ABI and SCD in a middle-aged biracial general population. Participants of the ARIC (Atherosclerosis Risk in Communities) study with an ABI measurement between 1987 and 1989 were included. ABI was categorized as low (≤0.90), borderline (0.90-1.00), normal (1.00-1.40), and noncompressible (>1.40). SCD was defined as a sudden pulseless condition presumed to be caused by a ventricular tachyarrhythmia in a previously stable individual and was adjudicated by a committee of cardiac electrophysiologists, cardiologists, and internists. Cox proportional hazards models were used to evaluate the associations between baseline ABI and incident SCD. Of the 15 081 participants followed for a median of 23.5 years, 556 (3.7%) developed SCD (1.96 cases per 1000 person-years). Low and borderline ABIs were associated with an increased risk of SCD (demographically adjusted hazard ratios [HRs], 2.27 [95% CI, 1.64-3.14] and 1.52 [95% CI, 1.17-1.96], respectively) compared with normal ABI. The association between low ABI and SCD remained significant after adjustment for traditional cardiovascular risk factors (HR, 1.63 [95% CI, 1.15-2.32]). Low ABI is independently associated with an increased risk of SCD in a middle-aged biracial general population. ABI could be incorporated into future SCD risk prediction models.

The Association of Total Meat Intake with Cardio-Metabolic Disease Risk Factors and Measures of Sub-Clinical Atherosclerosis in an Urbanising Community of Southern India: A Cross-Sectional Analysis for the APCAPS Cohort.

Meat is commonly consumed in India; however, in comparison to Western settings, it is eaten in relatively lower quantities and with minimal processing. The association between meat intake and cardio-metabolic diseases (CMDs) and their risk factors in India is currently uncertain. We examined whether meat intake is associated with risk factors for CMDs and the measures of subclinical atherosclerosis in urbanising villages in southern India. We conducted a cross-sectional analysis of 6012 adults (52.3% male) participating in the Andhra Pradesh Children and Parents' Study (APCAPS), which is a large prospective, intergenerational cohort study in Southern India that began with the long-term follow-up of the Hyderabad Nutrition Trial (1987-1990). We used cross-sectional data from the third wave of data collection conducted in 2010-2012, where total meat intake was assessed using 100-item, semi-quantitative validated food frequency questionnaires (FFQ). The FFQs were validated using multiple weighed 24 h dietary recalls. The main predictor, 'total meat intake', was calculated as the sum of chicken, red meat, and fish consumption. The risk factors for CMDs [systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), waist circumference (WC), fasting glucose, total cholesterol, homeostasis model assessment insulin resistance (HOMA-IR), total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, and C-reactive protein] and measures of subclinical atherosclerosis [Carotid Intima-Media Thickness, Pulse Wave Velocity, and Augmentation Index] were assessed using standardised clinical procedures. Stratified by gender, the association of meat intake with the risk factors of CMDs and measures of subclinical atherosclerosis was examined using linear multilevel models with random intercept at the household level. The mean (SD) age of the male (n = 3128) and female participants (n = 2828) was 34.09 years (15.55) and 34.27 years (12.73), respectively. The median (IQR) intake of meat was 17.79 g/day (8.90, 30.26) in males and 8.90 g/day (4.15, 18.82) in females. In males, a 10 g increase in total meat intake/1000 Kcal/day was positively associated with DBP, BMI, WC, total cholesterol, LDL-C, and triglycerides, whereas in females, a 10 g increase in total meat intake/1000 Kcal/day was positively associated with SBP, DBP, fasting glucose, HOMA-IR, total cholesterol, LDL-C, and triglycerides. There was no relationship between meat consumption and measures of subclinical atherosclerosis. Meat intake had a linear positive association with CMD risk factors among the relatively younger Indian population who were consuming meat at lower levels compared to their European counterparts.

Abstract WMP108: Association of Circulating Markers of Inflammation to Baseline and Progression of Carotid Artery Intima-Media Thickness

Introduction: There is strong evidence of an association between systemic inflammation and ischemic stroke. While the exact mechanism underpinning that association is unclear, there is evidence that systemic inflammation contributes to atherosclerosis progression. One measure of subclinical atherosclerosis, carotid artery intima-media thickness (CIMT), is independently associated with ischemic stroke. Because of mixed data on the association between systemic inflammation and CIMT progression, we sought to evaluate this relationship in a prospective cohort study. Hypothesis: Baseline elevation in circulating markers of inflammation are associated with CIMT progression in the Framingham Heart Study cohort. Methods: Among participants with two carotid ultrasounds (n=2350) about 10 years apart, 2,269 had data available on circulating markers of inflammation. Multivariable linear regression was used to assess the association between circulating markers of inflammation with internal carotid artery (ICA) CIMT. Analyses were adjusted for age, sex, hypertension, diabetes, APOE4, and body mass index (BMI), and baseline IMT. Results: Participants with higher baseline levels of C-reactive protein (CRP), interleukin-6 (IL-6), intracellular adhesion molecule, p-selectin, lipoprotein-associated phospholipase A2 (LPa) activity, homocysteine, isoprostanes (ISO), and CD40 ligand had significantly higher rates of ICA IMT progression adjusting for age, sex, hypertension, diabetes, APOE4, BMI, and baseline ICA IMT (Table). Participants with higher levels of CRP, IL-6, OPG, p-selectin, LPa activity, and ISO had greater follow-up ICA IMT adjusting for age, sex, hypertension, diabetes, APOE4, and BMI. Conclusion: Specific markers of inflammation are associated with increased later life carotid intima media thickening and carotid atherosclerosis progression, supporting a link between systemic inflammation and cerebrovascular disease.

Comparison of CIMT and FMD in the Brachial Artery between Children with Acyanotic Congenital Heart Disease and Healthy Controls: A Case-Control Study.

Congenital heart disease (CHD), a developmental abnormality of the heart and vessels, is encountered in the pediatric age group frequently. Brachial artery flow-mediated dilation (FMD) and carotid intima-media thickness (CIMT) are indicators of subclinical cardiovascular disease and are used as surrogate measures of subclinical atherosclerosis. The present study aimed to compare CIMT and FMD between children with acyanotic congenital heart disease (ACHD) and healthy controls. A case-control study on 50 children with ACHD and 43 healthy individuals was done in Isfahan, Iran, between 2021 and 2022. The case group was selected via non-random sampling, and healthy controls were recruited from the relatives of the patients. A checklist, including age, sex, body mass index, and blood pressure, was filled out for all the participants. Then, FMD and CIMT were measured with brachial and carotid artery ultrasonography. Fifty children with ACHD and 43 healthy individuals (controls) under 18 years old participated in this study. Of these, 44 (47.3%) were girls and 49 (52.7%) were boys. The mean FMD was significantly higher in the ACHD group than in the control group (0.084±0.027 vs 0.076±0.042; P=0.021; 95% CI, 007 to 0.122;). CIMT was significantly higher in the ACHD group than in the control group (0.39±0.12 vs 0.34±0.1; P=0.037; 95% CI, 0.009 to 0.102;). However, systolic and diastolic blood pressure did not show differences between the groups. Based on our results, CIMT and FMD assessment may help detect early changes in peripheral vessels associated with atherosclerosis in the future in ACHD. Further studies are needed to confirm our findings.

Nontraditional Risk Markers for Incident Coronary Artery Calcium Among Persons ≥65 Years of Age

BackgroundThe initiation of coronary artery calcium (CAC) is an important physiologic milestone associated with increased cardiovascular disease risk. However, traditional risk factors (RF) do not perform well for predicting incident CAC among the 54 million older U.S. adults. ObjectivesThe authors sought to assess the association between nontraditional cardiovascular disease RF and incident CAC in older persons. MethodsThere were 815 MESA (Multi-Ethnic Study of Atherosclerosis) participants ≥65 years of age who had CAC = 0 at Visit 1 and a follow-up CAC scan. Multivariable adjusted Cox hazards ratios (aHR) and C-statistics were calculated to examine the association of nontraditional RF with incident CAC. ResultsThe mean age was 70.2 years and 67% were women. The median follow-up time to repeat CAC scan was 3.6 years (IQR: 2.6-9.2 years) and 45% of participants developed incident CAC. Albuminuria (aHR: 1.50, 95% CI: 1.07-2.09), carotid plaque (aHR: 1.32, 95% CI: 1.04-1.66), and thoracic aortic calcification (TAC) (aHR: 1.38, 95% CI: 1.10-1.75) were significantly associated with incident CAC, while higher levels of nontraditional RF including apolipoprotein-B, lipoprotein(a), high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide were not. When added to demographics, albuminuria, carotid plaque, and TAC provided a greater C-statistic improvement (+0.047, P = 0.004) vs all traditional RF combined (+0.033, P = 0.05). ConclusionsAmong nontraditional RF and measures of subclinical atherosclerosis, only albuminuria, carotid plaque, and TAC were significantly associated with incident CAC in persons ≥65 years of age. Identification of albuminuria or extracoronary atherosclerosis may help guide the timing of repeat CAC scoring in older persons with baseline CAC = 0.

Depression and Subclinical Coronary Atherosclerosis in Adults Without Clinical Coronary Artery Disease.

The relationship between depression and subclinical coronary atherosclerosis in asymptomatic individuals is not clear. We evaluated this relationship in a Korean population. We analyzed 3920 individuals (mean age 54.7±7.9 years and 2603 men [66.4%]) with no history of coronary artery disease who voluntarily underwent coronary computed tomographic angiography and screening for depression using the Beck Depression Inventory as part of a general health examination. The degree and extent of subclinical coronary atherosclerosis were evaluated by coronary computed tomographic angiography, and ≥50% diameter stenosis was defined as significant. Participants were categorized into groups of those with or without depression using the Beck Depression Inventory scores ≥16 as a cutoff value. Of the study participants, 272 (6.9%) had a Beck Depression Inventory score of 16 or higher. After adjustment for cardiovascular risk factors, depression was not significantly associated with any coronary plaque (adjusted odds ratio [OR], 1.05 [95% CI, 0.78-1.41]; P=0.746), calcified plaque (OR, 0.95 [95% CI, 0.71-1.29]; P=0.758), noncalcified plaque (OR, 1.31 [95% CI, 0.79-2.17]; P=0.305), mixed plaque (OR, 1.16 [95% CI, 0.60-2.23]; P=0.659), or significant coronary artery stenosis (OR, 1.22 [95% CI, 0.73-2.03]; P=0.450). In the propensity score-matched population (n=1318) as well, none of the coronary artery disease measures of subclinical coronary atherosclerosis were statistically significantly associated with depression (all P>0.05). In this large cross-sectional study with asymptomatic individuals undergoing coronary computed tomographic angiography and Beck Depression Inventory evaluation, depression was not associated with an increased risk of subclinical coronary atherosclerosis.

Incremental Value of ABI and CAC Beyond Traditional Risk Markers in Long-term Prediction of Cardiovascular Disease Incidence in Participants with Diabetes: Multi-Ethnic Study of Atherosclerosis

IntroductionPrimary prevention of cardiovascular disease (CVD) emphasizes detection of subclinical atherosclerosis (SA). Diabetes Mellitus is a high-CVD risk condition with higher prevalence of systemic atherosclerosis. Ankle brachial index (ABI) and coronary artery calcium (CAC) are commonly used measures to detect SA. The primary objective of this study was to evaluate the improvement in CVD risk prediction beyond traditional risk factors after adding ABI and CAC within diabetic participants. MethodsMESA is an observational cohort of 6,814 participants free of clinical cardiovascular disease at baseline. Participants were included in this analysis if they had diabetes or impaired fasting glucose. Cox proportional hazard regression was used to assess the association between CAC score and ABI and outcomes (incident CVD and all-cause mortality). We compared the C-index between a model with traditional risk factors alone and models including ABI and/or CAC. Results1,719 participants were included in the analysis. Average age was 64 years, 55% male, 25% White, 13% Chinese, 34% Black, and 27% Hispanic. Higher CAC and lower ABI were associated with higher risk of CVD (Figure 1) and mortality among people with diabetes. Both ABI and CAC improved CVD discrimination over and above standard risk factors (C-index 0.689 for risk factors alone, 0.719 for CAC, 0.696 for ABI, and 0.721 for both). Similarly for mortality, discrimination was improved over risk factors alone (C-index 0.739) for CAC (0.746), ABI (0.747), and both (0.748). ConclusionThese two subclinical atherosclerosis measures may aid in clinical decision making among those with diabetes.

A study to Assess the Predictive Accuracy of Cardiovascular Risk Scores and its Correlation with Measures of Subclinical Atherosclerosis in Indian Population

A study to Assess the Predictive Accuracy of Cardiovascular Risk Scores and its Correlation with Measures of Subclinical Atherosclerosis in Indian Population

Abstract C121: Follow-up of moderate and severe coronary artery calcifications identified on lung cancer screening CT scans: An opportunity to improve cardiac health outcomes in Black men and women

Abstract Background: The USPSTF currently recommends lung cancer screening (LCS) by low-dose CT (LDCT) in those 50 to 80 years of age with 20+ pack-years of smoking who are currently smoking or quit smoking within the last 15 years. LCS LDCT often detects non-cancer related incidental findings, most commonly coronary artery calcifications (CAC). CAC is a measure of subclinical coronary atherosclerosis, is higher in those with tobacco use, and may require additional clinical assessment after LCS. In the National Lung Screening Trial, reductions in all-cause mortality were stronger among Black than White participants undergoing LDCT. It was hypothesized that this may have been due to follow-up and treatment of incidental findings such as CAC during the trial. Methods: In this on-going observational study, we are evaluating clinical follow-up of moderate or severe CAC within 12 months of LCS among individuals undergoing baseline LCS at two Michigan health systems, one urban and one rural. We report here our initial findings for individuals with a baseline LCS LDCT at Henry Ford Health in 2018. Pearson Chi Square and McNemar’s tests were used to determine differences between race and sex groups and in change in statin use and cardiology visits (yes/no) pre- to post-screening. Results: Of 1,630 individuals (18% Black) with a baseline LDCT in 2018, moderate or severe CAC was documented in 154 (9.4%). Moderate or severe CAC prevalence was significantly higher among Black versus Non-Black ( 17.7 % vs 7.1%; p= <0.001) individuals and men versus women ( 11.7% vs 7.1%; p=0.002 ). Pre- to post-LCS increases in statin use (68.2% vs. 76.0%; p=0.02) and cardiology visits (25.9% vs. 50.7%; p<0.01) were observed, overall. Statin use did not differ by race, sex, or race-sex group in the pre- or post- periods. Cardiology visits were less common among Blacks (18.2% vs. 28.9%; p=0.14) and women ( 18.2% vs. 28.9%; p= 0.14) in the pre-LCS period with Black women (8.3%) being the least likely to have a cardiology visit before LCS. Post-LCS, the cardiology gap between Black and Non-Black individuals (43.6% vs. 55.6%: p=0.16) narrowed and was eliminated between women and men (53.6 % vs. 50%; p=0.67). This was due in part to a substantial uptick of cardiology visits post-LCS in Black females. However, Black men, were significantly less likely than Non-Black men (32.3 % vs 56.7% ; p=0.024 ) and Black women (32.2% vs. 62.5%; p=0.024) to have a cardiology visit post-LCS . Conclusions: Our study is on-going; however, preliminary results suggest that in addition to reducing lung cancer mortality, LCS provides an opportunity for CAC detection and its related management. LCS, if implemented equitably with comprehensive follow-up of incidental findings, may help to close gaps in cardiac care for Black individuals and women. Further investigation is needed to assess whether appropriate follow-up of CAC decreases cardiovascular risks for those undergoing screening. Citation Format: Christine Neslund-Dudas, Katie R. Zarins, Punith Shetty, Andrea E. Cassidy-Bushrow, Nada Al-Antary, Katie A. Latack, Vritti Gupta, Michael Simoff, Riley Draper, Samuel Wilcox, Kendra Worden, Kathy LaRaia, Kelly Hirko. Follow-up of moderate and severe coronary artery calcifications identified on lung cancer screening CT scans: An opportunity to improve cardiac health outcomes in Black men and women [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C121.

Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.

Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. Using a Bonferroni-corrected significance threshold of P<1.6×10-4, we identified 3 genes (ATP1B1, ARVCF, and LIPG) associated with CAC and 2 genes (ABCG8 and EIF2B2) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both ATP1B1 and ARVCF also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis. These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

Age- and sex-based heterogeneity in coronary artery plaque presence and burden in familial hypercholesterolemia: A multi-national study

ObjectivesIndividuals with familial hypercholesterolemia (FH) are at an increased risk for coronary artery disease (CAD). While prior research has shown variability in coronary artery calcification (CAC) among those with FH, studies with small sample sizes and single-center recruitment have been limited in their ability to characterize CAC and plaque burden in subgroups based on age and sex. Understanding the spectrum of atherosclerosis may result in personalized risk assessment and tailored allocation of costly add-on, non-statin lipid-lowering therapies. We aimed to characterize the presence and burden of CAC and coronary plaque on computed tomography angiography (CTA) across age- and sex-stratified subgroups of individuals with FH who were without CAD at baseline. MethodsWe pooled 1,011 patients from six cohorts across Brazil, France, the Netherlands, Spain, and Australia. Our main measures of subclinical atherosclerosis included CAC ranges (i.e., 0, 1–100, 101–400, >400) and CTA-derived plaque burden (i.e., no plaque, non-obstructive CAD, obstructive CAD). ResultsNinety-five percent of individuals with FH (mean age: 48 years; 54% female; treated LDL-C: 154 mg/dL) had a molecular diagnosis and 899 (89%) were on statin therapy. Overall, 423 (42%) had CAC=0, 329 (33%) had CAC 1–100, 160 (16%) had CAC 101–400, and 99 (10%) had CAC >400. Compared to males, female patients were more likely to have CAC=0 (48% [n = 262] vs 35% [n = 161]) and no plaque on CTA (39% [n = 215] vs 26% [n = 120]). Among patients with CAC=0, 85 (20%) had non-obstructive CAD. Females also had a lower prevalence of obstructive CAD in CAC 1–100 (8% [n = 15] vs 18% [n = 26]), CAC 101–400 (32% [n = 22] vs 40% [n = 36]), and CAC >400 (52% [n = 16] vs 65% [n = 44]). Female patients aged 50–59 years were less likely to have obstructive CAD in CAC >400 (55% [n = 6] vs 70% [n = 19]). ConclusionIn this large, multi-national study, we found substantial age- and sex-based heterogeneity in CAC and plaque burden in a cohort of predominantly statin-treated individuals with FH, with evidence for a less pronounced increase in atherosclerosis among female patients. Future studies should examine the predictors of resilience to and long-term implications of the differential burden of subclinical coronary atherosclerosis in this higher risk population.

Home-based exercise improves subclinical atherosclerosis marker in multiple sclerosis.

Using a 12-week, randomized controlled trial coupled with social cognitive theory behavioral coaching, we aimed to assess the effect of a home-based aerobic training intervention versus an attention-control on aerobic fitness, subclinical atherosclerosis, and mobility in persons with MS. Persons with MS with an expanded disability status scale score between 0 and 4 were randomized to a 12-week aerobic exercise (EX) (n=26; 19 females; 49 yrs; 28.8kg/m2) or attention-control (CON) condition (stretching; n=22; 16 females; 44 yrs; 29.2kg/m2). Aerobic capacity was assessed via a graded cycle ergometry test with indirect calorimetry. The co-primary measures of subclinical atherosclerosis assessed included carotid intima media thickness, a test of vasodilatory reactivity, and arterial stiffness. Mobility was assessed via a timed 25-foot walk test (T25FW) and a 6min walk test. The EX group engaged in cycle ergometry 3d/wk with gradual increases in the intensity and duration of the exercise sessions. CON participated in standardized stretching designed to provide the same contact time as EX 3d/wk. Behavioral coaching took place via weekly phone/video chats to track adherence. Aerobic capacity, vasodilatory reactivity, and T25FW speed increased only in the EX group, 7%, 16%, and 13% (p<0.05), respectively; whereas the CON group did not change. The EX group had modest, yet significant, increases in aerobic capacity over the 12-week period, coupled with improvements in T25FW speed and vasodilatory reactivity. A home-based exercise intervention can improve outcomes of a subclinical marker of atherosclerosis, which provides a basis for examining these outcomes in persons prescreened for CVD-related comorbidities and/or mobility issues.

Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

A machine learning based approach to identify carotid subclinical atherosclerosis endotypes.

To define endotypes of carotid subclinical atherosclerosis. We integrated demographic, clinical, and molecular data (n = 124) with ultrasonographic carotid measurements from study participants in the IMPROVE cohort (n = 3340). We applied a neural network algorithm and hierarchical clustering to identify carotid atherosclerosis endotypes. A measure of carotid subclinical atherosclerosis, the c-IMTmean-max, was used to extract atherosclerosis-related features and SHapley Additive exPlanations (SHAP) to reveal endotypes. The association of endotypes with carotid ultrasonographic measurements at baseline, after 30 months, and with the 3-year atherosclerotic cardiovascular disease (ASCVD) risk was estimated by linear (β, SE) and Cox [hazard ratio (HR), 95% confidence interval (CI)] regression models. Crude estimates were adjusted by common cardiovascular risk factors, and baseline ultrasonographic measures. Improvement in ASCVD risk prediction was evaluated by C-statistic and by net reclassification improvement with reference to SCORE2, c-IMTmean-max, and presence of carotid plaques. An ensemble stacking model was used to predict endotypes in an independent validation cohort, the PIVUS (n = 1061). We identified four endotypes able to differentiate carotid atherosclerosis risk profiles from mild (endotype 1) to severe (endotype 4). SHAP identified endotype-shared variables (age, biological sex, and systolic blood pressure) and endotype-specific biomarkers. In the IMPROVE, as compared to endotype 1, endotype 4 associated with the thickest c-IMT at baseline (β, SE) 0.36 (0.014), the highest number of plaques 1.65 (0.075), the fastest c-IMT progression 0.06 (0.013), and the highest ASCVD risk (HR, 95% CI) (1.95, 1.18-3.23). Baseline and progression measures of carotid subclinical atherosclerosis and ASCVD risk were associated with the predicted endotypes in the PIVUS. Endotypes consistently improved measures of ASCVD risk discrimination and reclassification in both study populations. We report four replicable subclinical carotid atherosclerosis-endotypes associated with progression of atherosclerosis and ASCVD risk in two independent populations. Our approach based on endotypes can be applied for precision medicine in ASCVD prevention.

Coronary heart disease and ischemic stroke polygenic risk scores and atherosclerotic cardiovascular disease in a diverse, population-based cohort study.

The predictive ability of coronary heart disease (CHD) and ischemic stroke (IS) polygenic risk scores (PRS) have been evaluated individually, but whether they predict the combined outcome of atherosclerotic cardiovascular disease (ASCVD) remains insufficiently researched. It is also unclear whether associations of the CHD and IS PRS with ASCVD are independent of subclinical atherosclerosis measures. 7,286 White and 2,016 Black participants from the population-based Atherosclerosis Risk in Communities study who were free of cardiovascular disease and type 2 diabetes at baseline were included. We computed previously validated CHD and IS PRS consisting of 1,745,179 and 3,225,583 genetic variants, respectively. Cox proportional hazards models were used to test the association between each PRS and ASCVD, adjusting for traditional risk factors, ankle-brachial index, carotid intima media thickness, and carotid plaque. The hazard ratios (HR) for the CHD and IS PRS were significant with HR of 1.50 (95% CI: 1.36-1.66) and 1.31 (95% CI: 1.18-1.45) respectively for the risk of incident ASCVD per standard deviation increase in CHD and IS PRS among White participants after adjusting for traditional risk factors. The HR for the CHD PRS was not significant with an HR of 0.95 (95% CI: 0.79-1.13) for the risk of incident ASCVD in Black participants. The HR for the IS PRS was significant with an HR of 1.26 (95%CI: 1.05-1.51) for the risk of incident ASCVD in Black participants. The association of the CHD and IS PRS with ASCVD was not attenuated in White participants after adjustment for ankle-brachial index, carotid intima media thickness, and carotid plaque. The CHD and IS PRS do not cross-predict well, and predict better the outcome for which they were created than the composite ASCVD outcome. Thus, the use of the composite outcome of ASCVD may not be ideal for genetic risk prediction.

PREDICTION OF CAROTID INTIMA MEDIA THICKNESS AND STIFFNESS IN ADOLESCENCE AND YOUNG ADULTHOOD FROM FOUR BLOOD PRESSURE PARAMETERS AND RESTING HEART RATE

Objective: Childhood blood pressure (BP) is associated with hard outcomes and intermediate markers of cardiovascular disease several decades later but studies on more short-termed outcomes are scarce and and it is unclear whether different BP parameters are all predictive. This study investigates the association of four BP parameters and resting heart rate (RHR) at age 3 - 17 years with three carotid markers one decade later with population-based data. Design and method: 4,607 14- to 28-year old participants of the nationwide German pediatric cohort KiGGS had semi–automated sonography with measurements of carotid intima media thickness (CIMT), lumen diameter (LD) and distensibility coefficient (DC) at their 11-year follow–up. We investigated associations of both baseline and follow-up systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), pulse pressure (PP) and RHR, with CIMT and LD &gt; = 90th percentile and DC &gt; = 10th percentile in logistic regression models. Percentiles were computed by sex and age. Analyses were adjusted for a cardiovascular risk score from added z-scores of body mass index, triglycerides, total-/HDL-cholesterol-ratio and HbA1c. Results: In longitudinal analyses SBP, DBP, MAP and RHR were significantly associated with all measures of subclinical atherosclerosis 11 years later, with similar, however weak, effect estimates, e.g. an OR of 1.19 (CI 1.09 - 1.31) for a one standard deviation increase in SBP with elevated CIMT. Cross–sectionally, the strongest association was found for MAP with reduced DC (OR 1.76; CI 1.60 - 1.94). For PP not all of these associations were significant. RHR was associated with elevated LD and reduced DC and inversely associated with elevated CIMT. Associations were similar when adjusting for the composite cardiovascular risk score. Conclusions: This study fills a gap between previous findings of an association between childhood BP and adverse effects in the vasculature in mid-adulthood, several decades later, by giving evidence for the association already after one decade. While individual risk prediction based of single BP measurements in this study is only weak, its robustness and consistency over five haemodynamic parameters and three subclinical atherosclerosis measures underscore the importance of preventing high blood pressure already early in the life course.

Abstract 23: Genome Wide Association Study and Multi-Ancestry Meta-Analysis Identify Common Variants Associated With Carotid Artery Intima Media Thickness

Carotid artery intima-media thickness (cIMT) is a measurement of subclinical atherosclerosis that predicts future cardiovascular events, including stroke and myocardial infarction. Genome-wide association studies (GWAS) in the past have identified only a fraction of the genetic variants associated with cIMT. We performed the largest GWAS to date for cIMT in a multi-ancestry meta-analysis in up to 131,000 individuals of African, Asian (Chinese), Brazilian, European, and Hispanic ancestries. Our study identified 57 independent loci (51 loci from the multi-ancestry single variant analysis of which 17 are novel, P&lt;5x10 -8 ; 6 novel in gene-based analysis from single variant analysis, P = 2.6x10 -6 ) associated with cIMT. Gene-based, tissue-expression and gene-set enrichment analyses revealed novel genes of potential interest and highlighted significant relationships between vascular tissues (aorta, coronary and tibial arteries) and genetic associations. We found strong genome-wide correlation between cIMT and various cardiometabolic, smoking and lipid traits. Using Mendelian randomisation, our analyses provide robust evidence for causal associations between cIMT and several clinically relevant traits, including lipids, blood pressure, and waist circumference. Our results provide the first evidence of substantial pleiotropy in colocalisation signals between APOE SNPs and metabolite biomarkers for coronary artery disease and cIMT but not for Alzheimer's disease.In summary, we identify 57 loci robustly associated with cIMT that are expressed in a range of vascular tissue types including aorta, coronary and tibial arteries. Our findings suggest a bidirectional relationship between cIMT and hypertension but do not support a link between atherosclerosis and Alzheimer’s disease based on the APOE locus.

Abstract P669: Inflammatory Markers and Calcification of Coronary Arteries, Aorta and Cardiac Valves in Older Adults: Findings From the Atherosclerosis Risk in Communities (ARIC) Study

Background: Inflammation plays an important role in the pathophysiology of atherosclerosis. However, inflammatory biomarkers have been found to have a weak association with coronary artery calcium (CAC), a representative measure of subclinical atherosclerosis. Moreover, the existing evidence does not sufficiently explore extra coronary calcium (ECC) in this context. Aim: To characterize the association of two inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) and galectin-3, with CAC and ECC in a community-based cohort. Methods: Cardiac CT was performed among 1,934 ARIC participants (age 53-74 years) without coronary heart disease at visit 7 (2018-19). We examined the associations of hs-CRP and galectin-3 measured in middle age at visit 4 (1996-98) by quartile with the presence of CAC and ECC (Agatston score &gt;0 vs. 0) using multivariable logistic regression. Results: Higher hs-CRP was associated with calcifications in the ascending aorta, aortic valve ring, mitral valve and right coronary artery in the unadjusted model (Table). These associations were mostly attenuated after adjusting for potential confounders, but the associations with ascending aorta and right coronary artery calcifications remained significant (adjusted odds ratio (aOR) = 1.45 [95% CI = 1.02-2.07]) and (1.55 [1.12-2.16]) for the highest vs. lowest quartiles, respectively). Galectin-3 was also independently associated with right coronary artery calcification after adjusting for potential confounders (aOR 1.48 [1.02 - 2.01]) for the highest vs. lowest quartiles). These associations were generally consistent in demographic subgroups. Conclusions: Both hs-CRP and galectin-3 were associated with calcification of some but not all vascular beds tested, suggesting potentially unique atherosclerotic pathophysiology across different vascular beds. Robust associations of inflammatory markers with right coronary artery calcification deserve further investigation.

The association between leptin and subclinical cardiovascular disease explained by body fat: Observational and Mendelian randomization analyses

Background and aimsLeptin has been associated with adverse effects on cardiovascular disease, but the effect of confounding by body fat in these associations remains unclear. To investigate associations between leptin and heart function and subclinical cardiovascular disease adjusted for total body fat, and to investigate the causal relation between leptin and cardiovascular disease using Mendelian randomisation. Methods and resultsLeptin concentrations, total body fat and diverse measures of subclinical cardiovascular disease were determined in participants of the Netherlands Epidemiology of Obesity study. Linear regression between leptin concentration and measures of heart function, ECG measures, and carotid intima media thickness as a measure of subclinical atherosclerosis was adjusted for potential confounding factors, and additionally including total body fat. We analysed the combined effects of genetic variants from a GWAS on leptin concentrations in publicly-available summary statistics of coronary heart disease GWAS (CARDIoGRAMplusC4D, n = 184,305). As many as 6107 men and women, mean (SD) age 56 (6) years, BMI 26 (4) kg/m2, and median leptin concentration 12.1 μg (IQR: 6.7–22.6) were included.In observational analyses, leptin was weakly associated with heart function and subclinical cardiovascular disease, but these associations attenuated when adjusting for total body fat. A doubling of genetically-determined leptin concentration was associated with an odds ratio of cardiovascular disease of 0.69 (0.37, 1.27). ConclusionObservational associations between leptin and subclinical measures of cardiovascular disease were largely explained by differences in total body fat. Results of analyses of genetically-determined leptin and coronary heart disease risk were inconclusive due to a large confidence interval.