Clinical impact of admission urinary 8-hydroxydeoxyguanosine level for predicting cardiovascular mortality in patients with acute coronary syndrome.

The aim of the present study was to determine whether urinary 8-hydroxydeoxyguanosine (8-OHdG), which is a marker of oxidative stress, can predict future cardiovascular death in patients with acute coronary syndrome (ACS). A total of 551 consecutive patients with ACS who underwent admission urinary 8-OHdG measurements were enrolled in this study. The patients were divided into 2 groups according to the optimal cutoff value of admission urinary 8-OHdG determined by a receiver-operating characteristics curve for the prediction of cardiovascular death: a high admission urinary 8-OHdG group, 169 patients with admission urinary 8-OHdG ≥ 17.92 ng/mg creatinine; and a low admission urinary 8-OHdG group, 382 patients with admission urinary 8-OHdG < 17.92 ng/mg creatinine. The patients were followed up for a median period of 34 months. The primary and secondary end points were the incidence of cardiovascular death and major cardiovascular events (MACE) composed of cardiovascular death, non-fatal myocardial infarction, or urgent hospitalization for heart failure. Of the 551 patients, cardiovascular deaths and MACE occurred in 14 (2.5%) and 35 (6.4%), respectively. The Kaplan-Meier estimate of the event-free rate revealed cardiovascular deaths and MACE were more likely in the high admission 8-OHdG group than in the low admission 8-OHdG group (log rank, both P < 0.001). Multiple adjusted Cox proportional hazards analysis indicated that high admission urinary 8-OHdG was an independent predictor of cardiovascular death (hazard ratio [HR] 7.642, P = 0.011) and MACE (HR 2.153, P = 0.049). High admission urinary 8-OHdG levels predict cardiovascular mortality after adjustment in patients with ACS.

Effect of 1,5-anhydroglucitol levels on culprit plaque rupture in diabetic patients with acute coronary syndrome.

BACKGROUND: Postprandial hyperglycemia was reported to play a key role in established risk factors of coronary artery diseases (CAD) and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of short-term postprandial glucose (PPG) excursions. Low serum 1,5-AG levels have been associated with occurrence of CAD. However, the relationship between 1,5-AG levels and coronary plaque rupture has not been fully elucidated. The aim of this study was to evaluate 1,5-AG as a predictor of coronary plaque rupture in diabetic patients with acute coronary syndrome (ACS). METHODS: A total of 144 diabetic patients with ACS were included in this study. All patients underwent intravascular ultrasound examination, which revealed 49 patients with plaque rupture and 95 patients without plaque rupture in the culprit lesion. Fasting blood glucose (FBG), hemoglobin A1c (HbA1c) and 1,5-AG levels were measured before coronary angiography. Fasting urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) level was measured and corrected by creatinine clearance. RESULTS: Patients with ruptured plaque had significantly lower serum 1,5-AG levels, longer duration of diabetes, higher HbA1c and FBG levels than patients without ruptured plaque in our study population. In multivariate analysis, low 1,5-AG levels were an independent predictor of plaque rupture (odds ratio 3.421; P = 0.005) in diabetic patients with ACS. The area under the receiver-operating characteristic curve for 1,5-AG (0.658, P = 0.002) to predict plaque rupture was superior to that for HbA1c (0.587, P = 0.087). Levels of 1,5-AG were significantly correlated with urinary 8-iso-prostaglandin F2α levels (r = - 0.234, P = 0.005). CONCLUSIONS: Serum 1,5-AG may identify high risk for coronary plaque rupture in diabetic patients with ACS, which suggests PPG excursions are related to the pathogenesis of plaque rupture in diabetes.

microRNA-155 Is Decreased During Atherosclerosis Regression and Is Increased in Urinary Extracellular Vesicles During Atherosclerosis Progression.

Background: Atherosclerosis is a chronic inflammatory disease driven by macrophage accumulation in medium and large sized arteries. Macrophage polarization and inflammation are governed by microRNAs (miR) that regulate the expression of inflammatory proteins and cholesterol trafficking. Previous transcriptomic analysis led us to hypothesize that miR-155-5p (miR-155) is regulated by conjugated linoleic acid (CLA), a pro-resolving mediator which induces regression of atherosclerosis in vivo. In parallel, as extracellular vesicles (EVs) and their miR content have potential as biomarkers, we investigated alterations in urinary-derived EVs (uEVs) during the progression of human coronary artery disease (CAD). Methods: miR-155 expression was quantified in aortae from ApoE-/- mice fed a 1% cholesterol diet supplemented with CLA blend (80:20, cis-9,trans-11:trans-10,cis-12 respectively) which had been previously been shown to induce atherosclerosis regression. In parallel, human polarized THP-1 macrophages were used to investigate the effects of CLA blend on miR-155 expression. A miR-155 mimic was used to investigate its inflammatory effects on macrophages and on ex vivo human carotid endarterectomy (CEA) plaque specimens (n = 5). Surface marker expression and miR content were analyzed in urinary extracellular vesicles (uEVs) obtained from patients diagnosed with unstable (n = 12) and stable (n = 12) CAD. Results: Here, we report that the 1% cholesterol diet increased miR-155 expression while CLA blend supplementation decreased miR-155 expression in the aorta during atherosclerosis regression in vivo. CLA blend also decreased miR-155 expression in vitro in human THP-1 polarized macrophages. Furthermore, in THP-1 macrophages, miR-155 mimic decreased the anti-inflammatory signaling proteins, BCL-6 and phosphorylated-STAT-3. In addition, miR-155 mimic downregulated BCL-6 in CEA plaque specimens. uEVs from patients with unstable CAD had increased expression of miR-155 in comparison to patients with stable CAD. While the overall concentration of uEVs was decreased in patients with unstable CAD, levels of CD45+ uEVs were increased. Additionally, patients with unstable CAD had increased CD11b+ uEVs and decreased CD16+ uEVs. Conclusion: miR-155 suppresses anti-inflammatory signaling in macrophages, is decreased during regression of atherosclerosis in vivo and is increased in uEVs from patients with unstable CAD suggesting miR-155 has potential as a prognostic indicator and a therapeutic target.

Correlation of CYP2D6 allelic polymorphism to outcome of acute coronary syndrome in mid-Euphrates Iraqi patients on metoprolol therapy.

This study aims to investigate the different clinically relevant allele variants (allele frequencies) of CYP2D6 gene and to determine whether a specific genotype of CYP2D6 gene (based on genetic polymorphism "allelic types" and combination) have impact on metoprolol effectiveness (clinical outcome) in patients who have acute coronary syndrome (ACS). The study included 250 patients with ACS who were classified into 2 study groups, 125 patients received metoprolol and served as a study group (Group1) and 125 who received no metoprolol therapy (due to contraindication to the medication) and served as a control group (Group 2). Venous blood samples were taken from all participants for DNA extraction. Urine samples were also collected to assess the metabolic ratio using High-performance liquid chromatography (HPLC) technique. There was significant variation in the distribution of Iraqi patients with respect to CYP2D6 allelic polymorphism as compared to similar patients in other countries. Besides, this significant difference existed in patients' outcome in terms of morbidity and mortality in respect to variable genotypes and phenotypes. We recommend a dose individualization of metoprolol in patients with ACS is essential to improve patients' outcome.

Prognostic value of hyperuricemia in patients with acute coronary syndrome: A meta-analysis.

BACKGROUND: The prognostic significance of elevated circulating uric acid level in patients with acute coronary syndrome (ACS) is conflicting. This meta-analysis aimed to assess the prognostic value of hyperuricemia in patients with ACS. METHODS: A comprehensive literature search was performed in Pubmed, Embase, VIP, CNKI and WanFang databases up to 16 June 2018. All observational studies that investigated the prognostic value of hyperuricemia in ACS patients were selected. Outcome of interests was major adverse cardiovascular events (MACEs), all-cause mortality or cardiovascular mortality. RESULTS: A total of nine studies enrolling 8776 ACS patients were included and analysed. ACS patients with hyperuricemia had an increased risk of MACEs (risk ratio [RR]: 1.86; 95% confidence intervals [CI]: 1.47-2.35), all-cause mortality (RR 1.86; 95% CI: 1.49-2.32) and cardiovascular mortality (RR: 1.74; 95% CI: 1.36-2.22) after adjustment for the conventional risk factors. Stratified analysis showed that the prognostic significance of hyperuricemia was consistently observed in each subgroups. CONCLUSIONS: This meta-analysis suggests that hyperuricemia independently predicts MACEs and death in ACS patients. Determination of uric acid level has potential to improve risk stratification of adverse outcomes in ACS patients.

Urinary metabonomic study of patients with acute coronary syndrome using UPLC-QTOF/MS.

This urinary metabonomic study aimed to identify the potential metabolic biomarkers in acute coronary syndrome (ACS) patients. Ultra-performance liquid chromatography/mass spectrometry (UPLC/MS) was used to analyze the urine samples from ACS patients and healthy controls. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were applied to characterizing the endogenous metabolites and potential biomarker, respectively. Among twenty biomarkers that functioned in nine metabolic pathways, nine biomarkers were found up-regulated significantly, including of isobutyryl­l­carnitine, 3­methylglutarylcarnitine, cinnavalininate, l­tryptophan, 3­methyldioxyindole, palmitic acid, N4­acetylaminobutanal, 3­sulfino­l­alanine and S­adenosyl­l­homocysteine. The other eleven biomarkers were showed down-regulated, including of l­lactic acid, trigonelline, nicotinuric acid, l­alanine, d­alanyl­d­alanine, creatine, N4­acetylaminobutanoate, glutathionyl spermidine, 5­methoxytryptamine, kynurenic acid and xanthurenic acid. This study also implied that fatty acid metabolism, fatty acid ß­oxidation metabolism, amino acid metabolism and TCA cycle played important roles in ACS. Therefore, urinary metabolomics may improve the diagnosis efficacy of ACS and make it more accurate and comprehensive for ACS diagnosis.

Serum Uric Acid Could Differentiate Acute Myocardial Infarction and Unstable Angina Pectoris in Hyperuricemic Acute Coronary Syndrome Patients.

INTRODUCTION: Serum uric acid (SUA) is the final product of purine metabolism in humans. AIM: The present study aimed to identify a potential association between serum UA and cardiac troponin I (cTnI) levels and to find out whether uric acid could differentiate patients presenting with the acute myocardial infarction (AMI) and unstable angina pectoris (UAP) in hyperuricemic and normouricemic acute coronary syndrome (ACS) patients. METHODS: Eighty ACS patients, aged 50-83 years, were enrolled in the study, 40 of them presenting with AMI and 40 with UAP. Frequency of patients with serum uric level over threshold for hyperuricemia was investigated and two groups of patients were formed such as hyperuricemic and normouricemic groups (A and B groups, respectively) independently of type of ACS. Those groups of patients were also subjected to cTnI measurement. RESULTS: Levels of SUA are associated with the type of ACS in the hyperuricemic ACS patients (AMI versus UAP, 499(458-590), 425(400-447) mmol/L, p=0.007, respectively). Uric acid correlated significantly with cTnI, moderate positively in the group A (rho=0.358, p=0.038) and moderate negatively in the group B (r=-0.309, p=0.037) of ACS patients. Multiple logistic regression analysis revealed that cTnI and age were independently associated with the SUA levels in the group A of ACS patients. CONCLUSIONS: Serum uric acid differentiates AIM and UAP patients in hyperuricemic group of acute coronary syndrome. Therefore it can be used as nonspecific parameter for evaluation of the myocardial lesion extent only in hyperuricemic ACS patients. This is supported by finding that cTnI along with age predicts SUA level in hyperuricemic ACS patients.

Self-reported cocaine use is not associated with elevations in high-sensitivity troponin I.

OBJECTIVE: High-sensitivity troponin (hsTn) assays detect 10 times lower concentrations of cardiac troponin than conventional assays. We examined the effects of self-reported cocaine use to determine whether those with acute cocaine use being evaluated for ACS are more likely to have elevated hsTnI than those nonusers being evaluated for ACS. METHODS: We conducted a sub-analysis of a prospective cohort of ED patients evaluated for acute coronary syndrome. Recent cocaine use was determined by structured patient interviews. High-sensitivity troponin (Abbott) and conventional troponin I (Abbott, cTnI) were measured on samples drawn at presentation. Urine toxicology screen for cocaine metabolite was obtained at the discretion of treating clinicians. RESULTS: Of 1862 patients enrolled, 444 reported prior cocaine use and 99 reported cocaine use within the preceding month. Median hsTn in patients with last cocaine use within 24 h, 2-7 days, 1 week-1 month, >1 month, and no prior cocaine use were: 9 (IQR: 3-17) ng/L, 6 (IQR: 3-24.3) ng/L, 6 (IQR: 3-89.5) ng/L, 3 (IQR: 3-18.5) ng/L and 3 (IQR: 3-17) ng/L, respectively. Urine toxicology assays (UTox) for cocaine were performed in 640 (34.4%) patients. The median hsTn for those who were UTox+, UTox - and those without a UTox were: 9 ng/L (IQR: 3-48.5), 9 ng/L (IQR: 3-40) and 3 ng/L (IQR: 3-12), respectively. There were no differences in the prevalence of new troponin elevations (hsTn >99th percentile but cTnI <99th percentile) in those with recent cocaine use compared to those without recent cocaine use. CONCLUSIONS: In this first investigation of hsTn in patients with self-reported recent cocaine use, we have determined that hsTn does not lead to an increase in the prevalence of troponin elevation in cocaine users.

Prediction of acute coronary syndromes by urinary proteome analysis.

Identification of individuals who are at risk of suffering from acute coronary syndromes (ACS) may allow to introduce preventative measures. We aimed to identify ACS-related urinary peptides, that combined as a pattern can be used as prognostic biomarker. Proteomic data of 252 individuals enrolled in four prospective studies from Australia, Europe and North America were analyzed. 126 of these had suffered from ACS within a period of up to 5 years post urine sampling (cases). Proteomic analysis of 84 cases and 84 matched controls resulted in the discovery of 75 ACS-related urinary peptides. Combining these to a peptide pattern, we established a prognostic biomarker named Acute Coronary Syndrome Predictor 75 (ACSP75). ACSP75 demonstrated reasonable prognostic discrimination (c-statistic = 0.664), which was similar to Framingham risk scoring (c-statistics = 0.644) in a validation cohort of 42 cases and 42 controls. However, generating by a composite algorithm named Acute Coronary Syndrome Composite Predictor (ACSCP), combining the biomarker pattern ACSP75 with the previously established urinary proteomic biomarker CAD238 characterizing coronary artery disease as the underlying aetiology, and age as a risk factor, further improved discrimination (c-statistic = 0.751) resulting in an added prognostic value over Framingham risk scoring expressed by an integrated discrimination improvement of 0.273 ± 0.048 (P < 0.0001) and net reclassification improvement of 0.405 ± 0.113 (P = 0.0007). In conclusion, we demonstrate that urinary peptide biomarkers have the potential to predict future ACS events in asymptomatic patients. Further large scale studies are warranted to determine the role of urinary biomarkers in clinical practice.

Urinary Klotho measured by ELISA as an early biomarker of acute kidney injury in patients after cardiac surgery or coronary angiography.

BACKGROUND: Acute kidney injury (AKI) is a common complication after cardiac surgery and percutaneous coronary interventions which markedly worsens prognosis. In recent years, new early biomarkers of AKI have been identified, but many important aspects still remain to be solved. Klotho is a pleiotropic protein that acts as a paracrine and endocrine factor in multiple organs. Reduced renal Klotho levels have been show in several animal models of AKI. No study has been published in which Klotho was tested in humans as an early marker of AKI. The aim of this work is to assess the usefulness of measuring urinary Klotho for the early diagnosis of AKI in patients with acute coronary syndrome or heart failure undergoing cardiac surgery or coronary angiography. METHODS: Urinary Klotho was measured 12 hours after intervention in 60 patients admitted to the Intensive Care Unit with acute coronary syndrome or heart failure secondary to coronary or valvular conditions, who underwent coronary angiography (30 patients) or cardiac bypass surgery or heart valve replacement (30 patients). The primary endpoint used was the onset of AKI according to the RIFLE classification system. Human Klotho levels were measured using an ELISA assay. RESULTS: We found no differences in urinary Klotho levels between AKI patients and those who did not develop AKI. Moreover, there was not significant correlation between urinary Klotho levels and the presence of AKI. CONCLUSION: Urinary Klotho measured by ELISA does not seem to be a good candidate to be used as an early biomarker of AKI.

Plasma pro-inflammatory cytokines, IgM-uria and cardiovascular events in patients with chest pain: A comparative study.

BACKGROUND: Risk stratification of patients presenting with acute chest pain is crucial for immediate and long-term management. Traditional predictors are suboptimal; therefore inflammatory biomarkers are studied for clinical assessment of patients at risk. Recently, we reported the association of IgM-uria with worse cardiovascular outcome in patients with acute chest pain. In this study, in the same cohort of patients with chest pain, we compared the value of IgM-uria to pro-inflammatory cytokines in predicting the occurrence of subsequent cardiovascular events. METHODS: A total of 178 consecutive patients presenting with acute chest pain to the emergency department at the University Hospital of Lund, were recruited. Twenty-seven of 57 patients with acute coronary syndrome (ACS), and 18 of 118 patients with non-specific chest pain at baseline developed a subsequent major cardiovascular event during the 18 months follow-up. Urinary proteins (IgM-uria and Microalbuminuria) and plasma inflammatory markers (IL-6, Il-8, IL-10, IFN-γ and TNF-α) were measured at time of admission. RESULTS: Using the receiver operating characteristic curves, the area under the curve for predicting cardiovascular events was 0.71 (95%CI 0.61-0.81) for IgM-uria, 0.61 (95%CI 0.51-0.71) for IL-6, 0.63 (95%CI 0.53-0.72) for IL-8, 0.65 (95%CI 0.56-0.74) for IL-10, and 0.64 (95% CI 0.54-0.74) for TNF-α. In multivariate Cox-regression analysis adjusted for age, microalbuminuria, IgM-uria, IL-10, TNF-α, troponin T, hsCRP and ACS at baseline; IgM-uria was the only biomarker that remained an independent predictor of outcome (HR = 4.2, 95%CI 2.2-7.8, p < 0.001). CONCLUSION: In patients with chest pain with or without acute coronary syndrome, IgM-uria could better predict the occurrence of cardiovascular events than plasma pro-inflammatory cytokines.

[Neutrophil gelatinase-associated lipocain as a predictor of acute renal lesion in patients with acute coronary syndrome].

AIM: To estimate the possibility of using neutrophil gelatinase-associated lipocain (NGAL) as a predictor of acute renal lesion (ARL) in patients with acute coronary syndrome (ACS). Only those patients were included in whom coronarography was found to be impracticable which allowed to exclude the development of contrast-induced ARL. A total of 122 patients with ACS (69 men and 53 women, mean age 64 +/- 11 yr) were available for examination. 18 (15%) patients had acute myocardial infarction without ST elevation, 73 (60%) presented with unstable angina. ARL was diagnosed and classified following KDIGO recommendations (2012). Serum creatinine level was determined at admission. (Urine NGAL level was measured by an immunoenzyme assay. ARL was diagnosed in 27 (22%) patients (stage 1 in 26%. stage 2 in 1%). NGAL level above 82 ng/ml was a highly specific (99%) predictor of ARL in patients with ACS, but its sensitivity did not exceed 20%. It is concluded that urinary NGAL is a moderate predictor of ARL in patients with ACS whose specificity increases with increasing urinary level.

Urinary albumin concentration and long-term cardiovascular risk in acute coronary syndrome patients: a PROVE IT-TIMI 22 substudy.

Albuminuria has been shown to be associated with mortality and cardiovascular events, independent of traditional cardiovascular risk factors. This suggests that albuminuria may not just represent glomerular damage, but may be a marker of more diffuse endothelial dysfunction. We investigated the relationship between urinary albumin levels after an acute coronary syndrome and cardiovascular outcomes in statin treated subjects after acute coronary syndromes (ACS). Furthermore we assessed the effect of intensive statin treatment on albuminuria among patients in the PROVE IT-TIMI 22 trial, in which patients who had been hospitalized with ACS were randomized to pravastatin 40 mg (standard therapy) or atorvastatin 80 mg daily (intensive therapy). In univariate analyses, increasing urine albumin concentration was associated with increased risk of myocardial infarction, stroke, heart failure, and composite of death, myocardial infarction and stroke at 2 years. However, in a multivariable model containing traditional cardiovascular risk factors, albuminuria was not an independent predictor of the primary PROVE IT endpoint of death, myocardial infarction, unstable angina, revascularization and stroke, and was only an independent predictor of all-cause mortality at urinary albumin concentration >300 mcg/ml. There was no significant change in urinary albumin concentration from enrolment to end of study in either the standard or intensive statin therapy groups, and no significant difference between treatment groups. Our results suggest that after an acute coronary syndrome in statin treated patients, microalbuminuria may reflect traditional cardiovascular risk factor burden and offer little prognostic information independent of those factors.

Clinical significance of the measurements of urinary liver-type fatty acid binding protein levels in patients with acute coronary syndrome.

BACKGROUND: Recently, much attention has been focused on cardio-renal interaction. Urinary liver-type fatty acid binding protein (U-L-FABP), which is produced in the proximal tubule by renal hypoxia and oxidative stress, has been identified as a useful marker for diagnosis of acute kidney disease and a predictor of future events in chronic kidney disease. However, the clinical significance of U-L-FABP measurements in patients with acute coronary syndrome (ACS) has not been completely evaluated. METHODS AND RESULTS: This study included 50 consecutive patients with ACS [37 with acute myocardial infarction (AMI) and 13 with unstable angina pectoris (UAP)] and 47 subjects without coronary artery disease (control group). U-L-FABP levels, urinary albumin (U-Alb), and other serum parameters were measured at admission and at 24 h after percutaneous coronary intervention. RESULTS: U-L-FABP levels in patients with AMI were significantly higher (p=0.0019), than in control subjects, while patients with UAP did not exhibit such an increase. U-L-FABP levels at admission were positively correlated with brain natriuretic protein levels (p=0.001) and duration of hospitalization (p=0.025). At follow-up angiography, patients with restenosis had significantly higher U-L-FABP (p=0.047) and U-Alb levels (p<0.0001) than those without restenosis. After a median follow-up of 42 months, U-L-FABP levels at second measurement in patients with major adverse cardiocerebrovascular events (MACCEs) were significantly higher than those in patients without MACCEs (p=0.028). After adjusting for confounding factors, high U-L-FABP levels at second measurement were found to be independent factors for MACCEs (p=0.019). CONCLUSIONS: These data suggest that patients with ACS, especially those with AMI, have high U-L-FABP levels, and that U-L-FABP measurements may be useful in identifying high-risk patients for future cardiovascular events after ACS.

Betaine and secondary events in an acute coronary syndrome cohort.

BACKGROUND: Betaine insufficiency is associated with unfavourable vascular risk profiles in metabolic syndrome patients. We investigated associations between betaine insufficiency and secondary events in acute coronary syndrome patients. METHODS: Plasma (531) and urine (415) samples were collected four months after discharge following an acute coronary event. Death (34), secondary acute myocardial infarction (MI) (70) and hospital admission for heart failure (45) events were recorded over a median follow-up of 832 days. PRINCIPAL FINDINGS: The highest and lowest quintiles of urinary betaine excretion associated with risk of heart failure (p = 0.0046, p = 0.013 compared with middle 60%) but not with subsequent acute MI. The lowest quintile of plasma betaine was associated with subsequent acute MI (p = 0.014), and the top quintile plasma betaine with heart failure (p = 0.043), especially in patients with diabetes (p<0.001). Top quintile plasma concentrations of dimethylglycine (betaine metabolite) and top quintile plasma homocysteine both associated with all three outcomes, acute MI (p = 0.004, <0.001), heart failure (p = 0.027, p<0.001) and survival (p<0.001, p<0.001). High homocysteine was associated with high or low betaine excretion in >60% of these subjects (p = 0.017). Median NT-proBNP concentrations were lowest in the middle quintile of plasma betaine concentration (p = 0.002). CONCLUSIONS: Betaine insufficiency indicates increased risk of secondary heart failure and acute MI. Its association with elevated homocysteine may partly explain the disappointing results of folate supplementation. In some patients, especially with diabetes, elevated plasma betaine also indicates increased risk.

The contrasting relationships between betaine and homocysteine in two clinical cohorts are associated with plasma lipids and drug treatments.

BACKGROUND: Urinary betaine excretion positively correlated with plasma homocysteine in outpatients attending a lipid disorders clinic (lipid clinic study). We aimed to confirm this in subjects with established vascular disease. METHODS: The correlation between betaine excretion and homocysteine was compared in samples collected from subjects 4 months after hospitalization for an acute coronary episode (ACS study, 415 urine samples) and from 158 sequential patients visiting a lipid disorders clinic. PRINCIPAL FINDINGS: In contrast to the lipid clinic study, betaine excretion and plasma homocysteine did not correlate in the total ACS cohort. Differences between the patient groups included age, non-HDL cholesterol and medication. In ACS subjects with below median betaine excretion, excretion correlated (using log transformed data) negatively with plasma homocysteine (r = -0.17, p = 0.019, n = 199), with no correlation in the corresponding subset of the lipid clinic subjects. In ACS subjects with above median betaine excretion a positive trend (r = +0.10) between betaine excretion and homocysteine was not significant; the corresponding correlation in lipid clinic subjects was r = +0.42 (p = 0.0001). In ACS subjects, correlations were stronger when plasma non-HDL cholesterol and betaine excretion were above the median, r = +0.20 (p = 0.045); in subjects above median non-HDL cholesterol and below median betaine excretion, r = -0.26 (p = 0.012). ACS subjects taking diuretics or proton pump inhibitors had stronger correlations, negative with lower betaine excretion and positive with higher betaine excretion. CONCLUSIONS: Betaine excretion correlates with homocysteine in subjects with elevated blood lipids.

Plasma lipids and betaine are related in an acute coronary syndrome cohort.

BACKGROUND: Low plasma betaine has been associated with unfavorable plasma lipid profiles and cardiovascular risk. In some studies raised plasma betaine after supplementation is associated with elevations in plasma lipids. We aimed to measure the relationships between plasma and urine betaine and plasma lipids, and the effects of lipid-lowering drugs on these. METHODOLOGY: Fasting plasma samples were collected from 531 subjects (and urine samples from 415) 4 months after hospitalization for an acute coronary syndrome episode. In this cross-sectional study, plasma betaine and dimethylglycine concentrations and urine excretions were compared with plasma lipid concentrations. Subgroup comparisons were made for gender, with and without diabetes mellitus, and for drug treatment. PRINCIPAL FINDINGS: Plasma betaine negatively correlated with triglyceride (Spearman's r(s) = -0.22, p<0.0001) and non-high-density lipoprotein cholesterol (r(s) = -0.27, p<0.0001). Plasma betaine was a predictor of BMI (p<0.05) and plasma non-high-density lipoprotein cholesterol and triglyceride (p<0.001) independently of gender, age and the presence of diabetes. Using data grouped by plasma betaine decile, increasing plasma betaine was linearly related to decreases in BMI (p = 0.008) and plasma non-HDL cholesterol (p = 0.002). In a non-linear relationship betaine was negatively associated with elevated plasma triglycerides (p = 0.004) only for plasma betaine >45 µmol/L. Subjects taking statins had higher plasma betaine concentrations (p<0.001). Subjects treated with a fibrate had lower plasma betaine (p = 0.003) possibly caused by elevated urine betaine loss (p<0.001). The ratio of coenzyme Q to non-high-density lipoprotein cholesterol was higher in subjects with higher plasma betaine, and in subjects taking a statin. CONCLUSION: Low plasma betaine concentrations correlated with an unfavourable lipid profile. Betaine deficiency may be common in the study population. Controlled clinical trials of betaine supplementation should be conducted in appropriate populations to determine whether correction affects cardiovascular risk.

Sulfido-peptide leukotrienes in coronary heart disease - relationship with disease instability and myocardial ischaemia.

BACKGROUND: Urinary excretion of leukotriene (LT) E(4) is an index of LTC(4) biosynthesis and platelet-neutrophil interactions, which may occur in coronary heart disease and contribute to myocardial ischaemia. Enhanced LTC(4) biosynthesis may be a consequence of myocardial ischaemia or be linked to its pathogenetic substrate. METHODS AND RESULTS: Overnight urine collections were obtained from 17 patients with chronic stable angina, three patients with Prinzmetal's angina, 16 patients with non ST-elevation acute coronary syndromes (NSTE-ACS) and six patients with acute ST-elevation myocardial infarction (STEMI). LTE(4) excretion was measured by enzyme immunoassay after HPLC separation. Compared with healthy controls (51.1 +/- 21.3 pg mg(-1) creatinine, mean +/- SD, n = 11) and with non-coronary cardiac controls (36.6 +/- 9.8 pg mg(-1) creatinine, n = 9), LTE(4) excretion was unchanged in stable angina (40.5 +/- 25.8 pg mg(-1) creatinine), but significantly (P < 0.01) increased in NSTE-ACS (122.7 +/- 137.2 pg mg(-1) creatinine) and STEMI (213.4 +/- 172.4 pg mg(-1) creatinine). In these patients, LTE(4) excretion rapidly dropped after day 1, consistent with effective coronary reperfusion. In patients with NSTE-ACS, the increase in LTE(4) excretion was entirely restricted to patients with recent (< 48 h) spontaneous anginal episodes. Myocardial ischaemia elicited by a positive exercise stress test was not accompanied by any detectable increase in LTE(4) excretion, while a significant (P < 0.01) increase was detected after a single-vessel percutaneous coronary interventions (PCI) procedure (n = 10), as compared with diagnostic angiography (n = 9). CONCLUSIONS: In coronary heart disease, increased LTC(4) biosynthesis is restricted to ACS and not linked to myocardial ischaemia per se, but likely to the occurrence of plaque disruption.

Significance of urinary liver-fatty acid-binding protein in cardiac catheterization in patients with coronary artery disease.

OBJECTIVES: We investigated the significance of urinary liver fatty acid-binding protein (U-L-FABP) monitoring during cardiac catheterization in patients with cardiovascular disease (CVD). Methods The subjects included 27 consecutive patients with stable angina (SAP group) or acute coronary syndrome (ACS group) who had undergone successful percutaneous coronary intervention (PCI), and 12 patients were also enrolled as controls (C group). Urinary and serum parameters were measured immediately before and after and 1 day after PCI. RESULTS: The ratio of U-L-FABP to U-creatinine (U-Cr) (U-L-FABP/U-Cr) in the ACS group was significantly higher than those in both the SAP and C groups before PCI. In addition, none of the patients in the SAP group showed contrast-induced nephropathy (CIN) based on the levels of serum (S)-Cr and U-L-FABP/U-Cr after PCI. Although none of the patients in the ACS group showed CIN according to S-Cr, the level of U-L-FABP/U-Cr was continuously high throughout the study period. Moreover, since there were significant differences in U-L-FABP/U-Cr, U-N-acetyl-beta-D-glucosaminidase, S-uric acid and % medication with calcium channel blockers before PCI between the ACS and SAP groups, a multiple regression analysis was performed using these parameters. It showed that U-L-FABP/U-Cr was most closely associated with the classification of SAP and ACS (p<0.0001). The cut-off level for the greatest sensitivity and specificity for U-L-FABP for the diagnosis of ACS was 13.4 microg/g. Cr in all subjects (sensitivity 0.800, specificity 0.963). CONCLUSIONS: To the best of our knowledge, this is the first report indicating that the measurement of U-L-FABP can be beneficial for in the diagnosis of ACS.

Fibrates may cause an abnormal urinary betaine loss which is associated with elevations in plasma homocysteine.

PURPOSE: Betaine is an osmolyte, supplies methyl groups, and controls plasma homocysteine. Abnormal urinary loss of betaine is common in patients with the metabolic syndrome or diabetes mellitus. These patients are often treated with fibrates which alter renal function and raise plasma homocysteine concentrations. We suggest there is a connection between fibrate treatment and betaine excretion. METHODS: We identified 32 fibrate-treated patients in several studies (total of 740 subjects) and compared the betaine excretion by these with the excretion by other patients, both in the separate studies and in the combined group. We investigated the correlation of betaine excretion with homocysteine in these groups. RESULTS: Patients taking bezafibrate had higher betaine excretion than patients not taking fibrates, p < 0.00001 in some studies with n < 10. Of 32 patients taking bezafibrate, 20 had abnormal (>97.5 %-ile) betaine excretion. Plasma homocysteine correlated positively with betaine excretion in male patients with lipid disorders who were not taking fibrate (n = 68, p = 0.043), but the relationship was stronger if patients taking bezafibrate were included (n = 76, p < 0.00001). In elderly (>65 years) subjects with hypertension there was a similar correlation (n = 19, p = 0.047), which was stronger when a subject taking bezafibrate was included (n = 20, p = 0.013). CONCLUSIONS: Abnormal betaine excretion is common in patients treated with bezafibrate. Bezafibrate appears to exacerbate betaine loss, which will cause a rise in plasma homocysteine. Betaine supplementation could be considered in conjunction with fibrate therapy.