Markers Of Subclinical Cardiovascular Disease Research Articles

Peripheral Vascular Disease in Systemic Lupus Patients

Systemic lupus erythematosus (SLE) is an independent risk factor for cardiovascular disease (CVD). Ankle-brachial index (ABI) is a measure of peripheral vascular disease (PVD), low values of which are associated with CVD. Objectives were to identify the prevalence of PVD in SLE, to identify risk factors associated with PVD in SLE, and to determine whether SLE is an independent risk factor for PVD as assessed by ABI. In a cross-sectional analysis of SLE subjects and control subjects, free of known CVD, SLE-related variables and cardiovascular risk factors were measured. Peripheral vascular disease was assessed using ABI. The prevalence of PVD (ABI ≤ 1.0) and comparisons of mean ABI, between SLE and control subjects, were examined. Systemic lupus erythematosus was examined as an independent risk for PVD in the cohort using propensity score matching. Logistic regression was performed to identify independent risk factors for PVD in SLE. Ankle-brachial index was lower in the 134 SLE subjects compared with 77 control subjects: 1.05 versus 1.09 (P = 0.003), and the prevalence of PVD was higher in SLE than in control subjects (33% vs 20%; P = 0.037). Systemic lupus erythematosus was not an independent risk for PVD. In the SLE subjects, the only significant risk factor for PVD was smoking. Ankle-brachial index, a marker of subclinical CVD, is an inexpensive and easy method in which to assess PVD. There was a 33% prevalence of PVD in SLE, which was independently associated with smoking. As PVD is a coronary artery disease risk equivalent, screening and diagnosis may change lipid management in preventive cardiovascular risk assessment in patients with SLE. The combination of SLE and a smoking history may identify individuals for whom checking an ABI makes particular sense.

Subclinical cardiovascular disease and its association with risk factors in children with steroid-resistant nephrotic syndrome

The aim of this study was to evaluate the presence of subclinical cardiovascular disease (CVD) and its relation to risk factors in pediatric patients with steroid-resistant nephrotic syndrome (NS). Thirty-seven patients with normal renal function were compared with 22 healthy controls regarding the presence of subclinical CVD. Measurements included aortic pulse wave velocity (PWV), carotid intima media thickness (IMT), and left ventricular mass (LVM). Patients were additionally assessed for blood pressure (BP) pattern and the presence of hypertension by 24-h ambulatory blood pressure monitoring. Compared with the controls, patients had significantly higher mean aortic PWV-standard deviation scores (SDS), mean carotid IMT-SDS, and LVM index (p < 0.001 for all). Increased aortic PWV was noted in 5 % of patients, increased carotid IMT in 22 %, and increased LVM index in 19 %. Five patients (14 %) were hypertensive, and mean BP indexes, SDS, and BP loads during nighttime were significantly higher than those during daytime (p < 0.001 for all). Multivariate analysis revealed a significant relationship between PWV-SDS and ferritin (R(2) = 0.269, p = 0.006) and between carotid IMT-SDS and proteinuria (R(2) = 0.141, p = 0.022). The LVM index was independently associated only with higher body mass index SDS (R(2) = 0.317, p < 0.001). In addition, six patients (16 %) had multiple abnormal subclinical CVD markers, and increased subclinical CVD risk was independently associated only with higher low-density lipoprotein cholesterol (R(2) = 0.292, p = 0.044). Based on these results, steroid-resistant NS children generally are at high risk of cardiovascular complications, but the increased risk is likely to be multifactorial.

Coronary Artery Calcium Scores Using Nongated Computed Tomography

The coronary artery calcium (CAC) score is well established as a potent marker of increased cardiovascular risk that significantly improves risk prediction beyond traditional risk factors. A CAC score >300 has been shown to confer a 10-fold increase in the risk for a cardiovascular event compared with adults with a CAC of 0.1,2 The improvement in risk prediction is substantially greater with CAC than other imaging and serum markers of subclinical cardiovascular disease.3,4 Article see p 514 The cohort studies that have most informed our understanding of coronary calcium measured CAC scores with dedicated cardiac computed tomography (CT). Image acquisition was gated to diastole to minimize motion artifact and to decrease the likelihood that regions of CAC were missed. However, most chest CTs done for clinical purposes are ordered primarily to assess the lungs and other structures in the chest and thus are not gated. Without gating, there is a concern that assessment of CAC is not accurate. Rather than disregard readily available data, several investigators have sought to determine whether information about CAC burden from nongated CTs can be used effectively to predict cardiovascular risk. In this issue of Circulation: Cardiovascular Imaging , Xie et al5 compiled data from several studies to determine the validity and prognostic value of CAC scoring obtained on nongated thoracic CT scans. To assess the diagnostic performance, the authors performed a meta-analysis of 5 studies that directly compared CAC scores obtained using gated versus nongated CTs. The patient populations in the studies varied, with some representing adults consecutively referred for a chest CT, positron …

Pulse Pressure and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis

Brachial pulse pressure (PP) has been found to be associated with markers of subclinical cardiovascular disease, including carotid intima-media thickness and left-ventricular mass index (LVMI), but it is unclear whether these associations are independent of traditional cardiovascular risk factors and of the steady, nonpulsatile component of blood pressure (BP). Moreover, it is unknown whether these associations are modified by gender, age, or race/ethnicity. We used multivariate linear regression models to assess the relationship between brachial PP and three markers of subclinical cardiovascular disease (CVD) (common carotid intima-media thickness (CC-IMT), internal carotid intima-media thickness (IC-IMT), and LVMI) in four race/ethnic groups in the Multi-Ethnic Study of Atherosclerosis. The models were adjusted for traditional Framingham risk factors (age, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, diabetes, smoking status), use of lipid-lowering medication, use of antihypertensive medication, study site, and mean arterial pressure (MAP). The assessment was done on 6,776 participants (2,612 non-Hispanic white, 1,870 African-American, 1,494 Hispanic, and 800 Chinese persons). The associations between brachial PP and CC-IMT, IC-IMT, and LVMI were significant in fully adjusted models. The three subclinical markers also showed significant interactions with gender (P < 0.0001), with stronger interactions in men. There was an interaction with age for LVMI (P = 0.004) and IC-IMT (P = 0.008). Race/ethnicity modified the association of PP with CC-IMT. Brachial PP was independently associated with subclinical CVD after adjustment for cardiovascular risk factors and mean arterial pressure (MAP). The strength of the association differed significantly for strata of gender, age, and race/ethnicity.

Examining the association between salivary cortisol levels and subclinical measures of atherosclerosis: The Multi-Ethnic Study of Atherosclerosis

To investigate the association between salivary cortisol and two markers of subclinical cardiovascular disease (CVD), coronary calcification (CAC), and ankle-brachial index (ABI). Data from an ancillary study to the Multi-Ethnic Study of Atherosclerosis (MESA), the MESA Stress Study, were used to analyze associations of salivary cortisol data collected six times per day over three days with CAC and ABI. The authors used mixed models with repeat cortisol measures nested within persons to determine if specific features of the cortisol profile were associated with CAC and ABI. A total of 464 participants were included in the CAC analysis and 610 in the ABI analysis. The mean age of participants was 65.6 years. A 1-unit increase in log coronary calcium was associated with a 1.77% flatter early decline in cortisol (95% CI: 0.23, 3.34) among men and women combined. Among women low ABI was associated with a steeper early decline (-13.95% CI: -25.58, -3.39) and a marginally statistically significant flatter late decline (1.39% CI: -0.009, 2.81). The cortisol area under the curve and wake to bedtime slope were not associated with subclinical CVD. This study provides weak support for the link between cortisol and measures of subclinical atherosclerosis. We found an association between some features of the diurnal cortisol profile and coronary calcification and ABI but associations were not consistent across subclinical measures. There are methodological challenges in detecting associations of cortisol measures at a point in time with health outcomes that develop over a lifetime. Studies of short-term mechanisms linking stress to physiological processes related to the development of early atherosclerosis may be more informative.

Short Sleep Duration Is Associated With Carotid Intima-Media Thickness Among Men in the Coronary Artery Risk Development in Young Adults (CARDIA) Study

Carotid intima-media thickness (CIMT) is a subclinical marker of cardiovascular disease. Recent studies suggest that shorter sleep duration is a risk factor for cardiovascular disease, but there is limited evidence regarding this association using high-quality, objective assessments of sleep. The aim of this study is to determine whether sleep duration is associated with CIMT. The study used an observational cohort consisting of 617 black and white middle-aged healthy participants (37-52 years; 58% female) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Multivariable-adjusted linear regression analyses were performed. Sleep duration was measured using wrist actigraphy monitors. CIMT was calculated using the average of 20 measurements of the mean common carotid, bulb, and internal CIMT, which was assessed using ultrasound images. After adjusting for covariates, 1 hour of longer sleep duration was associated with 0.026 mm less CIMT among men (P=0.02; 95% CI, -0.047 to -0.005) and 0.001 mm less CIMT among women (P=0.91; 95% CI, -0.020 to 0.022). Segment-specific analyses indicated that the carotid bulb was a key driver of the observed association. Shorter objectively assessed sleep duration was associated with greater CIMT among men but not women.

Type I Interferons Are Associated with Subclinical Markers of Cardiovascular Disease in a Cohort of Systemic Lupus Erythematosus Patients

BackgroundSystemic lupus erythematosus (SLE) patients have a striking increase in cardiovascular (CV) comorbidity not fully explained by the Framingham risk score. Recent evidence from in vitro studies suggests that type I interferons (IFN) could promote premature CV disease (CVD) in SLE. We assessed the association of type I IFN signatures with functional and anatomical evidence of vascular damage, and with biomarkers of CV risk in a cohort of lupus patients without overt CVD.Methodology/Principal FindingsSerum type I IFN activity (induction of five IFN-inducible genes; IFIGs) from 95 SLE patient and 38 controls was quantified by real-time PCR. Flow mediated dilatation (FMD) of the brachial artery and carotid intima media thickness (CIMT) were quantified by ultrasound, and coronary calcification by computed tomography. Serum vascular biomarkers were measured by ELISA. We evaluated the effect of type I IFNs on FMD, CIMT and coronary calcification by first applying principal components analysis to combine data from five IFIGs into summary components that could be simultaneously modeled. Three components were derived explaining 97.1% of the total IFIG variation. Multivariable linear regression was utilized to investigate the association between the three components and other covariates, with the outcomes of FMD and CIMT; zero-inflated Poisson regression was used for modeling of coronary calcification. After controlling for traditional CV risk factors, enhanced serum IFN activity was significantly associated with decreased endothelial function in SLE patients and controls (p<0.05 for component 3), increased CIMT among SLE patients (p<0.01 for components 1 and 2), and severity of coronary calcification among SLE patients (p<0.001 for component 3).ConclusionsType I IFNs are independently associated with atherosclerosis development in lupus patients without history of overt CVD and after controlling for Framingham risk factors. This study further supports the hypothesis that type I IFNs promote premature vascular damage in SLE.

Abstract P174: Kidney Function and Progression of Coronary Artery Calcification in Community-Dwelling Older Adults: The Rancho Bernardo Study

Background: Despite growing evidence for the separate and joint contributions of declining estimated glomerular filtration rate (eGFR) and presence of albuminuria to cardiovascular death, longitudinal studies of the association of these risk factors with coronary artery calcification, a marker of subclinical cardiovascular disease (CVD), are contradictory. Methods: We evaluated 421 community-dwelling men and women (mean age 67 years) without known heart disease who had eGFR estimated by the Modification of Diet in Renal Disease equation and albuminuria assessed by urine albumin/creatinine ratio (ACR) between 1997-99. Coronary artery calcium (CAC) was measured by electron beam computed tomography between 2001-02; 338 participants returned for a repeat scan between 2005-06, a mean of 4.5 (0.5) years later. CAC progression was defined as a difference between the follow-up square-root transformed CAC volume score and the baseline square-root transformed score &gt; 2.5 mm 3 . Results: At baseline, mean eGFR was 78 mL/min/1.73m 2 , median ACR was 10 mg/g. Median total Agatston CAC score was 77 at the baseline scan and 112 at follow-up; 45% (191 of 421) of participants had CAC&gt;100 at baseline and 46% (157 of 338) showed CAC progression. Logistic regression analyses showed no separate or joint association between eGFR or ACR with baseline CAC or with CAC progression. Table 1 shows the odds ratio (95% CI) for CAC progression for each 1 SD decrease in eGFR or increase in ACR. Conclusions: In a cohort of community-dwelling older adults, we found no longitudinal association between eGFR or ACR with CAC progression. This information may enhance our understanding of CAC progression across the spectrum of kidney function in community-dwelling adults without prevalent CVD or kidney disease. 4 Year CAC Progression per 1 SD Decrease in eGFR or Increase in ACR 1997-99 Estimated Glomerular Filtration Rate Urine Albumin/Creatinine Ratio (n=338) (n=292) Covariates Odds Ratio (95% CI) p value Odds Ratio (95% CI) p value Model 1 1.07 (0.86, 1.33) 0.54 0.99 (0.78, 1.26) 0.93 Model 2 1.04 (0.84, 1.30) 0.69 0.97 (0.77, 1.24) 0.82 Model 3 1.06 (0.85, 1.33) 0.57 1.06 (0.82, 1.37) 0.67 Model 4 1.07 (0.85, 1.33) 0.57 1.05 (0.81, 1.36) 0.69 Model 5 1.05 (0.82, 1.36) 0.68 1.06 (0.82, 1.38) 0.66 Model 6 1.10 (0.83, 1.43) 0.53 0.99 (0.75, 1.30) 0.94 Model 1: Unadj; Model 2: Age, time lapse adj; Model 3: Age, time lapse, sex adj; Model 4: Age, timelapse, sex, BMI adj; Model 5: Age, time lapse, sex, BMI and (eGFR or ACR) adj; Model 6: Age, time lapse, sex, BMI, SBP, FPG, HDL and (eGFR or ACR) adj

25-Hydroxyvitamin D deficiency is associated with increased aortic stiffness in patients with systemic lupus erythematosus

Objective. To determine the relationship between serum vitamin D and markers of subclinical cardiovascular disease (CVD) in patients with SLE.Methods. We recruited SLE patients (≥4 ACR 1997 criteria) from outpatient clinics between January 2007 and January 2009. Vitamin D deficiency was defined as serum 25(OH)D <20 ng/ml measured by ELISA. Disease activity was measured using the SLEDAI-2K score. Aortic pulse wave velocity (aPWV) was measured using PulseTrace 3600 (Micromedical) and carotid plaque (CP) and intima–media thickness (IMT) assessed using B-mode Doppler US.Results. Seventy-five women with SLE were recruited with a median (interquartile range) disease duration of 16 (8–27) years. Patients with vitamin D deficiency had higher BMI (P = 0.014) and insulin resistance (P = 0.023) than those with 25(OH)D >20 ng/ml. Subjects with SLEDAI-2K ≥4 had lower 25(OH)D than those with SLEDAI-2K <4 (median 12.9 vs 20.3 ng/ml, P = 0.031). Aortic stiffness was significantly associated with serum 25(OH)D [log(aPWV) β (95% CI) −0.0217 (−0.038, −0.005), P = 0.010] independently of BMI, CVD risk factors and serum insulin. Adjustment for disease activity reduced the strength of the association. There was no association between 25(OH)D and CP or IMT.Conclusions. Vitamin D deficiency is associated with increased aortic stiffness in SLE, independent of CVD risk factors and insulin. Increased inflammatory disease activity may be the mechanism by which vitamin D deficiency mediates vascular stiffness in this patient group.

Differential effects of low-carbohydrate and low-fat diets on inflammation and endothelial function in diabetes

Objective To characterize acute (postprandial) and chronic (after a 6-month period of weight loss) effects of a low-carbohydrate vs. a low-fat diet on subclinical markers of cardiovascular disease (CVD) in adults with type 2 diabetes. Design At baseline and 6 months, measures of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule (sICAM) and soluble E-selectin were obtained from archived samples ( n=51) of participants randomized in a clinical trial comparing a low-carbohydrate and a low-fat diet. In a subset of participants ( n=27), postprandial measures of these markers were obtained 3 h after a low-carbohydrate or low-fat liquid meal. Endothelial function was also measured by reactive hyperemic peripheral arterial tonometry during the meal test. Paired t tests and unpaired t tests compared within- and between-group changes. Results There were no significant differences observed in postprandial measures of inflammation or endothelial function. After 6 months, CRP (mean±S.E.) decreased in the low-fat arm from 4.0±0.77 to 3.0±0.77 ( P=.01). In the low-carbohydrate arm, sICAM decreased from 234±22 to 199±23 ( P=.001), and soluble E-selectin decreased from 93±10 to 82±10 ( P=.05.) A significant correlation between change in high-density lipoprotein and change in soluble E-selectin ( r=−0.33, P=.04) and with the change in ICAM ( r=−0.43, P=.01) was observed. Conclusions Low-carbohydrate and low-fat diets both have beneficial effects on CVD markers. There may be different mechanisms through which weight loss with these diets potentially reduces CVD risk.

Genome-wide association study identifies genetic variants in GOT1 determining serum aspartate aminotransferase levels

We carried out a genome-wide association study of serum aspartate aminotransferase (AST) activity in 866 Amish participants of the Heredity and Phenotype Intervention Heart Study and identified significant association of AST activity with a cluster of single nucleotide polymorphisms located on chromosome 10q24.1 (peak association was rs17109512; P=2.80E-14), in the vicinity of GOT1, the gene encoding cytosolic AST (cAST). Sequencing of GOT1 revealed an in-frame deletion of three nucleic acids encoding asparagine at position 389 c.1165_1167delAAC (p.Asn389del) in the gene. Deletion carriers had significantly lower AST activity levels compared with homozygotes for the common allele (mean±s.d.: 10.0±2.8 versus 18.8±5.2 U l(-1); P=2.80E-14). Further genotyping of the deletion in other Amish samples (n=1932) identified an additional 20 carriers (minor allele frequency (MAF)=0.0052). The deletion was not detected in 647 outbred Caucasians. Asn at codon 389 is conserved among known mammalian cASTs. In vitro transient transfection of wild-type and mutant cAST indicated that mutant cAST protein was barely detectable in the cells. Furthermore, even after correction for cAST expression, mutant cAST had markedly diminished enzymatic activity. Remarkably, we did not find any association between the deletion and metabolic traits including serum fasting glucose or insulin, fasting and post-meal lipids, inflammatory markers, or sub-clinical markers of cardiovascular disease. In conclusion, we discovered a rare in-frame deletion in GOT1 gene, which inactivates cAST enzyme in the Old Order Amish. This finding will help us to understand structure and function of the enzyme and would be useful for predicting serum AST levels.

A Detailed Cardiovascular Characterization of Obesity Without the Metabolic Syndrome

Although obesity without metabolic disturbances has been regarded as harmless, we have recently shown that obese subjects without the metabolic syndrome (MetS) has an increased risk of cardiovascular (CV) disorders and mortality during long-term follow-up. To investigate the basis for that increased risk, we studied the impact of obesity without MetS on multiple markers of subclinical CV disease. At age 70, 1016 subjects were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors study. According to body mass index (BMI)/MetS status, they were categorized as normal weight (BMI <25 kg/m(2)) without MetS (National Cholesterol Education Program criteria, n=319), normal weight with MetS (n=19), overweight (BMI 25 to 29.9 kg/m(2)) without MetS (n=333), overweight with MetS (n=94), obese (BMI ≥30 kg/m(2)) without MetS (n=102), and obese with MetS (n=118). Several different measurements of endothelial reactivity, arterial compliance (plethysmography and ultrasound), carotid artery atherosclerosis, and echocardiography were performed, and 7 markers of coagulation/fibrinolysis were measured. Subjects with obesity without MetS showed impaired vasoreactivity, a more echolucent carotid artery wall, increased left ventricular mass and function together with impaired coagulation/fibrinolysis compared with normal-weight subjects without the MetS (P<0.05 to 0.001). The majority of these disturbances were also seen in overweight subjects without the MetS. In contrast to some previous studies, our data do not support that obesity without MetS is a benign condition, because obesity without MetS was associated with impairments in multiple markers of subclinical CV disease. This was also the case for overweight subjects without the MetS.

Is blunted heart rate decrease at night associated with prevalent organ damage in essential hypertension?

The association between a blunted decrease in day–night heart rate and subclinical organ damage has not been investigated earlier in human hypertension. Therefore, we assessed such an association in a cohort of 658 untreated essential hypertensive patients. All patients underwent procedures including cardiac and carotid ultrasonography, 24-h urine collection for microalbuminuria, ambulatory blood pressure monitoring with simultaneous assessment of heart rate over two 24-h periods within 4 weeks. Nondipping heart rate was defined as a mean heart rate reduction at night lower than 10% compared with daytime values. A reproducible nocturnal dipping (heart rate decrease >10% in both the ambulatory blood pressure monitoring periods) and nondipping profile was found in 513 (78%) and 76 patients (12%), respectively; 69 hypertensive patients (10%) had a variable dipping profile. The three groups did not differ with regard to age, sex, body size, metabolic variables, office and ambulatory blood pressures, left ventricular mass, carotid intima-media thickness, carotid plaque and microalbuminuria. In a univariate analysis, the decrease in nocturnal heart rate did not correlate with any parameter of subclinical organ damage. Our findings from a cross-sectional study do not support the view that a flattened heart rate circadian rhythm is related to a prevalent organ damage in essential hypertension and that this altered pattern is a marker for subclinical cardiovascular disease. The prognostic significance of this finding should be defined by prospective studies.

Stress-induced cardiovascular reactivity and atherogenesis in adolescents

ObjectiveTo examine the association between cardiovascular reactivity to a set of psychological stressors and carotid artery intima-media thickness, a marker of subclinical cardiovascular disease in healthy adolescents. MethodsParticipants were 25 boys and 23 girls age 14.2±0.9 years who were measured for heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure reactivity to mirror-tracing, reaction time, speech preparation and ad lib speech tasks and for common carotid artery intima-media thickness. Sequential regression analyses were used to establish the incremental increase in R2(Rinc2) for the prediction of intima-media thickness due to cardiovascular reactivity independent of age, BMI percentile, sex, socioeconomic status, and resting HR or BP. ResultsSBP reactivity while preparing (β=0.0019, Rinc2=0.09) and giving the speech (β=0.0014, Rinc2=0.10) and an aggregate reactivity score based on all 4 tasks (β=0.0026, Rinc2=0.11) independently predicted (p≤0.05) mean carotid artery intima-media thickness. Neither DBP reactivity nor HR reactivity during any task were independent predictors of intima-media thickness. ConclusionStress-induced cardiovascular reactivity, and especially SBP reactivity, is associated with carotid intima-media thickness and the early pathogenesis of cardiovascular disease. The use of an aggregate stress reactivity index provides a more reliable reflection of trait SBP reactivity to psychological stress and increases the confidence that youth with greater cardiovascular stress reactivity may indeed have greater progression of subclinical cardiovascular disease.

Depressive Symptoms and Subclinical Markers of Cardiovascular Disease in Adolescents

To examine the association between depressive symptoms and subclinical markers of cardiovascular disease (CVD), specifically arterial stiffness, as indexed by pulse wave velocity (PWV), and carotid artery intima media thickening (IMT), in a sample of healthy adolescents, and to explore adolescent hostility as a potential moderator of depression on subclinical markers of CVD. One hundred fifty-seven (n = 157) black and white adolescents between the ages of 16-21 completed a follow-up study of psychosocial stress and cardiovascular risk factors that included measures of PWV and carotid IMT. Psychosocial measures included the Center for Epidemiologic Studies Depression Scale (divided into tertiles), and the Cook-Medley Hostility Inventory subscales. Linear regression models controlled for sociodemographic variables, health behaviors, blood pressure, body mass index, and heart rate. Results show that more severe depressive symptoms were associated with higher levels of PWV (B = .17, R(2) = .30, ΔR(2) = .03, confidence interval = 2.2-47.0, p = .03) but not with higher IMT. Adolescent depression remained a significant predictor of PWV when controlling for adolescent hostility; hostility did not moderate the relationship between adolescent depression and PWV. Depression may be important in the development of arterial stiffness in adolescence. Further research is needed to delineate the relationship in adolescence and young adulthood between depressive symptoms and the pathogenesis of CVD.

Carotid artery intima media thickness associates with skin autofluoresence in non‐diabetic subjects without clinically manifest cardiovascular disease

Skin autofluorescence (skin AF) is determined in part by accumulation of advanced glycation end products. Increased skin AF was shown previously to predict cardiovascular events independently of conventional risk factors. We determined the association of carotid artery intima media thickness (IMT), a marker of subclinical cardiovascular disease, with skin AF in subjects without diabetes or clinically manifest cardiovascular disease. In a cross-sectional observational study, IMT, skin AF, lipids and apolipoproteins, C-reactive protein (CRP), insulin resistance and paraoxonase-1 activity were measured in 59 non-smoking, non-obese subjects without diabetes mellitus and cardiovascular disease (32 women; 12 subjects with metabolic syndrome (MetS)). In univariate analyses, skin AF was correlated with IMT (r = 0.265, P = 0.042), but not significantly with clinical factors, (apo)lipoproteins, CRP, insulin resistance and paraoxonase-1. In multiple linear regression analyses, IMT was determined independently by age (beta = 0.549, P < 0.001), apo B (beta = 0.236, P = 0.022) and skin AF (beta = 0.216, P = 0.035). IMT was also associated with skin AF (beta = 0.213, P = 0.046) in a model which included the presence of MetS. IMT is positively related to skin AF, independently of clinical factors, (apo)lipoproteins and MetS, suggesting that skin AF represents a determinant of subclinical atherosclerosis. Increased skin AF may reflect early abnormalities in processes involved in atherosclerosis development.

Uncontrolled isolated office hypertension is associated with subclinical markers of cardiovascular disease in hypertensive type 2 diabetic patients

Isolated office hypertension (IOH) has been associated with structural cardiac abnormalities; however, its relation to worse cardiovascular prognosis remains uncertain. Less is known regarding the consequences of uncontrolled IOH in treated hypertensives. The aim was to investigate whether uncontrolled IOH was independently associated with two subclinical markers of cardiovascular disease, aortic stiffness and left ventricular hypertrophy (LVH). Clinical laboratory and 24-h ambulatory blood pressure (BP) data were obtained in 523 hypertensive patients with type 2 diabetes. Controlled office-ambulatory hypertension was defined by office blood pressure <140/90 mm Hg and 24-h BP <130/80 mm Hg, whereas uncontrolled IOH by office blood pressure> or =140/90 mm Hg and 24-h BP <130/80 mm Hg. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) and left ventricular mass index (LVMI) by echocardiography. Statistics included multivariate linear and logistic regressions. According to BP patterns, 152 patients (29.1%) had controlled office-ambulatory hypertension, and 172 (32.9%) had uncontrolled IOH. Patients with uncontrolled IOH had greater LVMI (62.0+/-21.9 vs. 52.9+/-17.0 g m(-2.7), P<0.001) and PWV (11.5+/-2.4 vs. 10.2+/-2.1 m s(-1), P<0.001) than those with controlled hypertension. On linear model, after adjustment for several potential confounders, patients with uncontrolled IOH persisted with higher PWV (P=0.003) and LVMI (P=0.015). On logistic regression, the presence of uncontrolled IOH was independently associated with 2.7-fold (95% CI: 1.3-5.5) and 2.1-fold (95% CI: 1.1-4.0) higher risks of having increased aortic stiffness and LVH, respectively. In conclusion, uncontrolled IOH is associated with increased aortic stiffness and LVH in hypertensive type 2 diabetic patients. This may be a link to augmented cardiovascular risk.

Semiquantitative Assessment of Cardiovascular Disease Markers in Multislice Computed Tomography of the Chest

To investigate the interobserver and intraobserver agreements for the semiquantitative assessment of markers of subclinical cardiovascular disease as identified by routine care, diagnostic computed tomography (CT) of the chest, to improve the quality of reporting of these incidental findings. Two observers independently evaluated 109 consecutive chest CT scans in routine care, clinical patients from one tertiary referral center. All nongated, contrast-enhanced scans were acquired on a 16-slice CT scanner. Images were scored for the presence of aortic wall abnormalities and calcifications of the coronary artery, the heart valves, the thoracic aorta, and the proximal supraaortic arteries. Furthermore, the presence of left ventricular scarring and elongation of the aorta were recorded. All markers were scored on a semiquantitative scale. Interobserver and intraobserver agreements are presented as weighted kappa and intraclass correlation coefficients. Interobserver and intraobserver agreements for individual markers were good to excellent, with weighted kappa coefficients of 0.54 to 0.89 for interobserver agreement and 0.55 to 0.96 for intraobserver agreement. Semiquantitative assessment of subclinical cardiovascular disease markers in routine care, diagnostic chest CT scans is possible with good to excellent interobserver and intraobserver agreements. Use of these definitions in clinical practice will enable a more standardized assessment and reporting of incidental findings in diagnostic chest CT.

The epidemiology of subclavian stenosis and its association with markers of subclinical atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA)

BackgroundRecent 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. MethodsWe defined SS by an absolute SBPD ≥15mmHg. 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. ResultsOf 6743 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=1.12/10mmHg; 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). ConclusionsThe subclavian stenosis is positively associated with other markers of subclinical atherosclerosis.

The importance of considering both racial and socioeconomic disparities: A response to Collins and Alpert

We thank Collins and Alpert for their interest in and attention to our work in their commentary in this issue (Collins and Alpert, 2009). We also thank them for highlighting their recent publication (Collins, Somes, & Alpert, 2008) demonstrating racial/ethnic differences in pulse wave velocity (PWV) based on brachial-ankle compliance (as opposed to carotid-femoral PWV in our study). Collins and Alpert indicate that our publication “only confirms previously published work” (Collins and Alpert, 2009). We agree that important prior work does demonstrate racial/ethnic differences in PWV. However, race/ethnicity and socioeconomic status (SES) have not been examined jointly, particularly in relation to markers of subclinical cardiovascular disease (SCD) among adolescents. This joint analysis is important given that African American adults and youth are more often in lower SES positions. Thus, SES and race can be confounded when examined in isolation. We are interested in their relative associations with SCD. Collins and Alpert interpreted our findings to indicate that the only SES marker related to PWV in multivariable models was income (Collins and Alpert, 2009). We would like to clarify our findings. In multivariable models (controlling for age, gender, race/ethnicity, BMI, and SBP), income, neighborhood SES, and to a lesser extent education were all inversely related to PWV. Only when education and income were examined together in the same model (only individual-level predictors were in this last model) were significant effects observed for income alone in relation to PWV. In models stratified by race, we further found that low income was related to higher PWV primarily among African Americans, and low education was related to higher PWV primarily among Caucasians. We suggest that Collins and Alpert may find it informative to examine the joint association of race and SES in their adolescent sample. Collins and Alpert question the clinical significance of our study findings given these race-specific findings. We do not believe these race-specific findings diminish the clinical significance of the overall study results. In fact, we believe they underscore that all SES indicators are not interchangeable, particularly across racial/ethnic groups. However, we urge readers to interpret these racial differences, particularly with respect to income, with caution given the low representation of Caucasians in the low income group. In a related point, Collins and Alpert recommend comparing low SES Caucasians with high SES African Americans to understand the effect of SES on arterial stiffness. While this comparison is certainly an interesting one, we believe that it is more important to have the full SES range represented within both racial/ethnic groups to tease out the relative contributions of SES and race to health disparities. However, as we observed, given the concentration of African Americans within positions of poverty within the United States, this is not easily accomplished in population-based research. Finally, Collins and Alpert state that “Before we can accept that racial differences in cardiovascular risk are closely related to SES, and perhaps not due to inherent genetic differences as the majority of extant literature would suggest, stronger and more consistent statistical results need to be found and reported” (Collins and Alpert, 2009). They thereby raise the specter of what has been termed “stormy debates over race, genetics, and health disparities” (Krieger, 2005). Our intention was not to address the issue of genetic versus environmental origins of disparities in our publication, nor are we attempting to attribute racial/ethnic differences in health solely to SES differences. Moreover, while Collins and Alpert’s caution against assuming that racial/ethnic differences reflect SES differences per se, we also caution against the tendency to attribute phenotypic differences by race/ethnicity to genotypic differences. Quoting from the American Academy of Pediatrics’ Committee on Pediatric Research Report of Race/Ethnicity, Gender, and Socioeconomic Status: “Racial disparities in health generally do not reflect biologically determined differences in the genome or physiology. Indeed, genetic differences between racial groups are small compared with genetic differences within groups, so racial differences in diseases are, to a significant degree, currently unexplained” (2000; 1349). In sum, there is yet much to be learned about the early development of SCD in adolescents of all racial backgrounds.