Adipokines are secreted from adipose tissue, influence energy homeostasis and may contribute to the association between obesity and hypertension. Among 1,897 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, we examined associations between blood pressure and leptin, tumor necrosis factor – α [TNFα], resistin and total adiponectin. The mean age and body mass index was 64.7 years and 28.1 respectively, and 50% were female. After adjustment for risk factors, a 1-standard deviation increment higher leptin level was significantly associated with higher systolic (5.0 mmHg), diastolic (1.9), mean arterial (2.8) and pulse pressures (3.6), as well as a 34% higher odds for being hypertensive (p < 0.01 for all). These associations were not materially different when the other adipokines, as well as body mass index, waist circumference or waist to hip ratio, were additionally added to the model. Notably, the associations between leptin and hypertension were stronger in men, but were not different by race/ethnic group, body mass index or smoking status. Adiponectin, resistin and TNFα were not independently associated with blood pressure or hypertension. Higher serum leptin, but not adiponectin, resistin or TNFα, is associated with higher levels of all measures of blood pressure, as well as a higher odds of hypertension, independent of risk factors, anthropometric measures and other selected adipokines.
adipokine; leptin; blood pressure; hypertension; ethnicity
Elevation in plasma activity of von Willebrand Factor (vWF) reflects endothelial dysfunction and predicts death in pulmonary arterial hypertension (PAH). Higher vWF activity is also associated with lower right ventricular (RV) ejection fraction in PAH. Little is known about the relationship between vWF and RV structure and function in adults without cardiovascular disease. In the current investigation, we included 1,976 participants with MRI assessment of RV structure and function and measurement of vWF activity from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to estimate the associations between vWF activity and measures of RV structure and function after adjusting for demographics, anthropometrics, smoking, diabetes mellitus, hypertension and the corresponding left ventricular (LV) parameter. The average vWF activity was 140.7 ± 57.2%. Elevated vWF activity was independently associated with lower RV mass, RV end-diastolic volume and RV stroke volume in models with and without adjustment for the corresponding LV parameter (all p < 0.05). There was no association observed between vWF activity and RV ejection fraction. In conclusion, higher vWF activity is associated with lower RV mass, RV end-diastolic volume and RV stroke volume. These associations are independent of common cardiovascular risk factors and LV morphologic changes.
Cardiovascular Imaging; Biomarkers; Pulmonary Hypertension; Right Ventricle
The aim of the present study was to evaluate how torsion is influenced by left ventricular (LV) remodeling associated with age, gender and hypertension in a large community-based population.
Methods and Results
Myocardial shortening and torsion were assessed by tagged cardiac magnetic resonance (CMR) in 1478 participants without clinically apparent cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA). Torsion was defined as the difference between apical and basal rotation, divided by slice distance. In multivariable linear regression models, older age was associated with lower stroke volume (−3.6 ml/decade, p<0.001) and higher LV mass –to-volume ratio (0.03 g/ml/decade, p<0.001) along with lower circumferential shortening (−0.17%/decade, p<0.05). Torsion, however, was greater at older ages (0.14 °/decade, p<0.001) and in women (0.37°/cm vs. men, p<0.001). Hypertensive participants had higher LV mass and LV mass –to-volume ratio (15.5g and 0.07 g/ml, respectively, p<0.001 for both). Circumferential shortening was lower in hypertensive (−0.42%, p<0.01), whereas torsion was higher after adjustment for age and gender (0.17°/cm, p<0.05).
Older age is associated with lower LV volumes and greater relative wall thickness, and accompanied by lower circumferential myocardial shortening, whereas torsion is greater with older age. Hypertensive individuals have greater LV volumes and relative wall thickness and lower circumferential shortening. Torsion, however, is greater in hypertension independent of age and gender. Torsion may therefore represent a compensatory mechanism to maintain an adequate stroke volume and cardiac output in the face of progressively reduced LV volumes and myocardial shortening associated with hypertension and aging.
Torsion; Hypertension; Age; remodeling; Cardiac Magnetic Resonance
Systemic inflammation has been linked to the development of heart failure in population studies including MESA (Multi-Ethnic Study of Atherosclerosis) but little evidence exists regarding potential mechanism of this relationship. In this study, we used longitudinal MRI follow-up analysis to examine whether C-reactive protein (CRP) levels relate to progressive myocardial functional deterioration as a potential mechanism of incident heart failure.
Regional myocardial functional data from MESA participants who had baseline CRP measurement and also underwent tagged cardiac MRI both at baseline and at five-year follow-up were analyzed. Left ventricular (LV) midwall and mid-slice peak circumferential strain (Ecc), of which a more negative value denotes stronger regional myocardial function, was measured. Ecc change was calculated as the difference between baseline and follow-up Ecc.
During the follow-up period, participants (n=785) with elevated CRP experienced a decrease in strain, independent of age, gender and ethnicity (B=0.081; ΔEcc change per 1mg/L CRP change, 95% CI 0.036–0.126, p<0.001, Model 1), and additionally beyond systolic blood pressure, heart rate, diabetes, smoking status, body mass index, current medication and glomerular filtration rate (B=0.099, 0.052–0.145, p<0.001, Model 2). The relationship remained statistically significant after further adjustment for LV mass, coronary calcium score and interim clinical coronary events (B=0.098, 0.049–0.147, p<0.001, Model 3).
Higher CRP levels are related to progressive myocardial functional deterioration independent of subclinical atherosclerosis and clinical coronary events in asymptomatic individuals without previous history of heart disease.
inflammation; myocardial function; magnetic resonance imaging
Studying the effects of medications on endpoints in an observational setting is an important yet challenging problem due to confounding by indication. The purpose of this study is to describe methodology for estimating such effects while including prevalent medication users. These techniques are illustrated in models relating statin use to cardiovascular disease (CVD) in a large multi-ethnic cohort study.
The Multi-Ethnic Study of Atherosclerosis (MESA) includes 6814 participants aged 45-84 years free of CVD. Confounding by indication was mitigated using a two step approach: First, the untreated values of cholesterol were treated as missing data and the values imputed as a function of the observed treated value, dose and type of medication, and participant characteristics. Second, we construct a propensity-score modeling the probability of medication initiation as a function of measured covariates and estimated pre-treatment cholesterol value. The effect of statins on CVD endpoints were assessed using weighted Cox proportional hazard models using inverse probability weights based on the propensity score.
Based on a meta-analysis of randomized controlled trials (RCT) statins are associated with a reduced risk of CVD (relative risk ratio = 0.73, 95% CI: 0.70, 0.77). In an unweighted Cox model adjusting for traditional risk factors we observed little association of statins with CVD (hazard ratio (HR) = 0.97, 95% CI: 0.60, 1.59). Using weights based on a propensity model for statins that did not include the estimated pre-treatment cholesterol we observed a slight protective association (HR = 0.92, 95% CI: 0.54-1.57). Results were similar using a new-user design where prevalent users of statins are excluded (HR = 0.91, 95% CI: 0.45-1.80). Using weights based on a propensity model with estimated pre-treatment cholesterol the effects of statins (HR = 0.74, 95% CI: 0.38, 1.42) were consistent with the RCT literature.
The imputation of pre-treated cholesterol levels for participants on medication at baseline in conjunction with a propensity score yielded estimates that were consistent with the RCT literature. These techniques could be useful in any example where inclusion of participants exposed at baseline in the analysis is desirable, and reasonable estimates of pre-exposure biomarker values can be estimated.
Multiple imputation; Confounding by indication; Propensity score; Inverse probability of treatment weights; Statins
The integrated discrimination improvement (IDI) index is a popular tool for evaluating the capacity of a marker to predict a binary outcome of interest. Recent reports have proposed that the IDI is more sensitive than other metrics for identifying useful predictive markers. In this article, the authors use simulated data sets and theoretical analysis to investigate the statistical properties of the IDI. The authors consider the common situation in which a risk model is fitted to a data set with and without the new, candidate predictor(s). Results demonstrate that the published method of estimating the standard error of an IDI estimate tends to underestimate the error. The z test proposed in the literature for IDI-based testing of a new biomarker is not valid, because the null distribution of the test statistic is not standard normal, even in large samples. If a test for the incremental value of a marker is desired, the authors recommend the test based on the model. For investigators who find the IDI to be a useful measure, bootstrap methods may offer a reasonable option for inference when evaluating new predictors, as long as the added predictive capacity is large.
biological markers; bootstrap confidence interval; prediction; risk assessment; sampling distribution; sampling error; selection bias; type I error
Alcohol use has been consistently found to have a J-shaped association with coronary heart disease, with moderate drinkers exhibiting a decreased risk compared to both heavy drinkers and non-drinkers. However, studies of the association between alcohol use and subclinical coronary artery disease have conflicted.
To determine whether alcohol is associated with the presence, amount, or progression of coronary calcium over a 2- to 4-year period.
MESA is a prospective community-based cohort study of subclinical cardiovascular disease in a multi-ethnic cohort. In 2000–2002, 6814 participants free of clinical cardiovascular disease were enrolled at 6 participating centers.
There were 3766 (55.5%) current drinkers, 1635 (24.1%) former drinkers, and 1390 (20.5%) never drinkers included in the analysis. Although light to moderate alcohol consumption was associated with lower coronary heart disease risk, we found no evidence of a protective or J-shaped association of alcohol and coronary artery calcium (CAC). In fact there was evidence that heavy consumption of hard liquor was associated with greater CAC accumulation. Other alcoholic beverages were not associated with CAC prevalence, incidence or progression.
This is the first large study to evaluate the association of alcohol and coronary artery calcium in four racial/ethnic groups, and to evaluate progression of calcification. These results suggest that the cardiovascular benefits that may be derived from light to moderate alcohol consumption are not mediated through reduced CAC accumulation.
Racial/ethnic differences in the incidence and severity of heart failure (HF) are not well understood, but may be related to pre-existing variations in myocardial function.
To examine racial/ethnic differences in regional myocardial function among asymptomatic individuals free of known cardiovascular disease.
Design, setting and patients
The Multi-Ethnic Study of Atherosclerosis is a prospective, observational study of individuals without baseline cardiovascular disease, representing four major racial/ethnic groups. A total of 1099 study participants underwent cardiac MRI with tissue tagging; for each study, peak systolic strain (Ecc) and strain rate (SRs) were determined in four left ventricular (LV) regions.
Main outcome measures
Multiple linear regression was used to analyse the relationship between race/ethnicity and regional strain (Ecc and SRs) while adjusting for cardiovascular risk factors.
Compared with other racial/ethnic groups, Chinese-Americans had the greatest magnitude of Ecc in a majority of LV regions (–19.60±3.78, p<0.05); Chinese-Americans also had the greatest absolute values for SRs in all regions, reflecting higher rate of systolic contraction (–2.01±0.76, p<0.05). Conversely, African-Americans had the lowest Ecc values (–17.50±4.00, p<0.05) in the majority of wall regions while Hispanics demonstrated the lowest rate of contractility in all wall regions (–1.44±0.50, p≤0.001) in comparison with the other racial/ethnic groups. These race-based differences remained significant in the majority of LV wall regions after adjusting for multiple variables, including hypertension and LV mass.
Important race-based differences in regional LV systolic function in a large cohort of asymptomatic individuals have been demonstrated. Further research is needed to investigate the possible mechanisms related to the race/ethnicity-based variations found in this study.
Coronary artery calcium (CAC), carotid intima-media thickness, and left ventricular (LV) mass and geometry offer the potential to characterize incident cardiovascular disease (CVD) risk in clinically asymptomatic individuals. The objective of the study was to compare these cardiovascular imaging measures for their overall and sex-specific ability to predict CVD.
Methods and Results
The study sample consisted of 4965 Multi-Ethnic Study of Atherosclerosis participants (48% men; mean age, 62±10 years). They were free of CVD at baseline and were followed for a median of 5.8 years. There were 297 CVD events, including 187 coronary heart disease (CHD) events, 65 strokes, and 91 heart failure (HF) events. CAC was most strongly associated with CHD (hazard ratio [HR], 2.3 per 1 SD; 95% CI, 1.9 to 2.8) and all CVD events (HR, 1.7; 95% CI, 1.5 to 1.9). Most strongly associated with stroke were LV mass (HR, 1.3; 95% CI, 1.1 to 1.7) and LV mass/volume ratio (HR, 1.3; 95% CI, 1.1 to 1.6). LV mass showed the strongest association with HF (HR, 1.8; 95% CI, 1.6 to 2.1). There were no significant interactions for imaging measures with sex and ethnicity for any CVD outcome. Compared with traditional risk factors alone, overall risk prediction (C statistic) for future CHD, HF, and all CVD was significantly improved by adding CAC, LV mass, and CAC, respectively (all P<0.05).
There was no evidence that imaging measures differed in association with incident CVD by sex. CAC was most strongly associated with CHD and CVD; LV mass and LV concentric remodeling best predicted stroke; and LV mass best predicted HF.
imaging; cardiovascular diseases; sex
Biomarkers of inflammation and hemostasis have been associated with left ventricular (LV) mass. We studied relationships of C-reactive protein (CRP), interleukin-6 (IL6), D-dimer, soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor 1 (PAI-1), soluble thrombomodulin (sTM), soluble tumor necrosis factor type 1 receptor (sTNFR1), von Willebrand factor (vWF), soluble E-selectin (sE-selectin), factor VIII, fibrinogen, matrix metalloproteinase 3 (MMP3), and matrix metalloproteinase 9 (MMP9) with LV mass in an asymptomatic population. Multi-Ethnic Study of Atherosclerosis participants underwent magnetic resonance imaging to characterize LV mass; biomarkers were measured using standardized protocols (N = 763 to 4979). Adjusted models were used to associate each biomarker with LV mass while correcting for potential confounding.
LV mass was associated with many biomarkers after adjustment for demographic characteristics and traditional cardiovascular risk factors. Although the demographic and risk factor adjustments attenuated the association of CRP and IL6 with LV mass, further adjustment for weight changed regression coefficients from positive to negative for CRP and IL6 for LV mass. sTM, Factor VIII, and vWF were directly associated with LV mass in fully-adjusted models. For sTNFR1, sICAM-1, D-dimer, fibrinogen, and PAI-1, adjustment for risk factors and weight rendered associations with LV mass nonsignificant.
In this large cohort free of clinical cardiovascular disease, several hemostasis and inflammation markers were associated with LV mass. The unusual finding of a negative relationship of CRP and IL6 with LV mass only after adjustment for weight suggests that the effects of inflammation on LV mass are strongly influenced by obesity.
Left ventricle; biomarker; hemostasis; inflammation
The purpose of this study was to examine the association of both a low and a high ankle-brachial index (ABI) with incident cardiovascular events in a multi-ethnic cohort.
Abnormal ankle-brachial indices (ABIs), both low and high, are associated with elevated cardiovascular disease (CVD) risk. However, it is unknown whether this association is consistent across different ethnic groups, and whether it is independent of both newer biomarkers and other measures of subclinical atherosclerotic CVD.
6647 non-Hispanic white, African-American, Hispanic, and Chinese men and women aged 45–84 years from free-living populations in six United States field centers and free of clinical CVD at baseline had extensive measures of traditional and newer biomarker risk factors, and measures of subclinical CVD, including the ABI. Incident CVD, defined as coronary disease, stroke, or other atherosclerotic CVD death, was determined over a mean follow-up of 5.3 years.
Both a low (<1.00) and a high (≥ 1.40) ABI were associated with incident CVD events. Gender- specific and ethnic-specific analyses showed consistent results. Hazard ratios were 1.77 (p<.001) for a low and 1.85 (p=.050) for a high ABI after adjustment for both traditional and newer biomarker CVD risk factors, and the ABI significantly improved risk discrimination. Further adjustment for coronary artery calcium score, common and internal carotid intimal medial thickness, and major ECG abnormalities only modestly attenuated these hazard ratios.
In this study both a low and a high ABI were associated with elevated CVD risk in persons free of known CVD, independent of standard and novel risk factors, and independent of other measures of subclinical CVD. Further research should address the cost-effectiveness of measuring the ABI in targeted population groups.
peripheral arterial disease; ankle-brachial index; cardiovascular events; risk factors; subclinical atherosclerosis
We sought to examine the relationship between circulating interleukin-6 (IL-6) level and regional left-ventricular (LV) function among apparently healthy individuals free of cardiovascular disease.
Methods and results
Using magnetic resonance myocardial tagging, we determined peak systolic circumferential strain (Ecc) as a measure of regional systolic function in 894 asymptomatic participants in the Multi-Ethnic Study of Atherosclerosis. Ecc was analysed by harmonic phase imaging separately in the LV anterior wall, septum, lateral wall, and inferior wall. Global Ecc was calculated as the average of Ecc in all myocardial segments. We performed multivariable linear regression to evaluate the independent associations between log IL-6 and Ecc, after adjusting for demographic features, cardiovascular risk factors, and markers of subclinical atherosclerosis. The inverse relationships between IL-6 and absolute Ecc were similar in both genders. In multivariable analysis, higher IL-6 level was independently associated with reduced systolic function (less negative Ecc) in the septum [regression coefficient = 1.03 per unit higher log IL-6, 95% confidence interval (CI) 0.26–1.79, P = 0.008] and inferior wall (regression coefficient = 1.65, 95% CI 0.74–2.56, P < 0.001), but not in the anterior wall (P = 0.27) or lateral wall (P = 0.52). Overall, there was an independent inverse association between IL-6 and global Ecc (regression coefficient = 0.94, 95% CI 0.37–1.51, P = 0.001). Compared with C-reactive protein, higher IL-6 level demonstrates a stronger independent association with reduced regional systolic function.
In asymptomatic men and women without documented cardiovascular disease, there is a strong, independent, inverse relationship between IL-6 and regional LV systolic function. These findings suggest that IL-6 may underlie the pathogenetic link between inflammation, LV dysfunction and incipient heart failure. The observed variable relationships between IL-6 and systolic function across different LV regions warrant further investigations.
Heart failure; Myocardial contraction; Interleukin-6; Magnetic resonance imaging
To investigate the incidence of noncardiac vascular disease in patients with rheumatoid arthritis (RA) and its relationship to systemic extraarticular disease in a community-based cohort.
A retrospective medical record review of 609 patients with incident RA diagnosed during 1955–1994 was carried out in Olmsted County, Minnesota. Patients were followed up from 1955 to 2000 (median followup 11.8 years). Incident noncardiac vascular disease and severe extraarticular RA manifestations (including pericarditis, pleuritis, and vasculitis) were recorded according to predefined criteria, and incidence rates were estimated. Using Cox proportional hazards models, the risk (hazard ratio [HR]) of developing vascular events was assessed in patients with and without severe extraarticular RA.
Cerebrovascular and peripheral arterial events occurred in 139 patients (22.8%). The 30-year cumulative incidence rates of peripheral arterial events, cerebrovascular events, and venous thromboembolic events were estimated to be 19.6%, 21.6%, and 7.2%, respectively. The presence of severe extraarticular RA manifestations was found to be associated with all subgroups of noncardiac vascular disease except cerebrovascular disease alone (HR 2.3, 95% confidence interval [95% CI] 1.2–4.3 for peripheral arterial events; HR 3.7, 95% CI 1.3–10.3 for venous thromboembolic events; HR 1.5, 95% CI 0.7–3.2 for cerebrovascular events) after adjusting for age, sex, body mass index, smoking, and rheumatoid factor status.
This is the first study to assess the incidence of noncardiac vascular disease in RA. Severe extraarticular RA was associated with all forms of noncardiac vascular disease except cerebrovascular disease alone. Similar to cardiac disease, the excess risk of noncardiac vascular disease in RA is likely to be related, in part, to the systemic inflammation associated with the extraarticular manifestations of RA.
The purpose of this study was to evaluate the relationship of left ventricular (LV) remodeling assessed by cardiac magnetic resonance to various measures of obesity in a large population-based study.
Obesity is a well-known risk factor for cardiovascular disease, yet its relationship with LV size and function is poorly understood.
A total of 5,098 participants (age 45 to 84 years; 48% men) in the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent cardiovascular disease underwent cardiac magnetic resonance to assess LV size and function as well as measures of obesity, including body mass index, waist-to-hip ratio and waist circumference, and cardiovascular risk factors. Fat mass (FM) was estimated based on height-weight models derived from bioelectrical impedance studies. The associations of obesity measures with LV size and function were evaluated using linear spline regression models for body mass index and multivariable regression models for other measures of obesity; they were displayed graphically using generalized additive models.
LV mass and end-diastolic volume were positively associated with measures of obesity in both sexes after adjustment for risk factors (e.g., 5.7-g and 6.9-g increase in LV mass per 10-kg increase in FM in women and men, respectively [p < 0.001]). LV mass-to-volume ratio was positively associated with increased body mass index, waist-to-hip ratio, waist circumference, and estimated FM (e.g., 0.02-g/ml and 0.06-g/ml increase in mass-to-volume ratio per 10-kg increase in FM in women and men, respectively [p < 0.001]). The increased mass-to-volume ratio was due to a greater increase in LV mass relative to LV end-diastolic volume. All associations were stronger for men than for women. Ejection fraction showed no significant association with measures of obesity.
Obesity was associated with concentric LV remodeling without change in ejection fraction in a large, multiethnic cohort study.
cardiac magnetic resonance; cardiac morphology; epidemiology; left ventricular function; obesity
Coronary artery calcium score (CACS) has been shown to predict future coronary heart disease (CHD) events. However, the extent to which adding CACS to traditional CHD risk factors improves classification of risk is unclear.
To determine whether adding CACS to a prediction model based on traditional risk factors improves classification of risk.
Design, Setting and Participants
CACS was measured by computed tomography on 6,814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort without known cardiovascular disease. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2008. Participants with diabetes were excluded for the primary analysis. Five-year risk estimates for incident CHD were categorized as 0-<3%, 3-<10%, and ≥10% using Cox proportional hazards models. Model 1 used age, gender, tobacco use, systolic blood pressure, antihypertensive medication use, total and high-density lipoprotein cholesterol, and race/ethnicity. Model 2 used these risk factors plus CACS. We calculated the net reclassification improvement (NRI) and compared the distribution of risk using Model 2 versus Model 1.
Main Outcome Measures
Incident CHD events
Over 5.8 years median follow-up, 209 CHD events occurred, of which 122 were myocardial infarction, death from CHD, or resuscitated cardiac arrest. Model 2 resulted in significant improvements in risk prediction compared to Model 1 (NRI=0.25, 95% confidence interval 0.16-0.34, P<0.001). With Model 1, 69% of the cohort was classified in the highest or lowest risk categories, compared to 77% with Model 2. An additional 23% of those who experienced events were reclassified to high risk, and an additional 13% without events were reclassified to low risk using Model 2.
In the MESA cohort, addition of CACS to a prediction model based on traditional risk factors significantly improved the classification of risk and placed more individuals in the most extreme risk categories.
Previous longitudinal cohort studies have suggested an association between baseline depressive symptoms and incident hypertension. We assessed this possible association using data from the Multi-ethnic Study of Atherosclerosis, a population-based prospective cohort study of 6,814 US adults from 4 different racial/ethnic groups. Baseline users of antihypertensive medications and participants lost to follow-up were excluded leaving 3914 participants. Patients with baseline depressive symptoms (n=622) were defined using a high score on the Center for Epidemiologic Studies Depression Scale (≥ 16) or the use of an antidepressant medication. Hypertension was defined as systolic blood pressure ≥ 140, diastolic blood pressure ≥90 or new use of antihypertensive medications plus physician diagnosis. Estimates were adjusted for known risk factors including: age, sex, baseline blood pressure, diabetes, and body mass index. Untreated blood pressure was estimated using an imputation approach. A total of 477 participants developed hypertension. Using relative risk regression, patients with baseline depressive symptoms did not have an increased risk of incident hypertension (Relative Risk = 1.02; 95% Confidence Interval (CI):0.99 to 1.05) although an association between tricyclic antidepressants and hypertension (Relative Risk 1.20; 95% CI:1.05 to 1.37) was observed in sub-group analysis. Depression, even after adjustment for covariates, was associated with small changes in systolic (+2.4 mmHG; 95% CI: 0.2 to 4.7) and diastolic (+0.8 mmHG; 95% CI: −0.6 to 2.3) blood pressure. Depressive symptoms may be associated with slight increases in blood pressure in this multi-ethnic cohort but it is premature to conclude much without longer studies in other populations.
Multi-Ethnic Study of Atherosclerosis; depression; hypertension; blood pressure; imputation; censored normal regression
Elevated coronary artery calcium (CAC) is a marker for increase risk of coronary heart disease (CHD). While the majority of CHD events occur among individuals with advanced CAC, CHD can also occur in individuals with little or no calcified plaque. In this study, we sought to evaluate the characteristics associated with incident CHD events in the setting of minimal (score ≤10) or absent CAC (score of zero).
Asymptomatic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) (N=6,809), were followed for occurrence of all CHD events (including myocardial infarction(MI), angina, resuscitated cardiac arrest, or CHD death) and hard CHD events (MI or CHD death). Time to incident CHD was modeled using age-and gender-adjusted Cox regression.
The final study population consisted of 3,923 MESA asymptomatic participants (mean age: 58±9years,39% males) had with CAC scores of 0-10. Overall no detectable CAC was seen in 3415 individuals, whereas 508 had CAC scores of 1-10. During follow up (median 4.1 years) there were 16 incident hard events, and 28 all CHD events in individuals with absent or minimal CAC. In age, gender, race and CHD risk factors adjusted analysis, minimal CAC (1-10) was associated with an estimated 3-fold greater risk of a hard CHD event (HR: 3.23, 95% CI: 1.17-8.95), or of all CHD event (HR: 3.66, 95% CI 1.71-7.85) compared to those with CAC=0. Former smoking (HR=3.57; 1.08-11.77), current smoking (HR=4.93; 1.20-20.30), and diabetes (HR=3.09; 1.07-8.93) were significant risk factors for events in those with CAC=0.
Asymptomatic persons with absent or minimal CAC are at very low risk of future cardiovascular events. Individuals with minimal CAC (1-10) were significantly increased to three fold increased risk for incident CHD events relative to those with CAC scores of zero.
Computed Tomography; Prognosis; Coronary Artery Calcification; Atherosclerosis; Coronary Calcium Score; Cardiac Events
The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of 6,814 men and women. We sought to analyze the relationship between the extent of coronary calcium (CC) at baseline and the severity of coronary stenoses in clinically indicated coronary angiography studies during follow-up.
CC is an established predictor of major cardiovascular events. Yet, the relationship between CC and the distribution and severity of coronary artery stenoses has not been widely explored.
All MESA participants underwent non-contrast enhanced cardiac CT during enrollment to determine baseline CC. We analyzed 175 consecutive angiography reports from participants who underwent coronary catheterization for clinical indications during a median follow-up period of 18 months. The association between baseline CC and the severity of coronary stenosis detected in coronary angiographies was determined.
Baseline Agatston score was zero in only 7/175 (4%) MESA participants who underwent invasive angiography during follow-up. When coronary arteries were studied separately, 13–18% of coronary arteries with ≥75% stenosis had zero calcium mass scores at baseline. There was close association between baseline calcium mass score and the severity of stenosis in each of the coronary arteries (test for trend, p<0.001). As an example, mean calcium mass scores for <50, 50–74 and ≥75% stenosis in the left anterior descending coronary artery were 105.1 mg, 157.2 mg and 302.2 mg, respectively (p<0.001). Finally, there was a direct relationship between the total Agatston Score at baseline and the number of diseased vessels (test for trend, p<0.001)
The majority of patients with clinically indicated coronary angiography during follow up had detectable coronary calcification at baseline. While there is a significant relationship between the extent of calcification and mean degree of stenosis in individual coronary vessels, 16% of the coronary arteries with significant stenoses had no calcification at baseline.
To test the hypothesis that A1C is associated with subclinical cardiovascular disease (CVD) in a population without evident diabetes, after adjusting for traditional CVD risk factors and BMI.
RESEARCH DESIGN AND METHODS
This was a cross-sectional study of 5,121 participants without clinically evident CVD or diabetes (fasting glucose ≥7.0 mmol/l or use of diabetes medication), aged 47–86 years, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Measurements included carotid intimal-medial wall thickness (CIMT) and coronary artery calcification (CAC). Results were adjusted for age, sex, ethnicity, smoking, systolic blood pressure, LDL cholesterol, HDL cholesterol, antihypertensive medication use, lipid-lowering medication use, and BMI.
Compared with those in the lowest quartile for A1C ([mean ± SD] 5.0 ± 0.2%), participants in the highest quartile (6.0 ± 0.3%) had higher adjusted mean values for common CIMT (0.85 vs. 0.87 mm, P = 0.003) and internal CIMT (1.01 vs. 1.08 mm, P = 0.003). A1C quartile was not associated with prevalence of CAC in the entire cohort (P = 0.27); however, the association was statistically significant in women (adjusted prevalence of CAC in lowest and highest A1C quartiles 37.5 vs. 43.0%, P = 0.01). Among those with some CAC, higher A1C quartile tended to be associated with higher CAC score, but the results were not statistically significant (adjusted P = 0.11).
In this multiethnic cohort, there were small, positive associations between A1C, common CIMT, and internal CIMT in the absence of clinically evident diabetes. An association between higher A1C and CAC prevalence was evident only in women.
Previous research has suggested that emerging evidence from randomized controlled trials (RCTs) is often not reflected in physician selection of medication class for first-line anti-hypertensive therapy.
To evaluate the association of RCT evidence in December 2002 from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) on use of anti-hypertensive medications over time in a multi-ethnic cohort.
The Multi-Ethnic Study of Atherosclerosis study, a prospective cohort study of 6,814 adults from 4 ethnic groups, had four separate assessments of drug use. Users of anti-hypertensive medications at baseline were excluded. We evaluated temporal changes in the medication class reported by new users of antihypertensive medications.
After the exclusion of antihypertensive drug users at baseline, 32% of new users of anti-hypertensive drugs seen at exam 2 were prescribed a diuretic. The publication of ALLHAT was associated with a subsequent increase in the proportion of new users taking diuretics at exam 3 compared with exam 2 (Relative Risk (RR):1.31; 95% Confidence Interval (CI):1.09–1.59). After the report from ALLHAT, the proportion of users of diuretics seen at exam 3 rose to 44% (starting in 2004) and 39% in exam 4 (starting in 2005). This increase in the proportion of diuretic use among new users of anti-hypertensive medications declined slightly but could still be detected at exam 4 as compared to exam 2 (RR:1.28; 95% CI:1.04–1.57).
The randomized trial evidence from the ALLHAT study was temporally associated with a moderate increase in diuretic use.
Multi-Ethnic Study of Atherosclerosis; antihypertensive medications; drug utilization; longitudinal
Cardiac magnetic resonance imaging (MRI) is a non-invasive technique used to accurately and reproducibly measure biological parameters such as left ventricular mass. However, some subjects either refuse or are unable to complete testing, and the impact of excluding these missing data from predictive models is unknown.
Multiple imputation was applied to cardiac MRI data that were previously analyzed using a complete case approach. The model variables – 10 traditional cardiovascular risk factors and five sociodemographic variables – were used as a basis for imputation. Men and women were imputed separately. The primary focus was assessing the change in the cardiovascular predictors of left ventricular geometry and systolic function.
Although 27% of participants were missing cardiac MRI data, multiple imputation returned results similar to those of a complete case analysis. These results were robust to the point of including additional variables in the imputation analysis above and beyond the model variables. The degree of variance explained by the models increased marginally but the statistical inference was altered for only two predictors out of 53 cardiovascular risk factors using multiple imputation.
The results suggest that the cardiac MRI data in the Multi-Ethnic Study of Atherosclerosis (MESA) do not substantively change when missing data are handled using multiple imputation. Future analyses of cardiac MRI data may consider the complete case approach to be adequate despite the high rate of missing data in this population.
Comparison of methods; Complete case; Magnetic resonance imaging; Multiple imputation
There is evidence that the utilization of antidepressant medications (ADM) may vary between different ethnic groups in the United States population.
The Multi-Ethnic Study of Atherosclerosis is a population-based prospective cohort study of 6,814 US adults from 4 different ethnic groups. After excluding baseline users of ADM, we examined the relation between baseline depression and new use of ADM for 4 different ethnicities: African-Americans (n=1,822), Asians (n=784) Caucasians (n=2,300), and Hispanics (n=1,405). Estimates of the association of ethnicity and ADM use were adjusted for age, study site, gender, Center for Epidemiologic Studies Depression Scale (CES-D), alcohol use, smoking, blood pressure, diabetes, education, and exercise. Non-random loss to follow-up was present and estimates were adjusted using inverse probability of censoring weighting (IPCW).
Of the four ethnicities, Caucasian participants had the highest rate of ADM use (12%) compared with African-American (4%), Asian (2%) and Hispanic (6%) participants. After adjustment, non-Caucasian ethnicity was associated with reduced ADM use: African-American (HR: 0.42; 95% Confidence Interval (CI):0.31– 0.58), Asian (HR: 0.14; 95%CI: 0.08–0.26) and Hispanic (HR: 0.47; 95%CI: 0.31–0.65). Applying IPCW to correct for non-random loss to follow-up among the study participants weakened but did not eliminate these associations: African-American (HR: 0.48; 95%CI: 0.30–0.57), Asian (HR: 0.23; 95% CI: 0.13–0.37) and Hispanic (HR: 0.58; 95%CI: 0.47–0.67).
Non-Caucasian ethnicity is associated with lower rates of new ADM use. After IPCW adjustment, the observed ethnicity differences in ADM use are smaller although still statistically significant.
Inverse probability of censoring weighting; ethnicity; antidepressants; drug utilization; Multi-Ethnic Study of Atherosclerosis; non-random loss to follow-up
Age-related alterations of left ventricular (LV) structure and function that may predispose to cardiovascular events are not well understood.
Methods and Results
We used cardiac magnetic resonance imaging (MRI) to examine age-related differences in LV structure and function in 5004 participants without overt cardiovascular disease when enrolled in the Multi-Ethnic Study of Atherosclerosis; 1099 participants received additional strain analyses by MRI tagging. We also assessed the relation of age-associated remodeling with cardiovascular outcomes using Cox proportional hazard models adjusting for cardiovascular risk factors. Although LV mass decreased with age (−0.3 g per year), the mass-to-volume ratio markedly increased (+5 mg/mL per year, p<0.0001), driven by a substantial reduction in end-diastolic volume (−0.8 mL per year, p<0.0001). Age was also associated with a significant fall in stroke volume (−0.4 mL per year, p<0.0001) along with strain patterns reflecting systolic (p<0.0001) as well as diastolic (p<0.01) myocardial dysfunction – despite a modestly enhanced ejection fraction (+0.1% per year, p<0.0001). Increased mass-to-volume ratio conferred a significant risk for total cardiovascular events; this trend was strongest among younger (<65 years, HR 3.69 [CI 1.34–10.10]) versus older (≥65 years, HR 1.68 [CI 0.77–3.68]) individuals with the highest compared to lowest mass-to-volume ratio quintile (Pinteraction=0.013).
Age is associated with a phenotype of LV remodeling marked by increased mass-to-volume ratio and accompanied by systolic, as well as diastolic, myocardial dysfunction that is not reflected by preserved ejection fraction. This pattern of ventricular remodeling confers significant cardiovascular risk, particularly when present earlier in life.
aging; magnetic resonance imaging; myocardium; remodeling
The presence and extent of coronary artery calcium (CAC) correlates with the overall magnitude of coronary atherosclerotic plaque burden and with the development of subsequent coronary events. In this study we aim to establish whether age-gender specific percentiles of CAC predict cardiovascular outcomes better than the actual (absolute) CAC score.
MESA is a prospective cohort study of asymptomatic 6814 participants, followed for coronary heart disease (CHD) events including myocardial infarction, angina, resuscitated cardiac arrest, or CHD death. Time to incident CHD was modeled using Cox regression, and we compared models using percentiles based on age, gender and/or race/ethnicity to categories commonly used(0, 1-100, 101-400, 400+ Agatston units).
There were 163(2.4%) incident CHD events (median follow-up 3.75 years). Expressing CAC in terms of age and gender specific percentiles had significantly lower area under the ROC curve(AUC) than using absolute scores (women: AUC 0.73 versus 0.76,p=0.044; men: AUC 0.73 versus 0.77,p<0.001). Akaike’s information criterion (AIC) indicated better model fit using the overall score. Both methods robustly predicted events(>90th percentile associated with a hazard ratio(HR) of 16.4(95% c.i. 9.30,28.9), and score >400 associated with HR of 20.6(95% c.i. 11.8, 36.0). Within groups based on age/gender/race/ethnicity specific percentiles there remains a clear trend of increasing risk across levels of the absolute CAC groups. In contrast, once absolute CAC category is fixed, there is no increasing trend across levels of age/gender/race/ethnicity specific categories. Patients with low absolute scores are low risk, regardless of age-gender-ethnicity percentile rank. Persons with an absolute CAC score of >400 are high risk, regardless of percentile rank.
Using absolute CAC in standard groups performed better than age-gender-ethnicity percentiles in terms of model fit and discrimination. We recommend using cut-points based on the absolute CAC amount and the common CAC cutpoints of 100 and 400 appear to perform well.
prognosis; atherosclerosis; cardiac CT; coronary calcium
It has been proposed that coronary artery calcium (CAC) can be used to estimate an arterial age in adults. Supporting this concept is that chronologic age, as used in cardiovascular risk assessment, is a surrogate for atherosclerotic burden. This measure can provide the patient with a more understandable version of their CAC score (e.g. you are 55 years old, but your arteries are more consistent with an arterial age of 65). We describe a method of estimating arterial age by equating estimated coronary heart disease (CHD) risk for observed age and coronary artery calcium (CAC). Arterial age is then the risk-equivalent of coronary artery calcium. We use data from the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 participants free of clinical cardiovascular disease, followed for an average of 4 years. Estimated arterial age is obtained as a simple linear function of log-transformed CAC. In a model for incident CHD risk controlling for both age and arterial age, only arterial age was significant, indicating that observed age does not provide additional information after controlling for arterial age. Framingham risk calculated using this arterial age is more predictive of short-term incident coronary events than Framingham risk based on observed age (area under the ROC curve 0.75 for Framingham risk based on observed age, 0.79 using arterial age, p=0.006). In conclusion, arterial age provides a convenient transformation of CAC from Agatston units to a scale more easily appreciated by both patients and treating physicians.