Burden Of Subclinical Atherosclerosis Research Articles

Subclinical Atherosclerosis to Guide Treatment in Dyslipidemia and Diabetes Mellitus.

Dyslipidemia and type 2 diabetes mellitus are two common conditions that are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). In this review, we aimed to provide an in-depth and contemporary review of non-invasive approaches to assess subclinical atherosclerotic burden, predict cardiovascular risk, and guide appropriate treatment strategies. We focused this paper on two main imaging modalities: coronary artery calcium (CAC) score and computed tomography coronary angiography. Recent longitudinal studies have provided stronger evidence on the relationship between increased CAC, thoracic aorta calcification, and risk of cardiovascular events among those with primary hypercholesterolemia, highlighting the beneficial role of statin therapy. Interestingly, resilient profiles of individuals not exhibiting atherosclerosis despite dyslipidemia have been described. Non-conventional markers of dyslipidemia have also been associated with increased subclinical atherosclerosis presence and burden, highlighting the contribution of apolipoprotein B-100 (apoB)-rich lipoprotein particles, such as remnant cholesterol and lipoprotein(a), to the residual risk of individuals on-target for low-density lipoprotein cholesterol (LDL-C) goals. Regarding type 2 diabetes mellitus, variability in atherosclerotic burden has also been found, and CAC testing has shown significant predictive value in stratifying cardiovascular risk. Non-invasive assessment of subclinical atherosclerosis can help reveal the continuum of ASCVD risk in those with dyslipidemia and diabetes mellitus and can inform personalized strategies for cardiovascular disease prevention in the primary prevention setting.

Prevalence and Burden of Carotid and Femoral Atherosclerosis in Subjects Without Known Cardiovascular Disease in a Large Community Hospital in South-America.

Clinical guidelines recommend measurement of arterial (carotid and femoral) plaque burden by vascular ultrasound (VUS) as a risk modifier in individuals at low or moderate risk without known atherosclerotic cardiovascular disease (ASCVD). To evaluate the prevalence of carotid and femoral plaques by age and sex, the burden of subclinical atherosclerosis (SA), and its association with classic CVRF in subjects over 30 years of age without ASCVD. We prospectively enrolled 5775 consecutive subjects referred for cardiovascular evaluation and determined the prevalence and burden of SA using 2D-VUS in carotid and femoral arteries. Sixty-one percent were men with a mean age of 51.3 (SD 10.6) years. Overall, plaque prevalence was 51% in carotid arteries, 39.3% in femoral arteries, 62.4% in carotid or femoral arteries, and 37.6% in neither. The prevalence of plaques and SA burden showed an increasing trend with age, being higher in men than in women and starting before the age of 40, both in the carotid and femoral sites. There was also an increasing prevalence of plaques according to the number of CVRF, and interestingly we found a high prevalence of plaques in subjects with 0 or 1 classic CVRF. We observed an increased prevalence and burden of carotid or femoral SA, higher in men, beginning before the fourth decade of life and increasing with age. Despite a significant association with classic CVRF, a significant number of subjects with low CVRF were diagnosed with SA.

Association between subclinical atherosclerosis burden and unrecognized myocardial infarction detected by cardiac magnetic resonance in middle-aged adults.

Evidence on the association between subclinical atherosclerosis (SA) and cardiovascular (CV) events in low-risk populations is scant. To study the association between SA burden and an ischemic scar (IS), identified by cardiac magnetic resonance (CMR), as a surrogate of CV endpoint, in a low-risk population. A cohort of 712 asymptomatic middle-aged individuals from the Progression of Early SA (PESA-CNIC-Santander) study (median age 51 years, 84% male, median SCORE2 3.37) were evaluated on enrollment and at 3-year follow-up with 2D/3D vascular ultrasound (VUS) and coronary artery calcification scoring (CACS). A cardiac magnetic study (CMR) was subsequently performed, and IS defined as the presence of subendocardial or transmural late gadolinium enhancement (LGE). On CMR, 132 (19.1%) participants had positive LGE, and IS was identified in 20 (2.9%) participants. Individuals with IS had significantly higher SCORE2 at baseline and higher CACS and peripheral SA burden (number of plaques by 2DVUS and plaque volume by 3DVUS) at both SA evaluations. High CACS and peripheral SA (number of plaques) burden were independently associated with the presence of IS, after adjusting for SCORE2 (OR for 3rd tertile, 8.31; 95% CI 2.85-24.2; p<0.001; and 2.77; 95% CI, 1.02-7.51; p=0.045, respectively) and provided significant incremental diagnostic value over SCORE2. In a low-risk middle-aged population, SA burden (CAC and peripheral plaques) was independently associated with a higher prevalence of IS identified by CMR. These findings reinforce the value of SA evaluation to early implement preventive measures.

7-year follow-up atherosclerotic plaque progression in patients with antiphospholipid syndrome versus diabetes mellitus and healthy controls.

Patients with antiphospholipid syndrome (APS) carry a substantial burden of cardiovascular disease and subclinical atherosclerosis. We aimed to assess a 7-year follow-up atherosclerotic plaque progression in APS patients vs diabetes mellitus (DM) and healthy controls (HC). Eighty-six patients with thrombotic APS, 86 with DM and 86 HC (all age- and sex-matched) who underwent a baseline ultrasound of carotid and femoral arteries were invited for a 7-year follow-up ultrasonography examination. We compared atherosclerosis progression among the three groups and examined determinants of plaque progression in APS patients. Sixty-four APS patients (75% females, 43.8% with primary APS), 58 patients with DM and 66 HC were included in the 7-year ultrasound re-evaluation. New plaque was detected in 51.6%, 36.2% and 25.8% of APS, DM and HC subjects, respectively. After adjusting for traditional cardiovascular risk factors (CVRFs) and baseline plaque presence, APS patients showed a 3-fold (OR = 3.07, p= 0.007) higher risk for atherosclerosis progression vs HC and 2-fold (OR = 2.25, p= 0.047) higher risk than DM patients. In multivariate analysis in the APS group, plaque progression was independently associated with systemic lupus erythematosus (SLE) co-existence (OR = 7.78, p= 0.005) and number of CVRFs (OR = 3.02, p= 0.002), after adjusting for disease-related parameters and CVRF-related medications. Sustained low-density lipoprotein target attainment reduced plaque progression risk (OR = 0.34, p= 0.021). Half of APS patients develop new atherosclerotic plaques over a 7-year follow-up, having a three-times higher risk vs HC. Concomitant SLE and number of traditional CVRFs are associated with plaque progression, supporting the need for thorough CVRF assessment and control.

Early insulin resistance in normoglycemic low-risk individuals is associated with subclinical atherosclerosis

BackgroundElevated glycated hemoglobin (HbA1c) is associated with a higher burden of subclinical atherosclerosis (SA). However, the association with SA of earlier insulin resistance markers is poorly understood. The study assessed the association between the homeostatic model assessment of insulin resistance index (HOMA-IR) and SA in addition to the effect of cardiovascular risk factors (CVRFs) in individuals with normal HbA1c.MethodsA cohort of 3,741 middle-aged individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study with basal HbA1c < 6.0% (< 42 mmol/mol) and no known CV disease underwent extensive imaging (multiterritorial vascular ultrasound and coronary artery calcium score, CACS) to assess the presence, burden, and extent of SA.ResultsIndividuals with higher HOMA-IR values had higher rates of CVRFs. HOMA-IR showed a direct association with the multiterritorial extent of SA and CACS (p < 0.001) and with global plaque volume measured by 3-dimensional vascular ultrasound (p < 0.001). After adjusting for key CVRFs and HbA1c, HOMA-IR values ≥ 3 were associated with both the multiterritorial extent of SA (odds ratio 1.41; 95%CI: 1.01 to 1.95, p = 0.041) and CACS > 0 (odds ratio 1.74; 95%CI: 1.20 to 2.54, p = 0.004), as compared with the HOMA-IR < 2 (the reference HOMA-IR category). In a stratified analysis, this association remained significant in individuals with a low-to-moderate SCORE2 risk estimate (75.6% of the cohort) but not in high-risk individuals.ConclusionsThe use of HOMA-IR identified low-risk individuals with a higher burden of SA, after adjusting for the effects of key traditional CVRFs and HbA1c. HOMA-IR is a simple measure that could facilitate earlier implementation of primary CV prevention strategies in clinical practice.

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.

Metabolic health phenotype better predicts subclinical atherosclerosis than body mass index-based obesity phenotype in the non-alcoholic fatty liver disease population.

Non-alcoholic fatty liver disease (NAFLD), especially lean NAFLD is associated with an increased risk of atherosclerotic cardiovascular disease (CVD). It is not currently known which clinical phenotypes of NAFLD contribute most to individual subclinical atherosclerosis risk. We examined the relationship between body mass index (BMI), the metabolically healthy status, and subclinical atherosclerosis in the NAFLD population. Data from asymptomatic NAFLD subjects who participated in a routine health check-up examination were collected. Participants were stratified by BMI (cutoff values: 24.0-27.9 kg/m2 for overweight and ≥28.0 kg/m2 for obesity) and metabolic status, which was defined by Adult Treatment Panel III criteria. Subclinical atherosclerosis was evaluated by brachial-ankle pulse wave velocity (baPWV) in 27,738 participants and by carotid plaque in 14,323 participants. Within each BMI strata, metabolically unhealthy subjects had a significantly higher prevalence of subclinical atherosclerosis than metabolically healthy subjects, whereas fewer differences were observed across subjects within the same metabolic category. When BMI and metabolic status were assessed together, a metabolically unhealthy status was the main contributor to the association of clinical phenotypes with the subclinical atherosclerosis burden (all p < 0.001). When BMI and metabolic abnormalities were assessed separately, the incidence of subclinical disease did not increase across BMI categories; however, it increased with an increase in the number of metabolic abnormalities (0, 1, 2 and ≥3). A metabolically healthy status in NAFLD patients was closely correlated with subclinical atherosclerosis, beyond that of the BMI-based obesity phenotype. The application of metabolic phenotyping strategies could enable more precise classification in evaluating cardiovascular risk in NAFLD.

Subclinical atherosclerosis and accelerated epigenetic age mediated by inflammation: a multi-omics study.

Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association. Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, and IL10) and genes (IL1B, OSM, TLR5, and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration. The presence, extension, and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals are associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent cardiovascular disease.

Social Determinants of Cardiovascular Risk, Subclinical Cardiovascular Disease, and Cardiovascular Events.

Background Although there is research on the impact of social determinants of health (SDOHs) on cardiovascular health, most existing evidence is based on individual SDOH components. We evaluated the impact of cumulative SDOH burden on cardiovascular risk factors, subclinical atherosclerosis, and incident cardiovascular disease events. Methods and Results We included 6479 participants from the MESA (Multi-Ethnic Study of Atherosclerosis). A weighted aggregate SDOH score representing the cumulative number of unfavorable SDOHs, identified from 14 components across 5 domains (economic stability, neighborhood and physical environment, community and social context, education, and health care system access) was calculated and divided into quartiles (quartile 4 being the least favorable). The impact of cumulative SDOH burden on cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking, and obesity), systemic inflammation, subclinical atherosclerosis, and incident cardiovascular disease was evaluated. Increasing social disadvantage was associated with increased odds of all cardiovascular risk factors except dyslipidemia. Smoking was the risk factor most strongly associated with worse SDOH (odds ratio [OR], 2.67 for quartile 4 versus quartile 1 [95% CI, 2.13-3.34]). Participants within SDOH quartile 4 had 33% higher odds of increased high-sensitivity C-reactive protein (OR, 1.33 [95% CI, 1.11-1.60]) and 31% higher risk of all cardiovascular disease (hazard ratio, 1.31 [95% CI, 1.03-1.67]), yet no greater burden of subclinical atherosclerosis (OR, 1.01 [95% CI, 0.79-1.29]), when compared with those in quartile 1. Conclusions Increasing social disadvantage was associated with more prevalent cardiovascular risk factors, inflammation, and incident cardiovascular disease. These findings call for better identification of SDOHs in clinical practice and stronger measures to mitigate the higher SDOH burden among the socially disadvantaged to improve cardiovascular outcomes.

Potential Predictors of Cardiovascular Risk Improvement in Patients with Hidradenitis Suppurativa Treated with Adalimumab: A Pivotal Study of Factors Associated with Carotid Intima-Media Thickness Reduction.

Hidradenitis suppurativa (HS) has been linked to higher cardiovascular risk (CVR) due to its inflammatory burden. There is little evidence on how biologic treatment could modify the cardiovascular risk of patients with HS. The aims of the present study were to explore the modification of CVR in patients under adalimumab treatment and to explore the potential factors associated with CVR improvement. A prospective longitudinal study was performed. A cohort of patients with HS treated with adalimumab was followed up. Carotid intima-media thickness (IMT) and other clinical and biochemical CVR factors were collected at baseline and 32weeks after starting the treatment. Twenty-seven patients with severe HS were included. Overall, there were no differences in IMT between baseline (633μm) and 32weeks follow-up (634μm). However, 40.7% (11/27) of the patients presented an improvement in IMT. This group (IMT responders) had a higher prevalence of dyslipidemia, diabetes mellitus, higher HbA1c levels, consumed more tobacco, and had higher BMI at baseline. Moreover, these patients had lower IHS4 scores at baseline and tended to have a greater IMT basal value, indicating a higher burden of subclinical atherosclerosis. Adalimumab treatment might benefit a subset of patients with HS in terms of cardiovascular risk reduction. In light of the results of the present study patients with classical cardiovascular risk factors, and those with higher burden of subclinical atherosclerosis and with less inflammatory load, may be more likely to improve their IMT during adalimumab treatment.

Subclinical atherosclerosis burden in non-diabetic hypertensives treated in primary care center: the IMTABI study

BackgroundIdentifying patients at high risk of cardiovascular disease in primary prevention is a challenging task. This study aimed at detecting subclinical atherosclerosis burden in non-diabetic hypertensive patients in a primary care centre.MethodsClinical, anthropometric and analytical data were collected from patients with hypertension who were free from clinical vascular disease and diabetes. The cardiovascular risk was assessed using the SCORE system. Subclinical atherosclerosis burden was assessed by carotid ultrasonography (intima-medial thickness [IMT] and plaque) and measurement of the ankle-brachial index (ABI).ResultsOut of 140 patients, 59 (42%) have carotid plaque, 32 (23%) have IMT higher than 75% and 12 (9%) have an ABI < 0.9. Total atherosclerosis burden was present in 91 (65%) of the subjects. Consequently, 59 (42%) patients were re-classified into the very high-risk category. In multivariate analyses, smoking, creatinine levels and duration of hypertension were associated with atherosclerosis burden. In contrast, only smoking and age were associated with the presence of carotid plaque. Almost 90% of patients were treated with hypotensive drugs, half of them combined several drugs and 60% were well-controlled. Only 30% received statins in monotherapy and only less than 20% had an LDL cholesterol < 100 mg/dL.ConclusionsIn non-diabetic hypertensive patients managed at a primary care centre, 4 out of 10 had subclinical atherosclerosis burden and were re-classified into the very high- risk category. There was clear undertreatment with lipid-lowering drugs of most LDL cholesterol inappropriate levels, according to current clinical guidelines.

Abstract 14174: Abnormal Exercise Electrocardiography With Normal Stress Echocardiography is Associated With Increased Subclinical Coronary Atherosclerosis: Insights From the Project Baseline Health Study

Introduction Patients with an abnormal (positive) exercise electrocardiography (ECG), but normal stress echocardiography (+ECG/-Echo) have more adverse cardiac events than patients with a negative ECG and normal stress Echo (-ECG/-Echo). However, it is unclear if ECG/Echo discordance is associated with a greater burden of concurrent subclinical coronary atherosclerosis. Methods In the Project Baseline Health Study (PBHS), participants underwent stress Echo and a coronary artery calcium (CAC) scan. For this PBHS substudy, participants with no known coronary artery disease (CAD) were analyzed by stress result: -ECG/-Echo, +ECG/-Echo, or +Echo (with or without +ECG). Patients with a submaximal stress test, uninterpretable ECG, resting wall motion abnormality, and/or baseline ejection fraction &lt;50% were excluded. Clinical characteristics, exercise performance, and CAC results were compared between the -ECG/-Echo and +ECG/-Echo groups using the chi-squared test and Student’s t-test for categorical and continuous variables, respectively. ANOVA or Kruskal-Wallis test was used, as appropriate, to compare all 3 groups. Results Among 1466 participants, 1357 (92.6%) had a -ECG/-Echo; 85 (5.8%) had a +ECG/-Echo; and 24 (1.6%) had a +Echo. Compared to the -ECG/-Echo group, participants in the +ECG/-Echo group were older with shorter exercise duration, but younger with fewer risk factors than participants with a +Echo. The median 10-year ASCVD risk score was 2% for -ECG/-Echo, 3% for +ECG/-Echo, and 10% for +Echo (p&lt;0.001). Greater abnormalities by exercise stress Echo were associated with an increased burden of concurrent coronary atherosclerosis as assessed by CAC score and CAC volume (Table). Conclusions Individuals with positive exercise ECG, even with normal stress Echo, have a higher burden of subclinical coronary atherosclerosis than those with -ECG/-Echo, which may explain the increased risk for adverse cardiac events in the +ECG/-Echo population.

Diabetic retinopathy predicts cardiovascular disease independently of subclinical atherosclerosis in individuals with type 2 diabetes: A prospective cohort study

Diabetic retinopathy (DR) and preclinical atherosclerosis are associated with higher cardiovascular risk. However, no studies have investigated the predictive role of DR and preclinical atherosclerosis jointly on cardiovascular events in subjects with type 2 diabetes (T2D). We aimed to assess the contribution of DR and subclinical atherosclerosis on the risk of adverse cardiovascular events in subjects with T2D without previous cardiovascular disease (CVD). We included two prospective cohorts of subjects with T2D from the same geographical area. Assessment of subclinical atherosclerosis was performed by carotid ultrasound. An ophthalmologist classified DR according to standard criteria. Cardiovascular outcomes considered for analysis were the following: ischemic heart disease, stroke, heart failure, peripheral artery disease, revascularization procedures, and cardiovascular mortality. Bivariable and multivariable predictive models were performed. From a total of 374 subjects with T2D 44 developed cardiovascular events during the 7.1 years of follow-up. Diabetes duration, total cholesterol, and glycated hemoglobin (HbA1c) at baseline were higher in subjects who developed cardiovascular outcomes (p < 0.001, p = 0.026, and p = 0.040, respectively). Compared with subjects without events, those developing cardiovascular events had higher prevalence of retinopathy (65.9% vs. 38.8%, p = 0.001; respectively) and more than mild retinopathy (43.2% vs. 31.8%, p = 0.002; respectively). Furthermore, all-cause mortality was higher in subjects with MACE than those without events (13.6% vs. 3.3%, p = 0.009; respectively). The multivariable analyses showed that HbA1c and the presence of DR at baseline were predictive of cardiovascular outcomes (p = 0.045 and p = 0.023, respectively). However, the burden of subclinical atherosclerosis was not (p = 0.783 and p = 0.071, respectively). DR is a strong predictor of cardiovascular events in T2D individuals at primary CVD prevention, even after accounting for the presence of preclinical carotid atherosclerosis. These results may help to individualize CVD prevention strategies in T2D.

Association of α-klotho with subclinical carotid atherosclerosis in subjects with type 1 diabetes mellitus

BackgroundCompelling evidence suggests that the fibroblast growth factor 23 (FGF23) / α-klotho axis is impaired in subjects with diabetes mellitus. We examined the relationship between parameters related to calcium/phosphate homeostasis, including FGF23 and α-klotho, and subclinical carotid atherosclerosis burden in type 1 diabetes mellitus (T1D) subjects.MethodsThis cross-sectional study involved 226 subjects with T1D and 147 age-, sex- and plaque-matched, non-diabetic (non-T1D) subjects, both with normal renal function. Carotid ultrasound was performed to determine the presence and burden of atheromatous plaques. Concentrations of the intact form of FGF23 and α-klotho were assessed by ELISA. Calcium, phosphate, parathyroid hormone, and vitamin D levels were also determined. Negative binomial regression models were used to examine relationship between parameters studied and subclinical carotid atherosclerosis.ResultsOnly FGF23 was increased in T1D compared with non-diabetic subjects (> 2-fold; p < 0.05). α-klotho was higher in subjects with subclinical carotid atherosclerosis (1.4-fold, p < 0.05). Regression analysis revealed that the log α-klotho concentration was positively associated with the presence of subclinical carotid atherosclerosis both in T1D subjects (incidence rate ratio [IRR]: 1.41; 95% confidence interval [CI], 1.06–1.89; p < 0.05) and in non-T1D subjects (IRR: 1.65; 95% CI, 1.02–2.75; p < 0.05). The models also showed that age, smoking and albuminuria-to-creatinine ratio were positively associated with subclinical carotid atherosclerosis in T1D subjects. Interestingly, sex-related protection against plaque was also revealed in T1D women.ConclusionHigher α-klotho was associated with subclinical carotid atherosclerotic in the absence of kidney dysfunction. This finding also points to a new pathophysiological pathway involved in the development and progression of this complication.

Coronary CT angiography derived pericoronary inflammation and bespoke cardiovascular risk prediction in the lipid clinic: beyond the calcium score

Abstract Background Dyslipidaemia promotes atherosclerosis. Genetic dyslipidaemias, Familial Hypercholesterolaemia (FH) being the most common, are associated with heightened risk of coronary artery disease (CAD) and premature major adverse cardiovascular events (MACE). However, this risk is both heterogeneous and modifiable with treatment. CT coronary imaging can identify subclinical atherosclerosis, enabling personalised risk stratification and treatment targets. Coronary artery calcium scoring (CACS) is current first-line in European guidelines for asymptomatic patients. However, calcification occurs late in CAD pathogenesis and CACS has low specificity in young patients with severe FH. CT coronary angiography (CTCA) assesses non-calcific plaque and high-risk plaque (HRP) features unappreciable with CACS. Additionally, the pericoronary fat attenuation index (FAI) measures inflammation on routine CTCA and is the strongest non-invasive imaging biomarker of risk of fatal MI. Purpose To quantify and compare the reclassification of subclinical atherosclerosis burden in Lipid Clinic patients assessed via CACS vs CTCA with FAI analysis. Methods Analysis of a prospectively maintained clinical database of asymptomatic Lipid Clinic patients with both CACS and CTCA imaging from May 2019 to December 2020. CACS was reported with the standardised Agastston criteria and compared with (i) the CTCA-derived Coronary Artery Disease – Reporting and Data System (CAD RADS) grading of anatomical stenosis, including a modifier for HRP features, and (ii) FAI analysis. Significance was defined as two-tailed p75th percentile vs age and sex matched controls) was seen in 6/27 (22%) patients with none to mild calcification on CACS and 6/28 (21%) patients with none to mild CAD on CTCA, of whom 3/7 (43%) had HRP. High FAI was seen in all groups of calcification severity and CAD RADS score (Figure 2). The proportion with high FAI was higher in CAD RADS 0 vs CAD RADS 4, and CACS severity was not associated with level of inflammation (p=0.94). High FAI was observed in 16% of patients on treatment, suggesting treatment failure. This included patients with CACS ranging from 0 to severe (&amp;gt;400), and CAD RADS of minimal (1) to severe (4). Conclusion CTCA re-stratifies CAD presence and severity vs CACS in a high-risk, asymptomatic patient group and identified a high proportion of patients with HRP features. FAI provides incremental value in identification of patients at risk of future MACE regardless of CACS grade, including patients without evidence of overt CAD. Identifying high FAI on treatment may imply treatment failure. Funding Acknowledgement Type of funding sources: None.

Statin Use and Risk of Diabetes by Subclinical Atherosclerosis Burden (from a Multi-Ethnic Study of Atherosclerosis Report)

Although there is a significant reduction in atherosclerotic cardiovascular disease risk with statins, a higher risk of diabetes mellitus has been demonstrated in randomized clinical trials. The risk of incident diabetes with statins may be heterogeneous by presence of coronary artery calcium (CAC). We evaluated participants without prevalent diabetes at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of subjects free of clinical cardiovascular disease at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between statin use and incident diabetes, adjusting for sociodemographic and cardiovascular risk factors, including time-varying statin use and stratifying by baseline CAC (0, 1 to 100, ≥100). The study population included 5,943 participants with a mean (SD) age of 62 (10) years, 54% women, 41% White, 26% Black, 12% Chinese-American, and 21% Hispanic. In the unadjusted analyses, statin use was associated with a higher risk of incident diabetes (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.27 to 2.06). After adjustment, this risk was no longer significant (HR 1.13, 95% CI 0.83 to 1.54). Although imprecise, the HR expressing the association of statins with diabetes was lower for those with CAC=0 (HR 0.80, 95% CI 0.45 to 1.40) than for those with a higher CAC burden (HR 1.30, 95% CI 0.71 to 2.39 for CAC 1 to 100 and HR 1.39, 95% CI 0.85 to 2.28 for CAC ≥100), but this heterogeneity was not statistically significant. In conclusion, statin therapy was not significantly associated with incident diabetes mellitus in this observational study. The risk of incident diabetes did not significantly differ by baseline CAC.

In patients with non-alcoholic fatty liver disease, liver stiffness directly correlates with the carotid plaque burden

Background and Aims : It is now well established that non-alcoholic fatty liver disease (NAFLD) is associated with a significant increase in the risk of adverse cardiovascular events. NAFLD-specific cardiovascular risk scores, considering traditional and nontraditional risk factors, are needed to improve patient care. Liver fibrosis may be an integrative indicator of the burden of cardiometabolic risk factors. Liver fibrosis may also represent the burden of subclinical atherosclerosis. The aim of the study was to investigate the relationships between liver stiffness and carotid plaque burden in patients with NAFLD without established atherosclerotic cardiovascular disease.

Racial and Ethnic Differences in the Association Between Classical Cardiovascular Risk Factors and Common Carotid Intima-Media Thickness: An Individual Participant Data Meta-Analysis.

BackgroundThe major risk factors for atherosclerotic cardiovascular disease differ by race or ethnicity but have largely been defined using populations of European ancestry. Despite the rising prevalence of cardiovascular disease in Africa there are few related data from African populations. Therefore, we compared the association of established cardiovascular risk factors with carotid‐intima media thickness (CIMT), a subclinical marker of atherosclerosis, between African, African American, Asian, European, and Hispanic populations.Methods and ResultsCross‐sectional analyses of 34 025 men and women drawn from 15 cohorts in Africa, Asia, Europe, and North America were undertaken. Classical cardiovascular risk factors were assessed and CIMT measured using B‐mode ultrasound. Ethnic differences in the association of established cardiovascular risk factors with CIMT were determined using a 2‐stage individual participant data meta‐analysis with beta coefficients expressed as a percentage using the White population as the reference group. CIMT adjusted for risk factors was the greatest among African American populations followed by Asian, European, and Hispanic populations with African populations having the lowest mean CIMT. In all racial or ethnic groups, men had higher CIMT levels compared with women. Age, sex, body mass index, and systolic blood pressure had a significant positive association with CIMT in all races and ethnicities at varying magnitudes. When compared with European populations, the association of age, sex, and systolic blood pressure with CIMT was weaker in all races and ethnicities. Smoking (beta coefficient, 0.39; 95% CI, 0.09–0.70), body mass index (beta coefficient, 0.05; 95% CI, 0.01–0.08) and glucose (beta coefficient, 0.13; 95% CI, 0.06–0.19) had the strongest positive association with CIMT in the Asian population when compared with all other racial and ethnic groups. High‐density lipoprotein‐cholesterol had significant protective effects in African American (beta coefficient, −0.31; 95% CI, −0.42 to −0.21) and African (beta coefficient, −0.26; 95% CI, −0.31 to −0.19) populations only.ConclusionsThe strength of association between established cardiovascular risk factors and CIMT differed across the racial or ethnic groups and may be due to lifestyle risk factors and genetics. These differences have implications for race‐ ethnicity‐specific primary prevention strategies and also give insights into the differential contribution of risk factors to the pathogenesis of cardiovascular disease. The greatest burden of subclinical atherosclerosis in African American individuals warrants further investigations.

Variability of the Plasma Lipidome and Subclinical Coronary Atherosclerosis

While the risk of acute coronary events has been associated with biological variability of circulating cholesterol, the association with variability of other atherogenic lipids remains less understood. We evaluated the longitudinal variability of 284 lipids and investigated their association with asymptomatic coronary atherosclerosis. Approach and Results: Circulating lipids were extracted from fasting blood samples of 83 community-sampled symptom-free participants (age 41-75 years), collected longitudinally over 6 months. Three types of coronary plaque volume (calcified, lipid-rich, and fibrotic) were quantified using computed tomography coronary angiogram. We first deconvoluted between-subject (CVg) and within-subject (CVw) lipid variabilities. We then tested whether the mean lipid abundance was different across groups categorized by Framingham risk score and plaques phenotypes (lipid-rich, fibrotic, and calcified). Finally, we investigated whether visit-to-visit variability of each lipid was associated with plaque burden. Most lipids (72.5%) exhibited higher CVg than CVw. Among the lipids (n=145) with 1.2-fold higher CVg than CVw, 26 species including glycerides and ceramides were significantly associated with Framingham risk score and the 3 plaque phenotypes (false discovery rate <0.05). In an exploratory analysis of person-specific visit-to-visit variability without multiple testing correction, high variability of 3 lysophospholipids (lysophosphatidylethanolamines 16:0, 18:0, and lysophosphatidylcholine O-18:1) was associated with lipid-rich and fibrotic (noncalcified) plaque volume while high variability of diacylglycerol 18:1_20:0, triacylglycerols 52:2, 52:3, and 52:4, ceramide d18:0/20:0, dihexosylceramide d18:1/16:0, and sphingomyelin 36:3 was associated with calcified plaque volume. High person-specific longitudinal variation of specific nonsterol lipids is associated with the burden of subclinical coronary atherosclerosis. Larger studies are needed to confirm these exploratory findings.

Abstract 13319: Subclinical Atherosclerosis in American Indian Adolescents and Young Adults and the Risk of Fatal and Non-Fatal Cardiovascular Events: The Strong Heart Family Study (SHFS)

Introduction: Rates of cardiovascular disease (CVD) among American Indians (AI) have been increasing. Subclinical atherosclerosis is typically detected later in life and may develop into clinical CVD. Although investigators have established the association in older adults, the burden of subclinical atherosclerosis and its relation to CVD risk among AI youth is unclear. Hypothesis: Subclinical atherosclerosis will be prevalent and the risk of CVD will be higher in AI with atherosclerotic plaque in adolescence and early adulthood. Methods: We evaluated AI participants from the SHFS, who were 14-39 years old, CVD free, and had a carotid ultrasound at the baseline examination, 2001-2003 (n=1,376). We used carotid ultrasound to detect baseline atherosclerotic plaque. We identified fatal and/or non-fatal CVD events through the end of 2019 with a median follow-up of 17.8 years. We used shared frailty Cox Proportional Hazards models to assess the association between subclinical atherosclerosis and time to CVD events, while controlling for covariates. Results: Among 1,376 participants, 71 (5.2%) had atherosclerotic plaque at baseline. During follow-up, 120 (8.7%) participants had a fatal or non-fatal CVD event. CVD incidence was higher in participants with baseline plaque (13.51/1,000 person-years) than in those without (4.95/1,000 person-years, p=0.0003, Figure 1). Risk of CVD was higher in participants with baseline plaque compared to those without, while controlling for age and obesity (CVD HR=1.85, 95% CI=1.02-3.37, p=0.0420). Conclusions: AI adolescents and young adults have an unexpectedly high prevalence of atherosclerotic plaque, which is independently associated with incident CVD later in life. Thus, atherosclerosis begins early in life and interventions in adolescents and young adults to slow the progression of disease could prevent or delay CVD events later in life.