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1.  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
2.  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
3.  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
pulmonary hypertension; heart failure; inflammation; right ventricle; Mendelian randomization
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  Human immunodeficiency virus, hepatitis C, and inflammatory biomarkers in individuals with alcohol problems: a cross-sectional study 
BMC Infectious Diseases  2013;13:399.
Assessing whether hepatitis C (HCV) co-infection with human immunodeficiency virus (HIV) is associated with increased inflammation is complex. The liver, integral to inflammatory biomarker synthesis, is compromised by HCV and alcohol abuse. Using single liver-synthesized biomarkers (e.g. C-reactive protein) to represent inflammation may not be appropriate in HIV/HCV co-infection. We hypothesized that 1) detectable HIV/HCV RNA was independently associated with increased inflammation; 2) a composite inflammation measure describes inflammation differently from single inflammatory biomarkers.
We compared inflammation by HIV/HCV group in a cohort of 361 HIV infected participants from the HIV-Longitudinal Interrelationships of Viruses and Ethanol study. Inflammatory biomarkers >75th percentile were considered elevated. Associations between HIV/HCV group and elevated biomarkers were analyzed as a composite measure (inflammatory burden) or individually. We defined inflammatory burden as number of concurrently elevated biomarkers. Biomarkers included interleukin-6 (IL-6), C-reactive protein (CRP), cystatin C, serum amyloid-A (SAA), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10). Covariates: alcohol, liver fibrosis, comorbidities, CD4 count, antiretroviral therapy, substance use.
Detectable HIV and HCV RNA (OR = 2.49; 95% CI = 1.05–5.89) and detectable HCV RNA alone (2.95; 1.08–8.01) were independently associated with increased odds of having a greater inflammatory burden compared to undetectable viremia. Elevated IL-10 (7.79; 1.90–31.97) and TNF-α (7.70; 1.42–41.83) were independently associated with detectable HIV and HCV RNA. Elevated IL-10 was also associated with detectable HCV RNA alone (5.51; 1.17, 25.84).
Detectable HIV and HCV replication versus undetectable replication was associated with inflammatory burden and certain inflammatory biomarkers independently of alcohol consumption, liver fibrosis and other comorbidities.
PMCID: PMC3848623  PMID: 23987993
HIV; HCV; Inflammation; Alcohol; Liver; Comorbidity
11.  Plasma Fatty Acid–Binding Protein 4, Nonesterified Fatty Acids, and Incident Diabetes in Older Adults 
Diabetes Care  2012;35(8):1701-1707.
To examine the relation of fatty acid–binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults.
We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992–2007) based on the use of hypoglycemic medications, fasting glucose ≥126 mg/dL, or nonfasting glucose ≥200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993.
Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95% CI 1.10–1.65) for women and 1.45 (1.13–1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m2 (HR per SD: 1.78 [95% CI 1.13–2.81]). There was a modest and nonsignificant association of NEFA with diabetes (Ptrend = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95% CI 1.12–2.53), and 1.63 (1.07–2.50) across consecutive tertiles of NEFA (Ptrend = 0.03).
Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up.
PMCID: PMC3402261  PMID: 22584136
12.  Plasma Free Fatty Acids and Risk of Atrial Fibrillation (From the Cardiovascular Health Study) 
The American Journal of Cardiology  2012;110(2):212-216.
Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million people in the USA and 4.5 million people in the European Union. It is unclear whether plasma free fatty acids (FFA) influence the risk of AF among older adults. The aim of this study was to prospectively examine the association between plasma FFA and incident AF in a prospective cohort of 4,175 men and women aged ≥65 years from the Cardiovascular Health Study. Plasma concentrations of FFA were measured in duplicate during the 1992-93 examination. Incident AF was ascertained based on study EKG and hospitalization records during follow up. We used Cox regression to estimate relative risks of AF. The average age at baseline was 74.6 ± 5.1 years. During a mean follow up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFA. There was a positive association between plasma FFA and the risk of AF. Multivariable adjusted hazard ratios (95% CI) for incident AF were 1.00 (ref), 1.02 (0.85-1.21), 1.05 (0.88-1.26), and 1.29 (1.08-1.55) from lowest to the highest quartile of FFA, respectively. In a secondary analysis restricted to the first five years of follow up, this association persisted. In conclusion, our data show an elevated risk of AF with higher plasma FFA among community dwelling older adults.
PMCID: PMC3383877  PMID: 22503582
Free Fatty Acids; Atrial Fibrillation; Risk Factors; Epidemiology
13.  T‐Helper Type 1 Bias in Healthy People Is Associated With Cytomegalovirus Serology and Atherosclerosis: The Multi‐Ethnic Study of Atherosclerosis 
Although T‐helper type 1 (Th1) cells are considered important in atherosclerosis, the relationships between Th1 and Th2 cells and atherosclerosis have not been examined in population‐based studies.
Methods and Results
We measured Th cells as a percentage of lymphocytes by flow cytometry using CD4 staining (%CD4) in 917 participants of the Multi‐Ethnic Study of Atherosclerosis. We also measured interferon gamma–positive and interleukin‐4‐positive CD4+ cells, representing Th1 and Th2 subpopulations (%Th1 and %Th2), respectively. We found that %CD4 was 1.5% lower per 10 years of age (P<0.0001). Whites had higher %CD4 and lower %Th1 and %Th2 values than other race/ethnic groups. Body mass index (BMI) and blood pressure were associated with %CD4, but no traditional cardiovascular disease (CVD) risk factors were associated with %Th1 or %Th2. In multivariable models, the major independent variable associated with %Th1 was cytomegalovirus (CMV) antibody titer, with minor contributions from age, sex, seasonality, and interleukin‐6. In models with coronary artery calcification level as the outcome, significant independent variables included age, sex, smoking status, and %Th1 (β=0.25; P≤0.01). Both %Th1 and %Th2 were associated with common carotid intimal media thickness (β=0.02 and −0.02, respectively; both P<0.05), as were age, sex, race/ethnicity, blood pressure, and BMI.
Th1 bias is associated with subclinical atherosclerosis in a multiethnic population. The main Th1 correlate was CMV infectious burden. These findings are consistent with a role of Th1 cells in atherosclerosis and suggest the importance of prospective studies of T‐helper cell biasing in CVD.
PMCID: PMC3698770  PMID: 23688675
atherosclerosis; epidemiology; immunology; inflammation; T‐helper cell
14.  The Determinants of Plasma Plasminogen Activator Inhibitor 1 Levels Differ for American and Japanese Men Aged 40–49 
Elevated plasma plasminogen activator inhibitor-1 (PAI-1) levels were associated with higher incidence of type II diabetes. Elucidating the determinants of PAI-1 in various ethnicities may help to understand the susceptibility to developing diabetes. The aim of our study was to compare PAI-1 levels between Americans and the Japanese in the post-war generation and to elucidate the determinants of the PAI-1 levels.
We conducted a cross-sectional study on a total of 198 men aged 40–49 in the U.S. (Body-mass index (BMI): 27.0 ± 3.3 kg/m2) and Japan (BMI: 23.3 ± 3.1 kg/m2). Examination included physique measurement (BMI and waist girth), blood analysis (lipid profiles, glucose, insulin, C-reactive protein, and PAI-1), and life-style assessment by self-administered questionnaires.
PAI-1 levels were significantly lower in American than in Japanese men, even after adjustment for age, waist girth, cigarette smoking, habitual alcohol drinking, and other factors. In the Americans, waist girth, insulin, and cigarette smoking were significantly associated with PAI-1 levels, while waist girth and triglycerides were significantly associated with PAI-1 levels in the Japanese.
PAI-1 levels were significantly lower in American than in Japanese men and the determinants of PAI-1 levels differ for American and Japanese men aged 40–49.
PMCID: PMC3660558  PMID: 16325297
PAI-1; US; Japan; epidemiology; post-war generation
15.  Association Between Depression and Vascular Disease in Systemic Lupus Erythematosus 
The Journal of rheumatology  2011;39(2):262-268.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with increased prevalence of cardiovascular disease (CVD) and depression. Although depression may contribute to CVD risk in population-based studies, its influence on cardiovascular morbidity in SLE has not been evaluated. We evaluated the association between depression and vascular disease in SLE.
A cross-sectional study was conducted from 2002–2005 in 161 women with SLE and without CVD. The primary outcome measure was a composite vascular disease marker consisting of the presence of coronary artery calcium and/or carotid artery plaque.
In total, 101 women met criteria for vascular disease. In unadjusted analyses, several traditional cardiovascular risk factors, inflammatory markers, adiposity, SLE disease-related factors, and depression were associated with vascular disease. In the final multivariable model, the psychological variable depression was associated with nearly 4-fold higher odds for vascular disease (OR 3.85, 95% CI 1.37, 10.87) when adjusted for other risk factors of age, lower education level, hypertensive status, waist-hip ratio, and C-reactive protein.
In SLE, depression is independently associated with vascular disease, along with physical factors.
PMCID: PMC3632335  PMID: 22174200
16.  Midlife blood pressure, plasma β amyloid and the risk for Alzheimer’s disease: the Honolulu Asia Aging Study 
Hypertension  2012;59(4):780-786.
Beta-amyloid (Aβ), a vasoactive protein, and elevated blood pressure (BP) levels are associated with Alzheimer’s disease (AD) and possibly vascular dementia (VaD). We investigated the joint association of mid-life BP and Aβ peptide levels with the risk for late-life AD and VaD. Subjects were 667 Japanese-American men (including 73 with a brain autopsy), from the prospective Honolulu Heart Program/Honolulu Asia Aging Study (1965 – 2000). Mid-life BP was measured starting in 1971 participants mean age 58 years, Aβ was measured in specimens collected1980/82, and assessment of dementia and autopsy collection started in 1991/93. The outcome measures were prevalent (present in 1991/3) and incident AD (n= 53, including 38 with no contributing cardiovascular disease), and VaD (n=24). Cerebral amyloid angiopathy (CAA), β-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in post-mortem tissue. The risk for AD significantly increased with lower levels of plasma Aβ (Aβ1-40 hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.4 – 3.1; Aβ1-42 HR 1.6, 95% CI 1.1 – 2.3). Evidence of interaction between diastolic BP and plasma Aβ (1-40 pinteraction <0.05; 1-42 pinteraction <0.07) levels, indicated the Aβ-related risk for AD was higher when BP was higher. Low plasma Aβ was associated with the presence of CAA (ptrend<0.05), but not the other neuropathologies. Aβ plasma levels start decreasing at least 15 years before AD is diagnosed, and the association of Aβ to AD is modulated by mid-life diastolic BP. Elevated BP may compromise vascular integrity leading to CAA and impaired Aβ clearance from the brain.
PMCID: PMC3319436  PMID: 22392902
Amyloid; blood pressure; brain; aging; dementia
17.  Non-esterified Fatty Acids and Risk of Sudden Cardiac Death in Older Adults 
While non-esterified fatty acids (NEFA) have been positively associated with coronary heart disease risk factors, limited and inconsistent data are available on the relation between NEFA and sudden cardiac death.
Methods and Results
Using a prospective design, we studied 4,657 older men and women (mean age 75 y) from the Cardiovascular Health Study (1992-2006) to evaluate the association between plasma NEFA and the risk of sudden cardiac death in older adults. Plasma concentrations of NEFA were measured using established enzymatic methods and sudden death was adjudicated using medical records, death certificates, proxy interview, and autopsy reports. We used Cox proportional hazard models to estimate multivariable-adjusted relative risks. During a median follow-up of 10.0 years, 221 new cases of sudden cardiac death occurred. In a multivariable model adjusting for age, sex, race, clinic site, alcohol intake, smoking, prevalent coronary heart disease and heart failure, and self-reported health status, relative risks (95% CI) for sudden cardiac death were 1.0 (ref), 1.15 (0.81-1.64), 1.06 (0.72-1.55), and 0.91 (0.60-1.38) across consecutive quartiles of NEFA concentration. In secondary analyses restricted to the first five years of follow up, we also did not observe a statistically significant association between plasma NEFA and sudden cardiac death.
Our data do not provide evidence for an association between plasma NEFA measured late in life and the risk of sudden cardiac death in older adults.
PMCID: PMC3329563  PMID: 22281952
epidemiology; sudden death; fatty acid binding protein 4; risk factors
18.  Adiposity is Associated with Endothelial Activation in Healthy 2- to 3-Year-Old Children 
Adiposity is associated with C-reactive protein level in healthy 2–3 year old children and with other markers of endothelial activation adults, but data are lacking in very young children. Data from 491 healthy Hispanic children were analyzed. Mean age was 2.7 years (S.D. 0.5, range 2 to 3 years); mean body mass index (BMI) was 17.2 kg/m2 (S.D. 1.9) among boys and 17.1 kg/m2 (S.D. 2.1) among girls. E-selectin level was associated with BMI (R =0.11; p < 0.02), ponderal index (p < 0.02), waist circumference (p = 0.02), fasting insulin (p < 0.02), and insulin resistance (p ≤ 0.05); these associations remained significant after adjustment for age, sex and fasting glucose. sVCAM was also associated with BMI (R = 0.12; P<0.05). These observations indicate that adiposity is associated with inflammation and endothelial activation in very early childhood.
PMCID: PMC3603688  PMID: 20020578
children; adiposity; E-selectin; sICAM; sVAM
19.  Total and High-Molecular-Weight Adiponectin and Risk of Incident Diabetes in Older People 
Diabetes Care  2012;35(2):415-423.
To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults.
Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals.
Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95% CI 0.39–0.63]) and HMW adiponectin (0.42 [0.32–0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables.
In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation.
PMCID: PMC3263897  PMID: 22148099
20.  Inflammatory Biomarkers and Abacavir Use in the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study 
AIDS (London, England)  2010;24(11):1657-1665.
To assess associations between abacavir (ABC) use and systemic inflammation.
Retrospective case-control study.
MACS & WIHS cohort participants who initiated ABC were matched, using propensity score methods, to ABC-unexposed persons. Levels of hsCRP(μg/mL), IL-6(pg/mL), and D-dimer (μg/mL) were measured from pre-HAART and on-HAART plasma. Random-effects models compared markers by ABC exposure and by changes from pre-HAART levels.
Biomarkers were measured in N=508 matched pairs (328 women; 180 men). Pre-HAART levels did not differ by exposure group except that hsCRP levels were higher among WIHS women who subsequently used ABC (p=0.04). Regardless of ABC use, mean hsCRP increases and D-dimer reductions were seen when comparing pre- to on-HAART levels, in the overall group (28% and -27%), for MACS men (28% and -31%) and for WIHS women (29% and -24% (p<0.01 for all); IL-6 levels declined in MACS men (p=0.02). No adjusted biomarker level differences existed by ABC exposure at the on-HAART visit. HIV RNA reductions correlated with D-dimer (r = 0.14, p < 0.01) and IL-6 (r = 0.12, p < 0.01) reductions. Associations between ABC use and mean biomarker levels were modified by pre-HAART ART experience. Renal dysfunction was equally likely among non-ABC and ABC recipients.
ABC use was not associated with plasma elevations in hsCRP, IL-6 and d-dimer. Mechanisms other than increased systemic inflammation may account for ABC’s reported association with increased cardiovascular disease. HAART -associated reductions in D-dimer and IL-6 were apparent regardless of ABC use and were correlated with HIV RNA reductions.
PMCID: PMC3514460  PMID: 20588104
HIV infection; inflammation; HAART; abacavir; cytokines
21.  The Relationship between Serum Markers of Collagen Turnover and Cardiovascular Outcome in the Elderly: The Cardiovascular Health Study 
Circulation. Heart Failure  2011;4(6):733-739.
The deposition of collagen fibrils in the myocardial extracellular matrix increases with age and plays a key role in the pathophysiology of heart failure (HF). We sought to determine the predictive value of serum markers of collagen turnover for incident HF and cardiovascular (CV) morbidity, mortality and all-cause mortality in elderly individuals.
Methods and Results
In 880 participants in the Cardiovascular Health Study (mean age 77 ± 6 yrs, 48% female), serum levels of carboxyl-terminal peptide of procollagen type I (PIP), carboxyl-terminal telopeptide of collagen type I (CITP), and amino-terminal peptide of procollagen type III (PIIINP) were measured in 4 groups: HF with reduced ejection fraction (HFREF; n=146, EF < 55%); HF with preserved EF (HFPEF; n=175, EF ≥ 55%), controls with CV risk factors but not HF (CVD; n = 280) and healthy controls free of CV disease (n=279). Relationships between these serum markers and outcome at follow-up of 12 ± 4 years (range, 3-17 years) was determined in six models including those adjusted for conventional risk factors, renal function, NT-proBNP and agents which interfere with collagen synthesis. For the entire cohort, in unadjusted and adjusted models, both PIIINP and CITP were associated with myocardial infarction, incident HF, hospitalization for HF, cardiovascular and all-cause mortality. In healthy controls, CITP and PIIINP were associated with all-cause death. In controls with risk factors, CITP was associated with incident HF, and in participants with HFPEF, CITP was associated with hospitalization for HF. No collagen biomarker was associated with outcome in participants with HFREF, and PIP was not associated with outcome in the cohort or its subgroups.
In both healthy and elderly individuals with CV disease at risk of developing HF, CITP and PIIINP are significantly associated with multiple adverse cardiac outcomes including myocardial infarction, HF and death.
Clinical Trial Registration
URL: Unique Identifier: NCT00005133.
PMCID: PMC3263368  PMID: 21900186
biomarkers; collagen; elderly; heart failure; outcomes
22.  The Effect of Including Cystatin C or Creatinine in a Cardiovascular Risk Model for Asymptomatic Individuals 
American Journal of Epidemiology  2011;174(8):949-957.
The authors studied the incremental value of adding serum cystatin C or creatinine to the Framingham risk score variables (FRSVs) for the prediction of incident cardiovascular disease (CVD) among 6,653 adults without clinical CVD utilizing the Multi-Ethnic Study of Atherosclerosis (2000–2008). CVD events included coronary heart disease, heart failure, stroke, and peripheral arterial disease. Variables were transformed to yield optimal prediction of 6-year CVD events in sex-stratified models with FRSVs alone, FRSVs + cystatin C, and FRSVs + creatinine. Risk prediction in the 3 models was assessed by using the C statistic, and net reclassification improvement was calculated. The mean ages were 61.9 and 64.6 years for individuals with and without diabetes, respectively. After 6 years of follow-up, 447 (7.2%) CVD events occurred. In the total cohort, no significant change in the C statistic was noted with FRSVs + cystatin C and FRSVs + creatinine compared with FRSVs alone, and net reclassification improvement for CVD risk was extremely small and not significant with the addition of cystatin C or creatinine to FRSVs. Similar findings were noted after stratifying by baseline presence of diabetes. In conclusion, the addition of cystatin C or serum creatinine to FRSVs does not improve CVD risk prediction among adults without clinical CVD.
PMCID: PMC3218629  PMID: 21880578
cardiovascular diseases; creatinine; cystatin C; risk model
23.  A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium 
Human Molecular Genetics  2011;20(17):3525-3534.
Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50 000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2 000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16 324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12–13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.
PMCID: PMC3153310  PMID: 21676895
24.  Age as a modulator of inflammatory cardiovascular risk factors 
Levels of acute phase reactants are impacted by age. To what extent cardiovascular risk associated with aging is due to an increase in the inflammatory burden is not known. We assessed the relationship with age of inflammatory markers, representing a) systemic (C-reactive protein [CRP], fibrinogen and serum amyloid-A [SAA]) and b) vascular (lipoprotein-associated phospholipase A2 [Lp-PLA2] and pentraxin-3 [PTX-3]) inflammation.
Methods and Results
We determined Lp-PLA2 mass and activity, CRP, fibrinogen, SAA, and PTX-3 levels and other CVD risk factors in 336 Caucasians and 224 African Americans. Levels of systemic inflammatory markers increased significantly with age in both ethnic groups (P<0.05 for all), while trend patterns of vascular inflammatory markers did not change significantly with age for either group. In multivariate regression models adjusting for confounding variables, age remained independently associated with a composite z-score for systemic, but not vascular inflammation (β=0.250, P<0.001 and (β=0.276, P<0.001, for Caucasians and African Americans respectively).
We report an increase in the systemic, but not vascular, inflammatory burden over age. Levels of both categories of inflammatory markers over age were similar across ethnicity after adjustment for confounders. Our results underscore the importance of age in evaluating inflammatory markers to assess cardiovascular risk.
PMCID: PMC3158295  PMID: 21700927
Inflammation; aging; cardiovascular disease; epidemiology
25.  A Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension: ASA-STAT 
Circulation  2011;123(25):2985-2993.
Pulmonary arterial hypertension (PAH) is a progressive disease which causes exercise limitation, heart failure, and death. We aimed to determine the safety and efficacy of aspirin and simvastatin in PAH.
Methods and Results
We performed a randomized, double-blind, placebo-controlled 2 × 2 factorial clinical trial of aspirin and simvastatin in patients with PAH receiving background therapy at four centers. A total of 92 patients with PAH were to be randomized to aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo. The primary outcome was six-minute walk distance (6MWD) at six months. Sixty-five subjects were randomized when the trial was terminated by the DSMB after an interim analysis showed futility in reaching the primary end point for simvastatin. After adjustment for baseline 6MWD, there was no significant difference in the 6MWD at six months between aspirin (n = 32) and placebo (n = 33) [placebo-corrected difference = −0.5 m (95%CI, −28.4 – 27.4 m), p = 0.97] or between simvastatin (n = 32) and placebo (n = 33) [placebo-corrected difference = −27.6 m (95%CI, −59.6 – 4.3 m), p = 0.09]. There tended to be more major bleeding episodes with aspirin compared to placebo (4 events vs. 1 event, respectively, p = 0.17).
Neither aspirin nor simvastatin had a significant effect on the 6MWD, although patients randomized to simvastatin tended to have a lower 6MWD at six months. These results do not support the routine treatment of patients with PAH with these medications.
PMCID: PMC3427737  PMID: 21593252
pulmonary hypertension; clinical trial; anti-platelet agents; endothelial dysfunction

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