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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6277-6281
Copyright © 2004 by The Endocrine Society

Weight Loss Reduces Circulating Asymmetrical Dimethylarginine Concentrations in Morbidly Obese Women

Katarzyna Krzyzanowska, Friedrich Mittermayer, Hans-Peter Kopp, Michael Wolzt and Guntram Schernthaner

Department of Internal Medicine I (K.K., H.-P.K., G.S.), Rudolfstiftung Hospital, 1030 Vienna, Austria; and Department of Clinical Pharmacology (F.M., M.W.), Medical University of Vienna, 1090 Vienna, Austria

Address all correspondence and requests for reprints to: Katarzyna Krzyzanowska, M.D., Department of Internal Medicine I, Rudolfstiftung Hospital, Juchgasse 25, 1030 Vienna, Austria. E-mail: katarzyna.krzyzanowska{at}wienkav.at.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The endogenous nitric oxide-synthase inhibitor asymmetrical dimethyl-L-arginine (ADMA) is elevated in patients with increased risk for arteriosclerosis. Obesity is a risk factor for cardiovascular disease. We measured plasma ADMA concentrations in morbidly obese women before and after weight loss following gastroplastic surgery. ADMA and symmetrical dimethyl-L-arginine concentrations were analyzed by HPLC from 34 female patients (age 41 ± 7 yr) with a body mass index (BMI) of 49 ± 1 kg/m2 before and 14 months after vertical ring gastroplasty. Age-matched healthy women (BMI < 25 kg/m2; n = 24) were studied as controls. After gastroplastic surgery, BMI decreased to 34 ± 1 kg/m2 in obese women (P < 0.00001), and ADMA concentrations were reduced from 1.06 ± 0.06 µmol/liter at baseline to 0.81 ± 0.04 µmol/liter after weight loss (P < 0.00001). Symmetrical dimethyl-L-arginine plasma levels were not affected. ADMA correlated with high-sensitivity C-reactive protein at baseline (r = 0.42; P < 0.05) and after weight loss (r = 0.56; P < 0.005). No association with blood pressure or plasma lipids could be observed. ADMA concentrations were lower in controls (0.68 ± 0.04 µmol/liter; P < 0.05) compared with obese patients before or after weight reduction. The decrease of highly elevated ADMA concentrations in morbidly obese patients is paralleled by improvement of parameters associated with the metabolic syndrome after weight loss.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
NITRIC OXIDE (NO) is synthesized from the amino acid L-arginine by NO synthases (1) and regulates vascular tone, thrombocyte activation, neurotransmission, and host defense (2); L-arginine can also be methylated by intracellular methyltransferases (3), but the exact regulation of this pathway is not yet known. The methylated L-arginine metabolite asymmetrical dimethyl-L-arginine (ADMA) is a competitive NO synthase antagonist (4). Symmetrical dimethyl-L-arginine (SDMA) is produced in equivalent amounts but has no effect on NO synthesis (5). It has been speculated that increased levels of ADMA could reduce NO formation and influence vascular function. Increased ADMA concentrations have been described in hypercholesterolemia (6, 7), hypertension (8, 9), arterial occlusive disease (10), hyperthyroidism (11), chronic renal failure (12), preeclampsia (13), type 2 diabetes (14), and women with previous gestational diabetes (15).

The plasma concentrations of ADMA could therefore be used to monitor early changes in the L-arginine/NO metabolism. However, ADMA concentrations in obese patients who are at risk for diabetes mellitus and cardiovascular disease (16) are unknown. Weight control with a prepared meal plan in obese patients reduces the cardiovascular risk (17). The marked weight loss of morbidly obese patients after gastroplastic surgery is a valuable model for studying the impact of changes in body weight on cardiovascular risk factors (18). We have therefore quantified ADMA and SDMA plasma levels in morbidly obese women before and 14 months after gastroplastic surgery.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The study was approved by the institutional ethics committee and complies with the Declaration of Helsinki including current revisions and the Good Clinical Practice guidelines. The procedures followed were in accordance with institutional guidelines. All subjects gave written informed consent before the study.

Subjects

Plasma from 34 severely obese female patients undergoing open gastroplastic surgery with vertical banded gastroplasty was analyzed. The procedure was performed under general anesthesia. A circular window through the stomach, below the esophagus, was made. A surgical stapler was used to create a small vertical pouch (holding ~30 ml) by placing a row of staples from the window toward the esophagus. A polypropylene band was positioned through the window around the outlet of the pouch. The band was located to control the size of the outlet and to keep it from stretching (19). Baseline parameters are summarized in Table 1Go. Evaluation at follow-up was performed 14 ± 5 months after surgery. At that time, all patients were weight stable and not on hypocaloric nutrition. None of the subjects had a history of cerebro- or cardiovascular disease except for arterial hypertension. Patients with hepatic or renal failure, Cushing’s syndrome, thyroid dysfunction, other major endocrine disorders, or infectious diseases were excluded. Subjects with overt eating disorders, heavy alcohol consumption, and major psychiatric disease were omitted. None of the patients had lipid-lowering drug therapy before or after surgery. Before surgery, nine patients had taken angiotensin-converting enzyme inhibitors, two had ß-blockers, and two had calcium-channel blockers. In total, 10 patients were treated with antihypertensive drugs. Postoperatively, blood pressure normalized and antihypertensive treatment was stopped in all patients. Twenty-four age- and sex-matched control subjects with a body mass index (BMI) less than 25 kg/m2 were included. Fasting blood glucose, blood pressure, glycosylated hemoglobin A1c (HbA1c), triglycerides, total cholesterol, low-density lipoprotein (LDL)-cholesterol, and high-sensitivity C-reactive protein (hsCRP) were lower, and high-density lipoprotein (HDL)-cholesterol was higher in the nonobese control subjects (P < 0.05; Table 1Go).


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  		TABLE 1. Patient characteristics before and after gastroplasty

 
Blood for the determination of ADMA and SDMA was taken after an overnight fast and placed in tubes containing EDTA. A standard oral glucose tolerance test with 75 g glucose was performed, and glucose tolerance status was defined according to the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (20). The diagnostic criteria for type 2 diabetes mellitus (T2DM) were: fasting venous plasma glucose of at least 7 mmol/liter or a 2-h stimulated concentration of at least 11.1 mmol/liter. Blood pressure was measured using a mercury sphygmomanometer under resting conditions. Blood glucose, cholesterol, HDL-cholesterol, and triglycerides were measured by standard laboratory methods (Roche Diagnostics Corp., Indianapolis, IN); hsCRP was analyzed by ELISA (DRG Instruments GmbH, Marburg, Germany). The intra- and interassay coefficients of variation for hsCRP were 5.1 and 14.3%, respectively. Insulin sensitivity was estimated from oral glucose tolerance test glucose and insulin levels with the homeostasis model of assessment (HOMA)-index (21).

Determination of ADMA and SDMA

Venous blood was centrifuged and plasma was separated and stored at –30 C. ADMA and SDMA concentrations were quantified by HPLC with o-phthaldialdehyde precolumn fluorescence derivatization using a modified method previously described (6, 15, 22). Briefly, ADMA and SDMA were extracted from plasma by solid-phase extraction. The column (SCX 100 mg, 1 ml; Isolute, Mid Glamorgan, UK) was activated with methanol, conditioned with 2% trichloracetic acid, and loaded with sample. Subsequently, the column was rinsed with trichloracetic acid (2%), phosphate buffer (pH 8), and methanol. ADMA and SDMA were eluted in methanol containing triethylamine prepared fresh daily. The eluent was evaporated to dryness at +45 C and 1 mbar. The dried extract was redissolved in distilled water. After derivatization, ADMA and SDMA were separated using an isocratic method on a Spherisorb 5-µm phenyl column (Waters, Milford, MA). ADMA and SDMA were eluted from the column with 0.96% citric acid:methanol, 2:1, at a flow rate of 1 ml/min. Excitation was set at 340 nm and emission at 455 nm on the fluorescence detector. The limit of quantification of this method is 0.078 µmol/liter; intra- and between-assay variation is less than 6%.

Statistical analysis

Outcome parameters were tested for normal distribution using the Kolmogorov-Smirnov test. Within- and between-group differences were analyzed by Student’s paired and unpaired t tests. Correlations were calculated using the Pearson correlation. Statistica software version 6.0 (StatSoft, Tulsa, OK) was used for all analyses. A P < 0.05 was considered the level of significance. Data are presented as means ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Outcome parameters before and after gastroplasty are shown in Table 1Go. After weight loss, ADMA concentrations decreased by 19% (95% confidence interval: 11, 28) compared with baseline (P < 0.00001; Fig. 1Go), whereas SDMA plasma levels did not change. As expected, weight loss after gastroplasty significantly decreased BMI, blood pressure, fasting and stimulated 1-h and 2-h glucose and insulin levels, insulin resistance (IR), HbA1c, triglycerides, total cholesterol, LDL-cholesterol, and hsCRP, whereas HDL-cholesterol increased (all P < 0.05). Before surgery, the patients’ diet consisted of approximately 16% protein, 40% carbohydrates, and 43% fat. This was comparable with the macronutrient content of the diet at follow-up (containing 18% protein, 43% carbohydrates, and 38% fat).



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  		FIG. 1. Individual plasma concentrations of ADMA at baseline and after weight loss following gastroplasty (n = 34). Means and SD values are indicated. ADMA decreased significantly (P < 0.00001).

 
At baseline, 14 patients had a pathological glucose tolerance test [seven had impaired glucose tolerance (IGT) and seven had T2DM]. Normal glucose tolerance (NGT) was diagnosed in 20 obese women. Glucose tolerance was normalized in all subjects after weight loss except for one patient with IGT. Patients with NGT (ADMA, 1.00 ± 0.09 and 0.82 ± 0.06 µmol/liter; SDMA, 0.95 ± 0.14 and 0.96 ± 0.10 µmol/liter), IGT (ADMA, 1.09 ± 0.09 and 0.81 ± 0.11 µmol/liter; SDMA, 0.92 ± 0.23 and 1.10 ± 0.08 µmol/liter), and T2DM (ADMA, 1.23 ± 0.12 and 0.76 ± 0.04 µmol/liter; SDMA, 1.05 ± 0.35 and 0.97 ± 0.21 µmol/liter) at baseline had comparable dimethylarginine levels before and after weight loss, respectively. The decrease in ADMA levels was significantly greater in patients with T2DM compared with subjects with NGT (P < 0.03). BMI, weight loss, and the clinical parameters were comparable between these groups except for blood glucose, insulin, HbA1c, and triglycerides, which were lower in the NGT group (P < 0.05).

At baseline and after weight loss ADMA correlated with hsCRP (r = 0.42, P < 0.05; and r = 0.56, P < 0.005, respectively) but not with other parameters (Table 2Go). Patients in the highest tertile for BMI reduction (>18 kg/m2) had a significantly greater ADMA decline (0.42 ± 0.11 µmol/liter) compared with subjects in the lower tertiles (0.19 ± 0.05 µmol/liter; P < 0.03).


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  		TABLE 2. Pearson correlation coefficients between plasma ADMA and outcome parameters as well as the differences of outcome parameters ({Delta}) and ADMA ({Delta}ADMA; n = 34)

 
No relationship between antihypertensive medication and dimethylarginine plasma levels could be observed. Exclusion of patients on angiotensin-converting enzyme inhibitors, ß-blockers, or calcium channel blockers in a separate statistical calculation did not change the results.

ADMA concentrations of obese patients (Table 1Go) were significantly higher before and after surgery compared with nonobese healthy women (0.68 ± 0.04 µmol/liter; both P < 0.05). SDMA levels did not differ significantly between nonobese controls (0.76 ± 0.03 µmol/liter) and obese subjects (Table 1Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study demonstrates that ADMA plasma levels are significantly elevated in morbidly obese subjects and can be reduced by massive weight loss. SDMA concentrations did not change significantly after gastroplasty.

Obesity and weight reduction were shown to be associated with changes in endothelial function (23). In fact, a clinical study demonstrated reduced NO-dependent vasodilation in obese compared with lean subjects (24). It is possible that increased concentrations of ADMA could contribute to the development of endothelial dysfunction in obesity. Although there is no threshold for ADMA leading to endothelial impairment established so far, it can be speculated that elevated ADMA concentrations may cause endothelial hyporeactivity. This hypothesis is supported by a recent study in pregnant women, where impaired flow-mediated dilatation (FMD) of the brachial artery was correlated with elevated ADMA concentrations and associated with a higher risk of developing preeclampsia (25). An inverse correlation between endothelium-dependent vasodilation and ADMA has also been demonstrated after fat intake and experimental hyperhomocysteinemia in humans (26, 27, 28). The importance of increased circulating ADMA has recently been demonstrated in healthy volunteers who developed hypertension and cardiac dysfunction after exogenous administration of ADMA at concentrations equivalent to that in women with risk of preeclampsia (29).

Dietary changes can be excluded as reason for the decrease of ADMA because obese subjects under study reduced only their calorie intake and not the composition of their diet. Increased carbohydrate intake is associated with reduced ADMA plasma concentrations, whereas protein and fat intake seems to have no influence on ADMA (30).

The influence of antihypertensive drugs on ADMA is widely unknown. Long-term treatment with angiotensin- converting enzyme inhibitors was shown to lower ADMA plasma concentrations, whereas bisoprolol had no effect on ADMA in a study that included only a small number of patients (31). Exclusion of the patients on antihypertensive treatment from the statistical calculation did not change the results, and a confounding influence on our findings is therefore unlikely.

Inflammatory processes play a central role in the development of cardiovascular disease (32). Our results showed a significant association of ADMA with hsCRP. This confirms data from a previous study where a close relationship between ADMA and CRP has been described in patients with end-stage renal disease (33). However, in these patients, renal ADMA elimination is reduced and the association of these parameters, therefore, confounded. hsCRP is a strong marker for cardiovascular risk (34), which is according to recent results even more predictive for cardiovascular events than LDL-cholesterol (35). Only a minimal correlation between both markers has been observed in a large population study (35). This is compatible with our finding showing a significant correlation of ADMA with hsCRP but not with LDL-cholesterol. Chronic subclinical inflammation is closely related to obesity, and reduction of BMI results in a decrease of inflammatory markers (18). Thus, it can be speculated that a state of enhanced inflammation in obesity may be associated with elevated ADMA levels.

The mechanism leading to increased levels of ADMA in obese women cannot be explained by our results. ADMA is produced by methylation of protein-bound arginine by protein arginine N-methyltransferases (PRMT), which are widely distributed throughout the body. In the cardiovascular system, these enzymes are expressed in the heart, vascular smooth muscle cells, and endothelial cells (36). The amount of free ADMA seems to be dependent on degradation of proteins containing methylated arginine, on the activity of dimethylarginine dimethylaminohydrolases (DDAH), which decompose ADMA, and on renal excretion. Changes in the PRMT activity cannot be revealed from our study. Inflammation induced by TNF-{alpha} reduces the DDAH activity in endothelial cells in vitro (37). Thus, inflammation, which is present in severe obesity, might lead to increased ADMA levels. This is also reflected by the relationship between ADMA and hsCRP in our study. However, additional experimental studies will be needed to assess the role of PRMT and DDAH in the regulation of ADMA levels in obese subjects. Reduced renal clearance is unlikely to be the reason for increased ADMA seen in our study, because creatinine levels were comparable between patients and controls. Furthermore, SDMA plasma concentrations were not affected by gastroplasty, which would be anticipated from changes in renal function.

The metabolic syndrome is related to chronic inflammation and cardiovascular disease (38). In our study, metabolic parameters improved substantially after surgery. This goes in line with a noticeable reduction in markers associated with cardiovascular risk. Nevertheless, the observed decrease of ADMA concentrations was independent of these changes. Recent results addressing ADMA and its relation to hypercholesterolemia are controversial. Several studies demonstrated that ADMA is not associated with markers of the metabolic syndrome, like LDL-cholesterol and hypertension (15, 26, 39, 40). In contrast, other findings suggested a correlation of ADMA with LDL-cholesterol (41). This discrepancy may be due to different study designs. Whereas our design comprised a selected patient group with similar clinical characteristics, other studies included a more inhomogeneous population. Yet our findings confirm previous data that ADMA is independent of traditional cardiovascular risk factors linked to the metabolic syndrome (15, 42).

IR was shown to be associated with ADMA plasma concentrations (39). Nevertheless, this relationship was found in healthy normotensive subjects. Morbidly obese patients are characterized by many features of the metabolic syndrome that are linked to endothelial dysfunction, like dyslipidemia (43), visceral obesity (44), and prothrombotic or proinflammatory state (45). Thus, comparison with healthy lean subjects is difficult. In our study population, we did not find a relationship between parameters of glucose metabolism and ADMA. However, the number of subjects studied may be too small to draw a conclusion concerning ADMA and IR.

Endothelial dysfunction represents an early stage of atherosclerosis and can be regarded as a predictor of cardiovascular events (46). ADMA is considered an indicator for endothelial dysfunction (47) and a sensitive marker for cardiovascular risk, which was proved in an end-point study that linked serum concentrations of ADMA to acute coronary events (48). The increased cardiovascular risk of morbidly obese patients is reflected by increased levels of ADMA compared with normal-weight controls. This is confirmed by a recent large population study that demonstrated that obese subjects have a 76% higher risk to experience an acute coronary event compared with a normal-weight control group (49). Additive cardiovascular risk factors strongly contributed to the increased coronary risk in the obese patient group in the mentioned study (46). Because ADMA is not only a marker but also a potential pathogenic factor (44) in cardiovascular disease, it may be one link between high BMI and acute coronary events. End-point studies will be needed to evaluate the importance of ADMA as a cardiovascular risk marker in connection with the metabolic syndrome.

As a limitation to the study, we did not perform a clinical measurement of endothelial function. We considered the determination of FMD of the brachial artery. Unfortunately, we were not able to obtain reproducible results in this patient population. It was very difficult to place appropriate cuffs because of the vast circumference and conic shape of the upper arm. The day-to-day variability of FMD was too high to consider this method appropriate for determining endothelial function in this study population. There is currently no literature available on FMD in patients with a BMI as high as 49 kg/m2.

In conclusion, the decrease of highly elevated ADMA concentrations in morbidly obese patients is paralleled by improvement of parameters associated with the metabolic syndrome after weight loss.


   Footnotes
 
Abbreviations: ADMA, Asymmetrical dimethyl-L-arginine; BMI, body mass index; DDAH, dimethylarginine dimethylaminohydrolase; FMD, flow-mediated dilation; HbA1c, glycosylated hemoglobin A1c; HDL, high-density lipoprotein; HOMA, homeostasis model of assessment; hsCRP, high-sensitivity C-reactive protein; IGT, impaired glucose tolerance; IR, insulin resistance; LDL, low-density lipoprotein; NGT, normal glucose tolerance; NO, nitric oxide; PRMT, protein arginine N-methyltransferase; SDMA, symmetrical dimethyl-L-arginine; T2DM, type 2 diabetes mellitus.

Received April 7, 2004.

Accepted September 15, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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