Despite the recognized risk of accelerated atherosclerosis in patients with rheumatoid arthritis (RA), little is known about cardiovascular risk management in contemporary cohorts of these patients. We tested the hypotheses that major modifiable cardiovascular risk factors were more frequent and rates of treatment, detection, and control were lower in patients with RA than in non-RA controls.
The prevalence of hypertension, diabetes, elevated low-density lipoprotein (LDL) cholesterol, elevated body mass index, smoking, moderate-high 10-year cardiovascular risk and the rates of underdiagnosis, therapeutic treatment, and recommended management were compared in 197 RA patients and 274 frequency-matched control subjects, and their associations with clinical characteristics were examined.
Eighty percent of RA patients and 81% of control subjects had at least 1 modifiable traditional cardiovascular risk factor. Hypertension was more prevalent in the RA group (57%) than in controls [42%, P =0.001]. There were no statistically significant differences in the frequency of diabetes, elevated body mass index, smoking, intermediate-high 10-year coronary heart disease risk, or elevated LDL in patients with RA versus controls. Rates of newly identified diabetes, hypertension, and hyperlipidemia were similar in RA patients versus controls. Rates of therapeutic interventions were low in both groups but their use was associated with well-controlled blood pressure (OR = 4.55, 95% CI: 1.70, 12.19) and lipid levels (OR = 9.90, 95% CI: 3.30, 29.67).
Hypertension is more common in RA than in controls. Other traditional cardiovascular risk factors are highly prevalent, underdiagnosed, and poorly controlled in patients with RA, as well as controls.
rheumatoid arthritis; cardiovascular risk; epidemiology
We aimed to examine the relationship of birthweight to cognitive performance in middle aged participants of the Atherosclerosis Risk in Communities Study (ARIC).
Cognitive function, assessed by means of three neuropsychological tests - the Delayed Word Recall Test (DWR), the Digit Symbol Subtest of the Wechsler Adult Intelligence Scale-Revised (DSS/WAIS-R) and the Word Fluency (WF) Test, was evaluated in relation to birthweight, as recalled through standardized interviews, using data from the second and fourth follow-up visits of the ARIC study cohort (1990 to 1992 and 1996 to 1998, respectively). Overall, 6785 participants satisfied the inclusion criteria and were included in the analysis.
After adjusting for adult socio-demographic factors, childhood socio-economic environment and parental risk factors, and adult anthropometric, health status related and behavioral variables, linear trends were observed for the relationship of birthweight to WF scores, although the trend was statistically significant only for those reporting exact birthweights (p for trend= 0.004). For the other cognitive test results, results were either null or inconsistent with the a priori hypotheses.
Except for WF in those reporting exact birthweights, our study does not support the notion that birthweight influences cognitive function in adults.
birthweight; cognition disorders; fetal programming; cohort studies
To explore predictors of change in measures of carotid atherosclerosis among rheumatoid arthritis (RA) patients without known cardiovascular disease (CVD) at baseline
RA patients underwent carotid ultrasonography at two timepoints, separated by an average of 3.2 ± 0.3 years. The associations of baseline and average patient characteristics with the average yearly change in mean maximal intima-medial thickness (IMT) of the common (CCA) and internal carotid arteries (ICA), and with incident or progressive plaque in the ICA/carotid bulb, were explored.
Among the 158 RA patients, maxCCA-IMT increased in 82% (median=16 μm/year; p<0.001) and maxICA-IMT increased in 70% (median=25 μm/year; p<0.001). Incident plaque was observed in 14% without baseline plaque [incidence rate=4.2/100 person-years (95% CI 1.61–6.82)]. Plaque progression was observed in 5% with baseline plaque. Among RA predictors, the adjusted average yearly change in maxCCA-IMT was significantly greater in patients with earlier RA vs. longer disease. Those prescribed TNF inhibitors at baseline had a 37% lower adjusted rate of maxCCA-IMT progression vs. non-users (14 vs. 22 μm/year; p=0.026). For maxICA-IMT, cumulative prednisone exposure was associated with progression [1.2 μm/year per gram (95% CI 0.1–2.4)] after adjustment, and was lower in patients prescribed statins concomitant with prednisone. Higher swollen joint count and higher average CRP were both associated with incident or progressive plaque, primarily in patients with elevated baseline CVD risk based on the Framingham score.
These prospective data provide evidence for inflammation as a contributor to subclinical atherosclerosis progression in RA, potentially modified favorably by TNF inhibitors and detrimentally by glucocorticoids.
Atherosclerosis; Inflammation; prediction; carotid ultrasound
While metabolic syndrome (MetS) and diabetes confer greater cardiovascular disease (CVD) risk, recent evidence suggests that individuals with these conditions have a wide range of risk. We evaluated whether screening for coronary artery calcium (CAC) and carotid intimal-medial thickness (CIMT) can improve CVD risk stratification over traditional risk factors (RFs) in people with MetS and diabetes.
RESEARCH DESIGN AND METHODS
We assessed CAC and CIMT in 6,603 people aged 45–84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). Cox regression examined the association of CAC and CIMT with coronary heart disease (CHD) and CVD over 6.4 years in MetS and diabetes.
Of the subjects, 1,686 (25%) had MetS but no diabetes and 881 (13%) had diabetes. Annual CHD event rates were 1.0% among MetS and 1.5% for diabetes. Ethnicity and RF-adjusted hazard ratios for CHD for CAC 1–99 to ≥400 vs. 0 in subjects with neither MetS nor diabetes ranged from 2.6 to 9.5; in those with MetS, they ranged from 3.9 to 11.9; and in those with diabetes, they ranged from 2.9 to 6.2 (all P < 0.05 to P < 0.001). Findings were similar for CVD. CAC increased the C-statistic for events (P < 0.001) over RFs and CIMT in each group while CIMT added negligibly to prediction over RFs.
Individuals with MetS or diabetes have low risks for CHD when CAC or CIMT is not increased. Prediction of CHD and CVD events is improved by CAC more than by CIMT. Screening for CAC or CIMT can stratify risk in people with MetS and diabetes and support the latest recommendations regarding CAC screening in those with diabetes.
We hypothesized that insulin resistance, measured by the homeostatic model assessment of insulin resistance (HOMA), is independently associated with prevalent and incident extra-coronary calcification (ECC).
We studied calcium scores of the aortic valve (AVC), mitral valve (MVC), thoracic aorta (TAC) and aortic valve root (AVR) in 6,104 MESA participants not on diabetes medication who had baseline cardiac CT scans; 5,312 had follow-up scans (mean 2.4y). Relative-risk regression modeled prevalent and incident ECC adjusted for baseline demographics (model 1), and additionally for CVD risk factors (model 2).
In model 1, prevalence and incidence risk-ratios for the highest versus lowest quartile of HOMA were 20–30% higher in all ECC locations (p-value for trend ≤0.05 for all but incident-AVC). In model 2, all associations were attenuated, primarily by adjustment for metabolic syndrome components.
HOMA has a positive and graded association with ECC, but not independently of cardiovascular risk factors—particularly metabolic syndrome components.
cardiovascular calcification; insulin resistance; atherosclerosis; metabolic syndrome; computed tomography; valvular calcification; thoracic aortic calcification
High-sensitivity C-reactive protein (hsCRP) levels are closely associated with abdominal obesity, metabolic syndrome, and atherosclerotic cardiovascular disease. The JUPITER trial has encouraged using hsCRP ≥2 mg/L to guide statin therapy; however the association of hsCRP to atherosclerosis, independent of obesity, remains unknown.
Methods and Results
We studied 6,760 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were stratified into 4 groups: non-obese/low hsCRP, non-obese/high hsCRP, obese/low hsCRP, and obese/high hsCRP. Using multivariable logistic and robust linear regression, we described the association with subclinical atherosclerosis, using coronary artery calcium (CAC) and carotid intima-media thickness (cIMT). Mean BMI was 28.3 ± 5.5 kg/m2, and median hsCRP was 1.9 mg/L (0.84 – 4.26). High hsCRP, in the absence of obesity, was not associated with CAC and was mildly associated with cIMT. Obesity was strongly associated with CAC and cIMT independent of hsCRP. When obesity and high hsCRP were both present, there was no evidence of multiplicative interaction. Similar associations were seen among 2,083 JUPITER-eligible individuals.
High hsCRP, as defined by JUPITER, was not associated with CAC and was mildly associated with cIMT in the absence of obesity. In contrast, obesity was associated with both measures of subclinical atherosclerosis independent of hsCRP status.
obesity; hsCRP; high sensitivity C-reactive protein; subclinical atherosclerosis; coronary artery calcium; carotid intima-media thickness
An abnormally high ankle brachial index (ABI) is associated with increased all-cause and cardiovascular mortality. The relationship of obesity to incident high-ABI has not been characterized. We investigated the hypothesis that increased obesity—quantified by body weight, BMI, waist circumference, and waist-to-hip-ratio—is positively associated with a high-ABI (ABI ≥ 1.3) and with mean ABI increases over a four year follow-up. Prevalence and incidence ratios for a high-ABI were obtained for 6540 and 5045 participants respectively in the Multi-Ethnic Study of Atherosclerosis (MESA), using log-binomial regression models adjusted for demographic, cardiovascular, and inflammatory/novel risk factors. Linear regression was used to analyze mean ABI change. Both prevalence and incidence of a high-ABI were significantly higher for the highest versus the lowest quartile of every baseline measure of obesity, with weight and BMI demonstrating the highest incidence ratios (2.7 and 2.4, respectively). All prevalence and incidence ratios were positive and graded across obesity quartiles, and were persistent in the subpopulation without diabetes. Among those with normal baseline ABI values, one MESA-standard deviation increase in every baseline measure of obesity was associated with significant increases in mean ABI values. In conclusion, we observed an independent, positive and graded association of increasing obesity to both prevalent and incident high-ABI, and to mean increases in ABI values over time. Weight and BMI seemed to be at least as strongly, if not more strongly, associated with a high-ABI than were measures of abdominal obesity.
obesity; anthropometric measures; peripheral vascular disease; ankle-brachial index; epidemiology
Even among asymptomatic people at low risk (<10%) by Framingham Risk Score (FRS), high coronary artery calcium (CAC) scores signify higher predicted risk of coronary heart disease (CHD) events. We sought to determine non-invasive factors (without radiation exposure) significantly associated with CAC in low-risk, asymptomatic persons. In a cross-sectional analysis, we studied 3046 participants from MESA at low 10-year predicted risk (FRS <10%) for CHD events. Multivariable logistic regression was used to assess the association of novel markers with presence of any CAC (CAC >0) and advanced CAC (CAC ≥ 300). CAC >0 and CAC ≥ 300 were present in 30% and 3.5% of participants, respectively. Factor VIIIc, fibrinogen and sICAM were each associated with CAC presence (P ≤ 0.02); and C-reactive protein, D-dimer and carotid intima-media thickness (CIMT) with advanced CAC (P ≤ 0.03). The base model combining traditional risk factors had excellent discrimination for advanced CAC (C-statistic, 0.808). Addition of the 2 best-fit models combining biomarkers plus/minus CIMT improved the c-statistics to 0.822 and 0.820, respectively. All 3 models calibrated well, but were similar in estimating individual risk probabilities for advanced CAC (prevalence = 9.97%, 10.63% and 10.10% in the highest quartiles of predicted probabilities versus 0.26%, 0.26% and 0.26% in the lowest quartiles, respectively). In conclusion, in low risk individuals, traditional risk factors alone predicted advanced CAC with high discrimination and calibration. Biomarker combinations +/− CIMT were also significantly associated with advanced CAC, but improvement in prediction and estimation of clinical risk were modest compared to traditional risk factors alone.
coronary calcium; biomarkers; novel markers; low-risk; risk factors
We sought to determine whether insulin resistance predicts the incidence and progression of coronary artery calcification (CAC).
RESEARCH DESIGN AND METHODS
We studied 5,464 participants not on hypoglycemic therapy from the Multi-Ethnic Study of Atherosclerosis (MESA). Each had baseline homeostasis model assessment of insulin resistance (HOMA-IR) and baseline and follow-up CAC scores. Incident CAC was defined as newly detectable CAC; progression was defined as advancing CAC volume score at follow-up.
Median HOMA-IR was 1.2 (0.8–2.0). Across all ethnicities, there was a graded increase in CAC incidence and progression with increasing HOMA-IR. When compared with those in the 1st quartile, participants in the 2nd–4th quartiles had 1.2, 1.5, and 1.8 times greater risk of developing CAC. Median annualized CAC score progression was 8, 14, and 17 higher, respectively. However, HOMA-IR was not predictive after adjustment for metabolic syndrome components.
HOMA-IR predicts CAC incidence and progression, but not independently of metabolic syndrome.
Excessive non-subcutaneous fat deposition may impair the functions of surrounding tissues and organs through the release of inflammatory cytokines and free fatty acids.
We examined the cross-sectional association between non-subcutaneous adiposity and calcified coronary plaque, a non-invasive measure of coronary artery disease burden.
Participants in the Multi-Ethnic Study of Atherosclerosis underwent CT assessment of calcified coronary plaque. We measured multiple fat depots in 398 white and black participants (47% men and 43% black), ages 47–86 years, from Forsyth County, NC during 2002–2005, using cardiac and abdominal CT scans. In addition to examining each depot separately, we also created a non-subcutaneous fat index using the standard scores of non-subcutaneous fat depots.
A total of 219 participants (55%) were found to have calcified coronary plaque. After adjusting for demographics, lifestyle factors and height, calcified coronary plaque was associated with a one standard deviation increment in the non-subcutaneous fat index (OR = 1.41; 95% CI: 1.08, 1.84), pericardial fat (OR = 1.38; 95% CI: 1.04, 1.84), abdominal visceral fat (OR = 1.35; 95% CI: 1.03, 1.76), but not with fat content in the liver, intermuscular fat, or abdominal subcutaneous fat. The relation between non-subcutaneous fat index and calcified coronary plaque remained after further adjustment for abdominal subcutaneous fat (OR = 1.40; 95% CI: 1.00, 1.94). The relation did not differ by gender and ethnicity.
The overall burden of non-subcutaneous fat deposition, but not abdominal subcutaneous fat, may be a correlate of coronary atherosclerosis.
The aim of this study was to examine whether there are ethnic differences in the association of triglycerides (TG) with waist circumference (WC), blood pressure, high-density lipoprotein cholesterol (HDL-C), fasting glucose, and insulin resistance and to examine the disparities in the prevalence of the metabolic syndrome components between African Americans and non-Hispanic whites who do not have hypertriglyceridemia.
This study used the baseline data from the Multi-Ethnic Study of Atherosclerosis (MESA) study. The analysis included non-Hispanic whites (N = 2,427) and African Americans (N = 1,519) aged 45–84 years free of clinically evident cardiovascular disease and diabetes at baseline. The revised National Cholesterol Education Program (NCEP) criteria were used to define the metabolic syndrome and its components.
African Americans had lower prevalence of elevated TG as compared with non-Hispanic whites. The association of TG with other components of the metabolic syndrome appeared to be similar between African Americans and non-Hispanic whites except for one. There was significant association of TG with WC among white women but not among African American women after adjusting for demographic and other variables (P for interaction of TG with ethnicity <0.001). In participants with TG < 150 mg/dL, African American women had higher prevalence rates than white women of abdominal obesity, elevated blood pressure, low HDL-C, elevated fasting glucose and homeostasis model assessment of insulin resistance (HOMA-IR). In men, the prevalence rates of high blood pressure, elevated fasting glucose, and HOMA-IR were significantly higher in African Americans than in whites.
The study findings suggest that further evaluation is warranted regarding the cutoffs for elevated TG and its clustering effect with other cardiometabolic risk factors on predicting risk for diabetes and cardiovascular disease (CVD) in African Americans.
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
Pericardial fat has adverse effects on the surrounding vasculature. Previous studies suggest that pericardial fat may contribute to myocardial ischemia in symptomatic individuals. However, it is unknown if pericardial fat has similar effects in asymptomatic individuals.
We determined the association between pericardial fat and myocardial blood flow (MBF) in 214 adults with no prior history of cardiovascular disease from the Minnesota field center of the Multi-Ethnic Study of Atherosclerosis (43% female, 56% Caucasian, 44% Hispanic). Pericardial fat volume was measured by computed tomography. MBF was measured by MRI at rest and during adenosine-induced hyperemia. Myocardial perfusion reserve (PR) was calculated as the ratio of hyperemic to resting MBF.
Gender-stratified analyses revealed significant differences between men and women including less pericardial fat (71.9±31.3 vs. 105.2±57.5 cm3, p<0.0001) and higher resting MBF (1.12±0.23 vs. 0.93±0.19 ml/min/g, p<0.0001), hyperemic MBF (3.49±0.76 vs. 2.65±0.72 ml/min/g, p<0.0001), and PR (3.19±0.78 vs. 2.93±0.89, p = 0.03) in women. Correlations between pericardial fat and clinical and hemodynamic variables were stronger in women. In women only (p = 0.01 for gender interaction) higher pericardial fat was associated with higher resting MBF (p = 0.008). However, this association was attenuated after accounting for body mass index or rate-pressure product. There were no significant associations between pericardial fat and hyperemic MBF or PR after multivariate adjustment in either gender. In logistic regression analyses there was also no association between impaired coronary vasoreactivity, defined as having a PR <2.5, and pericardial fat in men (OR, 1.18; 95% CI, 0.82–1.70) or women (OR, 1.11; 95% CI, 0.68–1.82).
Our data fail to support an independent association between pericardial fat and myocardial perfusion in adults without symptomatic cardiovascular disease. Nevertheless, these findings highlight potentially important differences between asymptomatic and symptomatic individuals with respect to the underlying subclinical disease burden.
Abdominal adiposity, especially visceral adiposity, is an emerging cardiometabolic risk factor. How abdominal fat is distributed in rheumatoid arthritis (RA) and its RA-related determinants have not been explored.
Men and women with RA were compared to non-RA controls from the Multi-Ethnic Study of Atherosclerosis. Participants underwent anthropometric measures and quantification of visceral and subcutaneous fat areas (VFA, SFA) using abdominal computed tomography.
A total of 131 RA patients were compared with 121 controls. Despite similar body mass index and waist circumference between the RA and control groups, the adjusted mean VFA was 45cm2 higher (+51%) for RA vs. control men (p=0.005) but not significantly different by RA status in women. The adjusted mean SFA was 119cm2 higher (+68%) for RA vs. control women (p<0.001) but not significantly different by RA status in men. Elevated VFA (>75th percentile) was associated with a significantly higher adjusted probability of having an elevated fasting glucose, hypertension, or the composite definition of the metabolic syndrome for the RA group compared with controls. Within the RA group, rheumatoid factor seropositivity and higher cumulative prednisone exposure were significantly associated with a higher mean adjusted VFA. Higher C-reactive protein levels and lower Sharp scores were significantly associated with both VFA and SFA.
The distribution of abdominal fat differs significantly by RA status. Higher VFA in men with RA, and the more potent association of VFA with cardiometabolic risk factors in men and women with RA, may contribute to cardiovascular risk in RA populations.
To identify correlates of kidney stone disease in white and African American men and women in a population-based longitudinal study starting in four US communities, and to assess differences in correlates across racial groups.
12,161 middle-aged participants of the ARIC Study provided information on history of kidney stone disease between 1993–1995. Information on incident kidney stone-related hospitalizations was obtained from ICD-codes on hospital discharge records.
Kidney stone disease was reported by 12.0% of men and 4.8% of women. After multivariable adjustment, prevalent kidney stone disease was significantly (p<0.05) associated with male gender (PR=2.50), increased serum triglycerides (PR=1.07 per SD increase), diabetes (PR=1.27), gallstone disease (PR=1.54), white race (PR= 1.67), and region of residence. Male gender (HR=1.70), diabetes (HR=1.98) and hypertension (HR=1.69) were significantly associated (p<0.05) with incident kidney stone-related hospitalizations (n=94). Race-stratified analyses showed stronger associations of prevalent kidney stone disease with increased triglycerides, older age, and gallstone disease in African Americans compared to whites, whereas male gender showed stronger association in whites (all p-interaction<0.05).
We identified novel correlates of kidney stone disease (triglycerides, gallstone disease) and risk factor interactions by race (age, male gender, triglycerides, gallstone disease).
Kidney stones; risk factors; epidemiology
Recent studies indicate that subclavian stenosis (SS), diagnosed by a large systolic blood pressure difference (SBPD) between the right and left brachial arteries, is associated with cardiovascular disease (CVD) risk factors and outcomes. We sought to describe the epidemiology of SS and determine its association with markers of subclinical CVD in the baseline cohort of the Multi-Ethnic Study of Atherosclerosis.
We defined SS by an absolute SBPD ≥15 mmHg. Peripheral artery disease (PAD) was defined by an ankle-brachial index ≤0.90. The coronary artery calcium score (CAC) and the common-carotid artery intima-media thickness (CCA-IMT) were measured by computed tomography and B-mode ultrasound, respectively. Odds ratios for the associations of SS with risk factors and subclinical disease were estimated using logistic regression.
Of 6,743 subjects studied, 307 participants (4.6%) had SS, with a higher prevalence in women (5.1%) than men (3.9%), and in African-Americans (7.4%) and non-Hispanic whites (5.1%) than Hispanic (1.9%) or Chinese (1.0%) participants (p<0.01). In a model including age, gender, ethnicity, traditional and novel CVD risk factors, significant associations with SS were observed for C-reactive protein (highest vs. three lower quartiles: OR=1.41; 95%CI: 1.06-1.87) and brachial artery pulse pressure (OR=1.12 /10 mmHg; 95%CI: 1.03-1.21). Adjusted for age, gender, ethnicity, traditional and novel CVD risk factors, SS was significantly associated with PAD (OR=2.35; 1.55-3.56), with CCA-IMT (highest vs. the lower three quartiles: OR=1.32; 1.00-1.75), and high CAC (score >100 vs. score=0; OR=1.43; 1.03-2.01).
The subclavian stenosis is positively associated with other markers of subclinical atherosclerosis.
subclavian artery; blood pressure; atherosclerosis; epidemiology
Heart failure is a major contributor to cardiovascular morbidity and mortality in rheumatoid arthritis. However, little is known about myocardial structure and function in this population.
Using cardiac magnetic resonance imaging, measures of myocardial structure and function were assessed in men and women with rheumatoid arthritis enrolled in ESCAPE RA, a cohort study of subclinical cardiovascular disease in rheumatoid arthritis, and compared with controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis.
Myocardial measures were compared between 75 rheumatoid arthritis patients and 225 matched controls. After adjustment, mean left-ventricular mass was 26 grams lower for the RA group compared to controls (p<0.001), an 18% difference. After similar adjustment, mean left-ventricular ejection fraction, cardiac output, and stroke volume were modestly lower in the rheumatoid arthritis group vs. controls. Mean left-ventricular end-systolic and end-diastolic volumes did not differ by rheumatoid arthritis status. Within the rheumatoid arthritis group, higher levels of anti-CCP antibodies and current use of biologics, but not other disease activity or severity measures, were associated with significantly lower adjusted mean left-ventricular mass, end-diastolic volume, and stroke volume, but not ejection fraction. The combined associations of anti-CCP antibody level and biologic use on myocardial measures were additive, without evidence of interaction.
These findings suggest that the progression to heart failure in RA may occur through reduced myocardial mass rather than hypertrophy. Both modifiable and non-modifiable factors may contribute to lower levels of left-ventricular mass and volume.
myocardial dysfunction; heart failure; inflammation; cardiac imaging
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
We examined the frequency and significance of extracoronary findings in a sample of asymptomatic of Multiethnic Study of Atherosclerosis participants who had coronary magnetic resonance angiography (MRA).
Subjects and Methods
The Multiethnic Study of Atherosclerosis is a cohort study that, at baseline, included 6814 participants 45 to 84 years old, and free of clinical cardiovascular disease. A random subset of 254 participants underwent coronary MRA. Two experienced readers evaluated all images, and a consensus reading was performed. The findings were classified based on their clinical significance.
Extracoronary findings were detected in 101 (39.8%) of the 254 participants. Additional imaging or clinical referral was need for 15 (5.9%) of the 254 participants. None of the participants required emergency referral. Signal loss in a pulmonary artery branch due to navigator beam saturation occurred in 59 (23%) of the 254 participants simulating a pulmonary embolus.
The prevalence of reportable extracoronary findings on coronary MRA is high. Familiarity with noncardiac magnetic resonance imaging interpretation may help in avoiding unnecessary testing resulting from inconclusive identification of extracoronary abnormalities detected incidentally on coronary MRA.
coronary MRA; extracardiac findings; MR artifacts; MESA
Systemic inflammation is linked to cardiovascular risk, but the influence of persistent pathogens, which are conventionally dichotomously categorized, on circulating levels of inflammatory markers is not clear. Antibody levels of pathogens have not been examined in relation to inflammation.
Using data from a subsample of the Multi-Ethnic Study of Atherosclerosis, we examined circulating levels of interleukin-6 (IL-6), C-reactive protein (CRP) and fibrinogen in relation to five common persistent pathogens: cytomegalovirus, herpes simplex virus-1, Hepatitis A virus, Helicobacter pylori and Chlamydia pneumoniae. We tested the hypothesis that the number of seropositive pathogens (based on conventional cut-off points) would not be as sensitive a marker of inflammation as immune response measured by antibody levels to pathogens.
High antibody response to multiple pathogens showed graded and significant associations with IL-6 (p < 0.001), CRP (p = 0.04) and fibrinogen (p = 0.001), whereas seropositive pathogen burden did not. In multiple linear regression models, high antibody response to multiple pathogens maintained a positive association only with IL-6 (4.4% per pathogen exhibiting high antibody response, 95% CI 0.0-8.9).
High antibody response to pathogens was a more consistent marker of inflammatory outcomes compared to seropositivity alone and high antibody response to multiple pathogens was a stronger marker compared to any single pathogen.
We examined the cross-sectional relationships of subclinical atherosclerosis – expressed by carotid intimal–medial thickness and coronary calcification – with antibodies to Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, herpes simplex virus, hepatitis A virus, and pathogen burden (number of positive pathogens). A random sample of 1056 individuals chosen from 5030 Multi-Ethnic Study of Atherosclerosis cohort participants were included. After multiple adjustment, no associations were found between atherosclerosis measures and either individual pathogens or pathogen burden. Interactions with inflammatory and endothelial function markers, demographic factors, BMI, high-density lipoprotein, diabetes, and smoking were also explored. The only interaction that was large, qualitative, statistically significant (P < 0.05) and in the expected direction was that between hepatitis A virus and soluble intercellular adhesion molecule-1 with regard to Agatston calcium score: the difference between hepatitis A virus-positive and hepatitis A virus-negative participants was −86 units in participants with soluble intercellular adhesion molecule-1 below the median, and +162 units in those with soluble intercellular adhesion molecule-1 equal or above the median. However, given the number of interactions that were explored, these results must be interpreted cautiously.
Findings from the present analyses do not provide support for an infectious etiology for subclinical atherosclerosis. However, the study’s limitations, which include its cross-sectional design and insufficient statistical power, suggest that inferences from its findings should be made cautiously.
atherosclerosis; infections; pathogens
Coronary artery calcium (CAC), carotid intimal medial thickness (cIMT), and reduced ankle brachial indices (ABI) are markers of subclinical vascular disease strongly associated with aging. We identified factors associated with low levels of subclinical vascular disease in 1824 participants ≥70 years in the Multi-Ethnic Study of Atherosclerosis. 452 had low CAC (<25th percentile), 441 had low cIMT (<25th percentile), 1636 had normal ABI (>0.9), and 165 had a combination index indicating favorable values for all three parameters. This combination index was independently associated with younger age [OR=2.5 per 1 SD (95%CI 1.8–3.6)], female gender [OR=3.0(1.9–4.8)], lower BMI [OR=1.6 per 1 SD (1.2–2.0)], absence of hypertension [OR=1.8(1.2–2.6)], absence of dyslipidemia [OR=1.6 (1.04–2.4)], and never smoking [OR=1.7(1.1–2.6)]. No significant associations were observed for C-reactive protein, education, diet, or physical activity. Favorable levels of multiple traditional risk factors, but not several novel risk factors, were associated with subclinical markers of successful cardiovascular aging.
The biologic mechanisms linking socioeconomic position and psychosocial factors to cardiovascular disease (CVD) are not well understood. Immune response to persistent pathogens may be one of these mechanisms.
We analyzed cross-sectional data from the Multi-Ethnic Study of Atherosclerosis (N=999) composed of adults age 45–84. Log-binomial regression and ordinal logistic regression models were used to examine associations of socioeconomic factors and psychosocial factors with pathogen burden and immune response among those infected. Pathogen burden was assessed based on seroprevalence of Helicobacter pylori, cytomegalovirus, herpes simplex virus-1, and Chlamydia pneumoniae and antibody levels were used to characterize high immune response to all four pathogens.
Low education was a strong and significant independent predictor of higher pathogen burden after adjustment for covariates (adjusted odds ratio (OR) 95% confidence interval (CI) 1.37, 1.19–1.57). Among subjects seropositive for all four pathogens, low education and a higher level of chronic psychosocial stress showed a positive association with higher antibody response, although associations were no longer significant in models with all covariates included (OR = 1.64, 95%CI 0.82–3.31 for lowest vs. highest educational category and OR= 1.29, 95%CI 0.96–1.73 for a one level increase in chronic stress).
Pathogen burden and heightened immune response may represent a biological pathway by which low socioeconomic position and chronic stress are related to increased rates of cardiovascular disease.
Infection; inflammation; epidemiology; cardiovascular diseases
To assess associations of sex hormones with impaired fasting glucose (IFG) and type 2 diabetes in men.
RESEARCH DESIGN AND METHODS
A total of 3,156 African American, Non-Hispanic white, Hispanic, and Chinese-American men aged 45–84 years who participated in the baseline visit of the Multi-Ethnic Study of Atherosclerosis (MESA) were included. Oddsratios and95% CIs for type 2 diabetes and IFG compared with normal fasting glucose for quartiles of hormones were estimated.
After adjusting for age, ethnicity, BMI, and waist circumference, IFG and diabetes were associated inversely with total testosterone and sex hormone–binding globulin (SHBG) and positively with estradiol (E2). Dehydroepiandrosterone was positively associated with IFG but not with diabetes. Associations did not differ across ethnic groups.
Regardless of obesity, total testosterone and SHBG were associated inversely and E2 was associated positively with IFG and diabetes in men. Further research is warranted to better understand the underlying biological mechanisms.
We examined cross-sectional associations between sex hormones and carotid artery intimal-medial thickness (cIMT) and coronary artery calcium in women in the Multi-Ethnic Study of Atherosclerosis.
Serum testosterone, estradiol, sex hormone binding globulin (SHBG), and dehydroepiandrosterone levels were measured in 1,947 postmenopausal women aged 45-84 years (30% White, 14% Chinese-American, 31% Black, and 25% Hispanic) and not on hormone therapy. Using multiple linear regression we evaluated associations between log(sex hormone) levels and log(cIMT) adjusted for age, ethnicity, body mass index (BMI) and cardiac risk factors. Associations between sex hormone levels and the presence and extent of coronary calcium were evaluated.
Total and bioavailable testosterone were positively associated with common cIMT independent of age, BMI, hypertension, smoking, HDL-cholesterol, LDL-cholesterol and insulin sensitivity (p=0.009 and p=0.002 respectively). SHBG was negatively associated with common cIMT (p=0.001) but further adjustment for BMI, cardiovascular risk factors, and LDL- and HDL-cholesterol removed significance. Estradiol and dehydroepiandrosterone were not associated with common cIMT. Sex hormones were not associated with presence of coronary calcium. Among women with measurable coronary calcium, higher SHBG (p=0.012) and lower bioavailable testosterone (p=0.007) were associated with greater coronary calcium score. No heterogeneity by ethnicity was found. In postmenopausal women, testosterone is independently associated with greater common cIMT. SHBG is negatively associated and this may be mediated by LDL- and HDL-cholesterol. In contrast, SHBG and testosterone were associated with extent of coronary calcium but in the opposite direction compared to carotid intimal-medial thickness. These differences warrant further evaluation.
Gonadal steroid hormones; atherosclerosis; postmenopausal women; carotid intimal-medial thickness; coronary calcium