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. Author manuscript; available in PMC: 2022 Jun 29.
Published in final edited form as: Clin Biochem. 2020 Jun 4;83:37–42. doi: 10.1016/j.clinbiochem.2020.05.016

Elevated plasma levels of asymmetric dimethylarginine and the risk for arrhythmic death in ischemic and non-ischemic, dilated cardiomyopathy - a prospective, controlled long-term study

Achim Leo Burger 1, Stefan Stojkovic 1, André Diedrich 2, Svitlana Demyanets 3,*, Johann Wojta 1,4,5, Thomas Pezawas 1
PMCID: PMC9242549  NIHMSID: NIHMS1809519  PMID: 32504703

Abstract

Introduction.

Elevated plasma levels of asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase, are associated with adverse outcome. There is no data available, whether ADMA levels are associated with arrhythmic death (AD) in patients with ischemic cardiomyopathy (ICM) or non-ischemic, dilated cardiomyopathy (DCM).

Methods and Results.

A total of 110 ICM, 52 DCM and 30 control patients were included. Primary outcome parameter of this prospective study was arrhythmic death (AD) or resuscitated cardiac arrest (RCA). Plasma levels of ADMA were significantly higher in ICM (p<0.001) and in DCM (p<0.001) patients compared to controls. During a median follow-up of 7.0 years, 62 (32.3%) patients died. AD occurred in 26 patients and RCA was observed in 22 patients. Plasma levels of ADMA were not associated with a significantly increased risk of AD or RCA in ICM (hazard ratio (HR)=1.37, p=0.109) or in DCM (HR=1.06, p=0.848) patients. No significant association was found with overall mortality in ICM (HR=1.39, p=0.079) or DCM (HR=1.10, p=0.666) patients. Stratified Kaplan-Meier curves for ADMA levels in the upper tertile (>0.715 μmol/l) or the two lower tertiles (≤0.715 μmol/l) did not show a higher risk for AD or RCA (p=0.221) or overall mortality (p=0.548). In patients with left ventricular ejection fraction ≤35%, ADMA was not associated with AD or RCA (HR=1.35, p=0.084) or with overall mortality (HR=1.24, p=0.162).

Conclusions.

Plasma levels of ADMA were elevated in patients with ICM or DCM as compared to controls, but were not significantly predictive for overall mortality or the risk for arrhythmic death.

Keywords: asymmetric dimethyl arginine, arrhythmic death, ventricular arrhythmia, sudden cardiac death, risk stratification

INTRODUCTION

Asymmetric dimethylarginin (ADMA) is a competitive inhibitor of the endothelial nitric oxide (NO) synthase (1, 2). Endogenous NO plays a central role in endothelial function. It is a potent vasodilator, carries anti-inflammatory effects and inhibits thrombocyte activation (3–7). Elevated plasma levels of ADMA were associated with adverse outcome in multiple studies that investigated patients with coronary artery disease, chronic kidney disease, diabetes mellitus type II or in the general population (8–12). In addition, previous studies reported that higher plasma levels of ADMA were associated with worse outcome in patients with atrial fibrillation (13, 14), a higher risk for carotid restenosis after endarterectomy (15) and an increased risk of appropriate implantable cardioverter-defibrillator (ICD) interventions (16). So far, no data exists on a potential relationship between elevated plasma levels of ADMA and arrhythmic death (AD). This might be especially relevant for patients with ischemic cardiomyopathy (ICM) or non-ischemic, dilated cardiomyopathy (DCM) and reduced left ventricular ejection fraction (LVEF) who face a high risk for potentially fatal arrhythmic events (17, 18). Current risk stratification for ventricular arrhythmias and the indication for primary preventive ICD implantation is mainly based on the reduction of LVEF (≤35%) (19). However, this cut-off as a risk marker for arrhythmic events has important limitations in sensitivity and specificity (20, 21). The present study tests the hypothesis that elevated plasma levels of ADMA might be associated with an increased risk for AD or resuscitated cardiac arrest (RCA) and might improve prediction of arrhythmic events.

MATERIALS and METHODS

Study population.

This prospective study included a convenience sample of 110 patients with ICM, 52 patients with DCM and 30 controls with normal LVEF. Patients were eligible to participate if they had recently undergone coronary angiography with ventriculography as standard use of care at the physician’s discretion due to typical symptoms, an abnormal echocardiogram or abnormal magnetic resonance imaging. Patients were excluded from participation if they had a history of sustained ventricular arrhythmia or permanent atrial fibrillation or if they were dependent on ventricular pacing. Both groups had to be under optimal medical therapy for at least 8 weeks before study inclusion with reassessment of LVEF afterwards. The treatment of patients was not guided by this study. All study participants provided written informed consent. This research was conducted in compliance with all relevant national regulations, in accordance with the declaration of Helsinki and was approved by the local ethics committee.

Outcome parameters.

Primary outcome parameter of this study was AD or RCA. Only the first event (AD or RCA) was taken for statistical analysis. Secondary outcome parameter was overall mortality. Deaths were evaluated with an adapted form of the Hinkle classification (22). Detailed information on the circumstances of death and abruptness of loss of consciousness were gathered from witnesses, reports from emergency service and records from treating hospital and physician. Family members were interviewed for activities and the condition in the time before death. Autopsy reports were obtained from all deceased study participants. Appropriate ICD therapy without ventricular tachycardia (VT) acceleration that failed to save the patient’s life was classified as AD. An RCA was ventricular fibrillation or VT >240 bpm (beats per minute) leading to syncope before ICD therapy and multiple slower VT episodes (electrical storm) leading to syncope and ICD discharge without ICD therapy related acceleration. All other applied ICD therapies in cases with VT <240 bpm were not taken as surrogate for AD. All ICD devices were programmed to allow maximum possible detection duration.

ADMA measurement.

Venous blood samples were drawn from all patients at study enrollment. Blood samples were centrifuged and stored in aliquots at −80°C. Plasma levels of ADMA were determined with commercially available enzyme-linked immunosorbent assays (ELISA, DLD Diagnostika GmbH, Hamburg, Germany) as previously described and validated against high-performance liquid chromatography coupled to mass spectrometry (23, 24) The ELISA kits have a lower detection limit of 0,03 μmol/l. The intra-assay and inter-assay variation coefficient were 4.9-5.4% and 4.3-9.6%, respectively. Quantification of plasma levels was conducted by a person blinded to clinical outcomes and study endpoints.

Statistical analysis.

Categorical variables are presented as counts and percentages. Continuous variables are presented as median with 1st and 3rd quartile or mean ± standard deviation. For comparison of categorical variables, qui-square or Fisher’s exact test was used. Student’s t-test was applied to compare continuous variables and for comparison of plasma ADMA levels between ICM, DCM and control patients. The association between ADMA levels and the primary and secondary outcome parameters were only investigated in patients with ICM or DCM. Univariable Cox regression model was applied to investigate the association between plasma levels of ADMA and the risk for AD or RCA and for overall mortality. If the effect was significant, a multivariable model including the clinical confounders age, sex, LVEF ≤35%, New York Heart Association (NYHA) class 3 was fitted. Hazard ratios (HR) in the Cox regression models are depicted per 1 unit [nmol/cl] increase of ADMA. Kaplan Meier curves and log-rank tests were calculated to investigate if patients in the upper tertile have a higher risk for AD or RCA and overall mortality compared to patients in the combined two lower tertiles.

RESULTS

Baseline clinical characteristics of the overall study population stratified by the underlying heart disease are depicted in Table 1. During a median follow-up time of 7.0 years [interquartile range (IQR): 5.1-8.4], a total of 62 overall deaths were observed. Of these 62 deaths, 26 patients died of an arrhythmic event. An ICD was implanted in 70 patients at the time of study inclusion. Of the 26 patients who died of an AD, 11 had an ICD implanted, but the device could not abort an electrical storm. A total of 15 patients died of an arrhythmic event without an implanted ICD due to lack of primary preventive ICD indication. RCA occurred in 22 patients of the overall study population. Outcome parameters are depicted in Figure 1.

Table 1.

Baseline clinical characteristics stratified by the underlying heart disease*:

ICM DCM Control p-value
n 110 52 30
FU (years) 7.0 [4.6-7.9] 6.8 [2.3-7.0] 9.0 [8.9-9.0] <0.001
Age 61.7 [55.0-65.7] 57.2 [51.1-63.1] 58.6 [52.9-64.6] 0.066
Sex (male) 99 (90.0) 40 (76.9) 17 (56.7) <0.001
BMI 27.6 [24.8-30.8] 28.0 [25.6-30.8] 26.2 [24.1-29.2] 0.265
NYHA I 27 (24.5) 20 (38.5) 15 (50.0) 0.016
NYHA II 60 (54.5) 22 (42.3) 15 (50.0) 0.347
NYHA III 23 (20.9) 10 (19.2) 0 (0) 0.024
LVEF absolut 34 [28-38] 32 [28-36] 67 [65-72] <0.001
HTN 95 (86.4) 44 (84.6) 23 (76.7) 0.431
DM 2 43 (39.1) 13 (25.0) 2 (6.7) 0.002
CKD 29 (26.4) 15 (28.8) 0 (0) 0.005
HLP 84 (76.4) 27 (51.9) 10 (33.3) <0.001
ICD 61 (55.5) 9 (17.3) 0 (0) <0.001
CRT-P 12 (10.9) 10 (19.2) 1 (3.3) 0.089
QRS >0.12 sec. 36 (32.7) 27 (51.9) 0 (0) <0.001
ACE/ARB 106 (96.4) 49 (94.2) 19 (63.3) <0.001
BB 99 (90.0) 46 (88.5) 18 (60.0) <0.001
Amiodaron 17 (15.5) 8 (15.4) 0 (0) 0.070
Digitalis 16 (14.5) 14 (26.9) 0 (0) 0.005
Diuretics 77 (70.0) 32 (61.5) 7 (23.3) <0.001
Spironolacton 35 (31.8) 28 (53.8) 0 (0) <0.001
ADMA 0.702 ± 0.094 0.601 ± 0.101 0.425 ± 0.114 <0.001
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*

ACE = angiotensin converting enzyme, ADMA = asymmetric dimethyl arginine, ARB = angiotensin receptor blocker, BB = beta blocker, BMI = body mass index, CRT-P = cardiac resynchronisation therapy pacemaker, DCM = dilative cardiomyopathy, DM = diabetes mellitus, FU = follow-up, HLP = hyperlipidemia, HTN = hypertension, ICD = implantable cardioverter-defibrillator, ICM = ischemic cardiomyopathy, LVEF = left ventricular ejection fraction, NYHA = New York heart association;

Figure 1.

Figure 1.

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Flow-chart of primary (AD or RCA) and secondary outcome parameter (overall mortality). AD = arrhythmic death, RCA = resuscitated cardiac arrest

Group comparison.

Individuals with ICM and DCM had significantly higher plasma levels of ADMA compared to control patients (p<0.001, Figure 2). Plasma ADMA was significantly higher in ICM patients compared to DCM patients (p<0.001, Figure 2).

Figure 2.

Figure 2.

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Boxplots showing plasma ADMA levels in patients with ICM, DCM and control patients. ADMA = asymmetric dimethylarginine, DCM = dilated cardiomyopathy, ICM = ischemic cardiomyopathy

Plasma levels of ADMA and AD or RCA.

Plasma levels of ADMA were not higher in patients who died an AD or RCA (0.69±0.10 μmol/l) compared to patients without an arrhythmic event (0.66±0.11 μmol/l, p=0.076). Univariable Cox regression revealed that plasma levels of ADMA were not associated with an increased risk of AD or RCA (hazard ratio (HR)=1.28, 95% confidence interval (CI): 0.96-1.70; p=0.096). Stratified to the underlying heart disease, plasma levels of ADMA were not associated with an increased risk of AD or RCA in ICM (HR=1.37, 95%CI: 0.93-2.00, p=0.109) or in DCM patients (HR=1.06, 95%CI: 0.59-1.89, p=0.848). Kaplan Meier curves were calculated in patients divided into the upper tertile (>0.715 μmol/l) of ADMA levels and into the combined two lower tertiles (≤0.715μmol/l). Patients with ADMA levels in the upper tertile did not have a higher risk for AD or RCA compared to patients in the combined two lower tertiles (p=0.221, Figure 3). After 8 years of follow-up, the cumulative risk for AD or RCA was 41.7% in patients with ADMA levels in the upper tertile and 30.3% in patients with ADMA levels in the two lower tertiles. In the subgroup of patients with LVEF ≤35% (n=109), plasma levels of ADMA were not associated with an increased risk of AD or RCA (HR=1.35, 95%CI: 0.96-1.90, p=0.084).

Figure 3.

Figure 3.

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Kaplan Meier curves demonstrating the association between AD or RCA and plasma levels of ADMA stratified to the upper tertile (>0.715 μmol/l) and the combined two lower tertiles (≤0.715 μmol/l). AD = arrhythmic death, ADMA = asymmetric dimethylarginine, RCA = resuscitated cardiac arrest

Plasma levels of ADMA and overall mortality.

Plasma levels of ADMA were significantly higher in patients that died (0.68±0.10 μmol/l) compared to patients without an event (0.61±0.15 μmol/l, p<0.001). Univariable Cox regression demonstrated that elevated plasma levels of ADMA were not associated with a significantly increased risk of overall mortality (HR=1.15, 95% CI: 0.90-1.46, p=0.266). Stratified to the underlying heart disease, plasma levels of ADMA were not associated with an increased risk for death in ICM (HR=1.39, 95%CI: 0.96-2.02, p=0.079) or in DCM (HR=1.10, 95%CI: 0.71-1.10, p=0.666) patients. Kaplan Meier plots were calculated to compare patients in the upper tertile (>0.715 μmol/l) of ADMA levels with the combined two lower tertiles (≤0.715μmol/l). Kaplan Meier analysis did not reveal a significant difference in overall mortality between patients in the upper tertile and the two lower tertiles (p=0.548, Figure 4). In the patient group with LVEF ≤35%, plasma levels of ADMA were not associated with an increased risk of death (HR=1.28, 95%CI: 0.92-1.67, p=0.162).

Figure 4.

Figure 4.

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Kaplan Meier curves demonstrating the association between overall mortality and plasma levels of ADMA stratified to the upper tertile (>0.715 μmol/l) and the combined two lower tertiles (≤0.715 μmol/l). ADMA = asymmetric dimethylarginine

DISCUSSION

This prospective, controlled observational cohort study investigated the prognostic value of circulating ADMA for the prediction of arrhythmic death and overall mortality during a median follow-up time of 7 years. Plasma levels of ADMA were significantly higher in patients with ICM and DCM compared to control subjects (25, 26). Nevertheless, plasma ADMA was not associated with a significantly increased risk for arrhythmic death and overall mortality.

Ventricular tachyarrhythmia frequently occurs in patients with ICM or DCM and severely reduced LVEF and often requires ICD intervention (17, 27–30). Risk stratification for ventricular arrhythmias based on LVEF is widely acknowledged and respective guidelines recommend primary preventive implantation of an ICD in patients with structural heart disease and LVEF ≤35% (19). However, this cutoff is associated with important shortcomings in sensitivity and specificity (20, 31). Numerous invasive and non-invasive methods have been evaluated to refine risk stratification for ventricular arrhythmias, including microvolt T-wave alternans, signal averaged electrocardiogram, baroreflex testing, biomarkers and diastolic function (20, 32–36). To the best of our knowledge, the present study is the first study that investigated a potential role of ADMA in the prediction of arrhythmic death during long-term follow-up.

The pathophysiology of ventricular tachyarrhythmia in ICM and DCM patients encompasses a wide range of mechanisms with complex and dynamic interactions between anatomical/structural and functional characteristics (37, 38). The multifactorial origin of ventricular tachyarrhythmia can be attributed to structural alterations of the myocardium (LVEF reduction, ventricular hypertrophy, scars, fibrosis), multiple electrophysiological properties (abnormal automaticity, reentry mechanisms), variations in autonomic tone and ion channel function (19, 37–42). ADMA is a strong inhibitor of the endothelial NO system, which subsequently decreases endothelial function (1, 2). Previous studies reported that endothelial dysfunction is associated with significant worse outcome in heart failure patients, induces adverse left ventricular remodeling and LV dysfunction (43–45). In previous trials and a recent meta-analysis, elevated plasma levels of ADMA were associated with a significantly increased risk for overall and cardiovascular mortality in different subgroups with coronary heart disease, heart failure or chronic kidney disease and with worse outcome in patients with atrial fibrillation (8, 13, 46–48). In addition, Lehmann et al. demonstrated that higher levels of ADMA were associated with higher rates of appropriate ICD interventions (16).

The present study corroborated that patients with ischemic cardiomyopathy or non-ischemic, dilated cardiomyopathy show elevated levels of ADMA compared to healthy subjects (25, 26). In addition, plasma ADMA levels were significantly higher in patients that died during follow-up (46, 49). However, plasma ADMA levels were not significantly predictive for arrhythmic death or overall mortality, although a statistical trend was observed. The significant association between ADMA levels and ICD interventions demonstrated by Lehmann et al (16), may be a result of their combined endpoint of appropriate antitachycardia pacing and shock therapy, whereas the present study focused on the occurrence of arrhythmic death or resuscitated cardiac arrest. Nevertheless, the study by Lehman et al (16), and the findings of the present study might suggest that ADMA has a potential role in risk prediction for ventricular arrhythmias. Further prospective trials with larger study populations are warranted to verify the definite role of ADMA in risk stratification for arrhythmic death.

Study limitations.

This prospective, observational cohort study analyzed whether quantification of plasma levels of ADMA improves prediction of fatal arrhythmic events. Outcome parameters were carefully evaluated. However, some events classified as RCA may have not been fatal. In addition, the rather small sample size of the present study warrants further evaluation of ADMA in risk prediction for arrhythmic death in random samples with size calculation and larger study populations. It would be of considerable interest to analyze the prognostic value of ADMA with adequately powered sample sizes in different aetiologies and cardiomyopathies, which might have different plasma levels of ADMA.

Conclusion.

The present study demonstrated that patients with ICM or DCM have elevated plasma levels of ADMA compared to control patients. We did not find a significant association between plasma ADMA levels and an increased risk for arrhythmic death, although a statistical trend was observed. Larger prospective trials are warranted to clarify the definite role of ADMA in risk prediction for arrhythmic events.

Acknowledgements:

No other person has made substantial contributions to the manuscript.

Funding:

Research reported in this publication was partly supported by the National Institute of Health (NIH) under Award Number R01 HL142583 (co-author AD) and is solely the responsibility of the authors and does not necessarily represent official views of the NIH. All authors had access to all of the data in the study and take responsibility for the integrity and the accuracy of the data analysis. The NIH had no role in planning the study design, in the collection, analysis and interpretation of data, in writing the report and the decision to submit for publication.

Footnotes

Statement for all authors: There is no conflict of interest. All authors have seen and approved the paper. Authors take responsibility for all aspects of the reliability and freedom of bias of the data presented and their discussed interpretations.

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