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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2536.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Asymmetric Dimethylarginine Predicts Major Adverse Cardiovascular Events in Patients With Advanced Peripheral Artery Disease

Friedrich Mittermayer; Katarzyna Krzyzanowska; Markus Exner; Wolfgang Mlekusch; Jasmin Amighi; Schila Sabeti; Erich Minar; Markus Müller; Michael Wolzt; Martin Schillinger

From the Department of Clinical Pharmacology (F.M., M.M., M.W.), Medical University Vienna; the Department of Internal Medicine I (K.K.), Rudolfstiftung Hospital, Vienna; the Clinical Institute for Medical and Chemical Laboratory Diagnostics (M.E.), Medical University Vienna; and the Department of Internal Medicine II (W.M., J.A., S.S., E.M., M.S.), Division of Angiology, Medical University Vienna, Austria.

Correspondence to Friedrich Mittermayer, Medical University Vienna, Department of Clinical Pharmacology, AKH-Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. E-mail friedrich.mittermayer{at}meduniwien.ac.at

	Abstract

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Objective— Circulating concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, are elevated in conditions associated with increased cardiovascular risk. We investigated whether elevated ADMA concentrations predict major adverse cardiovascular events (MACE) in patients with advanced peripheral artery disease (PAD).

Methods and Results— We prospectively enrolled 496 of 533 consecutive patients with PAD (median age 70 years, 279 males). ADMA and L-arginine were assessed at baseline by high performance liquid chromatography. The occurrence of MACE (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, carotid revascularization, death) was evaluated during a follow-up of median 19 months (interquartile range 11 to 25). One hundred eighty-two MACE were observed in 141 patients (28%). MACE occurred in 39% of the patients in the highest quartile and 26% of those in the lowest quartile of ADMA (P=0.016, log-rank test for all quartiles). Adjusted hazard ratios for occurrence of MACE for increasing quartiles of ADMA compared with the lowest quartile were 0.87 (95% confidence interval [CI], 0.51 to 1.48), 1.12 (95% CI, 0.62 to 1.90), and 1.70 (95% CI, 1.02 to 2.88), respectively. We observed no association between cardiovascular outcome and L-arginine.

Conclusions— High ADMA plasma concentrations independently predict MACE in patients with advanced PAD. This indicates that ADMA may be a new cardiovascular risk marker in these patients.

Concentrations of the nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) are elevated in states of increased cardiovascular risk. We prospectively examined the relationship between ADMA and major adverse cardiovascular events (MACE) in patients with peripheral artery disease. High ADMA independently predicted MACE supporting its role as new cardiovascular risk marker.

Key Words: asymmetric dimethylarginine • major adverse cardiovascular events • nitric oxide • peripheral artery disease

	Introduction

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Peripheral artery disease (PAD) is a common condition with a prevalence of 3.6% in subjects older than 40 years in the Framingham Offspring Study.¹ Patients with advanced PAD are at increased risk for major adverse cardiovascular events (MACE).²

Nitric oxide (NO) is produced from L-arginine by NO synthases³ and is essential for physiological endothelial function.⁴ NO has important antiatherogenic properties and reduced NO bioavailability might substantially contribute to the development of cardiovascular disease.⁵ The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is increased in conditions associated with high cardiovascular risk such as hyperlipidemia,^6,7 arterial hypertension,⁸ renal impairment,⁹ or PAD.¹⁰ ADMA predicts cardiovascular events in patients with end-stage renal failure and in subjects with coronary artery disease.^11,12 ADMA has not only been shown to be associated with the presence of macrovascular disease^13,14 but also might be directly involved in the formation of vascular lesions.¹⁵ This renders ADMA as cardiovascular risk marker or even contributor to cardiovascular disease. Only inconsistent and preliminary data on the role of the NO precursor L-arginine are available in patients with coronary heart disease and PAD.^16–18

We hypothesized that ADMA is associated with future cardiovascular events in patients with advanced PAD and a pronounced adverse cardiovascular risk profile.

	Materials and Methods

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Study Design
Patients with advanced PAD, who were admitted to the Angiology department of a tertiary care university hospital from March 1, 2000 to March 1, 2001, were prospectively enrolled in a cohort study. Inclusion criteria were symptomatic PAD with intermittent claudication or critical limb ischemia and asymptomatic PAD with a history of surgical or endovascular lower limb revascularization. The study was approved by the local Ethics Committee, and all patients gave written informed consent.

Patients
At admission, demographic data, clinical characteristics, and current medication of the patients were recorded by 2 independent observers with special attention to cardiovascular risk factors and comorbidities. Age, sex, smoking habits, hyperlipidemia, arterial hypertension, diabetes mellitus, coronary artery disease, history of myocardial infarction (MI), and stroke were assessed. Subjects with end-stage renal disease were not included. Data were evaluated for inter-observer agreement at the day of patient discharge. In case of discrepancies the respective patient was re-evaluated by both investigators in consensus. To detect undiagnosed diabetes at admission, fasting blood glucose and hemoglobin A1c (HbA1c) levels were determined. During the hospital stay repeated blood pressure measurements were applied to detect undiagnosed hypertension in patients.

Laboratory Investigations
Routine laboratory investigations included complete blood cell count, coagulation tests and clinical chemistry. High-sensitivity C-reactive protein (hsCRP) was measured with a high-sensitivity assay (N Latex CRP Mono; DADE Behring, Vienna, Austria), with a detection level of 0.03 mg/dL, and a coefficient of variation of 4.6%. For determination of ADMA and L-arginine, venous blood was taken and plasma separated and stored at –80°C until batch analysis. Analysis was performed by high-performance liquid chromatography as described previously.^19,20 The coefficients of variation for inter- and intra-assay variations for this method are <3% for all analytes. The detection limit for methylarginines is 0.04 µmol/L.

Study End Points
The composite study end point was the occurrence of a first MACE consisting of MI, percutaneous coronary interventions (PCI), coronary artery bypass graft (CABG), stroke, carotid revascularization, and all-cause mortality. We analyzed the associations of ADMA with all-cause mortality as well as with MI, stroke, and death as secondary end points.

Follow-Up
Patients were clinically re-evaluated at 3, 6, and 12 months after hospital discharge and then annually to record clinical conditions until December 2002. Furthermore, a follow-up questionnaire was sent to each patient during December 2002 re-evaluating the occurrence of MACE during the whole follow-up period. Information from the follow-up questionnaire was validated by reviewing the original hospital discharge reports of corresponding re-admissions because of MACE. If the follow-up questionnaire was not returned, personal telephone contact to the patients, their relatives, or to the treating physicians was established. Further information was obtained by reviewing the hospital discharge reports of any other re-admission during the follow-up period. The performance of PCI, CABG, or carotid revascularization was validated by review of the original procedure protocols. Outcome was adjudicated for by 2 independent observers who were blinded with respect to the patients’ baseline clinical and laboratory data.

Definitions
The diagnosis of PAD was assessed by clinical evaluation, ankle brachial index measurements (ABI <0.9), duplex sonography, and confirmed by lower limb angiography (digital subtraction technique) in all patients. Diabetes mellitus was defined as fasting blood glucose levels >126 mg/dL on 3 separate days and was considered to be present in all patients taking anti-diabetic medication. Hyperlipidemia was defined as fasting total serum cholesterol >200 mg/dL, low-density lipoprotein (LDL) cholesterol >130 mg/dL or serum triglycerides >180 mg/dL and was considered to be present in all patients receiving lipid-lowering therapy (3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors [statins] were used routinely at our institution during the study period). Arterial hypertension was diagnosed in patients with resting blood pressure values >140/90 mm Hg, and was assumed to be present in patients with a history of hypertension taking anti-hypertensive drugs. Patients who were smoking >3 cigarettes per day were regarded as current smokers. Coronary artery disease was evaluated by treadmill exercise testing, dobutamine echocardiography, myocardial scintigraphy, or coronary angiography in selected cases. MI was defined according to the consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of MI as a transient increase of laboratory markers specific of myocardial necrosis (CK-MB, or troponin T) in combination with ischemic symptoms and/or typical ECG signs (development of pathologic Q-waves or ST segment elevation or depression).²¹ Stroke was defined as a neurological deficit that persisted >24 hours evaluated by a neurologist according to the modified Rankin stroke scale. Mandatory cranial computed tomography or, if available, magnetic resonance imaging, were used for confirmation of the diagnosis.

Statistics
Continuous data are presented as medians (interquartile range). Categorical data are given as counts (percentages). Mann Whitney U test was applied for univariate comparison of continuous data and Spearman rank correlation for assessment of associations between continuous variables. Event-free survival rates until the first cardiovascular adverse event according to baseline ADMA levels (in quartiles) were calculated using the Kaplan Meier method and compared by the Log Rank test. Multivariate Cox proportional hazards analysis was used to assess the independent effect of ADMA on the composite end point and to adjust for potential confounders. Quartiles of continuous variables were included as confounders if these variables were associated with ADMA according to Spearman rank correlation coefficients. Categorical variables were entered into the model if they influenced ADMA according to univariate analysis. In addition, adjustment for traditional cardiovascular risk factors was performed. Results of the Cox proportional hazards model are presented as hazard ratio and 95% confidence interval (CI) as well as survival curves according to quartiles of ADMA. A 2-sided P<0.05 was considered as statistically significant. Calculations were performed with SPSS for Windows (Version 12.0; SPSS Inc, Chicago, Ill).

	Results

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Five hundred thirty-three subjects with PAD were eligible for the study and 496 subjects (93%) with complete baseline and follow-up data were included in the present analysis. In 19 patients laboratory values for ADMA and L-arginine were missing and in 18 patients clinical follow-up data of MACE were not available. Demographic data and clinical characteristics at baseline did not differ between patients included and those not included in the study (data not shown). The median age of the patients included was 70 years (interquartile range [IQR], 60 to 76), 279 (56%) were male and follow-up duration was median 19 months (IQR, 11 to 25).

Median ADMA and L-arginine plasma concentration of all patients were 0.55 µmol/L (IQR, 0.48 to 0.64) and 78 µmol/L (IQR, 61 to 96), respectively. ADMA was elevated in females, patients with history of MI, and patients without hyperlipidemia, and correlated positively with age and creatinine but not with other continuous variables (Tables 1 and 2).

View this table: [in this window] [in a new window]   TABLE 1. Median (Interquartile Range) Plasma Concentrations of Asymmetric Dimethylarginine (ADMA) Grouped According to Categorical Baseline Variables

View this table: [in this window] [in a new window]   TABLE 2. Spearman Correlation Coefficients for Asymmetric Dimethylarginine and Continuous Baseline Variables of Patients With Peripheral Artery Disease (n=496)

During follow-up 182 MACE occurred in 141 subjects (28%) including 18 (3.6%) MIs, 41 (8.3%) PCIs, 7 (1.4%) CABGs, 27 (5.4%) carotid revascularizations, 25 (5.0%) strokes, and 64 (12.9%) deaths. Cumulative event free survival rates at 6, 12, 18, and 24 months were 90%, 84%, 79%, and 70%, respectively. Thirty-nine percent of the patients with ADMA concentrations in quartile 4, 29% of those with ADMA in quartile 3, 24% of those with ADMA in quartile 2, and 26% of those with ADMA in quartile 1 had a MACE during the observation period (P=0.016, log-rank test). Patients with ADMA concentrations in quartile 4 had a significantly higher hazard ratio for MACE during follow-up compared with patients in quartile 1 before and after adjustment for age, sex, history of MI, current smoking, hypertension, diabetes mellitus, statin therapy, body mass index, hsCRP, LDL cholesterol, and creatinine (Figure 1, Table 3). L-arginine (in quartiles) or the L-arginine/ADMA ratio (in quartiles) showed no significant association with MACE during follow-up (P=0.87 and P=0.33, respectively; log-rank test).

View larger version (9K): [in this window] [in a new window]   Cox regression survival curves for major adverse cardiovascular events (MACE) according to quartiles of asymmetric dimethylarginine (ADMA) at baseline adjusted for confounders and traditional cardiovascular risk factors (P=0.043).

View this table: [in this window] [in a new window]   TABLE 3. Cox Regression Analysis Assessing the Univariate and Multivariate Hazard Ratios for Quartiles of Asymmetric Dimethylarginine (ADMA) Compared to the Lowest Quartile

Analyzing the associations of ADMA with all-cause mortality as well as with MI, stroke and death consistent findings were observed. Adjusted hazard ratios for increasing quartiles of ADMA as compared with the lowest quartile were 1.25 (95% CI, 0.54 to 2.90), 2.15 (0.99 to 4.62), and 2.43 (1.16 to 5.10) for all-cause mortality, and 1.11 (0.62 to 1.97), 1.45 (0.84 to 2.51), and 1.77 (1.06 to 2.98) for MI, stroke, and death, respectively.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Elevated plasma ADMA concentrations were related to MACE in this prospective study in subjects with advanced PAD. Patients in the highest quartile of ADMA had >65% greater relative risk for future MACE compared with those in the lowest quartile. Traditional cardiovascular risk factors like hypertension, hyperlipidemia, diabetes mellitus, or increased body mass index did not influence these results. Our results therefore confirm the clinical importance of ADMA in patients with advanced PAD¹⁰ and indicate a predictive value of elevated ADMA concentrations for future cardiovascular events.

The mechanisms regulating ADMA concentrations are well described.²² Impaired renal function is of major relevance because ADMA is excreted via the kidneys.⁹ Consistent with these data we found a significant correlation between ADMA and creatinine. However, the relationship between increased ADMA and MACE was not affected by creatinine which indicates that kidney function only partly influences ADMA and hence the association with cardiovascular outcome. Degradation of ADMA by dimethylarginine dimethylaminohydrolase is considered the principal determinant for ADMA concentrations in subjects with normal renal function.²³

High concentrations of cholesterol, glucose, or inflammatory stimuli inhibited dimethylarginine dimethylaminohydrolase activity and consequently increased ADMA in in vitro experiments.^24,25 ADMA was not related to LDL cholesterol, hsCRP, or diabetes mellitus in our study. Although that does not exclude a clinical impact of these conditions, a confounding influence in our cohort of PAD patients is unlikely. Surprisingly, patients with hyperlipidemia had lower ADMA concentrations than other subjects, which is in contrast with previous clinical data.^6,7 Although concomitant lipid-lowering therapy could have biased our findings, the effect of statins on ADMA is controversial as most statins do not affect circulating ADMA concentrations in clinical studies,^26–30 with the exception of rosuvastatin.³¹ These results and the fact that statin use was not associated with ADMA in our study renders lipid-lowering therapy an unlikely reason for the lower ADMA concentrations found in subjects with hyperlipidemia. It is however unclear if stringent pharmacological cardiovascular risk factor management could have contributed to lower ADMA in the hyperlipidemic subjects. Treatment with rosiglitazone, metformin, angiotensin-converting enzyme inhibitors, and angiotensin 2 receptor blockers has been shown to decrease ADMA concentrations in humans.^32–36 Therefore, an effect of diabetes mellitus or hypertension on ADMA in our study might be obscured by the use of anti-diabetic or anti-hypertensive drugs.

Women had higher ADMA than men in the present cohort which is consistent with results from a study in healthy subjects that demonstrated that women older than 50 years of age have elevated ADMA compared with age-matched men.³⁷ These sex differences could be related to hormonal changes in the postmenopause as younger women have lower ADMA than men³⁷ and elevated ADMA is normalized by hormone replacement therapy in postmenopausal women.³⁸

Recently, prospective studies in patients with end-stage renal disease and coronary artery disease have identified ADMA as an important cardiovascular risk marker.^11,12 Our present findings are compatible with these data and add to the evidence that ADMA may be regarded as an independent predictor of future cardiovascular events also in a different group of patients. Considering the fact that ADMA is a competitive NO synthase inhibitor and that NO is a major antiatherogenic molecule it may be speculated that increased ADMA levels could even represent a therapeutic target and therefore be regarded as risk factor rather than plasma marker alone. This is supported by the fact that infusion of ADMA causes hypertension and increases systemic vascular resistance in healthy volunteers.²³ However, this hypothesis cannot be tested as selective ADMA-lowering drugs are not available yet. Further prospective studies in patients with mild PAD and other cohorts are mandatory to validate the clinical role of ADMA. In addition, it is necessary to develop new reliable methods for easy and efficient determination of ADMA plasma concentrations to establish ADMA as cardiovascular risk marker.

Several studies demonstrated that administration of the NO precursor L-arginine improves endothelial function in subjects at increased cardiovascular risk^39–41 and can reverse the actions of NO synthase inhibitors.⁴² This effect has been attributed to structural antagonism with preserved NO release. In contrast, a recent study found adverse effects of L-arginine supplementation in patients with acute MI.¹⁶ Our results do not support a role of circulating endogenous L-arginine for cardiovascular outcome.

In conclusion, this study has identified ADMA as an independent predictor for MACE in patients with advanced PAD. ADMA may represent a useful new risk marker for future adverse cardiovascular outcome in this cohort of subjects.

	Acknowledgments

 
Disclosures

None.

	Footnotes

 
Original received May 30, 2006; final version accepted August 8, 2006.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Murabito JM, Evans JC, Nieto K, Larson MG, Levy D, Wilson PW. Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study. Am Heart J. 2002; 143: 961–965.[CrossRef][Medline] [Order article via Infotrieve]
2. Fowkes FG. Epidemiological research on peripheral vascular disease. J Clin Epidemiol. 2001; 54: 863–868.[CrossRef][Medline] [Order article via Infotrieve]
3. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993; 329: 2002–2012.[Free Full Text]
4. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987; 327: 524–526.[CrossRef][Medline] [Order article via Infotrieve]
5. Davignon J, Ganz P Role of endothelial dysfunction in atherosclerosis. Circulation. 2004; 109: III27–III32.
6. Böger RH, Bode-Böger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation. 1998; 98: 1842–1847.[Abstract/Free Full Text]
7. Lundman P, Eriksson MJ, Stühlinger M, Cooke JP, Hamsten A, Tornvall P. Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine. J Am Coll Cardiol. 2001; 38: 111–116.[Abstract/Free Full Text]
8. Surdacki A, Nowicki M, Sandmann J, Tsikas D, Boeger RH, Bode-Boeger SM, Kruszelnicka-Kwiatkowska O, Kokot F, Dubiel JS, Froelich JC. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol. 1999; 33: 652–658.[CrossRef][Medline] [Order article via Infotrieve]
9. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992; 339: 572–575.[CrossRef][Medline] [Order article via Infotrieve]
10. Böger RH, Bode-Böger SM, Thiele W, Junker W, Alexander K, Frölich JC. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation. 1997; 95: 2068–2074.[Abstract/Free Full Text]
11. Zoccali C, Bode-Böger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frölich J, Böger R. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet. 2001; 358: 2113–2117.[CrossRef][Medline] [Order article via Infotrieve]
12. Schnabel R, Blankenberg S, Lubos E, Lackner KJ, Rupprecht HJ, Espinola-Klein C, Jachmann N, Post F, Peetz D, Bickel C, Cambien F, Tiret L, Munzel T. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ Res. 2005; 97: e53–59.[Abstract/Free Full Text]
13. Krzyzanowska K, Mittermayer F, Krugluger W, Schnack C, Hofer M, Wolzt M, Schernthaner G. Asymmetric dimethylarginine is associated with macrovascular disease and total homocysteine in patients with type 2 diabetes. Atherosclerosis. 2006;doi:10.1016/j.atherosclerosis.2005.12.007.
14. Kielstein JT, Böger RH, Bode-Böger SM, Schaffer J, Barbey M, Koch KM, Frölich JC. Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol. 1999; 10: 594–600.[Abstract/Free Full Text]
15. Suda O, Tsutsui M, Morishita T, Tasaki H, Ueno S, Nakata S, Tsujimoto T, Toyohira Y, Hayashida Y, Sasaguri Y, Ueta Y, Nakashima Y, Yanagihara N. Asymmetric dimethylarginine produces vascular lesions in endothelial nitric oxide synthase-deficient mice: involvement of renin-angiotensin system and oxidative stress. Arterioscler Thromb Vasc Biol. 2004; 24: 1682–1688.[Abstract/Free Full Text]
16. Schulman SP, Becker LC, Kass DA, Champion HC, Terrin ML, Forman S, Ernst KV, Kelemen MD, Townsend SN, Capriotti A, Hare JM, Gerstenblith G. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006; 295: 58–64.[Abstract/Free Full Text]
17. Böger RH, Bode-Böger SM, Thiele W, Creutzig A, Alexander K, Frölich JC. Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol. 1998; 32: 1336–1344.[Abstract/Free Full Text]
18. Bednarz B, Jaxa-Chamiec T, Maciejewski P, Szpajer M, Janik K, Gniot J, Kawka-Urbanek T, Drozdowska D, Gessek J, Laskowski H. Efficacy and safety of oral l-arginine in acute myocardial infarction. Results of the multicenter, randomized, double-blind, placebo-controlled ARAMI pilot trial. Kardiol Pol. 2005; 62: 421–427.[Medline] [Order article via Infotrieve]
19. Teerlink T, Nijveldt RJ, de Jong S, van Leeuwen PA. Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. Anal Biochem. 2002; 303: 131–137.[CrossRef][Medline] [Order article via Infotrieve]
20. Mittermayer F, Namiranian K, Pleiner J, Schaller G, Wolzt M. Acute Escherichia coli endotoxaemia decreases the plasma l-arginine/asymmetrical dimethylarginine ratio in humans. Clin Sci (Lond). 2004; 106: 577–581.[Medline] [Order article via Infotrieve]
21. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined–a consensus document of The Joint European Society of Cardiology/Am College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000; 36: 959–969.[Free Full Text]
22. Leiper JM, Vallance P The synthesis and metabolism of asymmetric dimethylarginine (ADMA). Eur J Clin Pharmacol. 2006; 62 Suppl 13: 33–38.[CrossRef]
23. Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAllister R, Vallance P. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol. 2003; 23: 1455–1459.[Abstract/Free Full Text]
24. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation. 1999; 99: 3092–3095.[Abstract/Free Full Text]
25. Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven GM, Cooke JP. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation. 2002; 106: 987–992.[Abstract/Free Full Text]
26. Paiva H, Laakso J, Lehtimaki T, Isomustajarvi M, Ruokonen I, Laaksonen R. Effect of high-dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors. J Cardiovasc Pharmacol. 2003; 41: 219–222.[CrossRef][Medline] [Order article via Infotrieve]
27. Valkonen VP, Laakso J, Paiva H, Lehtimaki T, Lakka TA, Isomustajarvi M, Ruokonen I, Salonen JT, Laaksonen R. Asymmetrical dimethylarginine (ADMA) and risk of acute coronary events. Does statin treatment influence plasma ADMA levels? Atheroscler Suppl. 2003; 4: 19–22.[Medline] [Order article via Infotrieve]
28. Shinohara K, Shoji T, Kimoto E, Yokoyama H, Fujiwara S, Hatsuda S, Maeno T, Fukumoto S, Emoto M, Koyama H, Nishizawa Y. Effect of atorvastatin on regional arterial stiffness in patients with type 2 diabetes mellitus. J Atheroscler Thromb. 2005; 12: 205–210.[Medline] [Order article via Infotrieve]
29. Eid HM, Eritsland J, Larsen J, Arnesen H, Seljeflot I. Increased levels of asymmetric dimethylarginine in populations at risk for atherosclerotic disease. Effects of pravastatin. Atherosclerosis. 2003; 166: 279–284.[CrossRef][Medline] [Order article via Infotrieve]
30. Pereira EC, Bertolami MC, Faludi AA, Salem M, Bersch D, Abdalla DS. Effects of simvastatin and L-arginine on vasodilation, nitric oxide metabolites and endogenous NOS inhibitors in hypercholesterolemic subjects. Free Radic Res. 2003; 37: 529–536.[CrossRef][Medline] [Order article via Infotrieve]
31. Lu TM, Ding YA, Leu HB, Yin WH, Sheu WH, Chu KM. Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia. Am J Cardiol. 2004; 94: 157–161.[CrossRef][Medline] [Order article via Infotrieve]
32. Stühlinger MC, Abbasi F, Chu JW, Lamendola C, McLaughlin TL, Cooke JP, Reaven GM, Tsao PS. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA. 2002; 287: 1420–1426.[Abstract/Free Full Text]
33. Asagami T, Abbasi F, Stuelinger M, Lamendola C, McLaughlin T, Cooke JP, Reaven GM, Tsao PS. Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes. Metabolism. 2002; 51: 843–846.[CrossRef][Medline] [Order article via Infotrieve]
34. Chen JW, Hsu NW, Wu TC, Lin SJ, Chang MS. Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Am J Cardiol. 2002; 90: 974–982.[CrossRef][Medline] [Order article via Infotrieve]
35. Napoli C, Sica V, de Nigris F, Pignalosa O, Condorelli M, Ignarro LJ, Liguori A. Sulfhydryl angiotensin-converting enzyme inhibition induces sustained reduction of systemic oxidative stress and improves the nitric oxide pathway in patients with essential hypertension. Am Heart J. 2004; 148: e5.[Medline] [Order article via Infotrieve]
36. Ito A, Egashira K, Narishige T, Muramatsu K, Takeshita A. Renin-angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension. Jpn Circ J. 2001; 65: 775–778.[CrossRef][Medline] [Order article via Infotrieve]
37. Schulze F, Maas R, Freese R, Schwedhelm E, Silberhorn E, Böger RH. Determination of a reference value for N(G), N(G)-dimethyl-L-arginine in 500 subjects. Eur J Clin Invest. 2005; 35: 622–626.[CrossRef][Medline] [Order article via Infotrieve]
38. Post MS, Verhoeven MO, van der Mooren MJ, Kenemans P, Stehouwer CD, Teerlink T. Effect of hormone replacement therapy on plasma levels of the cardiovascular risk factor asymmetric dimethylarginine: a randomized, placebo-controlled 12-week study in healthy early postmenopausal women. J Clin Endocrinol Metab. 2003; 88: 4221–4226.[Abstract/Free Full Text]
39. Bode-Böger SM, Muke J, Surdacki A, Brabant G, Böger RH, Frölich JC. Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med. 2003; 8: 77–81.[Abstract/Free Full Text]
40. Palloshi A, Fragasso G, Piatti P, Monti LD, Setola E, Valsecchi G, Galluccio E, Chierchia SL, Margonato A. Effect of oral L-arginine on blood pressure and symptoms and endothelial function in patients with systemic hypertension, positive exercise tests, and normal coronary arteries. Am J Cardiol. 2004; 93: 933–935.[CrossRef][Medline] [Order article via Infotrieve]
41. Piatti P, Fragasso G, Monti LD, Setola E, Lucotti P, Fermo I, Paroni R, Galluccio E, Pozza G, Chierchia S, Margonato A. Acute intravenous L-arginine infusion decreases endothelin-1 levels and improves endothelial function in patients with angina pectoris and normal coronary arteriograms: correlation with asymmetric dimethylarginine levels. Circulation. 2003; 107: 429–436.[Abstract/Free Full Text]
42. Wolzt M, Schmetterer L, Ferber W, Artner E, Mensik C, Eichler HG, Krejcy K. Effect of nitric oxide synthase inhibition on renal hemodynamics in humans: reversal by L-arginine. Am J Physiol. 1997; 272: F178–182.

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