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Arginine: HELP
Articles by Rainer H. Böger
Based on 74 articles published since 2008
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Between 2008 and 2018, R. Böger wrote the following 74 articles about Arginine.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Asymmetric dimethylarginine: understanding the physiology, genetics, and clinical relevance of this novel biomarker. Proceedings of the 4th International Symposium on ADMA. 2009

Böger, Rainer H. · ·Pharmacol Res · Pubmed #19853807.

ABSTRACT: -- No abstract --

2 Review The pharmacodynamics of L-arginine. 2014

Böger, Rainer H. · ·Altern Ther Health Med · Pubmed #24755570.

ABSTRACT: L-Arginine is a precursor for nitric oxide (NO) synthesis. NO is a ubiquitous mediator that is formed by a family of enzymes called NO synthases (NOSs). In the brain, NO acts as a neurotransmitter; in the immune system, it acts as a mediator of host defense; and in the cardiovascular system, it mediates the protective effects of the intact endothelium, acting as a vasodilator and endogenous, antiatherogenic molecule. About 5 g of L-arginine are ingested each day in a normal Western diet. Plasma levels of L-arginine are not significantly reduced in most diseases, except in end-stage renal failure during hemodialysis treatment. Nonetheless, intravenous or dietary (oral) administration of relatively large doses of L-arginine has been shown to result in enhanced NO formation in individuals with impaired endothelial function at baseline. In several controlled clinical trials, long-term administration of L-arginine has been shown to improve the symptoms of cardiovascular disease. However, in other trials, L-arginine was not beneficial, and in a recent study, the authors reported higher mortality for participants receiving L-arginine than for those receiving placebo. Recently, it became clear that endogenous levels of asymmetric dimethylarginine (ADMA), a competitive inhibitor of L-Arginine metabolism by NOS, may determine an individual's response to L-arginine supplementation. L-Arginine appears to exert no effect in individuals with low ADMA levels, whereas in those with high levels, L-arginine restores the L-arginine/ADMA ratio to normal and, thereby, normalizes endothelial function. In conclusion, the effects of L-arginine supplementation on human physiology appear to be multicausal and dose-related. Doses of 3-8 g/d appear to be safe and not to cause acute pharmacologic effects in humans.

3 Review The role of asymmetric and symmetric dimethylarginines in renal disease. 2011

Schwedhelm, Edzard / Böger, Rainer H. ·Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Martinistrasse 52, 20246 Hamburg, Germany. ·Nat Rev Nephrol · Pubmed #21445101.

ABSTRACT: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases. By inhibiting nitric oxide formation, ADMA causes endothelial dysfunction, vasoconstriction, elevation of blood pressure, and aggravation of experimental atherosclerosis. Levels of ADMA and its isomer symmetric dimethylarginine (SDMA), which does not inhibit nitric oxide synthesis, are both elevated in patients with kidney disease. Currently available data from prospective clinical trials in patients with chronic kidney disease suggest that ADMA is an independent marker of progression of renal dysfunction, vascular complications and death. High SDMA levels also negatively affect survival in populations at increased cardiovascular risk, but the mechanisms underlying this effect are currently only partly understood. Beyond glomerular filtration, other factors influence the plasma concentrations of ADMA and SDMA. Elevated plasma concentrations of these dimethylarginines might also indirectly influence the activity of nitric oxide synthases by inhibiting the uptake of cellular L-arginine. Other mechanisms may exist by which SDMA exerts its biological activity. The biochemical pathways that regulate ADMA and SDMA, and the pathways that transduce their biological function, could be targeted to treat renal disease in the future.

4 Review Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus. 2010

Anderssohn, Maike / Schwedhelm, Edzard / Lüneburg, Nicole / Vasan, Ramachandran S / Böger, Rainer H. ·Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ·Diab Vasc Dis Res · Pubmed #20382774.

ABSTRACT: Asymmetric dimethylarginine (ADMA) has evolved as an important regulator of nitric oxide (NO) synthesis in recent years. Elevated levels of ADMA have been reported in many conditions associated with a high cardiovascular risk. Moreover, ADMA is a biomarker for major cardiovascular events and mortality in cohorts with high, intermediate and low overall cardiovascular risk. Discrepant data have been reported on cardiovascular risk in people with and without diabetes mellitus, and the association of ADMA with diabetes mellitus per se has also remained controversial, possibly relating to type and stage of diabetes. Clinical and experimental data suggest that there is a multifaceted link between ADMA and insulin metabolism and action on one hand, and ADMA and glucose utilisation on the other. This interplay may be regulated by the enzyme involved in the metabolic degradation of ADMA, dimethylarginine dimethylaminohydrolase (DDAH). Recent data from prospective clinical studies suggest that whilst ADMA may be a marker for total mortality in patients without diabetes, elevated ADMA may exert beneficial effects in patients with diabetes. In this respect, ADMA could serve as a re-coupling agent overcoming endothelial nitric oxide synthase (eNOS) uncoupling in patients with diabetes. Anticipated advances in clinical and experimental investigation will help us to better understand this complex interrelationship between diabetes, eNOS, DDAH and ADMA.

5 Review The role of nitric oxide synthase inhibition by asymmetric dimethylarginine in the pathophysiology of preeclampsia. 2010

Böger, Rainer H / Diemert, Anke / Schwedhelm, Edzard / Lüneburg, Nicole / Maas, Renke / Hecher, Kurt. ·Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf Martinistrasse 52, DE-20246 Hamburg, Germany. boeger @ uke.uni-hamburg.de ·Gynecol Obstet Invest · Pubmed #19828999.

ABSTRACT: Preeclampsia is a major cause of maternal and neonatal morbidity and mortality worldwide. Despite recent advances in screening, sensitive and specific biomarkers that help to identify pregnant women at risk of developing preeclampsia are lacking. One of the major mediators from healthy endothelium is nitric oxide; its production is regulated by asymmetric dimethylarginine (ADMA). ADMA has been shown to be elevated in cardiovascular and metabolic diseases; elevated ADMA levels are a prognostic marker for major cardiovascular events and mortality in patients with established cardiovascular disease and in the general population. Several studies have reported elevated ADMA levels in preeclampsia; some studies also suggested that ADMA is elevated in early stages of pregnancy in women who later develop preeclampsia. Moreover, ADMA has been associated with uterine artery flow disturbances. Its plasma concentration is regulated by dimethylarginine dimethylaminohydrolase (DDAH). Single nucleotide polymorphisms in the gene encoding for DDAH have been associated with the incidence of preeclampsia. Recently, diagnostic assays for ADMA, e.g. by ELISA, have become available, which render ADMA a possible biomarker to identify pregnant women at risk of developing preeclampsia.

6 Review ADMA and the role of the genes: lessons from genetically modified animals and human gene polymorphisms. 2009

Maas, Renke / Böger, Rainer / Lüneburg, Nicole. ·Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander University, Erlangen-Nuremberg, Germany. renke.maas@pharmakologie.uni-erlangen.de ·Pharmacol Res · Pubmed #19666122.

ABSTRACT: In large population-based cohorts, elevated plasma levels of asymmetric dimethylarginine (ADMA) were found to be associated with cardiovascular events and mortality. Impairment of nitric oxide (NO) synthesis from l-arginine has been postulated as underlying mechanism. In the present review, we compare different experimental models of NOS deficiency or overexpression with corresponding models of altered metabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH). The latter models show a considerable overlap with the pathophysiological features of impaired NO synthesis, such as impaired endothelial function, elevation of blood pressure, and microvascular fibrosis. In line with these findings, first data regarding genetic variation of DDAH-metabolism in humans are reminiscent of the (rather modest) effects previously observed with polymorphisms of the eNOS gene. However, several peculiar observations suggest that ADMA- or DDAH-related pathology may extend beyond impairment of NO-mediated signalling. Notably, the complete knock out of DDAH1 appears to be lethal while triple NOS(-/-) mice are viable. Moreover, some ADMA-mediated pathology appears to respond rather to ACE-inhibition than to l-arginine. Here, a further investigation of alternative target enzymes for ADMA and other endogenous DDAH substrates is warranted.Taken together, the current data suggest that ADMA-related pathology can largely but not completely be explained by impaired NO metabolism.

7 Review Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality--an update on patient populations with a wide range of cardiovascular risk. 2009

Böger, Rainer H / Maas, Renke / Schulze, Friedrich / Schwedhelm, Edzard. ·Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany. boeger@uke.uni-hamburg.de ·Pharmacol Res · Pubmed #19596069.

ABSTRACT: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthases. By inhibiting NO formation, ADMA causes endothelial dysfunction, vasoconstriction, elevation of blood pressure, and aggravation of experimental atherosclerosis. Cross-sectional studies in humans have revealed that ADMA plasma concentration is elevated in numerous populations with vascular diseases or at high cardiovascular risk. However, the potential causal relationship between elevated ADMA and cardiovascular events and mortality in humans can only be revealed in prospective clinical studies. This review gives an overview of currently available data from prospective clinical studies in which ADMA has been measured in populations at high, intermediate, or low global vascular risk. Although the analytical methods used to quantify ADMA varied and statistical approaches to assess the association of ADMA with risk differed, these data reveal that ADMA is significantly associated with an increased risk of incident cardiovascular events and total mortality in subjects at a broad range of global risk. Hazard ratios were mostly in a range comparable to that of traditional cardiovascular risk markers even after multivariable adjustments, suggesting that ADMA may be suitable as a diagnostic marker for risk assessment, and that the biochemical pathways that regulate ADMA may be promising therapeutic approaches to treat cardiovascular disease in the future.

8 Article Relationship between exercise intervention and NO pathway in patients with heart failure with preserved ejection fraction. 2018

Baldassarri, Flavia / Schwedhelm, Edzard / Atzler, Dorothee / Böger, Rainer H / Cordts, Kathrin / Haller, Bernhard / Pressler, Axel / Müller, Stephan / Suchy, Christiane / Wachter, Rolf / Düngen, Hans-Dirk / Hasenfuss, Gerd / Pieske, Burkert / Halle, Martin / Edelmann, Frank / Duvinage, André. ·a Department of Prevention, Rehabilitation and Sports Medicine , Technische Universität München , Munich , Germany. · b DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance , Munich , Germany. · c Institute of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf , Hamburg , Germany. · d DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck , Hamburg , Germany. · e Institute for Cardiovascular Prevention (IPEK), Klinikum der Universität München, Ludwig-Maximilians-University Munich , Munich , Germany. · f Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich , Munich , Germany. · g Institute of Medical Statistics and Epidemiology, Technische Universität München , Munich , Germany. · h Department of Cardiology and Pneumology , University of Göttingen Medical Center , Göttingen , Germany. · i DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen , Göttingen , Germany. · j Department of Cardiology , Charite´ - Universita¨tsmedizin Berlin , Berlin , Germany. · k DZHK (German Centre for Cardiovascular Research), Partner Site Berlin , Berlin , Germany. · l Department of Cardiology , Deutsches Herzzentrum Berlin (DHZB) , Berlin , Germany. ·Biomarkers · Pubmed #29619838.

ABSTRACT: 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 CONCLUSIONS: Exercise intervention did not influence NO parameters in HFpEF patients, but L-hArg was related to change in peak [Formula: see text]O

9 Article Cognitive performance of 20 healthy humans supplemented with L-homoarginine for 4 weeks. 2018

Schönhoff, Mirjam / Weineck, Gabriele / Hoppe, Julia / Hornig, Sönke / Cordts, Kathrin / Atzler, Dorothee / Gerloff, Christian / Böger, Rainer / Neu, Axel / Schwedhelm, Edzard / Choe, Chi-Un. ·Institute of Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Experimental Neuropediatrics, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Institute of Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany. · Walther-Straub-Institut für Pharmakologie und Toxikologie, Munich, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Institute for Cardiovascular Prevention (IPEK), Munich, Germany. · Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: cchoe@uke.de. ·J Clin Neurosci · Pubmed #29396070.

ABSTRACT: l-homoarginine (l-hArg) is an endogenous non-proteinogenic amino acid. Low l-hArg concentrations are associated with increased all-cause mortality, fatal strokes, and worse outcome after stroke. On the other hand, oral supplementation with l-hArg in mice improved neurological deficits and preserved cardiac function in experimental models of stroke and heart failure, respectively. Recently, oral supplementation with 125 mg daily l-hArg capsules in healthy volunteers demonstrated increased l-hArg plasma levels. Therefore, oral l-hArg supplementation could represent a potential treatment for patients with cerebrovascular disease. In addition to vascular physiology, animal studies have suggested that l-hArg might play a role in synapse function, neurotransmitter metabolism and cognitive training. However the direct influence of l-hArg on cognitive function has not been studied so far. In this study, cognitive performance in healthy humans was analyzed concerning memory, learning, and attention following supplementation with placebo or l-hArg for 4 weeks. Our results did not reveal any effects on cognition, neither impairment nor improvement, upon l-hArg supplementation. Therefore, potential l-hArg treatment is not expected to cause any acute neurocognitive or behavioral side effects.

10 Article Asymmetric dimethylarginine and symmetric dimethylarginine prospectively relates to carotid wall thickening in black men: the SABPA study. 2017

Mels, Catharina M C / Schutte, A E / Huisman, H W / Smith, W / Kruger, R / van Rooyen, J M / Schwedhelm, E / Atzler, D / Böger, R H / Malan, N T / Malan, L. ·Hypertension in Africa Research Team (HART), North-West University (Potchefstroom Campus), Private Bag X6001, Potchefstroom, 2520, South Africa. carina.mels@nwu.ac.za. · MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa. carina.mels@nwu.ac.za. · Hypertension in Africa Research Team (HART), North-West University (Potchefstroom Campus), Private Bag X6001, Potchefstroom, 2520, South Africa. · MRC Research Unit for Hypertension and Cardiovascular Disease, North-West University, Potchefstroom, South Africa. · Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilians-University of Munich, Munich, Germany. ·Amino Acids · Pubmed #28831582.

ABSTRACT: The relationship of both asymmetric (ADMA) and symmetric (SDMA) dimethylarginine with carotid wall thickness is inconclusive especially among black populations. We aimed to compare carotid intima media thickness (cIMT) and dimethylarginine levels in 75 black and 91 white men at baseline and after a 3-year follow-up, and to investigate associations of percentage change in cIMT with percentage change in dimethylarginine levels (ADMA and SDMA). Plasma levels of ADMA and SDMA were determined with a liquid chromatography mass spectrometry method and B-mode ultrasonography was used to determine the cIMT at baseline and follow-up. In black men, mean cIMT (p = 0.79) and ADMA levels (p = 0.67) remained the same, but SDMA levels were lower (p < 0.001) when comparing baseline and follow-up. In white men, cIMT increased (p < 0.001), but both mean ADMA and SDMA levels decreased (p < 0.001) over time. In black men, percentage change in cIMT was positively associated with percentage change in ADMA (R

11 Article Cardiomyocyte dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays an important role in attenuating ventricular hypertrophy and dysfunction. 2017

Xu, Xin / Zhang, Ping / Kwak, Dongmin / Fassett, John / Yue, Wenhui / Atzler, Dorothee / Hu, Xinli / Liu, Xiaohong / Wang, Huan / Lu, Zhongbing / Guo, Haipeng / Schwedhelm, Edzard / Böger, Rainer H / Chen, Peijie / Chen, Yingjie. ·Department of Exercise Rehabilitation, Shanghai University of Sport, Shanghai, 200438, China. · Cardiovascular Division, University of Minnesota Medical School, Minneapolis, USA. · Department of Pharmacology and Toxicology, University of Graz, Graz, Austria. · Heart and Lung Institute, Shanghai 10th Renmin Hospital, Shanghai, China. · Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany. · DZHK (German Centre for Cardiovascular Research), Partner Site Munich and Hamburg/Kiel/Lübeck, Hamburg, Germany. · Shanxi Renmin Hospital, Taiyuan, China. · The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China. · Department of Exercise Rehabilitation, Shanghai University of Sport, Shanghai, 200438, China. Chenpeijie@sus.edu.cn. · Cardiovascular Division, University of Minnesota Medical School, Minneapolis, USA. chenx106@umn.edu. · Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN, 55455, USA. chenx106@umn.edu. ·Basic Res Cardiol · Pubmed #28819685.

ABSTRACT: 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.

12 Article Markers of nitric oxide are associated with sepsis severity: an observational study. 2017

Winkler, Martin Sebastian / Kluge, Stefan / Holzmann, Maximilian / Moritz, Eileen / Robbe, Linda / Bauer, Antonia / Zahrte, Corinne / Priefler, Marion / Schwedhelm, Edzard / Böger, Rainer H / Goetz, Alwin E / Nierhaus, Axel / Zoellner, Christian. ·Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. m.winkler@uke.de. · Center for Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. m.winkler@uke.de. · Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. · Center for Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. · Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. · Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany. ·Crit Care · Pubmed #28709458.

ABSTRACT: 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.

13 Article Long-Term Intermittent Exposure to High Altitude Elevates Asymmetric Dimethylarginine in First Exposed Young Adults. 2017

Lüneburg, Nicole / Siques, Patricia / Brito, Julio / De La Cruz, Juan José / León-Velarde, Fabiola / Hannemann, Juliane / Ibanez, Cristian / Böger, Rainer H. ·1 Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf , Hamburg, Germany . · 2 Institute of Health Studies , Universidad Arturo Prat, Iquique, Chile . · 3 Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid , Madrid, Spain . · 4 Department of Biological and Physiological Sciences, Facultad de Ciencias y Filosofía/IIA, Universidad Peruana Cayetano Heredia , Lima, Perú . ·High Alt Med Biol · Pubmed #28453332.

ABSTRACT: 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

14 Article Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease. 2017

Zewinger, Stephen / Kleber, Marcus E / Rohrer, Lucia / Lehmann, Marlene / Triem, Sarah / Jennings, Richard T / Petrakis, Ioannis / Dressel, Alexander / Lepper, Philipp M / Scharnagl, Hubert / Ritsch, Andreas / Thorand, Barbara / Heier, Margit / Meisinger, Christa / de Las Heras Gala, Tonia / Koenig, Wolfgang / Wagenpfeil, Stefan / Schwedhelm, Edzard / Böger, Rainer H / Laufs, Ulrich / von Eckardstein, Arnold / Landmesser, Ulf / Lüscher, Thomas F / Fliser, Danilo / März, Winfried / Meinitzer, Andreas / Speer, Thimoteus. ·Department of Internal Medicine IV, Kirrberger Strasse, 66421 Homburg/Saar, Saarland University Medical Centre, Germany. · Mannheim Medical Faculty, Medical Clinic V (Nephrology • Hypertensiology • Endocrinology • Diabetology • Rheumatology), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. · Institute of Nutrition, Dornburger Strasse, 07743 Friedrich Schiller University Jena, Germany. · Institute of Clinical Chemistry, University Hospital Zurich, Rämistrasse, 8091 Zurich, Switzerland. · Department of Internal Medicine V, Kirrberger Strasse, 66421 Homburg/Saar, Saarland University Medical Centre, Germany. · Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz, 8036 Graz, Austria. · Department of Internal Medicine, Medical University of Innsbruck, Christoph-Probst-Platz, 6020 Innsbruck, Austria. · Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology II, Ingolstaedter Landstrasse 1, 85764 Munich, Germany. · Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Albert-Einstein-Allee, 89081 Ulm, Germany. · German Centre of Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. · Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse 36, 80636 Munich, Germany. · Epidemiology and Medical Informatics, Campus Homburg/Saar, Saarland University, Institute for Medical Biometry, Kirrberger Strasse, 66421 Homburg/Saar, Germany. · University Medical Center Hamburg-Eppendorf, Institute of Experimental and Clinical Pharmacology and Toxicology, Martinistrasse, 20246 Hamburg, Germany. · Department of Internal Medicine III, Kirrberger Strasse, 66421 Homburg/Saar, Saarland University Medical Centre, Germany. · Department of Cardiology, Charité University Hospital, Hindenburgdamm, 12203 Berlin, Germany. · University Heart Center Zurich, Department of Cardiology, University Hospital and Center for Molecular Cardiology, University of Zurich, Rämistrasse, 8091 Zurich, Switzerland. · Center of Molecular Cardiology, University of Zurich, Wagistrasse, 8952 Zurich, Switzerland. · Synlab Academy, Synlab Holding Deutschland GmbH, P5, 7, 68161 Mannheim and Augsburg, Germany. ·Eur Heart J · Pubmed #28379378.

ABSTRACT: 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.

15 Article Higher serum asymmetric dimethylarginine is related to higher risk of heart failure in the EPIC-Potsdam study. 2017

Wirth, Janine / Atzler, Dorothee / di Giuseppe, Romina / Cordts, Kathrin / Menzel, Juliane / Böger, Rainer H / Boeing, Heiner / Weikert, Cornelia / Schwedhelm, Edzard. ·Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA, 02115, USA. jwirth@hsph.harvard.edu. · German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany. jwirth@hsph.harvard.edu. · DZHK, Partner Site Berlin/Potsdam, Potsdam, Germany. jwirth@hsph.harvard.edu. · Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. · DZHK, Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany. · Department of Cardiovascular Medicine, University of Oxford, Oxford, UK. · German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany. · DZHK, Partner Site Berlin/Potsdam, Potsdam, Germany. · Institute of Epidemiology, Christian-Albrechts University Kiel, Kiel, Germany. · Institute for Social Medicine, Epidemiology and Health Economics, Charité University Medical Center, Berlin, Germany. · Federal Institute of Risk Assessment, Department of Food Safety, Berlin, Germany. ·Amino Acids · Pubmed #27796501.

ABSTRACT: 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.

16 Article Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels. 2016

Zhang, Weihua / Jernerén, Fredrik / Lehne, Benjamin C / Chen, Ming-Huei / Luben, Robert N / Johnston, Carole / Elshorbagy, Amany / Eppinga, Ruben N / Scott, William R / Adeyeye, Elizabeth / Scott, James / Böger, Rainer H / Khaw, Kay-Tee / van der Harst, Pim / Wareham, Nicholas J / Vasan, Ramachandran S / Chambers, John C / Refsum, Helga / Kooner, Jaspal S. ·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: weihua.zhang@imperial.ac.uk. ·Thromb Haemost · Pubmed #27656708.

ABSTRACT: 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

17 Article Short-term esmolol attenuates remodeling of the thoracic aorta in hypertensive rats by decreasing concentrations of ADMA down-regulated by oxidative stress. 2016

Quintana-Villamandos, Begoña / González, María Carmen / Delgado-Martos, María Jesús / Condezo-Hoyos, Luis / Böger, Rainer H / Lüneburg, Nicole / Pazó-Sayós, Laia / Gutiérrez-Arzapalo, Perla Yareli / Delgado-Baeza, Emilio. ·Department of Anesthesiology, Hospital Gregorio Marañón, Health Research Institute of Hospital Gregorio Marañón, 28007 Madrid, Spain. Electronic address: begoquinti@gmail.com. · Department of Physiology Faculty of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain. Electronic address: m.c.gonzalez@uam.es. · Molecular Biology Laboratory, Department Experimental Medicine and Surgery, Hospital Gregorio Marañón, Health Research Institute of Hospital Gregorio Marañón, 28007 Madrid, Spain. Electronic address: mj.delgadomartos@gmail.com. · Department of Physiology Faculty of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain. Electronic address: lcondezotm@hotmail.com. · Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: boeger@uke.uni-hamburg.de. · Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: n.lueneburg@uke.de. · Department of Anesthesiology, Hospital Gregorio Marañón, Health Research Institute of Hospital Gregorio Marañón, 28007 Madrid, Spain. Electronic address: lpazosay8@gmail.com. · Department of Physiology Faculty of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain. Electronic address: pela.gutierrez@gmail.com. · Molecular Biology Laboratory, Department Experimental Medicine and Surgery, Hospital Gregorio Marañón, Health Research Institute of Hospital Gregorio Marañón, 28007 Madrid, Spain. Electronic address: delgadobaeza@gmail.com. ·Eur J Pharmacol · Pubmed #27639298.

ABSTRACT: 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.

18 Article Oral supplementation with L-homoarginine in young volunteers. 2016

Atzler, Dorothee / Schönhoff, Mirjam / Cordts, Kathrin / Ortland, Imke / Hoppe, Julia / Hummel, Friedhelm C / Gerloff, Christian / Jaehde, Ulrich / Jagodzinski, Annika / Böger, Rainer H / Choe, Chi-Un / Schwedhelm, Edzard. ·Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. · DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e.V.), partner site Hamburg/Kiel/Lübeck, Germany. · Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München Ludwig Maximilians-University of Munich, Munich, Germany. · Institute of Pharmacy Department of Clinical Pharmacy, University of Bonn, Bonn, Germany. · Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany. ·Br J Clin Pharmacol · Pubmed #27434056.

ABSTRACT: AIMS: Low blood concentrations of the naturally occurring amino acid L-homoarginine (L-hArg) are related to impaired cardiovascular outcome and mortality in humans and animals. L-hArg is a weak substrate of nitric oxide synthase and an inhibitor of arginases in vitro. The aim of our study was to obtain kinetic and dynamic data after oral L-hArg supplementation. METHODS: In a double-blind, randomized, placebo-controlled crossover study, 20 young volunteers received 125 mg L-hArg once daily for 4 weeks. Kinetic parameters (C RESULTS: One hour after ingestion (T CONCLUSION: Once daily orally applied 125 mg L-hArg raises plasma L-hArg four- and sevenfold after single dose and 4 weeks of supplementation, respectively, and is safe and well tolerated in young volunteers.

19 Article Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats Causes an Imbalance in the Asymmetric Dimethylarginine/Nitric Oxide Pathway and ROS Activity: A Possible Synergistic Mechanism for Altitude Pulmonary Hypertension? 2016

Lüneburg, Nicole / Siques, Patricia / Brito, Julio / Arriaza, Karem / Pena, Eduardo / Klose, Hans / Leon-Velarde, Fabiola / Böger, Rainer H. ·Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. · Institute of Health Studies, Arturo Prat University, Iquique, Chile. · Department of Pneumology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. · Department of Biological and Physiological Sciences, Faculty of Sciences and Philosophy/IIA, Cayetano Heredia University, Lima, Peru. ·Pulm Med · Pubmed #27313889.

ABSTRACT: Chronic intermittent hypoxia (CIH) and chronic hypoxia (CH) are associated with high-altitude pulmonary hypertension (HAPH). Asymmetric dimethylarginine (ADMA), a NO synthase (NOS) inhibitor, may contribute to HAPH. This study assessed changes in the ADMA/NO pathway and the underlying mechanisms in rat lungs following exposure to CIH or CH simulated in a hypobaric chamber at 428 Torr. Twenty-four adult Wistar rats were randomly assigned to three groups: CIH2x2 (2 days of hypoxia/2 days of normoxia), CH, and NX (permanent normoxia), for 30 days. All analyses were performed in whole lung tissue. L-Arginine and ADMA were analyzed using LC-MS/MS. Under both hypoxic conditions right ventricular hypertrophy was observed (p < 0.01) and endothelial NOS mRNA increased (p < 0.001), but the phosphorylated/nonphosphorylated vasodilator-stimulated phosphoprotein (VASP) ratio was unchanged. ADMA increased (p < 0.001), whereas dimethylarginine dimethylaminohydrolase (DDAH) activity decreased only under CH (p < 0.05). Although arginase activity increased (p < 0.001) and L-arginine exhibited no changes, the L-arginine/ADMA ratio decreased significantly (p < 0.001). Moreover, NOX4 expression increased only under CH (p < 0.01), but malondialdehyde (MDA) increased (up to 2-fold) equally in CIH2x2 and CH (p < 0.001). Our results suggest that ADMA and oxidative stress likely reduce NO bioavailability under altitude hypoxia, which implies greater pulmonary vascular reactivity and tone, despite the more subdued effects observed under CIH.

20 Article Asymmetric dimethylarginine, related arginine derivatives, and incident atrial fibrillation. 2016

Schnabel, Renate B / Maas, Renke / Wang, Na / Yin, Xiaoyan / Larson, Martin G / Levy, Daniel / Ellinor, Patrick T / Lubitz, Steven A / McManus, David D / Magnani, Jared W / Atzler, Dorothee / Böger, Rainer H / Schwedhelm, Edzard / Vasan, Ramachandran S / Benjamin, Emelia J. ·NHLBI's and Boston University's Framingham Study, Framingham, MA; Department of General and Interventional Cardiology, University Heart Center Hamburg, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany. Electronic address: r.schnabel@uke.de. · Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. · Data Coordinating Center, Boston University School of Public Health, Boston, MA. · NHLBI's and Boston University's Framingham Study, Framingham, MA. · NHLBI's and Boston University's Framingham Study, Framingham, MA; Department of Biostatistics, Boston University School of Public Health, Boston, MA. · NHLBI's and Boston University's Framingham Study, Framingham, MA; Evans Memorial Medicine Department, Boston University School of Medicine, Boston, MA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. · Cardiovascular Research Center, University of Massachusetts Medical School, Worcester, MA; Program in Medical Population Genetics, The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Program in Medical Population Genetics, The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Cardiology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, MA. · Sections of Cardiology, Boston University School of Medicine, Boston, MA. · Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom. · Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · NHLBI's and Boston University's Framingham Study, Framingham, MA; Evans Memorial Medicine Department, Boston University School of Medicine, Boston, MA; Sections of Cardiology, Boston University School of Medicine, Boston, MA; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA; Preventive Medicine, Boston University School of Medicine, Boston, MA. · NHLBI's and Boston University's Framingham Study, Framingham, MA; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA; Evans Memorial Medicine Department, Boston University School of Medicine, Boston, MA; Sections of Cardiology, Boston University School of Medicine, Boston, MA; Preventive Medicine, Boston University School of Medicine, Boston, MA; Epidemiology Department, Public Health School, Boston University, Boston, MA. ·Am Heart J · Pubmed #27264226.

ABSTRACT: BACKGROUND: Oxidative stress plays an important role in the development of atrial fibrillation (AF). Arginine derivatives including asymmetric dimethylarginine (ADMA) are central to nitric oxide metabolism and nitrosative stress. Whether blood concentrations of arginine derivatives are related to incidence of AF is uncertain. METHODS AND RESULTS: In 3,310 individuals (mean age 58 ± 10 years, 54% women) from the community-based Framingham Study, we prospectively examined the relations of circulating levels of ADMA, l-arginine, symmetric dimethylarginine (SDMA), and the ratio of l-arginine/ADMA to incidence of AF using proportional hazards regression models. Over a median follow-up time of 10 years, 247 AF cases occurred. Using age- and sex-adjusted regression models, ADMA was associated with a hazard ratio of 1.15 per 1-SD increase in loge-biomarker concentration (95% CI 1.02-1.29, P = .02) for AF, which was no longer significant after further risk factor adjustment (hazard ratio 1.09, 95% CI 0.97-1.23, P = .15). Neither l-arginine nor SDMA was related to new-onset AF. A clinical model comprising clinical risk factors for AF (for age, sex, height, weight, systolic blood pressure, diastolic blood pressure, current smoking, diabetes, hypertension treatment, myocardial infarction, and heart failure; c statistic = 0.781; 95% CI 0.753-0.808) was not improved by the addition of ADMA (0.782; 95% CI 0.755-0.809). CONCLUSIONS: Asymmetric dimethylarginine and related arginine derivatives were not associated with incident AF in the community after accounting for other clinical risk factors and confounders. Its role in the pathogenesis of AF needs further refinement.

21 Article Early regression of coronary artery remodeling with esmolol and DDAH/ADMA pathway in hypertensive rats. 2016

Quintana-Villamandos, Begoña / Arnalich-Montiel, Ana / Arribas, Silvia / Lüneburg, Nicole / Böger, Rainer H / Delgado-Martos, María Jesús / Fernández-Criado, Carmen / Delgado-Baeza, Emilio / González, María Carmen. ·Department of Anesthesiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Department of Pharmacology, Faculty of Medicine, Universidad Complutense, Madrid, Spain. · Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain. · Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Molecular Biology Laboratory, Department of Experimental Medicine and Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain. ·Hypertens Res · Pubmed #27250567.

ABSTRACT: Our preclinical study demonstrated that esmolol produces early regression of left ventricular hypertrophy in arterial hypertension. The aim of this study was to assess the effects of short-term esmolol therapy on the regression of left anterior descending artery remodeling in spontaneously hypertensive rats (SHRs), and to determine whether the asymmetric dimethylarginine (ADMA)/dimethylarginine dimethylaminohydrolase (DDAH) pathway, a regulator of nitric oxide (NO) bioavailability, accounted for this regression. Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=15) or esmolol (SHR-E, n=20) (300 μg kg

22 Article Homoarginine predicts mortality in treatment-naive patients with pulmonary arterial hypertension. 2016

Atzler, Dorothee / Cracowski, Jean-Luc / Cordts, Kathrin / Böger, Rainer H / Humbert, Marc / Schwedhelm, Edzard. ·Department of Cardiovascular Medicine, University of Oxford, United Kingdom; DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e.V.), Partner Site Hamburg/Kiel/Lübeck, Germany; Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. Electronic address: dorothee.atzler@gmail.com. · INSERM CIC1406, Clinical Pharmacology Department, University Hospital, Grenoble, France; Inserm U1042, Université Grenoble Alpes, France. · DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e.V.), Partner Site Hamburg/Kiel/Lübeck, Germany; Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. · Centre de Référence de l'Hypertension Pulmonaire Sévère' Pulmonology and Respiratory Intensive Care Department, Antoine Béclère Hospital, AP-HP, Clamart, France; INSERM U999, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France; University Paris-Sud, Kremlin-Bicêtre, France. ·Int J Cardiol · Pubmed #27174592.

ABSTRACT: -- No abstract --

23 Article Low Homoarginine Levels in the Prognosis of Patients With Acute Chest Pain. 2016

Atzler, Dorothee / Baum, Christina / Ojeda, Francisco / Keller, Till / Cordts, Kathrin / Schnabel, Renate B / Choe, Chi-un / Lackner, Karl J / Münzel, Thomas / Böger, Rainer H / Blankenberg, Stefan / Schwedhelm, Edzard / Zeller, Tanja. ·Department of Cardiovascular Medicine, University of Oxford, United Kingdom German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Germany dorothee.atzler@well.ox.ac.uk dorothee.atzler@gmail.com. · German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Germany Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany. · Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany. · Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Frankfurt, Germany German Center for Cardiovascular Research (DZHK), Partner Site Rhein/Main, Germany. · German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Germany Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · German Center for Cardiovascular Research (DZHK), Partner Site Rhein/Main, Germany Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. · German Center for Cardiovascular Research (DZHK), Partner Site Rhein/Main, Germany Department of Medicine II, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. ·J Am Heart Assoc · Pubmed #27076564.

ABSTRACT: BACKGROUND: The endogenous amino acid homoarginine predicts mortality in cerebro- and cardiovascular disease. The objective was to explore whether homoarginine is associated with atrial fibrillation (AF) and outcome in patients with acute chest pain. METHODS AND RESULTS: One thousand six hundred forty-nine patients with acute chest pain were consecutively enrolled in this study, of whom 589 were diagnosed acute coronary syndrome (ACS). On admission, plasma concentrations of homoarginine as well as brain natriuretic peptide (BNP), and high-sensitivity assayed troponin I (hsTnI) were determined along with electrocardiography (ECG) variables. During a median follow-up of 183 days, 60 major adverse cardiovascular events (MACEs; 3.8%), including all-cause death, myocardial infarction, or stroke, were registered in the overall study population and 43 MACEs (7.5%) in the ACS subgroup. Adjusted multivariable Cox regression analyses revealed that an increase of 1 SD of plasma log-transformed homoarginine (0.37) was associated with a hazard reduction of 26% (hazard ratio [HR], 0.74; 95% CI, 0.57-0.96) for incident MACE and likewise of 35% (HR, 0.65; 95% CI, 0.49-0.88) in ACS patients. In Kaplan-Meier survival curves, homoarginine was predictive for patients with high-sensitivity assayed troponin I (hsTnI) above 27 ng/L (P<0.05). Last, homoarginine was inversely associated with QTc duration (P<0.001) and prevalent AF (OR, 0.83; 95% CI, 0.71-0.95). CONCLUSION: Low plasma homoarginine was identified as a risk marker for incident MACEs in patients with acute chest pain, in particular, in those with elevated hsTnI. Impaired homoarginine was associated with prevalent AF. Further studies are needed to investigate the link to AF and evaluate homoarginine as a therapeutic option for these patients.

24 Article L-Arginine Derivatives Are Associated with the Hyperthyroid State in the General Population. 2016

Ittermann, Till / Bahls, Martin / Atzler, Dorothee / Friedrich, Nele / Schwedhelm, Edzard / Böger, Rainer H / Felix, Stephan B / Völzke, Henry / Dörr, Marcus. ·1 Institute for Community Medicine, University Medicine Greifswald , Germany . · 2 Department of Internal Medicine B-Cardiology, Intensive Care, Pulmonary Medicine, and Infectious Diseases, University Medicine Greifswald , Germany . · 3 Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford , United Kingdom . · 4 Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald , Germany . · 5 DZHK (German Center for Cardiovascular Research) , partner site Greifswald, Germany . · 6 Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf , Germany . · 7 DZHK (German Center for Cardiovascular Research) , partner site Hamburg/Kiel/Lübeck, Germany . ·Thyroid · Pubmed #26650143.

ABSTRACT: BACKGROUND: Arginine (ARG) derivatives and thyroid function independently influence atherosclerotic processes. Since thyroid hormones may mediate the association between ARG derivatives and atherosclerosis, this study investigated whether asymmetric and symmetric dimethylarginines (ADMA and SDMA, respectively) as well as homoarginine (hARG) are associated with parameters of thyroid function in the general population. METHODS: Cross-sectional data from 3689 individuals aged 20-81 years from the population-based Study of Health in Pomerania (SHIP-0) were analyzed. Thyroid function was defined according to serum concentrations of thyrotropin (TSH), free triiodothyronine (fT3), and free thyroxine (fT4). Low and high serum TSH were defined by the cutoffs 0.3 mIU/L and 3 mIU/L, respectively. Serum concentrations of ARG, ADMA, SDMA, and hARG were measured using liquid chromatography-tandem mass spectrometry. ARG, ADMA, SDMA, and hARG were associated with serum concentrations of TSH, fT3, and fT4 by median regression and with categorized TSH values by multinomial logistic regression adjusted for age, sex, smoking status, physical activity, body mass index, and estimated glomerular filtration rate. RESULTS: Levels of ADMA (relative risk [RR] = 5.40 [confidence interval (CI) 1.96-14.86]) and SDMA (RR = 3.55 [CI 1.01-12.70]) were associated with low TSH. In addition, ADMA (β = 0.38 [CI 0.23-0.45]) was positively associated with fT3, while both ADMA (β = 0.98 [CI 0.43-1.54]) and SDMA (β = 1.19 [CI 0.50-1.88]) were positively associated with fT4. No consistent associations of ARG and hARG with thyroid function were detected. CONCLUSIONS: The positive associations of ADMA and SDMA with low TSH, fT3, and fT4 argue for a relationship of arginine derivatives with increased thyroid function. This suggests that the atherogenic properties of ADMA and SDMA may be partially mediated by thyroid function.

25 Article ADMA and arginine derivatives in relation to non-invasive vascular function in the general population. 2016

Baum, Christina / Johannsen, Silke S / Zeller, Tanja / Atzler, Dorothee / Ojeda, Francisco M / Wild, Philipp S / Sinning, Christoph R / Lackner, Karl J / Gori, Tommaso / Schwedhelm, Edzard / Böger, Rainer H / Blankenberg, Stefan / Münzel, Thomas / Schnabel, Renate B / Anonymous2920851. ·Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany. · Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany; Radcliffe Department of Medicine, University of Oxford, UK. · Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany. · Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site RhineMain, Mainz, Germany. · Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site RhineMain, Mainz, Germany. · Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site RhineMain, Mainz, Germany. · Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany. · Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany. Electronic address: r.schnabel@uke.de. ·Atherosclerosis · Pubmed #26638011.

ABSTRACT: OBJECTIVE: Nitric oxide produced from l-arginine is central to vascular homeostasis. Little is known about the relationship between arginine derivatives including asymmetric dimethylarginine (ADMA) and non-invasive vascular function measures in the general population. APPROACH AND RESULTS: In 5000 individuals (median age 56; 25th/75th percentile: 46, 65; 49% women) taking part in the population-based Gutenberg Health Study (Mainz area, Germany), we measured the relationship between the arginine derivatives asymmetric dimethylarginine (ADMA), N-monomethyl l-arginine (NMMA), symmetric dimethylarginine (SDMA) and l-arginine with flow-mediated dilation (FMD) and peripheral arterial tonometry (PAT). Weak bivariate correlations were observed between all measured arginine derivatives and vascular function measures, except of l-arginine and FMD and SDMA and PAT ratio. In multivariate adjusted linear regression analyses we could show statistically significant relationships between arginine derivatives and vascular function measures, which were influenced by age, sex and body mass index (BMI). Thus, a negative relationship between ADMA and FMD in females who were normal (beta: -0.095, P < 0.001) to overweight (beta: -0.071, P < 0.001) and a negative association of SDMA and FMD for middle-aged females was seen. The relationship between ADMA and PAT was negative for males who were normal (beta: -0.089, P < 0.001) to overweight (beta: -0.051, P = 0.007) and positive for obese females (beta: 0.073, P = 0.021). CONCLUSIONS: We showed small but significant correlations between ADMA and related arginine derivatives and non-invasive vascular function measures representative of different vascular regions. The associations were markedly influenced by age, sex and BMI. These findings support a complex interplay of arginine metabolism and vascular function.

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