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Endocrinology and Metabolism |
1 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
2 LURIC Database nonprofit LLC, Freiburg, Germany.
3 Division of Endocrinology, Department of Medicine, University Hospital, Ulm, Germany.
4 Cardiology Group, Frankfurt-Sachsenhausen, Germany.
5 Synlab Center of Laboratory Diagnostics Heidelberg, Heidelberg, Germany.
aAddress correspondence to this author at: Synlab Center of Laboratory Diagnostics Heidelberg, PO Box 10 47 80, D-69037 Heidelberg, Germany. Fax 0049-6221-793-111; e-mail maerz{at}synlab.de.
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Abstract |
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Methods: In 2543 persons with and 695 without coronary artery disease (CAD) identified by angiography we measured ADMA and recorded total and cardiovascular mortality during a median follow-up of 5.45 years.
Results: ADMA was correlated positively to age, female sex, diabetes mellitus, former and current smoking, and C-reactive protein and inversely to HDL cholesterol and triglycerides. ADMA was not associated with body mass index, hypertension, LDL cholesterol, or the presence or absence of angiographic CAD. Glomerular filtration rate and homocysteine were the strongest predictors of ADMA. At the 2nd, 3rd and 4th quartile of ADMA, hazard ratios for all-cause mortality adjusted for age, sex, and cardiovascular risk factors were 1.12 [95% confidence interval (CI) 0.83–1.52], 1.35 (95% CI 1.01–1.81), and 1.87 (95% CI 1.43–2.44), respectively, compared with the 1st quartile. Hazard ratios for cardiovascular death were 1.13 (95% CI 0.78–1.63), 1.42 (95% CI 1.00–2.02), and 1.81 (95% CI 1.31–2.51). ADMA in the highest quartile remained predictive of mortality after accounting for medication at baseline. The predictive value of ADMA was similar to that in the entire cohort in persons with CAD, stable or unstable, but was not statistically significant in persons without angiographic CAD.
Conclusions: ADMA concentration predicts all-cause and cardiovascular mortality in individuals with CAD independently of established and emerging cardiovascular risk factors.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A few small studies have addressed the ability of ADMA to predict mortality and have found that high ADMA was related to mortality in critically ill patients (12)(13) and to unfavorable pulmonary hemodynamics and mortality (14). ADMA was predictive of cardiovascular events and total mortality in kidney disease (15), end-stage renal disease (ESRD) (3), and coronary artery disease (CAD) (16)(17)(18). We investigated the value of ADMA to predict total mortality in patients scheduled for coronary angiography.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CAD was assessed by angiography with maximum luminal narrowing estimated by visual analysis. Clinically relevant CAD was defined as the occurrence of 
1 stenosis of 20% in 1 of 15 coronary segments. Individuals with stenoses <20% were considered as not having CAD. The severity of CAD was quantified with the Friesinger score.
Diabetes mellitus was diagnosed if plasma glucose was >1.25 g/L in the fasting state, or >2.00 g/L 2 h after an oral glucose load (20), or if individuals were receiving antidiabetic treatment. Hypertension was diagnosed if the systolic and/or diastolic blood pressure exceeded 140 and/or 90 mmHg or if there was a history of hypertension, evident through the use of antihypertensive drugs. Women were categorized into pre-, peri- or postmenopausal according to menstrual bleeding history and the concentrations of follicle-stimulating hormone (19).
Measurements of ADMA, lipoproteins, C-reactive protein (CRP), fibrinogen, creatinine, and homocysteine were complete in 3238 of 3279 individuals with coronary angiograms. Study participants included 928 patients who presented within 7 days after onset of unstable angina, non–ST-elevation myocardial infarction (MI) (NSTEMI, troponin T >0.1 µg/L), or ST-elevation MI (STEMI, troponin T >0.1 µg/L) because the mean (SD) ADMA concentrations in these patients [827 (145) nmol/L] were close to those in the stable CAD patients [829 (150) nmol/L].
Information on vital status was obtained from local registries. No patients were lost to follow-up. Of the 3238 persons studied, 497 deaths (15.3%) occurred during a median follow-up of 5.45 years. Death certificates were missing for 15 decedents (3%) who were included in the total mortality analysis but excluded from the cardiovascular mortality analysis. Cardiovascular death included the following: sudden death, fatal MI, death because of congestive heart failure, death immediately following intervention to treat CAD, fatal stroke, and other causes of death due to CAD.
laboratory procedures
To perform ADMA and all other analyses we collected fasting blood samples before angiography to rule out ADMA alterations attributable to food intake (21). The standard laboratory methods have been described (19). Glomerular filtration rate (GFR) was calculated as GFR [mL · min–1 · (1.73 m2)–1] = 186 · creatinine–1.154 · age–0.203 and GFR [mL · min–1 · (1.73 m2)–1] = 138 · creatinine–1.154 · age–0.203 in males and in females, respectively (22).
ADMA was measured in frozen serum (–80 °C) with reversed-phase HPLC (23). Within-day and between-day CVs were 3.1% (620 nmol/L) and 1.0% (2000 nmol/L), and 9% (620 nmol/L) and 1.5% (2000 nmol/L), respectively. CRP was measured with high sensitivity immunonephelometry (Dade Behring), and fibrinogen with the Clauss method (Dade Behring).
statistical analysis
Triglycerides and CRP were transformed logarithmically. We established quartiles of continuous variables according to the values in individuals without CAD. Characteristics of individuals with and without CAD are presented as percentages for categorical variables and as mean (SD) or median and 25th and 75th percentiles for continuous variables. Associations of categorical and continuous variables were analyzed by logistic regression and univariate ANOVA, respectively, with covariables as indicated (Table 1
). Using ANOVA models in which we included those factors not under examination as covariables, we studied the effects on ADMA of sex, age, CAD, and cardiovascular risk factors (Table 2
) and of drugs. We used the Cox proportional hazards model to examine the relationship between ADMA and mortality (Tables 3
and 4
). As indicated by log-minus-log diagnostic plots, the proportional hazards assumption was met.
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Multivariable adjustment was carried out for sex, age, CAD, cardiovascular risk factors, and drugs (Tables 3
and 4
). All statistical tests were 2-sided; P <0.05 was considered significant. The SPSS 11.0 statistical package (SPSS Inc.) was used.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
association of adma with cardiovascular risk factors, cad status, and medication
For study participants as a whole, ADMA was significantly higher in women than in men (P <0.001). ADMA in pre- or perimenopausal women was similar to that in men, whereas ADMA was significantly higher in postmenopausal women (Table 2
). ADMA was positively related to age, diabetes mellitus, former and current smoking, CRP, and homocysteine. ADMA was increased at the lowest quartile of HDL-C and was decreased at the highest quartile of triglycerides. The GFR was inversely related to ADMA. We found no statistically significant relationships between ADMA and hypertension, LDL-C, or BMI.
Unadjusted ADMA concentrations were higher in patients with CAD than in persons without CAD (828 vs 814 nmol/L, P = 0.022), but this difference was not seen on multivariate analysis. When we stratified our cohort based on the severity of angiographic changes (the strata of the Friesinger scores were 0–1, 1.01–4, 4.01–8, and 8.01–15), unadjusted ADMA was higher in the 2nd, 3rd, and 4th strata (P <0.001, P = 0.031, P = 0.003, respectively) compared with the lowest stratum, but these differences were also insignificant on multivariate analysis (P = 0.075, P = 0.219, P = 0.450, respectively). By multiple linear regression with forward selection, significant predictors of ADMA were selected in the order of GFR > homocysteine > age > CRP > HDL-C > sex > triglycerides > smoking status > diabetes mellitus. The overall R2 was 0.095, suggesting that <10% of the variation of ADMA was explained by the selected covariates.
ADMA may be increased in morbid obesity (24), but we observed no significant difference when we compared ADMA between study participants with a BMI <25 kg/m2 (n = 903) and those with a BMI >35 kg/m2 (n = 137) or 40 kg/m2 (n = 30), respectively. Systolic blood pressure has also been reported to be related to ADMA (25), but we found no evidence of such a relationship whether or not we adjusted for confounding variables (age, sex, risk factors, and use of antihypertensive drugs).
We investigated whether common medications were associated with ADMA. In users of ACE inhibitors (+1.5%, P = 0.015) and diuretics (+3.6%, P <0.001), ADMA was significantly higher than in nonusers, whereas it was lower in users of lipid-lowering (97% statins, –2.1%, P <0.001) and antiplatelet drugs (–2.2%, P = 0.001). Administration of ß-blockers, AT1 receptor antagonists, calcium channel blockers, and insulin or oral anti-diabetics was not related to ADMA.
adma and mortality from all causes
Among the 3238 persons studied, 497 deaths (15.3%) occurred. Compared with patients in the lowest ADMA quartile, the age and sex-adjusted hazard ratios (HR) for death in the 2nd, 3rd and 4th quartiles were 1.09, 1.40, and 2.04, respectively (Table 3
, Fig. 1
). Inclusion of cardiovascular risk factors as covariables changed these estimates to 1.12, 1.35, and 1.87, respectively (Table 3
). Although HRs decreased, ADMA retained prognostic importance after additional adjustment for the use of drugs significantly associated with ADMA (Table 3
). Per quartile of ADMA, the HRs of death were 1.29, 1.23, and 1.16, respectively, in the 3 models incrementally adjusted for age and sex, risk factors, and the use of drugs (Table 3
).
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Among the 2543 patients with CAD, 440 died (17.3%). In this subgroup, HRs for death were slightly higher than those in the entire cohort (Table 3
).
Only 57 deaths (8.2%) occurred among the 695 study participants without CAD. Although there was a tendency toward an increased risk of death at high ADMA concentrations in this group (unadjusted HR of 1.88 for the 4th compared with the 1st quartile), the association did not reach statistical significance.
Among the patients with CAD, 1518 were studied at least 14 days past the onset of symptoms of an acute coronary event and were considered as having stable CAD. Nine hundred twenty eight patients underwent angiography within 7 days after the onset of symptoms of acute coronary syndromes (unstable angina, NSTEMI, or STEMI) and were classified as having unstable CAD. In this subgroup of patients, 277 (18.2%) and 150 deaths (16.1%), respectively, occurred in the stable and unstable CAD patients. In both groups, we found consistent and robust associations of ADMA with mortality from all causes, with slightly higher HRs in patients with unstable CAD (Table 3
).
adma and mortality from cardiovascular causes
Death certificates were not available from 15 deceased persons, therefore the analysis for cardiovascular mortality included a total of 3223 individuals. Among these, 334 (10.4%) died from cardiovascular causes, 31 (1%) died from fatal infection, 55 (1.7%) died from fatal cancer, and 62 (1.9%) died from miscellaneous causes. HRs for death from cardiovascular causes according to ADMA were similar to those obtained for mortality from all causes in all models and across all subgroups examined, whereby the HRs for mortality from cardiovascular causes were slightly higher than the HRs for all-cause mortality in patients presenting with unstable CAD (Table 4
, Fig. 1
). Compared with the lowest quartile, there were also increased HRs for death from noncardiovascular causes in the highest quartile of ADMA (HR 2.18, adjusted for age and sex).
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Discussion |
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To identify confounding variables, we examined the relationship between ADMA and conditions involved in the development of endothelial dysfunction or CAD. Multiple linear regression analysis revealed GFR as the strongest predictor of ADMA, which supports previous findings of increased ADMA in ESRD (1)(2)(3). Two mechanisms may account for the relationship between ADMA and renal function. First, ADMA itself is eliminated by renal excretion. Second, the enzyme dimethyl-arginine dimethylaminohydrolase (DDAH), which converts ADMA to citrulline and dimethylamine, is highly expressed in the kidney, so that a deterioration of renal function may go along with a decrease in DDAH (26). We emphasize, however, that the association of ADMA with mortality from all causes (HR per quartile 1.27, 95% CI 1.17–1.39) and cardiovascular causes (HR per quartile 1.23, 95% CI 1.10–1.37) also occurred among individuals with GFRs >60 mL/min and was thus independent of renal function.
The 2nd most important predictor of ADMA was plasma homocysteine. ADMA has been suggested to link hyperhomocysteinemia and endothelial dysfunction (9). Although not shown consistently (27)(28), experimental hyperhomocysteinemia may raise ADMA (29)(30). Three mechanisms may underlie the correlation between homocysteine and ADMA. First, because the formation of homocysteine and ADMA requires L-methionine as a methyl group donor, expansion of the L-methionine pool may fuel both pathways at an increased rate (31). Second, homocysteine may inhibit the degradation of ADMA (31). Third, as homocysteine is eliminated by the kidney, both ADMA and homocysteine may concurrently accumulate once the GFR declines. Partial correlation analysis suggests that the latter mechanism might indeed be operative: When we controlled for the GFR, the correlation coefficient between homocysteine and ADMA decreased from 0.212 (n = 3238, P <0.001) to 0.140 (n = 3238, P <0.001), which also reflects the strong and well-known (32) association between homocysteine and GFR (r = –0.390, n = 3238, P <0.001).
In women ADMA was higher than in men. This difference obviously originates from the fact that ADMA increases after menopause (33), and that the vast majority of the women participating in the LURIC study were postmenopausal.
The finding that ADMA was higher in smokers than in nonsmokers is in line with recent findings (34), but contrasts with a study in 563 elderly men in which smokers had lower ADMA than nonsmokers (35). However, the difference was no longer significant after adjustment for multiple confounding factors.
The relationship between LDL-C and ADMA has remained elusive. In their study of 49 hypercholesterolemic adults, Boger et al. (5) found an association between ADMA and LDL-C. This observation has not been confirmed by others (7)(21)(36) or by the current study.
Intravenous administration of ADMA increased systemic vessel resistance and arterial blood pressure (37), and systolic blood pressure has been found to be related to ADMA (25)(38). These findings, however, have not been confirmed by all studies. Interestingly, acute infusion of ADMA in healthy men, which led to an increase in mean (SD) plasma ADMA from 950 (270) to 22 950 (4910) nmol/L, increased mean arterial pressure from 83.9 (1.1) mmHg to only 88.3 (1.2) mmHg, (39), and mice with low ADMA as a consequence of DDAH overexpression exhibit a modest decrease in blood pressure (40). In the current study, we did not detect increased ADMA in hypertensive patients nor were we able to prove a relationship between ADMA and blood pressure. Taken together, the effect of ADMA on blood pressure may thus be minor.
Increased ADMA has been shown to coincide with other features of the metabolic syndrome (6)(8)(10). Krzyzanowksa and colleagues (24) found ADMA to be significantly increased in women with morbid obesity [n = 34, mean (SD) BMI 49 (1) kg/m2]. We did not detect any such association, however, and therefore suggest that variations in BMI across the commonly observed range would not appreciably affect ADMA.
ADMA has been found to be increased in persons with normotensive insulin-resistance (7) and diabetes mellitus (8). Consistently, ADMA was higher in diabetic than in nondiabetic individuals and inversely related to HDL-C. Finally, our results showed a significant correlation of ADMA with CRP and a tendency toward high ADMA at high fibrinogen. These findings are in line with reports that ADMA is increased in low-grade systemic inflammation (24).
Our attempt to identify confounding nonrandomized medications revealed higher ADMA in users of ACE inhibitors, a result that contrasts with a report suggesting that ACE inhibitors lower ADMA (41). Patients receiving diuretics had higher ADMA than those not on diuretics. Confirming some (42) but not all (36)(43)(44)(45)(46) pertinent earlier work, individuals treated with lipid-lowering drugs (97% statins) had lower ADMA than those untreated. The use of antiplatelet drugs was associated with lower ADMA. Insulin and oral antidiabetics were not related to ADMA, as would have been expected from earlier research (7)(13)(47). We stress, however, that these associations are cross-sectional in nature and do not prove any pharmacological effect of the drugs on ADMA.
So far, few small prospective studies have addressed the predictive value of ADMA for total mortality and cardiovascular mortality. In patients with mild to advanced chronic kidney disease, ADMA was a strong and independent risk marker for progression to ESRD and death (15). Zoccali et al.(3) examined 225 hemodialysis patients with a mean ADMA of 2520 nmol/L (interquartile range 1580–3850 nmol/L). Compared with the 1st and 2nd quartile, HRs for death at ADMA concentrations in the 3rd and 4th quartile were 1.72 and 3.11, respectively. An even higher mean ADMA concentration (3060 nmol/L) and corresponding associations with all-cause mortality and cardiovascular mortality were seen in a subsequent study of the same group (48). The overall risk of death and cardiovascular events is excessive in ESRD. In the 2 ESRD studies (3)(48), the annual mortality rate was nearly 5-fold that in the current study. The high cardiovascular mortality of dialyzed patients is not solely explained by classical risk factors. Uremia-specific risk factors may be important. Findings in ESRD, including interpretation of ADMA concentrations, are therefore difficult to extrapolate to other situations. Although we found relative increments of risk by quartiles of ADMA similar to those in ESRD (3)(48), our median and 75th percentile values of ADMA were one fourth to one fifth of the values in ESRD (3)(48). Thus, our work extends the information on ADMA and all-cause mortality in ESRD to a lower range of ADMA.
In a small nested case-control study of middle-aged nonsmoking men from Eastern Finland with (n = 70) or with no (n = 80) CAD, Valkonen et al. (16) observed a 3.9-fold increase in the risk of cardiovascular events in the highest quartile of ADMA compared with the remaining quartiles. The association of ADMA and acute coronary events was not significant in men with no history of CAD, nor was it significant in smokers. The relationship of ADMA and all-cause mortality was not reported. To compare our results with those by Valkonen et al. (16), we separately considered men and women, individuals who did not have a history of STEMI, and current or previous smokers. ADMA attained virtually identical prognostic importance in women and men. Furthermore, the predictive value of ADMA in former or current smokers was equivalent to that in the entire sample. ADMA also stayed predictive of total mortality in individuals with no previous STEMI (data not shown). Thus, by demonstrating that ADMA predicts all-cause and cardiovascular death in persons at intermediate risk regardless of sex, smoking status, or previous MI, our results add to those of Valkonen et al. (16).
Lu et al. (17) studied ADMA in 153 Chinese stable CAD patients undergoing percutaneous coronary intervention. Consistent with the current study, Lu et al. found ADMA to be associated with future death or nonfatal MI (17), but our study extends their observations by showing an association of high ADMA with adverse outcomes in patients with acute coronary syndromes. Schnabel et al. (18) reported that ADMA was predictive of death from cardiovascular causes or nonfatal MI in patients with CAD. Although their findings are basically consistent with ours, Schnabel et al. did not report on total mortality, nor did they differentiate between individuals presenting in a stable clinical condition or with acute coronary syndromes.
In our cohort total mortality was evidently driven by mortality from cardiovascular causes, and we also observed an association of ADMA with noncardiovascular mortality. Because the number of deaths from noncardiovascular causes was low and because this study was not designed to study diseases other than cardiovascular, this finding should not be considered definite.
The pooled analysis of patients with stable and unstable CAD is a possible limitation of our study. Another study of 48 patients with acute coronary syndromes and 48 healthy volunteers indicated that acute coronary syndromes might increase ADMA (49). Because that study did not include patients with stable CAD, it does not refute our finding of similar ADMA in stable and unstable CAD. Therefore a combined analysis of these groups appears justified and is supported by the fact that the separate analyses of stable and unstable patients in our study yielded very similar HRs.
The observation that ADMA predicts total and cardiovascular mortality in patients with CAD does not prove causality. We identified several biochemical markers of cardiovascular risk correlated with ADMA that may by themselves explain the current findings. Among the confounding factors, GFR may deserve particular attention because impaired renal function represents a cardiovascular risk factor by itself and high ADMA may merely indicate renal dysfunction. Nevertheless, after we controlled for confounding variables in multivariable models and for the use of drugs, ADMA retained predictive power. Other confounders that may be related to ADMA may have been disregarded in this study, however.
Our study population consisted of selectively enrolled middle-aged to elderly Caucasians; therefore the results cannot be generalized to younger persons or other races or ethnicities. That coronary angiography was indicated in each study participant may have produced referral bias. The definition of the coronary artery status, however, may be a strength of the study. The prevalence of clinically asymptomatic coronary atherosclerosis has been reported to be high at 50 years of age. Hence, angiography-based recruitment prevents inadvertent allocation of individuals with significant, clinically unapparent CAD to the control group. Surprisingly, among the study participants classified as having no CAD the major cardiovascular risk factors occurred at a frequency similar to that of the general population. For example, the prevalence of hypertension is close to that found in the German population (50). Diabetes mellitus in our group first appeared to be 2 to 3 times more frequent than in the German population, but this is likely due to the fact that we measured fasting glucose and performed an oral glucose challenge in individuals not known to have diabetes. Based on clinical history or fasting glucose measurements, the National Health and Nutrition Examination surveys 1999–2000 reports prevalences of diabetes mellitus of 9.2% and 19.3% in adults 40–59 or >60 years of age, respectively (51). In the current study, 12.1% of the persons without CAD had diabetes mellitus according to this criterion, and another 5.6% were detected by increased postchallenge glucose.
In this study, the largest to examine ADMA as a predictor of mortality, ADMA was a surprisingly robust predictor of mortality from all causes and from cardiovascular causes. The predictive value of ADMA was similar in patients with stable CAD or acute coronary syndromes and in those with or without history of STEMI. Because the association of ADMA with mortality did not reach statistical significance in persons with no CAD, investigation in asymptomatic persons is warranted.
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Acknowledgments |
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Footnotes |
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