Resistin and risks of incident heart failure subtypes and cardiac fibrosis: the Multi-Ethnic Study of Atherosclerosis.

AIMS: Resistin is a circulating inflammatory biomarker that is associated with cardiovascular disease. We investigated the associations of resistin and incident heart failure (HF) and its subtypes, as well as specific measures of subclinical HF (myocardial fibrosis and relevant biomarkers). METHODS: We analysed data from 1968 participants in the Multi-Ethnic Study of Atherosclerosis with measurements of plasma resistin levels at clinic visits from 2002 to 2005. Participants were subsequently followed for a median of 10.5 years for HF events. The associations between resistin levels and incident HF, HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF) were examined using multivariable Cox proportional hazards models. Linear regression models assessed the associations between resistin levels and myocardial fibrosis from cardiac magnetic resonance imaging, as well as hs-cTnT and NT-proBNP. RESULTS: The mean age of the cohort was 64.7 years, and 50.0% were female. Seventy-four participants (4%) developed incident HF during follow-up. In a Cox proportional hazards model adjusted for age, gender, education level, race/ethnicity, and traditional risk factors, higher resistin levels were significantly associated with incident HF (HR 1.44, CI 1.18-1.75, P = 0.001) and HFrEF (HR 1.47, CI 1.07-2.02, P = 0.016), but not with HFpEF (HR 1.25, CI 0.89-1.75, P = 0.195). Resistin levels showed no significant associations with myocardial fibrosis, NT-proBNP, or hs-cTnT levels. CONCLUSIONS: In a multi-ethnic cohort free of cardiovascular disease at baseline, elevated resistin levels were associated with incident HF, more prominently with incident HFrEF than HFpEF, but not with subclinical myocardial fibrosis or biomarkers of HF.

Cholesterol mass efflux capacity and risk of peripheral artery disease: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: We aimed to assess the relationship of HDL (high-density lipoprotein)-mediated cholesterol mass efflux capacity (CMEC) with risk of incident peripheral artery disease (PAD). METHODS: CMEC was measured in 1458 Multi-Ethnic Study of Atherosclerosis participants between 2000 and 2002 as part of a case-control study matched for incident cardiovascular disease and progression of carotid plaque by ultrasound. Incident clinical PAD, adjudicated on the basis of a positive history for the presence of disease-related symptoms or treatment, was ascertained through 2015 in 1419 individuals without clinical PAD at baseline. Subclinical PAD, defined as an ankle-brachial index (ABI) ≤1.0, was assessed among 1255 individuals with a baseline ABI >1.0 and at least one follow-up ABI measurement 3-10 years later. Cox proportional hazards and relative risk regression modeling per SD increment of CMEC were used to determine the association of CMEC with clinical and subclinical PAD, respectively. RESULTS: There were 38 clinical PAD and 213 subclinical PAD events that occurred over a mean follow-up of 6.0 and 6.5 years respectively. After adjustment for age, gender, and race, higher CMEC levels were not associated with clinical PAD (hazard ratio 1.25; 95% CI 0.89, 1.75) or subclinical PAD (risk ratio 1.02; 95% CI, 0.94, 1.11). CONCLUSIONS: These findings suggest that HDL-mediated cholesterol efflux is not significantly associated with incident clinical and subclinical PAD.

Virtual-Reality Guided Versus Fluoroscopy-Guided Transseptal Puncture in a Cardiac Phantom.

OBJECTIVES: We compared virtual-reality guided versus fluoroscopy-guided transseptal puncture by novice and experienced operators in a cardiac phantom. Outcome measures included accuracy, time, transseptal path distance, and a survey of the operator experience. METHODS: A transseptal simulator was created using a Plexiglas case and a 3D-printed cardiac phantom with a replaceable fossa ovalis, a customized support, and an electromagnetic tracking system. A precisely registered virtual-reality rendering was constructed. To display the transseptal instruments in virtual reality, we attached electromagnetic sensors to standard transseptal instruments, including the needle, dilator, and sheath. Each subject completed 6 simulated transseptal punctures (3 fluoroscopy-guided and 3 virtual-reality guided). We measured the distance traversed by the transseptal needle, accuracy, and time for each simulated transseptal puncture. Operators were then surveyed regarding their experience. RESULTS: A total of 8 subjects (6 faculty, 2 fellows) completed the trial. We found that virtual-reality guidance resulted in significantly more accurate puncture site selection and, subjectively, was more intuitive for the operator, particularly for novices. None of the participants experienced negative symptoms in virtual reality that required cessation of the procedure. CONCLUSIONS: Virtual reality compared with fluoroscopic guidance for transseptal puncture shows considerable promise, particularly for novice trainees, where it could lessen the learning curve. Current barriers to widespread implementation are discussed.

Assessment of rejection risk following subtherapeutic calcineurin inhibitor levels after pediatric heart transplantation.

CNIs are the mainstay of immunosuppressive therapy after pediatric HTx. While regular laboratory surveillance is performed to ensure blood levels are within targeted range, the risk of acute rejection associated with subtherapeutic CNI levels has never been quantified. This is a retrospective single-center review of 8413 CNI trough levels in 138 pediatric HTx recipients who survived >1 year after HTx. Subtherapeutic CNI levels were defined as <50% of the lower limit of target range. The risk of acute, late (>12 months post-transplant) rejection following recipients' subtherapeutic CNI levels was assessed using time-varying multivariable Cox proportional hazards analysis. We found that 79 of 138 recipients (57%) had at least one subtherapeutic CNI level on routine surveillance laboratories during a mean follow-up of 5.5 ± 3.6 years. Following an episode of subtherapeutic levels, 17 recipients (22%) had biopsy-proven rejection within the next 3 months; the majority (9/17) within the first 2 weeks. After presenting with subtherapeutic CNI levels, recipients incurred a 6.1 times increased risk of acute rejection in the following 3 months (HR = 6.11 [2.41, 15.51], P = <.001). Age at HTx, HLA sensitization, or positive crossmatch were not associated with acute late rejection, but rejection in the first post-transplant year was (HR 2.61 [1.27, 5.35], P = .009). Thus, maintaining therapeutic CNI levels is the most important factor in preventing acute rejection in recipients who are >12 months after pediatric HTx. Recipients who present with subtherapeutic CNI levels on surveillance monitoring are 6.1 times more likely to develop rejection in the following 3 months.

Cholesterol Mass Efflux Capacity, Incident Cardiovascular Disease, and Progression of Carotid Plaque.

Objective- To assess the role of HDL (high-density lipoprotein)-mediated cholesterol mass efflux capacity (CMEC) in incident cardiovascular disease and carotid plaque progression. Approach and Results- We measured CMEC in 2 cohorts aged 45 to 84 years at baseline derived from the MESA (Multi-Ethnic Study of Atherosclerosis). Cohort 1 comprised 465 cases with incident cardiovascular disease events during 10 years of follow-up and 465 age- and sex-matched controls; cohort 2 comprised 407 cases with progression of carotid plaque measured by ultrasonography at 2 exams >10 years and 407 similarly matched controls. Covariates and outcome events were ascertained according to the MESA protocol. CMEC level was modestly correlated with HDL cholesterol ( R=0.13; P<0.001) but was not associated with age, sex, race/ethnicity, body mass index, diabetes mellitus, alcohol use, smoking status, or statin use. Higher CMEC level was significantly associated with lower odds of cardiovascular disease (odds ratio, 0.82 per SD of CMEC [95% CI, 0.69-0.98; P=0.031] in the fully adjusted model) in cohort 1 but higher odds of carotid plaque progression (odds ratio, 1.24 per SD of CMEC [95% CI, 1.04-1.48; P=0.018] in the fully adjusted model) in cohort 2 but without dose-response effect. In subgroup analysis within cohort 1, higher CMEC was associated with lower risk of incident coronary heart disease events (odds ratio, 0.72 per SD of CMEC (95% CI, 0.5-0.91; P=0.007) while no association was found with stroke events. Conclusions- These findings support a role for HDL-mediated cholesterol efflux in an atheroprotective mechanism for coronary heart disease but not stroke.

Use of coronary artery calcium testing to improve coronary heart disease risk assessment in a lung cancer screening population: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Assessment of coronary artery calcium (CAC) during lung cancer screening chest computed tomography (CT) represents an opportunity to identify asymptomatic individuals at increased coronary heart disease (CHD) risk. We determined the improvement in CHD risk prediction associated with the addition of CAC testing in a population recommended for lung cancer screening. METHODS: We included 484 out of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants without baseline cardiovascular disease who met U.S. Preventive Service Task Force CT lung cancer screening criteria and underwent gated CAC testing. 10 year-predicted CHD risks with and without CAC were calculated using a validated MESA-based risk model and categorized into low (<5%), intermediate (5%-10%), and high (≥10%). The net reclassification improvement (NRI) and change in Harrell's C-statistic by adding CAC to the risk model were subsequently determined. RESULTS: Of 484 included participants (mean age = 65; 39% women; 32% black), 72 (15%) experienced CHD events over the course of follow-up (median = 12.5 years). Adding CAC to the MESA CHD risk model resulted in 17% more participants classified into the highest or lowest risk categories and a NRI of 0.26 (p = 0.001). The C-statistic improved from 0.538 to 0.611 (p = 0.01). CONCLUSIONS: CHD event rates were high in this lung cancer screening eligible population. These individuals represent a high-risk population who merit consideration for CHD prevention measures regardless of CAC score. Although overall discrimination remained poor with inclusion of CAC scores, determining whether those reclassified to an even higher risk would benefit from more aggressive preventive measures may be important.

Socioeconomic Status and Poor Health Outcome at 10 Years of Follow-Up in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND/OBJECTIVES: Predictors of healthy aging have not been well-studied using longitudinal data with demographic, clinical, subclinical, and genetic information. The objective was to identify predictors of poor health outcome at 10 years of follow-up in the Multi-Ethnic Study of Atherosclerosis (MESA). DESIGN: Prospective cohort study. SETTING: Population-based sample from 6 U.S. communities. PARTICIPANTS: 4,355 participants In the MESA Study. MEASUREMENTS: Poor health outcome at 10 years of follow-up was defined as having died or having clinical cardiovascular disease, depression, cognitive impairment, chronic obstructive pulmonary disease, or cancer other than non-melanoma skin cancer. Absolute risk regression was used to estimate risk differences in the outcome adjusting for demographic variables, clinical and behavioral risk factors, subclinical cardiovascular disease, and ApoE genotype. Models were weighted to account for selective attrition. RESULTS: Mean age at 10 years of follow-up was 69.5 years; 1,480 participants had a poor health outcome, 2,157 participants were in good health, and 718 were unknown. Older age, smoking, not taking a statin, hypertension, diabetes, and higher coronary calcium score were associated with higher probability of poor health outcome. After multivariable adjustment, participants in the lowest income and educational categories had 7 to 14% greater absolute risk of poor health outcome at 10 years of follow-up compared to those in the next highest categories of income or education (P = 0.002 for both). Those in the lowest categories of both income and education had 21% greater absolute risk of poor health outcome compared to those in the highest categories of both income and education. CONCLUSIONS: Low income and educational level predict poor health outcome at 10 years of follow-up in an aging cohort, independent of clinical and behavioral risk factors and subclinical cardiovascular disease.

10-Year Coronary Heart Disease Risk Prediction Using Coronary Artery Calcium and Traditional Risk Factors: Derivation in the MESA (Multi-Ethnic Study of Atherosclerosis) With Validation in the HNR (Heinz Nixdorf Recall) Study and the DHS (Dallas Heart Study).

BACKGROUND: Several studies have demonstrated the tremendous potential of using coronary artery calcium (CAC) in addition to traditional risk factors for coronary heart disease (CHD) risk prediction. However, to date, no risk score incorporating CAC has been developed. OBJECTIVES: The goal of this study was to derive and validate a novel risk score to estimate 10-year CHD risk using CAC and traditional risk factors. METHODS: Algorithm development was conducted in the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective community-based cohort study of 6,814 participants age 45 to 84 years, who were free of clinical heart disease at baseline and followed for 10 years. MESA is sex balanced and included 39% non-Hispanic whites, 12% Chinese Americans, 28% African Americans, and 22% Hispanic Americans. External validation was conducted in the HNR (Heinz Nixdorf Recall Study) and the DHS (Dallas Heart Study). RESULTS: Inclusion of CAC in the MESA risk score offered significant improvements in risk prediction (C-statistic 0.80 vs. 0.75; p < 0.0001). External validation in both the HNR and DHS studies provided evidence of very good discrimination and calibration. Harrell's C-statistic was 0.779 in HNR and 0.816 in DHS. Additionally, the difference in estimated 10-year risk between events and nonevents was approximately 8% to 9%, indicating excellent discrimination. Mean calibration, or calibration-in-the-large, was excellent for both studies, with average predicted 10-year risk within one-half of a percent of the observed event rate. CONCLUSIONS: An accurate estimate of 10-year CHD risk can be obtained using traditional risk factors and CAC. The MESA risk score, which is available online on the MESA web site for easy use, can be used to aid clinicians when communicating risk to patients and when determining risk-based treatment strategies.

Long-term exposure to air pollution and markers of inflammation, coagulation, and endothelial activation: a repeat-measures analysis in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Air pollution is associated with cardiovascular disease, and systemic inflammation may mediate this effect. We assessed associations between long- and short-term concentrations of air pollution and markers of inflammation, coagulation, and endothelial activation. METHODS: We studied participants from the Multi-Ethnic Study of Atherosclerosis from 2000 to 2012 with repeat measures of serum C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, D-dimer, soluble E-selectin, and soluble Intercellular Adhesion Molecule-1. Annual average concentrations of ambient fine particulate matter (PM2.5), individual-level ambient PM2.5 (integrating indoor concentrations and time-location data), oxides of nitrogen (NOx), nitrogen dioxide (NO2), and black carbon were evaluated. Short-term concentrations of PM2.5 reflected the day of blood draw, day prior, and averages of prior 2-, 3-, 4-, and 5-day periods. Random-effects models were used for long-term exposures and fixed effects for short-term exposures. The sample size was between 9,000 and 10,000 observations for CRP, IL-6, fibrinogen, and D-dimer; approximately 2,100 for E-selectin; and 3,300 for soluble Intercellular Adhesion Molecule-1. RESULTS: After controlling for confounders, 5 µg/m increase in long-term ambient PM2.5 was associated with 6% higher IL-6 (95% confidence interval = 2%, 9%), and 40 parts per billion increase in long-term NOx was associated with 7% (95% confidence interval = 2%, 13%) higher level of D-dimer. PM2.5 measured at day of blood draw was associated with CRP, fibrinogen, and E-selectin. There were no other positive associations between blood markers and short- or long-term air pollution. CONCLUSIONS: These data are consistent with the hypothesis that long-term exposure to air pollution is related to some markers of inflammation and fibrinolysis.

Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study.

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

Metabolic Syndrome Derived from Principal Component Analysis and Incident Cardiovascular Events: The Multi Ethnic Study of Atherosclerosis (MESA) and Health, Aging, and Body Composition (Health ABC).

Background. The NCEP metabolic syndrome (MetS) is a combination of dichotomized interrelated risk factors from predominantly Caucasian populations. We propose a continuous MetS score based on principal component analysis (PCA) of the same risk factors in a multiethnic cohort and compare prediction of incident CVD events with NCEP MetS definition. Additionally, we replicated these analyses in the Health, Aging, and Body composition (Health ABC) study cohort. Methods and Results. We performed PCA of the MetS elements (waist circumference, HDL, TG, fasting blood glucose, SBP, and DBP) in 2610 Caucasian Americans, 801 Chinese Americans, 1875 African Americans, and 1494 Hispanic Americans in the multiethnic study of atherosclerosis (MESA) cohort. We selected the first principal component as a continuous MetS score (MetS-PC). Cox proportional hazards models were used to examine the association between MetS-PC and 5.5 years of CVD events (n = 377) adjusting for age, gender, race, smoking and LDL-C, overall and by ethnicity. To facilitate comparison of MetS-PC with the binary NCEP definition, a MetS-PC cut point was chosen to yield the same 37% prevalence of MetS as the NCEP definition (37%) in the MESA cohort. Hazard ratio (HR) for CVD events were estimated using the NCEP and Mets-PC-derived binary definitions. In Cox proportional models, the HR (95% CI) for CVD events for 1-SD (standard deviation) of MetS-PC was 1.71 (1.54-1.90) (P < 0.0001) overall after adjusting for potential confounders, and for each ethnicity, HRs were: Caucasian, 1.64 (1.39-1.94), Chinese, 1.39 (1.06-1.83), African, 1.67 (1.37-2.02), and Hispanic, 2.10 (1.66-2.65). Finally, when binary definitions were compared, HR for CVD events was 2.34 (1.91-2.87) for MetS-PC versus 1.79 (1.46-2.20) for NCEP MetS. In the Health ABC cohort, in a fully adjusted model, MetS-PC per 1-SD (Health ABC) remained associated with CVD events (HR = 1.21, 95%CI 1.12-1.32) overall, and for each ethnicity, Caucasian (HR = 1.24, 95%CI 1.12-1.39) and African Americans (HR = 1.16, 95%CI 1.01-1.32). Finally, when using a binary definition of MetS-PC (cut point 0.505) designed to match the NCEP definition in terms of prevalence in the Health ABC cohort (35%), the fully adjusted HR for CVD events was 1.39, 95%CI 1.17-1.64 compared with 1.46, 95%CI 1.23-1.72 using the NCEP definition. Conclusion. MetS-PC is a continuous measure of metabolic syndrome and was a better predictor of CVD events overall and in individual ethnicities. Additionally, a binary MetS-PC definition was better than the NCEP MetS definition in predicting incident CVD events in the MESA cohort, but this superiority was not evident in the Health ABC cohort.

Association of lipoprotein-associated phospholipase A(2) and endothelial function in the Multi-Ethnic Study of Atherosclerosis (MESA).

Mechanisms underlying the role of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) in atherosclerotic development are not completely understood. We evaluated the relationship of Lp-PLA(2) with endothelial dysfunction, an early manifestation of atherosclerosis, in a cohort without known clinical cardiovascular disease. A total of 2809 participants in the Multi-Ethnic Study of Atherosclerosis underwent plasma Lp-PLA(2) mass and activity measurement and brachial artery flow-mediated vasodilation testing. In adjusted linear regression models, higher Lp-PLA(2) mass and activity levels were not associated with lower endothelial function (-0.04%, p = 0.51 and -0.09%, p = 0.10, respectively). Among individuals with subclinical atherosclerosis based on ankle-brachial index (ABI) or carotid intima-media thickness (IMT), Lp-PLA(2) mass and activity were not associated with lower endothelial function (-0.03%, p = 0.88 and -0.31%, p = 0.16 for ABI < 1.00; 0.01%, p = 0.94 and -0.15%, p = 0.20 for abnormal carotid IMT). In summary, Lp-PLA(2) is not associated with endothelial dysfunction, suggesting its role in atherosclerosis development is primarily related to other factors.

Coronary artery calcium score and risk classification for coronary heart disease prediction.

CONTEXT: The coronary artery calcium score (CACS) has been shown to predict future coronary heart disease (CHD) events. However, the extent to which adding CACS to traditional CHD risk factors improves classification of risk is unclear. OBJECTIVE: To determine whether adding CACS to a prediction model based on traditional risk factors improves classification of risk. DESIGN, SETTING, AND PARTICIPANTS: CACS was measured by computed tomography in 6814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort without known cardiovascular disease. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2008. Participants with diabetes were excluded from the primary analysis. Five-year risk estimates for incident CHD were categorized as 0% to less than 3%, 3% to less than 10%, and 10% or more using Cox proportional hazards models. Model 1 used age, sex, tobacco use, systolic blood pressure, antihypertensive medication use, total and high-density lipoprotein cholesterol, and race/ethnicity. Model 2 used these risk factors plus CACS. We calculated the net reclassification improvement and compared the distribution of risk using model 2 vs model 1. MAIN OUTCOME MEASURES: Incident CHD events. RESULTS: During a median of 5.8 years of follow-up among a final cohort of 5878, 209 CHD events occurred, of which 122 were myocardial infarction, death from CHD, or resuscitated cardiac arrest. Model 2 resulted in significant improvements in risk prediction compared with model 1 (net reclassification improvement = 0.25; 95% confidence interval, 0.16-0.34; P < .001). In model 1, 69% of the cohort was classified in the highest or lowest risk categories compared with 77% in model 2. An additional 23% of those who experienced events were reclassified as high risk, and an additional 13% without events were reclassified as low risk using model 2. CONCLUSION: In this multi-ethnic cohort, addition of CACS to a prediction model based on traditional risk factors significantly improved the classification of risk and placed more individuals in the most extreme risk categories.