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Background Asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of NO-synthase. In the last years ADMA has emerged as a cardiovascular risk factor. The aim of this study was to determine a reference value for ADMA. Methods Plasma samples of 500 healthy subjects in the 19–75 year age group were analyzed. Exclusion criteria from this study were smoking, any known significant disease, body-mass-index (BMI) above 30 kg m−2, elevated plasma lipid levels, impaired renal function, hypertension, and intake of any medication. The ADMA levels were determined by ELISA, (DLD Diagnostics, Hamburg, Germany). Results Mean ADMA plasma concentration of the total population was 0·69 µmol L−1 (SD 0·20) and 95% of the measured values were in the range from 0·36 µmol L−1 to 1·17 µmol L−1. Women below 50 years of age had lower ADMA levels than men below 50 years of age [0·62 (0·17) µmol L−1 vs. 0·69 (0·19) µmol L−1; P = 0·001] and woman above 50 years of age had higher ADMA levels than men above 50 years of age [0·80 (0·22) µmol L−1 vs. 0·73 (0·20) µmol L−1; P = 0·036]. A regression analysis of ADMA levels and age was performed for each sex. The regression factor was r = 0·444 for women in a squared regression model ( P < 0·001) and r = 0·212 for men in a linear regression model ( P < 0·001). Conclusion The study was able to define a reference value for ADMA plasma levels with 0·36–1·17 µmol L−1 and found sex dependent correlations between ADMA and age. Women showed a significant increase in ADMA plasma levels with onset of menopause. [ABSTRACT FROM AUTHOR]

Objectives: In rats with adjuvant arthritis measurements were taken of the urinary excretion of nitrate, reflecting endogenous nitric oxide (NO) formation, and cyclic guanosine monophosphate (cGMP).Methods: Urinary nitrate was determined by gas chromatography, cGMP by radioimmunoassay.Results: A significant (p < 0.001), more than three fold increase of urinary nitrate excretion was found in rats 20 days after induction of adjuvant arthritis compared with non-arthritic rats. There was no significant difference in urinary cGMP excretion between arthritic rats and control animals.Conclusion: The data suggest that the dramatic increase of urinary nitrate excretion is due to increase of NO synthesis by the inducible form of NO synthase. [ABSTRACT FROM AUTHOR]

Abstract Background Translocation of gut-derived bacterial products such as endotoxin is a major problem in liver cirrhosis. Methods To assess the hepatic clearance of bacterial products in individuals with cirrhosis, we tested concentrations of Gram-negative bacterial lipopolysaccharide (LPS), LPS-binding protein (LBP), and the precursor of nitric oxide (NO), L-arginine, in a cohort of 8 stable patients with liver cirrhosis before and after elective transjugular portosystemic shunt (TIPS) implantation, including central venous, hepatic venous, and portal venous measurements. Results Using an adapted LPS assay, we detected high portal venous LPS concentrations (mean 1743 ± 819 pg/mL). High concentrations of LPS were detectable in the central venous blood (931 ± 551 pg/mL), as expected in persons with cirrhosis. The transhepatic LPS gradient was found to be 438 ± 287 pg/mL, and 25 ± 12% of portal LPS was cleared by the cirrhotic liver. After TIPS, central venous LPS concentrations increased in the hepatic and central veins, indicating shunting of LPS with the portal blood through the stent. This paralleled a systemic increase of L-arginine, whereas the NO synthase inhibitor asymmetric dimethylarginine (ADMA) remained unchanged, suggesting that bacterial translocation may contribute to the pathogenesis of circulatory dysfunction post-TIPS. Conclusions This study provides quantitative estimates of the role of the liver in the pathophysiology of bacterial translocation. The data indicate that the cirrhotic liver retains the capacity for clearance of bacterial endotoxin from the portal venous blood and that TIPS implantation attenuates this clearance. Thus, increased endotoxin concentrations in the systemic circulation provide a possible link to the increased encephalopathy in TIPS patients.

Abstract Background Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of endothelial nitric oxide synthase (eNOS) that is associated with endothelial dysfunction, and is a risk marker for cardiovascular disease, a significant problem in Type 1 diabetes. The aim of the present study was to measure circulating ADMA, and define its association with endothelial dysfunction and endothelial markers in people with Type 1 diabetes with low likelihood of macrovascular disease. Methods Sixty-one young people with Type 1 diabetes without macrovascular disease or nephropathy and 62 healthy volunteers underwent brachial artery flow-mediated dilatation (FMD) and assay of plasma ADMA and adhesion molecules. Results Age, gender, BMI, lipid profile and renal function were similar in the two groups. People with Type 1 diabetes had impaired FMD compared to healthy controls (5.0 ± 0.4 vs 8.9 ± 0.4%; p < 0.001). Plasma ADMA levels were significantly lower in the people with diabetes compared to healthy controls (0.52 ± 0.12 vs 0.66 ± 0.20 μmol/l, p < 0.001). Plasma ICAM-1, E-selectin and PAI-1 levels were significantly higher in people with diabetes compared to healthy controls (median 201 (IQR 172–226) vs 180 (156–216) μg/l, p = 0.027; 44.2 (32.6–60.9) vs. 33.1 (22.4–51.0) μg/l; p = 0.003 and 70.8 (33.3–85.5) vs 46.3 (23.9–76.8) μg/l, p = 0.035). Plasma ADMA and VCAM-1 levels were positively correlated (r = 0.37, p = 0.003) in people with diabetes. There was no correlation between the plasma ADMA and FMD. Conclusion ADMA levels are not associated with endothelial dysfunction in young adults with Type 1 diabetes without microalbuminuria or known macrovascular disease. This suggests that the impaired endothelial function in these individuals is not a result of eNOS inhibition by ADMA.

Background: Atrial fibrillation (AF) is a stroke risk factor that often remains undetected at hospital admission. Long-term Holter monitoring helps to identify patients with previously unrecognized AF. Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are elevated in AF in cross-sectional studies. We analyzed ADMA, SDMA, and other L-arginine metabolites to assess their association with AF in the Find-AF trial., Methods and Results: We included 280 patients presenting with acute cerebral ischemia. Patients presenting in sinus rhythm received 7-day Holter-ECG. Biomarkers were quantified by ultra-performance liquid chromatography-tandem mass spectrometry. We also analyzed protein methylation and L-arginine-related metabolites in human induced pluripotent stem cell-derived cardiomyocytes in vitro. ADMA and SDMA were elevated in 44 patients who presented with AF. SDMA, but not ADMA, was significantly elevated in patients newly diagnosed with AF in Holter-ECG as compared with those in sinus rhythm. SDMA plasma concentration >0.571 μmol/L significantly predicted presence of AF in Holter-ECG (area under the curve=0.676 [0.530-0.822]; P =0.029; sensitivity 0.786, specificity 0.572). SDMA levels further increased in patients with AF during the first 24 hours in hospital, and ADMA levels remained stable. In vitro, induced pluripotent stem cell-derived cardiomyocytes showed increased symmetric protein methylation and elevated SDMA during rapid pacing (2.0 Hz versus 0.5 Hz), whereas asymmetric protein methylation and ADMA were unchanged., Conclusions: SDMA at admission was significantly elevated in stroke patients presenting with AF and showed a moderate but significant prospective association with previously unrecognized AF. Thus, stroke patients with elevated SDMA concentration at admission may specifically benefit from extended Holter-ECG monitoring.

Mortality of patients hospitalized with COVID-19 has remained high during the consecutive SARS-CoV-2 pandemic waves. Early discrimination of patients at high mortality risk is crucial for optimal patient care. Symmetric (SDMA) and asymmetric dimethylarginine (ADMA) have been proposed as possible biomarkers to improve risk prediction of COVID-19 patients. We measured SDMA, ADMA, and other L-arginine-related metabolites in 180 patients admitted with COVID-19 in four German university hospitals as compared to 127 healthy controls. Patients were treated according to accepted clinical guidelines and followed-up until death or hospital discharge. Classical inflammatory markers (leukocytes, CRP, PCT), renal function (eGFR), and clinical scores (SOFA) were taken from hospital records. In a small subgroup of 23 COVID-19 patients, sequential blood samples were available and analyzed for biomarker trends over time until 14 days after admission. Patients had significantly elevated SDMA, ADMA, and L-ornithine and lower L-citrulline concentrations than controls. Within COVID-19 patients, SDMA and ADMA were significantly higher in non-survivors (n = 41, 22.8%) than in survivors. In ROC analysis, the optimal cut-off to discriminate non-survivors from survivors was 0.579 µmol/L for SDMA and 0.599 µmol/L for ADMA (both p < 0.001). High SDMA and ADMA were associated with odds ratios for death of 11.45 (3.37-38.87) and 5.95 (2.63-13.45), respectively. Analysis of SDMA and ADMA allowed discrimination of a high-risk (mortality, 43.7%), medium-risk (15.1%), and low-risk group (3.6%); risk prediction was significantly improved over classical laboratory markers. We conclude that analysis of ADMA and SDMA after hospital admission significantly improves risk prediction in COVID-19., (© 2024. The Author(s).)

Background: Chronic obstructive lung disease (COPD) has diverse molecular pathomechanisms and clinical courses which, however, are not fully mirrored by current therapy. Intermittent hypoxemia is a driver of lung function decline and poor outcome, e.g., in patients with concomitant obstructive sleep apnea. Transient hypoxemia during physical exercise has been suggested to act in a similar manner. The PROSA study is designed to prospectively assess whether the clinical course of COPD patients with or without exertional desaturation differs, and to address potential pathophysiological mechanisms and biomarkers., Methods: 148 COPD patients (GOLD stage 2-3, groups B or C) will undergo exercise testing with continuous pulse oximetry. They will be followed for 36 months by spirometry, echocardiography, endothelial function testing, and biomarker analyses. Exercise testing will be performed by comparing the 6-min walk test (6MWT), bicycle ergometry, and a 15-sec breath-hold test. Exertional desaturation will be defined as SpO 2  < 90% or delta-SpO 2  ≥ 4% during the 6MWT. The primary endpoint will be the rate of decline of FEV1(LLN) between COPD patients with and without exertional desaturation., Discussion: The PROSA Study is an investigator-initiated prospective study that was designed to prove or dismiss the hypothesis that COPD patients with exertional desaturation have a significantly more rapid rate of decline of lung function as compared to non-desaturators. A 20% difference in the primary endpoint was considered clinically significant; it can be detected with a power of 90%. If the primary endpoint will be met, exercise testing with continuous pulse oximetry can be used as a ubiquitously available, easy screening tool to prospectively assess the risk of rapid lung function decline in COPD patients at an early disease stage. This will allow to introduce personalized, risk-adapted therapy to improve COPD outcome in the long run. PROSA is exclusively funded by public funds provided by the European Research Council through an ERC Advanced Grant. Patient recruitment is ongoing; the PROSA results are expected to be available in 2028., Trial Registration: The PROSA Study has been prospectively registered at clinicaltrials.gov (register no. NCT06265623, dated 09.02.2024)., (© 2024. The Author(s).)

Background: Night shift work is associated with sleep disturbances, obesity, and cardiometabolic diseases. Disruption of the circadian clock system has been suggested to be an independent cause of type 2 diabetes and cardiovascular disease in shift workers. We aimed to improve alignment of circadian timing with social and environmental factors with administration of melatonin., Methods: In a randomized, placebo-controlled, prospective study, we analysed the effects of 2 mg of sustained-release melatonin versus placebo on glucose tolerance, insulin resistance indices, sleep quality, circadian profiles of plasma melatonin and cortisol, and diurnal blood pressure profiles in 24 rotating night shift workers during 12 weeks of treatment, followed by 12 weeks of wash-out. In a novel design, the time of melatonin administration (at night or in the morning) depended upon the shift schedule. We also compared the baseline profiles of the night shift (NS) workers with 12 healthy non-night shift (NNS)-working controls., Results: We found significantly impaired indices of insulin resistance at baseline in NS versus NNS (p < 0.05), but no differences in oral glucose tolerance tests nor in the diurnal profiles of melatonin, cortisol, or blood pressure. Twelve weeks of melatonin treatment did not significantly improve insulin resistance, nor did it significantly affect diurnal blood pressure or melatonin and cortisol profiles. Melatonin administration, however, caused a significant improvement in sleep quality which was significantly impaired in NS versus NNS at baseline (p < 0.001)., Conclusions: Rotating night shift work causes mild-to-moderate impairment of sleep quality and insulin resistance. Melatonin treatment at bedtime improves sleep quality, but does not significantly affect insulin resistance in rotating night shift workers after 12 weeks of administration., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)