Asymmetrical Dimethylarginine Independently Predicts Total and Cardiovascular Mortality in Individuals with Angiographic Coronary Artery Disease (The Ludwigshafen Risk and Cardiovascular Health Study)

Meinitzer, Andreas; Seelhorst, Ursula; Wellnitz, Britta; Halwachs‐Baumann, Gabriele; Boehm, Bernhard O.; Winkelmann, Bernhard R.; März, Winfried

doi:10.1373/clinchem.2006.076711

Cited by 209 publications

(144 citation statements)

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“…Evidence for an association between high blood pressure and elevated ADMA levels comes from small clinical studies (29,35). Other reports, including several large-scale clinical studies, did not confirm such an association (25,31). Our blood pressure results are limited because we only used a noninvasive tail-cuff method, a technique that has received criticism in the past.…”

Section: Discussionmentioning

confidence: 80%

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Jacobi¹,

Maas²,

Cordasic³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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RH, Hilgers KF. Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am J Physiol Heart Circ Physiol 294: H1058-H1066, 2008. First published December 21, 2007 doi:10.1152/ajpheart.01103.2007.-The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n ϭ 28) were treated with 1.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, 3.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage. dimethylarginine dimethylaminohydrolase; hypertension; transgenic ASYMMETRIC DIMETHYLARGININE (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is increasingly recognized as a potential risk factor and prognostic biomarker in cardiovascular disease (38). Thus far, elevated ADMA levels have been associated with all established cardiovascular risk factors (38). Furthermore, recent data from genetic mouse models indicate a causal role for ADMA in the pathophysiology of vascular disease (7,19). ADMA derives from the posttranslational methylation of L-arginine residues within proteins catalyzed by enzymes called protein arginine methyltransferases (PRMTs). Upon proteolysis, methylarginines are released into the circulation. Although ϳ15% of ADMA are excreted via the urine, the major elimination occurs through enzymatic degradation (ϳ85%) (1). The enzyme dimethylarginine dimethylaminohydrolase (DDAH), of which two isoforms with distinct tissue distribution have been described, catalyzes the hydrolysis of ADMA to L-citrulline and dimethylamine (38).Thus far, clinical studies have mostly addressed the prognostic value of ADMA in cardiovascular or kidney disease as well as the impact of pharmacological interventions aimed at lowering ADMA levels ...

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Section: Discussionmentioning

confidence: 80%

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Jacobi¹,

Maas²,

Cordasic³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Several studies have shown that plasma ADMA level may predict the progression of renal injury in patients with early-stage CKD (12,13). In addition, high plasma ADMA level has been reported to be an independent risk factor for cardiovascular disease and allcause mortality in a community-based population (14), in patients with coronary artery disease (CAD) (15,16), and in patients with ESRD (17,18). However, evidence about the association between ADMA and patients with mild to moderate CKD is limited.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

Chung²,

Lin

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Elevated plasma level of asymmetric dimethylarginine (ADMA) have been reported to be associated with endothelial dysfunction and atherosclerosis risk factors, and may predict cardiovascular events in patients with ESRD. In this study, we aimed to assess the association between plasma ADMA and long-term outcome in a cohort of patients with stage 3 to 4 chronic kidney disease (CKD).Design, setting, participants, & measurements From July 2006 to June 2009, 298 consecutive patients with stage 3 to 4 CKD scheduled to undergo coronary angiography were recruited. Plasma ADMA levels were determined using HPLC. ResultsThe mean age was 73 Ϯ 10 years. Approximately half of the patients had diabetes and 88 patients had proteinuria. The baseline estimated GFR (eGFR) was 44 Ϯ 13 ml/min per 1.73 m 2 . The plasma ADMA levels of the patients with proteinuria were significantly higher than those without. The plasma ADMA levels correlated significantly with eGFR. During the median follow-up period of 2.7 years, we observed 26 all-cause deaths, 12 nonfatal myocardial infarctions, and 2 strokes. Multivariate Cox analysis revealed that an increase of 0.1 mol/L in plasma ADMA level was associated with a 37% increased risk of the composite outcomes of all-cause deaths, nonfatal myocardial infarctions, and strokes. ConclusionsIn this elder and high-risk population with stage 3 to 4 CKD, high plasma ADMA level was associated with low eGFR and macroalbuminuria. Furthermore, high plasma ADMA level appeared to be an independent predictor of long-term outcome.

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“…Of note, ADMA concentrations are higher in dialysis patients with clinically manifest atherosclerosis than in those without atherosclerotic disease (17), which suggests that accumulation of ADMA might be an important cardiovascular risk factor in end-stage renal disease. Moreover, the clinical importance of ADMA in coronary artery disease is highlighted in a recent trial by Meinitzer et al (18) in which ADMA predicted cardiovascular events in 3200 patients. In addition, ADMA predicts coronary events in middle-aged white men (19).…”

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confidence: 99%

Coronary Artery Calcification, ADMA, and Insulin Resistance in CKD Patients

Kobayashi¹,

Oka²,

Maesato³

et al. 2008

Clinical Journal of the American Society of Nephrology

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Background and objectives: It is known that coronary artery calcification (CAC) develops in chronic kidney disease (CKD) before initiation of renal replacement therapy, and factors associated with CKD mineral and bone disorders (CKD-MBDs) are involved. However, little information is available about any association between plasma levels of asymmetric dimethylarginine (ADMA), insulin resistance, and CAC.Design, setting, participants, & measurements: A total of 111 CKD patients (79 men, 32 women; glomerular filtration rate [GFR] median, 33.7 ml/min per 1.73 m 2 ), free of cardiovascular disease, were consecutively recruited along with 30 age-matched healthy subjects. Coronary artery calcification scores (CACS) were measured by multidetector-row CT according to Agatston score.Results: In CKD patients, CACS was distributed widely from 0 to 2901, while in age-matched, healthy control subjects (n ‫؍‬ 30), CACS showed a range from 0 to 307. GFR had a significant negative correlation with CACS. Plasma ADMA levels were negatively correlated with GFR and positively correlated with CACS. When CACS was divided into quartiles (<50, n ‫؍‬ 56; 50 to 300, n ‫؍‬ 24; 300 to 600, n ‫؍‬ 14; >600, n ‫؍‬ 17), the patients with CACS >600 had significantly higher values of HOMA-IR, plasma ADMA levels, and fibrinogen along with serum levels of phosphorus, compared with those in patients having CACS <50. Multivariate regression analysis determined HOMA-IR as an independent contributing factor to CACS.Conclusions: CAC becomes more prevalent and severe with a decline in GFR, and plasma ADMA levels and insulin resistance, independent of factors associated with CKD-MBD, are correlated with CAC.

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Asymmetrical Dimethylarginine Independently Predicts Total and Cardiovascular Mortality in Individuals with Angiographic Coronary Artery Disease (The Ludwigshafen Risk and Cardiovascular Health Study)

Abstract: Background: Asymmetrical dimethylarginine (ADMA) is increased in conditions associated with increased risk of atherosclerosis. We investigated the use of ADMA to predict total and cardiovascular mortality in patients scheduled for coronary angiography.

Cited by 209 publications

References 51 publications

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

Coronary Artery Calcification, ADMA, and Insulin Resistance in CKD Patients

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