To examine the relation of fatty acid–binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults.
RESEARCH DESIGN AND METHODS
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.
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.
Free Fatty Acids; Atrial Fibrillation; Risk Factors; Epidemiology
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.
atherosclerosis; epidemiology; immunology; inflammation; T‐helper cell
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.
PAI-1; US; Japan; epidemiology; post-war generation
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.
SYSTEMIC LUPUS ERYTHEMATOSUS; CARDIOVASCULAR DISEASE; DEPRESSION CALCIFICATION; CAROTID PLAQUE; PSYCHOSOCIAL FACTORS
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.
Amyloid; blood pressure; brain; aging; dementia
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.
epidemiology; sudden death; fatty acid binding protein 4; risk factors
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.
children; adiposity; E-selectin; sICAM; sVAM
To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults.
RESEARCH DESIGN AND METHODS
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.
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.
HIV infection; inflammation; HAART; abacavir; cytokines
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: http://www.chs-nhlbi.org. Unique Identifier: NCT00005133.
biomarkers; collagen; elderly; heart failure; outcomes
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.
cardiovascular diseases; creatinine; cystatin C; risk model
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.
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.
Inflammation; aging; cardiovascular disease; epidemiology
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.
pulmonary hypertension; clinical trial; anti-platelet agents; endothelial dysfunction
The lifetime risks of cardiovascular disease have not been reported across the age spectrum in black adults and white adults.
We conducted a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black men and women and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Blood pressure, cholesterol level, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event.
We observed marked differences in the lifetime risks of cardiovascular disease across risk-factor strata. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level, <180 mg per deciliter [4.7 mmol per liter]; blood pressure, <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking status; and nondiabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7% vs. 29.6% among men, 6.4% vs. 20.5% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs. 37.5% among men, <1% vs. 18.3% among women) and fatal or nonfatal stroke (2.3% vs. 8.3% among men, 5.3% vs. 10.7% among women). Similar trends within risk-factor strata were observed among blacks and whites and across diverse birth cohorts.
Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. (Funded by the National Heart, Lung, and Blood Institute.)
Plasminogen activator inhibitor-1 (PAI-1) production by adipose tissue is increased in obesity and its circulating levels are high in type 2 diabetes. PAI-1 increases cardiovascular risk by favoring clot stability and/or interfering with vascular remodeling. We investigated in obese diabetic persons whether an intensive lifestyle intervention for weight loss (ILI) would decrease PAI-1 levels independently of weight loss and whether PAI-1 reduction would be associated with changes in fibrinogen, an acute phase reactant, and/or fibrin fragment D-dimer (D-dimer), a marker of ambient coagulation balance.
Methods and Results
We examined 1-year changes in PAI-1, D-dimer and fibrinogen levels, adiposity, fitness, glucose and lipid control with ILI in 1,817 participants from Look AHEAD, a randomized trial investigating the effects of ILI, compared to usual care, on cardiovascular events in overweight/obese diabetic persons. Median PAI-1 levels decreased 29% with ILI, 2.5% with usual care (p<0.0001). Improvements in fitness, glucose control and HDL-cholesterol were associated with decreased PAI-1, independently of weight loss (p=0.03 for fitness, p<0.0001 for others). Fibrinogen and D-dimer remained unchanged.
Reductions in PAI-1 levels with ILI in obese diabetic individuals may reflect an improvement in adipose tissue health that could impact cardiovascular risk without changing fibrinogen or D-dimer levels.
HIV infection is associated with premature development of cardiovascular disease (CVD). Understanding the effects of HIV replication on endothelial dysfunction and platelet activation may identify treatment targets to reduce CVD risk.
A subgroup of HIV-infected participants in the Strategies for Management of Antiretroviral Therapy (SMART) study off antiretroviral therapy (ART) at entry enabled a randomized comparison of immediate versus deferred ART initiation of changes in asymmetric dimethylarginine (ADMA), soluble CD40L and P-selectin levels.
At study entry, median (IQR) levels of ADMA, sCD40L, and P-selectin were 0.57 (0.49-0.66) μg/mL, 251 (135-696) μmol/L, and 34 (28-44) pg/mL. Compared to those randomized to deferral of ART (n=114), participants randomized to immediate ART (n=134) had 10.3% lower ADMA levels (p=0.003) at 12 months; treatment differences in sCD40L (95% CI:-17 to 44%; p=0.53) and P-selectin (95% CI:-10 to 10%; p=0.95) were not significant. The difference in ADMA for those assigned immediate ART compared to those assigned ART deferral was greater among younger patients and those with higher levels of hsCRP and D-dimer (p≤0.05 for interaction for both), but not HIV RNA level at baseline (p=0.51).
ART initiation leads to declines in ADMA levels, a marker of nitric-oxide-mediated endothelial dysfunction. Improvement in ADMA levels was related to the degree of inflammation and coagulation, suggesting that up-regulation of these pathways contributes to premature vascular disease among individuals with HIV infection. Whether declines in ADMA levels impact risk of disease requires further research.
HIV infection; antiretroviral therapy; inflammation; endothelial dysfunction; asymmetric dimethylarginine (ADMA); CD40 ligand; P-selectin
Background. Elevated immune activation persists during treated human immunodeficiency virus (HIV) infection and is associated with blunted CD4 recovery and premature mortality, but its causes remain incompletely characterized. We hypothesized that asymptomatic cytomegalovirus (CMV) replication might contribute to immune activation in this setting.
Methods. Thirty antiretroviral therapy–treated HIV-infected CMV-seropositive participants with CD4 counts <350 cells/mm3 were randomized to receive valganciclovir 900 mg daily or placebo for 8 weeks, followed by an additional 4-week observation period. The primary outcome was the week 8 change in percentage of activated (CD38+ HLA-DR+) CD8+ T cells.
Results. Fourteen participants were randomized to valganciclovir and 16 to placebo. Most participants (21 [70%] of 30) had plasma HIV RNA levels <75 copies/mL. The median CD4 count was 190 (IQR: 134–232) cells/mm3, and 12 (40%) of 30 had detectable CMV DNA in saliva, plasma, or semen at baseline. CMV DNA continued to be detectable at weeks 4–12 in 7 (44%) of 16 placebo-treated participants, but in none of the valganciclovir-treated participants (P = .007). Valganciclovir-treated participants had significantly greater reductions in CD8 activation at weeks 8 (P = .03) and 12 (P = .02) than did placebo-treated participants. These trends were significant even among those with undetectable plasma HIV RNA levels.
Conclusions. CMV (and/or other herpesvirus) replication is a significant cause of immune activation in HIV-infected individuals with incomplete antiretroviral therapy–mediated CD4+ T cell recovery.
Clinical Trials Registration. NCT00264290.
Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent.
We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992–1993 and survived through 1997–1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews.
A total of 468 (41.2%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4% female, and 14.8% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95% confidence interval: 1.22–2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95% confidence interval: 1.32–5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95% confidence interval: 0.95–3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant.
These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.
Telomere; Mortality; Cause of death; Cardiovascular disease; Heart failure
The pleiotropic cytokine, interleukin-6 (IL-6), has emerged as a key factor in the biology of aging and the physiology of inflammation. Yet much of what we know about the normal functioning of IL-6 has been generated primarily from research on European populations and Americans of European descent. Our analyses compared IL-6 levels in 382 middle-aged and older Japanese to the values found in 1209 Caucasian- and African-Americans from the Midlife in the United States survey (MIDUS). Across the life span from 30–80 years of age, mean IL-6 levels were strikingly lower in Japanese individuals. Significantly lower levels of C-reactive protein (CRP) and fibrinogen (FBG) provided confirmatory evidence for a population difference in proinflammatory activity. Because IL-6 release has been associated with obesity, differences in body mass index (BMI) were taken into consideration. Japanese had the lowest, and African-Americans had the highest overall BMIs, but significant group differences in IL-6 persisted even after BMI was included as a covariate in the analyses. Additional support for distinct variation in IL-6 biology was generated when systemic levels of the soluble receptor for IL-6 (sIL-6r) were evaluated. Serum sIL-6r was higher in Japanese than Americans, but was most notably low in African-Americans. Our cytokine data concur with national differences in the prevalence of age-related illnesses linked to inflammatory physiology, including cardiovascular disease. The findings also highlight the importance of broadening the diversity of people included in population studies of health and aging, especially given the relative paucity of information for some Asian countries and on individuals of Asian heritage living in the US.
interleukin-6; soluble interleukin-6 receptor; aging; inflammation; Japanese; African-American; race; C-reactive protein; fibrinogen; body mass index; obesity
Because obstructive sleep apnea (OSA) is associated with increased levels of inflammatory cytokines, we examined the relationship between OSA and polymorphisms for interleukin-6 (IL-6).
6 single nucleotide polymorphisms (SNPs) within IL-6 were genotyped in 259 African-Americans from the Cleveland Family Study with replication conducted in the Cardiovascular Health Study (n=124). OSA was dichotomized into apnea hypopnea index (AHI)>15 or on treatment vs. absent: AHI<5. Logistic regression was conducted, adjusting for age and sex in models with and without body mass index (BMI).
SNP IL6-6021 was associated with a decreased risk of OSA after adjusting for BMI (Odds Ratio for T allele 0.24; 95%CI [0.09–0.67]; p=0.006; q=0.07) under an additive model. This same allele was associated with increased BMI. The results from the replication sample were consistent in direction though not statistically significant (p=0.23). The SNPs were studied in European-Americans, although the minor allele frequency in IL6-6021 was too low (4%) for meaningful comparisons.
A synonymous SNP within the IL-6 coding region was protective of OSA in African-Americans; with qualitatively similar findings observed in another cohort. This suggests that variants in IL-6 may influence the risk of OSA in a pathway that is not explained by obesity.
We examined whether a 1-year intensive lifestyle intervention (ILI) for weight loss reduced elevated high-sensitivity C-reactive protein (hs-CRP) levels in obese individuals with diabetes and identified metabolic and fitness predictors of hs-CRP change.
RESEARCH DESIGN AND METHODS
Look AHEAD (Action for Health in Diabetes) is an ongoing multicenter clinical trial examining the effects of weight loss achieved through ILI on cardiovascular events and overall mortality in obese/overweight adults with type 2 diabetes. We report on 1,759 Look AHEAD participants who had hs-CRP and fitness data at baseline and 1 year. Subjects were randomly assigned to ILI or to usual care (diabetes support and education [DSE]). ILI involved frequent counseling to increase moderate-intensity exercise to 175 min/week, reduce caloric and saturated fat intake, and change macronutrient composition to improve glycemic control.
ILI reduced median hs-CRP by 43.6% from baseline to 1 year, compared with a 16.7% reduction with DSE (P < 0.001). ILI decreased weight (8.8%), A1C (0.7%), and triglycerides (17%) and increased fitness (19%) and HDL cholesterol (7.5%) (P < 0.0001 vs. changes with DSE). Changes in adiposity and glucose control with ILI remained independent predictors of hs-CRP change at 1 year (P < 0.0001 for each) after adjustment for demographics, smoking, cardiovascular history, statin and thiazolidinedione use, and changes in fitness and lipid control. Neither statin nor insulin therapy modified the association between ILI and hs-CRP.
A 1-year lifestyle intervention for weight loss in obese individuals with diabetes was associated with substantial reductions in hs-CRP. Improved glycemic control and reduced adiposity had comparable effects on hs-CRP change.
Rationale: Individuals with sleep-disordered breathing (SDB) are at increased cardiovascular risk, possibly due to SDB-related stresses contributing to atherosclerosis.
Objectives: We postulate that pathways associated with a prothrombotic potential are up-regulated in SDB.
Methods: Morning and evening plasminogen activator inhibitor-1 (PAI-1), morning fibrinogen, and morning D-dimer were measured in 537 Cleveland Family Study adults. Piecewise multivariable linear mixed models estimated relative mean change or mean change in the biomarker per 5-unit increase in apnea-hypopnea index (AHI) in two groups: AHI less than 15 and AHI greater than or equal to 15, and hypoxia defined as percentage of sleep time with SaO2 less than 90% (< 2%, ≥ 2%).
Measurements and Main Results: Nonlinear associations were demonstrated: morning and evening PAI-1 increased by 12% (95% confidence interval [CI], 5–20%; P < 0.001) and 11% (95% CI, 2–20%; P = 0.01), respectively per 5-unit AHI increase until an AHI of 15, when no further increase in PAI-1 was demonstrated. The association between AHI and morning PAI-1 remained significant after adjusting for evening PAI-1 level (10%; 95% CI, 3–17%; P < 0.01). Morning fibrinogen increased on average by 8.4 mg/dl (95% CI, 3.12–13.65; P = 0.002) per five-unit AHI increase until an AHI of 15. There was no association between AHI and morning D-dimer. Hypoxia severity was not associated with thrombotic marker levels.
Conclusions: PAI-1 and fibrinogen levels increase monotonically with AHI at degrees of SDB considered mildly to moderately abnormal, suggesting that even mild SDB levels may increase prothrombotic processes. There may be a plateau in this effect, occurring at levels considered to reflect only moderate SDB severity. These relationships with mild-to-moderate SDB were not observed with D-dimer.
sleep apnea; thrombosis; cardiovascular disease
P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 × 10−61) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 × 10−23). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 × 10−41 and rs649129, P = 1.22 × 10−15, respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.