Publications by authors named "Rainer H Böger"

177 Publications

Asymmetric dimethylarginine and L-homoarginine prospectively relate to carotid wall thickness in a South African cohort.

Amino Acids 2020 Jul 29;52(6-7):965-973. Epub 2020 Jun 29.

Hypertension in Africa Research Team (HART), Faculty of Health Sciences, North-West University, Private Bag X1290, Potchefstroom, 2520, South Africa.

Background And Aims: The L-arginine derivatives asymmetric (ADMA) and symmetric dimethylarginine (SDMA), as well as L-homoarginine may have opposing effects in the pathogenesis of atherosclerosis. We aimed to investigate (i) 5-year changes in arginine derivatives, and (ii) the association between baseline arginine derivatives and follow-up measures of carotid wall thickness in South Africans.

Methods And Results: This study included men (n = 187) and women (n = 396) who took part in the 2010 and 2015 data collections of the South African arm of the Prospective Urban and Rural Epidemiology (PURE) study. Arginine derivatives were determined in plasma with liquid chromatography-tandem mass spectrometry. Carotid intima-media thickness (cIMT) and cross-sectional wall area (CSWA) were determined with B-mode ultrasonography.

Results: Mean values of arginine derivatives did not change over time. In the study group, follow-up cIMT (β = - 0.10 p = 0.018) and CSWA (β = - 0.12; p = 0.004) inversely associated with baseline L-homoarginine, and cIMT inversely associated with ADMA (β = - 0.09; p = 0.033). In women, CSWA inversely associated with both ADMA (β = - 0.11; p = 0.034) and L-homoarginine (β = - 0.11; p = 0.024). No such associations were found in men.

Conclusion: These results suggest that higher levels of L-homoarginine may play a protective role against vascular injury and delay progression of carotid wall thickening in this cohort. The role of ADMA in atherosclerosis deserves further investigation in this population.
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http://dx.doi.org/10.1007/s00726-020-02866-9DOI Listing
July 2020

Arginine derivatives in atrial fibrillation progression phenotypes.

J Mol Med (Berl) 2020 07 6;98(7):999-1008. Epub 2020 Jun 6.

School of Medicine - Cardiovascular Medicine, Boston University, Boston, USA.

Arginine, homoarginine (hArg), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) affect nitric oxide metabolism and altered concentrations are associated with cardiovascular morbidity and mortality. We analyzed these metabolites using liquid chromatography-tandem mass spectrometry in patients with atrial fibrillation (AF) (n = 241) with a focus on heart rhythm at blood withdrawal, AF progression phenotypes, and successful sinus rhythm (SR) restoration (n = 22). AF progression phenotypes were defined as paroxysmal AF with/without low voltage areas (LVA) and persistent AF with/without LVA. While arginine, ADMA, and hArg were within reference limits for healthy controls, SDMA was higher in the AF cohort (0.57 ± 0.12 vs. 0.53 μmol/L (97.5th percentile in reference cohort)). SR restoration in AF patients resulted in normalization of SDMA concentrations (0.465 ± 0.082 vs. 0.570 ± 0.134 μmol/L at baseline, p < 0.001). Patients with AF at the time of blood sampling had significantly lower hArg (1.65 ± 0.51 vs. 1.85 ± 0.60 μmol/L, p = 0.006) and higher ADMA concentrations (0.526 ± 0.08 vs. 0.477 ± 0.08 μmol/L, p < 0.001) compared with AF patients in SR. hArg concentrations were lower in patients with advanced AF progression phenotypes (persistent AF with LVA (p = 0.046)) independent of heart rhythm at blood sampling. Summarizing, arginine metabolism imbalance is associated with AF in general and AF progression and may contribute to associated risk. KEY MESSAGES: • Heart rhythm at blood withdrawal affects ADMA and hArg level in AF patients. • SDMA is higher in AF patients. • SDMA levels normalize after sinus rhythm restoration. • hArg levels decrease in advanced AF progression phenotypes.
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http://dx.doi.org/10.1007/s00109-020-01932-9DOI Listing
July 2020

Blood pressure and nitric oxide synthesis capacity in physically active and inactive groups: the SABPA study.

J Hum Hypertens 2020 May 7. Epub 2020 May 7.

Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa.

Physical activity affects the vasculature through mechanisms related to nitric oxide bioavailability, oxidative stress, and inflammation; with endothelial function at the centre of this triad. In a South African setting, with the prevalence of hypertension and physical inactivity being alarmingly high, we aimed to investigate relationships of vascular function with markers of oxidative stress, inflammation and nitric oxide synthesis capacity in physically active and inactive groups. Based on the 2010 World Health Organisation guidelines, black and white school teachers were divided into physically active (n = 84) and physically inactive (n = 132) groups. Twenty-four-hour blood pressure (24 h BP), total peripheral resistance and Windkessel compliance were measured. Markers of oxidative stress, inflammation and nitric oxide synthesis capacity were analysed. Windkessel compliance (p = 0.041) and homoarginine (p = 0.006) were higher in the physically active group. In the same group, 24 h diastolic BP associated with total glutathione (β = 0.17; p = 0.056), and 24 h BP (systolic blood pressure: β = 0.23, p = 0.006; diastolic blood pressure: β = 0.22, p = 0.019) associated with homoarginine. In the physically inactive group, 24 h BP (systolic blood pressure: β = 0.26, p < 0.001; diastolic blood pressure: β = 0.23, p = 0.007) associated with symmetric dimethylarginine (SDMA). These associations were independent of inflammation. Despite only reaching moderate physical activity levels, vascular function and nitric oxide synthesis capacity were more favourable in the physically active population compared to the physically inactive population. These results may suggest that even moderate physical activity could increase nitric oxide synthesis capacity, which in turn may mitigate the development of cardiovascular disease in this population.
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http://dx.doi.org/10.1038/s41371-020-0344-2DOI Listing
May 2020

Determinants of Serum- and Plasma Sphingosine-1-Phosphate Concentrations in a Healthy Study Group.

TH Open 2020 Jan 23;4(1):e12-e19. Epub 2020 Jan 23.

German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck (GD, ES, MvL) and Greifswald (EM), Berlin, Germany.

 To correctly interpret plasma- or serum-sphingosine-1-phosphate (S1P) concentrations measured in clinical studies it is critical to understand all major determinants in healthy controls.  Serum- and plasma-S1P from 174 healthy blood donors was measured by liquid chromatography-tandem mass spectrometry and correlated to clinical laboratory data. Selected plasma samples, 10 with high and 10 with low S1P concentrations, were fractionated into very low-density lipoprotein (VLDL)-, low density lipoprotein (LDL)-, high density lipoprotein (HDL)-, and lipoprotein-free fractions. S1P was then measured in each fraction to determine its distribution.  The mean S1P concentration in serum (1.04 ± 0.24 nmol/mL) was found 39% higher compared with plasma (0.75 ± 0.16 nmol/mL) and overall was not different between men and women. Only when stratified for age and gender, older women were found to exhibit higher circulatory S1P levels than men. In plasma, S1P levels correlate to red blood cell (RBC) counts but not to platelet counts. Conversely, serum-S1P correlates to platelet counts but not to RBC counts. In addition, eosinophil counts are strongly associated with serum-S1P concentrations. Both serum- and plasma-S1P correlate to total cholesterol but not to HDL-C. The distribution of S1P between VLDL-, LDL-, HDL-, and lipoprotein-free fractions is independent of total plasma-S1P concentrations. S1P concentrations in HDL but not in LDL are highly variable.  These data indicate S1P concentrations in plasma and serum to be differentially associated with cell counts and S1P carrier proteins. Besides platelets, eosinophil counts are identified as a novel determinant for serum-S1P concentrations further suggesting a role for S1P in eosinophil pathologies.
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http://dx.doi.org/10.1055/s-0040-1701205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978167PMC
January 2020

Low homoarginine/SDMA ratio is associated with poor short- and long-term outcome after stroke in two prospective studies.

Neurol Sci 2020 Jan 3;41(1):149-153. Epub 2019 Sep 3.

Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds, UK.

Background: Guanidino compounds, including asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and L-homoarginine (hArg), have been associated with cardio- and cerebrovascular events and risk. We aimed to study if low hArg/ADMA and hArg/SDMA ratios are associated with mortality and outcome after stroke.

Methods: In two prospective cohorts of acute stroke patients from Germany and the UK, we analyzed hArg, ADMA, and SDMA to determine hArg/ADMA and hArg/SDMA ratios. The guanidino compound levels were associated with mortality, adverse events, and neurological impairment, i.e., National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS).

Results: During 7.4 years, high hArg/ADMA and hArg/SDMA ratios were both associated with a reduction in all-cause mortality in patients with ischemic stroke in a UK stroke cohort (hArg/ADMA: hazard ratio (HR) 0.75 [95% confidence interval (CI) 0.62-0.92]; n = 394; P = 0.006; hArg/SDMA: HR 0.68 [0.54-0.85]; n = 394; P = 0.001). In a German stroke cohort, patients with high hArg/SDMA ratio experienced fewer adverse events compared with those with low hArg/SDMA ratios within 30 days after stroke (HR 0.73 [0.57-0.92]; n = 135; P = 0.009), whereas hArg/ADMA was not predictive. Furthermore, hArg/SDMA ratios inversely correlated with the degree of neurological impairment (NIHSS) (r = - 0.27; P = 0.001; n = 138). Lower hArg/SDMA ratios were also found in dependent (mRS 3-6) compared with independent patients (mRS < 3; P = 0.007; n = 138), whereas hArg/ADMA did not.

Conclusion: These results from two prospective stroke studies reveal that hArg/SDMA ratio could prove a valuable blood-based biomarker to discriminate patients with poor short- and long-term outcome, increased neurological impairment, and severe disability after stroke.
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http://dx.doi.org/10.1007/s10072-019-04058-0DOI Listing
January 2020

The P2-receptor-mediated Ca signalosome of the human pulmonary endothelium - implications for pulmonary arterial hypertension.

Purinergic Signal 2019 09 8;15(3):299-311. Epub 2019 Aug 8.

Department of Pneumology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Dysfunction of the pulmonary endothelium is associated with most lung diseases. Extracellular nucleotides modulate a plethora of endothelial functions in the lung such as vessel integrity, vasodilatation, inflammatory, and thrombotic responses as well as survival and DNA repair, mostly via Ca signaling pathways. However, a comprehensive analysis of the molecular components of the underlying P2 receptor-mediated Ca signaling pathways in the lung has not been conducted so far. Therefore, our aim was to identify the principal P2 receptor Ca signalosome in the human pulmonary endothelium and investigate potential dysregulation in pulmonary vascular disease. Comparative transcriptomics and quantitative immunohistochemistry were performed on publicly available RNA sequencing and protein datasets to identify the specific expression profile of the P2-receptor Ca signalosome in the healthy human pulmonary endothelium and endothelial cells (EC) dysfunctional due to loss of or defective bone morphogenetic protein receptor (BMPR2). Functional expression of signalosome components was tested by single cell Ca imaging. Comparative transcriptome analysis of 11 endothelial cell subtypes revealed a specific P2 receptor Ca signalosome signature for the pulmonary endothelium. Pulmonary endothelial expression of the most abundantly expressed Ca toolkit genes CALM1, CALM2, VDAC1, and GNAS was confirmed by immunohistochemistry (IHC). P2RX1, P2RX4, P2RY6, and P2YR11 showed strong lung endothelial staining by IHC, P2X5, and P2Y1 were found to a much lesser extent. Very weak or no signals were detected for all other P2 receptors. Stimulation of human pulmonary artery (HPA) EC by purine nucleotides ATP, ADP, and AMP led to robust intracellular Ca signals mediated through both P2X and P2Y receptors. Pyrimidine UTP and UDP-mediated Ca signals were generated almost exclusively by activation of P2Y receptors. HPAEC made dysfunctional by siRNA-mediated BMPR2 depletion showed downregulation of 18 and upregulation of 19 P2 receptor Ca signalosome genes including PLCD4, which was found to be upregulated in iPSC-EC from BMPR2-mutant patients with pulmonary arterial hypertension. In conclusion, the human pulmonary endothelium expresses a distinct functional subset of the P2 receptor Ca signalosome. Composition of the P2 receptor Ca toolkit in the pulmonary endothelium is susceptible to genetic disturbances likely contributing to an unfavorable pulmonary disease phenotype found in pulmonary arterial hypertension.
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http://dx.doi.org/10.1007/s11302-019-09674-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737170PMC
September 2019

Association of Asymmetric Dimethylarginine and Diastolic Dysfunction in Patients with Hypertrophic Cardiomyopathy.

Biomolecules 2019 07 13;9(7). Epub 2019 Jul 13.

Clinic of General and Interventional Cardiology, University Heart Center, 20246 Hamburg, Germany.

Despite genetic heterogeneity, early manifestation of diastolic dysfunction (DD) is common in hypertrophic cardiomyopathy (HCM). Nitric oxide (NO) may contribute to myocardial relaxation. NO synthases (NOS) use l-arginine (Arg) as a substrate, as asymmetric dimethylarginine (ADMA) is a direct endogenous inhibitor of NOS. This study aimed to analyze the association of Arg and its derivates, i.e., l-homoarginine (hArg), ADMA and symmetric dimethylarginine (SDMA), with DD in HCM patients. In 215 HCM patients (mean age 54 ± 15 years, 58% male) transmitral and mitral annulus velocities were echocardiographically analyzed. Plasma concentrations of Arg derivatives were measured by liquid chromatography tandem-mass spectrometry. In 143 (70%) patients suffering from DD, ADMA showed the strongest association with DD (0.66 ± 0.16, 0.72 ± 0.24, and 0.76 ± 0.26 µmol/L, < 0.01 for trend). In linear regression analyses, positive association per standard deviation increase of ADMA was found with E-wave (beta coefficient (95% confidence interval): 4.72 (0.43-9.01); < 0.05) and mean E/E' (1.76 (0.73-2.79) < 0.001). Associations were adjusted for age, sex, body mass index (BMI), diabetes mellitus, coronary artery disease, and arterial hypertension. Elevated ADMA is associated with the severity of DD in HCM. Higher ADMA level might lead to decreased NO production and thus an impaired myocardial relaxation pattern.
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http://dx.doi.org/10.3390/biom9070277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681289PMC
July 2019

Asymmetric Dimethylarginine at Sea Level Is a Predictive Marker of Hypoxic Pulmonary Arterial Hypertension at High Altitude.

Front Physiol 2019 27;10:651. Epub 2019 May 27.

Institute DECIPHER, German-Chilean Institute for Research on Pulmonary Hypoxia and its Health Sequelae, Hamburg, Germany and Iquique, Chile.

Prolonged exposure to altitude-associated chronic hypoxia (CH) may cause high-altitude pulmonary hypertension (HAPH). Chronic intermittent hypobaric hypoxia (CIH) occurs in individuals who commute between sea level and high altitude. CIH is associated with repetitive acute hypoxic acclimatization and conveys the long-term risk of HAPH. As nitric oxide (NO) regulates pulmonary vascular tone and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, we investigated whether ADMA concentration at sea level predicts HAPH among Chilean frontiers personnel exposed to 6 months of CIH. In this prospective study, 123 healthy army draftees were subjected to CIH (5 days at 3,550 m, 2 days at sea level) for 6 months. In 100 study participants with complete data, ADMA, symmetric dimethylarginine (SDMA), L-arginine, arterial oxygen saturation (SaO), systemic blood pressure, and hematocrit were assessed at months 0 (sea level), 1, 4, and 6. Acclimatization to altitude was determined using the Lake Louise Score (LLS) and the presence of acute mountain sickness (AMS). Echocardiography was performed after 6 months of CIH in 43 individuals with either good ( = 23) or poor ( = 20) acclimatization. SaO acutely decreased at altitude and plateaued at 90% thereafter. ADMA increased and SDMA decreased during the study course. The incidence of AMS and the LLS was high after the first ascent (53 and 3.1 ± 2.4) and at 1 month of CIH (47 and 3.0 ± 2.6), but decreased to 20 and 1.4 ± 2.0 at month 6 (both  < 0.001). Eighteen participants (42%) showed a mean pulmonary arterial pressure (mPAP) >25 mm Hg, out of which 9 (21%) were classified as HAPH (mPAP ≥ 30 mm Hg). ADMA at sea level was significantly associated with mPAP at high altitude in month 6 ( = 0.413;  = 0.007). In ROC analysis, a cutoff for baseline ADMA of 0.665 μmol/L was determined to predict HAPH (mPAP > 30 mm Hg) with a sensitivity of 100% and a specificity of 63.6%. ADMA concentration increases during CIH. ADMA at sea level is an independent predictive biomarker of HAPH. SDMA concentration decreases during CIH and shows no association with HAPH. Our data support a role of impaired NO-mediated pulmonary vasodilation in the pathogenesis of HAPH.
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http://dx.doi.org/10.3389/fphys.2019.00651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545974PMC
May 2019

The protective effect of dronedarone on the structure and mechanical properties of the aorta in hypertensive rats by decreasing the concentration of symmetric dimethylarginine (SDMA).

PLoS One 2019 21;14(5):e0216820. Epub 2019 May 21.

Molecular Biology Laboratory, Department Experimental Medicine and Surgery, Hospital Gregorio Marañón, Madrid, Spain.

Background And Aims: Dronedarone is a new multichannel-blocking antiarrhythmic for the treatment of patients with atrial fibrillation. Our group has demonstrated that dronedarone produces regression of cardiac remodeling; however, its effect on the remodeling of the elastic arteries has not yet been reported. We aim to assess the effects of dronedarone on the regression of thoracic aortic remodeling in spontaneously hypertensive rats (SHRs).

Method: Ten-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where the animals received dronedarone treatment (100 mg/kg), to a control group (SHR) where rats were given vehicle, or to a group (SHR-A) where they were given amiodarone. A fourth group of normotensive control rats (Wistar-Kyoto rats, WKY) was also added. After two weeks of treatment, we studied the structure, the elastic fiber content of the thoracic aorta using histological techniques and confocal microscopy, and the vascular mechanical properties using an organ bath and isometric tension analysis. A mass spectrometric determination of symmetric dimethylarginine (SDMA) concentrations was performed.

Results: SHR group developed the classic remodeling expected from the experimental model: outward hypertrophic remodeling, increased elastic fiber content and wall stiffness. However, the SHR-D group showed statistically significantly lower values for aortic tunica media thickness, wall to lumen ratio, external diameter, cross-sectional area, volume density of the elastic fibers, wall stiffness, and aortic SDMA concentration when compared to the SHR group. These parameters were similar in the SHR and SHR-A groups. Interestingly, the values for tunica media thickness, volume density of the elastic fibers, wall stiffness, and SDMA concentration obtained from the SHR-D group were similar to those measured in the WKY group.

Conclusion: These results suggest that dronedarone improves the structure and passive mechanical properties of the thoracic aorta in hypertensive rats, and that this protective effect could be associated with a reduction in the concentration of aortic SDMA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216820PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529158PMC
January 2020

Exercise training prior to night shift work improves physical work capacity and arterial stiffness.

Eur J Prev Cardiol 2020 05 8;27(8):891-893. Epub 2019 May 8.

University Institute of Sports Medicine, Prevention and Rehabilitation and Research Institute of Molecular Medicine and Rehabilitation, Paracelsus Medical University, Salzburg, Austria.

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http://dx.doi.org/10.1177/2047487319848196DOI Listing
May 2020

Dronedarone induces regression of coronary artery remodeling related to better global antioxidant status.

Hypertens Res 2019 10 16;42(10):1485-1494. Epub 2019 Apr 16.

Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.

Our group previously demonstrated that dronedarone induces regression of left ventricular hypertrophy in spontaneously hypertensive rats (SHRs). We assessed changes in vascular remodeling and oxidative stress following short-term use of this agent. The coronary artery was isolated from 10-month-old male SHRs treated with 100 mg kg dronedarone once daily for 14 days (SHR-D group), and age-matched untreated SHRs were used as hypertensive controls. We analyzed the geometry and composition of the artery and constructed dose-response curves for acetylcholine and serotonin (5-HT). We calculated a global score (OXY-SCORE) from plasma biomarkers of oxidative status: carbonyl levels, thiol levels, reduced glutathione levels, total antioxidant capacity, and superoxide anion scavenging activity. Finally, we analyzed asymmetric dimethylarginine (ADMA) concentrations in plasma. Dronedarone significantly decreased wall thickness (medial and adventitial layer thickness and cell count) and the cross-sectional area of the artery. Dronedarone significantly improved endothelium-dependent relaxation and reduced the contraction induced by 5-HT. The OXY-SCORE was negative in the SHR model group (suggesting an enhanced oxidative status) and was positive in the SHR-D group (suggesting enhanced antioxidant defense). Dronedarone significantly decreased the concentrations of ADMA. We conclude that dronedarone improves coronary artery remodeling in SHRs. The better global antioxidant status after treatment with dronedarone and decreased plasma ADMA levels could contribute to the cardiovascular protective effect of dronedarone.
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http://dx.doi.org/10.1038/s41440-019-0257-zDOI Listing
October 2019

Guanidino compound ratios are associated with stroke etiology, internal carotid artery stenosis and CHADS-VASc score in three cross-sectional studies.

J Neurol Sci 2019 02 31;397:156-161. Epub 2018 Dec 31.

Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Electronic address:

Introduction: Guanidino compounds, including l-homoarginine (l-hArg), symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA) and l-arginine (l-Arg) are associated with mortality, fatal strokes, stroke incidence, and atherosclerosis.

Objectives: We aimed to study the association of guanidino compounds (l-hArg/ADMA and l-hArg/SDMA) with stroke etiology, internal carotid artery (ICA) stenosis and CHADS-VASc score in patients with cerebrovascular disease.

Methods: We analyzed l-hArg, SDMA, ADMA, l-Arg, and compound molar ratios, i.e. l-hArg/ADMA and l-hArg/SDMA, in 272 patients with cerebrovascular disease in a cross-sectional discovery cohort and two cross-sectional validation cohorts of acute stroke patients from Germany (n = 137) and UK (n = 394). The guanidino compound levels were compared with clinical, imaging, and ultrasound parameters.

Results: Low l-hArg/ADMA and l-hArg/SDMA molar ratios predicted territorial infarcts (OR 1.74; 95% CI 1.34-2.26 and OR 1.64; 95% CI 1.26-2.15, respectively) and were associated with stroke subtypes due to large vessel disease or cardio-embolism (OR 1.52; 95% CI 1.12-2.06 and OR 2.01; 95% CI 1.35-3.00, respectively) in meta-analysis of the discovery and validation cohort data. In line with these results, a low l-hArg/ADMA and l-hArg/SDMA molar ratio was found in patients with ICA stenosis (OR 0.73; 95% CI 0.55-0.97 and OR 0.69; 95% CI 0.50-0.94, respectively) in the discovery and validation cohort. Furthermore, guanidino compound ratios (i.e. l-hArg/ADMA and l-hArg/SDMA) were strongly correlated with CHADS-VASC score (p < .001) in all three cohorts.

Discussion: The results from these three cross-sectional studies reveal that guanidino compound ratios (i.e. l-hArg/ADMA and l-hArg/SDMA) can discriminate stroke etiologies, predict ICA stenosis and estimate risk prediction in patients with cerebrovascular disease.
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http://dx.doi.org/10.1016/j.jns.2018.12.037DOI Listing
February 2019

Symmetrical (SDMA) and asymmetrical dimethylarginine (ADMA) in sepsis: high plasma levels as combined risk markers for sepsis survival.

Crit Care 2018 09 19;22(1):216. Epub 2018 Sep 19.

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background: Nitric oxide (NO) regulates processes involved in sepsis progression, including vascular and immune function. NO is generated by nitric oxide synthases (NOS) from L-arginine. Cellular L-arginine uptake is inhibited by symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) is a competitive inhibitor of NOS. Increased inhibitor blood concentrations lead to reduce NO bioavailability. The aim of this study was to determine whether plasma concentrations of SDMA and ADMA are markers for sepsis survival.

Method: This prospective, single center study involved 120 ICU patients with sepsis. Plasma SDMA and ADMA were measured on admission (day 1), day 3 and day 7 by mass spectrometry together with other laboratory markers. The sequential organ failure assessment (SOFA) score was used to evaluate sepsis severity. Survival was documented until day 28. Groups were compared using the Mann-Whitney U test, chi-squared test or non-parametric analysis of variance (ANOVA). Mortality was assessed using Kaplan-Meier curves and compared using the log-rank test. Specific risk groups were identified using a decision tree algorithm.

Results: Median plasma SDMA and ADMA levels were significantly higher in non-survivors than in survivors of sepsis: SDMA 1.14 vs. 0.82 μmol/L (P = 0.002) and ADMA 0.93 vs. 0.73 μmol/L (P = 0.016). ANOVA showed that increased plasma SDMA and ADMA concentrations were significantly associated with SOFA scores. The 28-day mortality was compared by chi-square test: for SDMA the mortality was 12% in the lower, 25% in the intermediate and 43% in the 75th percentile (P = 0.018); for ADMA the mortality was 18-20% in the lower and intermediate but 48% in the 75th percentile (P = 0.006). The highest mortality (61%) was found in patients with plasma SDMA > 1.34 together with ADMA levels > 0.97 μmol/L.

Conclusions: Increased plasma concentrations of SDMA and ADMA are associated with sepsis severity. Therefore, our findings suggest reduced NO bioavailability in non-survivors of sepsis. One may use individual SDMA and ADMA levels to identify patients at risk. In view of the pathophysiological role of NO we conclude that the vascular system and immune response are most severely affected when SDMA and ADMA levels are high.
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http://dx.doi.org/10.1186/s13054-018-2090-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145330PMC
September 2018

Cross-Sectional Associations between Homoarginine, Intermediate Phenotypes, and Atrial Fibrillation in the Community-The Gutenberg Health Study.

Biomolecules 2018 08 30;8(3). Epub 2018 Aug 30.

Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Homoarginine has come into the focus of interest as a biomarker for cardiovascular disease. Atrial fibrillation (AF) causes a substantial increase in morbidity and mortality. Whether circulating homoarginine is associated with occurrence or persistence of AF and may serve as a new predictive biomarker remains unknown. We measured plasma levels of homoarginine in the population-based Gutenberg health study (3761 patients included, of them 51.7% males), mean age 55.6 ± 10.9 years-old. Associations between homoarginine and intermediate electrocardiographic and echocardiographic phenotypes and manifest AF were examined. Patients with AF (124 patients, of them 73.4% males) had a mean age 64.8 ± 8.6 years-old compared to a mean age of 55.3 ± 10.9 in the population without AF (-value < 0.001) and showed a less beneficial risk factor profile. The median homoarginine levels in individuals with and without AF were 1.9 μmol/L (interquartile range (IQR) 1.5⁻2.5) and 2.0 μmol/L (IQR 1.5⁻2.5), respectively, = 0.56. In multivariable-adjusted regression analyses homoarginine was not statistically significantly related to electrocardiographic variables. Among echocardiographic variables beta per standard deviation increase was -0.12 (95% confidence interval (CI) -0.23⁻(-0.02); = 0.024) for left atrial area and -0.01 (95% CI -0.02⁻(-0.003); = 0.013) for E/A ratio. The odds ratio between homoarginine and AF was 0.91 (95% CI 0.70⁻1.16; = 0.45). In our large, population-based cross-sectional study, we did not find statistically significant correlations between lower homoarginine levels and occurrence or persistence of AF or most standard electrocardiographic phenotypes, but some moderate inverse associations with echocardiographic left atrial size and E/A. Homoarginine may not represent a strong biomarker to identify individuals at increased risk for AF. Further investigations will be needed to elucidate the role of homoarginine and cardiac function.
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http://dx.doi.org/10.3390/biom8030086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165554PMC
August 2018

Low-Circulating Homoarginine is Associated with Dilatation and Decreased Function of the Left Ventricle in the General Population.

Biomolecules 2018 07 30;8(3). Epub 2018 Jul 30.

Department of Internal Medicine B, University Medicine Greifswald, 17475 Greifswald, Germany.

Low homoarginine is an independent marker of mortality in heart failure patients and incident cardiovascular events. Whether homoarginine is related with healthier cardiac structure and function is currently unclear. We used data of the population-based "Study of Health in Pomerania" (SHIP-Trend) to assess this relation. Homoarginine was measured in serum using liquid chromatography-tandem mass spectrometry. Linear regression models assessed the relation between homoarginine and several structural as well as functional parameters and N-terminal pro B-type natriuretic peptide (NTproBNP). All models were adjusted for age, sex, body mass index, and renal function. A total of 3113 subjects (median age 48 (25th percentile 37 to 75th percentile 60) years, 46% male) were included. A standard deviation decrease in homoarginine was associated with a larger left ventricular diastolic diameter (0.3; 95%-confidence interval (CI): 0.2 to 0.5 mm; < 0.001), left ventricular systolic diameter (0.38; 95%-CI: -0.22 to 0.54 mm; < 0.001) as well as a less relative wall thickness (⁻0.003 95%-CI: -0.006 to -0.0008; = 0.01), left ventricular ejection fraction (⁻0.47; 95%-CI: ⁻0.79 to -0.15%; < 0.01) and fractional shortening (-0.35; 95%-CI: -0.62 to 0.07%; = 0.01). Low homoarginine was also related to higher NTproBNP (-0.02 95%-CI: -0.034 to -0.009 log pg/mL; < 0.01). Lower serum homoarginine is associated with dilatation of the heart and decreased function. Prospective clinical studies should assess if homoarginine supplementation improves cardiac health in subjects with low serum concentrations.
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http://dx.doi.org/10.3390/biom8030063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165018PMC
July 2018

Long-Term Intermittent Work at High Altitude: Right Heart Functional and Morphological Status and Associated Cardiometabolic Factors.

Front Physiol 2018 22;9:248. Epub 2018 Mar 22.

Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Living at high altitude or with chronic hypoxia implies functional and morphological changes in the right ventricle and pulmonary vasculature with a 10% prevalence of high-altitude pulmonary hypertension (HAPH). The implications of working intermittently (day shifts) at high altitude (hypobaric hypoxia) over the long term are still not well-defined. The aim of this study was to evaluate the right cardiac circuit status along with potentially contributory metabolic variables and distinctive responses after long exposure to the latter condition. A cross-sectional study of 120 healthy miners working at an altitude of 4,400-4,800 m for over 5 years in 7-day commuting shifts was designed. Echocardiography was performed on day 2 at sea level. Additionally, biomedical and biochemical variables, Lake Louise scores (LLSs), sleep disturbances and physiological variables were measured at altitude and at sea level. The population was 41.8 ± 0.7 years old, with an average of 14 ± 0.5 (range 5-29) years spent at altitude. Most subjects still suffered from mild to moderate symptoms of acute mountain sickness (mild was an LLS of 3-5 points, including cephalea; moderate was LLS of 6-10 points) (38.3%) at the end of day 1 of the shift. Echocardiography showed a 23% mean pulmonary artery pressure (mPAP) >25 mmHg, 9% HAPH (≥30 mmHg), 85% mild increase in right ventricle wall thickness (≥5 mm), 64% mild right ventricle dilation, low pulmonary vascular resistance (PVR) and fairly good ventricle performance. Asymmetric dimethylarginine (ADMA) (OR 8.84 (1.18-66.39); < 0.05) and insulin (OR: 1.11 (1.02-1.20); < 0.05) were associated with elevated mPAP and were defined as a cut-off. Interestingly, the correspondence analysis identified association patterns of several other variables (metabolic, labor, and biomedical) with higher mPAP. Working intermittently at high altitude involves a distinctive pattern. The most relevant and novel characteristics are a greater prevalence of elevated mPAP and HAPH than previously reported at chronic intermittent hypobaric hypoxia (CIHH), which is accompanied by subsequent morphological characteristics. These findings are associated with cardiometabolic factors (insulin and ADMA). However, the functional repercussions seem to be minor or negligible. This research contributes to our understanding and surveillance of this unique model of chronic intermittent high-altitude exposure.
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http://dx.doi.org/10.3389/fphys.2018.00248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874329PMC
March 2018

Relationship between exercise intervention and NO pathway in patients with heart failure with preserved ejection fraction.

Biomarkers 2018 Sep 12;23(6):540-550. Epub 2018 Apr 12.

a Department of Prevention, Rehabilitation and Sports Medicine , Technische Universität München , Munich , Germany.

Objective: Elevated levels of arginine derivatives in the NO pathway, such as asymmetric dimethylarginine (ADMA), are related to disease severity and reduced exercise capacity in heart failure (HF). We investigated the influence of exercise intervention on these parameters and on L-arginine (L-Arg) and L-homoarginine (L-hArg) in HF with preserved ejection fraction (HFpEF) patients.

Material And Methods: Sixty-two patients (65 ± 6 years) were included in this analysis and randomized to supervised endurance/resistance training (ET) or to usual care (UC). EDTA-plasma was analysed for NO metabolites.

Results: There were baseline associations for adjusted values of maximum workload with ADMA (r= -0.322, p = 0.028) and L-Arg/ADMA ratio (r = 0.331, p = 0.015), and for the 6-min walk test (6MWT) with ADMA (r= -0.314, p = 0.024) and L-Arg/ADMA ratio (r = 0.346, p = 0.015). No significant differences between UC and ET changes of NO parameters were observed at 3-month follow-up. Higher L-hArg levels were associated with a greater improvement in peak oxygen uptake (peak [Formula: see text]O) at follow-up: 3.4 ± 2.8 vs. 1.1 ± 2.9 mL/min/kg (p = 0.005).

Conclusions: Exercise intervention did not influence NO parameters in HFpEF patients, but L-hArg was related to change in peak [Formula: see text]O.
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http://dx.doi.org/10.1080/1354750X.2018.1460762DOI Listing
September 2018

Asymmetric and Symmetric Dimethylarginines are Markers of Delayed Cerebral Ischemia and Neurological Outcome in Patients with Subarachnoid Hemorrhage.

Neurocrit Care 2018 08;29(1):84-93

Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Delayed cerebral ischemia (DCI) is the major cause of lethality and neuronal damage in patients who survived the primary subarachnoid hemorrhage (SAH). Asymmetric and symmetric dimethylarginines (ADMA and SDMA) inhibit nitric oxide production from L-arginine via distinct mechanisms. Elevated ADMA levels are associated with vasospasm after SAH. We aimed to study the time course of ADMA and SDMA in plasma and ventricular cerebrospinal fluid (CSF) and their associations with DCI and outcome.

Methods: We measured ADMA and SDMA in 34 SAH patients with an external ventricular drain at admission and on days 3, 6, 8, 12, and 15 and followed them up for clinical status and neurological outcome until 30 days post-discharge. DCI was defined as the appearance of new infarctions on cerebral computed tomography or magnetic resonance imaging.

Results: ADMA and SDMA plasma concentrations did not differ significantly at baseline between patients who suffered DCI (N = 14; 41%) and not; however, plasma ADMA reached a peak on days 8 and 15 after hemorrhage in patients with DCI (0.81-0.91 µmol/l). Baseline plasma L-arginine/ADMA ratio was significantly lower in patients with DCI (57.1 [34.3; 70.8] vs. 68.7 [55.7; 96.2]; p < 0.05). ADMA and SDMA concentrations in CSF were significantly higher in patients with DCI than without. In multivariable-adjusted linear regression models, CSF ADMA was negatively associated with the incidence of DCI (OR 0.03 [0.02-0.70]; p = 0.04), whereas CSF SDMA on the day of hemorrhage predicted poor neurological outcome until 30 days after discharge (OR 22.4 [1.21-416.02]; p = 0.04).

Conclusions: Our study shows that ADMA and the L-arginine/ADMA ratio are associated with the incidence of DCI after SAH. By contrast, SDMA was associated with initial neuronal damage and poor neurological outcome after SAH. These data support the hypothesis that ADMA and L-arginine affect the pathophysiology of cerebral ischemia after SAH, while SDMA is a biomarker of neurological outcome after SAH.
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http://dx.doi.org/10.1007/s12028-018-0520-1DOI Listing
August 2018

Plasma Nitrate and Incidence of Cardiovascular Disease and All-Cause Mortality in the Community: The Framingham Offspring Study.

J Am Heart Assoc 2017 11 18;6(11). Epub 2017 Nov 18.

Cardiology Division and Section of Preventive Medicine and Epidemiology, Boston University Schools of Public Health and Medicine, Boston, MA.

Background: Nitrate is a dietary component as well as an endogenously formed metabolite and source of the signaling molecule nitric oxide. Harmful as well as beneficial effects of nitrate have been advocated. Data regarding the prognostic relevance of plasma nitrate are limited. The aim of this study was to evaluate the prospective association of plasma nitrate with cardiovascular disease (CVD) and all-cause mortality.

Methods And Results: We assayed plasma nitrate in 2855 Framingham Offspring Study participants (mean age 59 years, 54% women) by gas chromatography-mass spectrometry and evaluated its association with all-cause mortality and incident CVD. On follow-up (median 17.3 years), 775 participants died and 522 developed new-onset CVD (of 2546 participants free of CVD at baseline). In multivariable models adjusting for standard risk factors, plasma nitrate was associated with an increased risk of death in participants (hazard ratio per unit increase in log-nitrate 1.21; 95% confidence interval, 1.04-1.40 [=0.015]). The strength of the association was attenuated by additional adjustment for estimated glomerular filtration rate (hazard ratio, 1.16; 95% confidence interval, 1.00-1.35 [=0.057]). In contrast, no evidence was found for an association of plasma nitrate with incident CVD (multivariable-adjusted hazard ratio per unit increase log-nitrate 1.08; 95% confidence interval, 0.89-1.31 [=0.42]).

Conclusions: In our prospective community-based investigation, a higher plasma nitrate concentration was associated with all-cause mortality but not with incident CVD. The association of nitrate with mortality may at least in part be attributable to its association with renal function.
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http://dx.doi.org/10.1161/JAHA.117.006224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721741PMC
November 2017

Cardiomyocyte dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays an important role in attenuating ventricular hypertrophy and dysfunction.

Basic Res Cardiol 2017 08 17;112(5):55. Epub 2017 Aug 17.

Cardiovascular Division, University of Minnesota Medical School, Minneapolis, USA.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases that limits nitric oxide bioavailability. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) exerts a critical role for ADMA degradation and plays an important role in NO signaling. In the heart, DDAH1 is observed in endothelial cells and in the sarcolemma of cardiomyocytes. While NO signaling is important for cardiac adaptation to stress, DDAH1 impact on cardiomyocyte homeostasis is not clear. Here we used the MerCreMer-LoxP model to specifically disrupt cardiomyocyte DDAH1 expression in adult mice to determine the physiological impact of cardiomyocyte DDAH1 under basal conditions and during hypertrophic stress imposed by transverse aortic constriction (TAC). Under control conditions, cardiomyocyte-specific DDAH1 knockout (cDDAH KO) had no detectable effect on plasma ADMA and left ventricular (LV) hypertrophy or function in adult or aging mice. In response to TAC, DDAH1 levels were elevated 2.5-fold in WT mice, which exhibited no change in LV or plasma ADMA content and moderate LV hypertrophy and LV dysfunction. In contrast, cDDAH1 KO mice exposed to TAC showed no increase in LV DDAH1 expression, slightly increased LV tissue ADMA levels, no increase in plasma ADMA, but significantly exacerbated LV hypertrophy, fibrosis, nitrotyrosine production, and LV dysfunction. These findings indicate cardiomyocyte DDAH1 activity is dispensable for cardiac function under basal conditions, but plays an important role in attenuating cardiac hypertrophy and ventricular remodeling under stress conditions, possibly through locally confined regulation of subcellular ADMA and NO signaling.
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http://dx.doi.org/10.1007/s00395-017-0644-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502637PMC
August 2017

Markers of nitric oxide are associated with sepsis severity: an observational study.

Crit Care 2017 Jul 15;21(1):189. Epub 2017 Jul 15.

Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background: Nitric oxide (NO) regulates processes involved in sepsis progression, including vascular function and pathogen defense. Direct NO measurement in patients is unfeasible because of its short half-life. Surrogate markers for NO bioavailability are substrates of NO generating synthase (NOS): L-arginine (lArg) and homoarginine (hArg) together with the inhibitory competitive substrate asymmetric dimethylarginine (ADMA). In immune cells ADMA is cleaved by dimethylarginine-dimethylaminohydrolase-2 (DDAH2). The aim of this study was to investigate whether concentrations of surrogate markers for NO bioavailability are associated with sepsis severity.

Method: This single-center, prospective study involved 25 controls and 100 patients with surgical trauma (n = 20), sepsis (n = 63), or septic shock (n = 17) according to the Sepsis-3 definition. Plasma lArg, hArg, and ADMA concentrations were measured by mass spectrometry and peripheral blood mononuclear cells (PBMCs) were analyzed for DDAH2 expression.

Results: lArg concentrations did not differ between groups. Median (IQR) hArg concentrations were significantly lower in patient groups than controls, being 1.89 (1.30-2.29) μmol/L (P < 0.01), with the greatest difference in the septic shock group, being 0.74 (0.36-1.44) μmol/L. In contrast median ADMA concentrations were significantly higher in patient groups compared to controls, being 0.57 (0.46-0.65) μmol/L (P < 0.01), with the highest levels in the septic shock group, being 0.89 (0.56-1.39) μmol/L. The ratio of hArg:ADMA was inversely correlated with disease severity as determined by the Sequential Organ Failure Assessment (SOFA) score. Receiver-operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for the hArg:ADMA ratio compared to the SOFA score. DDAH2 expression was lower in patients than controls and lowest in the subgroup of patients with increasing SOFA.

Conclusions: In patients with sepsis, plasma hArg concentrations are decreased and ADMA concentrations are increased. Both metabolites affect NO metabolism and our findings suggest reduced NO bioavailability in sepsis. In addition, reduced expression of DDAH2 in immune cells was observed and may not only contribute to blunted NO signaling but also to subsequent impaired pathogen defense.
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http://dx.doi.org/10.1186/s13054-017-1782-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513203PMC
July 2017

Akrinor, a Cafedrine/ Theodrenaline Mixture (20:1), Increases Force of Contraction of Human Atrial Myocardium But Does Not Constrict Internal Mammary Artery .

Front Pharmacol 2017 23;8:272. Epub 2017 May 23.

Department of Anesthesia and Critical Care Medicine, Leipzig UniversityLeipzig, Germany.

Intraoperative hypotension is a common problem and direct or indirect sympathomimetic drugs are frequently needed to stabilize blood pressure. Akrinor consists of the direct and the indirect sympathomimetic noradrenaline and norephedrine. Both substances are covalently bound to the phosphodiesterase (PDE) inhibitor theophylline, yielding theodrenaline and cafedrine, respectively. We investigated pharmacodynamic effects of Akrinor and its constituents on contractile force and tension in human atrial trabeculae and internal A. mammaria rings. Isometric contractions were measured in human atrial trabeculae at 1 Hz and 37°C. CGP 20712A and ICI 118,551 were used to elaborate β- and β-adrenoceptor (AR) subtypes involved and phenoxybenzamine to estimate indirect sympathomimetic action. PDE-inhibition was measured as a potentiation of force increase upon direct activation of adenylyl cyclase by forskolin. Human A. mammaria preparations were used to estimate intrinsic vasoconstriction and impact on the noradrenaline-induced vasoconstriction. Clinically relevant concentrations of Akrinor (4.2-420 mg/l) robustly increased force in human atrial trabeculae (EC 41 ± 3 mg/l). This direct sympathomimetic action was mediated via β-AR and the effect size was as large as with high concentrations of calcium. Only the highest and clinically irrelevant concentration of Akrinor increased the potency of forskolin to a minor extent. Norephedrine has lost its indirect sympathomimetic effect when bound to theophylline. Increasing concentrations of Akrinor (4.2-168 mg/l) alone did not affect the tension of human A. mammaria interna rings, but shifted the noradrenaline curve rightward from -logEC 6.18 ± 0.08 to 5.23 ± 0.05 M. Akrinor increased cardiac contractile force by direct sympathomimetic actions and PDE inhibition, did not constrict A. mammaria preparations, but shifted the concentration-response curve to the right, compatible with an α-AR antagonistic effect or PDE inhibition. The pharmacodynamic profile and potency of Akrinor differs from noradrenaline and norephedrine . We anticipate metabolism of theodrenaline and cafedrine resulting in a different pharmacodynamic profile of Akrinor.
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http://dx.doi.org/10.3389/fphar.2017.00272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441130PMC
May 2017

Long-Term Intermittent Exposure to High Altitude Elevates Asymmetric Dimethylarginine in First Exposed Young Adults.

High Alt Med Biol 2017 Sep 28;18(3):226-233. Epub 2017 Apr 28.

1 Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf , Hamburg, Germany .

Lüneburg, Nicole, Patricia Siques, Julio Brito, Juan José De La Cruz, Fabiola León-Velarde, Juliane Hannemann, Cristian Ibanez, and Rainer Böger. Long-term intermittent exposure to high altitude elevates asymmetric dimethylarginine in first exposed young adults. High Alt Med Biol. 18:226-233, 2017.-Hypoxia-induced dysregulation of pulmonary and cerebral circulation may be related to an impaired nitric oxide (NO) pathway. We investigated the effect of chronic intermittent hypobaric hypoxia (CIH) on metabolites of the NO pathway. We measured asymmetric and symmetric dimethylarginine (ADMA and SDMA) and monomethyl-L-arginine (L-NMMA) and assessed their associations with acclimatization in male draftees (n = 72) undergoing CIH shifts at altitude (3550 m) during 3 months. Sixteen Andean natives living at altitude (3675 m) (chronic hypobaric hypoxia [CH]) were included for comparison. In CIH, ADMA and L-NMMA plasma concentrations increased from 1.14 ± 0.04 to 1.95 ± 0.09 μmol/L (mean ± SE) and from 0.22 ± 0.07 to 0.39 ± 0.03 μmol/L, respectively, (p < 0.001 for both) after 3 months, whereas SDMA did not change. The concentrations of ADMA and L-NMMA were higher in CH (3.48 ± 0.07, 0.53 ± 0.08 μmol/L; p < 0.001) as compared with CIH. In both CIH and CH, ADMA correlated with hematocrit (r = 0.07, p < 0.05; r = 0.26; p < 0.01). In CIH, an association of ADMA levels with poor acclimatization status was observed. We conclude that the endogenous NO synthase inhibitors, ADMA and L-NMMA, are elevated in hypoxia. This may contribute to impaired NO production at altitude and may also be predictive of altitude-associated health impairment.
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http://dx.doi.org/10.1089/ham.2016.0123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649417PMC
September 2017

Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease.

Eur Heart J 2017 May;38(20):1597-1607

Department of Internal Medicine IV, Kirrberger Strasse, 66421 Homburg/Saar, Saarland University Medical Centre, Germany.

Aims: The vascular effects of high-density lipoproteins (HDL) differ under certain clinical conditions. The composition of HDL is modified in patients with chronic kidney disease (CKD). As a consequence, uremic HDL induces endothelial dysfunction. We have previously shown that accumulation of symmetric dimethylarginine (SDMA) in HDL causes these adverse effects of HDL in CKD. The aim of the study is to determine the impact of the accumulation of SDMA on the association between HDL and mortality.

Methods And Results: Mortality, renal function, serum SDMA and HDL-cholesterol (HDL-C) were assessed in the LURIC study including 3310 subjects undergoing coronary angiography. All-cause mortality was 30.0% during median follow-up of 9.9 years. Serum SDMA levels significantly predicted all-cause and cardiovascular mortality, and were significantly correlated with SDMA accumulation in HDL. Notably, higher serum SDMA was independently associated with lower cholesterol efflux (P = 0.004) as a measure of HDL functionality. In subjects with low SDMA levels, higher HDL-C was associated with significantly lower mortality. In contrast, in subjects with high SDMA, HDL-C was associated with higher mortality. These findings were confirmed in 1424 participants of the MONICA/KORA S3 cohort. Of note, we derived an algorithm allowing for calculation of biologically effective HDL-C' based on measured HDL-C and SDMA. We corroborated these clinical findings with invitro evidence showing that SDMA accumulation abolishes the anti-inflammatory and regenerative properties of HDL.

Conclusion: The data identify SDMA as a marker of HDL dysfunction. These findings highlight on the pivotal role of SDMA accumulation in HDL as a mediator of pre-mature cardiovascular disease in patients with CKD.
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http://dx.doi.org/10.1093/eurheartj/ehx118DOI Listing
May 2017

Data on subgroup specific baseline characteristics and serum sphingosine-1-phosphate concentrations in the Study of Health in Pomerania.

Data Brief 2017 Jun 11;12:46-50. Epub 2017 Mar 11.

Institute of Pharmacology, Department of General Pharmacology, University Medicine Greifswald, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Germany.

In this data article, we provide subgroup specific baseline characteristics and serum sphingosine-1-phosphate (S1P) concentrations for healthy individuals within the Study of Health in Pomerania (SHIP)-TREND cohort. After exclusion of subjects with cardiovascular disease, diabetes mellitus, hypertension, metabolic syndrome, elevated liver enzymes and/or chronic kidney disease stadium III or IV, four subgroups were defined according to different limits for body mass index (BMI), alterations in blood lipid levels and smoking status. Tables show respective clinical and laboratory parameters stratified by gender. Serum S1P concentrations are also stratified by age groups. The data presented herein is related to the research article entitled "Reference intervals for serum sphingosine-1-phosphate in the population-based Study of Health in Pomerania" (E. Moritz, D. Wegner, S. Groß, M. Bahls, M. Dörr, S.B. Felix, T. Ittermann, S. Oswald, M. Nauck, N. Friedrich, R.H. Böger, G. Daum, E. Schwedhelm, B.H. Rauch, Clin Chim Acta. 468 (2017) 25-31) [1].
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http://dx.doi.org/10.1016/j.dib.2017.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369692PMC
June 2017

Reference intervals for serum sphingosine-1-phosphate in the population-based Study of Health in Pomerania.

Clin Chim Acta 2017 May 31;468:25-31. Epub 2017 Jan 31.

Institute of Pharmacology, Department of General Pharmacology, University Medicine Greifswald, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Germany. Electronic address:

Background: The bioactive signaling lipid sphingosine-1-phosphate (S1P) is a potential biomarker for cardiovascular disease (CVD). To date, no reference intervals for S1P have been defined. This study aims to establish a reference range for serum S1P in healthy individuals.

Methods: We determined reference intervals for S1P levels according to gender and age in a sample of 1339 healthy participants of the Study of Health in Pomerania (SHIP)-TREND cohort after exclusion of subjects with CVD, diabetes mellitus, hypertension, metabolic syndrome, elevated liver enzymes, chronic kidney disease stadium III or IV, or body mass index (BMI)>30kg/m. Serum S1P was measured by liquid chromatography-tandem mass spectrometry.

Results: The median age of the participants was 41 (25th; 75th percentile 32; 51) years, 65% were women. The median serum concentration of S1P was 0.804 (0.694; 0.920) μmol/L. No association with gender and age was observed. The overall reference interval was 0.534-1.242μmol/L (2.5th; 97.5th percentile). Further exclusion of smokers, individuals with BMI>25kg/m or elevated lipid levels did not significantly affect median S1P concentrations.

Conclusions: This study provides reference intervals for serum S1P in healthy individuals. Total serum S1P concentrations vary irrespectively of age, gender, BMI or smoking status.
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http://dx.doi.org/10.1016/j.cca.2017.01.029DOI Listing
May 2017

Acute effects of exercise on the inflammatory state in patients with idiopathic pulmonary arterial hypertension.

BMC Pulm Med 2016 11 11;16(1):145. Epub 2016 Nov 11.

Center for Pulmonary Arterial Hypertension, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Exercise training positively influences exercise tolerance and functional capacity of patients with idiopathic pulmonary arterial hypertension (IPAH). However, the underlying mechanisms are unclear. We hypothesized that exercise modulates the activated inflammatory state found in IPAH patients.

Methods: Single cardiopulmonary exercise testing was performed in 16 IPAH patients and 10 healthy subjects. Phenotypic characterization of peripheral blood mononuclear cells and circulating cytokines were assessed before, directly after and 1 h after exercise.

Results: Before exercise testing, IPAH patients showed elevated Th2 lymphocytes, regulatory T lymphocytes, IL-6, and TNF-alpha, whilst Th1/Th17 lymphocytes and IL-4 were reduced. In IPAH patients but not in healthy subject, exercise caused an immediate relative decrease of Th17 lymphocytes and a sustained reduction of IL-1-beta and IL-6. The higher the decrease of IL-6 the higher was the peak oxygen consumption of IPAH patients.

Conclusions: Exercise seems to be safe from an immune and inflammatory point of view in IPAH patients. Our results demonstrate that exercise does not aggravate the inflammatory state and seems to elicit an immune-modulating effect in IPAH patients.
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http://dx.doi.org/10.1186/s12890-016-0301-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5106767PMC
November 2016

Higher serum asymmetric dimethylarginine is related to higher risk of heart failure in the EPIC-Potsdam study.

Amino Acids 2017 01 28;49(1):173-182. Epub 2016 Oct 28.

Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

L-Arginine is the substrate of endothelial nitric oxide (NO) synthase forming NO which inherits various biological cardio-protective functions. The dimethylarginines asymmetric (ADMA) and symmetric dimethylarginine (SDMA) can impair the synthesis of NO and are elevated in patients with cardiovascular disease, including heart failure (HF). We investigated the association between dimethylarginines and HF risk in a case-cohort study of the European Prospective Investigation into Cancer and Nutrition (n = 27,548), comprising a random subcohort (n = 2224 including 19 HF cases), and all remaining HF cases (n = 176) that occurred within 8.3 years of follow-up. Serum concentrations of dimethylarginines were measured using liquid chromatography-tandem mass spectrometry. Hazards ratios (HRs) and 95% confidence intervals (CI) were estimated across quartiles and per doubling of ADMA and SDMA concentrations using Cox's proportional hazards regression. After multivariable adjustment, each doubling of ADMA was associated with a 60% higher HF risk (HR [95% CI] 1.60 [1.10-2.31]). Between SDMA and HF risk a U-shaped association was observed (HR [95% CI] for the second, third and fourth quartile compared to the first: 0.52 [0.33-0.82], 0.63 [0.40-0.99], and 0.71 [0.46-1.10], p for nonlinearity <0.01). We provide substantiated evidence for a relationship between ADMA and cardiovascular endpoints. In addition to the established relation between ADMA and myocardial infarction, our findings indicate a positive association between ADMA and HF incidence in persons without apparent myocardial infarction. Targeting the ADMA metabolism might open up new therapeutic perspective for HF prevention and treatment. Further investigations are needed to shed more light on mechanisms involved in the pathogenesis of HF related to elevated ADMA levels.
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http://dx.doi.org/10.1007/s00726-016-2348-3DOI Listing
January 2017

Short-term esmolol attenuates remodeling of the thoracic aorta in hypertensive rats by decreasing concentrations of ADMA down-regulated by oxidative stress.

Eur J Pharmacol 2016 Nov 14;791:502-509. Epub 2016 Sep 14.

Molecular Biology Laboratory, Department Experimental Medicine and Surgery, Hospital Gregorio Marañón, Health Research Institute of Hospital Gregorio Marañón, 28007 Madrid, Spain. Electronic address:

Esmolol produces early regression of left ventricular hypertrophy and improves coronary artery remodeling, although the impact of short-term treatment with this beta-blocker on remodeling in large arteries has not yet been studied. We hypothesized that even a short (48h) course of esmolol might alter remodeling of the aorta in the spontaneously hypertensive rat (SHR). Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=8) or esmolol (SHR-E, n=8) (300μg/kg/min). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=8) served as controls. After 48h, we studied the structure, volume density of elastic fibers, and passive mechanical properties of the aorta. Determination of asymmetrical dimethylarginine concentrations and total protein carbonyls in the aorta were analyzed. Esmolol significantly attenuated abnormal aortic wall thickness, cross-sectional area, wall-to-lumen ratio, volume density of elastic fibers, and wall stiffness. The protective effect of esmolol could be related to a decrease in asymmetrical dimethylarginine levels after down-regulation by oxidative stress. These findings could play a key role in the selection of antihypertensive therapy in patients with hypertension and aortic remodeling.
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http://dx.doi.org/10.1016/j.ejphar.2016.09.020DOI Listing
November 2016

Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels.

Thromb Haemost 2016 Nov 22;116(6):1041-1049. Epub 2016 Sep 22.

Weihua Zhang, PhD, Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, UK, Tel.: +44 20 8242 5926, Fax: +44 20 8967 5007, E-mail:

L-arginine is the essential precursor of nitric oxide, and is involved in multiple key physiological processes, including vascular and immune function. The genetic regulation of blood L-arginine levels is largely unknown. We performed a genome-wide association study (GWAS) to identify genetic factors determining serum L-arginine levels, amongst 901 Europeans and 1,394 Indian Asians. We show that common genetic variations at the KLKB1 and F12 loci are strongly associated with serum L-arginine levels. The G allele of single nucleotide polymorphism (SNP) rs71640036 (T/G) in KLKB1 is associated with lower serum L-arginine concentrations (10 µmol/l per allele copy, p=1×10), while allele T of rs2545801 (T/C) near the F12 gene is associated with lower serum L-arginine levels (7 µmol/l per allele copy, p=7×10). Together these two loci explain 7 % of the total variance in serum L-arginine concentrations. The associations at both loci were replicated in independent cohorts with plasma L-arginine measurements (p<0.004). The two sentinel SNPs are in nearly complete LD with the nonsynonymous SNP rs3733402 at KLKB1 and the 5'-UTR SNP rs1801020 at F12, respectively. SNPs at both loci are associated with blood pressure. Our findings provide new insight into the genetic regulation of L-arginine and its potential relationship with cardiovascular risk.
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http://dx.doi.org/10.1160/TH16-02-0151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215702PMC
November 2016