Urinary metabolites and risk of coronary heart disease: A prospective investigation among urban Chinese adults.

BACKGROUND AND AIMS: Studies have linked several metabolites to the risk of coronary heart disease (CHD) among Western populations, but prospective studies among Asian populations on the metabolite-CHD association remain limited. METHODS AND RESULTS: We evaluated the association of urinary metabolites with CHD risk among Chinese adults in a nested case-control study of 275 incident cases and 275 matched controls (127 pairs of men and 148 pairs of women). Fifty metabolites were measured by a predefined metabolomics panel and adjusted using urinary creatinine. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). After adjusting for traditional CHD risk factors, urinary tryptophan showed a positive association with incident CHD: OR (95% CI) for the highest vs. lowest quartiles was 2.02 (1.15-3.56) among all study participants (p-trend = 0.02). The tryptophan-CHD association was more evident among individuals with dyslipidemia than among those without the condition (OR [95% CI] for the highest vs. lowest quartiles = 3.90 [1.86-8.19] and 0.74 [0.26-2.06], respectively; p-interaction<0.01). Other metabolites did not show significant associations with CHD risk among all study participants. However, a positive association of methionine with CHD risk was observed only among women (OR [95% CI] for the highest vs. lowest quartiles = 2.77 [1.17-6.58]; p-interaction = 0.03), and an inverse association of inosine with CHD risk was observed only among men (OR [95% CI] for the highest vs. lowest quartiles = 0.29 [0.11-0.81]; p-interaction = 0.04). CONCLUSION: Elevated urinary tryptophan may be related to CHD risk among Chinese adults, especially for those with dyslipidemia.

A Large-Scale, Multi-Center Urine Biomarkers Identification of Coronary Heart Disease in TCM Syndrome Differentiation.

Coronary heart disease (CHD) threatens human health. The discovery and assessment of potential biometabolic markers for different syndrome types of CHD may contribute to decipher pathophysiological mechanisms and identify new targets for diagnosis and treatment. On the basis of UPLC-Q-TOF/MS metabolomics technology, urine samples of 1072 participants from nine centers, including normal control, phlegm and blood stasis (PBS) syndrome and Qi and Yin deficiency (QYD) syndrome, and other syndromes of CHD, were conducted to find biomarkers. Among them, the discovery set ( n = 125) and the test set ( n = 337) were used to identify and validate biomarkers, and the validation set ( n = 610) was used for the application and evaluation of the support vector machine (SVM) prediction model. We discovered 15 CHD-PBS syndrome biomarkers and 12 CHD-QYD syndrome biomarkers, and the receiver-operator characteristic (ROC) area-under-the-curve (AUC) values of them were 0.963 and 0.990. The established SVM model has a good diagnostic ability and can well distinguish the two syndromes of CHD with a high predicted accuracy >98.0%. The discovery of biomarkers and metabolic pathways in different syndrome types of CHD provides a basis for the diagnosis and evaluation of CHD, thereby improving the accurate diagnosis and precise treatment level of Chinese medicine.

Urinary phthalate metabolites, coronary heart disease, and atherothrombotic markers.

Cross-sectional studies have described an association between exposure to phthalate esters and cardiovascular risk factors. However, the association with coronary heart disease (CHD) is still unclear. A total of 180 subjects randomly selected from 336 CHD patients, and 360 age- and sex-matched non-CHD controls were included from 2008 to 2011. Urinary metabolites of phthalate esters were measured by liquid chromatography-tandem mass spectrometry. The geometric means of urinary phthalates metabolites were significantly higher for the three Di-(2-ethylhexyl)-phthalate (DEHP) metabolites, mono-2-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate, and mono-(2-ethyl-5-oxohexyl) phthalate among CHD patients in-hospital than those of being discharged. Excluding 89 CHD patients of in-hospital and hospital discharge within 2 days, we found the urinary concentrations of MEHP, mono-n-butyl phthalate (MnBP), and mono-isobutyl phthalate (MiBP) of 91 CHD patients discharged ≥ 3 days were higher than those of controls. Among 451 participants, those with higher tertile levels of urinary MEHP, MnBP, and MiBP showed an increased risk for CHD compared to those with lowest tertile levels; the corresponding odds ratios (95% CI) were 2.77 (1.22-6.28), 2.90 (1.32-6.4), and 3.19 (1.41-7.21), respectively, after adjustment for confounders. Higher levels of hs-CRP, fibrinogen, and D-dimer were linked with increased levels of all DEHP metabolites in CHD patients. In conclusion, exposure to DEHP and dibutyl phthalates was positively associated with CHD and this relationship may be probably mediated via atherothrombosis.

Noninvasive and prospective diagnosis of coronary heart disease with urine using surface-enhanced Raman spectroscopy.

A prospective diagnosis method for coronary heart disease (CHD) using human urine based on surface-enhanced Raman spectroscopy (SERS) is proposed, and could provide valuable information for judging whether to perform percutaneous coronary intervention (PCI) in clinics. Here, urine samples from 87 patients with CHD, including patients with PCI before operation (degree of cardiovascular congestion above 70%) and without PCI (degree of cardiovascular congestion under 70%), and 20 healthy humans were measured using SERS. Principal component analysis (PCA) combined with linear discriminant analysis (LDA) was employed to analyze the SERS spectra, revealing that the classification sensitivity and specificity were 90% and 78.9%, respectively, and the absolute value for loading of PC1 at 1509 cm-1 was the largest. Since platelet-derived growth factor-BB (PDGF-BB) is closely related to CHD, PDGF-BB aqueous solutions with various concentrations (1, 0.5, 0.1, 0.05 and 0.01 ppm) and a mixture of healthy human urine and PDGF-BB aqueous solutions were then investigated in this work, and it was found that the Raman peak at 1509 cm-1 may be attributed to PDGF-BB. Moreover, the measured SERS spectra of all the urine samples from the 87 patients with CHD were compared with the clinical data provided by a hospital, and it was revealed that the appearance of a peak at 1509 cm-1 in the SERS spectra was in good agreement with the results of coronary angiography tests when cardiovascular congestion was above 70%. This indicated that the classification sensitivity and specificity were 87.9% and 87.0%, respectively, through identification of the Raman peak at 1509 cm-1.

Abuse, nocturnal stress hormones, and coronary heart disease risk among women with HIV.

This study investigated the relationships among abuse, nocturnal levels of cortisol and norepinephrine (NE), and coronary heart disease (CHD) risk as measured by the Framingham risk score among women with human immunodeficiency virus (HIV). Participants (n = 53) from the Chicago Women's Interagency HIV Study (WIHS), a longitudinal prospective cohort study initiated in 1994, were enrolled in this study during 2012. At WIHS baseline and annual follow-up visits, women were asked about recent experiences of abuse. Summary variables captured the proportion of visits for which women reported recent (past 12 months) physical, sexual, and domestic abuse. Cortisol and NE were assayed in overnight urine samples and adjusted for creatinine levels. Recent abuse was not significantly associated with levels of cortisol, NE, or NE/cortisol ratio. However, higher NE/cortisol ratio was significantly related to higher CHD risk score, higher cortisol was significantly related to lower CHD risk score, and NE was not associated with CHD risk score. In addition, higher proportions of visits with recent sexual abuse, physical abuse, and domestic abuse were significantly related to higher CHD risk score. The association between abuse exposure and CHD risk in the context of HIV infection is likely complex and may involve dysregulation of multiple neurobiological systems. Future research is needed to better understand these relationships and prevention and intervention efforts are needed to address abuse among women with HIV.

Relationship of urine dopamine with phosphorus homeostasis in humans: the heart and soul study.

BACKGROUND: Urine dopamine (DA) is produced in the proximal tubule and has been found to increase in response to dietary phosphorus intake, and to contribute to greater urinary phosphorus excretion in animal models. Whether urine DA is associated with phosphorus homeostasis in humans is uncertain. METHODS: This was a cross-sectional study of 884 outpatients. DA was measured from 24-hour urine collections. We examined cross-sectional associations between urine DA and serum phosphorus, 24-hour urine phosphorus (as an indicator of dietary phosphorus absorption), fractional excretion of phosphorus (FEphos), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). Models were adjusted for age, sex, race, eGFR, albuminuria, hypertension, heart failure, tobacco use, body mass index, and diuretic use. RESULTS: Mean age was 66.6 ± 11 years and mean eGFR was 71 ± 21.3 ml/min/1.73 m(2). The mean urine DA was 193 ± 86 µg/day, mean serum phosphorus was 3.6 ± 0.6 mg/dl, mean daily urine phosphorus excretion was 671 ± 312 mg/day, and mean FEphos was 17 ± 9%. In adjusted models, each standard deviation higher DA was associated with 78.4 mg/day higher urine phosphorus and 0.9% lower FEphos (p < 0.05 for both). There was no statistically significant association between urine DA, serum phosphorus, FGF-23 or PTH in adjusted models. CONCLUSIONS: Higher dietary phosphorus absorption is associated with higher urine DA in humans, consistent with animal models. However, higher urine DA is not associated with FGF-23 or PTH, suggesting that known mechanisms of renal tubular handling of phosphorus may not be involved in the renal dopamine-phosphorus regulatory pathway in humans.

Research on the difference between patients with coronary heart disease and healthy controls by surface enhanced Raman spectroscopy.

Coronary heart disease (CHD) is one of the primary causes of death globally. There are several diagnostic techniques for CHD at present, but they are invasive and with limited accuracy. In the work, measurement of human urine based on surface-enhanced Raman spectroscopy (SERS) was proposed to diagnose CHD. Urine samples of 157 CHD patients and 63 healthy controls (HC) were investigated by SERS. Statistical analysis of the measured data was then performed. It was found that there were intensity differences in nine Raman peaks (1223/1243/1272/1463/1481/1516/1536/1541/1550 cm-1) between CHD and HC in their average SERS spectrum. Furthermore, principal component analysis (PCA)-linear discriminant analysis (LDA) was then utilized to establish a prediction model to classify CHD and HC. It revealed that the accuracy, specificity and sensitivity of the prediction model validated by leave-one-patient-out cross validation (LOPOCV) were 84.09%, 92.06% and 80.89%, respectively. Therefore, the proposed method can be employed as a non-invasive, rapid and accurate tool for CHD diagnosis in clinical application.

Urinary metabolomic profiling reveals difference between two traditional Chinese medicine subtypes of coronary heart disease.

The World Health Organization has shown that coronary heart disease (CHD) is a more common cause of death than cancer. In traditional Chinese medicine (TCM), CHD is classified as a form of thoracic obstruction that can be divided in different subtypes including Qi stagnation with blood stasis (QS) and Qi deficiency with blood stasis (QD). Different treatment strategies are used based on this subtyping. Owing to the lack of scientific markers in the diagnosis of these subtypes, subjective judgments made by clinicians have limited the objective manner for utility of TCM in the treatment of CHD. Untargeted (UHPLC-QTOF-MS) and targeted (UHPLC-MS/MS) metabolomics approaches were employed to search significantly different metabolites related to the QS or QD subtypes of CHD with angina pectoris in this study. A total of 42 metabolites were obtained in the untargeted metabolomics analysis and 34 amino acids were detected in the targeted metabolomics analysis. In total, 16 metabolites were found significantly different among different groups. The results showed distinct metabolic profiles of urine samples not only between CHD patients and healthy controls, but also between the two subtypes of CHD. Pathway analysis of the significantly varied metabolites revealed that there were subtype-related differences in the activity of pathways. Therefore, urinary metabolomics can reveal the pathological changes of CHD in different subtypes, make the diagnosis of CHD in different subtypes in an objective manner and comprehensive and contribute to personalized treatment by providing scientific evidence.

Associations between urinary 6-sulfatoxymelatonin excretion and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes.

AIMS/INTRODUCTION: There are limited reports on the association between melatonin levels and vascular complications in patients with type 2 diabetes. The aim of this study was to determine the association between urinary 6-sulfatoxymelatonin, which is a urinary metabolite of melatonin, and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes. MATERIALS AND METHODS: This retrospective study included patients (167 patients with type 2 diabetes and 27 patients without diabetes adjusted for age and sex) admitted to the hospital who underwent measurement of urinary 6-sulfatoxymelatonin. The urinary 6-sulfatoxymelatonin/creatinine ratio (6-SMT) was calculated. RESULTS: The natural logarithmically scaled 6-SMT level (Ln 6-SMT) was significantly lower in type 2 diabetes patients (1.9 ± 1.1) compared with patients without diabetes (2.8 ± 1.0, P < 0.001). Multivariate linear regression analysis identified duration of diabetes, smoking status, urinary albumin-to-creatinine ratio, retinopathy and coronary heart disease as factors that could influence Ln 6-SMT levels in type 2 diabetes patients (R2  = 0.232, P < 0.001). Ln 6-SMT was associated with decreased odds of diabetic retinopathy, even after adjustment for various confounding factors (odds ratio 0.559, 95% confidence interval 0.369-0.846, P = 0.006). Similarly, Ln 6-SMT was associated with decreased odds of coronary heart disease (odds ratio 0.442, P = 0.030). CONCLUSIONS: Our results showed the presence of low levels of Ln 6-SMT in type 2 diabetes patients relative to patients without diabetes. Furthermore, Ln 6-SMT is an independent risk factor of diabetic retinopathy and coronary heart diseases. These findings suggest that 6-SMT could be a useful biomarker for the prediction of micro- and macrovasculopathies in patients with type 2 diabetes.

Cadmium levels in urine and mortality among U.S. adults.

BACKGROUND: Cadmium exposure has been associated with increased all-cause, cancer, and cardiovascular disease mortality. However, studies investigating this association have included participants with considerably higher levels of cadmium than those found in the general population. OBJECTIVE: We aimed to evaluate the association of creatinine-corrected urinary cadmium levels with all-cause and cause-specific mortality in the U.S. general population. METHODS: We analyzed the relationship between cadmium measured in 13,958 adults who participated in the Third National Health and Nutrition Examination Survey in 1988-1994 and were followed through 31 December 2000, and all-cause, cancer, cardiovascular disease, and coronary heart disease mortality. RESULTS: The geometric mean levels of urinary cadmium per gram of urinary creatinine in study participants were 0.28 and 0.40 microg/g for men and women, respectively (p < 0.001). After multivariable adjustment, including smoking, a major source of cadmium exposure in nonoccupationally exposed populations, the hazard ratios [95% confidence interval (CI)] for all-cause, cancer, cardiovascular disease, and coronary heart disease mortality associated with a 2-fold higher creatinine-corrected urinary cadmium were, respectively, 1.28 (95% CI, 1.15-1.43), 1.55 (95% CI, 1.21-1.98), 1.21 (95% CI, 1.07-1.36), and 1.36 (95% CI, 1.11-1.66) for men and 1.06 (95% CI, 0.96-1.16), 1.07 (95% CI, 0.85-1.35), 0.93 (95% CI, 0.84-1.04), and 0.82 (95% CI, 0.76-0.89) for women. CONCLUSIONS: Environmental cadmium exposure was associated with an increased risk of all-cause, cancer, and cardiovascular disease mortality among men, but not among women. Additional efforts are warranted to fully explain gender differences on the impact of environmental cadmium exposure.

Evaluation of urinary biomarkers for coronary artery disease, diabetes, and diabetic kidney disease.

BACKGROUND: In this study we sought to validate urinary biomarkers for diabetes and two common complications, coronary artery disease (CAD) and diabetic nephropathy (DN). METHODS: A CAD score calculated by summing the product of a classification coefficient and signal amplitude of 15 urinary polypeptides was previously developed. Five sequences of biomarkers in the panel were identified as fragments of collagen alpha-1(I) and alpha-1(III). Prospectively collected urine samples available for analysis from 19 out of 20 individuals with CAD (15 with type 1 diabetes [T1D] and four without diabetes) and age-, sex-, and diabetes-matched controls enrolled in the Coronary Artery Calcification in Type 1 Diabetes study were analyzed for the CAD score using capillary electrophoresis and electrospray ionization mass spectrometry. Two panels of biomarkers that were previously defined to distinguish diabetes status were analyzed to determine their relationship to T1D. Three biomarker panels developed to distinguish DN (DNS) and two biomarker panels developed to distinguish renal disease (RDS) were examined to determine their relationship with renal function. RESULTS: The CAD score was associated with CAD (odds ratio with 95% confidence interval, 2.2 [1.3-5.2]; P = 0.0016) and remained significant when adjusted individually for age, albumin excretion rate (AER), blood pressure, waist circumference, intraabdominal fat, glycosylated hemoglobin, and lipids. DNS and RDS were significantly correlated with AER, cystatin C, and serum creatinine. The biomarker panels for diabetes were both significantly associated with T1D status (P < 0.05 for both). CONCLUSIONS: We validated a urinary proteome pattern associated with CAD and urinary proteome patterns associated with T1D and DN.

Identification of coronary heart disease biomarkers with different severities of coronary stenosis in human urine using non-targeted metabolomics based on UPLC-Q-TOF/MS.

BACKGROUND: Coronary heart disease (CHD) is the leading cause of death worldwide, and its pathogenesis has attracted much attention. Metabolomics serves as an important tool for diagnosing diseases and exploring their pathogenesis in recent years. In this study, CHD patients were studied by comparing them with normal subjects to elucidate biomarkers that are linearly correlated with the severity of coronary stenosis. METHODS: An ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to analyze the urine metabolites of CHD patients and normal subjects. A total of 131 subjects included 27 patients who presented with 50-69% coronary stenosis, 22 with 70-89% stenosis, 29 with 90-99% stenosis, 24 with 100% stenosis, and 29 normal subjects. RESULTS: A total of 14 potential biomarkers associated with CHD were identified, and among them 4 biomarkers were linearly correlated with the severity of coronary stenosis in CHD patients. The metabolic pathways involved were amino acid metabolism, fatty acid metabolism, energy metabolism, and other pathways. CONCLUSION: This study identified the biomarkers and metabolic pathways that may be involved in the occurrence and development of CHD, laying a theoretical foundation for better diagnosis and treatment of CHD in the future.

Urinary Levels of Trimethylamine-N-Oxide and Incident Coronary Heart Disease: A Prospective Investigation Among Urban Chinese Adults.

Background Trimethylamine-N-oxide ( TMAO ), a diet-derived, gut microbial-host cometabolite, has been associated with adverse cardiovascular outcomes in patient populations; however, evidence is lacking from prospective studies conducted in general populations and non-Western populations. Methods and Results We evaluated urinary levels of TMAO and its precursor metabolites (ie, choline, betaine, and carnitine) in relation to risk of coronary heart disease ( CHD ) among Chinese adults in a nested case-control study, including 275 participants with incident CHD and 275 individually matched controls. We found that urinary TMAO , but not its precursors, was associated with risk of CHD . The odds ratio for the highest versus lowest quartiles of TMAO was 1.91 (95% CI, 1.08-3.35; Ptrend=0.008) after adjusting for CHD risk factors including obesity, diet, lifestyle, and metabolic diseases and 1.75 (95% CI, 0.96-3.18; Ptrend=0.03) after further adjusting for potential confounders or mediators including central obesity, dyslipidemia, inflammation, and intake of seafood and deep-fried meat or fish, which were associated with TMAO level in this study. The odds ratio per standard deviation increase in log- TMAO was 1.30 (95% CI, 1.03-1.63) in the fully adjusted model. A history of diabetes mellitus modified the TMAO - CHD association. A high TMAO level (greater than or equal to versus lower than the median) was associated with odds ratios of 6.21 (95% CI, 1.64-23.6) and 1.56 (95% CI, 1.00-2.43), respectively, among diabetic and nondiabetic participants ( Pinteraction=0.02). Diabetes mellitus status also modified the associations of choline, betaine, and carnitine with risk of CHD ; significant positive associations were found among diabetic participants, but null associations were noted among total and nondiabetic participants. Conclusions Our study suggests that TMAO may accelerate the development of CHD , highlighting the importance of diet-gut microbiota-host interplay in cardiometabolic health.

Influence of drugs on the prospective diagnostic method for coronary heart disease with urine.

The morbidity of coronary heart disease (CHD) with high risks has been rising in recent years. A novel and noninvasive method based on surface-enhanced Raman spectroscopy (SERS) was proposed by Yang et al. (Analyst 143: 2235, 2018) to prospectively diagnose the arterial blockage by detecting platelet-derived growth factor-BB (PDGF-BB) in urine. Clinically, anti-platelet drugs (such as aspirin, statins and clopidogrel) are often used for ordinary CHD patients or patients with percutaneous coronary intervention (PCI). Therefore, whether the previous developed method can be applied to the CHD patients on long-term medication (more than 6 months) or post-PCI patients was investigated here. Firstly, urine samples of 13 CHD patients on long-term medication (aspirin, rosuvastatin, clopidogrel bisulfate) and 13 post-PCI patients were measured by the proposed method. Clinical data of coronary angiography results provided by Xin Hua Hospital and Yangpu District Central Hospital Antu Branch revealed that these 26 patients were with serious arterial blockage, however, characteristic Raman peak at 1509 cm-1 attributed to PDGF-BB was not observed in the SERS spectra of these 26 patients. In addition, an eight-day follow-up investigation was performed on a CHD patient with PCI three years ago and on long-term medication. It was found that the Raman peak at 1509 cm-1 could be only observed in the third and fourth day after suspending the drugs. Furthermore, SERS spectra of mixed solutions of PDGF-BB and aspirin, rosuvastatin, mixed solutions of these two drugs and clopidogrel bisulfate were analyzed. The Raman peak at 1509 cm-1 was not found in all these spectra, it indicated that all the three kinds of drugs could influence on the SERS signal of PDGF-BB. Therefore, the previous developed method is not suitable for CHD patients on long-term medication and post-PCI patients.

Influence of albuminuria on cardiovascular risk in patients with stable coronary artery disease.

BACKGROUND: Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and the risks for death and cardiovascular events among patients with stable coronary disease. METHODS AND RESULTS: We studied patients enrolled in the Prevention of Events with an ACE inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed up for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate and outcomes. The majority of patients (73%) had a baseline ACR within the normal range (<17 mug/mg for men and <25 mug/mg for women). Independent of the estimated glomerular filtration rate and other baseline covariates, a higher ACR, even within the normal range, was associated with increased risks for all-cause mortality (P<0.001) and cardiovascular death (P=0.01). The effect of trandolapril therapy on outcomes was not modified significantly by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 versus 14.6 mug/mg, P=0.0002), after adjustment for baseline ACR, time between collections, and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (hazard ratio per log ACR 1.74, 95% CI 1.08 to 2.82). CONCLUSIONS: Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.

Association of a serotonin transporter polymorphism (5-HTTLPR) with depression, perceived stress, and norepinephrine in patients with coronary disease: the Heart and Soul Study.

OBJECTIVE: The short allele of a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to interact with stressful life events to predict depression in otherwise healthy individuals. Whether the short allele increases risk for depression associated with the stress of a chronic illness has not been established. METHOD: In a cross-sectional genetic association study, the authors examined the association of 5-HTTLPR with current depression (measured by the Computerized Diagnostic Interview Schedule), perceived stress (measured by the Perceived Stress Scale), and 24-hour urinary norepinephrine excretion in 557 outpatients with chronic coronary disease. RESULTS: Among individuals carrying an s allele, 25% (97 of 383) had current depression, compared with 17% (29 of 174) of l/l homozygotes. The unadjusted odds ratio was 1.6, with a 95% confidence interval (CI) of 1.0-2.6; the age- and gender-adjusted odds ratio was also 1.6 (95% CI=1.0-2.5). Participants carrying an s allele had a higher mean score for perceived stress than l/l homozygotes (5.4 versus 4.7) and a higher rate of moderate or high perceived stress (adjusted odds ratio=1.6, 95% CI=1.1-2.3). Mean 24-hour norepinephrine excretion was higher in s allele carriers (55.6 versus 50.2 mg/day), who were more likely to have norepinephrine values in the highest quartile (adjusted odds ratio=1.7, 95% CI=1.0-3.0). CONCLUSIONS: Among patients with chronic illness, carriers of the s allele of 5-HTTLPR are more vulnerable to depression, perceived stress, and high norepinephrine secretion. These factors may contribute to worse cardiovascular outcomes in these patients.

Proteinuria and risk for stroke and coronary heart disease during 27 years of follow-up: the Honolulu Heart Program.

BACKGROUND: Urinary protein excretion has been linked to coronary heart disease (CHD); the relationship to stroke is less clear. We assessed whether urine dipstick screening for protein predicted stroke and CHD in the Honolulu Heart Program cohort. METHODS: Prospective, observational study of 6252 Japanese American men in Honolulu aged 45 to 68 years. Proteinuria was detected by means of urine dipstick screening during the first and third examinations. Subjects were classified as having no proteinuria if results were negative at both examinations, transient proteinuria if results were positive at 1 examination, and persistent proteinuria if results were positive at both examinations. Relative risk was derived using those subjects with no proteinuria as the reference. Outcomes were assessed through 27 years. RESULTS: No proteinuria was found in 92.8% of subjects, transient proteinuria in 6.1%, and persistent proteinuria in 1.1%. The age-adjusted incident stroke rates were 3.7, 7.3, and 11.8 per 1000 person-years in subjects with no, transient, or persistent proteinuria, respectively (P<.001). Age-adjusted rates of incident CHD were 9.4, 15.8, and 35.2 events per 1000 person-years, respectively (P<.001). Using Cox proportional hazards models, adjusting for age, body mass index, physical activity, smoking status, cholesterol level, presence of hypertension or diabetes mellitus, and alcohol consumption, the relative risk for 27-year incident stroke was 1.66 (95% confidence interval, 1.21-2.30; P = .002) with transient proteinuria and 2.84 (95% confidence interval, 1.51-5.34; P = .001) with persistent proteinuria, and relative risk for 27-year incident CHD was 1.48 (95% confidence interval, 1.19-1.83; P<.001) with transient proteinuria and 3.72 (95% confidence interval, 2.62-5.27; P<.001) with persistent proteinuria. CONCLUSION: Proteinuria detected at urine dipstick screening independently predicted increased risk for incident stroke and incident CHD over 27 years in this cohort.

Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus.

AIM: To investigate the associations of serum α-Klotho and ß-Klotho levels with type 2 diabetes mellitus (T2DM) progression. METHODS: We evaluated 106 healthy controls and 261 cases of T2DM with or without diabetic complications (range: 45-84years). Serum α-Klotho and ß-Klotho levels were analyzed using enzyme-linked immunosorbent assays. RESULTS: Compared to the healthy controls, α-Klotho and ß-Klotho levels were significantly lower among patients with T2DM and with or without diabetic complications (P<0.05). Furthermore, α-Klotho levels were lower in the microalbuminuric and macroalbuminuric groups, compared to the normoalbuminuric group. However, ß-Klotho levels were only lower in the macroalbuminuric group (P<0.05). Multiple linear regression analyses revealed that α-Klotho and ß-Klotho levels were positively correlated with the creatinine clearance rate, and negatively correlated with the urinary albumin to creatinine ratio and randomly sampled serum levels of creatinine, blood urea nitrogen, and blood glucose. Moreover, α-Klotho and ß-Klotho levels were positively correlated among patients with T2DM (r=0.693, P<0.001). CONCLUSIONS: Serum levels of α-Klotho and ß-Klotho are down-regulated in patients with T2DM. Thus, these proteins may participate in the pathological mechanism of diabetes, and the positive correlation of α-Klotho and ß-Klotho levels indicates that they might have similar mechanisms in T2DM.

Association of Chronic Kidney Disease with Coronary Heart Disease and Stroke Risks in Patients with Type 2 Diabetes Mellitus: An Observational Cross-sectional Study in Hangzhou, China.

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease (CVD). However, the association between CKD and CVD risk in patients with type 2 diabetes mellitus (T2DM) in China has not yet been well investigated. This study aimed to determine the association of CKD with the risks of coronary heart disease (CHD) and stroke in a Chinese population with T2DM. METHODS: A total of 1401 inpatients with T2DM at the Second Affiliated Hospital of Zhejiang University School of Medicine between April 2008 and November 2013 were included in this study. The CKD-Epidemiology Collaboration equation for Asians was used to classify CKD. The UK Prospective Diabetes Study risk engine was used to estimate the risks of CHD and stroke. RESULTS: CHD risk was significantly increased with CKD stage (20.1%, 24.8%, and 34.3% in T2DM patients with no CKD, CKD Stage 1-2, and Stage 3-5, respectively; P < 0.001 for all). The stroke risk was also increased with CKD stage (8.6%, 12.7%, and 25.4% in T2DM patients with no CKD, CKD Stage 1-2, and Stage 3-5, respectively; P < 0.001 for all). Compared with no-CKD group, the odds ratios (OR s) for high CHD risk were 1.7 (P < 0.001) in the CKD Stage 1-2 group and 3.5 (P < 0.001) in the CKD Stage 3-5 group. The corresponding OR s for high stroke risk were 1.9 (P < 0.001) and 8.2 (P < 0.001), respectively. CONCLUSION: In patients with T2DM, advanced CKD stage was associated with the increased risks of CHD and stroke.

Increased urinary albumin excretion rates can be a marker of coexisting coronary artery disease in patients with peripheral arterial disease.

Coexisting coronary artery disease (CAD) is an important cause of morbidity and mortality in patients with peripheral arterial disease (PAD). Clinical evaluation and noninvasive tests have some important limitations for the detection of CAD in patients with PAD. The purpose of this study was to investigate whether urinary albumin excretion (UAE) was a sign of atherosclerotic involvement of coronary arteries in patients with PAD. Our study consisted of 65 consecutive patients (56 men, 9 women, mean age; 59.7+/-7.9 years) with PAD who underwent coronary angiography. Urinary albumin excretion was measured in 24-hour urine samples by immunoprecipitation technique. PAD was defined as the presence of > or =50% stenotic lesions in at least 1 of the iliac, femoral, popliteal, tibialis anterior, tibialis posterior, or peroneal arteries. CAD was defined as > or =25% diameter stenosis in at least 1 coronary artery. Patients without any coronary lesions were accepted as having normal coronaries. Age, sex, distributions of coronary risk factors, and UAE rates were compared between patients with and without CAD. Mean UAE was 17.9+/-15.6 mg/day in the total population. Thirty-seven percent of patients had CAD, and 63% had no coronary lesion. UAE rates were 22.33+/-18.74 and 15.32+/-13.01 mg/day in patients with CAD and those with normal coronary arteries, respectively (p = 0.021). Microalbuminuria was detected in 25% in patients with CAD and 12% in those without coronary artery lesions (p = 0.184). The difference was not statistically significant. The distributions of other risk factors and sex were not different between the 2 groups. These data suggest that in patients with PAD, urinary albumin excretion rates may be used to determine those with a high probability of CAD. Further studies are required to decide whether this noninvasive testing is appropriate in detecting high-risk patients.