[Show abstract][Hide abstract] ABSTRACT: Increased chronic immune activation and inflammation are hallmarks of HIV/SIV infection and are highly correlated with progression to AIDS and development of non-AIDS comorbidities, such as hypercoagulability and cardiovascular disease. Intestinal dysfunction resulting in microbial translocation has been proposed as a lead cause of systemic immune activation and hypercoagulability in HIV/SIV infection. Our goal was to assess the biological and clinical impact of a therapeutic strategy designed to reduce microbial translocation through reduction of the microbial content of the intestine (Rifaximin-RFX) and of gut inflammation (Sulfasalazine-SFZ). RFX is an intraluminal antibiotic that was successfully used in patients with hepatic encephalopathy. SFZ is an antiinflammatory drug successfully used in patients with mild to moderate inflammatory bowel disease. Both these clinical conditions are associated with increased microbial translocation, similar to HIV-infected patients. Treatment was administered for 90 days to five acutely SIV-infected pigtailed macaques (PTMs) starting at the time of infection; seven untreated SIVsab-infected PTMs were used as controls. RFX+SFZ were also administered for 90 days to three chronically SIVsab-infected PTMs. RFX+SFZ administration during acute SIVsab infection of PTMs resulted in: significantly lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4+ T cells and significantly lower levels of hypercoagulation biomarkers. This effect was clear during the first 40 days of treatment and was lost during the last stages of treatment. Administration of RFX+SFZ to chronically SIVsab-infected PTMs had no discernible effect on infection. Our data thus indicate that early RFX+SFZ administration transiently improves the natural history of acute and postacute SIV infection, but has no effect during chronic infection.
[Show abstract][Hide abstract] ABSTRACT: Studies associating coagulopathic changes with burn injury have relied on limited tests such as PTT and INR. Understanding the clotting dynamics and associated risk factors following burn injury could influence management. This work aimed to identify real time changes in coagulation following burn injury not indicated by PTT or INR alone.
[Show abstract][Hide abstract] ABSTRACT: Whether circulating biomarker levels increase shortly before an ischemic heart disease (IHD) event is unknown. We studied whether levels of D-dimer, C-reactive protein (CRP), and serum amyloid A (SAA) are higher within 2 months of an IHD event compared to time periods more than 2 months before the IHD event. We assembled 595 participants with peripheral artery disease (PAD) and followed them for up to 3 years. Blood samples were obtained every 2 months. The primary outcome was IHD events: myocardial infarctions, unstable angina, or IHD death. We used a nested case-control design. Fifty participants (cases) had events and were each matched by age, sex, duration in the study, and number of blood draws to two controls without events. Among cases, the mean D-dimer value of 1.105 obtained within 2 months of the event was higher than values obtained 10 months (0.68 mg/L, p<0.001), 12 months (0.71 mg/L, p=0.001), 16 months (0.65 mg/L, p=0.008), 20 months (p=0.032), 22 months (p=0.033), 26 months (p=0.038), and 32 months (p=0.04) before the event. Compared to controls, median D-dimer levels in cases were higher 4 months (p=0.017), 6 months (p=0.005), and 8 months (p=0.028) before the event. Values of CRP and SAA obtained within two months of an IHD event not consistently higher than values obtained during the prior months. In PAD participants with an IHD event, D-dimer was higher within 2 months of the event, compared to most values obtained 10 to 32 months previously. D-dimer was also higher in cases as compared to controls during most visits within 8 months of the IHD event.
No preview · Article · Dec 2015 · Vascular Medicine
[Show abstract][Hide abstract] ABSTRACT: Objective:
We sought to evaluate the cardiovascular impact of coding variants in the apolipoprotein L1 gene APOL1 that protect against trypanosome infection but have been associated with kidney disease among African Americans.
Approach and results:
As part of the Cardiovascular Health Study, a population-based cohort of Americans aged ≥65 years, we genotyped APOL1 polymorphisms rs73885319 and rs71785153 and examined kidney function, subclinical atherosclerosis, and incident cardiovascular disease and death over 13 years of follow-up among 91 African Americans with 2 risk alleles, 707 other African Americans, and 4964 white participants. The high-risk genotype with 2 risk alleles was associated with 2-fold higher levels of albuminuria and lower ankle-brachial indices but similar carotid intima-media thickness among African Americans. Median survival among high-risk African Americans was 9.9 years (95% confidence interval [CI], 8.7-11.9), compared with 13.6 years (95% CI, 12.5-14.3) among other African Americans and 13.3 years (95% CI, 13.0-13.6) among whites (P=0.03). The high-risk genotype was also associated with increased risk for incident myocardial infarction (adjusted hazard ratio 1.8; 95% CI, 1.1-3.0) and mortality (adjusted hazard ratio 1.3; 95% CI 1.0-1.7). Albuminuria and risk for myocardial infarction and mortality were nearly identical between African Americans with 0 to 1 risk alleles and whites.
APOL1 genotype is associated with albuminuria, subclinical atherosclerosis, incident myocardial infarction, and mortality in older African Americans. African Americans without 2 risk alleles do not differ significantly in risk of myocardial infarction or mortality from whites. APOL1 trypanolytic variants may account for a substantial proportion of the excess risk of chronic disease in African Americans.
No preview · Article · Dec 2015 · Arteriosclerosis Thrombosis and Vascular Biology
[Show abstract][Hide abstract] ABSTRACT: High-sensitivity C-reactive protein (hs-CRP) has been associated with coronary heart disease (CHD) in numerous but not all
observational studies, and whether low levels of low-density lipoprotein cholesterol (LDL-C) alter this association is unknown.
In the Multi-Ethnic Study of Atherosclerosis (2000–2012), we prospectively assessed the association of hs-CRP concentrations
with incident CHD in participants who did not receive lipid-lowering therapy, as well as in those with LDL-C concentrations
less than 130 mg/dL (n = 3,106) and those with LDL-C concentrations of 130 mg/dL or greater (n = 1,716) at baseline (2000–2002). Cox proportional hazard analyses were used to assess the associations after adjustment
for socioeconomic status, traditional risk factors, body mass index, diabetes, aspirin use, kidney function, and coronary
artery calcium score. Loge hs-CRP was associated with incident CHD in participants with LDL-C concentrations of 130 mg/dL or higher (hazard ratio (HR)
= 1.29, 95% confidence interval (CI): 1.05, 1.60) but not in those with LDL-C concentrations less than 130 mg/dL (HR = 0.88,
95% CI: 0.74, 1.05; P for interaction = 0.003). As a whole, loge hs-CRP was not associated with incident CHD in participants who had not received lipid-lowering therapy at baseline (HR =
1.05, 95% CI: 0.92, 1.20) and who had mean LDL-C concentrations less than 130 mg/dL. These findings suggest that LDL-C concentrations
might be a moderator of the contribution of hs-CRP to CHD.
No preview · Article · Nov 2015 · American Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration.
These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage
of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000
Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on
the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified
41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals
on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent
signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
Full-text · Article · Nov 2015 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Rationale:
Pulmonary arterial hypertension (PAH) is a rare progressive disease of the pulmonary vasculature that is characterized by endothelial dysfunction, inflammation and right ventricular dysfunction.
The main objective was to determine whether endothelial, inflammatory, and cardiac biomarkers would be associated with the World Health Organization (WHO) functional assessment and survival in patients with PAH.
We performed a retrospective cohort study of PAH patients enrolled in the clinical trial ASA-STAT. Biomarkers (N-terminal fragment of pro-BNP (NT-pro-BNP), von Willebrand factor (vWF), soluble P-selectin, C-reactive protein, total and HDL cholesterol, triglycerides, tumor necrosis factor, interleukin-6, beta-thromboglobulin and thromboxane B2) were measured at baseline. Patients from the study were followed until lung transplantation, death, or August 1, 2013. Ordinal logistic regression and Cox regression analyses were performed.
Measurements and main results:
Sixty-five PAH patients were enrolled. The mean age was 51 years and 86% were female. Higher vWF activity, lower high-density lipoprotein cholesterol and higher thromboxane B2 levels were associated with worse WHO functional class after adjustment for age, sex and etiology of PAH. Higher NT-pro-BNP levels, lower vWF activity, and lower total cholesterol were associated with an increased risk of death or lung transplant after adjustment for age, sex, etiology of PAH and 6-minute walk distance.
In patients with PAH, lower vWF activity and cholesterol levels and higher NT-pro-BNP levels at baseline were associated with an increased risk of death or transplantation. Clinical Trial registered with ClinicalTrials.gov (NCT00384865) Primary Source of Funding: The study was funded by National Institutes of Health (NIH) grants R01HL082895 and R01HL082895-S1 and K24HL103844.
No preview · Article · Oct 2015 · Annals of the American Thoracic Society
[Show abstract][Hide abstract] ABSTRACT: Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.
Full-text · Article · Oct 2015 · Nature Communications
[Show abstract][Hide abstract] ABSTRACT: Objective:
Distinct lymphocyte subpopulations have been implicated in the regulation of glucose homeostasis and obesity-associated inflammation in mouse models of insulin resistance. Information on the relationships of lymphocyte subpopulations with type 2 diabetes remain limited in human population-based cohort studies.
Circulating levels of innate (γδ T, natural killer (NK)) and adaptive immune (CD4+ naive, CD4+ memory, Th1, and Th2) lymphocyte subpopulations were measured by flow cytometry in the peripheral blood of 929 free-living participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Cross-sectional relationships of lymphocyte subpopulations with type 2 diabetes (n = 154) and fasting glucose and insulin concentrations were evaluated by generalized linear models.
Each standard deviation (SD) higher CD4+ memory cells was associated with a 21% higher odds of type 2 diabetes (95% CI: 1-47%) and each SD higher naive cells was associated with a 22% lower odds (95% CI: 4-36%) (adjusted for age, gender, race/ethnicity, and BMI). Among participants not using diabetes medication, higher memory and lower naive CD4+ cells were associated with higher fasting glucose concentrations (p<0.05, adjusted for age, sex, and race/ethnicity). There were no associations of γδ T, NK, Th1, or Th2 cells with type 2 diabetes, glucose, or insulin.
A higher degree of chronic adaptive immune activation, reflected by higher memory and lower naive CD4+ cells, was positively associated with type 2 diabetes. These results are consistent with a role of chronic immune activation and exhaustion augmenting chronic inflammatory diseases, and support the importance of prospective studies evaluating adaptive immune activation and type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: Production of very low-density lipoprotein (VLDL) is increased in states of metabolic syndrome, leading to hypertriglyceridemia. However, metabolic syndrome is often associated with non-alcoholic fatty liver disease, which leads to liver fibrosis and inflammation that may decrease VLDL production. In this study, we aim to determine the interactive impact on VLDL profiles from insulin resistance, impairment in liver synthetic function and inflammation.
[Show abstract][Hide abstract] ABSTRACT: Objective:
We evaluated whether metabolic syndrome (MetS) is associated with an increased incidence of lower extremity peripheral artery disease (PAD) in community dwelling people free of clinical cardiovascular disease at baseline. We assessed whether higher levels of inflammatory biomarkers may mediate the association of MetS with incident PAD.
MetS was defined at baseline as the presence of three or more of the following components: elevated waist circumference, triglycerides ≥150 mg/dL, reduced high-density lipoprotein (HDL) cholesterol, blood pressure ≥130/85 mm Hg or taking blood pressure medication, and fasting glucose ≥100 mg/dL and <126 mg/dL. People with diabetes were excluded. Incident New PAD was defined among people with a normal ankle brachial index (ABI) at baseline (i.e. baseline ABI of 0.90 to 1.40) and consisted of one of the following outcomes during 3-year follow-up: ABI decline to < 0.90 combined with a decline ≥0.15 or medical record confirmed PAD outcome. Multivariable Poisson regression was used to estimate the association between MetS and incident PAD.
Among 4817 participants without PAD at baseline, 1382 (29%) had MetS. Adjusting for age, sex, race, smoking, physical activity, low-density lipoprotein cholesterol, baseline ABI, and other confounders, 23/1382 (1.7%) people with MetS developed PAD vs. 30/3435 (0.87%) people without MetS (risk ratio = 1.78 [95% Confidence Interval (CI), 1.04 to 2.82], P = 0.031). Adjusting for C-reactive protein, fibrinogen, or interleukin-6 did not attenuate this association.
People free of clinical cardiovascular disease with MetS are at increased risk for PAD. Our findings suggest that this association is not mediated by inflammation.
[Show abstract][Hide abstract] ABSTRACT: Background:
High-density lipoprotein (HDL) particles have properties beyond reverse cholesterol transport. We hypothesized that their protection extends to inflammation-related disease. The predictive value of HDL particle subclasses and inflammatory markers was studied for noncardiovascular, noncancer chronic inflammation-related death and hospitalization, and for incident cardiovascular disease (CVD).
Methods and results:
A multiethnic, multicenter, prospective observational study was conducted in 6475 men and women (aged 45 to 84 years) free of known CVD at baseline with median follow-up of 10.1 years. Fasting venous samples were analyzed for baseline lipid profile and lipoprotein particles. We focused on the HDL family of variables (small-, medium-, and large-diameter HDL particles and HDL cholesterol). Analyses identified the sum of small- plus medium-diameter HDL particles as important. Small- plus medium-diameter HDL particles were inversely associated with diagnostic code-based noncardiovascular, noncancer chronic inflammation-related death and hospitalization (n=1054) independent of covariates: relative risk per SD 0.85 (95% CI: 0.79 to 0.91, P<0.0001). Small- plus medium-diameter HDL particles were also associated with adjudicated fatal and nonfatal coronary heart disease events (n=423): relative risk per SD 0.88 (95% CI 0.77 to 0.98, P=0.02).
Small- plus medium-diameter HDL particles are an independent predictor for noncardiovascular, noncancer chronic inflammation-related death and hospitalization and for coronary heart disease events in subjects initially free of overt CVD. These findings support the hypothesis that smaller HDL particles of diameter <9.4 nm have anti-inflammatory properties in the general population.
Preview · Article · Sep 2015 · Journal of the American Heart Association
[Show abstract][Hide abstract] ABSTRACT: Background:
HIV infection and associated immune activation predict risk of cardiovascular disease (CVD) in resource-rich areas. Less is known about these relationships in sub-Saharan Africa.
Beginning in 2005, we enrolled subjects in southwestern Uganda into a cohort at anti-retroviral therapy (ART) initiation. Multiple immune activation measures were assessed pre-ART and 6 months after ART initiation. Beginning in 2013, participants over 40 years underwent metabolic profiling including hemoglobin A1c, lipids, and carotid ultrasonography. We fit regression models to identify traditional and HIV-specific correlates of common carotid intima media thickness (CCIMT).
105 participants completed carotid ultrasonography, a median of 7 years following ART initiation. Age, low-density lipoprotein and pre-ART viral load were correlated with CCIMT. No association was found between CCIMT and any pre-ART biomarkers of immune activation. However, in multivariable models adjusted for CVD risk factors, lower absolute levels of sCD14 and IL-6 and greater declines in CD14 and kynurenine-tryptophan ratio after 6 months of ART predicted lower CCIMT years later (P<0.01).
Persistent immune activation despite ART-mediated viral suppression predicts future atherosclerotic burden among HIV-infected Ugandans. Future work should focus on clinical correlates of these relationships to elucidate the long-term health priorities for HIV-infected people in the region.
No preview · Article · Sep 2015 · The Journal of Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Objective
Obesity is associated with changes in both right (RV) and left (LV) ventricular morphology, but the biological basis of this finding is not well established. We examined whether adipokine levels were associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease.
We examined relationships of leptin, resistin, TNF-α, and adiponectin with RV morphology and function (from cardiac MRI) in participants (n = 1,267) free of clinical cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of each adipokine with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF).
Higher leptin levels were associated with significantly lower levels of RV mass, RVEDV, RVESV and stroke volume, but not RVEF, after adjustment for age, gender, race, height and weight. These associations were somewhat attenuated but still significant after adjustment for traditional risk factors and covariates, and were completely attenuated when correcting for the respective LV measures. There were no significant interactions of age, gender, or race/ethnicity on the relationship between the four adipokines and RV structure or function.
Leptin levels are associated with favorable RV morphology in a multi-ethnic population free of cardiovascular disease, however these associations may be explained by a yet to be understood bi-ventricular process as this association was no longer present after adjustment for LV values. These findings complement the associations previously shown between adipokines and LV structure and function in both healthy and diseased patients. The mechanisms linking adipokines to healthy cardiovascular function require further investigation.
[Show abstract][Hide abstract] ABSTRACT: Background N-terminal-pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (TnT) predict cardiovascular disease (CVD) risk in a variety of populations. Whether their predictive value varies by ethnicity is unknown. We sought to determine whether NT-proBNP and TnT improve prediction of incident coronary heart disease (CHD) and CVD, independent of CVD risk factors, in a multiethnic population; whether NT-proBNP improves prediction compared with the Framingham Risk Score or the Pooled Cohort Risk Equation; and whether a second NT-proBNP further improves prediction. Methods Both NT-proBNP and TnT were measured in 5,592 MESA white, black, Hispanic, and Chinese participants (60% nonwhite; mean age 62.3 ± 10.3 years) in 2000 to 2002 and 2004 to 2005. We evaluated adjusted risk of incident CHD and CVD based on baseline and change in biomarker concentration. Results Participants were followed up through 2011 and incurred 370 CVD events (232 CHD). Concentrations of NT-proBNP and TnT varied by ethnicity. Both NT-proBNP and TnT were associated with an increased risk of events (adjusted hazard ratio [HR] for CHD [95% CI] for fifth quintile vs other 4 quintiles of NT-proBNP, 2.03 [1.50-2.76]; HR for CHD for detectable vs undetectable TnT, 3.95 [2.29-6.81]). N-terminal-pro-B-type natriuretic peptide improved risk prediction and classification compared with the Framingham Risk Score and the Pooled Cohort Risk Equation. Change in NT-proBNP was independently associated with events (HR for CHD per unit increase in ΔlogNT-proBNP, 1.95 [1.16-3.26]). None of the observed associations varied by ethnicity. Conclusions Both NT-proBNP and TnT are predictors of incident CHD, independent of established risk factors and ethnicity, in a multiethnic population without known CVD. Change in NT-proBNP may add additional prognostic information.
[Show abstract][Hide abstract] ABSTRACT: Background and aims:
Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification).
Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993.
Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele (P < 0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70-1.00) for rs2248690 and 0.97 (95% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048).
Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.