Persistent Asthma Is Associated With Carotid Plaque in MESA.

Background Asthma and atherosclerotic cardiovascular disease share an underlying inflammatory pathophysiology. We hypothesized that persistent asthma is associated with carotid plaque burden, a strong predictor of atherosclerotic cardiovascular disease events. Methods and Results The MESA (Multi-Ethnic Study of Atherosclerosis) enrolled adults free of known atherosclerotic cardiovascular disease at baseline. Subtype of asthma was determined at examination 1. Persistent asthma was defined as asthma requiring use of controller medications, and intermittent asthma was defined as asthma without controller medications. B-mode carotid ultrasound was performed to detect carotid plaques (total plaque score [TPS], range 0-12). Multivariable regression modeling with robust variances evaluated the association of asthma subtype and carotid plaque burden. The 5029 participants were a mean (SD) age of 61.6 (10.0) years (53% were women, 26% were Black individuals, 23% were Hispanic individuals, and 12% were Chinese individuals). Carotid plaque was present in 50.5% of participants without asthma (TPS, 1.29 [1.80]), 49.5% of participants with intermittent asthma (TPS, 1.25 [1.76]), and 67% of participants with persistent asthma (TPS, 2.08 [2.35]) (P≤0.003). Participants with persistent asthma had higher interleukin-6 (1.89 [1.61] pg/mL) than participants without asthma (1.52 [1.21] pg/mL; P=0.02). In fully adjusted models, persistent asthma was associated with carotid plaque presence (odds ratio, 1.83 [95% confidence interval, 1.21-2.76]; P<0.001) and TPS (ß=0.66; P<0.01), without attenuation after adjustment for baseline interleukin-6 (P=0.02) or CRP (C-reactive protein) (P=0.01). Conclusions Participants with persistent asthma had higher carotid plaque burden and higher levels of inflammatory biomarkers, compared with participants without asthma. Adjustment for baseline inflammatory biomarkers did not attenuate the association between carotid plaque and asthma subtype, highlighting the increased atherosclerotic cardiovascular disease risk among those with persistent asthma may be multifactorial.

Baseline Characteristics of Patients with Symptomatic Carotid Webs: A Matched Case Control Study.

BACKGROUND AND PURPOSE: The baseline characteristics of patients with symptomatic carotid web (CaW) are unclear. We investigate demographic and cerebrovascular risk factors in patients with this overlooked stroke etiology. METHODS: We identified consecutive patients diagnosed with symptomatic CaW at a comprehensive stroke center from July 2014-December 2018. These patients were matched at a 1:4 ratio (based on age and NIHSS scores) to create a control group of acute ischemic stroke (AIS) patients with non-CaW etiologies from the local GetWithTheGuidelines stroke database. RESULTS: Thirty patients with symptomatic CaW were compared to 120 AIS patients with non-CaW etiologies. Symptomatic CaW patients were more likely to be female (73.3 vs. 44.2%; p = 0.004) and black (86.7 vs. 64.2%; p = 0.02). Symptomatic CaWs patients had a fewer absolute number of modifiable cerebrovascular risk factors (1.7±1.1 vs. 2.5±1.2; p = 0.002), lower rates of hypertension (43.4 vs. 63.3%; p = 0.04), and a more favorable lipid profile with lower average LDL (89.5±30.3 vs. 111.2±43.7 mg/dL; p = 0.01) and higher average HDL (47.9±11.3 vs. 42.2±13.8 mg/dL; p = 0.01) as compared to strokes with non-CaW etiology. Symptomatic CaW patients were more likely to have a large vessel occlusion (80.0 vs. 51.7%; p = 0.005), despite similar e-ASPECTS between the groups (8.1±2.1 vs. 8.3±2.2; p = 0.30). On multivariable analysis, symptomatic CaW was an independent predictor of independence at discharge (OR 3.72; 95%CI 1.27-10.94). CONCLUSION: A gender and racial predilection of symptomatic CaWs may exist as females and blacks were were found to be more likely affected. Symptomatic CaW patients have a more benign cerebrovascular risk factor profile corroborating the proposed mechanism of local stasis and thromboembolism. Despite presenting more commonly with LVO, symptomatic CaW was associated with good functional outcome, warranting further studies.

Association of "hypertriglyceridemic waist" with increased 5-year risk of subclinical atherosclerosis in a multi-ethnic population: a prospective cohort study.

BACKGROUND: Hypertriglyceridemic waist (HTGW), which incorporates measures of waist circumference and levels of triglyceride in blood, could act as an early-stage predictor to identify the individuals at high-risk for subclinical atherosclerosis. Previous studies have explored the cross-sectional association between HTGW and atherosclerosis; however, understanding how this association might change over time is necessary. This study will assess the association between HTGW with 5-year subclinical carotid atherosclerosis. METHODS: 517 participants of Aboriginal, Chinese, European, and South Asian ethnicities were examined for baseline HTGW and 5-year indices of subclinical atherosclerosis (intima media thickness (mm), total area (mm2), and plaque presence). Family history of cardiovascular disease, sociodemographic measures (age, sex, ethnicity, income level, maximum education), and traditional risk factors (systolic blood pressure, smoking status, total cholesterol, high-density lipoprotein cholesterol, body mass index) were incorporated into the models of association. These models used multiple linear regression and logistic regression. RESULTS: Baseline HTGW phenotype is a statistically significant and clinically meaningful predictor of 5-year intima media thickness (ß = 0.08 [0.04, 0.11], p < 0.001), total area (ß = 0.20 [0.07, 0.33], p = 0.002), and plaque presence (OR = 2.17 [1.13, 4.19], p = 0.02) compared to the non-HTGW group independent of sociodemographic factors and family history. However, this association is no longer significant after adjusting for the traditional risk factors of atherosclerosis (p = 0.27, p = 0.45, p = 0.66, respectively). Moreover, change in status of HTGW phenotype does not correlate with change in indices of atherosclerosis over 5 years. CONCLUSIONS: Our results suggest that when the traditional risk factors of atherosclerosis are known, HTGW may not offer additional value as a predictor of subclinical atherosclerosis progression over 5 years.

Cardiovascular Disease Risk Factor Burden During the Menopause Transition and Late Midlife Subclinical Vascular Disease: Does Race/Ethnicity Matter?

Background The extent to which cardiovascular disease (CVD) risk factors across the menopause explain racial/ethnic differences in subclinical vascular disease in late midlife women is not well documented and was explored in a multi-ethnic cohort. Methods and Results Participants (n=1357; mean age 60 years) free of clinical CVD from the Study of Women's Health Across the Nation had common carotid artery intima-media thickness, interadventitial diameter, and carotid plaque presence assessed by ultrasonography on average 13.7 years after baseline visit. Early to late midlife time-averaged cumulative burden of traditional CVD risk factors calculated using serial measures from baseline to the ultrasound visit were generally less favorable in black and Hispanic women compared with white and Chinese women, including education and smoking status and time-averaged cumulative blood pressure, high-density lipoprotein cholesterol, and fasting insulin. Independent of these risk factors, BMI, and medications, common carotid artery intima-media thickness was thicker in black women, interadventitial diameter was wider in Chinese women, yet plaque presence was lower in black and Hispanic women compared with white women. CVD risk factor associations with subclinical vascular measures did not vary by race/ethnicity except for high-density lipoprotein cholesterol on common carotid artery intima-media thickness; an inverse association between high-density lipoprotein cholesterol and common carotid artery intima-media thickness was observed in Chinese and Hispanic but not in white or black women. Conclusions Race/ethnicity did not particularly moderate the association between traditional CVD risk factors measured across the menopause transition and late midlife subclinical vascular disease. Unmeasured socioeconomic, cultural, and nontraditional biological risk factors likely play a role in racial/ethnic differences in vascular health and merit further exploration.

[Prevalence and influencing factors of carotid plaque in population at high-risk for cardiovascular disease in Jiangsu province].

Objective: To understand the prevalence of carotid plaque (CP) in population at high-risk for cardiovascular disease (CVD) in Jiangsu province and identify related influencing factors. Methods: Based on the China Patient-centered Evaluative Assessment of Cardiac Events Million Persons Project from 2015 to 2016, a total of 11 392 persons at high-risk for CVD were selected from six project areas in Jiangsu province for the questionnaire survey, physical measurement, laboratory test and bilateral ultrasound examination of carotid arteries. The prevalence of CP and influencing factors of abnormal carotid arteries, CP and plaque burden (CP≥2) were analyzed. Results: Among the persons surveyed, 4 821 (42.3%) were males. The age of the persons surveyed was (59.4±8.9) years. There were 5 971 abnormal carotid arteries cases (52.4%), including 1 782 carotid intima-media thickness thickening cases (15.6%), 3 811 CP cases (33.5%) and 378 carotid stenosis cases (3.3%). Older age (OR=2.253, 95%CI: 2.127-2.386), urban residence (OR=2.622, 95%CI: 2.375-2.895), hypertension (OR=1.439, 95%CI: 1.195-1.732), smoking (OR=1.441, 95%CI: 1.259- 1.650), pulse pressure difference (OR=1.270, 95%CI: 1.198-1.347), fasting plasma glucose (FPG) (OR=1.109, 95%CI: 1.059-1.161) and LDL-C/HDL-C (OR=1.225, 95%CI: 1.164-1.288) were possible risk factors of CP in population at high risk for CVD. Being women (OR=0.558, 95%CI: 0.494-0.630), high BMI (OR=0.948, 95%CI: 0.904-0.994), higher levels of education (OR=0.708, 95%CI: 0.531-0.945), and higher annual household income (OR=0.773, 95%CI: 0.669-0.894) were the possible protective factors. Conclusions: Over half of the population at high-risk for CVD in Jiangsu showed abnormal carotid arteries. High blood pressure, high blood glucose, high blood lipids and smoking were the main factors that could be changed.

Race-Based Differences in Lipoprotein(a)-Associated Risk of Carotid Atherosclerosis.

Objective- Lp(a) [lipoprotein(a)] is a well-described risk factor for atherosclerosis, but Lp(a)-associated risk may vary by race/ethnicity. We aimed to determine whether race/ethnicity modifies Lp(a)-related risk of carotid atherosclerotic plaque outcomes among black, white, Chinese, and Hispanic individuals. Approach and Results- Carotid plaque presence and score were assessed by ultrasonography at baseline (n=5155) and following a median 9.4 year period (n=3380) in MESA (Multi-Ethnic Study of Atherosclerosis) participants. Lp(a) concentrations were measured by immunoassay and examined as a continuous and categorical variable using clinically-based cutoffs, 30 and 50 mg/dL. Lp(a) was related to greater risk of prevalent carotid plaque at baseline in whites alone (all P<0.001): per log unit (relative risk, 1.05); Lp(a)≥30 mg/dL (relative risk, 1.16); and Lp(a)≥50 mg/dL (relative risk, 1.20). Lp(a) levels over 50 mg/dL were associated with a higher plaque score at baseline in whites (all P<0.001) and Hispanics ( P=0.04). In prospective analyses, whites with Lp(a) ≥50 mg/dL were found to have greater risk of plaque progression (relative risk, 1.12; P=0.03) and higher plaque scores (all P<0.001) over the 9.4-year follow-up. Race-based differences between whites and black participants were significant for cross-sectional associations and for carotid plaque score following the 9.4 year study period. Conclusions- Race was found to be a modifying variable in Lp(a)-related risk of carotid plaque, and Lp(a) levels may have greater influence on plaque burden in whites than in black individuals. Borderline results in Hispanics suggest that elevated Lp(a) may increase the risk of carotid plaque, but follow-up studies are needed.

Carotid Intima-Media Thickness and Carotid Plaque: A Pilot Study of Risk Factors in an Indigenous Nigerian Population.

BACKGROUND: Risk factors for carotid intima-media thickness (cIMT) and carotid plaque (CP) differ by ethnicity; however, this is not well understood in some ethnic populations. This work examines the risk factors for cIMT and CP in an indigenous Nigerian population. METHODS: We assessed cIMT and CP in 122 participants and then performed biochemical analysis: fasting blood glucose (FBG), hemoglobin A1c, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and total cholesterol (TC). The clinical history and anthropometric characteristics of participants were recorded. Linear models were used to assess the factors associated with cIMT and CP, and stepwise multivariate regression analyses were conducted to assess the predictors of cIMT and CP. RESULTS: The cIMT thickness varied from .5 mm to 1.3 mm. Family history of heart disease (FHHDx), physical activity, FBG, HDL-C, TG, TC, body mass index (BMI), systolic pressure, and waist circumference were significantly associated with cIMT (P ≤ .01). High systolic (ß = .008) and diastolic (ß = .17) pressure, FHHDx (ß = .24), age (ß = .004), physical activity (ß = -.09), and waist circumference (ß = -.017) significantly predicted 85% of the variation in cIMT (P < .001 for all). Family history of hypertension (FHH), LDL-C, and high blood pressure were significantly associated with CP (P ≤ .05). The significant predictors of CP were FHH (ß = .145, P = .03), smoking (ß = .167, P = .01), HDL-C (ß = .283, P < .001), weight (ß = .150, P = .04), and BMI (ß = .183, P = .01), explaining most of the 43.2% variation in CP. CONCLUSIONS: Some of the risk factors differ from those of other ethnicities, suggesting a need for population-specific approach to risk assessment and early detection of subclinical disease.

A Systematic Literature Review of Patients With Carotid Web and Acute Ischemic Stroke.

Background and Purpose- Carotid web (CW) is a rare form of focal fibromuscular dysplasia defined as an abnormal shelf-like projection of intimal fibrous tissue into the carotid bulb. It is theorized that CW leads to ischemic stroke secondary to blood flow stasis and subsequent embolization. The natural history and optimal management of CW are unclear. To address this knowledge gap, we performed a systematic literature review (SLR) of CW. Methods- Our librarians performed a SLR for CW and related terminology. Patient-level demographics, stroke risk factors, neuroimaging findings, stroke recurrence or stroke free-duration, and treatment modality were extracted. We used descriptive statistics to characterize our results. When specific patient-level metrics were not reported, the denominators for reporting percentage calculations were adjusted accordingly. Results- Our literature search produced 1150 articles. Thirty-seven articles including 158 patients (median age 46 years [range 16-85], 68% women, 76% symptomatic) met entry criteria and were included in our SLR. Of the symptomatic CW patients: 57% did not have stroke risk factors, 56% who received medical therapy had recurrent stroke (median 12 months, range 0-97), and 72% were ultimately treated with carotid revascularization (50% carotid stenting, 50% carotid endarterectomy). There were no periprocedural complications or recurrent strokes in carotid revascularization patients. Conclusions- CW leads to ischemic stroke in younger patients without conventional stroke risk factors. We found a high stroke recurrence rate in medically managed symptomatic CW patients, whereas carotid revascularization effectively prevented recurrent stroke. Our findings should be interpreted with caution because of risk of publication and reporting bias.

The prevalence and correlates of subclinical atherosclerosis among adults with low-density lipoprotein cholesterol <70 mg/dL: The Multi-Ethnic Study of Atherosclerosis (MESA) and Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

BACKGROUND AND AIMS: The prevalence and correlates of subclinical atherosclerosis when low-density lipoprotein cholesterol (LDL-C) levels are low remain unclear. Therefore, we examined the association of cardiovascular risk factors and subclinical atherosclerosis among individuals with untreated LDL-C <70 mg/dL. METHODS: We included participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) cohorts. To optimize accuracy, LDL-C was calculated by the validated Martin/Hopkins equation that uses an adjustable factor for the ratio of triglycerides to very low-density lipoprotein cholesterol. We defined subclinical atherosclerosis as a coronary artery calcium (CAC) score >0 in the combined cohort or common carotid intima media thickness (cIMT) in the 4th quartile, using cohort-specific cIMT distributions at baseline. Logistic regression models examined the cross-sectional associations of cardiovascular risk factors and subclinical atherosclerosis. RESULTS: Among 9411 participants not on lipid lowering therapy, 263 (3%) had LDL-C <70 mg/dL (MESA: 206, ELSA: 57). Mean age in this population was 58 (SD 12) years, with 43% men, and 41% Black. The prevalence of CAC >0 in those with untreated LDL-C<70 mg/dL was 30%, and 18% were in 4th quartile of cIMT. In demographically adjusted models, only ever smoking was significantly associated with both CAC and cIMT. Similar results were obtained in risk factor-adjusted models (smoking: OR, 2.29; 95% CI, 1.10-4.80 and OR, 3.44; 95% CI, 1.41-8.37 for CAC and cIMT, respectively). CONCLUSIONS: Among middle-aged to older individuals with untreated LDL-C <70 mg/dL, subclinical atherosclerosis remains moderately common and is associated with cigarette smoking.

Racial and Socioeconomic Disparities After Carotid Procedures.

BACKGROUND: Race has been associated with inferior outcomes after multiple procedures, but the association of socioeconomic status with procedures for cerebrovascular disease is not well established. MATERIALS AND METHODS: Elective carotid artery stenting (CAS) and carotid endarterectomy (CEA) procedures were identified in the National Inpatient Sample, 2012 to 2014. Median household income was estimated from patient ZIP codes. Chi-square and multivariable logistic regression analysis evaluated outcomes, accounting for age, race, gender, comorbidities, procedure, income, insurance, and hospital characteristics. RESULTS: We identified 234 825 carotid procedures (205 835 CEA and 28 990 CAS). Blacks and Hispanics were more likely to be among the lowest quartile income patients (LQIPs) compared to whites (53.5% and 38.7% vs 27.0%, respectively; P < .0002). Compared to highest income quartile patients, LQIP had lower rates of private insurance (16.3% vs 22.0%) and higher Medicaid use (4.7% vs 2.0%; all P < .0002). Lowest quartile income patients were more likely to receive CAS (odds ratio [OR] = 1.32, 95% confidence interval [CI]: 1.27-1.37), as were blacks and Hispanics (OR = 1.09, 95% CI: 1.02-1.26; OR = 1.31, 95% CI: 1.24-1.40, respectively). In multivariable regression, postoperative stroke was associated with LQIP, black race, and Hispanic ethnicity (OR = 1.16, 95% CI: 1.06-1.28; OR = 1.52, 95% CI: 1.33-1.73; OR = 1.43, 95% CI: 1.24-1.64, respectively). Subgroup analysis demonstrated that whites also had higher odds of stroke in the lower income quartile (OR = 1.2, 95% CI: 1.1-1.4). Mortality was associated with LQIP (OR = 1.6, 95% CI: 1.2-2.1), black race (OR = 1.8, 95% CI: 1.4-2.5), and CAS (OR = 1.3, 95% CI: 1.1-1.6). Length of stay in the lowest income quartile was longer than in patients with the highest income ( P < .0001). CONCLUSIONS: Race was associated with increased hospital mortality, postoperative stroke, and overall complications after carotid procedures. Lower income was significantly associated with increased stroke and mortality irrespective of race. Disparate utilization and outcomes for carotid procedures are multifactorial. Efforts to reduce disparities will need to focus on race and other socioeconomic factors.

A genetic association study of carotid intima-media thickness (CIMT) and plaque in Mexican Americans and European Americans with rheumatoid arthritis.

BACKGROUND AND AIMS: Little is known about specific genetic determinants of carotid-intima-media thickness (CIMT) and carotid plaque in subjects with rheumatoid arthritis (RA). We have used the Metabochip array to fine map and replicate loci that influence variation in these phenotypes in Mexican Americans (MAs) and European Americans (EAs). METHODS: CIMT and plaque were measured using ultrasound from 700 MA and 415 EA patients with RA and we conducted association analyses with the Metabochip single nucleotide polymorphism (SNP) data using PLINK. RESULTS: In MAs, 12 SNPs from 11 chromosomes and 6 SNPs from 6 chromosomes showed suggestive associations (p < 1 × 10-4) with CIMT and plaque, respectively. The strongest association was observed between CIMT and rs17526722 (SLC17A2 gene) (ß ± SE = -0.84 ± 0.18, p = 3.80 × 10-6). In EAs, 9 SNPs from 7 chromosomes and 7 SNPs from 7 chromosomes showed suggestive associations with CIMT and plaque, respectively. The top association for CIMT was observed with rs1867148 (PPCDC gene, ß ± SE = -0.28 ± 0.06, p = 5.11 × 10-6). We also observed strong association between plaque and two novel loci: rs496916 from COL4A1 gene (OR = 0.51, p = 3.15 × 10-6) in MAs and rs515291 from SLCA13 gene (OR = 0.50, p = 3.09 × 10-5) in EAs. CONCLUSIONS: We identified novel associations between CIMT and variants in SLC17A2 and PPCDC genes, and between plaque and variants from COL4A1 and SLCA13 that may pinpoint new candidate risk loci for subclinical atherosclerosis associated with RA.

The impact of race on outcomes after carotid endarterectomy in the United States.

OBJECTIVE: Black patients undergoing carotid endarterectomy (CEA) in the United States are more often symptomatic at presentation and have more comorbidities compared with white patients. However, the impact of race on outcomes after CEA is largely unknown. METHODS: We identified CEA patients in the Vascular Quality Initiative registry (2012-2017) and compared them by race (black vs white). All other nonwhite races (891 [1.4%]) and Hispanics (2222 [3.4%]) were excluded. We used multilevel logistic regression to account for differences in demographics and comorbidities. We assessed long-term survival using multivariable Cox regression. The primary outcome was perioperative stroke/death, with long-term survival as a secondary outcome. RESULTS: We included 57,622 CEA patients; 2909 (5.0%) were black, of whom 983 (34%) were symptomatic. Of the 54,713 white patients, 16,132 (30%) were symptomatic. Black patients, compared with white patients, had a higher vascular disease burden and were less likely to be operated on in a high-volume hospital or by a high-volume surgeon. In addition, black symptomatic patients, compared with white symptomatic patients, were more often operated on <2 weeks after the index neurologic symptom (47% vs 40%; P < .001). Perioperative stroke/death was comparable between black and white patients (symptomatic, 2.8% vs 2.2% [P = .2]; asymptomatic, 1.6% vs 1.3% [P = .2]), as was unadjusted survival at 3 years (93% vs 93%; P = .7). However, after adjustment, black patients did experience better long-term survival compared with white patients (hazard ratio, 0.8; 95% confidence interval, 0.7-0.9; P = .01). On multilevel logistic regression, race was not associated with perioperative stroke/death (odds ratio, 1.0; 95% confidence interval, 0.8-1.3; P = .98). CONCLUSIONS: Despite the greater prevalence of vascular risk factors in black patients and racial inequalities in surgical treatment, rates of perioperative stroke/death and unadjusted survival were similar between white and black patients. Moreover, black patients experienced better adjusted long-term survival after CEA.

Effect of Serum Adiponectin Levels on the Association Between Childhood Body Mass Index and Adulthood Carotid Intima-Media Thickness.

Childhood obesity predicts adult cardiovascular risk. We hypothesized that the association between childhood body mass index (BMI) and adult carotid intima-media thickness (CIMT) may be modified by levels of adiponectin, an adipocytokine that connects body fatness with cardiovascular risk. The study sample included 1,052 adults (71% white and 29% black, 57% female) aged 23.8 to 43.5 years who were previously examined as children in the Bogalusa Heart Study cohort, with an average follow-up period of 26.5 (range 14.1 to 29.6) years. Childhood BMI, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and systolic blood pressure were standardized to age-specific z-scores. General linear models were used for data analyses. Childhood BMI (p = 0.034), low-density lipoprotein cholesterol (p <0.001), and systolic blood pressure (p = 0.005), along with adult adiponectin levels (p = 0.002) were associated with adult CIMT, adjusted for race, sex, adult age, and cigarette smoking. Further, adult adiponectin levels significantly modified the association between childhood BMI and adult CIMT (P for interaction = 0.0003) such that a significant association between childhood BMI and adult CIMT (p <0.0001) was only observed in those with adiponectin levels below the median. In conclusion, these results suggest that serum adiponectin levels modify the association between childhood obesity and adult atherosclerosis, which has implications for risk stratification and targeted intervention for obese children with low levels of adiponectin.

Factors Associated with Intima-Media Complex Thickness of the Common Carotid Artery in Japanese Noncardioembolic Stroke Patients with Hyperlipidemia: The J-STARS Echo Study.

AIMS: There may be ethnic differences in carotid atherosclerosis and its contributing factors between Asian and other populations. The purpose of this study was to examine intima-media complex thickness (IMT) of the carotid artery and associated clinical factors in Japanese stroke patients with hyperlipidemia from a cohort of the Japan Statin Treatment Against Recurrent Stroke Echo Study. METHODS: Patients with hyperlipidemia, not on statins, who developed noncardioembolic ischemic stroke were included in this study. Mean IMT and maximum IMT of the distal wall of the common carotid artery were centrally measured using carotid ultrasonography. Significant factors related to mean IMT and maximum IMT were examined using multivariable analysis. RESULTS: In 793 studied patients, mean IMT was 0.89±0.15 mm and maximum IMT was 1.19±0.32 mm.Age (per 10 years, parameter estimate=0.044, p＜0.001), smoking (0.022, p=0.004), category of blood pressure (0.022, p=0.006), HDL cholesterol (per 10 mg/dl, －0.009, p=0.008), and diabetes mellitus (0.033, p=0.010) were independently associated with mean IMT. Age (per 10 years, 0.076, p＜0.001), smoking (0.053, p=0.001), HDL cholesterol (－0.016, p=0.036), and diabetes mellitus (0.084, p=0.002) were independently associated with maximum IMT. CONCLUSION: Baseline mean and maximum values of carotid IMT in Japanese noncardioembolic stroke patients with hyperlipidemia were 0.89±0.15 mm and 1.19±0.32 mm, respectively, which were similar to those previously reported from Western countries. Age, smoking, hypertension, HDL cholesterol, and diabetes mellitus were associated with mean IMT, and those, except for hypertension, were associated with maximum IMT.

Polymorphism rs2073618 of the osteoprotegerin gene as a potential marker of subclinical carotid atherosclerosis in Caucasians with type 2 diabetes mellitus.

BACKGROUND: The OPG/RANKL/RANK (osteoprotegerin/receptor-activator of nuclear factor κB ligand/receptor-activator of nuclear factor κB) axis has been recently linked to the development of atherosclerosis and plaque destabilization. We have investigated whether polymorphism rs2073618 of the OPG gene is associated with subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: 595 subjects with T2DM were enrolled in the cross-sectional study. Subclinical markers of carotid atherosclerosis (carotid intima media thickness, plaque thickness, and plaques presence) were assessed with ultrasound at the time of recruitment. Genotyping for rs2073618 (a missense variant located in exon I of the OPG gene) was performed, and OPG serum levels were determined by ELISA. RESULTS: Compared to the GG genotype, the CC genotype of the rs2073618 polymorphism had a significantly increased risk for the presence of carotid plaque (OR = 2.54, 95 % CI = 1.22-5.28, p = 0.01). No statistically significant difference could be detected (p = 0.68) upon comparing median values of serum OPG levels among studied genotype groups in subjects with T2DM. Multivariable linear regression analyses in T2DM subjects demonstrated that GC and CC genotypes (p = 0.03 and p = 0.003), together with statin therapy (p = 0.009), were independent predictors of the number of carotid segments with plaques. CONCLUSIONS: Despite the fact that OPG rs2073618 genotypes failed to predict the serum OPG levels as there was no statistical difference among compared genotypes, our results demonstrate that the rs2073618 polymorphism could be a possible genetic marker for the prediction of increased risk for carotid plaque burden as a measure of advanced subclinical atherosclerosis in T2DM subjects.

The predictive relationship between baseline insulin and glucose with subclinical carotid atherosclerosis after 5 years in a multi-ethnic cohort.

BACKGROUND AND AIMS: We aimed at exploring the relationship between baseline insulin and glucose and the progression of carotid atherosclerosis in a multi-ethnic cohort. METHODS: Males and females (n = 797) of European, Chinese, South Asian and Aboriginal origin were assessed as part of the Multicultural Community Health Assessment Trial (MCHAT) study for socio-demographics, smoking status, fasting insulin and glucose at baseline. IMT, plaque area and total area were assessed after 5 years. RESULTS: A total of 545 participants returned after 5 years for a follow-up assessment. Average age of the study participants was 47.5 (SD 8.9) years. At baseline, the median and interquartile range for insulin was 62.0 (49.5) pmol/L, and glucose was 5.2 (0.60) mmol/L. Baseline glucose and insulin predicted the 5-year progression of atherosclerosis in our models, after adjusting for covariates. We found significant insulin-ethnicity interactions in the IMT model (p = 0.044) with the slope of the relationship showing that for every percentage change in insulin the Europeans experienced 7.3% more increase in IMT at 5 years than the Aboriginals. In the plaque area and total area models, there were significant glucose-ethnicity interactions (p = 0.009 and p=0.016 respectively), with the slope showing a 101% and 121% increase for plaque area and total area, respectively, in Europeans, at 5 years per percent change in glucose at baseline. Logistic regression found a significant glucose-ethnicity interaction with the presence of plaques (OR = 0.31, p = 0.03) such that compared to the Europeans, the South Asians had a lower odds of developing plaque presence. Similarly, we found glucose-ethnicity interactions in the logistic regression when comparing the Chinese to the Europeans (OR = 0.2, p=0.005), with the Chinese being less likely to develop plaque presence. CONCLUSIONS: Ethnicity modifies the predictive relationship between insulin and glucose with sub-clinical indicators of carotid atherosclerosis but not consistently so.

Apelin concentrations are associated with altered atherosclerotic plaque stability mediator levels and atherosclerosis in rheumatoid arthritis.

BACKGROUND AND AIMS: Apelin-APJ signaling reduces cardiovascular disease (CVD) risk. In rheumatoid arthritis (RA), the atherosclerosis burden and plaque vulnerability to rupture are increased. We explored relationships between apelin concentrations and subclinical CVD in RA. METHODS: Apelin levels were measured in 235 (114 black, 121 white) RA patients. Associations between apelin concentrations and ultrasound determined carotid artery intima-media thickness (cIMT) and plaque, and levels of matrix metalloproteinase (MMP)-2 and -9 that mediate plaque stability and vulnerability respectively, were identified in confounder adjusted multivariate regression analysis. RESULTS: In all patients, apelin concentrations were directly associated with those of MMP-2 (ß (SE) = 0.324 (0.112), p = 0.004) and inversely with those of MMP-9 (ß (SE) = -0.239 (0.060), p = 0.000). Apelin concentration-subclinical CVD relations were influenced by population origin, RA disease activity, erythrocyte sedimentation rate (ESR) and interleukin (IL)-6 concentrations (interaction p = 0.001 to 0.04). Accordingly, the apelin-MMP-2 concentration relationship was reproduced in white (ß (SE) = 0.367 (0.146), p = 0.01) but not black RA patients (ß (SE) = 0.197 (0.220), p = 0.4), and only in those without (but not with) large erythrocyte sedimentation rates (ß (SE) = 0.428 (0.143), p = 0.003) or interleukin-6 levels (ß (SE) = 0.485 (0.288), p = 0.04). By contrast, the apelin-MMP-9 concentration relation was reproduced more consistently. Apelin levels were inversely related to cIMT in patients with RA remission or mild (ß (SE) = -0.068 (0.033), p = 0.04) but not moderate or high disease activity (ß (SE) = 0.015 (0.112), p = 0.7). CONCLUSIONS: Apelin concentrations are associated with altered plaque stability mediator levels and atherosclerosis in patients with RA. These relations are partially dependent on population origin and systemic inflammatory status.

Bone Mineral Density and Progression of Subclinical Atherosclerosis in African-Americans With Type 2 Diabetes.

CONTEXT: Relative to European Americans, calcified atherosclerotic plaque (CP) is less prevalent and severe in African-Americans (AAs). OBJECTIVE: Predictors of progression of CP in the aorta, carotid, and coronary arteries were examined in AAs over a mean 5.3 ± 1.4-year interval. DESIGN: This is the African American-Diabetes Heart Study. SETTING: A type 2 diabetes (T2D)-affected cohort was included. PARTICIPANTS: A total of 300 unrelated AAs with T2D; 50% female, mean age 55 ± 9 years, baseline hemoglobin A1c 8.1 ± 1.8% was included. MAIN OUTCOME MEASURES: Glycemic control, renal parameters, vitamin D, and computed tomography-derived measures of adiposity, vascular CP, and volumetric bone mineral density (vBMD) in lumbar and thoracic vertebrae were obtained at baseline and follow-up. RESULTS: CP increased in incidence and quantity/mass in all three vascular beds over the 5-year study (P < .0001). Lower baseline lumbar and thoracic vBMD were associated with progression of abdominal aorta CP (P < .008), but not progression of carotid or coronary artery CP. Lower baseline estimated glomerular filtration rate was associated with progression of carotid artery CP (P = .0004), and higher baseline pericardial adipose volume was associated with progression of coronary artery (P = .001) and aorta (P = .0006) CP independent of body mass index. There was a trend for an inverse relationship between change in thoracic vBMD and change in aortic CP (P = .05). CONCLUSIONS: In this longitudinal study, lower baseline thoracic and lumbar vBMD and estimated glomerular filtration rate and higher pericardial adipose volumes were associated with increases in CP in AAs with T2D. Changes in these variables and baseline levels and/or changes in glycemic control, albuminuria, and vitamin D were not significantly associated with progression of CP.

The haptoglobin 2-2 genotype is associated with inflammation and carotid artery intima-media thickness.

The haptoglobin 2-2 genotype is associated with atherosclerosis in type 2 diabetes mellitus. We examined the associations of the haptoglobin 2-2 genotype with C-reactive protein (high-sensitivity C-reactive protein) and carotid artery intima-media thickness, adjusting for age, gender, ethnicity, type 2 diabetes mellitus, smoking status, body mass index, blood pressure, glycated haemoglobin, non-high-density lipoprotein cholesterol and medications via logistic multivariate regression in 200 subjects (160 type 2 diabetes mellitus versus 40 healthy individuals). The prevalence of the haptoglobin 2-2 genotype was 58% (115/200), higher in the Indians than in Chinese (72% versus 45%, p = 0.001). Multivariate analysis showed that the haptoglobin 2-2 genotype was associated with high-sensitivity C-reactive protein [mean: 3.5 ± 3.9 versus 2.2 ± 2.6 mg/L (non-haptoglobin 2-2), p < 0.001], haptoglobin concentration [mean: 116.9 ± 54.4.0 versus 147.2 ± 54.5 mg/dL (non-haptoglobin 2-2), p < 0.001] and average carotid artery intima-media thickness (multiplied by 10) [6.15 ± 1.22 versus 5.98 ± 1.20 mm (non-haptoglobin 2-2), p = 0.013]. This pilot study shows an association of the haptoglobin 2-2 genotype with low-grade inflammation, haptoglobin concentration and carotid artery intima-media thickness in multi-ethnic Singapore.

Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events.

BACKGROUND: Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events. METHODS: We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity. RESULTS: Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites. CONCLUSION: The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.