Toxic Metals and Subclinical Atherosclerosis in Carotid, Femoral, and Coronary Vascular Territories: The Aragon Workers Health Study.

OBJECTIVE: Studies evaluating the association of metals with subclinical atherosclerosis are mostly limited to carotid arteries. We assessed individual and joint associations of nonessential metals exposure with subclinical atherosclerosis in 3 vascular territories. Approach and Results: One thousand eight hundred seventy-three Aragon Workers Health Study participants had urinary determinations of inorganic arsenic species, barium, cadmium, chromium, antimony, titanium, uranium, vanadium, and tungsten. Plaque presence in carotid and femoral arteries was determined by ultrasound. Coronary Agatston calcium score ≥1 was determined by computed tomography scan. Median arsenic, barium, cadmium, chromium, antimony, titanium, uranium, vanadium, and tungsten levels were 1.83, 1.98, 0.27, 1.18, 0.05, 9.8, 0.03, 0.66, and 0.23 µg/g creatinine, respectively. The adjusted odds ratio (95% CI) for subclinical atherosclerosis presence in at least one territory was 1.25 (1.03-1.51) for arsenic, 1.67 (1.22-2.29) for cadmium, and 1.26 (1.04-1.52) for titanium. These associations were driven by arsenic and cadmium in carotid, cadmium and titanium in femoral, and titanium in coronary territories and mostly remained after additional adjustment for the other relevant metals. Titanium, cadmium, and antimony also showed positive associations with alternative definitions of increased coronary calcium. Bayesian Kernel Machine Regression analysis simultaneously evaluating metal associations suggested an interaction between arsenic and the joint cadmium-titanium exposure. CONCLUSIONS: Our results support arsenic and cadmium and identify titanium and potentially antimony as atherosclerosis risk factors. Exposure reduction and mitigation interventions of these metals may decrease cardiovascular risk in individuals without clinical disease.

Elevated N-acetyl-ß-d-glucosaminidase, a urinary tubular damage marker, is a significant predictor of carotid artery atherosclerosis in type 1 diabetes, independent of albuminuria: A cross-sectional study.

AIMS: Recent evidence has shown that renal tubulointerstitial injuries play an important role in diabetic nephropathy. In this study, we evaluated the association between urinary N-acetyl-ß-d-glucosaminidase (uNAG), an early renal tubular damage marker, and carotid artery atherosclerosis in patients with type 1 diabetes (T1D). METHODS: This was a cross-sectional study of 88 patients with T1D. Demographic and laboratory data; urinary indices, including urinary NAG-to-creatinine ratio (uNCR), and albumin-to-creatinine ratio (uACR); and carotid ultrasonography were investigated. RESULTS: Eighty-eight subjects were divided into three groups based on uNCR tertiles. Subjects belonging to the highest tertile of uNCR had the highest average mean and maximum carotid intima-media thickness (IMT). An elevated uNCR was also significantly correlated with increased average mean and maximum carotid IMT, whereas an elevated uACR was not. Even after adjusting for confounding factors, uNCR continued to be a meaningful predictive marker for increased average mean and maximum IMT. Conversely, the uACR could not predict carotid IMT after adjustment for confounding factors. CONCLUSIONS: Elevated levels of uNAG are significantly associated with carotid artery atherosclerosis in patients with T1D independently of albuminuria, a marker of glomerular damage.

The renal tubular damage marker urinary N-acetyl-ß-D-glucosaminidase may be more closely associated with early detection of atherosclerosis than the glomerular damage marker albuminuria in patients with type 2 diabetes.

BACKGROUND: To determine the association between urinary N-acetyl-ß-D-glucosaminidase (NAG), a marker of renal tubulopathy, and carotid intima-media thickness (IMT) and plaques in patients with type 2 diabetes mellitus (T2D) and to compare the predictive value of NAG versus albuminuria, a marker of renal glomerulopathy. METHODS: A total of 343 participants were enrolled in this retrospective cross-sectional study. We recruited participants with T2D who were tested for blood glucose parameters, urinary NAG, and urinary albumin-to-creatinine ratio (ACR) and had been checked for carotid ultrasonography. RESULTS: We classified participants into a below-median urinary NAG group (Group I; n = 172) or an above-median group (Group II; n = 171). Mean, maximum, and mean of maximum carotid IMT and the proportion of patients with carotid plaques were significantly higher in Group II compared with Group I. In multiple linear regression analyses, high urinary NAG (Group II) was significantly associated with carotid IMT, independently of urinary ACR and other confounding factors. In terms of carotid plaques, both urinary NAG and ACR were significantly higher in participants with carotid plaques than in those without carotid plaques. After adjustment for confounding factors, both urinary NAG and ACR were significantly associated with the presence of carotid plaques. CONCLUSIONS: Elevated urinary NAG, a marker of renal tubular damage, was related to increased carotid IMT and the presence of carotid plaques in patients with T2D. Urinary NAG may be a more sensitive biomarker than urinary albumin for early detection of atherosclerosis.

Association between plasma homocysteine levels and end-organ damage in newly diagnosed type 2 diabetes mellitus patients.

PURPOSE: The aim of the present study was to investigate the association between plasma homocysteine (Hcy) levels and carotid, cardiac, and renal end-organ damage in newly diagnosed type 2 diabetes mellitus (T2DM) patients. METHODS: Newly diagnosed normotensive T2DM patients (n = 390) were enrolled in this study. The patients were not taking any medications over the duration of the study. The left ventricular mass index (LVMI), carotid intima media thickness (CIMT), and creatinine levels and 24-h microalbuminuria were used to determine cardiac, carotid, and kidney end-organ diseases, respectively. RESULTS: Using univariate logistic regression analysis; age, 24-h microalbuminuria, fasting blood glucose, CIMT, creatinine level, and LVMI were found to be significantly associated with the Hcy level. When those six variables were included in a multivariate regression model, CIMT, LVMI, and creatinine were found to be significantly associated with the Hcy level. We determined that an Hcy level >12.5 µmol/L was predictive of high LVMI, with a sensitivity of 70.1% and a specificity of 68%. An Hcy level >13.5 µmol/L was predictive of high CIMT, with a sensitivity of 67.5% and a specificity of 63.1%. CONCLUSION: In this study, LVMI, CIMT, and creatinine level were positively correlated with the Hcy level. We believe that the Hcy level may be a useful predictor of end-organ damage, including cardiac, carotid, and renal diseases, in newly diagnosed T2DM patients.

Urinary Sodium and Potassium Excretion and Carotid Atherosclerosis in Chinese Men and Women.

Limited studies have examined the association between sodium (Na) and potassium (K) levels and the risk of atherosclerosis. This study examined whether higher Na and Na/K levels and low K levels were independent risk factors for atherosclerosis. This community-based cross-sectional study included 3290 subjects (1067 men and 2223 women) 40 to 75 years of age in Guangzhou, China, between 2011 and 2013. Urinary excretion of Na and K were measured from the first morning void, and creatinine-adjusted values were used. The intima-media thickness (IMT) of the carotid common artery and the carotid bifurcation was measured with high-resolution B-mode ultrasonography. Dietary K and Na intake and other covariates were obtained by face-to-face interviews. A significant positive association was seen between urinary Na excretion and carotid atherosclerosis after adjustment for age, sex, and other lifestyle covariates. The odds ratios (OR) and 95% confidence interval (CI) of the highest (vs. lowest) quartile of urinary Na were 1.32 (1.04-1.66) for carotid plaques, 1.48 (1.18-1.87) for increased common carotid artery IMT, and 1.55 (1.23-1.96) for increased carotid bifurcation IMT (all p-trend < 0.01). A similar positive association was observed between urinary Na/K levels and carotid plaque and increased IMT, and between dietary Na intake and increased bifurcation IMT. Regarding potassium data, we only found a significantly lower presence of carotid plaque (OR 0.72, 95% CI 0.57-0.91) for quartile 2 (vs. 1) of urinary K. Our findings suggest that higher levels of urinary excretion Na and Na/K are significantly associated with greater presence of carotid atherosclerosis in Chinese adults.

High normal albuminuria is associated with arterial stiffness and carotid atherosclerosis in Korean patients with type 2 diabetes.

BACKGROUND AND AIMS: Current evidence suggests that high normal albuminuria is significantly associated with increased cardiovascular risk. This study investigated the association between urine albumin-to-creatinine ratio (ACR) within the normal range and subclinical atherosclerosis in Korean patients with type 2 diabetes. METHODS AND RESULTS: This cross-sectional study involved 521 type 2 diabetic patients with normoalbuminuria. Brachial-ankle pulse wave velocity (baPWV) measurement and ultrasound assessment of carotid atherosclerosis was done. Subclinical atherosclerosis was assessed by the presence of high baPWV (>1682 cm/s), carotid atherosclerosis (intima-media thickness >0.8 mm or the presence of plaques), and carotid stenosis (≥50% of luminal narrowing). Across the tertiles of ACR, there was a trend for an increasing prevalence of high baPWV (16.8%, 20.0%, and 38.2%, P < 0.001), carotid atherosclerosis (46.9%, 55.4%, and 64.7%, P < 0.001), and carotid stenosis (12.7%, 16.0%, and 30.1%, P < 0.001). In multivariate analysis, patients in the highest ACR tertile had an odds ratio of 2.05 (95% confidence interval [CI], 1.13-3.72, P = 0.019) for high baPWV, 1.78 (95% CI, 1.08-2.93, P = 0.024) for carotid atherosclerosis, and 2.72 (95% CI, 1.44-5.11, P = 0.002) for carotid stenosis compared to those in the lowest tertile. The relation of ACR with carotid atherosclerosis and stenosis remained significant even in patients without diabetic retinopathy. CONCLUSION: High normal albuminuria was significantly associated with atherosclerotic vascular changes, independent of retinopathy and other cardiovascular risk factors. High normal albuminuria may be an early marker for subclinical atherosclerosis in type 2 diabetes.

Decreased urine uric acid excretion is an independent risk factor for chronic kidney disease but not for carotid atherosclerosis in hospital-based patients with type 2 diabetes: a cross-sectional study.

BACKGROUND: The associations between urine uric acid excretion (UUAE) and chronic kidney disease (CKD)/atherosclerosis have not been investigated. Our aims were to investigate the relationships between UUAE and CKD and carotid atherosclerotic lesions in hospitalized Chinese patients with type 2 diabetes. METHODS: This was a cross-sectional study that was conducted with 2627 Chinese inpatients with type 2 diabetes. UUAE was determined enzymatically using a single 24-h urine collection. The subjects were stratified into quartiles according to their UUAE levels. Carotid atherosclerotic lesions, including carotid intima-media thickness (CIMT), plaque and stenosis, were assessed by Doppler ultrasound. Both CKD and carotid atherosclerotic lesions were compared between the UUAE quartile groups. RESULTS: After adjustment for confounding factors, there was a significant decrease in the prevalence of CKD in the patients with type 2 diabetes across the UUAE quartiles (16.9%, 8.5%, 5.9%, and 4.9%; p < 0.001). Multiple logistic regression analyses revealed that the UUAE quartiles were significantly and inversely associated with the presence of CKD (p < 0.001). Compared with the diabetics in the highest UUAE quartile, those in the lowest quartile exhibited a nearly 4.2-fold increase in the risk of CKD (95% CI: 2.272-7.568; p < 0.001). The CIMT value (0.91 ± 0.22 mm for the diabetics with CKD and 0.82 ± 0.20 mm for the diabetics without CKD, p = 0.001) and the prevalence of carotid plaques (62.1% for the diabetics with CKD and 41.8% for the diabetics without CKD, p = 0.025) were significantly higher in the diabetics with CKD than in those without CKD. However, there was no obvious difference in carotid atherosclerotic lesions across the UUAE quartiles after controlling for the confounding factors. CONCLUSIONS: Decreased UUAE was closely associated with the presence of CKD but not with carotid atherosclerotic lesions in hospitalized Chinese patients with type 2 diabetes. Our results suggest that UUAE is an independent risk factor for CKD in type 2 diabetes. In selected populations, such as patient with type 2 diabetes, the role of uric acid in atherosclerosis might be the result of other concomitant atherosclerotic risk factors, such as CKD.

Higher normal ranges of urine albumin-to-creatinine ratio are independently associated with carotid intima-media thickness.

BACKGROUND: High normal values of urine albumin-to-creatinine ratio (UACR) have been reported to have predictive values for hypertension, incident stroke, and higher mortality in the general population. This study aimed to investigate the association between normal ranges of UACR and carotid intima-media thickness (CIMT) in adult population. METHODS: We performed a cross-sectional study in adults aged 45 to 74 years who were living in Namwon City, South Korea. Both common CIMTs were measured, and mean values were calculated. Normal values of UACR were defined as <30mg/g and categorized into quintiles; less than 6.50, 6.51-9.79, 9.80-13.49, 13.50-18.89, and more than 18.90 mg/g. The association between the quintiles of UACR and common CIMT was analyzed and stratified by sex. RESULTS: A total of 7555 participants (3084 men and 4471 women) with normal UACR were enrolled in the present study. Common CIMT was positively and independently associated with increasing quintiles of UACR in men and women, even after adjusting for potential confounders including age and cardiovascular risk factors. Compared to the first quintile, the fifth quintile showed odds ratios of 1.80 (95% confidence intervals, 1.26-2.55) and 1.97 (1.28-3.04) for increased CIMT (>0.9mm) in men and women, respectively. CONCLUSION: Higher UACR values within normal ranges (<30 mg/g) were positively and independently associated with CIMT in a Korean general population, suggesting that higher normal values of UACR might be a risk marker of subclinical carotid atherosclerosis.

Plaque regression in one artery is not necessarily associated with parallel changes in other vascular beds.

It remains unclear whether atherosclerosis in one vascular bed progresses in parallel with that in other vascular beds. We investigated serial changes in vessel wall areas (VWAs) in various vessels over 2 years of follow-up. Vessel wall areas in the thoracic descending aorta (TDA), common carotid artery (CCA), right (RCA), and left main trunk (LMT) of coronary artery were determined in 52 patients with coronary artery disease (CAD) using 64-slice multidetector computed tomography. Plasma levels of high-sensitivity CRP (hs-CRP) and matrix metalloproteinase (MMP)-9, as well as urinary 8-iso-prostaglandin F2α (PGF2α) were determined at the baseline. After the follow-up period, plaque progression in a specific vessel did not parallel that of other vessels, although changes in TDA-VWAs were weakly correlated with those of LMT-VWAs. Basal levels of hs-CRP, MMP-9, and PGF2α did not predict progression or regression of VWAs in any vessels. Multivariate analyses showed that LDL-cholesterol < 100 mg/dl and use of statin emerged as predictors of regressing VWAs in TDA (p < 0.05 and p < 0.05, respectively) and LMT (p < 0.05 and p = 0.13, respectively). Changes in soft plaques over 2 years paralleled those of VWAs in both coronary arteries. In conclusion, the progression or regression of atherosclerotic plaques is inhomogeneous among the vascular beds of patients with CAD.

Association of carotid intima-media thickness with progression of urine albumin-creatinine ratios in The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: The association between measures of subclinical cardiovascular disease and progression of urine albumin-creatinine ratios (UACRs) over time is uncertain. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: The Multi-Ethnic Study of Atherosclerosis (MESA), a cohort of adults aged 45-84 years without baseline clinical cardiovascular disease. Examinations were completed approximately every 1.5 years, and UACR was measured during the first 3 examinations. Analysis was limited to 4,878 participants without baseline micro- or macroalbuminuria. PREDICTOR: 1-standard deviation (SD) unit difference in baseline maximum common and internal carotid intima-media thickness (CIMT) measured using ultrasonography. OUTCOMES & MEASUREMENTS: Baseline UACR was categorized as normal or high-normal. UACR progression was categorized as no progression (consistent UACR category across all 3 examinations or regression to a lower category) and definite progression (higher UACR category at examination 2 compared with baseline, then stabilizing or progressing at examination 3). UACR changes not consistent with definite or no UACR progression were classified as intermediate UACR progression. Change in log UACR also was examined. RESULTS: In the 4,878 participants, median baseline UACR was 4.6 mg/g (range, 0.4-24.6 mg/g). Definite and intermediate UACR progression was noted in 279 and 807, respectively. Every 1-SD unit difference in common CIMT was associated with a 22% increased adjusted odds of definite compared with no UACR progression (95% CI, 1.07-1.41). No significant association was noted between 1-SD unit difference in maximum internal CIMT and definite UACR progression after adjusting for covariates (OR, 1.08; 95% CI, 0.96-1.21). In the mixed-effects model, changes in log UACR were 0.029 (95% CI, 0.012-0.046) and 0.019 mg/g (95% CI, 0.001-0.037) per 1-SD difference in maximum common and internal CIMT after adjustment for covariates, respectively. LIMITATIONS: UACR was measured in a single spot urine specimen at each exam. CONCLUSION: Higher common CIMT is associated with UACR progression.

Urinary adiponectin excretion: a novel marker for vascular damage in type 2 diabetes.

OBJECTIVE: Markers reliably identifying vascular damage and risk in diabetic patients are rare, and reports on associations of serum adiponectin with macrovascular disease have been inconsistent. In contrast to existing data on serum adiponectin, this study assesses whether urinary adiponectin excretion might represent a more consistent vascular damage marker in type 2 diabetes. RESEARCH DESIGN AND METHODS: Adiponectin distribution in human kidney biopsies was assessed by immunohistochemistry, and urinary adiponectin isoforms were characterized by Western blot analysis. Total urinary adiponectin excretion rate was measured in 156 patients with type 2 diabetes who had a history of diabetic nephropathy and 40 healthy control subjects using enzyme-linked immunosorbent assay. Atherosclerotic burden was assessed by common carotid artery intima-media-thickness (IMT). RESULTS: A homogenous staining of adiponectin was found on the endothelial surface of glomerular capillaries and intrarenal arterioles in nondiabetic kidneys, whereas staining was decreased in diabetic nephropathy. Low-molecular adiponectin isoforms ( approximately 30-70 kDa) were detected in urine by Western blot analysis. Urinary adiponectin was significantly increased in type 2 diabetes (7.68 +/- 14.26 vs. control subjects: 2.91 +/- 3.85 microg/g creatinine, P = 0.008). Among type 2 diabetic patients, adiponectinuria was associated with IMT (r = 0.479, P < 0.001) and proved to be a powerful independent predictor of IMT (beta = 0.360, P < 0.001) in multivariable regression analyses. In a risk prediction model including variables of the UK Prospective Diabetes Study coronary heart disease risk engine urinary adiponectin, but not the albumin excretion rate, added significant value for the prediction of increased IMT (P = 0.007). CONCLUSIONS: Quantification of urinary adiponectin excretion appears to be an independent indicator of vascular damage potentially identifying an increased risk for vascular events.

Microalbuminuria, but not cystatin C, is associated with carotid atherosclerosis in middle-aged adults.

BACKGROUND: Cystatin C, a marker of renal function, has been shown to be an independent predictor of cardiovascular disease (CVD) in older adults, but few data are available in middle-aged adults. Moreover, no study has compared cystatin C and microalbuminuria as risk factors for CVD outcomes in middle-aged adults, and it is not known whether cystatin C is related to an early stage of atherosclerosis. METHODS: We evaluated the relationships between serum creatinine, estimated glomerular filtration rate (GFR), serum cystatin C (all divided into tertiles), microalbuminuria and carotid atherosclerosis in a population-based random sample of 523 adults aged 35-64 years from the Seychelles (Indian Ocean). GFR was estimated using the modification of diet in renal disease (MDRD) equation. Intima-media thickness (IMT) was assessed by B-mode ultrasound. RESULTS: The mean age of the study sample was 52 years, and 55% were women. Carotid IMT was higher in participants with microalbuminuria (802 vs 732 microm, P<0.001) and was inversely associated with GFR tertiles (from 728 to 809 microm, P for trend=0.002). IMT was not associated with cystatin C or creatinine (P for trend=0.10 and 0.16, respectively). In multivariate analyses adjusted for cardiovascular risk factors, the association between microalbuminuria and IMT remained (P=0.047), while the association between GFR and IMT disappeared (P for trend=0.33). CONCLUSIONS: Microalbuminuria, but not cystatin C, is associated with carotid atherosclerosis beyond traditional cardiovascular risk factors among middle-aged adults. Cystatin C does not have a stronger relationship with carotid atherosclerosis in middle-aged adults than creatinine.

Relationship between serum uric acid concentration, metabolic syndrome and carotid atherosclerosis.

OBJECTIVE: Carotid intima-media thickness (IMT) is a useful surrogate marker of cardiovascular disease. Associations between hyperuricemia, metabolic syndrome and carotid IMT have been reported, but few of the studies have been conducted in a Japanese population. METHODS: A total of 1,128 subjects (498 men aged, 68+/-14 years and 630 women aged 72+/-12 years) were divided into 4 groups according to serum uric acid (SUA) quartiles. We first investigated the association between SUA concentrations and metabolic syndrome; then, we assessed whether there is an independent association of SUA with carotid IMT in a population subdivided according to gender and metabolic syndrome status. RESULTS: In women, the prevalence of visceral obesity and metabolic syndrome were significantly increased with increased SUA quartiles, but not in men. After adjusting for age, smoking status, LDL-cholesterol, creatinine and history of diabetes mellitus, the odds ratios (95% CI) of sex-specific quartiles of SUA for metabolic syndrome were 1.0, 1.37 (0.79-2.37), 1.37 (0.79-2.38), and 1.80 (1.03-3.15) in men, and 1.0, 1.04 (0.56-1.94), 2.35 (1.30-4.22), and 2.20 (1.16-4.20) in women. After adjusting for various known risk factors, the prevalence of carotid atherosclerosis (IMT> or =1.0 mm) was higher in subjects in the second, third and fourth quartiles of SUA concentration with odds ratios (95% CI) of 2.41 (1.08-5.37), 3.33 (1.49-7.42), and 2.73 (1.17-6.35), respectively in men without metabolic syndrome but not in men with metabolic syndrome or in women with or without metabolic syndrome. CONCLUSION: The prevalence of metabolic syndrome was significantly increased according to SUA values only in women. In men without metabolic syndrome, SUA was found to be an independent risk factor for incidence of carotid atherosclerosis.

Effect of plasma homocysteine level and urinary monomethylarsonic acid on the risk of arsenic-associated carotid atherosclerosis.

Arsenic-contaminated well water has been shown to increase the risk of atherosclerosis. Because of involving S-adenosylmethionine, homocysteine may modify the risk by interfering with the biomethylation of ingested arsenic. In this study, we assessed the effect of plasma homocysteine level and urinary monomethylarsonic acid (MMA(V)) on the risk of atherosclerosis associated with arsenic. In total, 163 patients with carotid atherosclerosis and 163 controls were studied. Lifetime cumulative arsenic exposure from well water for study subjects was measured as index of arsenic exposure. Homocysteine level was determined by high-performance liquid chromatography (HPLC). Proportion of MMA(V) (MMA%) was calculated by dividing with total arsenic species in urine, including arsenite, arsenate, MMA(V), and dimethylarsinic acid (DMA(V)). Results of multiple linear regression analysis show a positive correlation of plasma homocysteine levels to the cumulative arsenic exposure after controlling for atherosclerosis status and nutritional factors (P < 0.05). This correlation, however, did not change substantially the effect of arsenic exposure on the risk of atherosclerosis as analyzed in a subsequent logistic regression model. Logistic regression analyses also show that elevated plasma homocysteine levels did not confer an independent risk for developing atherosclerosis in the study population. However, the risk of having atherosclerosis was increased to 5.4-fold (95% CI, 2.0-15.0) for the study subjects with high MMA% (> or =16.5%) and high homocysteine levels (> or =12.7 micromol/l) as compared to those with low MMA% (<9.9%) and low homocysteine levels (<12.7 micromol/l). Elevated homocysteinemia may exacerbate the formation of atherosclerosis related to arsenic exposure in individuals with high levels of MMA% in urine.

Urinary albumin excretion is independently associated with carotid and femoral artery atherosclerosis in the general population.

AIMS: In diabetic patients, increased urinary albumin excretion (UAE), termed microalbuminuria when in the range between 30 and 300 mg/dL per day, is associated with a higher risk of atherosclerosis and its complications. Whether or not this notion applies to the general population is a matter of ongoing controversy because none of the few previous investigations among non-diabetics strictly represent the general community. METHODS AND RESULTS: Urinary albumin-to-creatinine ratio (uACR), a measure of UAE, was assessed from overnight spot urine samples in a population-based cohort of 684 individuals. The ratio was significantly related to age, gender, blood pressure, diabetes, markers of systemic inflammation, liver enzymes, and parathyroid hormone levels (P<0.001 each). Moreover, uACR emerged as a highly significant risk predictor of carotid and femoral artery atherosclerosis in the general community and the non-diabetic subpopulation alike (age/sex-adjusted P<0.001 each). In multivariable logistic regression analyses, odds ratios (95% CI) of carotid and femoral atherosclerosis amounted to 1.28 (1.01-1.61) and 1.44 (1.15-1.81) for a one unit increase in log(e)-transformed uACR (P=0.040 and 0.002). Corresponding odds ratios in non-diabetic subjects were 1.41 (1.09-1.84) and 1.54 (1.19-1.99) (P=0.010 and 0.001). Multivariable linear regression analyses yielded significant, or near significant, relations with carotid and femoral artery intima-media thickness and atherosclerosis scores (P=0.058-0.001). CONCLUSION: The uACR is significantly and independently associated with the presence and severity of atherosclerosis in the general population. The relation obtained was of a dose-response type and extended to levels far below what is termed microalbuminuria. The novel aspects of our study are its focus on various vascular territories and representivity of the general healthy population.

Microalbuminuria is an integrated marker of subclinical organ damage in primary hypertension.

Increased urine albumin excretion is associated with an unfavourable cardiovascular risk profile and prognosis in primary hypertension, even though its pathogenesis is currently unknown. Microalbuminuria (Mi) has been proposed as an integrated marker to identify patients with subclinical organ damage, but its routine use is still too often neglected in clinical practice. The aim of our study was to evaluate the relationship between urinary albumin excretion and early signs of subclinical target organ damage (TOD), namely left ventricular hypertrophy and carotid atherosclerosis in a large group of non diabetic hypertensive patients. A group of 346 never treated patients with primary hypertension (212 men, 134 women, mean age 47 +/- 9 years) referred to our clinic were included in the study. They underwent the following procedures: (1) family and personal medical history and physical examination; (2) clinical blood pressure measurement; (3) routine blood chemistry and urine analysis including determination of urinary albumin excretion (ACR); (4) electrocardiogram; (5) ultrasound evaluation of left ventricular mass (LVMI) and carotid artery thickness (IMT). The overall prevalence of Mi, left ventricular hypertrophy, and carotid plaque was 13, 51, and 24% respectively. Mi was significantly correlated with LVMI (P < 0.0001), IMT (P < 0.0001) and several metabolic and non-metabolic risk factors (blood pressure, body mass index, serum lipids). Cluster analysis identified three subgroups of patients who differ significantly with regards to TOD and albuminuria (P < or = 0.001 for each of the examined variables). Patients with higher IMT and LVMI values also showed increased ACR levels. Furthermore, patients with microalbuminuria were more likely to have both LVH and IMT values above the median for the study population (OR 21, C.I. 4.6-99.97, P < 0.0001). Mi is an integrated marker of subclinical organ damage in patients with primary hypertension. Evaluation of urinary albumin excretion is a specific, cost-effective way to identify patients at higher risk for whom additional preventive and therapeutic measures are advisable.

Cortisol in urine and saliva: relations to the intima media thickness, IMT.

OBJECTIVE: The objective of the study was to analyse the relations between excretion of cortisol in urine and saliva and the intima media thickness (IMT) of the artery carotis communis. DESIGN AND METHODS: In a cross-sectional study, 121 healthy participants completed a comprehensive questionnaire. Additionally, three samples of urine and four samples of saliva were collected in the 24 h before the examination, which included an ultrasound examination of the artery carotis communis, measuring height, weight, hip and waist width, blood pressure after 10 min of rest, and analysis of blood samples for cholesterol, high density lipoprotein (HDL)-cholesterol, and HbA(1c). The highest average of three measurements of IMT immediately before cartosis bulbous from either left or right side was used in the analyses as the dependent variable IMT. RESULTS: Values of cortisol in urine adjusted for creatinine were not related to IMT, but the level of salivary cortisol 1 h after awakening and the reactivity in salivary cortisol the first hour after awakening were significantly associated with IMT in women i.e. high cortisol was associated with low IMT. This result remained significant in multiple regression analysis including age, body mass index (BMI), cholesterol, HbA(1c), and alcohol. CONCLUSION: The reactivity in salivary cortisol the first hour in the morning might be used in research relating to stress, hormonal changes and early atherosclerosis.

Carotid atherosclerosis in adolescents and young adults with IDDM. Relation to urinary endothelin, albumin, free cortisol, and other factors.

OBJECTIVE: To investigate 1) alterations of carotid intimal-plus-medial thickness (IMT) in subjects with IDDM and 2) the relation of IMT to indexes of diabetic angiopathy and to risk factors of atherosclerosis. RESEARCH DESIGN AND METHODS: IMT was assessed by ultrasound B-mode imaging in 39 subjects with IDDM (23 male, 16 female young adults aged 17.5 +/- 5.2 years, diabetes duration 8.8 +/- 5.9) and in 22 control subjects (healthy siblings of the IDDM subjects) of comparable age. Urinary endothelin (UET1) and urinary free cortisol (UFC) were determined by radioammunoassay (RIA), urinary albumin by nephelometry, HbA1c by high-performance liquid chromatography (HPLC), and plasma renin by immunoradiometric assay (IRMA). RESULTS: The IMT values were greater in IDDM subjects than in control subjects (0.49 +/- 0.1 mm, 0.44 +/- 0.09 mm, respectively; P = 0.048) and greater in IDDM male subjects than in control male subjects (0.52 +/- 0.09 and 0.44 +/- 0.06 mm, respectively; P = 0.015), with no difference between IDDM and control female subjects. The IMT values were greater in diabetic male subjects than in female subjects (0.52 +/- 0.09 and 0.45 +/- 0.1 mm, respectively; P = 0.017). In IDDM subjects, but not in control subjects, there was a positive correlation of IMT to urinary albumin (P = 0.008), systolic blood pressure (P = 0.023), UET1 (P = 0.016), UFC (P = 0.002), and BMI (P = 0.021). Multiple regression analysis demonstrated that in IDDM subjects the variable that interacts independently with IMT was the BMI (P = 0.001). CONCLUSIONS: IMT, an index of atherosclerosis (macroangiopathy), is increased in IDDM subjects quite early (already in adolescence), and it is positively related to urinary albumin, UET1, blood pressure, and UFC.

Risk factors for carotid atherosclerosis and platelet activation.

Thromboxane A2 biosynthesis was studied in healthy subjects, in patients in whom the extent of carotid atherosclerosis was determined, and in patients receiving chronic aspirin treatment, to determine what factors activate platelets to develop carotid atherosclerosis. Urinary 11-dehydrothromboxane B2, a major metabolite of thromboxane A2, was measured by radioimmunoassay after purification by reverse-phase HPLC. The extent of carotid atherosclerosis was determined by real-time B-mode ultrasonography. The severity of carotid atherosclerosis in each subject was evaluated by plaque score, which was computed by summing the maximum thickness of plaque measured in millimeters. Urinary excretion of 11-dehydrothromboxane B2 in healthy subjects was higher (P < 0.01) in cigarette smokers (1063 +/- 244 ng/g creatinine) than in non-smokers (815 +/- 183 ng/g creatinine). Aspirin significantly suppressed 11-dehydrothromboxane B2 excretion (266 +/- 114 ng/g creatinine). In the 24 patients in whom the plaque score was measured, multivariate analysis indicated a significant positive correlation between urinary excretion of 11-dehydrothromboxane B2 and plaque score, age, smoking and hypercholesteremia. Our results indicate that risk factors such as age, hypercholesteremia, atherosclerosis and smoking activate platelets in vivo to develop carotid atherosclerosis.