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Article ; Online: Homoarginine and methylarginines independently predict long-term outcome in patients presenting with suspicion of venous thromboembolism

Roman N. Rodionov / Jan Beyer-Westendorf / Stefanie M. Bode-Böger / Lisa Eggebrecht / Stavros Konstantinides / Jens Martens-Lobenhoffer / Markus Nagler / Jürgen Prochaska / Philipp Wild

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 12

Abstract: Abstract Endogenous arginine derivatives homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethyarginine (SDMA) are independent mortality predictors in atherosclerotic cardiovascular disease (CVD). Our study reports the first analysis, ... ...

Abstract	Abstract Endogenous arginine derivatives homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethyarginine (SDMA) are independent mortality predictors in atherosclerotic cardiovascular disease (CVD). Our study reports the first analysis, whether homoarginine, ADMA and SDMA predict venous thromboembolism (VTE) recurrence and overall mortality in patients with suspected acute VTE. We assessed serum levels of homoarginine, ADMA and SDMA by LC–MS/MS in 865 individuals from a prospective consecutive cohort of patients with clinical suspicion of VTE. The median follow-up time for mortality was 1196 days. VTE was confirmed by imaging in 418 patients and excluded in 447 patients. Low levels of homoarginine and high levels of ADMA or SDMA independently predicted all-cause mortality after adjustment for sex, age, oral anticoagulants, body mass index, arterial hypertension, diabetes mellitus, smoking, dyslipidemia, chronic heart failure, history of stroke, creatinine and cancer both in patients with VTE and without VTE. Interestingly, none of those parameters was predictive for VTE recurrence. We provide the first report that low circulating levels of homoarginine and high circulating levels of ADMA and SDMA independently predict all-cause mortality in patients with suspected VTE. These parameters might serve as markers of “frailty” and should be considered for future risk stratification approaches in this clinical population. Taking into account that homoarginine supplementation is protective in animal models of CVD and safe in healthy human volunteers, our study provides the basis for future homoarginine supplementation studies in patients with suspected VTE to investigate possible direct protective effects of homoarginine in this population.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Second Life of Methylarginines as Cardiovascular Targets

Natalia Jarzebska / Arduino A. Mangoni / Jens Martens-Lobenhoffer / Stefanie M. Bode-Böger / Roman N. Rodionov

International Journal of Molecular Sciences, Vol 20, Iss 18, p

2019 Volume 4592

Abstract: Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The initial studies were primarily focused on the ... ...

Abstract	Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The initial studies were primarily focused on the endogenous inhibitors of nitric oxide synthases asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) and the main enzyme regulating their clearance dimethylarginine dimethylaminohydrolase 1 (DDAH1). To date, all the screens for DDAH1 activators performed with the purified recombinant DDAH1 enzyme have not yielded any promising hits, which is probably the main reason why interest towards this research field has started to fade. The relative contribution of the second DDAH isoenzyme DDAH2 towards ADMA and MMA clearance is still a matter of controversy. ADMA, MMA and symmetric dimethylarginine (SDMA) are also metabolized by alanine: glyoxylate aminotransferase 2 (AGXT2), however, in addition to methylarginines, this enzyme also has several cardiovascular protective substrates, so the net effect of possible therapeutic targeting of AGXT2 is currently unclear. Recent studies on regulation and functions of the enzymes metabolizing methylarginines have given a second life to this research direction. Our review discusses the latest discoveries and controversies in the field and proposes novel directions for targeting methylarginines in clinical settings.
Keywords	asymmetric dimethylarginine (ADMA) ; symmetric dimethylarginine (SDMA) ; dimethylarginine dimethylaminohydrolase (DDAH) ; alanine:glyoxylate aminotransferase 2 (AGXT2) ; asymmetric α-keto-dimethylguanidinovaleric acid (ADGV) ; symmetric α-keto-dimethylguanidinovaleric acid (SDGV) ; Homoarginine ; beta-aminoisobutyric acid (BAIBA) ; 6-guanidino-2-oxocaproic acid (GOCA) ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	540
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 13

Abstract: Abstract Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by ... ...

Abstract	Abstract Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.
Keywords	Medicine ; R ; Science ; Q
Subject code	630
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase

Vinitha N. Ragavan / Pramod C. Nair / Natalia Jarzebska / Ramcharan Singh Angom / Luana Ruta / Elisa Bianconi / Silvia Grottelli / Natalia D. Tararova / Daniel Ryazanskiy / Steven R. Lentz / Sara Tommasi / Jens Martens-Lobenhoffer / Toshiko Suzuki-Yamamoto / Masumi Kimoto / Elena Rubets / Sarah Chau / Yingjie Chen / Xinli Hu / Nadine Bernhardt /

Peter M. Spieth / Norbert Weiss / Stefan R. Bornstein / Debabrata Mukhopadhyay / Stefanie M. Bode-Böger / Renke Maas / Ying Wang / Antonio Macchiarulo / Arduino A. Mangoni / Barbara Cellini / Roman N. Rodionov

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 16

Abstract: Abstract Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA ...

Abstract	Abstract Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.
Keywords	Science ; Q
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Markers of endothelial pathology to support detection of atrial fibrillation in embolic stroke of undetermined source

Nora L. Ziegler / Jan-Thorben Sieweke / Saskia Biber / Maria M. Gabriel / Ramona Schuppner / Hans Worthmann / Jens Martens-Lobenhoffer / Ralf Lichtinghagen / Stefanie M. Bode-Böger / Udo Bavendiek / Karin Weissenborn / Gerrit M. Grosse

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 8

Abstract: Abstract A relevant part of embolic strokes of undetermined source (ESUS) is assumed to be cardiogenic. As shown previously, certain biomarkers of endothelial pathology are related to atrial fibrillation (AF). In this long-term follow-up study, we aimed ... ...

Abstract	Abstract A relevant part of embolic strokes of undetermined source (ESUS) is assumed to be cardiogenic. As shown previously, certain biomarkers of endothelial pathology are related to atrial fibrillation (AF). In this long-term follow-up study, we aimed to investigate whether these biomarkers are associated with subsequently diagnosed AF and with atrial cardiopathy. In 98 patients who suffered ischemic stroke of known and unknown origin L-arginine, Asymmetric (ADMA) and Symmetric Dimethylarginine (SDMA) have been measured on follow-up at least one year after index stroke. Stroke-diagnostics were available for all patients, including carotid Intima-Media-Thickness (CIMT) and comprehensive echocardiography studies. CIMT was larger in AF- compared with ESUS-patients (P < 0.001), independently from CHA2DS2VASC in the regression analysis (P = 0.004). SDMA-values were stable over time (P < 0.001; r = 0.788), whereas for ADMA moderate correlation with the initial values could be found (P = 0.007; r = 0.356). According to Kaplan-Meier-analyses, AF-detection rates were associated with CIMT (P = 0.003) and SDMA (P < 0.001). SDMA correlated with left atrial volume-index within the whole collective (P = 0.003, r = 0.322) and within the ESUS-subgroup (P = 0.003; r = 0.446). These associations were independent from CHA2DS2VASC and renal function in the regression analysis (P = 0.02 and P = 0.005, respectively). In conclusion, these results highlight SDMA and CIMT as potential markers of atrial cardiopathy and AF in ESUS-patients.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Opposite Associations of Plasma Homoarginine and Ornithine with Arginine in Healthy Children and Adolescents

Andrzej Surdacki / Stefanie M. Bode-Böger / Jarosław Rycaj / Bernadeta Chyrchel / Olga Kruszelnicka / Jens Martens-Lobenhoffer / Aleksandra Jaźwińska-Kozuba

International Journal of Molecular Sciences, Vol 14, Iss 11, Pp 21819-

2013 Volume 21832

Abstract: Homoarginine, a non-proteinogenic amino acid, is formed when lysine replaces ornithine in reactions catalyzed by hepatic urea cycle enzymes or lysine substitutes for glycine as a substrate of renal arginine:glycine amidinotransferase. Decreased ... ...

Abstract	Homoarginine, a non-proteinogenic amino acid, is formed when lysine replaces ornithine in reactions catalyzed by hepatic urea cycle enzymes or lysine substitutes for glycine as a substrate of renal arginine:glycine amidinotransferase. Decreased circulating homoarginine and elevated ornithine, a downstream product of arginase, predict adverse cardiovascular outcome. Our aim was to investigate correlates of plasma homoarginine and ornithine and their relations with carotid vascular structure in 40 healthy children and adolescents aged 3–18 years without coexistent diseases or subclinical carotid atherosclerosis. Homoarginine, ornithine, arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were measured by liquid chromatography-tandem mass spectrometry with stable isotope-labeled internal standards. Intima-media thickness (IMT) and extra-medial thickness (EMT) of common carotid arteries were estimated by B-mode ultrasound. Homoarginine correlated with arginine (r = 0.43, p = 0.005), age (r = 0.42, p = 0.007) and, weakly, with an increased arginine-to-ornithine ratio, a putative measure of lower arginase activity (r = 0.31, p = 0.048). Ornithine correlated inversely with arginine (r = −0.64, p < 0.001). IMT, EMT or their sum were unrelated to any of the biochemical parameters (p > 0.12). Thus, opposite associations of plasma homoarginine and ornithine with arginine may partially result from possible involvement of arginase, an enzyme controlling homoarginine degradation and ornithine synthesis from arginine. Age-dependency of homoarginine levels can reflect developmental changes in homoarginine metabolism. However, neither homoarginine nor ornithine appears to be associated with carotid vascular structure in healthy children and adolescents.
Keywords	homoarginine ; ornithine ; arginine ; children ; carotid vascular structure ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	571
Language	English
Publishing date	2013-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Associations between Endogenous Dimethylarginines and Renal Function in Healthy Children and Adolescents

Urszula Godula-Stuglik / Stefanie M. Bode-Böger / Aleksandra Jaźwińska-Kozuba / Jens Martens-Lobenhoffer / Jarosław Rycaj / Andrzej Surdacki / Olga Kruszelnicka

International Journal of Molecular Sciences, Vol 13, Iss 11, Pp 15464-

2012 Volume 15474

Abstract: The structural isomer of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), is eliminated almost entirely by urinary excretion and considered a sensitive index of glomerular filtration rate (GFR). However, reports on this relationship ...

Abstract	The structural isomer of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), is eliminated almost entirely by urinary excretion and considered a sensitive index of glomerular filtration rate (GFR). However, reports on this relationship in healthy subjects younger than 18 years of age are rare. Therefore, our aim was to investigate relations between endogenous dimethylarginines and renal function indices in healthy children and adolescents. We studied 40 subjects aged 3–18 years free of coexistent diseases or subclinical carotid atherosclerosis. A serum creatinine-derived estimated GFR (eGFR) was calculated by the revised bedside Schwartz equation. L-arginine, ADMA and SDMA were measured by liquid chromatography-tandem mass spectrometry. Mean eGFR was 122 ± 22 (SD) mL/min per 1.73 m2. Creatinine and eGFR exhibited closer correlations with the SDMA/ADMA ratio (r = 0.64, p < 0.0001; r = −0.63, p < 0.0001, respectively) than with SDMA (r = 0.31, p = 0.05; r = −0.35, p = 0.03). Neither creatinine nor eGFR correlated with ADMA or L-arginine. Adjustment for age or height only slightly attenuated the associations between the SDMA/ADMA ratio and eGFR or creatinine. Our findings suggest the superiority of the SDMA/ADMA ratio over SDMA as a renal function index in healthy children. Thus, further studies are warranted to verify our preliminary results in a larger group of subjects below 18 years of age.
Keywords	children ; asymmetric dimethylarginine ; symmetric dimethylarginine ; renal function ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2012-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Successful treatment of extensively drug-resistant Pseudomonas aeruginosa osteomyelitis using a colistin- and tobramycin-impregnated PMMA spacer

Krajewski, Jochen / Hagen Mittelstädt / Jens Martens-Lobenhoffer / Johannes K.-M. Knobloch / Martin Russlies / Rainer Kirchner / Stefanie M. Bode-Böger / Thomas Mulrooney / Uwe Tröger

International journal of antimicrobial agents. 2014 Oct., v. 44, no. 4

2014

Abstract: Discovered in 1949, the antibiotic colistin was initially used for therapeutic purposes. Parenteral use of colistin was gradually abandoned because of its side-effect profile, especially its nephrotoxicity and neurotoxicity. Despite the risk of these ... ...

Abstract	Discovered in 1949, the antibiotic colistin was initially used for therapeutic purposes. Parenteral use of colistin was gradually abandoned because of its side-effect profile, especially its nephrotoxicity and neurotoxicity. Despite the risk of these potentially serious adverse effects, increasing resistance of Gram-negative bacteria has led to a renaissance of intravenous use of colistin in the last few years. Local administration of colistin is an alternative method to minimise the risk of systemic toxicity.We present a case of extensively drug-resistant Pseudomonas aeruginosa osteomyelitis treated successfully with high-dose colistin- and tobramycin-impregnated bone cement as a drug delivery vehicle. For the first time, local colistin concentrations in drainage and synovial fluid were quantified in order to determine the optimal dose and to minimise serious side effects. Insertion of a bone cement spacer loaded with a high dose of tobramycin and colistin resulted in local colistin levels at the infection site that exceeded the minimum inhibitory concentration (MIC) of colistin against the isolated P. aeruginosa five-fold on Day 4. Thus, the treatment may be expected to exert a prolonged effect. Whereas systemic administration of colistin alone was not sufficient to treat the infection, combined local and parenteral therapy led to eradication of P. aeruginosa in this patient. Plasma colistin levels remained in the therapeutic range, which confirms the systemic safety of the method.
Keywords	adverse effects ; cement ; colistin ; drainage ; drug carriers ; drug resistance ; Gram-negative bacteria ; intravenous injection ; minimum inhibitory concentration ; nephrotoxicity ; neurotoxicity ; osteomyelitis ; patients ; polymethylmethacrylate ; Pseudomonas aeruginosa ; risk ; synovial fluid ; tobramycin
Language	English
Dates of publication	2014-10
Size	p. 363-366.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	1093977-5
ISSN	1872-7913 ; 0924-8579
ISSN (online)	1872-7913
ISSN	0924-8579
DOI	10.1016/j.ijantimicag.2014.05.023
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Asymmetrical dimethylarginine--more sensitive than NT-proBNP to diagnose heart failure in adults with congenital heart disease.

Oktay Tutarel / Agnieszka Denecke / Stefanie M Bode-Böger / Jens Martens-Lobenhoffer / Svjetlana Lovric / Johann Bauersachs / Bernhard Schieffer / Mechthild Westhoff-Bleck / Jan T Kielstein

PLoS ONE, Vol 7, Iss 3, p e

2012 Volume 33795

Abstract: BACKGROUND: Chronic heart failure is an important cause for morbidity and mortality in adults with congenital heart disease (ACHD). While NT-proBNP is an established biomarker for heart failure of non-congenital origin, its value in ACHD has limitations. ...

Abstract	BACKGROUND: Chronic heart failure is an important cause for morbidity and mortality in adults with congenital heart disease (ACHD). While NT-proBNP is an established biomarker for heart failure of non-congenital origin, its value in ACHD has limitations. Asymmetrical dimethylarginine (ADMA) correlates with disease severity and independently predicts adverse clinical events in heart failure of non-congenital origin. Its role in ACHD has not been investigated. METHODS: In 102 patients ADMA and NT-proBNP were measured and related to NYHA class, systemic ventricular function and parameters of cardiopulmonary exercise testing. RESULTS: In contrast to NT-proBNP ADMA differentiated between NYHA classes I-III. Both, ADMA and NT-proBNP showed a good correlation with parameters of cardiopulmonary exercise testing with comparable receiver-operating characteristic curves for identifying patients with severely limited cardiopulmonary exercise capacity. CONCLUSION: ADMA seems to be a better biomarker than NT-proBNP for the assessment of NYHA class and as a good as NT-proBNP for the estimation of maximum exercise capacity in adults with congenital heart disease. Its use in clinical routine should be evaluated.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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