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ABSTRACT: In terms of time, effort and quality, multiplex technology is an attractive alternative for well-established single-biomarker measurements in clinical studies. However, limited data comparing these methods are available.
We measured, in a large ongoing cohort study (n = 574), by means of both a 4-plex multi-array biomarker assay developed by MesoScaleDiscovery (MSD) and single-biomarker techniques (ELISA or immunoturbidimetric assay), the following biomarkers of low-grade inflammation: C-reactive protein (CRP), serum amyloid A (SAA), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). These measures were realigned by weighted Deming regression and compared across a wide spectrum of subjects' cardiovascular risk factors by ANOVA.
Despite that both methods ranked individuals' levels of biomarkers very similarly (Pearson's r all≥0.755) absolute concentrations of all biomarkers differed significantly between methods. Equations retrieved by the Deming regression enabled proper realignment of the data to overcome these differences, such that intra-class correlation coefficients were then 0.996 (CRP), 0.711 (SAA), 0.895 (sICAM-1) and 0.858 (sVCAM-1). Additionally, individual biomarkers differed across categories of glucose metabolism, weight, metabolic syndrome and smoking status to a similar extent by either method.
Multiple low-grade inflammatory biomarker data obtained by the 4-plex multi-array platform of MSD or by well-established single-biomarker methods are comparable after proper realignment of differences in absolute concentrations, and are equally associated with cardiovascular risk factors, regardless of such differences. Given its greater efficiency, the MSD platform is a potential tool for the quantification of multiple biomarkers of low-grade inflammation in large ongoing and future clinical studies.
PLoS ONE 01/2013; 8(3):e58576. · 4.09 Impact Factor
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Marieke H Kroon,
Katja van den Hurk,
Marjan Alssema,
Otto Kamp,
Coen D A Stehouwer, Ronald M A Henry,
Michaela Diamant,
Frans Boomsma,
Giel Nijpels,
Walter J Paulus,
Jacqueline M Dekker
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ABSTRACT: OBJECTIVE
Heart failure is common in individuals with type 2 diabetes and early detection of individuals at risk may offer opportunities for prevention. We aimed to explore: 1) prospective associations of B-type natriuretic peptide (BNP) levels in a non-heart failure range with changes in markers of left ventricular (LV) function, and 2) possible effect modification by type 2 diabetes in a population-based cohort.RESEARCH DESIGN AND METHODS
Echocardiographic measurements were performed at baseline (2000-2001) and follow-up (2007-2009), together with standardized physical examinations and BNP measurements on 300 individuals (mean age 66 years, 32% with type 2 diabetes) of the longitudinal Hoorn Study. Multivariate linear regression analyses were performed to investigate associations of baseline BNP (<100 pg/mL) in individuals without prevalent heart failure at baseline with changes in LV mass index, LV ejection fraction, left atrial volume index, and ratio of early diastolic LV inflow velocity (E) to early diastolic lengthening velocity (e') (E/e').RESULTSIn all individuals, higher BNP was associated with 8-year increases in left atrial volume index. Higher BNP was also associated with increasing LV mass index and E/e'. These associations were significantly stronger in individuals with type 2 diabetes compared with the nonsignificant associations in individuals without type 2 diabetes.CONCLUSIONS
This 8-year follow-up study shows that higher BNP levels in a non-heart failure range were associated with an increased LV mass and deteriorated LV diastolic function, particularly in individuals with type 2 diabetes. This implies that the presence or absence of type 2 diabetes should be taken into account if BNP levels are used to assess future heart failure risk.
Diabetes care 10/2012; · 8.09 Impact Factor
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ABSTRACT: Biomarkers of low-grade inflammation and endothelial dysfunction are associated with cardiovascular disease. Arterial stiffening may be a mechanism through which low-grade inflammation and (or) endothelial dysfunction lead to cardiovascular disease. Therefore, we investigated whether low-grade inflammation and endothelial dysfunction were associated with greater carotid stiffness in a population-based cohort of elderly individuals.
We determined biomarkers of low-grade inflammation (C-reactive protein, serum amyloid A, interleukin 6, interleukin 8, tumour necrosis factor α and soluble intercellular adhesion molecule 1), and of endothelial dysfunction (von Willebrand factor, soluble vascular cell adhesion molecule 1, soluble endothelial selectin, soluble thrombomodulin, soluble intercellular adhesion molecule 1 and flow-mediated dilation), and combined these into mean z-scores (n = 572; women = 286; age 67.5 ± 6.6 years). Additionally, we determined by ultrasonography carotid diameter, distension, pulse pressure and intima-media thickness. Carotid stiffness indices were determined by calculation of the distensibility and compliance coefficient, Young's elastic modulus and β stiffness index.
The study population was characterized by a high prevalence of cardiovascular disease (46%), hypertension (66%) and the use of lipid-lowering (16%) and antihypertensive (34%) medication. After adjustment for the above in addition to sex, age, glucose tolerance status and current smoking, the low-grade inflammation z-score was positively associated with Young's elastic modulus [β (95% confidence interval) 0.080 (0.021-0.139), P = 0.008]. This association was primarily driven through greater diameter. After adjustment for the variables above, the endothelial dysfunction z-score was not associated with carotid stiffness.
These data suggest that low-grade inflammation, in the elderly, plays an important role in carotid artery remodelling and stiffening.
Journal of hypertension 02/2012; 30(4):744-52. · 4.02 Impact Factor
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ABSTRACT: A healthy diet rich in fish, fruit, and vegetables, moderate in alcoholic beverages, and low in dairy products has been associated with lower circulating concentrations of biomarkers of endothelial dysfunction (ED) and low-grade inflammation (LGI). It is, however, unknown how consumption of these food groups affects ED and/or LGI over time. We measured diet by the computer-assisted crosscheck dietary history method at 36 ± 0.63 y of age (n = 301, women = 161). At 36 and 42 y of age, we measured von Willebrand factor, soluble intercellular adhesion molecule 1 (sICAM-1), soluble endothelial selectin, soluble vascular cell adhesion molecule 1 and soluble thrombomodulin (circulating biomarkers of ED); and C-reactive protein, serum amyloid A, IL-6, IL-8, TNFα, and sICAM-1 (circulating biomarkers of LGI). We investigated the associations between food groups and changes in combined biomarker Z-scores of ED and LGI [higher scores associated with greater risk of (incident) cardiovascular disease]. After adjustment for sex, energy intake, BMI, physical activity, alcohol consumption, smoking behavior, and other food groups, consumption of fish (per 100 g/wk), but none of the other food groups, was inversely associated with changes in ED [β (95%CI) = -0.06 (-0.10; -0.02); P = 0.003] and LGI [-0.05 (-0.09; -0.003); P = 0.036]. Additionally, EPA+DHA intake was inversely associated with changes in ED [β (95%CI) = -0.13 (-0.19; -0.07); P ≤ 0.001] and LGI [-0.09 (-0.16; -0.02); P = 0.013] and explained 83 and 40% of the association between fish and changes in ED and LGI. In conclusion, fish consumption, but not fruit, vegetable, alcoholic beverage, or dairy product consumption, was associated with decreased ED and LGI in healthy adults.
Journal of Nutrition 09/2011; 141(9):1719-25. · 3.92 Impact Factor
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Ronald M A Henry
Atherosclerosis 07/2011; 219(2):390-1. · 3.79 Impact Factor
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ABSTRACT: The metabolic syndrome (MetS) is associated with an increased risk of stroke. Arterial remodeling could play an important role herein as maladaptive remodeling is a risk factor for stroke. The purpose of this study was to investigate whether MetS was associated with maladaptive remodeling of the carotid artery and if any such association was independent of hemodynamic variables.
We studied 385 (n = 195 women) nondiabetic, elderly subjects. A MetS z-score (average of sex-specific z-scores of the five MetS traits) was constructed. Intima-media thickness (IMT) and interadventitial diameter (IAD) were assessed by ultrasonography, and lumen diameter (LD), and circumferential wall stress (CWS) were calculated. Multiple linear regression analysis was used to investigate the association between MetS and carotid remodeling.
After adjustment for age, sex, height, prior cardiovascular disease (CVD), dyslipidemia, and smoking, MetS was independently associated with a greater IAD (regression coefficient (β) per s.d. increase in MetS z-score (95% confidence interval), 0.45 mm (0.28; 0.63)), LD (0.41 mm (0.25; 0.58)) and CWS (5.56 kPa (3.71; 7.42)). These associations were attenuated after additional adjustment for inflammatory, metabolic and particularly hemodynamic variables, but remained statistically significant. No significant association was found between MetS and IMT (0.020 mm (-0.006; 0.046)).
MetS is associated with maladaptive remodeling of the carotid artery, which is the result of changes in LD, IAD, and, to a lesser extent, IMT. This process is independent of hemodynamic variables. Whether this association and process will be observed in a broader population and explains the increased risk of stroke in MetS deserves further study.
American Journal of Hypertension 01/2011; 24(4):429-36. · 3.18 Impact Factor
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ABSTRACT: Myeloperoxidase (MPO), a biomarker related to inflammation, oxidative stress, and nitric oxide scavenging, has been shown to impair endothelium-dependent vasodilation. Because elevated hydrogen peroxide concentrations in diabetic vessels may enhance MPO activity, we hypothesized that a stronger association of MPO with flow-mediated dilation (FMD) may be found in subjects with abnormal glucose metabolism. Myeloperoxidase concentrations were measured in EDTA plasma samples from participants of a population-based cohort study, including 230 subjects with normal glucose metabolism and 386 with abnormal glucose metabolism. Vascular function was expressed as FMD and nitroglycerin-mediated dilation of the brachial artery. In subjects with abnormal glucose metabolism, MPO was negatively associated with FMD (-20.9 [95% confidence interval {CI}, -41.7 to -0.2] -μm change in FMD per SD increment of MPO). This association remained significant after adjustment for nitroglycerin-mediated dilation (-31.1 [95% CI, -50.0 to -12.3]) and was not attenuated after further adjustment for established risk factors. In subjects with normal glucose metabolism, MPO was not significantly associated with FMD (2.0 [95% CI, -16.0 to 20.0]). In conclusion, in subjects with abnormal glucose metabolism, plasma levels of MPO are inversely associated with endothelium-dependent vasodilation, possibly reflecting enhancement of MPO activity by vascular oxidative stress.
Metabolism: clinical and experimental 12/2010; 59(12):1723-9. · 2.59 Impact Factor
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ABSTRACT: We evaluated the associations of diabetic complications and underlying pathology with daily walking activity in type 2 diabetic patients without manifest mobility limitations.
100 persons with type 2 diabetes (mean age 64.5 ± 9.4 years) were studied. Persons with manifest mobility limitations were excluded. Possible determinants measured: peripheral neuropathy, neuropathic pain, peripheral arterial disease, cardiovascular disease, decreased muscle strength (handgrip strength), BMI, depression, falls and fear of falling. Walking activity was measured during one week with a pedometer. Functional capacity was measured with the 6 min walk test, the timed "up and go" test and a stair climbing test.
prevalence of neuropathy (40%) and obesity (53%) was high. Persons took a median of 6429 steps/day. In multivariate regression analysis, adjusted for age and sex, neuropathy was associated with a reduction of 1967 steps/day, decreased muscle strength with 1782 steps/day, and an increase in BMI of 1 kg/m(2) with a decrease of 210 steps/day (all p<0.05). Decreased muscle strength and BMI, but not neuropathy, were associated with outcome of functional capacity tests in multiple regression analysis.
peripheral neuropathy, decreased muscle strength and obesity are strongly associated with walking in persons with type 2 diabetes without manifest mobility limitations.
Diabetes research and clinical practice 10/2010; 91(1):32-9. · 2.16 Impact Factor
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Lian Engelen,
Isabel Ferreira,
Katrien H J Gaens, Ronald M A Henry,
Jacqueline M Dekker,
Giel Nijpels,
Robert J Heine,
Leen M 't Hart,
Marleen M J van Greevenbroek,
Carla J H van der Kallen,
Ellen E Blaak,
Edith J M Feskens,
Hugo Ten Cate,
Coen D A Stehouwer,
Casper G Schalkwijk
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ABSTRACT: Receptor for advanced glycation endproducts (RAGE)-ligand interaction may lead to vascular complications. Genetic variation in RAGE has been shown to alter expression, activity of RAGE or both. We, therefore, investigated whether RAGE single-nucleotide polymorphisms (SNPs) and haplotypes were associated with vascular disease.
Nine tag SNPs that cover the common RAGE gene variation were genotyped in 1291 individuals from two Dutch population-based cohort studies, aged 64.5 +/- 8.6 years, with normal glucose metabolism (44%), impaired glucose metabolism (23%) or type 2 diabetes mellitus (33%). We used multiple regression analyses to compare prevalent cardiovascular disease and markers of atherosclerosis, blood pressure and arterial stiffness across genotypes, and examine effect modification by glucose metabolism status.
In unstratified analyses, no consistent associations between RAGE SNPs and prevalent cardiovascular disease and markers of atherosclerosis were found. However, the AA genotype of SNP rs1800624 (-374T/A) was consistently associated with lower SBP [-5.0 mmHg (95% confidence interval -10.4 to 0.3)] and DBP [-4.2 (-7.2 to -1.3)], pulse pressure [-0.8 (-5.0 to 3.4)] as well as with less arterial stiffness [-0.56 SD (-1.04 to -0.09)] in individuals with normal glucose metabolism, but with higher SBP [6.2 (0.9-11.5)], DBP [2.1 (-0.7 to 5.0)] and pulse pressure [4.1 (-0.2 to 8.4)] in individuals with impaired glucose metabolism or type 2 diabetes mellitus (P for interaction <or=0.05 in all analyses). Similar results were found for a haplotype that includes the -374A allele.
In individuals with normal glucose metabolism, the -374A allele of the RAGE gene is protectively associated with blood pressure and arterial stiffness, whereas in individuals with impaired glucose metabolism or type 2 diabetes mellitus, it is adversely associated with these variables.
Journal of hypertension 02/2010; 28(2):285-93. · 4.02 Impact Factor
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ABSTRACT: Circulating oxidized LDL (oxLDL) levels are strongly correlated to LDL-cholesterol (LDL-c) and apolipoprotein-B100 (apoB100), making it difficult to disentangle their independent contributions to cardiovascular risk. We explored the determinants of oxLDL and the relation between oxLDL and flow-mediated dilation (FMD) of the brachial artery to investigate whether the oxLDL/LDL-c and oxLDL/apoB100 ratios are more informative than the separate variables. FMD of the brachial artery and plasma concentrations of oxLDL, LDL-cholesterol, and apoB100 were measured in 624 men and women (age range 50 to 87 years), participating in a population-based cohort study. OxLDL was strongly correlated with apoB100 (r = 0.82, P < 0.001) and LDL-c (r = 0.67, P < 0.001). Other major independent determinants of oxLDL were sex, HDL-cholesterol, and LDL particle size. LDL-c and apoB100 concentrations were not significantly associated with FMD. After adjustment for age, sex, glucose tolerance status, and Framingham risk score, the oxLDL/apoB100 ratio was negatively related to FMD (P = 0.017). This association was weaker for the oxLDL/ LDL-c ratio (P = 0.062) and absent for oxLDL level (P = 0.27). In contrast to oxLDL, the oxLDL/apoB100 ratio, and to a lesser extent the oxLDL/LDL-c ratio, are related to a functional measure of atherosclerosis. Therefore correction of oxLDL for LDL particle number may improve the clinical usefulness of oxLDL measurement.
The Journal of Lipid Research 10/2008; 50(2):342-9. · 5.56 Impact Factor
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ABSTRACT: Arterial remodeling aims to maintain a constant circumferential wall stress (sigmac). A failing remodeling process is associated with stroke. Data on the relationship between chronic kidney disease and arterial remodeling are scarce.
We investigated the association between a lower glomerular filtration rate (GFR) and microalbuminuria with arterial remodeling of the common carotid artery (CCA) in a population-based study of 806 patients. CCA properties including intima-media thickness and interadventitial diameter (IAD) were assessed. Lumen diameter, circumferential wall tension (CWT), and circumferential wall stress (sigmac) were calculated. GFR was estimated (eGFR) by the Modification of Diet in Renal Disease formula. Albuminuria was expressed as urinary albumin/creatinine ratio.
Mean eGFR was 60.3 (+/-10.8) ml/min/1.73 m2; median urinary albumin/creatinine ratio was 0.57 (range 0.10-26.6 mg/mmol). After adjustment for age, sex, glucose tolerance status, and prevalent cardiovascular disease, eGFR was not independently associated with CCA properties. A greater urinary albumin/creatinine ratio (per quartile) was associated with a greater lumen diameter [regression coefficient beta with 95% confidence interval, 0.14 (0.08-0.20; P < 0.01)], IAD [0.15 (0.09-0.21; P < 0.01)], CWT [0.95 (0.52-1.38; P < 0.01)], and sigmac [1.7 (0.5-2.9; P < 0.01)] but not with a greater IMT [0.01 (-0.002-0.02; P = 0.12)]. Additional adjustments for mean arterial pressure, pulse pressure, and eGFR did not change the results.
Greater albuminuria is independently associated with an increase in lumen diameter and IAD of the CCA. In addition, greater albuminuria is associated with a maladaptive carotid remodeling process as shown by an increase in CWT and sigmac. These findings may explain, why microalbuminuria is associated with a greater risk of cardiovascular disease and especially stroke.
Journal of Hypertension 05/2008; 26(4):791-7. · 4.02 Impact Factor
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ABSTRACT: It has been hypothesized that microvascular dysfunction affects endothelial dysfunction of the large arteries, which may explain the relationship of microvascular disease with macrovascular disease. The aim of the present study was to investigate the relationship of retinal microvascular disorders with endothelium-dependent FMD (flow-mediated vasodilatation) and carotid IMT (intima-media thickness). A total of 256 participants, aged 60-85 years, 70 with normal glucose metabolism, 69 with impaired glucose metabolism and 109 with Type II diabetes, were included in this study. All participants were ophthalmologically examined, including funduscopy and two field 45 degrees fundus photography, and were graded for retinal sclerotic vessel abnormalities and retinopathy. Retinal arteriolar and venular diameters were measured with a computer-assisted method. Brachial artery, endothelium-dependent FMD and carotid IMT were assessed ultrasonically as measurements of endothelial function and early atherosclerosis respectively. After adjustment for age, sex and glucose tolerance status, retinal vessel diameters, retinal sclerotic vessel abnormalities and retinopathy were not significantly associated with FMD. In contrast with other retinal microvascular abnormalities, retinal venular dilatation was associated with increased IMT [standardized beta value (95% confidence interval), 0.14 (0.005-0.25)]. This association was attenuated and lost statistical significance after adjustment for cardiovascular risk factors, in particular after correction for fasting insulin. In the present study, retinal microvascular disorders are not independently associated with impaired FMD. In addition, retinal venular dilatation is associated with increased IMT, although non-significantly after multivariable adjustment for cardiovascular risk factors. Therefore our data provide evidence that retinal microvascular disease is of limited value in risk stratification for future cardiovascular events.
Clinical Science 06/2006; 110(5):597-604. · 4.61 Impact Factor
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ABSTRACT: Mild renal insufficiency has recently been recognized as an important risk factor for cardiovascular disease (CVD). The mechanisms underlying this association are incompletely understood. Increased left ventricular mass (LVM) is an independent risk factor for CVD, which is particularly common in end-stage renal disease (ESRD) and which has been shown to be associated with mild renal insufficiency. Increased arterial stiffness has also been shown to be an independent risk factor for CVD in ESRD and has also been associated with mild renal insufficiency. We hypothesized that the association between mild renal insufficiency and increased LVM could be mediated through increased arterial stiffness, and that this may be one of the pathways linking mild renal insufficiency to CVD. We therefore investigated, in a cross-sectional population-based study, the influence of increased arterial stiffness on the association between renal function and LVM.
The study population consisted of 742 elderly individuals (373 men and 369 women). Renal function was estimated by the serum creatinine level in micromol/L; by the Cockcroft-Gault formula in mL/min and by the Modification of Diet in Renal Disease (MDRD) formula. LVM was obtained by echocardiography.
The mean estimates of renal function in men and women were, respectively, 103.7 (SD 17.0) and 86.8 (SD 11.2) micromol/L for the serum creatinine level; 63.4 (SD 12.9) and 61.4 (SD 11.0) mL/min/1.73 m(2) for the Cockcroft-Gault formula; and 59.7 (SD 10.8) and 60.9 (SD 10.5) mL/min per 1.73 m(2) for the MDRD formula. LVM was 93.1 (SD 26.4) g/m(2) in men and 86.7 (SD 22.3) g/m(2) in women. In men, impaired renal function, as estimated by the Cockcroft-Gault and the MDRD formula, was significantly associated with greater LVM after adjustment for age, glucose tolerance, hypertension, and prior CVD [regression coefficient beta (95% CI), 1.28 (0.22 to 2.33) g/m(2) and 1.63 (0.41 to 2.86) g/m(2) per 5 mL/min/1.73 m(2) decrease, respectively]. However, the association between impaired renal function and increased LVM was not statistically significant after adjustment for arterial stiffness estimates [regression coefficient beta (95% CI), 0.02 (-1.60 to 1.64) g/m(2) and 0.54 (-1.25 to 2.33) g/m(2) per 5 mL/min/1.73 m(2) decrease, respectively]. In women, impaired renal function was not significantly associated with greater LVM.
Our study shows that in a general elderly population, even mild impairment of renal function is associated with adverse changes in left ventricular structure. In men, but not in women, this leads to greater LVM, a process that may be related to increases in arterial stiffness. Importantly, these novel findings suggest that such changes occur early in the process of renal functional deterioration, which may explain, in part, the increase in cardiovascular risk in men with mildly impaired renal function.
Kidney International 09/2005; 68(2):673-9. · 6.61 Impact Factor
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ABSTRACT: The mechanisms that link the metabolic syndrome to increased cardiovascular risk are incompletely understood, especially in young people. We therefore examined whether the metabolic syndrome was associated with arterial stiffness and whether any such associations were independent of cardiopulmonary fitness and subcutaneous trunk fat.
Cross-sectional analyses of data on 364 men and women aged 36 years from the Amsterdam Growth and Health Longitudinal Study (ninth follow-up measurement, year 2000). The prevalence of the metabolic syndrome was defined by a slightly modified National Cholesterol Education Program (NCEP) definition. Arterial stiffness was ultrasonically estimated by distensibility and compliance of the carotid, femoral, and brachial arteries and by the carotid elastic modulus.
The prevalence of the metabolic syndrome in this young adult population was 18.3% in men and 3.2% in women. Individuals with the syndrome compared with individuals without risk factors had 11.2% and 17.0% less distensibility and 9.0% and 18.2% less compliance of the carotid and femoral arteries, respectively, and 15.9% higher carotid elastic modulus. After adjustment for cardiopulmonary fitness and subcutaneous trunk fat, the metabolic syndrome remained significantly associated with stiffness of the carotid but not the femoral artery. In addition, poor cardiopulmonary fitness and high subcutaneous trunk fat were associated with arterial stiffness, and this was independent of the metabolic syndrome.
A modified NCEP definition of the metabolic syndrome identified young individuals with increased arterial stiffness. The mechanisms that link the metabolic syndrome, poor cardiopulmonary fitness, and high subcutaneous trunk fat to greater arterial stiffness overlap but are partly independent of each other.
Archives of Internal Medicine 05/2005; 165(8):875-82. · 11.46 Impact Factor
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ABSTRACT: To estimate the relation of precisely measured regional body composition with peripheral and central arterial stiffness in the elderly.
We investigated 648 participants (mean age 69.0 +/- 6.0 years) of the Hoorn Study, a population-based cohort study. Trunk fat, leg fat, trunk lean and leg lean mass were distinguished by dual-energy X-ray absorptiometry. We used ultrasound to measure the distensibility and compliance of the carotid, femoral and brachial arteries, and carotid Young's elastic modulus, as estimates of peripheral stiffness. As estimates of central stiffness we measured carotid-femoral transit time, aortic augmentation index and systemic arterial compliance.
After adjustment for sex, age, height, mean arterial pressure, leg lean and leg fat mass, a larger trunk fat mass was consistently associated with higher peripheral arterial stiffness (standardized beta (beta) of mean Z-scores of all three large arteries -0.24, P < 0.001). In contrast, larger leg fat mass (beta = 0.15, P = 0.009) and leg lean mass (beta = 0.09, P = 0.20) were associated with lower peripheral arterial stiffness. Trunk or leg fat mass were not associated with central arterial stiffness. Leg lean mass, however, was consistently associated with lower central arterial stiffness (beta = 0.29, P < 0.001).
Trunk fat mass may have adverse effects on peripheral, but not on central arterial stiffness, while leg fat was not harmful and may have a slight protective effect. Larger leg lean mass was the most important determinant of lower central arterial stiffness. These results provide a pathophysiological framework to explain not only the higher cardiovascular risk in individuals with larger trunk fat mass, but also the reduced cardiovascular risk in individuals with larger leg lean and fat mass.
Journal of Hypertension 01/2005; 22(12):2339-47. · 4.02 Impact Factor
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ABSTRACT: Extensive endothelial dysfunction (i.e., affecting many aspects of endothelial function) has been hypothesized to explain why microalbuminuria (MA) is associated with cardiovascular disease risk. However, it is not clear whether MA is specifically associated with impaired endothelial nitric oxide (NO) synthesis in individuals without and with type 2 diabetes.
We did a population-based study in 645 individuals (mean age 68 years; 248 with normal glucose metabolism, 137 with impaired glucose metabolism, and 260 with type 2 diabetes) and investigated associations of MA [present (urinary albumin-creatinine ratio > or = 2 mg/mmol) versus absent, and in four categories (< 2, > or = 2 to 5, > or = 5 to 10, > or = 10 mg/mmol)] with ultrasonically measured brachial artery endothelium-dependent, flow-mediated (FMD; an estimate of endothelial NO synthesis) and endothelium-independent, nitroglycerin-induced vasodilation (NID).
FMD was 0.12 mm in the presence of MA (N=93; 49 with diabetes), and 0.18 in its absence (P=0.002). After adjustment for age, sex, baseline arterial diameter, and other potential confounders, FMD was 0.038 mm (95% CI, 0.001 to 0.075) lower in the presence of MA (P=0.04), and decreased linearly across MA categories [by 0.027 mm (0.007 to 0.046) per category increase of MA; P=0.007]. NID was similar in individuals with and without MA. Results were similar in individuals without and with diabetes.
Microalbuminuria is linearly associated with impaired endothelium-dependent, flow-mediated vasodilation in elderly individuals without and with diabetes. These findings support the concept that impaired endothelial nitric oxide synthesis plays a role in the association of microalbuminuria with cardiovascular disease risk.
Kidney international. Supplement 12/2004;
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ABSTRACT: Type 2 diabetes (DM2) and impaired glucose metabolism (IGM) are associated with an increased cardiovascular disease risk. Impaired endothelial synthesis of nitric oxide (NO) is an important feature of atherothrombosis and can be estimated from endothelium-dependent flow-mediated dilation (FMD). It is controversial whether or not FMD is impaired in DM2 and IGM. We investigated this issue in a population-based setting.
In the study population (n = 650; 246 with normal glucose metabolism (NGM), 135 with IGM and 269 with DM2; mean age: 67.6 years), FMD and endothelium-independent nitroglycerine-mediated dilation (NMD) were ultrasonically estimated from the brachial artery and expressed as the absolute change in diameter in mm. The increase in diameter (mean +/- standard deviation) in NGM, IGM and DM2 was 0.19 +/- 0.15, 0.19 +/- 0.18 and 0.13 +/- 0.17 MD and 0.45 +/- 0.21, 0.43 +/- 0.24 and 0.45 +/- 0.25 for NMD. After adjustment for age, sex, baseline diameter and percentage increase in peak systolic velocity, DM2, as compared to NGM, remained associated with impaired FMD (regression coefficient beta (95%CI)) as compared to NGM, -0.06 mm (-0.09 to -0.03). IGM was not associated with impaired FMD (beta, 0.01 mm (-0.02 to 0.04)). Additional adjustment for conventional cardiovascular risk factors did not alter these associations. Hyperglycemia or hyperinsulinemia explained 2% of the association between DM2 and FMD. NMD was not associated with glucose tolerance.
This study shows that DM2 is independently associated with impaired FMD. Hyperglycemia and hyperinsulinemia contribute minimally to this association. Impaired FMD may therefore, in part, explain the increased cardiovascular disease risk in DM2, whereas the normal FMD in IGM suggests that other forms of endothelial dysfunction are important in explaining the increased cardiovascular disease risk in IGM.
Atherosclerosis 06/2004; 174(1):49-56. · 3.79 Impact Factor
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ABSTRACT: Deteriorating glucose tolerance is associated with an increased cardiovascular disease (CVD) risk. The underlying mechanisms remain unclear. Arterial remodeling is the change in structural properties through time in response to atherogenic and/or hemodynamic alterations and aims to maintain circumferential wall stress constant (sigma(C)). Arterial remodeling has not been studied in relation to glucose tolerance.
The study population consisted of 278 people with normal glucose metabolism, 168 with impaired glucose metabolism, and 301 with type 2 diabetes (DM-2); their mean age was 67.8 years. We assessed carotid intima-media thickness (IMT), interadventitial diameter (IAD), lumen diameter (LD), and sigma(C).
After adjustment for age, sex, height, body mass index, and prior CVD, DM-2 was associated with increased IAD, IMT, and sigma(C) but not LD (regression coefficients: 0.24 mm; 95% confidence interval [CI], 0.07 to 0.41; 0.050 mm; 95% CI, 0.024 to 0.077; 5.00 kPa; 95% CI, 0.92 to 9.08; and 0.13 mm; 95% CI, -0.03 to 0.29, respectively). After additional adjustment for pulse pressure, the association between DM-2 and IAD disappeared, whereas the association with IMT remained. After adjustment, impaired glucose metabolism was not significantly associated with LD (0.12 mm; 95% CI, -0.06 to 0.33), sigma(C) (0.25 kPa; 95% CI, -4.49 to 4.98), IAD (0.08 mm; 95% CI, -0.11 to 0.27), or IMT (0.029 mm; 95% CI, -0.002 to 0.060). However, the IMT regression coefficient was half that of DM-2.
DM-2 is associated with preserved LD at increased IMT, which, however, does not normalize the increased sigma(C). In contrast, impaired glucose metabolism is not associated with changes in LD or IAD, whereas IMT is moderately increased but sigma(C) remains constant. Carotid remodeling in DM-2 thus appears maladaptive, which may explain the increased CVD risk, especially stroke, in DM-2.
Stroke 04/2004; 35(3):671-6. · 5.73 Impact Factor
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ABSTRACT: Type 2 diabetes and impaired glucose metabolism (IGM) are associated with an increased cardiovascular disease (CVD) risk. Increased left ventricular mass (LVM) is thought to increase CVD risk through several unfavorable cardiac changes. Type 2 diabetes and IGM are associated with increased LVM, but the underlying mechanism is unclear. We investigated the association between glucose tolerance status (GTS) and LVM and explored whether any such association could be mediated through increased arterial stiffness, impaired endothelial function, or the presence of atherosclerosis.
We used ultrasound to measure LVM, carotid and femoral stiffness, carotid-femoral transit time, and flow-mediated vasodilation (FMD) and tonometry to estimate compliance and augmentation index. The study population (n = 780) consisted of 287 individuals with normal glucose metabolism (NGM), 179 with IGM, and 314 with type 2 diabetes, and the mean age was 68.4 years.
In women, after adjusting for age, height, BMI, and mean arterial pressure, LVM increased significantly with deteriorating GTS (LVM 157 g in NGM, 155 g in IGM, and 169 g in type 2 diabetes; P for trend <0.018). Additional adjustment for arterial stiffness, FMD, or the presence of atherosclerosis did not materially alter the results, even though these variables were significantly associated with both GTS and LVM. Indexes of hyperglycemia/-insulinemia or insulin resistance explained at most 7% of the association between GTS and LVM. In men, no statistically significant associations were observed.
Our data expand the conceptual view of the pathogenesis of GTS-related changes in LVM because we show that the increase in LVM in women is independent of increased arterial stiffness, impaired FMD, or the presence of atherosclerosis. In addition, we show that this increase in LVM is only minimally explained by indexes of hyperglycemia/-insulinemia or insulin resistance. Our data may, in part, explain the increased CVD risk seen in women with deteriorating GTS.
Diabetes Care 03/2004; 27(2):522-9. · 8.09 Impact Factor
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ABSTRACT: Impaired glucose metabolism (IGM) and type 2 diabetes (DM-2) are associated with high cardiovascular disease risk. Increases in peripheral and central artery stiffness may represent pathophysiologic pathways through which glucose tolerance status leads to cardiovascular disease. Peripheral artery stiffness increases with deteriorating glucose tolerance status, whereas this trend remains unclear for central artery stiffness. Therefore, we investigated the associations between glucose tolerance status and estimates of central arterial stiffness. We performed a population-based study of 619 individuals (normal glucose metabolism, n=261; IGM, n=170; and DM-2, n=188) and assessed central artery stiffness by measuring total systemic arterial compliance, aortic pressure augmentation index, and carotid-femoral transit time. After adjustment for sex, age, heart rate, height, body mass index, and mean arterial pressure, DM-2 was associated with decreased total systemic arterial compliance, increased aortic augmentation index, and decreased carotid-femoral transit time. IGM was borderline significantly associated with decreased total systemic arterial compliance. Respective regression coefficients (95% confidence intervals) for IGM and DM-2 compared with normal glucose metabolism were -0.05 (-0.11 to 0.01) and -0.13 (-0.19 to -0.07) mL/mm Hg for total systemic arterial compliance; 1.1 (-0.2 to 2.5) and 1.6 (0.2 to 3.0) percentage points for aortic augmentation index; and -0.85 (-5.20 to 3.49) and -4.95 (-9.41 to -0.48) ms for carotid-femoral transit time. IGM and DM-2 are associated with increased central artery stiffness, which is more pronounced in DM-2. Deteriorating glucose tolerance is associated with increased central and peripheral arterial stiffness, which may partly explain why both DM-2 and IGM are associated with increased cardiovascular risk.
Hypertension 03/2004; 43(2):176-81. · 6.21 Impact Factor
