Plasma Asymmetric Dimethylarginine and Incidence of Cardiovascular Disease and Death in the Community
Background— Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction. Although elevated ADMA has been associated with an increased risk of cardiovascular disease events and death in referral samples, the prognostic significance of ADMA in the community has not been adequately evaluated.
Methods and Results— We related plasma ADMA, l-arginine (Arg), and the ratio of Arg to ADMA to the incidence of cardiovascular disease (fatal or nonfatal myocardial infarction, coronary insufficiency, angina pectoris, stroke or transient ischemic attack, intermittent claudication, or heart failure) and death in 3320 Framingham Offspring Study participants (1769 women; mean age, 59 years). Over a follow-up period of 10.9 years, 281 individuals of 2956 free of cardiovascular disease at baseline developed incident cardiovascular disease, and 285 participants died. In multivariable models adjusting for established risk factors and other biomarkers (B-type natriuretic peptide, renin, homocysteine, urine albumin excretion, and C-reactive protein), ADMA and the ratio of Arg to ADMA were significantly associated with all-cause mortality (adjusted-hazard ratio [HR] per 1-SD increment, 1.21; 95% CI, 1.07 to 1.37; and HR per 1-SD increment, 0.80; 95% CI, 0.69 to 0.93, respectively), whereas Arg was not (HR per 1-SD increment, 0.89; 95% CI, 0.77 to 1.02). We noted effect modification by diabetes status; ADMA was associated with death in individuals without diabetes (adjusted HR per 1-SD increment, 1.30; 95% CI, 1.13 to 1.50) but not in individuals with diabetes (adjusted HR per 1-SD increment, 0.85; 95% CI, 0.62 to 1.16). ADMA, Arg, and the ratio of Arg to ADMA were not associated with cardiovascular disease incidence (P>0.10).
Conclusions— In our large community-based sample, ADMA was significantly associated with all-cause mortality, particularly in nondiabetic individuals.
Received August 30, 2008; accepted January 26, 2009.
The endothelium plays a major role in regulating vascular tone, mainly by secreting the potent vasodilator nitric oxide (NO), which is antiatherogenic.1 NO is synthesized from its precursor, l-arginine (Arg), by endothelial NO synthase (NOS).2 NOS is competitively inhibited by asymmetric dimethylarginine (ADMA), an endogenous compound that is elevated in renal failure, cardiovascular disease (CVD), and diabetes mellitus.3,4 A low ratio of Arg to ADMA (Arg/ADMA ratio) is also a marker of endothelial dysfunction. Prospective investigations of ADMA have highlighted its role as a predictor of CVD events or death in patients with established coronary artery disease,5–7 advanced renal failure,8 or other high-risk conditions.9
Clinical Perspective p 1600
Only limited information is available from comparatively small studies regarding whether higher ADMA or a diminished Arg/ADMA ratio is associated with risk of death and CVD events in the general population. Two recent studies10,11 suggested that elevated ADMA is associated with a 2-fold risk of death in nonsmoking healthy men. Given the lack of data on the prognostic significance of ADMA in the community, we related ADMA, Arg, and the Arg/ADMA ratio to the incidence of CVD and death in a large ambulatory community-based cohort, adjusting for traditional risk factors, including newer biomarkers.12
The design of the Framingham Offspring Study has been described previously.13 The 3532 attendees at the sixth examination (1995 to 1998) were eligible for the present investigation. We excluded 212 individuals for the following reasons: serum creatinine >2.0 mg/dL (n=15), unavailable ADMA or Arg (n=79), and missing covariates (n=118). After exclusions, 3320 participants remained eligible. At each heart study examination, participants undergo standardized measurements of blood pressure (BP), anthropometry, medical history, physical examination, and laboratory assessment of risk factors.14 The study protocol was approved by the Institutional Review Board of the Boston University Medical Center and the Ethics Committee of the Hamburg Board of Physicians. All participants provided written informed consent.
Assays for ADMA, Arg, and Other Biomarkers
Laboratory assessment of several biomarkers was conducted on fasting samples drawn at the sixth examination cycle (details are given in the Appendix in the online Data Supplement). Plasma samples that were stored for ≈8 years at −80°C without freeze-thaw cycles were used for mass spectrometric determination of ADMA and Arg using a validated high-throughput liquid chromatographic-tandem mass spectrometric assay.15,16 The following biomarkers were used as covariates because of prior association with CVD/death in our cohort12: high-sensitivity C-reactive protein (CRP), plasma B-type natriuretic peptide (BNP), plasma renin concentration, plasma homocysteine, and the urinary albumin-to-creatinine ratio (UACR) assessed on a spot urine specimen.
The outcomes of interest were incidence of a first CVD event and all-cause mortality during follow-up from the baseline examination through December 2006. Major CVD events included fatal or nonfatal coronary heart disease (myocardial infarction, coronary insufficiency, and angina pectoris), stroke or transient ischemic attack, intermittent claudication, or heart failure. Criteria for these events have been described elsewhere (see the Appendix in the Data Supplement).14
We used multivariable linear regression to relate ADMA and Arg to the following variables: age, sex, systolic and diastolic BPs, hypertension treatment, ratio of total to high-density lipoprotein (HDL) cholesterol, diabetes, body mass index (BMI), glomerular filtration rate (GFR), smoking status, and alcohol consumption. The Modification of Diet in Renal Disease equation17 was used to calculate an estimated GFR (eGFR).
We used Cox regression18 to relate ADMA, Arg, and the Arg/ADMA ratio to the incidence of a first CVD event and death (separate analyses for each biomarker and for each outcome) after confirming the assumption of proportionality of hazards. Individuals with prior CVD were excluded from analyses of incident CVD (leaving 2956 eligible participants) but were eligible for death analyses. We performed pooled sex analyses to maximize statistical power because tests of interaction for sex with these biomarkers were not statistically significant. The biomarkers were normally distributed and analyzed as continuous variables and as quartiles.
Multivariable analyses adjusted for age, sex, diabetes, systolic and diastolic BPs, treatment for hypertension, smoking, ratio of total to HDL cholesterol, and serum creatinine. For CVD analyses, we additionally adjusted for BNP and UACR because these 2 biomarkers have been associated with CVD in our sample.12 For death analyses, we also adjusted for prevalent CVD, BNP, UACR, homocysteine, CRP, and renin (given associations of the last 4 with death in our sample).12 We evaluated the contributions of ADMA, Arg, and the Arg/ADMA ratio to the prediction of CVD and death by evaluating the increment in C statistic (to models incorporating established risk factors and other biomarkers).12
We examined whether the relations of ADMA, Arg, and the Arg/ADMA ratio to CVD/death varied according to age, obesity (BMI ≥30 kg/m2), hypertension, diabetes, smoking, and low eGFR (<60 m/min). A 2-sided value of P<0.05 was considered statistically significant.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
The baseline characteristics of our sample are shown in Table 1. ADMA was positively correlated with Arg (age-, sex-adjusted r=0.30, P<0.0001).
Cross-Sectional Correlates of ADMA
ADMA was associated positively with age, BMI, and smoking but inversely related to diastolic BP (Table 2). Importantly, ADMA was not related to renal function. Arg was positively related to age, male sex, smoking, and eGFR but inversely associated with BMI, diabetes, and alcohol consumption. The Arg/ADMA ratio was positively related to male sex and inversely associated with age, BMI, diabetes, and alcohol consumption. Clinical variables explained only ≈3.5% of interindividual variation in ADMA. All 3 biomarkers studied were only weakly associated with other novel biomarkers included in multivariable models (all pairwise r<0.10, except ADMA and homocysteine, r=0.13).
Relations of ADMA to CVD Incidence
Over a follow-up period of 10.9 years, there were 281 incident CVD events (119 in women) among 2956 individuals at risk. Neither biomarker nor their ratio was associated with CVD incidence (Table 3). These results were similar to multivariable analyses that did not adjust for novel biomarkers (data not shown). There was no effect modification by age, sex, hypertension, obesity, diabetes, smoking, or eGFR. With our sample size and at α=0.05, we had good power (82% and 96%) to detect hazard ratios (HRs) per 1-SD increment of 1.5 and 1.75, respectively. We had limited power to detect HRs <1.5.
Relations of ADMA to All-Cause Mortality
On follow-up, there were 285 deaths among the 3320 at-risk participants. Death rates rose across ADMA quartiles but declined with increasing Arg/ADMA ratio (Table 4). Although ADMA was positively associated with death, Arg was not (Table 4). The Arg/ADMA ratio was inversely associated with death, which was especially evident for the fourth quartile. In analyses adjusting for all covariates other than the novel biomarkers, results were similar to those shown in Table 4 (data not shown). Figure 1 shows the relations of ADMA, Arg, and Arg/ADMA ratio with death using regression splines.
Neither ADMA nor the Arg/ADMA ratio improved the model C statistic incrementally over traditional risk factors (C for models without and with ADMA=0.772 and 0.768, respectively; C for models without and with Arg/ADMA=0.772 and 0.775, respectively) or when other novel biomarkers were added (C for models without and with ADMA=0.805 and 0.801, respectively; C for models without and with Arg/ADMA=0.805 and 0.804, respectively).
Because the pathogenetic mechanism relates to a molecular interaction between ADMA and Arg, we modeled these biomarkers together as quartiles (instead of as a ratio) for display purposes (Figure 2). The increase in risk of death with increasing ADMA was consistent across Arg quartiles. However, this trend was less clear for Arg; the highest risk of death was associated with high ADMA and low Arg, whereas the lowest risk of death was associated with low ADMA and high Arg.
In secondary analyses, we evaluated the associations of the 3 biomarkers to CVD death versus non-CVD death (Tables I and II of the online Data Supplement). We observed strong and statistically significant associations of ADMA (positive) and the Arg/ADMA ratio (inverse) to non-CVD death but did not find a significant association with CVD death. Of note, the lower proportion of deaths resulting from CVD in these analyses is the result of an emphasis on specificity in the adjudication process in the Framingham study, which may have limited our statistical power.
Interaction Between ADMA and Diabetes for Risk of Death
Despite the fact that people with and without diabetes had similar mean ADMA levels (0.553 μmol/L [SD, 0.13 μmol/L] versus 0.546 μmol/L [SD, 0.126 μmol/L], respectively; P=NS), we observed significant interactions between ADMA (and Arg/ADMA ratio) and diabetes for death risk (P=0.03 for both); no such interaction was evident for Arg. Therefore, the analyses of death rates for ADMA and the Arg/ADMA ratio were stratified by diabetes status (Tables 5 and 6⇓). Of 285 deaths, 216 occurred in subjects without diabetes (n=2948), and 69 deaths occurred among individuals with diabetes (n=372). In multivariable analyses, ADMA and the Arg/ADMA ratio were associated with death in participants without diabetes but not in participants with diabetes.
First, higher ADMA and a lower Arg/ADMA ratio were associated with death in our community-based sample. Regression splines confirmed these linear relations. The strength of the association (increase in risk of 21% per 1-SD increase [0.13 μmol/L] in ADMA) is comparable to that for a 4.2-year (0.4 SD) increase in age in our sample. However, we observed no incremental contribution of ADMA to the prediction of risk of death. Prior observations indicate modest increments in the C-statistic with the addition of biomarkers.12 Accordingly, we do not propose ADMA as a predictive marker for death but as an important pathophysiological mechanism. Second, the association of ADMA with death was strongest in participants without diabetes, whereas there was no association in those with diabetes. Third, neither ADMA nor Arg (or their ratio) was associated with CVD incidence in our sample.
Potential Mechanisms Underlying the Association With Death
ADMA is an endogenous inhibitor of all 3 NOS isoforms. ADMA impairs NO production, possibly by competing with Arg for the substrate-binding site of NOS.19
Clinical studies indicate that reduced NO release in the presence of elevated ADMA results in endothelial dysfunction that is reversible by Arg.20,21 A recent study demonstrated that ADMA is a strong determinant of flow-mediated, endothelium-dependent vasodilation in healthy people,22 similar to findings reported in hypercholesterolemic individuals.20 Patients with endothelial dysfunction are at increased risk of CVD/death.23 A systemic infusion of ADMA results in increased peripheral resistance, elevated BP, and impaired cerebral blood flow in healthy people.24,25 Recent studies also indicate that higher ADMA increases death risk in patients who are critically ill as a result of cardiac (eg, cardiogenic shock)26 or noncardiac (eg, septic shock) illnesses,27 suggesting that depletion of Arg accompanied by increased ADMA may be a marker of death risk resulting from cardiovascular or noncardiovascular causes. In secondary analyses, we observed an association of higher ADMA with non-CVD death but not with CVD death. The latter observations are hypothesis generating and warrant evaluation in further studies with a greater number of outcome events.
Interestingly enough, mice that lack all 3 NOS isoforms develop spontaneous myocardial infarction, renal disease, ileus, and glucose intolerance more frequently than wild-type mice or mice lacking a single NOS isoform.28 Because ADMA is a nonselective inhibitor of all 3 NOS isoforms, slight changes in its concentration may affect multiorgan function much more than anticipated from reduced endothelial NOS activity alone, a phenomenon that might also explain the stronger association of ADMA with death than with incident CVD in our cohort. Indeed, recent data show that even small changes in ADMA in the extracellular space, which correspond to the difference between the lowest and highest quartiles of ADMA, or in those between wild-type and dimethylarginine dimethylaminohydrolase (DDAH) transgenic mice are sufficient to induce significant changes in the Arg/ADMA ratio and in NOS activity in cultured endothelial cells.21
In a recent study, ADMA was predictive of death in patients with coronary disease but not in those without coronary artery disease.29 In the Population Study of Women in Gothenburg, ADMA was associated with an HR of 1.12 for death in healthy women,30 which is consistent with our study.
Experimental studies have substantiated the adverse consequences of higher ADMA. Genetically modified mice that overexpress DDAH-1 (the enzyme that clears ADMA) show enhanced NO production,31 whereas heterozygous DDAH-1 knockout mice show impaired NO signaling and pulmonary hypertension, and homozygotes are not viable.32
Taken together, these data may explain the relation between high ADMA and death in our cohort. Our data suggest that ADMA may be a marker of death risk, but its role as a causal factor or as a promising therapeutic target merits further study.
Lack of Association With CVD Incidence: Comparison With the Literature
We did not observe an association of ADMA with CVD incidence. This may be related to a true lack of association or to limited statistical power to discern modest hazards in our sample. In 2 recent studies,10,11 ADMA was positively related to coronary events in nonsmoking men. A recent population-based study of women revealed that those in the highest ADMA quintile (>0.71 μmol/L) had a 29% increased risk of myocardial infarction and stroke over 24 years of follow-up30; however, the incidence curves for women with ADMA above versus below this threshold did not separate until 13 years of follow-up. It is possible that the follow-up period in our study was too short to demonstrate a significant increase in CVD incidence in our sample, which overall had an intermediate risk of vascular events. Previous studies in high-risk samples have shown that ADMA is associated with CVD events in coronary artery disease patients,5,7 patients with peripheral arterial occlusive disease,33 chronic renal disease patients,8 and unselected patients undergoing major elective surgery.34
ADMA and Death: Effect Modification by Diabetes
In prespecified analyses, we observed significant association of ADMA and the Arg/ADMA ratio with death in individuals without diabetes but no association in those with diabetes. There are several possible explanations for these observations. First, studies suggest that in patients with diabetes, ADMA may change with progression of the disease; lower ADMA concentrations are observed during the initial period of mild renal damage and increased GFR,35 whereas levels are higher in diabetes-associated chronic renal failure.36 Second, in some studies, the elevation of ADMA in diabetes may actually have been overestimated because of the technical difficulty of separating ADMA and its biologically inactive isomer, symmetric dimethylarginine, by chromatography.37 Our method was designed to specifically separate dimethylarginines by differences in their mass spectra rather than by differences in retention times and thus allows highly reliable and accurate quantitation of ADMA.16 Third, physiological effects of ADMA in diabetes may be complex. In diabetes, the burden of reactive oxygen species is generated by hyperglycemia in the vessel wall.38 Reactive oxygen species such as superoxide anion or hydrogen peroxide almost instantly react with NO, forming hazardous species like peroxinitrite and nitroxyl anion. In addition, there are conditions in which NOS turns into a generator of oxygen-derived free radicals rather than NO, eg, during substrate depletion or cofactor deficiency.38,39 There is evidence for enhanced NOS-derived free radical production in diabetes.40,41 ADMA competes with Arg for binding to NOS and to the amino acid transporter and thereby reduces intracellular availability of substrate for NOS. Thus, inhibition of NO production by ADMA may result in variable effects in terms of oxidative damage to the vessel wall in diabetes. Additional studies evaluating a larger sample of individuals with diabetes are warranted.
Strengths and Limitations
The strengths of our investigation are its prospective design, longitudinal surveillance for outcomes, and adjustment for novel biomarkers. The biological plausibility that higher ADMA, lower Arg, or a low Arg/ADMA ratio mediates death risk is reflected by the strength of the associations, temporal relations, and the overall consistency of the associations across analyses. Several limitations merit comment. Establishing that ADMA is a “risk factor” for death would require additional mechanistic studies that assess systemic oxidative/nitrosative stress and cause-specific mortality. The modest sample size of participants with diabetes and the limited number of deaths in this group may have limited our statistical power to detect associations in this subgroup. In addition, future studies that compare the relative predictive utilities of endothelial function measures with ADMA may help clarify whether factors other than NO availability may influence CVD risk. Finally, our sample was white of European descent and comprised middle-aged individuals with a vascular risk factor profile consistent with this age group, limiting the generalizability to other ethnicities and to younger and healthier samples.
In our large community-based sample, higher ADMA was significantly associated with all-cause mortality but not with CVD incidence. This relation was observed in individuals without baseline diabetes, whereas no association was noted in persons with diabetes. Additional investigations are warranted to confirm these observations and to elucidate the mechanisms underlying the associations in select strata.
We thank Mariola Kastner and Anna Steenpaß for their technical assistance.
Sources of Funding
This work was supported through National Institutes of Health/National Heart, Lung, and Blood Institute contracts N01-HC-25195, K23-HL074077-01 (Dr Wang), N01HV28178, and 2K24HL04334 (Dr Vasan) and by the Deutsche Forschungsgemeinschaft grant Bo 1431/4-1 (Dr Böger).
Drs Böger, Schwedhelm, and Maas are named as inventors on patents relating to analytical assays for methylarginines and receive royalties from them. The other authors report no conflicts.
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The endothelium plays a major role in regulating vascular tone by secreting the potent vasodilator nitric oxide, which is synthesized from l-arginine (Arg) by endothelial nitric oxide synthase. Nitric oxide synthase is competitively inhibited by asymmetric dimethylarginine (ADMA), an endogenous compound that is elevated in renal failure, cardiovascular disease, and diabetes mellitus. Higher ADMA and low ratio of Arg to ADMA are markers of endothelial dysfunction. Prospective investigations have highlighted the role of ADMA as a predictor of cardiovascular disease events and death in patients with coronary artery disease, renal failure, and other high-risk conditions. Data are limited regarding the relations of ADMA and Arg/ADMA ratio to cardiovascular disease incidence and death in the general population. We related plasma ADMA, Arg, and the Arg/ADMA ratio to the incidence of cardiovascular disease and death in 3320 participants from the community-based Framingham study cohort who were followed up for 10.9 years. In multivariable models adjusting for established risk factors, ADMA was associated positively with death, whereas the Arg/ADMA ratio was inversely related. We noted effect modification by diabetes status; ADMA was associated with death in individuals without diabetes but not in individuals with diabetes. ADMA and the Arg/ADMA ratio were not associated with cardiovascular disease incidence. Additional studies evaluating a larger sample of individuals (including those with diabetes) and with longer follow-up are warranted to confirm these observations.
↵*The first and last authors contributed equally to this work.
Guest Editor for this article was William S. Weintraub, MD.
The online Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.838268/DC1.