Prospective studies have identified chronic inflammation as a risk factor for type 2 diabetes. However, it is not known whether infection by specific pathogens or having a greater “pathogen burden” is associated with diabetes. The aim of this study was to examine the cross-sectional relation of seropositivity to five pathogens (C. pneumoniae, cytomegalovirus, H. pylori, hepatitis A virus, herpes simplex virus) and prevalent diabetes.
Baseline data from a random sample of MultiEthnic Study of Atherosclerosis (MESA) participants (n=1,000; age: 45-84) were used. Diabetes was defined by ADA 2003 criteria, and “pathogen burden” by the number of pathogens (0–5) for which an individual was seropositive. Logistic regression was used to test differences in diabetes prevalence by seropositivity. Linear regression was used to explore associations between pathogen seropositivity and the inflammation markers CRP, IL-6, and fibrinogen.
Diabetes prevalence was 12.7%, while seropositivity for C. pnuemoniae was 76%, cytomegalovirus 77%, H. pylori 45%, hepatitis A 58%, and herpes simplex virus 85%. 72% were seropositive for ≥3 pathogens. In crude analyses, the prevalence of diabetes was higher among those with a pathogen burden ≥3, and with seropositivity to cytomegalovirus, H. pylori, hepatitis A, and herpes simplex virus. After adjustment for demographic covariates (particularly race) all associations became nonsignificant. Pathogen seropositivity was also not related to inflammation marker levels.
Following demographic adjustments, no associations were observed between infection by several pathogens and diabetes status, suggesting no etiologic role for them in the occurrence of diabetes.
diabetes; infection; pathogen; seropositivity
Data accumulated from mouse studies and in vitro studies of human arteries support the notion that soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play important roles in the inflammation process involved in atherosclerosis. However, at the population level, the utility of sICAM-1 and MCP-1 as biomarkers for subclinical atherosclerosis is less clear. In the follow-up exam of the NHLBI Family Heart Study, we evaluated whether plasma levels of sICAM-1 and MCP-1 were associated with coronary artery calcification (CAC), a measure of the burden of coronary atherosclerosis.
CAC was measured using the Agatston score with multidetector computed tomography. Information on CAC and MCP-1 was obtained in 2246 whites and 470 African Americans (mean age 55 years) without a history of coronary heart disease (CHD). Information on sICAM-1 was obtained for white participants only.
In whites, after adjustment for age and gender, the odds ratios (ORs) of CAC (CAC > 0) associated with the second, third, fourth, and fifth quintiles of sICAM-1 compared to the first quintile were 1.22 (95% confidence interval [CI]: 0.91–1.63), 1.15 (0.84–1.58), 1.49 (1.09–2.05), and 1.72 (1.26–2.36) (p = 0.0005 for trend test), respectively. The corresponding ORs for the second to fifth quintiles of MCP-1 were 1.26 (0.92–1.73), 0.99 (0.73–1.34), 1.42 (1.03–1.96), and 2.00 (1.43–2.79) (p < 0.0001 for trend test), respectively. In multivariable analysis that additionally adjusted for other CHD risk factors, the association of CAC with sICAM-1 and MCP-1 was attenuated and no longer statistically significant. In African Americans, the age and gender-adjusted ORs of CAC associated with the second and third tertiles of MCP-1 compared to the first tertile were 1.16 (0.64–2.08) and 1.25 (0.70–2.23) (p = 0.44 for trend test), respectively. This result did not change materially after additional adjustment for other CHD risk factors. Test of race interaction showed that the magnitude of association between MCP-1 and CAC did not differ significantly between African Americans and whites. Similar results were obtained when CAC ≥ 10 was analyzed as an outcome for both MCP-1 and sICAM-1.
This study suggests that sICAM-1 and MCP-1 are biomarkers of coronary atherosclerotic burden and their association with CAC was mainly driven by established CHD risk factors.
To describe the prevalence of retinal vein occlusion (RVO) and its association with cardiovascular, inflammatory and hematological risk factors in a multi-ethnic cohort.
A population-based, cross-sectional study of 6,147 participants (whites, blacks, Hispanics, Chinese) from 6 U.S. communities. RVO was defined from retinal photographs taken from both eyes according to a standardized protocol. Risk factors were assessed from interviews, examinations, and laboratory and radiological investigations.
The prevalence of RVO was 1.1% (0.9% for branch RVO and 0.2% for central RVO) and was similar across different ethnic groups: 0.9% in whites, 1.2% in blacks, 1.2% in Hispanics and 1.1% in Chinese (p=0.76). Independent risk factors associated with RVO were hypertension (odds ratio [OR] 2.06; 95% confidence interval [CI]: 1.18, 3.59), older age (OR 1.34, 95% CI: 1.00, 1.81, per decade increase), less education (OR 4.08, 95% CI: 2.20, 7.54), hypertriglyceridemia (OR 1.98; 95% CI: 1.10, 3.56), renal dysfunction (OR 1.85; 95% CI: 1.01, 3.39) and the presence of retinal arteriovenous nicking (OR 4.01; 95% CI: 2.06, 7.81) and focal arteriolar narrowing (OR 4.38; 95% CI: 1.44, 13.34). RVO was not significantly associated with direct measures of subclinical atherosclerosis (e.g., carotid intima media thickness and coronary artery calcium scores) or markers of inflammation (e.g., C reactive protein, interleukin-6), and endothelial dysfunction (e.g., soluble intercellular adhesion molecule-1) or coagulation (e.g., D-Dimer).
The prevalence of RVO is similar across different racial/ethnic groups. In the general population, RVO is associated with hypertension, dyslipidemia and renal dysfunction, but not with atherosclerotic disease, systemic inflammation and hematological abnormalities.
Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) may be important contributors to the development and progression of atherosclerosis. Using a stratified random sample of 2,880 participants of the Multi-Ethnic Study of Atherosclerosis we investigated the relationship of 12 ICAM1 and 17 VCAM1 SNPs and coronary artery calcium (CAC) and ICAM1 SNPs and circulating levels of soluble ICAM-1 (sICAM-1). There were no ICAM1 or VCAM1 SNPs significantly associated with CAC in any of the four race/ethnic groups. In a subset of 1,451 subjects with sICAM-1 measurements, we observed a significant association with rs5491 in all four race/ethnic groups corroborating previous research that has shown that the T-allele of rs5491 interferes with the monoclonal antibody used to measure sICAM-1 in this study. After excluding all rs5491 T-allele carriers, several ICAM1 SNPs were significantly associated with sICAM-1 levels; rs5496 in African Americans, rs5498 and rs3093030 in European Americans, and rs1799969 in Hispanics. Our results identified ICAM1 polymorphisms that were significantly associated with sICAM-1 level but not CAC, a subclinical marker of atherosclerosis.
coronary artery calcium; intercellular adhesion molecule-1 (ICAM-1); vascular adhesion molecule-1 (VCAM-1); soluble intercellular adhesion molecule-1 (sICAM-1); gene; single nucleotide polymorphism (SNP); haplotypes
Relationship of hepatitis C virus (HCV) infection with an increased risk of cardiovascular disease (CVD) in HIV-infected patients remains controversial. We evaluated endothelial function and subclinical atherosclerosis in HIV-infected patients with and without HCV.
Flow-mediated dilatation (FMD) of the brachial artery and circulating levels of cell adhesion molecules (CAM) were measured in HCV/HIV-coinfected and HIV-monoinfected patients. Subclinical atherosclerosis was assessed by carotid intima-media thickness (cIMT).
63 (31%) HCV/HIV-coinfected and 138 (69%) HIV-monoinfected patients were included. Median soluble vascular CAM-1 (sVCAM-1) and intercellular CAM-1 (sICAM-1) levels were significantly higher in HIV/HCV-coinfected patients (P < 0.001 for both cases). Median (interquartile range) FMD was 6.21% (2.86-9.62) in HCV/HIV-coinfected and 5.54% (2.13-9.13) in HIV-monoinfected patients (P = 0.37). Adjustment for variables associated with HCV and FMD disclosed similar results. FMD correlated inversely with cIMT and age. Carotid IMT did not differ between HCV/HIV-coinfected and HIV-monoinfected patients in unadjusted (0.61 [0.55-0.65] mm vs 0.60 [0.53-0.72] mm; P = 0.39) or adjusted analyses.
HCV infection was associated with higher levels of sICAM-1 and sVCAM-1, but no evidence of increased subclinical atherosclerosis was found when endothelial function was evaluated through FMD, or when assessing the cIMT.
A cluster of metabolic abnormalities termed metabolic syndrome (MetS) is associated with vascular endothelial dysfunction and oxidative internal milieu. We examined whether the association of MetS with subclinical atherosclerosis is explained by biomarkers of endothelial damage and oxidative stress.
MESA is a population based study of 45-84 year old individuals of four US ethnicities without clinical cardiovascular disease. A random sample of 997 MESA participants had data on the following biomarkers: von Willebrand Factor, soluble intercellular adhesion molecule-1 (sICAM1), CD40 ligand, soluble thrombomodulin, E-selectin, and oxidized LDL (oxLDL). We examined whether the associations of MetS with B-mode ultrasound-defined common and internal carotid intimal medial thickness (IMT) and coronary artery calcium (CAC) measured using computerized tomography were explained by the biomarkers using multiple regression methods.
MetS was associated with higher levels of each of the biomarkers (p<0.001, CD40L suggestive association p=0.004), with greater IMT (p<0.001), and with greater extent of CAC in those in whom CAC was detectable (p=0.01). The association of MetS with measures of subclinical atherosclerosis remained unchanged after adjustment for the biomarkers. After adjusting for MetS, oxLDL was suggestively associated with greater prevalence of detectable CAC (p=0.005) and thicker internal carotid IMT (p=0.002), while sICAM-1was significantly associated with greater prevalence of detectable CAC (p=0.001).
The association of MetS with subclinical atherosclerosis was independent of its association with biomarkers of endothelial damage and oxidative stress, suggesting that metabolic abnormalities and oxidative endothelial damage may lead to atherosclerotic disease through distinct mechanisms.
Metabolic syndrome; biomarkers; coronary artery atherosclerosis; carotid arteries
Adaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4+ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis.
Methods and Findings
We examined cross-sectional relationships of circulating CD4+ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4+ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and H. Pylori titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI)) = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β = 0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)].
These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4+ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by putting a greater burden on the innate immune system, and suggest the importance of prospective studies and research into strategies to modulate adaptive immune activation in chronic disease states such as atherosclerosis.
Endothelial cell-selective adhesion molecule (ESAM) is a junctional-type cellular adhesion molecule (CAM) that is uniquely expressed in vascular endothelium and activated platelets and mediates neutrophil and monocyte diapedesis across the endothelium. Given its role in endothelial pathobiology, we hypothesized that soluble ESAM (sESAM) would be independently associated with atherosclerosis and vascular stiffness.
Methods and Results
We measured sESAM, soluble intercellular adhesion molecule (sICAM)-1 and soluble vascular cell adhesion molecule (sVCAM)-1 in 3222 subjects participating in the Dallas Heart Study, a probability-based population sample. Coronary artery calcium (CAC) was measured by electron beam computed tomography, and abdominal aortic wall thickness (AWT), aortic plaque burden (APB), and aortic compliance (AC) by magnetic resonance imaging (MRI). Increasing levels of sESAM were associated with all major cardiovascular risk factors as well as with inflammatory markers such as monocyte chemoattractant protein-1, but only weakly correlated with sICAM-1 and sVCAM-1. In multivariate analyses, sESAM was independently associated with prevalent CAC (OR 1.2 per SD increase, 95% CI 1.1–1.3; p=0.005), AWT (p=0.035), and AC (p=0.006), but not APB (p=0.15). In contrast, no independent associations were observed between sICAM-1 or sVCAM-1 and any of the atherosclerosis phenotypes.
In this first reported clinical study of sESAM in humans, sESAM levels were independently associated with CAC, AWT, and AC, while sICAM-1 and sVCAM-1 were not. These findings support a unique role of this cellular adhesion molecule in atherosclerosis and suggest the need for further exploration of sESAM as a predictive biomarker and potential mediator of atherosclerosis.
Inflammation; Adhesion molecules; Atherosclerosis; Aortic compliance; Coronary calcium; Biomarkers
The purpose of this study was to assess coronary arterial remodeling as a marker of subclinical atherosclerosis using coronary wall MRI in an asymptomatic population-based cohort.
In early atherosclerosis, compensatory enlargement of both the outer wall of the vessel as well as the lumen, termed compensatory enlargement or positive remodeling, occurs before luminal narrowing.
179 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated using black-blood coronary wall MRI. Coronary cross-sectional area (vessel size), lumen area, and mean wall thickness of the proximal coronary arteries were measured.
Men had a greater vessel size, lumen area, and mean wall thickness than women (38.3±11.3 versus 32.6±9.4 mm2, 6.7±3.2 versus 5.3±2.4 mm2, and 2.0±0.3 versus 1.9±0.3 mm, respectively, p<0.05). No significant coronary artery narrowing was present by magnetic resonance angiography. Overall, coronary vessel size increased 25.9 mm2 per millimeter increase in coronary wall thickness, while lumen area increased only slightly at 3.1 mm2 for every millimeter increase in wall thickness (difference in slopes, p<0.0001). Adjusting for age and gender, participants with Agatston score greater than zero were more likely to have wall thickness greater than 2.0 mm (odds ratio 2.0, 95% CI 1.01–3.84).
Coronary wall MRI detected positive arterial remodeling, in asymptomatic men and women with subclinical atherosclerosis.
subclinical atherosclerosis; magnetic resonance imaging; coronary artery disease; plaque
Vitamin K is integral to haemostatic function, and in vitro and animal experiments suggest that vitamin K can suppress production of inflammatory cytokines. To test the hypothesis that higher vitamin K status is associated with lower hemostatic activation and inflammation in community-dwelling adults, we analyzed the cross-sectional association between serum phylloquinone (vitamin K1) with haemostatic and inflammatory biomarkers in 662 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) [mean(SD) age=62(10)y; 46% female; 37% Caucasian, 25% African-American, 25% Hispanic, 13% Chinese-American]. Following adjustment for demographic and lifestyle characteristics, medication use, triglycerides and BMI, those in the highest quartile of serum phylloquinone had significantly lower circulating interleukin-6 [adjusted mean(SEM) pmol/L: quartile 4 (Q4)=1.22(0.07), quartile 1(Q1)=1.45(0.07); p-trend<0.01], CRP [adjusted mean(SEM) mg/dl: Q4=1.57(0.11), Q1=2.08(0.18); p-trend=0.02], soluble intercellular adhesion molecule-1 [adjusted mean(SEM) ng/ml: Q4=247(11), Q1=288(11); p-trend=0.02], and plasmin-antiplasmin complex [adjusted mean(SEM) nmol/L: Q4=4.02(0.1), Q1=4.31(0.1), p-trend=0.04]. We detected an interaction between age and serum phylloquinone with respect to factor VIII and D-dimer (interaction p-values=0.03 and 0.09 respectively). Among participants ≥70y, serum phylloquinone was inversely associated with factor VIII activity (p-trend=0.06) and positively associated with D-dimer (p-trend=0.01), but was not associated with either marker among participants <70y (both p≥0.38). In contrast, dietary phylloquinone intake was not associated with any inflammatory or haemostatic biomarker evaluated (all p-trend>0.11). These findings are consistent with laboratory-based studies that suggest a possible anti-inflammatory role for vitamin K. Whether or not these associations predict clinical outcomes linked to elevated inflammation or haemostatic activation remains to be determined.
Background: Arsenic exposure is a risk factor for atherosclerosis in adults, but there is little information on arsenic and early risk biomarkers for atherosclerosis in children. Carotid intima-media thickness (cIMT) is an indicator of subclinical atherosclerotic burden that has been associated with plasma asymmetric dimethylarginine (ADMA), a predictor of cardiovascular disease risk.
Objectives: The aim of this study was to investigate associations of arsenic exposure with cIMT, ADMA, and endothelial adhesion molecules [soluble intercellular cell adhesion molecule-1 (sICAM-1); soluble vascular cell adhesion molecule-1 (sVCAM-1)] in children who had been exposed to environmental inorganic arsenic (iAs).
Methods: We conducted a cross-sectional study in 199 children 3–14 years of age who were residents of Zimapan, México. We evaluated cIMT using ultrasonography, and plasma lipid profiles by standard methods. We analyzed ADMA, sICAM-1, and sVCAM-1 by ELISA, and measured the concentrations of total speciated arsenic (tAs) in urine using hydride generation cryotrapping atomic absorption spectrometry.
Results: In the multiple linear regression model for cIMT, tAs categories were positively associated with cIMT increase. The estimated cIMT diameter was greater in 35- to 70-ng/mL and > 70-ng/mL groups (0.035 mm and 0.058 mm per 1-ng/mL increase in urinary tAs, respectively), compared with the < 35-ng/mL group. In addition to tAs level, plasma ADMA was a significant predictor of cIMT. In the adjusted regression model, cIMT, percent iAs, and plasma sVCAM-1 were significant predictors of ADMA levels (e.g., 0.419-μmol/L increase in ADMA per 1-mm increase in cIMT).
Conclusions: Arsenic exposure and plasma ADMA levels were positively associated with cIMT in a population of Mexican children with environmental arsenic exposure through drinking water.
Citation: Osorio-Yáñez C, Ayllon-Vergara JC, Aguilar-Madrid G, Arreola-Mendoza L, Hernández-Castellanos E, Barrera-Hernández A, De Vizcaya-Ruíz A, Del Razo LM. 2013. Carotid intima-media thickness and plasma asymmetric dimethylarginine in Mexican children exposed to inorganic arsenic. Environ Health Perspect 121:1090–1096; http://dx.doi.org/10.1289/ehp.1205994
Although cardiovascular morbidity and mortality are increased in rheumatoid arthritis, little is known about the burden of subclinical coronary atherosclerosis in these patients.
Using computed tomography, coronary artery calcification was measured in 195 men and women with rheumatoid arthritis aged 45 to 84 years without clinical cardiovascular disease and compared with 1,073 controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis.
The prevalence of coronary calcification (Agatston score > 0) was significantly higher in men, but not women, with rheumatoid arthritis after adjusting for sociodemographic and cardiovascular risk factors (prevalence ratio = 1.19; P = 0.012). Among participants with prevalent calcification, those with rheumatoid arthritis had adjusted mean Agatston scores 53 units higher than controls (P = 0.002); a difference greater for men than women (P for interaction = 0.017). In all analyses, serum IL-6 attenuated the association between rheumatoid arthritis and coronary calcification, suggesting its role as a potential mediator of enhanced atherosclerosis. Notably, increasing severity of rheumatoid arthritis was associated with a higher prevalence and extent of coronary calcification among both men and women with rheumatoid arthritis, and for all age categories. The largest percentage difference in coronary arterial calcification between rheumatoid arthritis patients and their nonrheumatoid arthritis counterparts was observed in the youngest age category.
Increasing rheumatoid arthritis disease severity was associated with a higher prevalence and greater extent of coronary artery calcification, potentially mediated through an atherogenic effect of chronic systemic inflammation. Gender and age differences in association with coronary calcification suggest that preventive measures should be emphasized in men with rheumatoid arthritis, and considered even in younger rheumatoid arthritis patients with low levels of traditional cardiovascular risk factors.
Exhaustion, a consequence of prolonged stress characterized by unusual fatigue, is associated with increased risk of cardiac morbidity and mortality. In patients recovering from coronary artery bypass (CABG), little is known about the relationship of 1) immune-mediated inflammation and resultant endothelial activation, and 2) cumulative exposure to infectious pathogens (pathogen burden (PB)) implicated in coronary atherosclerosis to exhaustion.
The aim of this exploratory study was to investigate the association of PB, inflammatory markers (interleukin (IL)-6, IL-10) and a marker of endothelial activation (soluble intercellular adhesion molecule-1 (sICAM-1)) to exhaustion.
One to two months post-CABG, 42 individuals who met inclusion criteria were assessed for exhaustion using the Maastricht Interview for Vital Exhaustion. Serum IgG antibodies to herpes simplex virus (HSV)-1, HSV-2, cytomegalovirus, Epstein Barr virus, and inflammatory and endothelial activation markers were measured by enzyme-linked immunosorbent assay. Pathogen burden was defined as the total number of seropositive exposures: low (0–1), moderate (2–3), and high (4).
Prevalence of exhaustion was 40.5%. Relative to non-exhausted patients, exhausted patients demonstrated a higher frequency of moderate PB (h=0.73, p=0.04) but lower frequency of high PB (h=1.05, p=0.03). Exhaustion showed a non-significant trend for positive correlations with IL-6 and sICAM-1 levels, and inverse relation to PB. In subgroup analysis, exhausted patients had stronger correlations with IL-6 and IL-6:IL-10 and a tendency towards higher serum IL-10 concentrations compared with their non-exhausted counterparts.
This hypothesis-generating study provides preliminary evidence that elevated post-CABG exhaustion may be associated with PB, inflammation, and endothelial activation.
Coronary heart disease; cytokines; herpesviruses; inflammation; pathogen burden; vital exhaustion
Inflammatory markers predict coronary heart disease (CHD). However, associations with coronary artery calcium (CAC), a marker of subclinical CHD, are not established.
We examined cross-sectional associations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with CAC presence (Agatston score > 0 by computed tomography) in 6,783 Multi-Ethnic Study of Atherosclerosis (MESA) participants.
In all participants, those in the highest, compared to lowest, quartile of CRP had a relative risk (RR, 95% confidence interval) of 1.13 (1.06-1.19; p<0.01) for CAC in age, sex and ethnicity adjusted models. For highest versus lowest quartiles, relative risks were 1.22 (1.15-1.30; p<0.01) for IL-6 and 1.18 (1.11-1.24; p<0.01) for fibrinogen. Adjusting for CHD risk factors (smoking, diabetes, blood pressure, obesity and dyslipidemia) attenuated RRs. RRs for CAC were 1.05 (0.99-1.12; p=0.63) for CRP, 1.12 (1.06-1.20; p<0.01) for IL-6 and 1.09 (1.02-1.16; p=0.01) for fibrinogen in multivariable adjusted models. Results were similar for men and women and across ethnic groups.
Inflammatory markers were weakly associated with CAC presence and burden in MESA. Our data support the hypothesis that inflammatory biomarkers and CAC reflect distinct pathophysiology.
Atherosclerosis; Calcium; Inflammation; Population
Air pollution is associated with cardiovascular disease, and systemic inflammation may mediate this effect. We assessed associations between long- and short-term concentrations of air pollution and markers of inflammation, coagulation, and endothelial activation.
We studied participants from the Multi-Ethnic Study of Atherosclerosis from 2000 to 2012 with repeat measures of serum C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, D-dimer, soluble E-selectin, and soluble Intercellular Adhesion Molecule-1. Annual average concentrations of ambient fine particulate matter (PM2.5), individual-level ambient PM2.5 (integrating indoor concentrations and time–location data), oxides of nitrogen (NOx), nitrogen dioxide (NO2), and black carbon were evaluated. Short-term concentrations of PM2.5 reflected the day of blood draw, day prior, and averages of prior 2-, 3-, 4-, and 5-day periods. Random-effects models were used for long-term exposures and fixed effects for short-term exposures. The sample size was between 9,000 and 10,000 observations for CRP, IL-6, fibrinogen, and D-dimer; approximately 2,100 for E-selectin; and 3,300 for soluble Intercellular Adhesion Molecule-1.
After controlling for confounders, 5 µg/m3 increase in long-term ambient PM2.5 was associated with 6% higher IL-6 (95% confidence interval = 2%, 9%), and 40 parts per billion increase in long-term NOx was associated with 7% (95% confidence interval = 2%, 13%) higher level of D-dimer. PM2.5 measured at day of blood draw was associated with CRP, fibrinogen, and E-selectin. There were no other positive associations between blood markers and short- or long-term air pollution.
These data are consistent with the hypothesis that long-term exposure to air pollution is related to some markers of inflammation and fibrinolysis.
Infection with co-pathogens is one of the postulated factors contributing to persistent inflammation and non-AIDS events in virologically-suppressed HIV-infected patients. We aimed to investigate the relationship of human herpesvirus-8 (HHV-8), a vasculotropic virus implicated in the pathogenesis of Kaposi's sarcoma, with inflammation and subclinical atherosclerosis in HIV-infected patients.
Prospective study including virologically suppressed HIV-infected patients. Several blood biomarkers (highly-sensitive C-reactive protein [hsCRP], tumour necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, malondialdehyde, plasminogen activator inhibitor [PAI-1], D-dimer, sCD14, sCD163, CD4/CD38/HLA-DR, and CD8/CD38/HLA-DR), serological tests for HHV-8 and the majority of herpesviruses, carotid intima-media thickness, and endothelial function through flow-mediated dilatation of the brachial artery were measured.
A total of 136 patients were included, 34.6% of them infected with HHV-8. HHV-8-infected patients were more frequently co-infected with herpes simplex virus type 2 (HSV-2) (P<0.001), and less frequently with hepatitis C virus (HCV) (P = 0.045), and tended to be older (P = 0.086). HHV-8-infected patients had higher levels of hsCRP (median [interquartile range], 3.63 [1.32–7.54] vs 2.08 [0.89–4.11] mg/L, P = 0.009), CD4/CD38/HLA-DR (7.67% [4.10–11.86]% vs 3.86% [2.51–7.42]%, P = 0.035) and CD8/CD38/HLA-DR (8.02% [4.98–14.09]% vs 5.02% [3.66–6.96]%, P = 0.018). After adjustment for the traditional cardiovascular risk factors, HCV and HSV-2 infection, the associations remained significant: adjusted difference between HHV-8 positive and negative patients (95% confidence interval) for hsCRP, 74.19% (16.65–160.13)%; for CD4/CD38/HLA-DR, 89.65% (14.34–214.87)%; and for CD8/CD38/HLA-DR, 58.41% (12.30–123.22)%. Flow-mediated dilatation and total carotid intima-media thickness were not different according to HHV-8 serostatus.
In virologically suppressed HIV-infected patients, coinfection with HHV-8 is associated with increased inflammation and immune activation. This might contribute to increase the risk of non-AIDS events, including accelerated atherosclerotic disease.
"Hypertriglyceridemic waist" (HTGW) phenotype, an inexpensive early screening tool for detection of individuals at risk for type 2 diabetes and cardiovascular disease was found to be associated with subclinical atherosclerosis in various patient populations such as those with diabetes mellitus, chronic kidney disease, and those infected with human immunodeficiency virus. However, less is known regarding an association between HTGW and subclinical atherosclerosis in the apparently healthy, multiethnic population. Therefore, the aim of the study was to explore the association between HTGW and sub-clinical atherosclerosis in an apparently healthy, multiethnic population; and to investigate whether the effect of HTGW on sub-clinical atherosclerosis persists over and above the traditional atherosclerosis risk factors.
We studied 809 individuals of Aboriginal, Chinese, European and South Asian origin who were assessed for indices of sub-clinical atherosclerosis (intima-media thickness (IMT), total area and presence of carotid plaques), socio-demographic and lifestyle characteristics, anthropometrics, lipids, glucose, blood pressure, and family history of cardiovascular disease.
We found that, compared to individuals without HTGW and after adjusting for age, ethnicity, smoking, and physical activity; men and women with HTGW had a significantly higher: IMT (men: B (95%CI = 0.084 (0.037, 1.133), p < 0.001; women: B (95%CI) = 0.041 (0.006, 0.077), p = 0.020); and total area (men: B (95%CI = 0.202 (0.058, 0.366), p = 0.005; women: B (95%CI) = 0.115 (0.006, 0.235), p = 0.037). The association between HTGW waist and presence of plaques was significant for men (OR (95%CI) = 1.904 (1.040, 3.486), p = 0.037 vs. men without HTGW), but not for women (p = 0.284). Once analyses were adjusted for additional, traditional risk factors for atherosclerosis, the effect of HTGW on sub-clinical atherosclerosis was no longer significant.
In conclusion, HTGW may serve as an early marker of subclinical atherosclerosis in men and women, irrespective of ethnicity. However, once individuals are assessed for all traditional risk factors for atherosclerosis, the additional assessment for HTGW is not warranted.
Hypertriglyceridemic waist; Sub-clinical atherosclerosis; Intima-media thickness; Atherosclerotic plaque; Ethnicity
Background and objective
Systemic inflammation is a well-known risk factor for diseases such as atherosclerosis and is augmented by the presence of obesity. In addition, it has been shown that inflammation may be negatively influenced by certain macronutrients, specifically the omega-3 and omega-6 fatty acids. The primary aim of this study is to determine whether obesity modifies the association between plasma phospholipid polyunsaturated fatty acids (PUFAs) and markers of inflammation and endothelial activation in Multi-Ethnic Study of Atherosclerosis (MESA) participants.
A sample of 2848 adults (25% African American, Chinese, Hispanic, and White) randomly selected from the MESA cohort.
Relative plasma PUFA concentrations were determined using gas chromatography-flame ionization detection. Levels of three inflammatory markers (high-sensitivity C-reactive protein, interleukin (IL)-6 and tumor necrosis factor-receptor 1) and two endothelial activation markers (soluble intercellular adhesion molecule-1 (sICAM-1) and E-selectin) were determined with enzyme immunoassays. Linear regression analysis was used to evaluate the relationship between these markers and plasma PUFAs.
Obesity modified the associations of linoleic acid (Pint=0.01), dihomo-γ-linolenic (Pint=0.07) and eicosapentaenoic acid (EPA) (Pint=0.04) with sICAM-1 concentrations; in addition, obesity modified the association of IL-6 with dihomo-γ-linolenic (Pint=0.01). In obese individuals, sICAM-1 was inversely related to EPA levels (P=0.02), but directly related to linoleic acid levels (P<0.001). Conversely, sICAM-1 was inversely related to linoleic acid levels in normal weight individuals (P=0.04). IL-6 concentrations were significantly and directly related to dihomo-γ-linolenic acid (DGLA) in normal weight (P=0.01) and obese participants (P<0.001), but the scale of increase across tertiles was greater in obese adults. Main effects of fatty acid and inflammatory marker associations are also reported.
The modifying effect of obesity on the association of plasma PUFAs with IL-6 and sICAM-1 suggests differences in fatty acid metabolism and may also have implications in dietary fatty acid intake for obese individuals, particularly for linoleic and EPAs. Further study is warranted to confirm and explain the strong associations of DGLA with inflammatory and endothelial activation markers.
fatty acids; inflammation; epidemiology; omega-3
There is considerable interest in identifying biomarkers that predict high risk for the development of macrovascular complications in patients with diabetes. Therefore, the longitudinal association between subclinical atherosclerosis as measured by internal carotid artery intima-media thickness (IMT) and acute-phase reactants, cytokines/adipokines, thrombosis, and adhesion molecules was examined.
RESEARCH DESIGN AND METHODS
Biomarkers were measured at four time points over 20 years in 886 DCCT/EDIC participants with type 1 diabetes. Four composite scores were created by combining z scores generated from within the data set of individual biomarkers: acute-phase reactants (fibrinogen, C-reactive protein), thrombosis (fibrinogen, active and total plasminogen activator inhibitor [PAI]-1), cytokines/adipokines (tumor necrosis factor receptor-1 and -2, active and total PAI-1, IL-6), and endothelial dysfunction (soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble E-selectin). Internal carotid IMT was measured at EDIC years 1, 6, and 12, with elevated IMT defined at each time point as being in the upper quintile of its distribution.
Logistic regression models indicate that while individual biomarkers were not predictive of or associated with subclinical atherosclerosis, composite scores of acute-phase reactants (odds ratio [OR] 2.78 [95% CI 1.42, 5.42]), thrombolytic factors (OR 2.83 [95% CI 1.45, 5.52]), and cytokines/adipokines (OR 2.83 [95% CI 1.48, 5.41]) measured at our final time point EDIC years 8–11 were associated with higher levels of atherosclerosis at EDIC year 12, but findings were not consistent at early time points. The endothelial dysfunction score was not appreciably predictive of or associated with subclinical atherosclerosis at any of the time points measured.
The pathophysiologic relationship between higher biomarker levels and progression of subclinical atherosclerosis remains unclear.
Acute phase proteins highlight the dynamic interaction between inflammation and oncogenesis. GlycA, a novel nuclear magnetic resonance (NMR) inflammatory marker that identifies primarily circulating N-acetyl glycan groups attached to acute phase proteins, may be a future CRC risk biomarker.
We examined the association between GlycA and incident CRC and mortality in two prospective cohorts (N = 34,320); Discovery cohort: 27,495 participants from Women's Health Study (WHS); Replication cohort: 6,784 participants from Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable Cox models were adjusted for clinical risk factors and compared GlycA to acute phase proteins (high-sensitivity C-reactive protein [hsCRP], fibrinogen, and soluble intercellular adhesion molecule-1 [sICAM-1]).
In WHS (median follow-up 19 years, 337 cases, 103 deaths), adjusted HRs (95% CIs) per SD increment of GlycA for CRC incidence and mortality were 1.19 (1.06–1.35; p = 0.004) and 1.24 (1.00–1.55; p = 0.05), respectively. We replicated findings in MESA (median follow-up 11 years, 70 cases, 23 deaths); HRs (95% CIs) per SD of GlycA for CRC incidence and mortality were 1.32 (1.06–1.65; p = 0.01) and 1.54 (1.06–2.23; p = 0.02), respectively, adjusting for age, sex, and race. Pooled analysis, adjusted HR (95% CI) per SD of GlycA for CRC incidence and mortality was 1.26 (1.15–1.39; p = 1 x 10−6). Other acute phase proteins (hsCRP, fibrinogen, and sICAM-1) had weaker or no association with CRC incidence, while only fibrinogen and GlycA were associated with CRC mortality.
The clinical utility of GlycA to personalize CRC therapies or prevention warrants further study.
ClinicalTrials.gov: WHS NCT00000479, MESA NCT00005487
To evaluate the influence of food habits, specifically adherence to the Mediterranean diet, on carotid intima-media thickness (CIMT) and the presence of plaques in HIV-infected patients taking antiretroviral therapy (ART) and non-HIV-infected participants and to determine if HIV infection contributes independently to subclinical atherosclerosis.
We conducted a cross-sectional study of 110 HIV-infected patients on ART and 131 non-HIV-infected participants at the University Hospital for Infectious Diseases in Zagreb, Croatia, from 2009-2011. CIMT measurement and determination of carotid plaque presence was detected by ultrasound. Adherence to the Mediterranean diet was assessed by a 14-point food-item questionnaire. Subclinical atherosclerosis was defined by CIMT≥0.9 mm or ≥1 carotid plaque.
In HIV-infected patients, subclinical atherosclerosis was associated with older age (P < 0.001; Mann-Whitney test), higher body mass index (P = 0.051; Mann-Whitney test), hypertension (P < 0.001; χ2 test), and a lower Mediterranean diet score (P = 0.035; Mann-Whitney test), and in non-HIV-infected participants with older age (P < 0.001; Mann-Whitney test) and hypertension (P = 0.006; χ2 test). Multivariate analysis showed that decreased adherence to the Mediterranean diet was associated with higher odds of subclinical atherosclerosis (odds ratio [OR] 2.28, 95% confidence interval [CI] 1.10-4.72, P = 0.027) as was current smoking (OR 2.86, 95% CI 1.28-6.40), hypertension (OR 3.04, 95% CI 1.41-6.57), and male sex (OR 2.35, 95% CI 0.97-5.70). There was a significant interaction of age and HIV status, suggesting that older HIV-infected patients had higher odds of subclinical atherosclerosis than controls (OR 3.28, 95% CI 1.24-8.71, P = 0.017 at the age of 60 years).
We confirmed the association between lower adherence to the Mediterranean diet and increased risk of subclinical atherosclerosis and found that treated HIV infection was a risk factor for subclinical atherosclerosis in older individuals.
Interleukin (IL)-18 levels have been identified as important predictors of cardiovascular mortality and are often elevated in human immunodeficiency virus (HIV) infected individuals. To investigate a possible role for IL-18 in atherogenesis in the context of early HIV infection, the simian immunodeficiency model of HIV infection was used. Acutely simian immunodeficiency virus-infected and uninfected rhesus monkeys (Macaca mulatta) on an atherogenic diet were evaluated prospectively for atherosclerotic lesion development relative to a panel of plasma markers including IL-18, IL-8, IL-1β, IL-6, C-reactive protein, soluble vascular cell adhesion molecule-1, soluble E-selectin, and soluble intercellular adhesion molecule-1. While no significant differences in lesion development were identified between groups after 35 days of infection, levels of plasma IL-18 measured 1 month prior to virus inoculation correlated significantly with atherosclerotic plaque cross-sectional area at the carotid bifurcation (P < 0.001, R=0.946), common iliac bifurcation (P < 0.01, R = 0.789), and cranial abdominal aorta (P < 0.01, R = 0.747), as well as with extent of CD3+ and CD68+ cellular infiltration in vascular lesions (both P < 0.001, R ≥ 0.835) in both groups. Atherosclerotic plaque area at the carotid and common iliac bifurcations also showed a weaker inverse correlation with baseline interleukin-8 levels, as did CD68+ signal area. Results implicate a strong role for IL-18 in early atherosclerosis progression and raise the possibility that the chronically elevated IL-18 levels seen in later stages of HIV-infection may contribute significantly to accelerated atherogenesis in this population.
Atherosclerosis; endothelial activation markers; human immunodeficiency virus (HIV); interleukin-8 (IL-8); interleukin-18 (IL-18); simian immunodeficiency virus (SIV); vascular cell adhesion molecule-1 (VCAM-1)
That infections with certain pathogens, by initiating an inflammatory response, may contribute to the development of atherosclerosis is suggested by clinical and experimental evidence.
To analyse atherosclerotic plaques of the carotid artery, samples of apparently healthy greater saphenous veins and circulating leucocytes from the same individual patients for the presence of Helicobacter pylori and Mycoplasma pneumoniae.
Samples from 36 patients undergoing carotid endarterectomy for symptomatic carotid artery stenosis were analysed by polymerase chain reaction for the presence of DNA specific for H pylori and M pneumoniae. IgG antibody titres against H pylori and M pneumoniae and plasma levels of soluble E‐selectin, soluble intercellular adhesion molecule‐1 and soluble vascular cell adhesion molecule‐1 were determined.
M pneumoniae‐specific DNA was detected in the atherosclerotic plaques of 13 of 36 (36.1%) patients, in the saphenous veins of 9 of 36 (25%) patients and in the leucocytes of 27 of 36 (75%) patients. No salient association was observed between the presence of M pneumoniae‐specific DNA in leucocytes and atherosclerotic plaques or veins. A marked correlation between the presence of M pneumoniae in the respective specimens and the studied inflammatory markers or the presence of anti‐M pneumoniae antibodies was not observed. H pylori‐specific DNA could not be detected in the specimens tested.
The absence of H pylori and the random distribution of M pneumoniae in tissue samples obtained from patients with symptomatic carotid artery stenosis do not support a role for these pathogens in the development of atherosclerosis due to a direct interaction of the bacteria with the vasculature.
Prospective studies reporting a positive association of lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with incident cardiovascular disease (CVD) have included primarily white individuals. We evaluated associations of Lp-PLA2 and first-time cardiovascular events in a healthy multi-ethnic cohort characterized by presence or absence of baseline subclinical atherosclerosis.
Lp-PLA2 mass and activity were measured at baseline in 5456 participants in the Multi-Ethnic Study of Atherosclerosis. Individuals were characterized for presence of baseline subclinical disease (coronary artery calcium score>0 or carotid intima-media thickness value>80th percentile) and followed prospectively for development of CVD events (coronary heart disease, ischemic stroke, and cardiovascular death).
516 incident CVD events occurred over median follow-up of 10.2 years. In adjusted Cox proportional hazards models, each higher standard deviation of both Lp-PLA2 activity and mass was associated with an increased risk of cardiovascular events; hazard ratios (HR; 95% confidence intervals (CI)) 1.12 (1.01–1.26) for Lp-PLA2 activity and 1.10 (1.01–1.21) for mass. Associations did not differ by subclinical disease status (p-value for interaction 0.99 for Lp-PLA2 activity and 0.32 for Lp-PLA2 mass) and there was no confounding by subclinical atherosclerosis measures. Associations of Lp-PLA2 activity but not mass were weaker in Chinese participants but there were relatively few events among Chinese in race-stratified analysis.
In this multi-ethnic cohort, Lp-PLA2 was positively associated with CVD risk, regardless of the presence of coronary artery calcium or a thickened carotid-intimal media.
Lipoprotein-associated Phospholipase A2; Cardiovascular Disease; Inflammation; Ethnicity; Biomarker
This study assessed the cross-sectional association between coronary artery calcification (CAC) and myocardial perfusion in an asymptomatic population.
Clinical studies showed that the prevalence of stress-induced ischemia increased with CAC burden among patients with coronary heart disease (CHD). Whether an association between CAC and myocardial perfusion exists in subjects without a history of CHD remains largely unknown.
A total of 222 men and women, ages 45 to 84 years old and free of CHD diagnosis, in the Minnesota field center of the MESA (Multi-Ethnic Study of Atherosclerosis) were studied. Myocardial blood flow (MBF) was measured using magnetic resonance imaging during rest and adenosine-induced hyperemia. Perfusion reserve was calculated as the ratio of hyperemic to resting MBF. Agatston CAC score was determined from chest multidetector computed tomography.
Mean values of hyperemic MBF and perfusion reserve, but not resting MBF, were monotonically lower across increasing CAC levels. After adjusting for age and gender, odds ratios (95% confidence intervals) of reduced perfusion reserve (<2.5) for subjects with CAC scores of 0, 0.1 to 99.9, 100 to 399, and ≥400 were 1.00 (reference), 2.16 (0.96 to 4.84), 2.81 (1.04 to 7.58), and 4.99 (1.73 to 14.4), respectively. Further adjustment for other coronary risk factors did not substantially modify the association. However, the inverse association between perfusion reserve and CAC attenuated with advancing age (p for interaction < 0.05).
Coronary vasodilatory response was associated inversely with the presence and severity of CAC in asymptomatic adults. Myocardial perfusion could be impaired by or manifest the progression to subclinical coronary atherosclerosis in the absence of clinical CHD.