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1.  Carotid artery plaque and progression of coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis 
Carotid and coronary atherosclerosis are associated to each other in imaging and autopsy studies. We evaluated whether carotid artery plaque seen on carotid ultrasound can predict incident coronary artery calcification (CAC).
Materials and Methods
We repeated Agatston calcium score measurements in 5445 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 57.9 years; 62.9% female). Internal carotid artery lesions were graded as 0%, 1-24%, >25% diameter narrowing and intima-media thickness (IMT) was measured. Plaque was present for any stenosis > 0%. CAC progression was evaluated with multivariable relative risk regression in cases with CAC = 0 at baseline and with multivariable linear regression for CAC > 0 adjusting for cardiovascular risk factors, body mass index, ethnicity, and common carotid IMT.
CAC was positive at baseline in 2708/5445 (49.7%) participants and became positive in 458/2837 (16.1%) at mean interval of 2.4 years between repeat examinations. Plaque and ICA IMT were both strongly associated with presence of CAC. After statistical adjustment, presence of carotid artery plaque significantly predicted incident CAC with a relative risk(RR) of 1.37 (95% Confidence Intervals: 1.12, 1.67). Incident CAC was associated with ICA IMT with an RR of 1.13 (95% Confidence Intervals: 1.03, 1.25) for each mm increase. Progression of CAC was also significantly associated (p < 0.001) with plaque and ICA IMT.
In individuals free of cardiovascular disease, subjective and quantitative measures of carotid artery plaques by ultrasound imaging are associated with CAC incidence and progression.
PMCID: PMC4084492  PMID: 23522805
2.  Prospective Association Between Inflammatory Markers and Progression of Coronary Artery Calcification in Adults With and Without Type 1 Diabetes 
Diabetes Care  2013;36(7):1967-1973.
The role of inflammation in the increased risk of cardiovascular disease in type 1 diabetes is unclear. We examined the association of inflammation and progression of coronary artery calcification (CAC)—a marker of subclinical atherosclerosis—in adults with and without type 1 diabetes.
A nested case-control study was performed within the prospective cohort of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. Participants underwent two CAC measurements ∼2.5 years apart. Case subjects (n = 204) were those with significant progression of CAC. Control subjects (n = 258) were frequency-matched to case subjects on diabetes status, sex, age, and baseline CAC status. Inflammatory marker assessments were performed on stored blood samples from baseline. A principal components analysis (PCA) was performed and a composite score derived from that analysis. The composite score was constructed by assigning a value of 1 for each PCA component where at least one of the markers exceeded the 75th percentile (range 0–4). Conditional logistic regression was used for the matching strategy.
The first two components of the PCA were modestly (odds ratio 1.38 [95% CI 1.08–1.77] and 1.27 [1.02–1.59], respectively) associated with CAC progression after adjustment for other risk factors. The composite score was more strongly associated with CAC progression for those with elevated markers in three or four of the principal components compared with those with none.
Measures of inflammation were associated with progression of CAC in a population of adults with and without type 1 diabetes.
PMCID: PMC3687315  PMID: 23340891
3.  Circulating Levels of Tissue Factor Microparticle Procoagulant Activity are Reduced with Antiretroviral Therapy and are Associated with Persistent Inflammation and Coagulation Activation among HIV Positive Patients 
Activation of coagulation pathways may contribute to risk for non-AIDS related conditions among HIV positive patients. We measured tissue factor-dependent procoagulant activity on circulating microparticles (MP-TF) in the plasma of 163 HIV positive participants, both untreated and treated, with viral suppression. MP-TF activity was 39% lower among treated versus untreated participants (p<0.001), which persisted in adjusted models (−36%; p=0.03). Among treated participants, MP-TF activity correlated modestly with D-dimer (r=0.24; p=0.01), vWF (r=0.36; p<0.001), and IL-6 (r=0.20; p=0.04) levels. Future research should focus on mechanisms driving residual functional TF activity and whether these alterations have clinical consequences for non-AIDS defining complications.
PMCID: PMC3683107  PMID: 23507662
4.  A genome-wide association study for venous thromboembolism: the extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium 
Genetic epidemiology  2013;37(5):512-521.
Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a 2-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended CHARGE VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to ~2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (p≤0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG) (p<5.0×10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (p<5.0×10-6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
PMCID: PMC3990406  PMID: 23650146
venous thrombosis; genetics; genome-wide association; genetic epidemiology
5.  n-3 and n-6 Fatty acids are independently associated with lipoprotein-associated phospholipase A2 in the Multi-Ethnic Study of Atherosclerosis 
The British journal of nutrition  2013;110(9):1664-1671.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent risk factor for CVD and has been proposed as a marker of vascular inflammation. Polyunsaturated n-3 fatty acids (FA) and several n-6 FA are known to suppress inflammation and may influence Lp-PLA2 mass and activity. The associations of n-3 and n-6 plasma FA with Lp-PLA2 mass and activity were analysed using linear regression analysis in 2246 participants of the Multi-Ethnic Study of Atherosclerosis; statistical adjustments were made to control for body mass, inflammation, lipids, diabetes, and additional clinical and demographic factors. Lp-PLA2 mass and activity were significantly lower in participants with the higher n-3 FA EPA (β = −4·72, P<0·001; β = −1·53; P=0·023) and DHA levels (β = −4·47, β = −1·87; both P<0·001). Those in the highest quintiles of plasma EPA and DHA showed 12·71 and 19·15 ng/ml lower Lp-PLA2 mass and 5·7 and 8·90 nmol/min per ml lower Lp-PLA2 activity than those in the first quintiles, respectively. In addition, lower Lp-PLA2 mass and activity were associated with higher levels of n-6 arachidonic acid (β = −1·63, β = −1·30; both P<0·001), while γ-linolenic acid was negatively associated with activity (β = −27·7, P=0·027). Lp-PLA2 mass was significantly higher in participants with greater plasma levels of n-6 linoleic (β = 0·828, P=0·011) and dihomo-γ-linolenic acids (β = 4·17, P=0·002). Based on their independent associations with Lp-PLA2 mass and activity, certain n-3 and n-6 FA may have additional influences on CVD risk. Intervention studies are warranted to assess whether these macronutrients may directly influence Lp-PLA2 expression or activity.
PMCID: PMC4060439  PMID: 23551952
Fatty acids; n-3; Atherosclerosis; Lipoprotein-associated phospholipase; Lipoprotein-associated phospholipase A2
6.  Competing Cardiovascular Outcomes Associated with Subclinical Atherosclerosis (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;111(11):1541-1546.
Subclinical atherosclerosis measured by coronary artery calcium (CAC) is associated with increased risk for multiple cardiovascular disease (CVD) outcomes and non-CVD death simultaneously, and we sought to determine the competing risks of specific cardiovascular disease (CVD) events and non-CVD death associated with varying burdens of subclinical atherosclerosis. We included 3095 men and 3486 women from the Multi-Ethnic Study of Atherosclerosis, aged 45–84 years, and from 4 ethnic groups. Participants were stratified by CAC scores: 0, 1–99, and ≥ 100. We used competing Cox models to determine competing cumulative incidences and hazards ratios within a group (e.g., among those with CAC ≥ 100) and hazards ratios for specific events between groups (e.g., CAC ≥ 100 vs. CAC = 0). We compared risks for specific CVD events and also compared against non-CVD death. In women, during a mean follow up of 7.1 years, the hazards ratios (HR) for any CVD event compared with a non-CVD death occurring first for CAC = 0 and CAC ≥ 100 were 1.40 (95% CI, 0.97–2.04) and 3.07 (2.02–4.67), respectively. CHD was the most common first CVD event type at all levels of CAC, and CHD rates were 9.5% vs. 1.6% (HR 6.24; 3.99–9.75) for women with CAC ≥100 compared with CAC = 0. We observed similar results in men. In conclusion, at all levels of CAC, CHD was the most common first CVD event and this analysis represents a novel approach to understanding the temporal sequence of cardiovascular events associated with atherosclerosis.
PMCID: PMC3657323  PMID: 23499272
coronary artery calcium; competing risks
7.  Treatment-related changes in serum lipids and inflammation: clinical relevance remains unclear. Analyses from the Women's Interagency HIV Study 
AIDS (London, England)  2013;27(9):1516-1519.
Among 127 HIV-infected women, the magnitude of HDLc increases after HAART initiation predicted the magnitude of concurrent decreases in inflammation biomarkers. After HAART initiation, changes in LDLc and inflammation were unrelated. In the same population, predicted risk of coronary heart disease based upon levels of standard clinical risk factors was similar before and after HAART treatment. Thus, it remains unknown whether short-term treatment-related changes in standard risk factors may appreciably change risk of CVD.
PMCID: PMC3909663  PMID: 23435295
lipids; HAART; HIV infection; inflammation
8.  Pentraxin-3 and the right ventricle: the Multi-Ethnic Study of Atherosclerosis–Right Ventricle Study 
Pulmonary Circulation  2014;4(2):250-259.
Pentraxin-3 (PTX3) is a protein mediator of innate immunity that is elevated in the setting of left heart disease and pulmonary arterial hypertension. The relationship between PTX3 and right ventricular (RV) structure and function is not known. We included men and women with magnetic resonance imaging assessment of RV structure and function and measurement of PTX3 from the Multi-Ethnic Study of Atherosclerosis, a study of individuals free of clinical cardiovascular disease. Multivariable linear regression estimated associations between PTX3 protein levels and RV measures after adjusting for demographic characteristics, anthropometrics, smoking status, diabetes mellitus, hypertension, and corresponding left ventricular (LV) parameters. Instrumental variable analysis exploiting Mendelian randomization was attempted using two-stage least squares regression. The study sample included 1,779 participants with available PTX3 levels, RV measures, and all covariables. Mean PTX3 level was 2.1 ng/mL. Higher PTX3 was independently associated with greater RV mass and larger RV end-diastolic volume with and without adjustment for the corresponding LV parameters or C-reactive protein (all P < .05). There was no association between PTX3 and RV ejection fraction or stroke volume. Single-nucleotide polymorphisms were not associated with PTX3 protein levels or RV measures after accounting for race. Instrumental variable analysis could not be reliably performed. Higher PTX3 protein levels were associated with greater RV mass and larger RV end-diastolic volume. These associations were independent of common cardiovascular risk factors and LV morphologic changes. Inflammation is associated with differences in the pulmonary circulation-RV axis in adults without clinical cardiovascular disease.
PMCID: PMC4070771  PMID: 25006444
pulmonary hypertension; heart failure; inflammation; right ventricle; Mendelian randomization
9.  Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication 
The Journal of Clinical Investigation  2014;124(6):2802-2806.
Damage to the intestinal mucosa results in the translocation of microbes from the intestinal lumen into the circulation. Microbial translocation has been proposed to trigger immune activation, inflammation, and coagulopathy, all of which are key factors that drive HIV disease progression and non-HIV comorbidities; however, direct proof of a causal link is still lacking. Here, we have demonstrated that treatment of acutely SIV-infected pigtailed macaques with the drug sevelamer, which binds microbial lipopolysaccharide in the gut, dramatically reduces immune activation and inflammation and slightly reduces viral replication. Furthermore, sevelamer administration reduced coagulation biomarkers, confirming the contribution of microbial translocation in the development of cardiovascular comorbidities in SIV-infected nonhuman primates. Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit noninfectious comorbidities associated with AIDS.
PMCID: PMC4089442  PMID: 24837437
10.  Fetuin-A, Type 2 Diabetes, and Risk of Cardiovascular Disease in Older Adults 
Diabetes Care  2013;36(5):1222-1228.
Fetuin-A, a hepatic secretory protein that simultaneously inhibits arterial calcification and insulin action, is associated with type 2 diabetes, but its association with cardiovascular disease (CVD) is uncertain. Preliminary studies suggest that the association of fetuin-A with CVD might differ among individuals with or without type 2 diabetes.
This was a prospective study of 3,810 community-living individuals older than 65 years (511 with type 2 diabetes) and free of CVD in 1992 when fetuin-A levels were measured. Participants were followed-up for incident CVD through June 2008.
Mean age was 75 years, and 61% were women; 1,456 participants had an incident CVD event (248 among individuals with type 2 diabetes). The association of fetuin-A with CVD was modified by type 2 diabetes (P interaction = 0.02). Higher fetuin-A was associated with lower CVD risk among persons without type 2 diabetes [hazard ratio per SD 0.1 g/L higher fetuin-A, 0.93 (95% CI, 0.88–0.99)], whereas a trend in the opposite direction was observed among individuals with type 2 diabetes, although it was not statistically significant [1.07 (0.93–1.22)]. Among individuals without type 2 diabetes, similar effect modification was observed by obesity and insulin resistance. Consistently, higher fetuin-A was associated with lower CVD risk only in the subgroups without obesity or with HOMA-IR below the median [0.91 (0.85–0.97) and 0.87 (0.79–0.95), respectively].
The association of fetuin-A with risk of CVD differs among elderly individuals with and without insulin resistance or type 2 diabetes.
PMCID: PMC3631840  PMID: 23250801
11.  A Community-Based Exercise and Support Group Program in African-American Breast Cancer Survivors (ABCs) 
African-American (AA) women have higher rates of breast cancer (BCa) mortality than Caucasian women, and a recent study using data from the Surveillance, Epidemiology and End Results (SEER) registry suggests that this disparity may be due, in part, to the poorer health status of AAs at diagnosis and not treatment related issues. Randomized controlled trials involving supervised aerobic and resistance exercise have shown improved body composition and improvement in cancer-related biomarkers in BCa patients and may lead to improved recurrence and survival rates; however, most trials have focused on Caucasians and many have been conducted in academic- and clinic-based settings. We evaluated the feasibility of conducting a 20-week, supervised, resistance training, group exercise intervention coupled with a support group and home walking program utilizing facilities and personnel at a community cancer support center (The Gathering Place, Beachwood, Ohio) in AA Stage I–III BCa survivors who were within 12 months of completing treatment (surgery, chemotherapy, and/or breast irradiation); and, evaluated the potential effects of this intervention on physical measures and cancer-related biomarkers. 27 patients provided informed consent and 19 participated in the program. On average, attendance rates were 70.0% ± 19.1% for the exercise sessions and 63.1% ± 13.8% for the support group. We observed a significant decrease in circulating C-peptide levels (B: 893.9 ± 399.1 pg/mL; EOI: 723.9 ± 319.0 pg/mL; p=0.01). Although we did not observe a significant decrease in weight in the entire sample, there was a significant decrease in waist circumference and percent total body fat among those who attended 70% or more of the exercise sessions. In summary, we demonstrated that conducting lifestyle interventions in AA BCa survivors in a community setting is feasible. Future interventions should invoke strategies to enhance adherence and include a structured dietary intervention to enable greater weight loss.
PMCID: PMC3975605  PMID: 24707505
Breast Cancer; Exercise; African-American; Community-Based; Biomarkers
12.  Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study 
European Journal of Heart Failure  2012;15(4):394-399.
To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure.
Methods and results
In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95% confidence interval (CI) 1.25–1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95% CI 1.01–1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion.
An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.
PMCID: PMC3707430  PMID: 23223158
Epidemiology; Adiposity; Heart failure; Fatty acid-binding protein 4
13.  Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction: A Randomized Clinical Trial 
JAMA : the journal of the American Medical Association  2013;309(12):10.1001/jama.2013.2024.
Studies in experimental and human heart failure suggest that phosphodiesterase type-5 inhibitors may enhance cardiovascular function, and thus, exercise capacity in heart failure with preserved ejection fraction.
To determine the effect of the phosphodiesterase type-5 inhibitor, sildenafil, in comparison to placebo on exercise capacity and clinical status in heart failure with preserved ejection fraction.
Design, setting, and patients
Multicenter, double-blind, placebo-controlled, parallel design, randomized clinical trial of 216 stable outpatients with heart failure, ejection fraction ≥ 50%, elevated N-terminal pro-brain natriuretic peptide or elevated invasively-measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in the United States and Canada.
Sildenafil (n=113) or placebo (n=103) administered orally at 20 mg three times daily for 12 weeks followed by 60 mg three times daily for 12 weeks.
Main outcome measures
Primary endpoint was change in peak oxygen consumption after 24 weeks of therapy. Secondary endpoints included change in six-minute walk distance and a three tier hierarchical composite clinical status score where patients were ranked (range 1-N) based on time to death, time to cardiovascular or cardiorenal hospitalization and change in quality of life for participants alive without cardiovascular or cardiorenal hospitalization at 24 weeks.
Median age was 69 years and 48% of patients were female. At baseline, median peak oxygen consumption (11.7 ml/kg/min) and six-minute walk distance (308 meters) were reduced and median E/e′ (16), left atrial volume index (44 ml/m2) and pulmonary artery systolic pressure (41 mmHg) were consistent with chronically-elevated left ventricular filling pressures. At 24 weeks, median (interquartile range) changes in peak oxygen consumption (ml/kg/min) in patients who received placebo [−0.20 (−0.70, 1.00)] or sildenafil [−0.20 (−1.20, 1.10); p=0.90] were not significantly different. The mean clinical status rank score (higher value indicates better status; expected value with no treatment effect = 95) was not significantly different (p=0.85) at 24 weeks in patients who received placebo (95.8) or sildenafil (94.2). Changes in six-minute walk distance (meters) at 24 weeks in patients who received placebo [15.0 (−26.0, 45.0)] or sildenafil [5.0 (−37.0, 55.0); p=0.92] were also not significantly different. Adverse events occurred in 78 (76%) of patients who received placebo and 90 (80%) of patients who received sildenafil. Serious adverse events occurred in 16 (16%) of patients who received placebo and 25 (22%) of patients who received sildenafil.
Chronic phosphodiesterase type-5 inhibitor therapy with sildenafil for 24 weeks did not alter exercise capacity or clinical status compared to placebo in patients with heart failure and preserved ejection fraction.
Trial registration number, NCT00763867
PMCID: PMC3835156  PMID: 23478662
14.  Associations of Total and High-Molecular-Weight Adiponectin with All-Cause and Cardiovascular Mortality in Older Persons: The Cardiovascular Health Study 
Circulation  2012;126(25):2951-2961.
Adiponectin shows opposite associations with adverse outcomes in healthy middle-aged populations (lower risk), and cohorts with prevalent cardiovascular disease (CVD), heart failure (HF) or advanced age (higher risk).
Methods and Results
In a population-based study of older adults, we examined the relationships of total and high-molecular-weight (HMW) adiponectin with mortality among subgroups defined by baseline cardiovascular status: no CVD, HF or atrial fibrillation (AF) (Group 1); CVD but no HF/AF (Group 2); and HF/AF (Group 3). We found significant differences in the associations with all-cause mortality across the groups. The association in Group 1 was U-shaped; increasing levels of total adiponectin up to 12.4 mg/L were associated with lower mortality after adjustment for confounders (HR=0.81 per 1-SD [0.65–0.95]), but above this cutpoint, higher levels conferred greater risk (HR=1.19 [1.12–1.27]). Further adjustment for diabetes or insulin resistance, protection against which has been proposed to mediate adiponectin’s beneficial relationships with outcome, attenuated the association in the lower range. There was no significant association in Group 2, but in Group 3, total adiponectin showed a direct adjusted association. Additional adjustment for putative metabolic/inflammatory intermediates suggested a direct association for Group 2, and magnified the one for Group 3 (HR=1.31 [1.15–1.50]). Results were similar for HMW adiponectin, and for cardiovascular mortality.
Adiponectin exhibits distinct associations with mortality in elders, which shift from U-shaped to flat to direct with greater baseline cardiovascular dysfunction, but become more consistently adverse after accounting for metabolic/inflammatory factors presumed to be favorably regulated by the adipokine. These findings advance understanding of the adiponectin paradox as relates to older adults.
PMCID: PMC3968250  PMID: 23159554
Adiponectin; Aging; Mortality
15.  Association Of Hepatitis C With Markers Of Hemostasis In HIV-Infected and Uninfected Women in the Women’s Interagency HIV Study (WIHS) 
Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common. HIV infection and treatment are associated with hypercoaguability; thrombosis in HCV is under-investigated. Proposed markers of hemostasis in HIV include higher D-dimer, Factor VIII% and Plasminogen Activator Inhibitor-1 (PAI-1Ag), and lower total Protein S% (TPS), but have not been examined in HCV. We assessed the independent association of HCV with these four measures of hemostasis in a multicenter, prospective study of HIV: the Women’s Interagency HIV Study (WIHS).
We randomly selected 450 HCV-infected (anti-HCV+ with detectable plasma HCV RNA) and 450 HCV-uninfected (anti-HCV−) women. HCV was the main exposure of interest in regression models.
443 HCV+ and 425 HCV− women were included. HCV+ women had higher Factor VIII% (124.4% ±3.9 vs. 101.8% ±3.7, p <0.001) and lower TPS (75.7% ±1.1 vs. 84.3% ±1.1, <0.001) than HCV−, independent of HIV infection and viral load; there was little difference in PAI-1Ag or log10 D-dimer. After adjustment for confounders, these inferences remained. HIV infection was independently associated with higher Factor VIII% and log10 D-dimer, and lower TPS.
HCV was independently associated with higher Factor VIII% and lower TPS consistent with hypercoaguability. Higher Factor VIII % and D-dimer and lower total Protein S % were also strongly associated with HIV infection and levels of HIV viremia, independent of HCV infection. Further investigation is needed to determine if there is increased thrombotic risk from HCV. Studies examining hemostasis markers in HIV infection must also assess the contribution of HCV infection.
PMCID: PMC3652915  PMID: 23221984
16.  Markers of Decongestion, Dyspnea Relief and Clinical Outcomes Among Patients Hospitalized with Acute Heart Failure 
Circulation. Heart failure  2012;6(2):10.1161/CIRCHEARTFAILURE.112.969246.
Congestion is a primary driver of symptoms in patients with acute heart failure (AHF), and relief of congestion is a critical goal of therapy. Monitoring of response to therapy through the assessment of daily weights and net fluid loss is the current standard of care, yet the relationship between commonly used markers of decongestion and both patient reported symptom relief and clinical outcomes are unknown.
Methods and Results
We performed a retrospective analysis of the randomized clinical trial -Diuretic Optimization Strategy Evaluation in Acute Heart Failure (DOSE-AHF), enrolling patients hospitalized with a diagnosis of acute decompensated heart failure (ADHF). We assessed the relationship between 3 markers of decongestion at 72 hours—weight loss, net fluid loss and % reduction in serum NT-proBNP level—and relief of symptoms as defined by the dyspnea visual analog scale area under the curve (VAS AUC). We also determined the relationship between each marker of decongestion and 60-day clinical outcomes defined as time to death, first re-hospitalization or ER visit. Mean age was 66 years, mean EF was 35% and 27% had EF ≥50%. Of the 3 measures of decongestion assessed, only % reduction in NT-proBNP was significantly associated with symptom relief (r=0.13, P = 0.04). There was no correlation between either weight loss or net fluid loss and symptom relief, (r=0.04, P=0.54 and r=0.07, P=0.27, respectively). Favorable changes in each of the 3 markers of decongestion were associated with improvement in time to death, re-hospitalization or ED visit at 60 days [weight: HR 0.91 (95% confidence interval 0.85, 0.97) per 4 lbs. weight lost; fluid HR 0.94 (0.90, 0.99) per 1000mL fluid loss; NT-proBNP HR 0.95 (0.91, 0.99) per 10% reduction]. These associations were unchanged after multivariable adjustment with the exception that % reduction in NT-proBNP was no longer a significant predictor (HR 0.97; 0.93, 1.02). Patients with 2 or 3 markers of decongestion (above the median value for each marker) had improved clinical outcomes versus those with 0 or 1 marker above the median value (39.0% versus 53.8%; P=0.03).
Weight loss, fluid loss and NT-proBNP reduction at 72 hours are poorly correlated with dyspnea relief. However, favorable improvements in each of the 3 markers were associated with improved clinical outcomes at 60 days. These data suggest the need for ongoing research to understand the relationships between symptom relief, congestion, and outcomes in patients with ADHF.
Clinical Trial Registration
URL: Unique identifier: NCT00577135.
PMCID: PMC3865520  PMID: 23250981
heart failure; dyspnea; diuretics
17.  Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans: The Candidate Gene Association Resource (CARe) Study 
Using data from four community-based cohorts of African Americans (AA), we tested the association between genome-wide markers (SNPs) and cardiac phenotypes in the Candidate-gene Association REsource (CARe) study.
Methods and Results
Among 6,765 AA, we related age, sex, height and weight-adjusted residuals for nine cardiac phenotypes (assessed by echocardiogram or MRI) to 2.5 million SNPs genotyped using Genome-Wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within cohort genome-wide association analysis was conducted followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10−07). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested look-ups in one consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (p=1.43 × 10−07) for left ventricular mass (LVM); rs7213314 in WIPI1 (p=1.68 × 10−07) for LV internal diastolic diameter (LVIDD); rs1571099 in PPAPDC1A (p= 2.57 × 10−08) for interventricular septal wall thickness (IVST); and rs9530176 in KLF5 (p=4.02 × 10−07) for ejection fraction (EF). Associated variants were enriched in three signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry were confirmed in look-ups in EchoGEN.
In the largest GWAS of cardiac structure and function to date in AA, we identified 4 genetic loci related to LVM, IVST, LVIDD and EF that reached genome-wide significance. Replication results suggest that these loci may represent unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
PMCID: PMC3591479  PMID: 23275298
echocardiography; ethnic; genome-wide association studies; Left atrium genetics; left ventricular mass genetics
18.  Insulin Resistance and Risk of Incident Heart Failure: Cardiovascular Health Study 
Circulation. Heart failure  2013;6(3):364-370.
Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance (IR) as compared with matched controls. IR leads to structural abnormalities in the heart, such as increased left atrial (LA) size, left ventricular (LV) mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether IR precedes the development of HF or whether the relationship between IR and HF is present among adults with HF due to non-ischemic heart disease.
Methods and Results
We examined 4425 participants (60% female) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry.
There were 1216 cases of incident HF (1103 without antecedent MI) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (HR = 1.10, 95% CI 1.05, 1.15, per SD change) when adjusted for age, gender, race, field center, physical activity, smoking, alcohol intake, HDL cholesterol, total cholesterol, and systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent MI (HR= 1.10, 95% CI 1.05, 1.15). Measures of LA size, LV mass, and peak A velocity at baseline were associated both with fasting insulin levels and with heart failure ; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (HR= 1.08, 95% CI 1.03, 1.14 per1-SD increase in fasting insulin).
Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in CHS participants, including those without an antecedent MI.
PMCID: PMC3888807  PMID: 23575256
heart failure; insulin; epidemiology
19.  Soluble CD14: genome-wide association analysis and relationship to cardiovascular risk and mortality in the older adults 
Arteriosclerosis, thrombosis, and vascular biology  2012;33(1):10.1161/ATVBAHA.112.300421.
CD14 is a glycosylphosphotidylinositol-(GPI)-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes.
Methods and Results
We measured baseline levels of sCD14 in over 5,000 European-American (EA) and African-American (AA) adults 65 years and older from the Cardiovascular Health Study, who were well-characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease (CVD), and who have been followed for clinical CVD and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional CVD risk factors), and was also inversely correlated with body mass index. In genome-wide association analyses of sCD14, we (a) confirmed the importance of the CD14 locus on chromosome 5q21 in EA; (b) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in AA; (c) identified a putative novel association in EA of a non-synonymous variant of PIGC, which encodes an enzyme required for the first step in GPI anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident CVD, and strongly and independently predicts all-cause mortality in older adults.
CD14 independently predicts risk mortality in older adults.
PMCID: PMC3826541  PMID: 23162014
CD14; glycosylphosphotidylinositol; coronary heart disease; mortality
20.  Plasma Fatty Acid Binding Protein 4 and Risk of Sudden Cardiac Death in Older Adults 
Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95% CI: 0.95–1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95% CI: 1.07–1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95% CI: 0.62–1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted.
PMCID: PMC3888692  PMID: 24455402
21.  Von Willebrand Factor and the Right Ventricle (The MESA-Right Ventricle Study) 
The American journal of cardiology  2012;110(12):1846-1851.
Elevation in plasma activity of von Willebrand Factor (vWF) reflects endothelial dysfunction and predicts death in pulmonary arterial hypertension (PAH). Higher vWF activity is also associated with lower right ventricular (RV) ejection fraction in PAH. Little is known about the relationship between vWF and RV structure and function in adults without cardiovascular disease. In the current investigation, we included 1,976 participants with MRI assessment of RV structure and function and measurement of vWF activity from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to estimate the associations between vWF activity and measures of RV structure and function after adjusting for demographics, anthropometrics, smoking, diabetes mellitus, hypertension and the corresponding left ventricular (LV) parameter. The average vWF activity was 140.7 ± 57.2%. Elevated vWF activity was independently associated with lower RV mass, RV end-diastolic volume and RV stroke volume in models with and without adjustment for the corresponding LV parameter (all p < 0.05). There was no association observed between vWF activity and RV ejection fraction. In conclusion, higher vWF activity is associated with lower RV mass, RV end-diastolic volume and RV stroke volume. These associations are independent of common cardiovascular risk factors and LV morphologic changes.
PMCID: PMC3696516  PMID: 22995970
Cardiovascular Imaging; Biomarkers; Pulmonary Hypertension; Right Ventricle
22.  Association of subclinical atherosclerosis with lipid levels amongst antiretroviral-treated and untreated HIV-infected women in the Women’s Interagency HIV Study 
Atherosclerosis  2012;225(2):408-411.
We examined serum lipids in association with carotid artery intima-media thickness (CIMT) in HIV-infected and HIV-uninfected women.
In 2003–4, among 1827 Women’s Interagency HIV Study participants, we measured CIMT and lipids (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], total cholesterol [TC], non-HDL-c). A subset of 520 treated HIV-infected women had pre-1997 lipid measures. We used multivariable linear regression to examine associations between lipids and CIMT.
In HIV-uninfected women, higher TC, LDL-c and non-HDL-c were associated with increased CIMT. Among HIV-infected women, associations of lipids with CIMT were observed in treated but not untreated women. Among the HIV-infected women treated in 2003–4, CIMT was associated both with lipids measured a decade earlier in infection, and with late lipid measurements.
Among HIV-infected women, hyperlipidemia is most strongly associated with subclinical atherosclerosis in treated women. Among treated women, the association appeared strongest early in the disease course.
PMCID: PMC3696584  PMID: 23089369
cardiovascular diseases; carotid arteries; HAART; HIV; lipids
23.  Cigarette smoking and airway wall thickness on CT scan in a multi-ethnic cohort: The MESA Lung Study 
Respiratory medicine  2012;106(12):1655-1664.
Autopsy studies show that smoking contributes to airway wall hyperplasia and narrowing of the airway lumen. Studies of smoking and airway measures on computed tomography (CT) scan are limited to case-control studies of measures that combine airway lumen and wall thickness.
We hypothesized that cumulative cigarette smoking would be associated with increased airway wall thickness in a large, population-based cohort.
The Multi-Ethnic Study of Atherosclerosis enrolled participants age 45-84 years from the general population. Smoking history was assessed via standardized questionnaire items; current smoking was confirmed in half the cohort with cotinine. Airway lumen and wall thickness were measured in two dimensions in posterior basal segmental bronchi on cardiac-gated CT scans. Analyses were adjusted for age, gender, genetic ancestry, education, height, weight, asthma history, particulate matter, scanner type, and scanner current.
Half of the 7,898 participants had smoked and 14% were current smokers. Pack-years of smoking were associated with thicker airway walls (mean increase 0.002 mm per ten pack-years [95% CI: 0.00002, 0.004] p=0.03). Current smoking was associated with narrower airway lumens (mean decrease −0.11 mm [95% CI: −0.2, −0.02] p=0.02). There was no evidence that either association was modified by genetic ancestry, and findings persisted among participants without clinical disease.
Long-term cigarette smoking was associated with subclinical increases in wall thickness of sub-segmental airways whereas current smoking was associated with narrower airway lumen diameters. Smoking may contribute to airway wall thickening prior to the development of overt chronic obstructive pulmonary disease.
PMCID: PMC3549633  PMID: 22974831
smoking; airway remodeling; Pi10; wall thickness; lumen; chronic obstructive pulmonary disease
24.  No Association between Circulating Levels and Genetic Variants of IL-6 and TNF-α and Colon Adenoma 
Gastroenterology research  2013;6(2):10.4021/gr529w.
Background & Aims
Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), two important inflammatory cytokines, have been inconsistently associated with risk of colon neoplasia in epidemiological studies. However, research to date has not adequately assessed whether race-specific differences may exist in associations between biomarkers and genetic variants of these cytokines and colorectal adenoma – the precursor lesions of colorectal cancer. We sought to determine whether circulating levels of IL-6 and TNF-α, or genetic polymorphisms in IL-6and TNF-α were associated with colon adenoma and if so, whether that association differed by race.
We analyzed the associations of circulating levels and single nucleotide polymorphisms (SNPs) of IL-6 and TNF-α with risk of colon adenomas in a colonoscopy -based case-control study of 401 incident adenoma cases and 1,050 controls. We used multivariate unconditional logistic regression models to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) for levels or genotypes (log additive models) of IL-6 and TNF-α.
Compared to the bottom tertile of IL-6, the adjusted ORs were: 1.06 (0.75–1.44), 1.01 (0.72–1.40), respectively for the 2nd and 3rd tertiles (ptrend = 0.10); the corresponding ORs for TNF-α were: 0.85 (0.63–1.15) and 1.01 (0.75–1.36), respectively (ptrend = 0.39). Race-stratified analyses did not reveal any significant association. There were also no statistically significant associations between IL-6 and TNF-α SNPs and colon adenoma.
Our results do not support pre-diagnostic levels of IL-6, TNF-α or their genetic variants as significant risk factors for the development of colon adenoma.
PMCID: PMC3825207  PMID: 24235998
25.  Prospective Study of Particulate Air Pollution Exposures, Subclinical Atherosclerosis, and Clinical Cardiovascular Disease 
American Journal of Epidemiology  2012;176(9):825-837.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45–84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter

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