Rare variants in previously identified linkage regions associated with carotid plaque in Dominican Republic families

Carotid plaque is a subclinical measure of atherosclerosis. We have previously shown measures of carotid plaque to be heritable in a sample of 100 Dominican families and found evidence for linkage and association of common variants (CVs) on 7q36, 11p15, 14q32 and 15q23 with plaque presence. Our current study aimed to refine these regions further and identify rare variants (RVs) influencing plaque presence. Therefore, we performed targeted sequencing of the one LOD unit down region on 7q36, 11p15, 14q32 and 15q23 in 12 Dominican families with evidence for linkage to plaque presence. Gene-based RV analyses were performed using the Sequence Association Test for familial data (F-SKAT) under two filtering algorithms; 1. all exonic RVs and 2. non-synonymous RVs. Replication analyses were performed using a sample of 22 Dominican families and 556 unrelated Dominicans with Exome Array data. To identify additional non-synonymous RVs influencing plaque, we looked for co-segregation of RVs with plaque in each of the sequenced families. Our most strongly associated gene with evidence for replication was AMPD3 which showed suggestive association with plaque presence in the sequenced families (exonic RV p = 0.003, nonsynonymous RV p = 0.005) and replication families (exonic RV p = 0.04, nonsynonymous RV p = 0.02). Examination of the sequenced family pedigrees revealed two missense variants on chromosome 11 which co-segregated with plaque presence in one of our families; rs61751342 (located in DENND2B), and rs61760882 (located in RNF141). The rs61751342 missense variant is an eQTL for SCUBE2 in the atrial appendage. Notably, SCUBE2 encodes a protein which interacts with vascular endothelial growth factor (VEGF) receptor 2 to regulate VEGF-induced angiogenesis, thus providing biologic plausibility for this gene in atherosclerosis. In conclusion, using targeted sequencing of previously-identified linkage regions, we have identified suggestive evidence for the role of RVs in carotid plaque pathogenesis.

Sex Differences in Plaque Composition and Morphology Among Symptomatic Patients With Mild-to-Moderate Carotid Artery Stenosis

Background and Purpose: Incidence of ischemic stroke differs between men and women, with substantially higher rates in men. The underlying mechanism of this difference remains poorly understood but may be because of differences in carotid atherosclerosis. Using an in-depth imaging-based approach, we investigated differences between carotid plaque composition and morphology in male and female patients with stroke, taking into account differences in total plaque burden. Additionally, we investigated all possible within-artery combinations of plaque characteristics to explore differences between various plaque phenotypes. Methods: We included 156 men and 68 women from the PARISK (Plaque At Risk) study, a prospective cohort study of patients with recent ischemic cerebrovascular symptoms and <70% ipsilateral carotid stenosis. Plaque characteristics (intraplaque hemorrhage [IPH], lipid-rich necrotic core [LRNC], calcifications, thin-or-ruptured fibrous cap, ulcerations, total plaque volume) were assessed with magnetic resonance imaging and multidetector-row computed tomography angiography. We used multivariable logistic and linear regression analyses to assess sex differences in plaque characteristics. Results: We found significant difference in total plaque volume between men and women (β=22.9 mm 3 [95% CI, 15.4–30.5]; mean volume in men 1399±425 mm 3 , in women 1011±242 mm 3 ). Additionally, men were more likely to have IPH (odds ratio [OR]=2.8 [95% CI, 1.3–6.3]; IPH proportion in men 49%, in women 16%) and LRNC (OR=2.4 [95% CI, 1.2–4.7]; LRNC proportion in men 73%, in women 41%) even after adjustment for total plaque volume. We found no sex-specific differences in plaque volume-corrected volumes of IPH, LRNC, and calcifications. In terms of coexistence of plaque characteristics, we found that men had more often a plaque with coexistence of calcifications, LRNC, and IPH (OR=2.7 [95% CI, 1.2–7.0]), with coexistence of thin-or-ruptured fibrous cap/ulcerations, LRNC, and IPH (OR=2.4 [95% CI, 1.1–5.9]), and with coexistence of all plaque characteristics (OR=3.0 [95% CI, 1.2–8.6]). Conclusions: In symptomatic patients with mild-to-moderate carotid stenosis, men are more likely to have a high-risk carotid plaque with IPH and LRNC than women, regardless of total plaque burden. Men also have more often a plaque with multiple vulnerable plaque components, which could comprise an even higher stroke risk. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01208025.

Associations Among Diffusion Tensor Image Along the Perivascular Space (DTI-ALPS), Enlarged Perivascular Space (ePVS), and Cognitive Functions in Asymptomatic Patients With Carotid Plaque

Background and Aim: Carotid atherosclerosis (CAS) is a common pathogenesis of cerebrovascular disease closely related to stroke and silent cerebrovascular disease (SCD), while the insufficient brain perfusion mechanism cannot quite explain the mechanism. The purpose of this study was to utilize diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate the glymphatic system activity and correlated DTI-ALPS with enlarged perivascular spaces (ePVS), carotid intima-media thickening (CIMT), mini-mental state examination (MMSE), and serological indicator in individuals with carotid plaque.Methods: Routine MRI and diffusion tensor images scan of the brain, carotid ultrasound, and blood examination were conducted on 74 individuals (52 carotid plaque subjects, 22 non-carotid plaque subjects), whose demographic and clinical characteristics were also recorded. DTI-ALPS index between patients with carotid plaque and normal controls were acquired and the correlations with other variables were analyzed.Results: The values of ALPS-index in the carotid plaque group was significantly lower compared to normal controls (2.12 ± 0.39, 1.95 ± 0.28, respectively, p = 0.034). The ALPS-index was negatively correlated with the basal ganglia (BG)-ePVS score (r = −0.242, p = 0.038) while there was no significant difference in the centrum semiovale (CSO)-ePVS score. Further analysis showed that there are more high-grade ePVS in the BG compared to the carotid plaque group than in the non-carotid plaque group (84.6% vs. 40.9%, p = 0.001).Conclusions: ALPS-index reflects the glymphatic system of the brain, which is associated with early high-risk cerebrovascular diseases. There may be damage in the function of the glymphatic system which induces the expansion of the perivascular space (PVS) in the BG in individuals with carotid plaque.

Association of Chinese Visceral Adiposity Index and Its Dynamic Change With Risk of Carotid Plaque in a Large Cohort in China

Background We aimed to evaluate the association between the Chinese visceral adiposity index (CVAI) and its dynamic change and risk of carotid plaque based on a large Chinese cohort. Methods and Results This cohort included 23 522 participants aged 20 to 80 years without elevated carotid intima‐media thickness and carotid plaque at baseline and who received at least 2 health checkups. CVAI was calculated at baseline and at every checkup. The dynamic change in CVAI was calculated by subtracting CVAI at baseline from that at the last follow‐up. Cox proportional hazard regression model was used to estimate hazard ratios (HRs) and 95% CIs. The restricted cubic spline was applied to model the dose‐response association between CVAI and carotid plaque risk. During the 82 621 person‐years of follow‐up, 5987 cases of carotid plaque developed (7.25/100 person‐years). We observed a significant positive correlation between CVAI and carotid plaque risk (HR, 1.53; 95% CI, 1.48–1.59 [ P <0.001]) in a nonlinear dose‐response pattern ( P nonlinearity <0.001). The sensitivity analyses further confirmed the robustness of the results. The association was significant in all subgroup analyses stratified by sex, hypertension, and fatty liver disease except for the diabetes subgroup. The association between CVAI and carotid plaque risk was much higher in men than in women. No significant association was identified between change in CVAI and carotid plaque risk. Conclusions CVAI was positively associated with carotid plaque risk in a nonlinear dose‐response pattern in this study. Individuals should keep their CVAI within a normal level to prevent the development of carotid plaque.

Subclinical Measures of Peripheral Atherosclerosis and the Risk of New‐Onset Atrial Fibrillation in the General Population: the Rotterdam Study

Background Limited population‐based data on the (sex‐specific) link between subclinical measures of peripheral atherosclerosis and new‐onset atrial fibrillation (AF) exist. Methods and Results Subclinical measures of peripheral atherosclerosis including carotid intima‐media thickness (cIMT), carotid plaque, and ankle‐brachial index (ABI) were assessed at baseline and follow‐up examinations. A total of 12 840 participants free of AF at baseline from the population‐based Rotterdam Study were included. Cox proportional hazards models and joint models, adjusted for cardiovascular risk factors, were used to determine the associations between baseline and longitudinal measures of cIMT, carotid plaque, and ABI with new‐onset AF. During a median follow‐up of 9.2 years, 1360 incident AF cases occurred among 12 840 participants (mean age 65.2 years, 58.3% women). Higher baseline cIMT (fully‐adjusted hazard ratio [HR], 95% CI, 1.81, 1.21–2.71; P =0.0042), presence of carotid plaque (fully‐adjusted HR, 95% CI, 1.19, 1.04–1.35; P =0.0089), lower ABI (fully‐adjusted HR, 95% CI, 1.57, 1.14–2.18; P =0.0061) and longitudinal measures of higher cIMT (fully‐adjusted HR, 95% CI, 2.14, 1.38–3.29; P =0.0021), presence of carotid plaque (fully‐adjusted HR, 95% CI, 1.61, 1.12–2.43; P =0.0112), and lower ABI (fully‐adjusted HR, 95% CI, 4.43, 1.83–10.49; P =0.0007) showed significant associations with new‐onset AF in the general population. Sex‐stratified analyses showed that the associations for cIMT, carotid plaque, and ABI were mostly prominent among women. Conclusions Baseline and longitudinal subclinical measures of peripheral atherosclerosis (carotid atherosclerosis, and lower extremity peripheral atherosclerosis) were significantly associated with an increased risk of new‐onset AF, especially among women. Registration URL: https://www.trialregister.nl , https://www.apps.who.int/trialsearch/ ; Unique identifier: NL6645/NTR6831.

Association between Insomnia and Subclinical Atherosclerosis Among Chinese Steelworkers: A Cross-sectional Survey

Background: Insomnia is a common prevalent sleep disorder. Difficulty maintaining sleep or poor in quality in insomnia caused by disrupted or misaligned circadian rhythms may play an important role in the development of atherosclerosis. This study aimed to examine the association between insomnia and subclinical atherosclerosis in Chinese steelworkers.Methods: A total of 3582 subjects from a large enterprise located in northern China were included in this study. The Athens Insomnia Scale (AIS) was used to assess the status of insomnia. Subclinical atherosclerosis was evaluated using ultrasonographic measurements of carotid plaque. Multivariable logistic regression was used to identify association between insomnia and carotid atherosclerosis.Results: The overall prevalence of insomnia and carotid plaque were 35.1% and 29.9% in the study population. Compared with non-insomnia workers, significantly increased odds of carotid plaque were observed among insomnia workers after adjustment for potential confounders, odds ratio (OR) = 1.38, 95% confidence interval (CI): 1.17 to 1.62. Exposure to current shift work and insomnia simultaneously can significantly elevated odds of carotid plaque. No significant association was found in female workers between insomnia and carotid plaque.Conclusion: Insomnia is associated with elevated odds of carotid atherosclerosis in male steelworkers. Insomnia problems of workers should receive further attention in occupational worker health interventions.

Associations of Occupational Heat Stress and Noise Exposure with Carotid Atherosclerosis among Chinese Steelworkers: A Cross-Sectional Survey

Occupational exposure to heat stress and noise at the workplace are widespread physical hazards and have been associated with an increase in both morbidity and mortality. This study aims to examine the association between occupational heat stress and noise exposure and carotid atherosclerosis in Chinese steelworkers. A total of 3471 subjects were included in this study. Carotid plaque was measured using ultrasonography. The occupational information was collected by face-to-face personal interviews and all of the reported information was verified with the company’s records. Workers were divided into non-exposure and exposure groups according to the company’s records regarding previous and/or current heat stress and noise exposure status in the workplace. The prevalence of carotid plaque was 30.1% in the study population and workers exposed to both occupational heat stress and noise had the highest prevalence of carotid plaque at 37.2%. The odds of carotid plaque in individuals of different exposure status were significantly elevated after adjustment for potential confounders, especially in the heat stress and noise exposure combination group: OR = 1.32, 95% CI: 1.06 to 1.65, in individuals who had experienced heat stress exposure; OR = 1.49, 95% CI: 1.18 to 1.88, in individuals who had experienced noise exposure; OR = 2.02, 95% CI: 1.60 to 2.56, in the combination group. No significant association in female workers and no significant multiplicative or additive interactions were found between occupational heat stress and noise exposure and carotid plaque. Exposure to occupational heat stress and noise are statistically associated with carotid atherosclerosis among male steelworkers.

SCORE2 Assessment in the Calculation of Cardiovascular Risk in Patients with Rheumatoid Arthritis

Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease (CVD). Risk chart algorithms, such as the Systematic Coronary Risk Assessment (SCORE), often underestimate the risk of CVD in patients with RA. In this sense, the use of noninvasive tools, such as the carotid ultrasound, has made it possible to identify RA patients at high risk of CVD who had subclinical atherosclerosis disease and who had been included in the low or moderate CVD risk categories when the SCORE risk tables were applied. The 2003 SCORE calculator was recently updated to a new prediction model: SCORE2. This new algorithm improves the identification of individuals from the general population at high risk of developing CVD in Europe. Our objective was to compare the predictive capacity between the original SCORE and the new SCORE2 to identify RA patients with subclinical atherosclerosis and, consequently, high risk of CVD. 1168 non-diabetic patients with RA and age > 40 years were recruited. Subclinical atherosclerosis was searched for by carotid ultrasound. The presence of carotid plaque and the carotid intima media wall thickness (cIMT) were evaluated. SCORE and SCORE2 were also calculated. The relationships of SCORE and SCORE2 to each other and to the presence of subclinical carotid atherosclerosis were studied. The correlation between SCORE and SCORE2 was found to be high in patients with RA (Spearman’s Rho = 0.961, p < 0.001). Both SCORE (Spearman’s Rho = 0.524) and SCORE2 (Spearman’s Rho = 0.521) were similarly correlated with cIMT (p = 0.92). Likewise, both calculators showed significant and comparable discriminations for the presence of carotid plaque: SCORE AUC 0.781 (95%CI 0.755–0.807) and SCORE2 AUC 0.774 (95%CI 0.748–0.801). Using SCORE, 80% and 20% of the patients were in the low or moderate and high or very high CVD risk categories, respectively. However, when the same categories were evaluated using SCORE2, the percentages were different (58% and 42%, respectively). Consequently, the number of RA patients included in the high or very high CVD risk categories was significantly higher with SCORE2 compared to the original SCORE. (p < 0.001). In conclusion, although predictive capacity for the presence of carotid plaque is equivalent between SCORE and SCORE2, SCORE2 identifies a significantly higher proportion of patients with RA who are at high or very high risk of CVD.