Kidney disease and hypertension commonly coexist, yet the direction of their association is still debated.
To evaluate whether early kidney dysfunction, measured by serum cystatin C levels and urinary albumin excretion, predates hypertension in adults without clinically recognized kidney or cardiovascular disease.
Observational cohort study using data from 2000 to 2005.
The MESA (Multi-Ethnic Study of Atherosclerosis), a community-based study of subclinical cardiovascular disease in adults age 45 to 84 years.
2767 MESA participants without prevalent hypertension, cardiovascular disease, or clinically recognized kidney disease (an estimated glomerular filtration rate <60 mL/min per 1.73 m2 or microalbuminuria).
Cystatin C was measured by using a nephelometer, and urinary albumin and creatinine were measured from a spot morning collection. The primary outcome was incident hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or use of an antihypertensive medication.
During a median follow-up of 3.1 years, 19.7% of the cohort (545 participants) developed hypertension. After adjustment for established hypertension risk factors, each 15-nmol/L increase in cystatin C was associated with a statistically significant 15% greater incidence of hypertension (P = 0.017). The highest sex-specific quartile of urinary albumin–creatinine ratio was associated with a statistically insignificant 16% greater incidence of hypertension (P = 0.192) compared with the lowest quartile. No statistical evidence suggested a multiplicative interaction.
Unmeasured characteristics may have confounded observed associations of kidney markers with hypertension. Follow-up was relatively short. Hypertension that may have occurred between study visits or hypertension that was not captured by standard cuff measurements may have been missed.
Differences in kidney function, indicated by cystatin C levels, are associated with incident hypertension among individuals without clinical kidney or cardiovascular disease. These population-based findings complement experimental work implicating early kidney damage in the pathogenesis of essential hypertension.
Carotid intima-media thickness (IMT) is a marker of cardiovascular disease derived from ultrasound images of the carotid artery. In most outcome studies, human readers identify and trace the key IMT interfaces. We evaluate an alternate approach using automated edge detection.
We study a subset of 5640 participants with an average age 61.7 years (48% men) of the Multi-Ethnic Study of Atherosclerosis composed of whites, Chinese, Hispanic and African-Americans that are part of the MESA IMT progression study. Manual tracing IMT (mt_IMT) and edge-detected IMT (ed_IMT) measurements of the far wall of the common carotid artery (CCA) served as outcome variables for multivariable linear regression models using Framingham cardiovascular risk factors and ethnicity as independent predictors.
Measurements of mt_IMT was obtainable in 99.9% (5633/5640) and of ed_IMT in 98.9% (5579/5640) of individuals. Average ed_IMT was 0.19 mm larger than mt_IMT. Inter-reader systematic differences (bias) in IMT measurements were apparent for mt_IMT but not ed_IMT. Based on complete data on 5538 individuals, associations of IMT with risk factors were stronger (p < 0.0001) for mt_IMT (model r2: 19.5%) than ed_IMT (model r2: 18.5%).
We conclude that this edge-detection process generates IMT values equivalent to manually traced ones since it preserves key associations with cardiovascular risk factors. It also decreases inter-reader bias, potentially making it applicable for use in cardiovascular risk assessment.
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness
Systematic differences between readers or equipment in imaging studies are not uncommon; failure to account for such differences when using Carotid Ultrasonography may introduce bias into associations between carotid intima media thickness (cIMT) and outcomes. We demonstrate the impact of this source of systematic measurement error (SME) using data on 5,521 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and 661 participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Participants were between 37 and 78 years old. Two outcomes were considered: (1) the effect of HIV infection on cIMT (between study) and (2) the association of cIMT with cardiovascular events (within study). All estimates were adjusted for demographics (age, gender, and ethnicity) and for traditional cardiovascular disease risk factors (smoking, blood pressure, diabetes and cholesterol). When comparing the FRAM and MESA cohorts to estimate the association of HIV infection on common cIMT, accounting for machine and reader variability (between study variability) reduced the difference associated with HIV infection from +0.080 mm (95% Confidence Interval (CI):0.065–0.095) to +0.037 mm (95% CI:0.003 to 0.072) while internal cIMT declined from +0.254 mm (95% CI:0.205–0.303) to +0.192 mm (95% CI:0.076–0.308). Attenuation of the association between cIMT and cardiovascular endpoints occurred when within study reader variability was not accounted for. The effect of SME due to use of multiple readers or machines is most important when comparisons are made between two different study populations. Within-cohort measurement error dilutes the association with events.
Carotid intima media thickness; Measurement error; Bias; Carotid ultrasonography
Carotid artery intima-media thickness (IMT) is a marker of cardiovascular disease associated with incident stroke. We study whether IMT rate-of-change is associated with stroke.
Materials and Methods
We studied 5028 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) composed of whites, Chinese, Hispanic and African-Americans free of cardiovascular disease. In this MESA IMT progression study, IMT rate-of-change (mm/year) was the difference in right common carotid artery (CCA) far-wall IMT (mm) divided by the interval between two ultrasound examinations (median interval of 32 months). CCA IMT was measured in a region free of plaque. Cardiovascular risk factors and baseline IMT were determined when IMT rate-of-change was measured. Multivariable Cox proportional hazards models generated Hazard risk Ratios (HR) with cardiovascular risk factors, ethnicity and education level/income as predictors.
There were 42 first time strokes seen during a mean follow-up of 3.22 years (median 3.0 years). Average age was 64.2 years, with 48% males. In multivariable models, age (HR: 1.05 per year), systolic blood pressure (HR 1.02 per mmHg), lower HDL cholesterol levels (HR: 0.96 per mg/dL) and IMT rate-of-change (HR 1.23 per 0.05 mm/year; 95% C.L. 1.02, 1.48) were significantly associated with incident stroke. The upper quartile of IMT rate-of-change had an HR of 2.18 (95% C.L.: 1.07, 4.46) compared to the lower three quartiles combined.
Common carotid artery IMT progression is associated with incident stroke in this cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline.
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness; stroke
Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).
Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.
In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.
In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
Left Ventricular Hypertrophy (LVH) is associated with end-stage renal disease and chronic kidney disease, but the association of LVH with mild impairment in kidney function is not known. We hypothesized that mild and moderate reductions in kidney function, reflected in higher serum cystatin C concentrations, would be linearly associated with a higher prevalence of LVH.
Cross-sectional observational study.
Settings and Participants:
4,971 participants participating in baseline examinations in the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study with several sites in the U.S.
Cystatin C-based estimated glomerular filtration rate (eGFRcysC)
LVH and left ventricular (LV) mass index.
Serum cystatin C and creatinine, LV mass obtained by magnetic resonance imaging (MRI). LVH cutoffs for males and females were defined by the upper 95th percentile of LV mass index of all MESA participants without hypertension.
LVH was distinctly more prevalent (>12%) only in the lowest two deciles of eGFRcysC (<75 ml/min/1.73 m2). When participants with stage III or higher chronic kidney disease (creatinine eGFR <60 ml/min/1.73 m2) were excluded, the odds for LVH increased for each lower category of eGFRcysC below 75 ml/min/1.73 m2: 1.6 the odds for LVH with an eGFRcysC between 60-75 ml/min/1.73 m2 (95% confidence interval 1.20-2.07, P = 0.001), and 2.0 the odds for an eGFRcysC <60 ml/min/1.73 m2 (1.03-3.75, P = 0.04), after adjustment for demographic factors, study site, diabetes, and smoking. The association of the a lower eGFRcysC with LVH was attenuated after further adjustment for hypertension.
Cross-sectional, rather than longitudinal design, lack of participants with more advanced kidney disease, lack of a direct measurement of glomerular filtration rate.
Among subjects without CKD, eGFRcysC ≤ 75 ml/min/1.73 m2 was associated with a higher odds of LVH.
kidney disease; cystatin C; glomerular filtration rate; left ventricular hypertrophy; left ventricular mass; magnetic resonance imaging (MRI)
Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence.
To assess whether maximum carotid IMT or CAC (Agatston Score) is the better predictor of incident CVD.
Design, Setting, Patients
Prospective cohort study of 45–84 year-olds initially free of CVD (n = 6,698) in four ethnic groups, with standardized carotid IMT and CAC measures at baseline, in six field centers of the Multi-Ethnic Study of Atherosclerosis (MESA).
Main Outcome Measure(s)
Incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up.
There were 222 CVD events during follow-up. CAC was associated more strongly than carotid IMT with risk of incident CVD. After adjustment for each other and traditional CVD risk factors, the hazard of CVD increased 2.1-fold (95% CI 1.8–2.5) for each standard deviation greater level of log-transformed CAC, versus 1.3-fold (95% CI 1.1–1.4) for each standard deviation greater maximum IMT. For coronary heart disease, the hazard ratios per standard deviation increment were 2.5-fold (95% CI 2.1–3.1) for CAC and 1.2-fold (95% CI 1.0–1.4) for IMT. An ROC analysis also suggested that CAC predicted incident CVD better than IMT did.
Although whether and how to clinically use bio-imaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC predicts subsequent CVD events better than does carotid IMT.
Common carotid artery inter-adventitial diameter (IAD) and intima-media thickness (IMT) are measurable by ultrasound. IAD may be associated with left ventricular mass (LV mass) while IMT is a marker of subclinical atherosclerosis. It is not clear if IAD is associated with LV mass after accounting for IMT and traditional cardiovascular risk factors.
IAD and IMT were measured on participants of the Multi-Ethnic Study of Atherosclerosis (MESA) IMT progression study. A total of 5641 of the originally enrolled 6814 MESA participants were studied. LV mass was measured by magnetic resonance imaging. Multivariable linear regression was used with IAD as the outcome and adjustment for risk factors, as well as IMT and LV mass.
Traditional cardiovascular risk factors, height, weight and ethnicity were significantly associated with IAD. After adjustment for risk factors, a one mm difference in IMT was associated with a 1.802 mm (95% CI: 1.553, 2.051) higher mean IAD. A one gm difference in LV mass was associated with a 0.006 mm (95% CI: 0.005, 0.007) higher mean IAD. LV mass was independently associated with IAD after adjusting for cardiovascular risk factors and IMT. These associations were slightly different for men and women.
Inter-adventitial diameters are associated with left ventricular mass after adjusting for cardiovascular risk factors and IMT. IAD might serve as a surrogate for left ventricular mass and have predictive value for cardiovascular outcomes.
carotid arteries; ultrasonics; hypertrophy; magnetic resonance imaging; remodeling; risk factors; left ventricle
Carotid intima-media thickness (IMT) is a sub-clinical marker of atherosclerosis and a strong predictor of stroke. Pericardial fat (PF), the fat depot around the heart, has been associated with several atherosclerosis risk factors. We sought to examine the association between carotid IMT and PF, and to examine whether such an association is independent from common atherosclerosis risk factors including measures of overall adiposity.
Unadjusted and multivariable adjusted linear regression analysis was used to examine associations between common (CCA-IMT) and internal (ICA-IMT) carotid IMT with PF in a random sample of 996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent carotid ultrasound and chest CT at baseline examination.
A significant positive correlation was observed between PF and CCA-IMT (r =0.27, P<0.0001) and ICA-IMT (r =0.17, P<0.0001). In an unadjusted sex-specific linear regression analysis, there was a significant association between PF (1-SD difference) and CCA-IMT (mm) in both women (β coefficient (95% CI): 0.06 (0.04, 0.08), P<0.0001) and men (0.03 (0.01, 0.05), P<0.0002), an association that persisted after further adjusting for age and ethnicity (0.02 (+0.00, 0.04), P=0.0120 for women, and 0.02 (+0.00, 0.03), P=0.0208 for men). However, after additional adjustment for atherosclerosis risk factors and either BMI or waist circumference, these relations were no longer significant in either sex. In similar analyses, PF was significantly associated with ICA-IMT in both men (0.11 (0.06, 0.15), P<0.0001) and women (0.08 (0.02, 0.13), P=041). These relations were no longer significant in women in multivariable adjusted models, but persisted in men in all models except after adjusting for age, ethnicity and waist circumference.
In the general population PF is associated with carotid IMT, an association that possibly not independent from markers of overall adiposity or common atherosclerosis risk factors.
Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied.
Methods and Results
Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole.
Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole.
Clinical Trial Registration
URL: www.ClinicalTrials.gov. Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.)
atherosclerosis; blood pressure; carotid arteries; diastole; epidemiology; risk factors; systole; ultrasonics
Occupation has been linked to cardiovascular disease (CVD) incidence and mortality, but few studies have investigated occupation in relation to early atherosclerotic disease. This study examined associations between various occupational characteristics and carotid artery intima-media thickness (IMT) in a multi-ethnic sample.
The Multi-Ethnic Study of Atherosclerosis (MESA) recruited 6814 adults aged 45e84 years and free of clinical CVD (response rate 60%, 51% female). Questionnaire data were used to determine occupational group (managerial/professional, sales/office, service, blue-collar), psychosocial job characteristics (ie, job demands, job control) and other sociodemographic information.
Common carotid artery (CCA)-IMT was greater for blue-collar jobs than for management/professional jobs (mean difference=0.012 mm, p=0.049) after adjustment for age, sex, race, place of birth (US or foreign born) and CVD risk factors. Compared to management/professional jobs, internal carotid artery (ICA)-IMT was greater for sales/office, service and blue-collar jobs (mean difference=0.071 mm, p<0.001; 0.057 mm, p=0.009; and 0.110 mm, p<0.001, respectively) after adjustment for age, sex, race and place of birth. The difference between blue-collar jobs and management/professional jobs remained significant after additional adjustment for CVD risk factors, income and education (mean difference=0.048 mm, p=0.045). Higher levels of control at work were associated with thinner CCA-IMT (mean difference=‒0.009 mm, p=0.016, adjusted for age, sex, race and place of birth) but not with ICA-IMT. Job demands had no significant association with IMT.
Blue-collar jobs and low levels of job control were associated with the development of subclinical atherosclerosis.
Carotid intima-media thickness (cIMT) is an independent predictor of cardiovascular risk. Furthermore, ethnicity and gender-specific normative data are required to assess cIMT, which are not available for Andean-Hispanics. In addition, data regarding correlates of subclinical atherosclerosis in ethnic population are needed.
We studied 1448 adults enrolled in a population-based study in Peru. cIMT and carotid plaque were measured with high-resolution ultrasonography. A healthy reference sample (n=472) with no cardiovascular disease, normal weight and normal metabolic parameters was selected to establish normative cIMT values. Correlates of abnormal cIMT and carotid plaque were assessed in the entire population.
In the reference sample, 95th-percentile cIMT values were both age and gender-dependent. In stepwise regression, selected predictors of increasing cIMT were: older age, impaired fasting glucose, diabetes mellitus, higher systolic blood pressure, higher LDL-cholesterol, smoking and male gender. Predictors of carotid plaque included older age, male gender, higher systolic blood pressure, lower diastolic blood pressure and higher LDL-cholesterol. HDL-cholesterol and C-reactive protein were not associated with cIMT or carotid plaque. The lack of association with HDL-cholesterol was confirmed using high performance liquid chromatography.
We present ethnic-specific cutoffs for abnormal cIMT applicable to Andean-Hispanics and correlates of subclinical atherosclerosis in this population. Pending longitudinal studies, our data supports several risk associations seen in other populations and can be used to identify Andean-Hispanics at increased risk for atherosclerotic cardiovascular disease. The lack of association between HDL-C and cIMT or carotid plaque in this population requires further investigation.
carotid intima-media thickness; Andean-Hispanics; definitions; cardiovascular disease; Latin America
Chronic kidney disease (CKD) remains asymptomatic until its late stage, and also significantly increases the risk of cardiovascular (CV) disease morbidity and mortality. However, information in scant on the prevalence of CKD, and its association with subclinical atherosclerosis as depicted by carotid-intima media thickness (IMT) in younger adults.
This cross-sectional study included 1193 participants (43% males, 30% blacks) aged 23–43 years, residing in the semi-rural biracial (black-white) community of Bogalusa, LA. The measured variables include estimated glomerular filtration rate (eGFR) to determine functional renal changes and urine album creatinine ratio (ACR) to diagnose albuminuria, along with CV risk factor variables, and both segmental and composite carotid IMT.
Ninety nine (8.5%) subjects had CKD, with blacks showing higher prevalence than whites (p=0.01). Subjects with albuminuria had significantly higher internal carotid IMT (p=0.03), common carotid IMT (p=0.005), and composite carotid IMT (p=0.04) than those without. In the multivariate logistic regression model, albuminuria was associated with black race (OR 1.92, p=0.005), female sex (OR 2.24, p=0.002), diabetes (OR 6.26. p <0.001), hypertension (OR 2.36, p <0.001), obesity (OR 1.73, p=0.02), and composite carotid IMT (OR 1.83, p=0.02), after adjusting for age. However, reduction in eGFR did not show significant independent association with carotid IMT.
Among asymptomatic young adults, subclinical atherosclerosis and structural renal damage depicted by albuminuria coexist, which have implications for early prevention and control.
chronic kidney failure; glomerular filtration rate; albuminuria; carotid IMT; atherosclerosis; young adult
Compared with controls, HIV-infected persons have a greater prevalence of kidney disease as assessed by high levels of cystatin C and albuminuria, but not as assessed by creatinine level. However, the clinical importance of elevated cystatin C and albuminuria in the HIV-infected population has not been studied.
We conducted an observational cohort study to determine the association of kidney disease (measured by albuminuria, cystatin C, and serum creatinine) with mortality.
Setting & Participants
922 HIV-infected persons enrolled in the FRAM (Fat Redistribution and Metabolic Change in HIV infection) study.
Serum cystatin C and serum creatinine were used to estimate glomerular filtration rate (eGFR). Albuminuria was defined as a positive urine dipstick (≥1+) or a urine albumin-creatinine ratio > 30 mg/g.
At baseline, reduced kidney function (eGFRSCysC <60 mL/min/1.73m2) or albuminuria was present in 28% of participants. After five years of follow-up, mortality was 48% among those with both eGFRSCysC <60 mL/min/1.73m2 and albuminuria, 23% in those with eGFRSCysC <60 mL/min/1.73m2 alone, 20% in those with albuminuria alone, and 9% in those with neither condition. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, and inflammatory markers, eGFRSCysC <60 mL/min/1.73m2 and albuminuria were associated with nearly a twofold increase in mortality, whereas eGFRSCr <60 mL/min/1.73m2 did not appear to have any substantial association with mortality. Together, eGFRSCysC <60 mL/min/1.73m2 and albuminuria accounted for 17% of the population-level attributable risk for mortality.
Vital status was unknown in 261 participants from the original cohort.
Kidney disease marked by albuminuria or increased cystatin C levels appears to be an important risk factor for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on serum creatinine to estimate kidney function in clinical practice.
kidney disease; mortality; HIV infection
Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors.
Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors.
For internal carotid, mean IMT was 1.17±0.50mm for HIV-infected participants and 1.06±0.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm).
Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
HIV; carotid IMT; smoking; cholesterol; diabetes; atherosclerosis
The growing burden and morbidity of chronic kidney disease (CKD) warrant effective strategies for identifying those at increased risk. We examined the association of cystatin C and albuminuria with development of CKD stage 3.
Prospective observational study.
Setting and Participants
5,422 participants from the Multi-Ethnic Study of Atherosclerosis with estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m2.
Participants were categorized into four mutually exclusive groups: presence or absence of microalbuminuria (albumin-creatinine ratio >17 and > 25 µg/mg in men and women, respectively) in those with or without cystatin C ≥ 1.0 mg/L.
Outcomes and Measurements
Incident CKD stage 3 was defined as eGFR < 60 ml/min/1.73m2 at the 3rd or 4th visit and an annual decline of > 1 ml/min/1.73 m2. Poisson regression was used to evaluate incident rate ratios in unadjusted and adjusted analyses that include baseline eGFR.
Mean age was 61 years, 49% were men, 38% white, 11% had diabetes, 13.7% had cystatin C ≥ 1mg/L, 8.4% had microalbuminuria, and 2.7 % had cystatin C ≥ 1 mg/L with microalbuminuria. 554 (10%) participants developed CKD stage 3 over a median follow-up of 4.7 years and the adjusted incidence rate ratios (95% CI) were 1.57 (1.19–2.07), 1.37 (1.13–1.66), and 2.12 (1.61–2.80) in those with microalbuminuria, cystatin C ≥ 1 mg/L, and both, respectively, compared to those with neither.
Relatively short follow up and absence of measured GFR.
Cystatin C and microalbuminuria are independent risk factors for incident CKD stage 3 and could be useful as screening tools to identify those at increased risk.
Purpose of Review
To discuss recent studies which have evaluated determinants of cystatin C and to focus on the relationship of cystatin C with mortality, cardiovascular disease (CVD) and non-cardiovascular outcomes.
In the Chronic Kidney Disease Epidemiology Study cystatin C was associated with demographic characteristics independent of measured glomerular filtration rate (GFR), although this was to a smaller extent than creatinine. In patients with established CKD, cystatin C was strongly and inversely correlated with measured GFR, suggesting that although cystatin C may have other determinants, it is primarily a measure of kidney function. Several cohort studies, particularly in older adults, have now demonstrated that cystatin C is linearly associated with mortality, CVD and non-CVD outcomes, whereas creatinine is primarily associated with risk in individuals with more advanced kidney disease. A recent study has also shown that changes in kidney function as ascertained by cystatin C, even within the relatively normal range, are associated with subsequent CVD and all-cause mortality among older adults.
Cystatin C appears to capture an association of mild kidney disease with increased risk of mortality, CVD and non-CVD outcomes. Future studies should evaluate whether cystatin C can improve medical decision-making and lead to favorable patient outcomes.
cystatin C; kidney disease; cardiovascular disease; mortality
Circulating adiponectin has been associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were Caucasian (n=712), African-American (n=712), Chinese (n=718), and Hispanic (n=705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African-Americans with genotypes AG/GG of rs2241767 had 36% greater (95% CI (16%, 59%), p=0.0001) CAC prevalence; they also had a larger common cIMT (p=0.0043). Also in African-Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), p=0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), p=0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or Caucasian participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African-American and Hispanics. Replication as well as assessment of other ADIPOQ SNPs appears warranted.
To estimate the heritability of carotid intima-media thickness (IMT), a surrogate marker for atherosclerosis, independent of traditional coronary risk factors.
Methods and Results
We performed a classical twin study of carotid IMT using 98 middle-aged male twin pairs, 58 monozygotic (MZ) and 40 dizygotic (DZ) pairs, from the Vietnam Era Twin Registry. All twins were free of overt cardiovascular disease. Carotid IMT was measured by ultrasound. Bivariate and multivariate analyses were used to determine the association between traditional cardiovascular risk factors and carotid IMT. Intraclass correlation coefficients and genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in carotid IMT. In our sample, the mean of the maximum carotid IMT was 0.75 ± 0.11. Age, systolic blood pressure and HDL were significantly associated with carotid IMT. The intraclass correlation coefficient for carotid IMT was larger in MZ (0.66; 95% confidence interval [CI], 0.62–0.69) than in DZ twins (0.37; 95% CI, 0.29–0.44), and the unadjusted heritability was 0.69 (95% CI, 0.54–0.79). After adjusting for traditional coronary risk factors, the heritability of carotid IMT was slightly reduced but still of considerable magnitude (0.59; 95% CI, 0.39–0.73).
Genetic factors have a substantial influence on the variation of carotid IMT. Most of this genetic effect occurs through pathways independent of traditional coronary risk factors.
heritability; carotid intima-media thickness; twin study; atherosclerosis
The amount of cholesterol per LDL particle is variable and related in part to particle size, with smaller particles carrying less cholesterol. This variability causes concentrations of LDL cholesterol (LDL-C) and LDL particles (LDL-P) to be discordant in many individuals.
LDL-P measured by nuclear magnetic resonance (NMR) spectroscopy, calculated LDL-C, and carotid intima-media thickness (IMT) were assessed at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA), a community-based cohort of 6814 persons free of clinical CVD at entry and followed for CVD events (n=319 during 5.5-year follow-up). Discordance, defined as values of LDL-P and LDL-C differing by ≥ 12 percentile units to give equal-sized concordant and discordant subgroups, was related to CVD events and to carotid IMT in models predicting outcomes for a 1 SD difference in LDL-C or LDL-P, adjusted for age, sex and race.
LDL-C and LDL-P were associated with incident CVD overall: hazard ratios (HR [95% CI]) 1.20 [1.08, 1.34] and 1.32 [1.19, 1.47], respectively, but for those with discordant levels, only LDL-P was associated with incident CVD (HR: 1.45 [1.19, 1.78]) (LDL-C HR: 1.07 [0.88, 1.30])). IMT also tracked with LDL-P rather than LDL-C, i.e., adjusted mean IMT of 958, 932, and 917 μm in the LDL-P > LDL-C discordant, concordant, and LDL-P < LDL-C discordant subgroups, respectively, with the difference persisting after adjustment for LDL-C (p=0.002) but not LDL-P (p=0.60).
For individuals with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P.
LDL particle number; LDL cholesterol; cardiovascular disease risk; NMR; lipoproteins
Introduction. Reduced kidney function, approximated by elevated cystatin C, is associated with diastolic dysfunction, heart failure, and cardiovascular mortality; however, the precise mechanism(s) that account for these relationships remains unclear. Understanding the relationship between cystatin C and subclinical left ventricular (LV) remodeling, across ethnically diverse populations, may help explain the mechanisms underlying the association of kidney dysfunction with heart failure and cardiovascular mortality. Methods. Measures of cystatin C and LV parameters were obtained from the multi-ethnic study of atherosclerosis (MESA) cohort at baseline (N = 4, 970 with complete data on cystatin C and LV parameters). LV parameters; LV end-diastolic (LVEDV) and end-systolic volumes (LVESV), LV mass (LVM), concentricity (LV mass/LV end-diastolic volume), and LV ejection fraction (LVEF) were measured using magnetic resonance imaging. Nested linear models were used to examine the relationship between higher quartiles of cystatin C and LV parameters, with and without adjustment for demographics, height, and weight, and traditional cardiovascular risk factors. Similar analyses were performed stratified by ethnicity and gender. Results. A fully adjusted model demonstrated a linear relationship between higher quartiles of cystatin C and lower LVEDV, (Mean ± SE, 128 ± 0.7, 128 ± 0.7, 126 ± 0.7, 124 ± 0.8 mL; P = 0.0001). Associations were also observed between higher quartiles of cystatin C and lower LVESV (P = 0.04) and concentricity (P = 0.0001). In contrast, no association was detected between cystatin C and LVM or LVEF. In analyses stratified by race and gender, the patterns of association between cystatin C quartiles and LV parameters were qualitatively similar to the overall association. Conclusion. Cystatin C levels were inversely associated with LVEDV and LVESV with a disproportionate decrease in LVEDV compared to LVM in a multi-ethnic population. This morphometric pattern of concentric left ventricular remodeling, may in part explain the process by which kidney dysfunction leads to diastolic dysfunction, heart failure and cardiovascular mortality.
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
Defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, chronic kidney disease (CKD) is strongly and independently associated with cardiovascular and overall mortality. We hypothesized that reduced kidney function would be characterized by abnormalities of hemostasis.
We tested cross-sectional associations between (eGFR) and multiple hemostatic markers among 6751 participants representing a broad spectrum of kidney function in the Multi-Ethnic Study of Atherosclerosis (MESA). Kidney function was measured using cystatin C (eGFRcys) or creatinine, using CKD Epidemiology Collaboration (eGFRcr). Hemostatic markers included soluble thrombomodulin (sTM), soluble tissue factor (sTF), D-Dimer, von Willebrand factor (vWF), factor VIII, plasmin-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen. Associations were tested using multivariable linear regression with adjustment for demographics and comorbidities.
In comparison to persons with eGFRcys >90 ml/min/1.73 m2, subjects with eGFRcys < 60 ml/min/1.73 m2 had adjusted levels of sTM, sTF, D-Dimer, PAP, Factor VIII, TFPI, vWF and fibrinogen that were respectively 86%, 68%, 44%, 22%, 17%, 15%, 12% and 6% higher. Subjects with eGFRcys 60-90 ml/min/1.73 m2 had adjusted levels that were respectively 16%, 14%, 12%, 6%, 6%, 6%, 11% and 4% higher (p < 0.05 for all). Percent differences were not significantly different when groups were categorized by eGFRcr.
Throughout a broad spectrum of kidney function, lower eGFR was associated with higher levels of hemostatic markers. Dysregulation of hemostasis may be a mechanism by which reduced kidney function promotes higher cardiovascular risk.
Biomarkers of carotid atherosclerosis range from those that are widely available and relatively simple to measure such as serum cholesterol levels, and B-mode Ultrasound measurement of intima media thickness (IMT) to those that are more complex and technologically demanding but perhaps potentially more sensitive and specific to disease such as total plaque volume and total plaque area measured from 3-dimensional ultrasound images. In this study we measured and compared intima media thickness (IMT), total plaque volume (TPV) and total plaque area (TPA) in two separate populations, both vulnerable to carotid atherosclerosis.
In total, 88 subjects (mean age 72.8) with carotid stenosis of at least 60%, based on a peak Doppler flow, and 82 subjects (mean age 60.9) with diabetic nephropathy were assessed in a cross-sectional study. Conventional atherosclerotic risk factors were examined and the associations and correlations between these and carotid ultrasound phenotypes measured from B-mode and 3-dimensional ultrasound images were assessed.
IMT and TPV were only modestly correlated in the two separate populations (r = .6, p < .01). ANOVA analyses indicated that both IMT and TPV were significantly associated with age (p < .001) and Framingham score (p < .05), but only TPV was associated with diabetes (p < .001) and presence of plaque ulcerations (p < .01)
IMT and TPV were modestly correlated in a diabetic patient population and only TPV was associated with diabetes and the presence of plaque ulcerations in a diabetic population and carotid stenosis group. The 3-dimensional information provided by TPV can be critically important in unmasking association with risk factors not observed with less complex single-dimension assessments of carotid atherosclerosis such as those provided by IMT.
Atherosclerosis is the leading cause of cardiovascular disease (CVD). Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis; however, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis.
A case-control study was performed using microarray gene expression profiling of peripheral blood from 119 healthy women in the Multi-Ethnic Study of Atherosclerosis cohort aged 50 or above. All participants had low (<10%) to intermediate (10% to 20%) predicted Framingham risk; cases (N = 48) had coronary artery calcium (CAC) score >100 and carotid intima-media thickness (IMT) >1.0 mm, whereas controls (N = 71) had CAC<10 and IMT <0.65 mm. We identified two major expression profiles significantly associated with significant atherosclerosis (odds ratio 4.85; P<0.001); among those with Framingham risk score <10%, the odds ratio was 5.30 (P<0.001). Ontology analysis of the gene signature reveals activation of a major innate immune pathway, toll-like receptors and IL-1R signaling, in individuals with significant atherosclerosis.
Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals.