Clinical and Population Studies

Symmetrical Dimethylarginine Predicts Mortality in the General PopulationSignificance

Observations From the Dallas Heart Study

M. Odette Gore, Nicole Lüneburg, Edzard Schwedhelm, Colby R. Ayers, Maike Anderssohn, Amit Khera, Dorothee Atzler, James A. de Lemos, Peter J. Grant, Darren K. McGuire, Rainer H. Böger
https://doi.org/10.1161/ATVBAHA.113.301219
Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:2682-2688
Originally published October 16, 2013

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Abstract

Objective—Increased asymmetrical dimethylarginine (ADMA), a NO synthase inhibitor, and its congener symmetrical dimethylarginine (SDMA), predict cardiovascular and all-cause mortality in at-risk populations. Their prognostic value in the general population remains uncertain. We investigated the correlations of SDMA and ADMA with atherosclerosis and cardiovascular/all-cause mortality in the Dallas Heart Study, a multiethnic probability-based cohort aged 30 to 65 years.

Approach and Results—SDMA and ADMA were measured by liquid chromatography-tandem mass-spectrometry (n=3523), coronary artery calcium by electron-beam computed tomography, and abdominal aortic wall thickness by MRI. In unadjusted analyses, categories of increasing SDMA and ADMA were associated with higher prevalence of cardiovascular risk factors, increased risk markers, and all-cause and cardiovascular mortality (median follow-up, 7.4 years). After adjustment for age, sex, and race, traditional cardiovascular risk factors, and renal function, SDMA and ADMA analyzed as continuous variables were associated with coronary artery calcium >10, but only SDMA was associated with abdominal aortic wall thickness. SDMA, but not ADMA, was associated with cardiovascular mortality (hazard ratio per log unit change, 3.36 [95% confidence interval, 1.49–7.59]; P=0.004). SDMA and ADMA were both associated with all-cause mortality, but after further adjustment for N-terminal pro–brain-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity cardiac troponin T, only SDMA was associated with all-cause mortality (hazard ratio per log unit change, 1.86 [95% confidence interval, 1.04–3.30]; P=0.01).

Conclusions—SDMA, but not ADMA, was an independent predictor of all-cause and cardiovascular mortality in a large multiethnic population-based cohort.

Introduction

Asymmetrical dimethylarginine (ADMA) and its congener symmetrical dimethylarginine (SDMA) are endogenous products of methylated protein turnover that are present in the circulation at micromolar levels and have differing clearance pathways.1 ADMA directly inhibits NO synthesis by competitively binding to NO synthases; SDMA and ADMA may also reduce NO synthesis indirectly by inhibiting the cellular uptake of the NO precursor L-arginine.1 NO has multiple functions in the physiology and pathophysiology of the nervous, immune, and cardiovascular systems, including vasodilatatory, antithrombotic, and antiatherogenic effects in the vasculature.2

Elevated circulating ADMA was predictive of death or combined end points such as fatal and nonfatal cardiovascular events in at-risk populations,3 but whether elevated ADMA can predict mortality or cardiovascular events in the general population is less clear. Current evidence is limited to nonsmoking men in 2 small nested case–control studies4,5 and to cohort studies of initially healthy women6 and middle-aged or older individuals.7 The evidence regarding a role for SDMA is scarce. One recent study showed that elevated SDMA, but not ADMA, predicted mortality in patients with ischemic stroke,8 and another suggested that SDMA and ADMA had similar predictive values for a broad cardiovascular composite in a population-based cohort of older individuals (mean age >65 years).9

No data are available on the prognostic significance of SDMA and ADMA in the general population, including younger individuals. Furthermore, prior studies of SDMA and ADMA were conducted primarily in white cohorts,4–9 and the prognostic value of SDMA and ADMA in the general population including other races/ethnicities is uncertain. To address these knowledge gaps, we investigated the correlation of SDMA and ADMA with atherosclerosis, cardiovascular mortality, and all-cause mortality in a multiethnic population-based cohort of individuals aged 30 to 65 years.

Materials and Methods

Materials and Methods are available in the online-only Supplement.

Results

Baseline Cohort Characteristics by Race and Categories of SDMA and ADMA

Selected baseline demographic characteristics and cardiovascular risk factors of study participants are presented in Table I in the online-only Data Supplement for the entire cohort and for the subsets of black and white participants. As shown in Tables II and III in the online-only Data Supplement, common characteristics of increasing SDMA and ADMA levels in univariable analyses included positive associations with increasing age and with higher prevalence of hypertension, current smoking, prior heart failure, coronary heart disease, and stroke. Increasing SDMA and ADMA categories were also positively associated with N-terminal pro–brain-type natriuretic peptide and with cardiac troponin T and inversely associated with glomerular filtration rate. The prevalence of diabetes mellitus and obesity (body mass index ≥30) and plasma levels of C-reactive protein increased across categories of increasing ADMA but had an inverse association with SDMA. The prevalence of hypercholesterolemia and the proportion of study participants with a high 10-year risk of coronary heart disease (Framingham Risk Score >20) increased across categories of increasing SDMA (Table II in the online-only Data Supplement) but were not significantly associated with categories of ADMA (Table III in the online-only Data Supplement).

Association of SDMA and ADMA With Markers of Atherosclerosis

In unadjusted analyses, the prevalence of coronary artery calcium >10 in the study population was associated with both SDMA (odds ratio, 1.4 per SD increase [95% confidence interval (CI), 1.26–1.54]; P<0.0001) and ADMA (odds ratio, 1.2 per SD increase [95% CI, 1.09–1.33]; P=0.0003) analyzed as log-transformed continuous variables. SDMA, but not ADMA, remained significantly associated with coronary artery calcium >10 after adjustment for age, sex, race, and traditional cardiovascular risk factors (odds ratio per SD increase for SDMA, 1.14 [95% CI, 1.02–1.28]; P=0.026; for ADMA, 1.03 [95% CI, 0.92–1.16]; P=0.593), as well as after further adjustment for glomerular filtration rate (odds ratio per SD increase for SDMA, 1.21 [95% CI, 1.06–1.37]; P=0.004; for ADMA, 1.04 [95% CI, 0.91–1.16]; P=0.569). In similar adjusted analyses, aortic wall thickness was associated with both SDMA (P<0.0001) and ADMA (P=0.0104).

Association of SDMA and ADMA With Mortality

A total of 172 all-cause deaths and 67 cardiovascular deaths occurred in the study population during a median follow-up period of 7.4 years (interquartile range, 7.0–7.8 years). The unadjusted cumulative incidence of death at 7 years increased from 1.9% (95% CI, 1.1%–3.2%) in the lowest SDMA cate gory to 9.3% (95% CI, 7.3%–11.6%) in the highest SDMA category (P<0.01) for all-cause mortality (Figure 1A) and from 0.15% (95% CI, 0.02%–1.04%) to 4.1% (95% CI, 2.8%–5.8%; P<0.01) for cardiovascular mortality (Figure 1B). Mortality trends across categories of ADMA were similar but less steep, increasing from 2.8% (95% CI, 1.8%–4.3%) to 7.3% (95% CI, 5.6%–9.5%; P<0.01) for all-cause mortality (Figure 1C) and from 0.70% (95% CI, 0.29%–1.68%) to 2.7% (95% CI, 1.7%–4.2%; P<0.01) for cardiovascular mortality (Figure 1D). Associations of SDMA levels with all-cause mortality remained consistent after exclusion of participants with prevalent cardiovascular disease (CVD), CVD or diabetes mellitus, and CVD or chronic kidney disease, as well as in subgroups defined by sex, diabetes mellitus status, hypertension, obesity, Framingham Risk Score, and coronary artery calcium (Figure 2). Of note, the unadjusted association of SDMA with mortality was evident among blacks, but not among white and Hispanic participants. As compared with SDMA, the same analyses conducted for ADMA yielded fewer statistically significant associations and numerically lower hazard ratios (HRs) for most subgroups (Figure 2).

Figure 1.
Figure 1.

Unadjusted Kaplan-Meier curves for all-cause and cardiovascular mortality across categories of symmetrical dimethylarginine (SDMA; A and B) and asymmetrical dimethylarginine (ADMA; C and D).

Figure 2.
Figure 2.

Unadjusted hazard ratios for all-cause mortality in the highest vs the lowest categories of symmetrical dimethylarginine (SDMA; 0.500–2.690 µmol/L vs 0.010–0.339 µmol/L) and asymmetrical dimethylarginine (ADMA; 0.580–1.323 µmol/L vs 0.020–0.400 µmol/L) in selected subgroups. BMI indicates body mass index; CAC, coronary artery calcium; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease; DM, diabetes mellitus; EBCT, single electron beam-computed tomography; FRS, Framingham Risk Score; and HR, hazard ratio.

In Cox proportional hazards models with serial adjustment for multiple covariates including age, race, and sex (model 1), traditional cardiovascular risk factors (model 2), glomerular filtration rate (model 3), high-sensitivity C-reactive protein and N-terminal pro–brain-type natriuretic peptide (model 4), and high-sensitivity cardiac troponin T (model 5), higher SDMA categories were consistently associated with increasing all-cause and cardiovascular mortality risk across all models (Table 1). The association of SDMA with all-cause mortality was preserved even after exclusion of individuals with prevalent CVD in the fully adjusted model (highest versus lowest SDMA category, HR, 2.44 [95% CI, 1.16–5.17]; P=0.019). Qualitatively similar results were obtained from sensitivity analyses using log-transformed SDMA as continuous variable, including in model 3 for cardiovascular mortality (HR per log unit change, 3.36 [95% CI, 1.49–7.59]; P=0.004) and in the fully adjusted model (model 5) for all-cause mortality (HR per log unit change, 1.86 [95% CI, 1.04–3.3]; P=0.01).

View this table:
Table 1.

Multivariable-Adjusted Associations Between SDMA Categories and All-Cause and Cardiovascular Mortality

The same set of multivariable Cox proportional hazards models applied to ADMA revealed less robust trends of increasing all-cause and cardiovascular mortality risk across categories of increasing ADMA (Table 2). The association of ADMA with all-cause mortality was preserved after exclusion of individuals with prevalent CVD only in model 1 (highest versus lowest ADMA category, HR, 1.86 [95% CI, 1.06–3.26]; P=0.029) but not with further adjustment (models 2–5). Analyses of log-transformed ADMA as continuous variable yielded qualitatively similar results. ADMA was associated with all-cause mortality (HR per log unit change, 2.91 [95% CI, 1.45–5.86]; P=0.003) but not with cardiovascular mortality (HR per log unit change, 2.68 [95% CI, 0.87–8.23] P=0.085) after adjusting for age, sex, race, traditional cardiovascular risk factors, and estimated renal function (model 3). In contrast with SDMA, ADMA analyzed as log-transformed continuous variable did not remain independently associated with all-cause mortality in the fully adjusted model (HR per log unit change, 1.32 [95% CI, 0.42–4.12]; P=0.222).

View this table:
Table 2.

Multivariable-Adjusted Associations Between ADMA Categories and All-Cause and Cardiovascular Mortality

Predictive Value of SDMA and ADMA for All-Cause and Cardiovascular Mortality

After adjustment for age, race, sex, and traditional cardiovascular risk factors (diabetes mellitus, body mass index, hypertension, hypercholesterolemia, history of myocardial infarction or chronic heart failure, and current smoking; model 2), the addition of SDMA to the baseline models significantly improved the C-statistic (0.822 versus 0.815; P=0.049) and integrated discrimination index (0.0192 [95% CI, 0.0093–0.0291]; P=0.0002) for all-cause mortality, as well as the C statistic (0.880 versus 0.858, P=0.014) for cardiovascular mortality (Table 1). The addition of SDMA significantly improved integrated discrimination index (0.0083 [95% CI, 0.002–0.0146]; P=0.01) for all-cause mortality even after additional adjustment for high-sensitivity C-reactive protein, N-terminal pro–brain-type natriuretic peptide, and high-sensitivity cardiac troponin T (model 5). When the same analyses were conducted for ADMA, improvements in the C-statistic were not statistically significant after adjustment for traditional cardiovascular risk factors, and ADMA did not significantly improve integrated discrimination index for all-cause mortality in the fully adjusted model (Table 2).

Discussion

Key Findings

There are 3 major findings from these analyses of a population-based multiethnic cohort comprising >3500 individuals aged 30 to 65 years. First, SDMA was an independent predictor of all-cause and cardiovascular mortality, after multiple adjustments for traditional risk factors, renal function, and other biomarkers. Second, although ADMA was also associated with all-cause mortality, only SDMA remained an independent predictor of mortality after adjustment for other established risk markers associated with death in our cohort, including N-terminal pro–brain-type natriuretic peptide, high-sensitivity C-reactive protein, and cardiac troponin T. Third, SDMA was independently associated with markers of subclinical atherosclerosis, including coronary artery calcium and aortic wall thickness. To our knowledge, this is the first study to demonstrate the prognostic value of SDMA in a multiethnic general population sample, including younger individuals who would most benefit from early risk assessment.

Pathophysiological Context

There is an urgent need for biomarkers that better identify persons at high risk of cardiovascular disease and mortality, to facilitate individualized treatment strategies. Because of its direct inhibitory effect on NO synthesis, the prognostic value of ADMA for cardiovascular events and death has been investigated in multiple studies.3–7 Of these, only one study was sufficiently powered to detect an association between ADMA and all-cause mortality in a community-based population sample that comprised older individuals.7 Our results for ADMA in a relatively younger cohort are consistent with this prior report, suggesting that ADMA is a predictor of all-cause mortality across adult age groups. These findings extend previous reports that ADMA is associated with all-cause mortality in high-risk cohorts.10–12

Unlike ADMA, SDMA does not directly inhibit NO synthesis, and until recently, it has been viewed as a biologically inert molecule that may be a novel marker of renal function because of its close association with glomerular filtration rate.1,13 However, recent experimental data suggest that SDMA may contribute to proinflammatory events in the vascular wall by opening store-operated calcium channels in monocytes and leading to monocyte activation.14

Comparison With Previous Studies

In cohort studies in which SDMA and ADMA were concomitantly assessed, only SDMA was associated with all-cause mortality after ischemic stroke,8 and both SDMA and ADMA had similar predictive values for a com posite end point of all cardiovascular events in a population-based cohort that comprised individuals >65 years.9 In the Framingham Offspring Cohort that comprised mostly older subjects of white descent, only ADMA predicted all-cause mortality.7 The present study is the first to assess the prognostic value of SDMA and ADMA in younger adults, in a multiethnic cohort comprising ≈50% black participants, and the first to demonstrate that SDMA is a better predictor of all-cause and cardiovascular mortality than ADMA in this segment of the general population.

Subgroup analyses revealed a strong association of SDMA with mortality among black participants in our study, whereas the association was no longer statistically significant in the subset of white participants. These differential associations by race may hinge on statistical power because a disproportionate number of the mortality events observed in our study occurred in the subset of black participants, and there were ≈30% more black than white participants in the cohort. However, ethnic differences have been previously reported for SDMA and ADMA in their associations with clinical risk, for example, in their associations with components of the metabolic syndrome,15,16 and could also underpin the apparent discrepancy between the present findings and our previous study in the Framingham Offspring Cohort.7

Limitations

The principal limitations of this study are the relatively small number of cardiovascular deaths, limiting statistical power for analyses of this outcome, and the absence of adjudicated nonfatal cardiovascular outcome data, not yet available from the Dallas Heart Study. In the absence of nonfatal outcome data, we could not conduct a complete evaluation of the incremental predictive value of SDMA and ADMA when added to current risk assessment tools such as the Framingham Risk Score. Other limitations include the measurement of SDMA, ADMA, and other covariates from a single blood sample collected at baseline, and the availability of imaging data for a subset of the overall cohort.

Summary

Our findings in a large multiethnic population-based cohort suggest that SDMA is an independent predictor of all-cause and cardiovascular mortality in the general population and that SDMA has a higher prognostic value than ADMA for these outcomes. The pathophysiological underpinnings of the association between SDMA and mortality require further exploration.

Acknowledgments

The excellent technical assistance of Anna Steenpaß, Mariola Kastner, and Cornelia Woermann in performing the ADMA and SDMA analyses is gratefully acknowledged.

Sources of Funding

This work was supported by the Deutsche Stiftung für Herzforschung (German Heart Research Foundation, E. Schwedhelm). The Dallas Heart Study was supported by the Donald W. Reynolds Foundation and by a General Clinical Research Center grant from the US National Center for Research Resources of the National Institutes of Health (M01-RR00633).

Disclosures

M.O. Gore is supported by a training grant from the US National Heart, Lung and Blood Institute (T32-HL007360). R.H. Böger and E. Schwedhelm are named as inventors on patents relating to ADMA and SDMA assays and receive royalties from them. The other authors report no conflicts.

Footnotes

  • Received January 21, 2013.
  • Accepted August 13, 2013.

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Significance

This is the first study to demonstrate that circulating symmetrical dimethylarginine (SDMA), an endogenous product of methylated protein turnover that may interfere with NO synthesis, is a strong and independent predictor of all-cause and cardiovascular mortality in a relatively young general population sample, particularly among black individuals. SDMA was also associated with markers of subclinical atherosclerosis, including coronary artery calcium and aortic wall thickness. SDMA remained a predictor of mortality in our cohort even after multiple adjustments for traditional risk factors, renal function, and other established risk markers, including N-terminal pro–brain-type natriuretic peptide, high-sensitivity C-reactive protein, and cardiac troponin T measured with a highly sensitive assay. These findings indicate that SDMA is a potentially useful biomarker for clinical risk stratification in the general population and firmly establish the need for further studies of the role of SDMA in the pathophysiology of atherosclerosis and cardiovascular mortality.

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  • Symmetrical Dimethylarginine Predicts Mortality in the General PopulationSignificance
    M. Odette Gore, Nicole Lüneburg, Edzard Schwedhelm, Colby R. Ayers, Maike Anderssohn, Amit Khera, Dorothee Atzler, James A. de Lemos, Peter J. Grant, Darren K. McGuire and Rainer H. Böger
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:2682-2688, originally published October 16, 2013
    https://doi.org/10.1161/ATVBAHA.113.301219
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