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Background: Alterations in gut microbiota and blood metabolomic profiles have been implicated in HIV infection and cardiovascular disease. However, it remains unclear whether alterations in gut microbiota may contribute to disrupted host blood metabolomic profiles in relation to atherosclerosis, especially in the context of HIV infection. Methods: We analyzed cross-sectional associations between gut microbiota features and carotid artery plaque in 361 women with or at high risk of HIV (67% HIV+), and further integrated plaque-associated microbial features with plasma lipidomic/metabolomic profiles. Furthermore, in 737 women and men, we examined prospective associations of baseline gut bacteria-associated lipidomic and metabolomic profiles with incident carotid artery plaque over 7-year follow-up. Results: We found 2 potentially pathogenic bacteria, Fusobacterium and Proteus , were associated with carotid artery plaque; while the beneficial butyrate producer Odoribacter was inversely associated with plaque. Fusobacterium and Proteus were associated with multiple lipids/metabolites which were clustered into 8 modules in network. A module comprised of 9 lysophosphatidylcholines and lysophosphatidylethanolamines and a module comprised of 9 diglycerides were associated with increased risk of carotid artery plaque (risk ratio [95% CI], 1.34 [1.09–1.64] and 1.24 [1.02–1.51] per SD increment, respectively). Functional analyses identified bacterial enzymes in lipid metabolism associated with these plasma lipids. In particular, phospholipase A1 and A2 are the key enzymes in the reactions producing lysophosphatidylcholines and lysophosphatidylethanolamines. Conclusions: Among individuals with or at high risk of HIV infection, we identified altered gut microbiota and related functional capacities in the lipid metabolism associated with disrupted plasma lipidomic profiles and carotid artery atherosclerosis.

Objective— To investigate the effect of LPA gene variants and renal function on lipoprotein(a) [Lp(a)] levels in people with chronic kidney disease and determine the association between elevated Lp(a) and myocardial infarction and death in this setting. Approach and Results— The CRIC Study (Chronic Renal Insufficiency Cohort) is an ongoing prospective study of 3939 participants with chronic kidney disease. In 3635 CRIC participants with genotype data, carriers of the rs10455872 or rs6930542 variants had a higher median Lp(a) level (mg/dL) compared with noncarriers (73 versus 23; P P 61.3. There were 315 myocardial infarctions and 822 deaths during a median follow-up of 7.5 years. The second quartile had the lowest event rate. After adjusting for potential confounders and using a Cox proportional hazards model, the highest quartile of Lp(a) was associated with increased risk of myocardial infarction (hazard ratio, 1.49; 95% confidence interval, 1.05–2.11), death (hazard ratio, 1.28; 95% confidence interval, 1.05–1.57), and the composite outcome (hazard ratio, 1.29; 95% confidence interval, 1.07–1.56) compared with the second quartile of Lp(a). Conclusions— Among adults with chronic kidney disease, elevated Lp(a) is independently associated with myocardial infarction and death. Future studies exploring pharmacological Lp(a) reduction in this population are warranted.

Background: Grayscale ultrasound atherosclerotic plaque characteristics may predict cardiovascular disease (CVD) events, though they have not been investigated in a large primary prevention cohort. This study determined if CVD risk factors were associated with carotid plaque ultrasound characteristics and if these characteristics could predict future coronary heart disease (CHD) and stroke/transient ischemic attack (TIA) events in a multi-ethnic cohort free of known CVD at baseline. Methods: We measured carotid artery total plaque area (TPA) and grayscale carotid plaque features (grayscale median, black areas, and discrete white areas) at baseline in participants of the Multi-Ethnic Study of Atherosclerosis that had B-mode carotid ultrasound examinations. There were 2205 participants with images available for TPA analyses and 1703 with images available for grayscale analyses. Multivariable linear regression analysis was used to examine relationships between baseline ultrasound carotid plaque features and CVD risk factors. Cox proportional hazards models were used to assess their ability to predict incident CHD and stroke/TIA events over an average follow-up of 13.3 years. The predictive characteristics of TPA and carotid plaque features were compared to carotid plaque score and coronary artery calcification (CAC) score. Results: Participants were mean (standard deviation) 65.4 (9.6) years old, 49% male, 39% White, 28% Black, 22% Hispanic, and 11% Chinese. Mean TPA (27.7 [24.7] mm 2 ), but not grayscale plaque features, were associated with several CVD risk factors. In risk factor-adjusted models, TPA was the only plaque feature that predicted incident CHD events (HR 1.23; 95% CI 1.11-1.36; p Conclusions: In middle-aged individuals free of known CVD, carotid TPA was associated with CVD risk factors and predicted incident CHD events while grayscale plaque features did not. For CHD, predictive characteristics of TPA were similar to carotid plaque score but lower than CAC score.

Objective— We sought to assess the impact of smoking status, cumulative pack-years, and time since cessation (the latter in former smokers only) on 3 important domains of cardiovascular disease: inflammation, vascular dynamics and function, and subclinical atherosclerosis. Approach and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) cohort enrolled 6814 adults without prior cardiovascular disease. Smoking variables were determined by self-report and confirmed with urinary cotinine. We examined cross-sectional associations between smoking parameters and (1) inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP], interleukin-6, and fibrinogen); (2) vascular dynamics and function (brachial flow-mediated dilation and carotid distensibility by ultrasound, as well as aortic distensibility by MRI); and (3) subclinical atherosclerosis (coronary artery calcification, carotid intima–media thickness, and ankle-brachial index). We identified 3218 never smokers, 2607 former smokers, and 971 current smokers. Mean age was 62 years and 47% were male. There was no consistent association between smoking and vascular distensibility or flow-mediated dilation outcomes. However, compared with never smokers, the adjusted association between current smoking and measures of either inflammation or subclinical atherosclerosis was consistently stronger than for former smoking (eg, odds ratio for hsCRP>2 mg/L of 1.7 [95% confidence interval, 1.5–2.1] versus 1.2 [1.1–1.4], odds ratio for coronary artery calcification>0 of 1.8 [1.5–2.1] versus 1.4 [1.2–1.6], respectively). Similar associations were seen for interleukin-6, fibrinogen, carotid intima–media thickness, and ankle-brachial index. A monotonic association was also found between higher pack-year quartiles and increasing inflammatory markers. Furthermore, current smokers with hsCRP>2 mg/L were more likely to have increased carotid intima–media thickness, abnormal ankle-brachial index, and coronary artery calcification>75th percentile for age, sex, and race (relative to smokers with hsCRPP 2 mg/L of 0.91 [0.88–0.95] and odds ratio for coronary artery calcification>0 of 0.94 [0.90–0.97] for every 5-year cessation interval). Conclusions— These findings expand our understanding of the harmful effects of smoking and help explain the cardiovascular benefits of smoking cessation.

Background: Ultrasound texture “contrast” can be used to characterize the arterial wall non-invasively. Texture contrast provides information about the distribution and gray level differences of the pixels in the arterial wall and may describe early changes related to arterial injury. We determined if ultrasound texture contrast was associated with cardiovascular disease (CVD) risk factors and subclinical arterial disease. Methods: We evaluated ultrasound images of the distal right common carotid artery from a convenience sample of 151 participants from the first examination of the Multi-Ethnic Study of Atherosclerosis, a population-based cohort of individuals without clinical CVD. Images were digitized, normalized, and standardized to a pixel density of 20/mm. Plaque texture analysis software (LifeQ Medical, Cyprus) used the gray level difference statistics method to determine the contrast of the far wall of the carotid intima-media complex. Multivariable linear regression models (adjusted for age, sex and race/ethnicity) were used to examine relationships between contrast, CVD risk factors (age, BMI, total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol, triglycerides, hypertension, diabetes mellitus, smoking, glomerular filtration rate, C-reactive protein, interleukin-6, D-dimer, fibrinogen, alcohol consumption, education level, physical activity level, statin use), carotid intima-media thickness (IMT), coronary artery calcium (CAC), and CVD risk score. Results: The 151 participants were mean (standard deviation) 68.1 (9.2) years old (54% female; 31% Hispanic, 28% Black, 10% Chinese, and 31% White). In models that included age, sex, and race, contrast was associated independently with age (beta [standard error] -0.9 [0.4] per year; p=0.02), HDL-C (0.6 [0.2] per mg/dL; p=0.02), C-reactive protein (-2.3 [0.9] per mg/L; p=0.02), and carotid IMT (-1.3 [0.4] microns; p=0.001). Other CVD risk factors and CAC were not associated independently with contrast. Conclusions: Lower contrast, an ultrasound texture feature, is associated with increasing age, lower HDL-C, higher CRP, and higher carotid IMT, supporting its potential use for evaluating arterial injury and CVD risk.

Introduction: Coronary artery calcium (CAC) volume and density differentially predict incident cardiovascular disease (CVD), with CAC density inversely associated with these outcomes. Whether similar associations exist between descending thoracic aortic calcium (DTAC) volume and density and all cause mortality (ACM) are unknown. We hypothesized that DTAC volume and density predict ACM independently of CAC. Methods: The Multi-Ethnic Study of Atherosclerosis enrolled 6,814 participants free of clinical CVD at baseline and followed them for incident adverse events. Cardiac CT at baseline visualized the segment of the descending thoracic aorta posterior to the heart. Only participants with prevalent DTAC were included (necessary to evaluate DTAC density). DTAC and CAC volumes were natural log transformed to adjust for skewness. Cox regression models estimated the associations of DTAC volume and density with ACM after adjustment for age, gender, ethnicity, CVD risk factors, statin use, and CAC volume and density. The incremental predictive values of DTAC volume and density were evaluated by area under receiver operating characteristic (AUC) curves. Results: Of the total cohort, 1,850 participants (27%) had prevalent DTAC and 491 deaths occurred over 10.3 years. In separate regression models, DTAC volume was independently associated with ACM after adjustment for CAC volume (HR 1.21 [95% CI 1.09-1.35]) and additional adjustment for CAC density (1.18 ([1.06-1.32]). After the same adjustments, DTAC density was not significantly associated with ACM (0.94 [0.84-1.06]). The AUC for the base Model 1 (risk factors + CAC volume) was 0.706 (0.680-0.732), which increased to 0.716 (0.690-0.742) with the addition of DTAC volume in Model 2 (p=0.03 compared to Model 1). Further addition of DTAC density in Model 3 did not improve the AUC significantly (0.717 [0.692-0.743], p=0.23 compared to Model 2). Conclusions: In a cohort free of baseline clinical CVD, DTAC visualized on cardiac CT was common. When DTAC was present, DTAC volume (but not density) was independently associated with ACM. DTAC volume also significantly improved ACM risk prediction beyond risk factors and CAC volume.

Objective— To determine whether long-term exposure to moderate elevations in plasma plant sterol levels increases risk for atherosclerosis. Methods and Results— In Old Order Amish participants aged 18 to 85 years, with (n=110) and without (n=181) 1 copy of the ABCG8 G574R variant, we compared mean plasma levels of plant sterols and cholesterol precursors and carotid intima-media wall thickness. Carriers of a single 574R allele had increased plant sterol levels (eg, 35%–37% higher plasma levels of sitosterol, campesterol, and stigmasterol) and increased plant sterol/cholesterol ratios ( P P =0.03). Adjustment for body weight, blood pressure, and standard lipid measures (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides) did not alter this association. Conclusion— Although the G574R variant is associated with moderately elevated plant sterol levels, carriers of the 574R allele had modestly lower levels of carotid wall thickness compared with noncarriers.

Objective— The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC). Methods and Results— We genotyped single-nucleotide polymorphisms (SNPs) in GC , CYP27B1, CYP24A1 , and VDR and tested their association with CAC quantity, as measured by electron beam computed tomography. Initial association studies were carried out in a discovery sample comprising 697 Amish subjects, and SNPs nominally associated with CAC quantity (4 SNPs in CYP24A1 , P =0.008 to 0.00003) were then tested for association with CAC quantity in 2 independent cohorts of subjects of white European ancestry (Genetic Epidemiology Network of Arteriopathy study [n=916] and the Penn Coronary Artery Calcification sample [n=2061]). One of the 4 SNPs, rs2762939, was associated with CAC quantity in both the Genetic Epidemiology Network of Arteriopathy ( P =0.007) and Penn Coronary Artery Calcification ( P =0.01) studies. In all 3 populations, the rs2762939 C allele was associated with lower CAC quantity. Metaanalysis for the association of this SNP with CAC quantity across all 3 studies yielded a P value of 2.9×10 −6 . Conclusion— A common SNP in the CYP24A1 gene was associated with CAC quantity in 3 independent populations. This result suggests a role for vitamin D metabolism in the development of CAC quantity.

Objective— Lipoprotein(a) [Lp(a)] is a risk factor for calcific aortic valve disease (CAVD) but has not been evaluated across multiple races/ethnicities. This study aimed to determine whether Lp(a) cutoff values used in clinical laboratories to assess risk of cardiovascular disease identify subclinical CAVD and its severity and whether significant relations are observed across race/ethnicity. Approach and Results— Lp(a) concentrations were measured using a turbidimetric immunoassay, and subclinical CAVD was measured by quantifying aortic valve calcification (AVC) through computed tomographic scanning in 4678 participants of the Multi-Ethnic Study of Atherosclerosis. Relative risk and ordered logistic regression analysis determined cross-sectional associations of Lp(a) with AVC and its severity, respectively. The conventional 30 mg/dL Lp(a) clinical cutoff was associated with AVC in white (relative risk: 1.56; confidence interval: 1.24–1.96) and was borderline significant ( P =0.059) in black study participants (relative risk: 1.55; confidence interval: 0.98–2.44). Whites with levels ≥50 mg/dL also showed higher prevalence of AVC (relative risk: 1.72; confidence interval: 1.36–2.17) than those below this level. Significant associations were observed between Lp(a) and degree of AVC in both white and black individuals. The presence of existing coronary artery calcification did not affect these associations of Lp(a) and CAVD. There were no significant findings in Hispanics or Chinese. Conclusions— Lp(a) cutoff values that are currently used to assess cardiovascular risk seem to be applicable to CAVD, but our results suggest race/ethnicity may be important in cutoff selection. Further studies are warranted to determine whether race/ethnicity influences Lp(a) and risk of CAVD incidence and its progression.

Objective— The goal of this study was to compare and contrast coronary artery calcium (CAC) with abdominal aortic calcium (AAC) in terms of their associations with traditional and novel cardiovascular disease (CVD) risk factors. Methods and Results— We measured both AAC and CAC using computed tomography scans in 1974 men and women aged 45 to 84 years from a multiethnic cohort. Traditional and novel CVD risk factors were examined separately in relation to AAC and CAC, using logistic regression for qualitative categorical comparisons and multiple linear regression for quantitative continuous comparisons. AAC was significantly associated with cigarette smoking and dyslipidemia and showed no gender difference. In contrast, CAC showed much weaker associations with smoking and dyslipidemia and a strong male predominance. Age and hypertension were associated similarly and significantly with AAC and CAC. Novel risk factors generally showed no independent association with either calcium measure, although in subset analyses, phosphorus, but not calcium, was related to CAC. The receiver operating characteristic curves for the qualitative results and the r 2 values for the quantitative analyses were both much higher for AAC than for CAC. Conclusion— AAC showed stronger correlations with most CVD risk factors than did CAC. The predictive value of AAC compared with CAC for incident CVD events remains to be evaluated.