Accuracy of the Society of Radiologists in Ultrasound (SRU) Carotid Doppler Velocity Criteria for Grading North American Symptomatic Carotid Endarterectomy Trial (NASCET) Stenosis: A Meta-Analysis.

PURPOSE: The Society of Radiologists in Ultrasound (SRU) consensus panel proposed six Doppler velocity cut points for classifying internal carotid artery (ICA) stenosis of 50% and 70% according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method. Their relative accuracies have not been compared. MATERIALS AND METHODS: Meta-analysis performed following comprehensive literature review and identification of manuscripts with graphs of individual patient NASCET ICA stenosis measured by arteriography versus ICA peak-systolic velocity (PSV), end-diastolic velocity (EDV) and ICA PSV to common carotid artery (CCA) PSV. True positives, true negatives, false positives, and false negatives were calculated and used in two-level mixed effects models. Hierarchical summary receiver operating characteristic (ROC) curves were generated. Areas under the ROC curves were estimated. RESULTS: Nine studies performed between 1993 and 2016 were identified after review of 337 manuscripts. There were 1738 bifurcation data points extracted for PSV, 1026 for EDV, and 775 for ICA/CCA ratio. The highest sensitivity was 96% (95% CI: 93%, 98%) for PSV of 125 cm/s (50% stenosis) and highest specificity 86% (95% CI: 71%, 93%) for PSV of 230 cm/s (70% stenosis). Areas under the ROC curves ranged from a high of 0.93 (95% CI: 0.92, 0.95) for PSV (50% stenosis) to a low of 0.86 (95% CI: 0.84, 0.88) for EDV (70% stenosis). CONCLUSIONS: The SRU consensus Doppler cut points vary in their accuracies for predicting ICA stenosis. The PSV cut points have tradeoffs: high sensitivity/low specificity for 50% stenosis and high specificity/moderate sensitivity for 70% stenosis.

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

Background The 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 Results Cross-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. Conclusions The 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.

Association of Carotid Intima Media Thickening with Future Brain Region Specific Amyloid-ß Burden.

BACKGROUND: Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-ß (Aß) burden. OBJECTIVE: We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aß on 11C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aß burden. METHODS: We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aß on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aß in brain regions associated with Alzheimer's disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors. RESULTS: Participants with higher mean ICA IMT had more Aß in the precuneus (beta±standard error [ß±SE]: 0.466±0.171 mm, p = 0.01) and the frontal, lateral, and retrosplenial regions (ß±SE: 0.392±0.164 mm, p = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aß or progression of ICA or CCA IMT and Aß. CONCLUSION: Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aß burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology.

Interleukin-6 Predicts Carotid Plaque Severity, Vulnerability, and Progression.

BACKGROUND: IL-6 (interleukin-6) has important roles in atherosclerosis pathophysiology. To determine if anti-IL-6 therapy warrants evaluation as an adjuvant stroke prevention strategy in patients with carotid atherosclerosis, we tested whether circulating IL-6 levels predict carotid plaque severity, vulnerability, and progression in the prospective population-based CHS (Cardiovascular Health Study). METHODS: Duplex carotid ultrasound was performed at baseline and 5 years. Baseline plaque severity was scored 0 to 5 based on North American Symptomatic Carotid Endarterectomy Trial grade of stenosis. Plaque vulnerability at baseline was the presence of markedly irregular, ulcerated, or echolucent plaques. Plaque progression at 5 years was a ≥1 point increase in stenosis severity. The relationship of baseline plasma IL-6 levels with plaque characteristics was modeled using multivariable linear (severity) or logistic (vulnerability and progression) regression. Risk factors of atherosclerosis were included as independent variables. Stepwise backward elimination was used with P>0.05 for variable removal. To assess model stability, we computed the E-value or minimum strength of association (odds ratio scale) that unmeasured confounders must have with log IL-6 and the outcome to suppress the association. We performed internal validation with 100 bootstrap samples. RESULTS: There were 4334 participants with complete data (58.9% women, mean age: 72.7±5.1 years), including 1267 (29.2%) with vulnerable plaque and 1474 (34.0%) with plaque progression. Log IL-6 predicted plaque severity (ß=0.09, P=1.3×10-3), vulnerability (OR, 1.21 [95% CI, 1.05-1.40]; P=7.4×10-3, E-value=1.71), and progression (OR, 1.44 [95% CI, 1.23-1.69], P=9.1×10-6, E-value 2.24). In participants with >50% predicted probability of progression, mean log IL-6 was 0.54 corresponding to 2.0 pg/mL. Dichotomizing IL-6 levels did not affect the performance of prediction models. CONCLUSIONS: Circulating IL-6 predicts carotid plaque severity, vulnerability, and progression. The 2.0 pg/mL cutoff could facilitate the selection of individuals that would benefit from anti-IL-6 drugs for stroke prevention.

Coronary Artery Disease Events and Carotid Intima-Media Thickness in Type 1 Diabetes in the DCCT/EDIC Cohort.

Background Carotid artery intima-media thickness (IMT) is associated with the risk of subsequent cardiovascular events in the general population. This association has not been established in type 1 diabetes. Methods and Results We studied if carotid IMT is associated with the risk of a first coronary artery disease event in participants with type 1 diabetes in the EDIC (Epidemiology of Diabetes Interventions and Complications) study, the long-term observational follow-up of the DCCT (Diabetes Control and Complications Trial). Between 1994 and 1996, common carotid artery and internal carotid artery IMT were measured with high-resolution ultrasound in 1309 study participants with a mean age of 35 years and diabetes duration of 13.8 years; 52% were men. Cox proportional hazards models evaluated the association of standardized common carotid artery IMT and internal carotid artery IMT with subsequent cardiovascular events over the next 17 years. Models were adjusted for age, sex, mean hemoglobin A1c levels, and traditional cardiovascular risk factors. Associations of common carotid artery IMT with subsequent CAD were significant after adjustment for imaging device, sex, and age (hazard ratio [HR], 1.23 per 0.09 mm [95% CI, [1.04-1.45]; P=0.0141), but did not remain significant after further adjustment for traditional risk factors and hemoglobin A1c (HR, 1.14 per 0.09 mm [95% CI, 0.97-1.33]; P=0.1206). No significant associations with subsequent coronary artery disease events were seen for internal carotid artery IMT. Conclusions In the DCCT/EDIC cohort with type 1 diabetes, common carotid artery IMT, but not internal carotid artery IMT, is weakly associated with subsequent coronary artery events, an association eliminated after adjusting for coexistent traditional cardiovascular risk factors. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00360815 and NCT00360893.

Long-Term Prognostic Implications and Role of Further Testing in Adults Aged ≤55 Years With a Coronary Calcium Score of Zero (from the Multi-Ethnic Study of Atherosclerosis).

The long-term prognostic significance of a coronary artery calcium (CAC) score of 0 is poorly defined in younger adults. We evaluated this among participants aged 45 to 55 years from the Multi-Ethnic Study of Atherosclerosis, and assessed whether additional biomarkers can identify subgroups at increased absolute risk. We included 1,407 participants (61% women) without diabetes or severe hypercholesterolemia, with estimated 10-year risk <20% and CAC = 0. We evaluated all and hard cardiovascular disease (CVD) events, overall and among subjects with each of the following: high-sensitivity C-reactive protein levels ≥2 mg/L, homocysteine ≥10 µmol/L, high-sensitivity cardiac troponin T ≥95th percentile, lipoprotein (a) >50 mg/dl, triglycerides ≥175 mg/dl, apolipoprotein B ≥130 mg/dl, albuminuria, thoracic aortic calcium, aortic valve calcium (AVC), mitral annular calcium, ankle-brachial index <0.9, any carotid plaque, and maximum internal carotid artery intima-media thickness (ICA-IMT) ≥1.5 mm. Median follow-up was 16 years, and overall CVD event rates were low (4% at 15 years). For most exposures evaluated, rates of all CVD events were <6 per 1,000 person-years, except for ICA-IMT ≥1.5 mm (6.43) and AVC (13.8). The number needed to screen to detect ICA-IMT ≥1.5 mm was 8, and 84 for AVC. Among participants with borderline/intermediate risk or premature family history, hard CVD event rates were <7 per 1,000 for most exposures, except for ICA-IMT ≥1.5 mm (8.25), albuminuria (8.30), and AVC (13.47). Nonsmokers and those with ICA-IMT <1.5 mm had very low rates. In conclusion, our results demonstrate a favorable long-term prognosis of CAC = 0 among adults aged ≤55 years, particularly among nonsmokers. ICA-IMT testing could be considered for further risk assessment in adults ≤55 years with CAC = 0 and uncertain management.

Serum Non-Esterified Fatty Acids, Carotid Artery Intima-Media Thickness and Flow-Mediated Dilation in Older Adults: The Cardiovascular Health Study (CHS).

Backgrounds and aims: Elevated common carotid artery intima-media thickness (carotid IMT) and diminished flow-mediated dilation (FMD) are early subclinical indicators of atherosclerosis. Serum total non-esterified fatty acid (NEFA) concentrations have been positively associated with subclinical atherosclerosis. The relations between individual NEFA, carotid IMT and FMD have as yet to be assessed. Methods: We investigated the associations between fasting serum individual NEFA, carotid IMT and FMD among Cardiovascular Health Study (CHS) participants with (n = 255 for carotid IMT, 301 for FMD) or without (n = 1314 for carotid IMT, 1462 for FMD) known atherosclerotic cardiovascular disease (ASCVD). Using archived samples (fasting) collected from 1996-1997 (baseline), 35 individual NEFAs were measured using gas chromatography. Carotid IMT and estimated plaque thickness (mean of maximum internal carotid IMT) were determined in 1998-1999. FMD was measured in 1997-1998. Linear regression adjusted by the Holm-Bonferroni method was used to assess relations between individual NEFA, carotid IMT and FMD. Results: In multivariable adjusted linear regression models per SD increment, the non-esterified trans fatty acid conjugated linoleic acid (trans-18:2 CLA) was positively associated with carotid IMT [ß (95% CI): 44.8 (19.2, 70.4), p = 0.025] among participants with, but not without, ASCVD [2.16 (-6.74, 11.5), p = 1.000]. Non-esterified cis-palmitoleic acid (16:1n-7c) was positively associated with FMD [19.7 (8.34, 31.0), p = 0.024] among participants without, but not with ASCVD. No significant associations between NEFAs and estimated plaque thickness were observed. Conclusions: In older adults, serum non-esterified CLA and palmitoleic acid were positively associated with carotid IMT and FMD, respectively, suggesting potential modifiable biomarkers for arteriopathy.

Comparison of the Relation of Carotid Intima-Media Thickness With Incident Heart Failure With Reduced Versus Preserved Ejection Fraction (from the Multi-Ethnic Study of Atherosclerosis [MESA]).

Increased carotid intima-media thickness (cIMT) is associated with heart failure (HF) in previous studies, but it is not known whether the association of cIMT differs between HF with reduced (HFrEF) versus preserved ejection fraction (HFpEF). We studied 6699 participants (mean age 62 ± 10 years, 47% male, and 38% white) from the Multi-Ethnic Study of Atherosclerosis (MESA) with baseline cIMT measurements. We classified HF events as HFrEF (EF <50%) or HFpEF (EF ≥ 50%) at the time of diagnosis. Cox proportional hazard regression was used to compute hazard ratios (HR), and 95% confidence intervals (CI) for the association between the IMT Z-score (measured maximum IMT of Internal Carotid (IC) and Common Carotid (CC) sites as the mean of the maximum IMT of the near and far walls of right and left sides), and incident HFrEF or HFpEF. Models were adjusted for covariates and interim coronary artery disease (CAD) events. A total of 191 HFrEF and 167 HFpEF events occurred during follow-up. In multivariable analysis, each 1 standard deviation increase in the measured maximum IMT (Z-score) was associated with both HFrEF and HFpEF in the unadjusted and demographically adjusted models [HR, 95% CI 1.57 (1.43 to 1.73)] and [HR, 95% CI 1.61 (1.47 to 1.77)] but not in the fully adjusted models [HR, 95% CI 1.11 (0.96 to 1.28)] and [HR, 95% CI 1.13 (0.98 to 1.30)]. In conclusion, cIMT was significantly associated with incident HF, but the association is partially attenuated with adjustment for demographic factors and becomes non-significant after adjustment for other traditional heart failure risk factors and interim CAD events. There was no difference in the association of IMT measures with HFrEF versus HFpEF.

Predicting Long-Term Absence of Coronary Artery Calcium in Metabolic Syndrome and Diabetes: The MESA Study.

OBJECTIVES: The purpose of this study was to identify predictors of healthy arterial aging (long-term coronary artery calcification [CAC] of 0) among individuals with metabolic syndrome (MetS) or type 2 diabetes (T2D), which may improve primary prevention strategies. BACKGROUND: Individuals with MetS or T2D have a heterogeneously increased risk of atherosclerotic cardiovascular disease and not all have a high-intermediate risk. METHODS: We included 574 participants from the MESA (Multi-Ethnic Study of Atherosclerosis) with MetS or T2D who had CAC=0 at baseline and a repeat CAC scan 10 years later. Multivariable logistic regression assessed the association of traditional and novel atherosclerotic cardiovascular disease risk factors and the MetS severity score (based on the 5 MetS criteria) with healthy arterial aging. RESULTS: The mean age of participants was 58.9 years, 67% were women, 422 participants had MetS, and 152 had T2D. The proportion with long-term CAC=0 was similar for MetS (42%) and T2D (44%). A younger age was the only individual low/normal traditional risk factor associated with an increased likelihood of long-term CAC=0 (odds ratio [OR]: 1.50; 95% confidence interval [CI]: 1.22 to 1.85 per 10-years younger). The strongest associations of nontraditional risk factors were observed for an absence of thoracic calcification (OR: 2.42; 95% CI: 1.24 to 4.72), absence of carotid plaque (OR: 1.81; 95% CI: 1.25 to 2.61), and among persons with a high sensitivity troponin <3 ng/ml (OR: 1.55; 95% CI: 1.01 to 2.38). In addition, persons with the lowest quartile MetS severity score had a substantially higher odds of healthy long-term CAC=0 (OR: 2.71; 95% CI: 1.27 to 5.76). CONCLUSIONS: More than 40% of adults with MetS or T2D and baseline CAC=0 had long-term absence of CAC, which was most strongly associated with an absence of extracoronary atherosclerosis and a low MetS score. An optimal overall cardiovascular profile appears to be more important than an ideal value of any individual risk factor to maintain healthy arterial aging.

The progression of carotid atherosclerosis and imaging markers of dementia.

INTRODUCTION: We studied the association of carotid intima-media thickness (CIMT) with hippocampal volume (HV) in community dwelling individuals, testing the hypothesis that persons with carotid atherosclerosis progression would have lower HV. METHODS: We studied 1376 Framingham Offspring participants with two carotid ultrasounds and brain magnetic resonance imaging (MRIs). We used multivariable linear regression analyses to relate CIMT progression and HV and total brain volume. Regression models were adjusted for demographics and vascular risk factors, time interval between imaging examinations, and baseline CIMT. We assessed effect modification by hypertension treatment (HRx). RESULTS: Participants with higher ICA IMT progression had significantly lower HV after adjustment for vascular risk factors and baseline IMT (standardized beta ± standard error: -0.067 ± 0.027, P = .01). We observed weaker association between ICA IMT change and HV among subjects treated for hypertension (ß = -0.047, P = .19 vs ß = -0.096, P = .026). DISCUSSION: Cumulative vascular risk factor exposure, reflected by CIMT progression, may increase the risk of neurodegeneration.

Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium.

AIMS: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. METHODS AND RESULTS: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. CONCLUSION: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.

Ankle-brachial index and incident heart failure with reduced versus preserved ejection fraction: The Multi-Ethnic Study of Atherosclerosis.

This study investigated the relationship between ankle-brachial index (ABI) and risk for heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). ABI has previously been associated with mortality, cardiovascular disease (CVD), and overall HF but the relationship between ABI and risk of HF stratified by EF has not been well characterized. We analyzed data from 6553 participants (53% female; mean age 62 ± 10 years) enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of known clinical CVD/HF at baseline (2000-2002) and had baseline ABI measured. Participants were classified as low (≤ 0.90), borderline-low (0.91-1.00), normal (1.01-1.40), and high (> 1.40) ABI. Incident hospitalized HF was determined over a median follow-up of 14 years; we classified HF events (n = 321) as HFrEF with EF < 50% (n = 155, 54%) or HFpEF with EF ⩾ 50% (n = 133, 46%). Low ABI was associated with incident HFrEF (hazard ratio (HR): 2.02, 95% CI 1.19-3.40, p = 0.01) and had no significant association with HFpEF (HR: 0.67, 95% CI 0.30-1.48, p = 0.32). Borderline-low and high ABI were not significantly associated with HFrEF or HFpEF. Cubic spline analyses showed association with both low and high ABI for HFrEF and high ABI for HFpEF. A 1 SD lower ABI (for ABI < 1.1) was associated with incident HFrEF in multivariable analysis (HR: 1.27, 95% CI 1.05-1.54) but was not significant after additionally adjusting for interim myocardial infarction (HR: 1.21, 95% CI 0.99-1.48). Low ABI was associated with higher risk for incident HFrEF but not HFpEF in persons free of known CVD. Future studies of a larger size are needed for high ABI analyses.

Nonalcoholic Fatty Liver Disease Is Associated With Arterial Distensibility and Carotid Intima-Media Thickness: (from the Multi-Ethnic Study of Atherosclerosis).

Nonalcoholic fatty liver disease (NAFLD) is considered a potential independent risk factor for cardiovascular disease (CVD). The Multi-Ethnic Study of Atherosclerosis cohort enrolled 6,814 adults without previous CVD. We excluded 2,692 participants who had missing variables, were heavy drinkers, or history of steroid use and/or chronic liver disease. NAFLD was defined using noncontrast cardiac CT and a liver/spleen Hounsfield Unit attenuation ratio <1. Ultrasound-measured carotid arterial compliance and stiffness, was expressed as distensibility coefficient and Young's modulus. Common and internal carotid intima-media thickness (CIMT) and coronary artery calcium (CAC) >0 were used as markers of subclinical CVD. A multivariate robust linear regression and logistic regression analysis were done to evaluate the association of NAFLD and this subclinical CVD markers. Our analysis of 4,123 participants showed 55% were female with a mean age of 63 (±10) years, 39% white, 10% Chinese, 28% black, and 23% were Hispanic. The prevalence of NAFLD was 17% (n = 729). Patients with NAFLD had higher distensibility coefficient and higher CIMT. Multivariate linear regression analysis showed the presence of NAFLD was associated with both the common carotid and internal carotid IMT and logCAC. Logistic analysis showed an independent association with CAC > 0 (odds ratio [OR] 1.44 95% confidence interval [CI] 1.18, 1.75) and CIMT > 1 mm (OR 1.30 95% 1.08, 1.56). When stratified by race the association with CIMT > 1 mm was significant in whites (OR 1.37 95% 1.00, 1.90) and Hispanic (OR 1.53 95% 1.08, 2. 17) and CAC > 0 was significant in Hispanics (OR 1.52 95% 1.06, 2.19). In conclusion, NAFLD is modestly associated with carotid IMT and coronary artery calcification in a multiethnic population.

Relationship of fibroblast growth factor 21 with subclinical atherosclerosis and cardiovascular events: Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Fibroblast growth factor 21 (FGF21) has been suggested as a novel biomarker for cardiovascular disease (CVD), especially in people with high CVD risk. However, it is not known whether FGF21 is a CVD biomarker in an initially healthy cohort. We therefore investigated the relationship of plasma FGF21 levels with measures of subclinical atherosclerosis and cardiovascular events in Multi-Ethnic Study of Atherosclerosis participants without known CVD at baseline. METHODS: A total of 5788 participants had plasma FGF21 levels measured at the baseline exam (2000-2002). Carotid intima-media thickness (IMT), ankle-brachial index (ABI) and coronary artery calcification (CAC) were measured at baseline. Participants were followed up for incident CVD events over a median period of 14 years. RESULTS: In cross-sectional analyses adjusting for socio-demographic variables, participants with higher FGF21 levels had higher carotid IMT, lower ABI, and higher prevalence of CAC (p < 0.001). However, these associations were not significant after simultaneously adjusting for demographic, socioeconomic and lifestyle factors, traditional CVD risk factors, and biomarkers of inflammation and hemostasis. Among 5768 patients with follow-up data, 820 developed incident CVD endpoints. Higher baseline FGF21 levels were not associated with the risk for incident CVD endpoints after adjusting for multiple confounding factors (odds ratio 1.03; 95% confidence interval, 0.94-1.12, per SD increase in ln-transformed FGF21 levels). CONCLUSIONS: Although FGF21 has been suggested as a CVD biomarker for people with high CVD risk, our findings do not support a role of FGF21 as a CVD biomarker in those without a history of CVD.

Doppler Velocity Estimates of Internal Carotid Artery Stenosis: Angle Correction Parallel to the Color Doppler Lumen Versus Parallel to the Artery Wall.

OBJECTIVES: We compared internal carotid artery Doppler peak systolic velocities (PSVs) measured with angle correction parallel to the artery wall (// wall) on grayscale images and parallel to the direction of blood flow (// flow) on color Doppler images. METHODS: We studied 25 internal carotid lesions with PSVs higher than 125 cm/s. The PSVs were measured in the same imaging plane, at the stenosis orifice (0 cm) and at 0.5 and 1 cm downstream by both methods. Linear regression and correlation analyses were used to study the effects of the angle correction method on changes in PSVs as a function of the differences in angle adjustment and distance from the stenosis. RESULTS: The 23 patients studied included 9 women and 14 men. There was a mean difference in absolute PSVs ± SD of -17.2 ± 29.5 cm/s (P < .008) between methods at the stenosis. The difference in the PSVs was associated with the angle difference between the flow jet and the artery wall (P < .01). At 1 cm from the stenosis, // flow PSVs were more strongly correlated with PSVs at the stenosis (r = 0.61; 95% confidence interval, 0.28, 0.82; P = .001) than // wall PSVs (r = 0.39; 95% confidence interval, -0.003, 0.68; P = .052). CONCLUSIONS: Blood flow velocity measurements made with angle correction parallel to the direction of the color Doppler blood flow lumen remain more consistent with the distance from the stenosis than blood flow velocity measurements made with angle correction parallel to the outer artery walls.

Total brachial artery reactivity and first time incident coronary heart disease events in a longitudinal cohort study: The multi-ethnic study of atherosclerosis.

BACKGROUND: Brachial artery reactivity (BAR) is usually determined as the maximum brachial artery diameter (BAD) following release of an occluding pressure cuff compared to a BAD before cuff inflation. BAD early after cuff deflation can also serve as baseline for estimating total brachial artery reactivity (TBAR). We investigate whether TBAR is associated with first time coronary heart disease events. METHODS: Participants of the Multi-Ethnic Study of Atherosclerosis (n = 5499) consisting of whites, African-Americans, Chinese and Hispanics were followed longitudinally for a mean of 12.5 years. Brachial artery ultrasound was performed following five minutes of cuff occlusion at the forearm. TBAR was estimated from BAD following cuff release as the difference between maximum and minimum brachial artery diameters divided by the minimum diameter multiplied by 100%. TBAR was added to multivariable Cox proportional hazards models with Framingham risk factors as predictors and time to first coronary heart disease event as outcome. RESULTS: Average TBAR was 9.7% (9.7 SD). Mean age was 61.7 years, 50.9% women. Increased TBAR was associated with lower risk of CHD events with a hazard rate of 0.78 per SD increase (95% C.I. 0.67, 0.91; p = 0.001). A TBAR below the median of 7.87% (Inter Quartile Range: 4.16%, 13.0%) was associated with a 31% lower risk of coronary heart disease event (Hazard Ratio: 0.69; 95% C.I.: 0.55, 0.87). CONCLUSION: TBAR is an independent predictor of first time coronary heart disease events and is exclusively measured after release of a blood pressure occlusion cuff.

Associations of edge-detected and manual-traced common carotid artery intima-media thickness with incident peripheral artery disease: The Multi-Ethnic Study of Atherosclerosis.

Common carotid artery (CCA) intima-media thickness (IMT) is associated with coronary heart disease and can be measured on ultrasound images either by hand or with an automated edge detector. The association of CCA IMT with incident peripheral artery disease (PAD) is poorly studied. We studied 5467 participants of the Multi-Ethnic Study of Atherosclerosis composed of non-Hispanic white, Chinese, Hispanic, and African American participants with a mean age of 61.9 years (47.8% men). Framingham Risk Factors, manual-traced IMT (mt-IMT), and edge-detected IMT (ed-IMT) were entered into multivariable Cox proportional hazards models with incident PAD as the outcome. There were 87 events during a median follow-up of 12.2 years. In fully adjusted models and expressing the hazard ratios (HR) as an increment in SD values, both mt-IMT and ed-IMT were significantly associated with incident PAD: HR 1.36 (95% CI: 1.15, 1.61) and 1.29 (95% CI: 1.04, 1.60), respectively. We conclude that ed- and mt-CCA IMT measurements are associated with incident PAD. ClinicalTrials.gov Identifier: NCT00063440.

Multisite atherosclerosis in subjects with metabolic syndrome and diabetes and relation to cardiovascular events: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: The extent and relation of multisite atherosclerosis to cardiovascular disease (CVD) in metabolic syndrome (MetS) and diabetes (DM) are not well documented. We examined the extent of multisite atherosclerosis and its prognostic value for CVD events in MetS and DM. METHODS: In CVD-free subjects from the Multi-Ethnic Study of Atherosclerosis, multisite atherosclerosis was measured as: (1) the number of arterial beds involved (coronary calcium>0, abdominal aortic calcium>0, carotid intima-media thickness ≥1 mm and ankle brachial index<1 or ≥1.4); (2) a composite score summing the quartile rank for each atherosclerosis measure. Hazard ratios (HRs) and c-statistics were calculated for incident CVD and coronary heart disease (CHD) over 10.6 years. RESULTS: Of 1675 individuals (mean age 64 years, 51% male), 33.4% had MetS and 15.9% had DM. The number of atherosclerotic sites was higher in those with DM (mean ±â€¯SD = 1.67 ±â€¯1.15) and MetS (1.49 ±â€¯1.12) versus neither MetS/DM (1.09 ±â€¯1.09) (p < 0.0001). CVD rates per 1000 person-years ranged from 3.5, 8.2, and 10.0 in those with 0 sites positive to 35.1, 79.6 and 103.4 in those with 4 sites positive among neither DM/MetS, MetS and DM groups, respectively. HRs (95% CI) for CVD comparing those with 4 vs. 0 atherosclerotic sites were 4.0 (0.8-19.1), 4.9 (2.0-12.0), and 14.4 (3.6-57.6), respectively. C-statistics adding multisite atherosclerosis measures increased over models without the measures and with CIMT or ABI but not CAC. CONCLUSIONS: Multisite atherosclerosis is greater with MetS or DM, and predicts CVD and CHD events. Risk prediction is improved over CIMT and ABI but not CAC.

Carotid Artery Wall Thickness and Incident Cardiovascular Events: A Comparison between US and MRI in the Multi-Ethnic Study of Atherosclerosis (MESA).

Purpose To compare common carotid artery (CCA) wall thickness measured manually by using US and semiautomatically by using MRI, and to examine their associations with incident coronary heart disease and stroke. Materials and Methods This prospective study enrolled 698 participants without a history of clinical cardiovascular disease (CVD) from the Multi-Ethnic Study of Atherosclerosis (MESA) from July 2000 to December 2013 (mean age, 63 years; range, 45 to 84 years; same for men and women). All participants provided written informed consent. CCA wall thickness was measured with US as well as both noncontrast proton-density-weighted and intravenous gadolinium-enhanced MRI. Cox proportional hazards models were used to assess the associations between wall thickness measurements by using US and MRI with CVD outcomes. Results The adjusted hazard ratios for coronary heart disease, stroke, and CVD associated with per standard deviation increase in intima-media thickness were 1.10, 1.08, and 1.14, respectively. The corresponding associations for mean wall thickness measured with proton-density-weighted MRI were 1.32, 1.48, and 1.37, and for mean wall thickness measured with gadolinium-enhanced MRI were 1.27, 1.58, and 1.38. When included simultaneously in the same model, MRI wall thickness, but not intima-media thickness, remained associated with outcomes. Conclusion For individuals without known cardiovascular disease at baseline, wall thickness measurements by using MRI were more consistently associated with incident cardiovascular disease, particularly stroke, than were intima-media thickness by using US. © RSNA, 2018 Online supplemental material is available for this article.