Author + information
- Received April 28, 2016
- Revision received April 17, 2018
- Accepted May 10, 2018
- Published online August 6, 2018.
- John D. Horowitz, MBBS, PhDa,∗ (, )@UniofAdelaide,
- Raffaele De Caterina, MD, PhDb,c,
- Tamila Heresztyn, BSca,
- John H. Alexander, MDd,
- Ulrika Andersson, PhDe,
- Renato D. Lopes, MD, PhDd,
- Philippe Gabriel Steg, MDf,g,h,i,
- Elaine M. Hylek, MD, MPHj,
- Puneet Mohan, MD, PhDk,
- Michael Hanna, MDk,
- Petr Jansky, MDl,
- Christopher B. Granger, MDd,
- Lars Wallentin, MD, PhDe,m,
- on behalf of the ARISTOTLE Investigators
- aCardiology Unit, Basil Hetzel Institute, Queen Elizabeth Hospital, University of Adelaide, Adelaide, South Australia, Australia
- bG. d’Annunzio University, Chieti, Italy
- cG. Monasterio Foundation, Pisa, Italy
- dDuke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
- eUppsala Clinical Research Center, Uppsala, Sweden
- fINSERM-Unité 698, Paris, France; Assistance Publique-Hôpitaux de Paris, Paris, France
- gDépartement Hospitalo-Universitaire FIRE, Hôpital Bichat, Paris, France
- hUniversité Paris-Diderot, Sorbonne-Paris Cité, Paris, France
- iNHLI Imperial College, ICMS, Royal Brompton Hospital, London, United Kingdom
- jBoston University Medical Center, Boston, Massachusetts
- kBristol-Myers Squibb, Princeton, New Jersey
- lCardiovascular Centre, University Hospital Motol, Prague, Czech Republic
- mDepartment of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
- ↵∗Address for correspondence:
Dr. John D. Horowitz, Cardiology and Clinical Pharmacology Unit, Basil Hetzel Institute, Queen Elizabeth Hospital, University of Adelaide, Woodville Road, Woodville, SA 5011 Australia.
Background There is little mechanistic information on factors predisposing atrial fibrillation (AF) patients to thromboembolism or bleeding, but generation of nitric oxide (NO) might theoretically contribute to both.
Objectives The authors tested the hypothesis that plasma levels of the methylated arginine derivatives asymmetric and symmetric dimethylarginine (ADMA/SDMA), which inhibit NO generation, might be associated with outcomes in AF.
Methods Plasma samples were obtained from 5,004 patients with AF at randomization to warfarin or apixaban in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. ADMA and SDMA concentrations were measured by high-performance liquid chromatography. Relationships to clinical characteristics were evaluated by multivariable analyses. Associations with major outcomes, during a median of 1.9 years follow-up, were evaluated by adjusted Cox proportional hazards models.
Results Both ADMA and SDMA plasma concentrations at study entry increased significantly with patients’ age, female sex, renal impairment, permanent AF, or congestive heart failure. ADMA and SDMA increased (p < 0.001) with both increased CHA2DS2-VASc and HAS-BLED scores, but decreased in the presence of diabetes. On multivariable analysis adjusting for established risk factors and treatment, tertile groups of ADMA concentrations were significantly associated with stroke/systemic embolism (p = 0.034), and death (p < 0.0001), whereas tertile groups of SDMA were associated with major bleeding and death (p < 0.001 for both). Incorporating ADMA and SDMA into CHA2DS2-VASc or HAS-BLED predictive models improved C-indices for those outcomes. Neither ADMA nor SDMA predicted differential responses to warfarin or apixaban.
Conclusions In anticoagulated patients with AF, elevated ADMA levels are weakly associated with thromboembolic events, elevated SDMA levels with bleeding events and both are strongly associated with increased mortality. These findings suggest that disturbances of NO function modulate both thrombotic and hemorrhagic risk in anticoagulated patients with AF. (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]; NCT00412984)
Atrial fibrillation (AF), the prevalence of which increases markedly with age, is a well-recognized risk factor for thrombotic cerebrovascular accident (CVA) and for cardiac death (1,2). The pathogenesis of AF, once regarded as consisting essentially of atrial distension and resultant electrical “remodeling,” is now recognized to include disturbances of cardiovascular physiology, such as endothelial dysfunction and inflammatory activation. Impaired nitric oxide (NO) signaling (3,4) and increased release of myeloperoxidase (MPO) within atria (5) may play important roles. On the other hand, pathophysiological understanding of the thromboembolic complications of AF has remained limited. Indeed, the risk of CVA in AF is generally estimated using clinical algorithms such as the CHADS2 and CHA2DS2-VASc scores (6,7) rather than results of mechanistic evaluation. Similarly, the risk of major bleeding in anticoagulant-treated AF patients is generally predicted by the clinically based HAS-BLED score (8). Implicit in the utility of these clinically based scores is the contribution of their components (for example, advanced age, associated hypertension, heart failure, diabetes mellitus, and female sex) to the thrombotic risk. One potential mechanism for this association might be disturbance of endothelial function. In particular, diminution of NO generation and/or signaling can arise as a consequence of inflammatory activation, with “scavenging” of NO by reactive oxygen species (9). This has been observed with normal aging and indeed in association with most of the clinical risk factors for AF (10,11). We have recently demonstrated that recent onset of AF is associated with marked diminution of platelet responsiveness to NO, perhaps reflecting inflammatory activation (12–14).
Impaired generation of NO, with consequent endothelial dysfunction, may be mediated by the methylated arginine derivative asymmetric dimethylarginine (ADMA), which functions in part as a competitive inhibitor of nitric oxide synthase (NOS) (11,15). Increased plasma concentrations of ADMA occur in many forms of heart disease (16,17), and represent independent markers of morbidity and mortality in these conditions. Although less potent than ADMA in inhibiting NOS, the symmetrical analogue symmetric dimethylarginine (SDMA) also has been shown to represent a risk marker in several forms of cardiovascular disease (18,19).
On the basis of these premises, the currently reported investigation, carried out as a prospectively pre-defined substudy of the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial (20), was conducted:
1. To evaluate the potential relationships between plasma ADMA and SDMA concentrations and outcomes in anticoagulated patients with chronic AF; and
2. To determine whether clinical risk factors and published risk algorithms, both for thromboembolism and for bleeding risk, are associated with ADMA or SDMA concentrations.
The ARISTOTLE trial
The ARISTOTLE trial (20) enrolled 18,201 patients with AF and at least 1 CHADS2 risk factor for stroke. The trial was based on a double-blind, placebo-controlled comparison between dose-adjusted warfarin and apixaban 5 mg (2.5 mg at higher age, higher creatinine, or low body weight) twice-daily therapy. The primary efficacy endpoint was stroke or systemic embolism, and the primary safety endpoint major bleeding. The follow-up lasted a mean of 1.9 years. The trial results have been published, showing relative reductions of 21% for stroke or systemic embolism, 31% for major bleeding, and 11% for mortality (20). The study contained a pre-defined biomarker program in which plasma samples were obtained at randomization. A pre-planned subset of the biomarker program included blood sampling from 5,000 patients for the ADMA/SDMA substudy. All patients provided informed consent, and the trial was approved by institutional review boards or ethics committees.
Endpoints and clinical risk classification
Clinical scores of thromboembolic risk (CHADS2 and CHA2DS2-VASc) and of bleeding risk (HAS-BLED) were calculated for each patient based on risk factors present at randomization. The clinical endpoints were evaluated by an independent event adjudication committee. Pre-defined criteria for the main endpoints, including stroke and systemic embolism, acute myocardial infarction, all-cause mortality, cardiovascular death (excluding hemorrhagic stroke), and International Society on Thrombosis and Haemostasis (ISTH) major bleeding, have been published (21).
Venous blood samples were drawn by venesection from patients (N = 5,004) participating in the ARISTOTLE study at the time of study entry. For this ADMA/SDMA substudy, samples were placed in heparinized tubes, centrifuged, and the plasma stored frozen in aliquots. The samples were later transported frozen to the assaying laboratory (Cardiology Laboratory, Basil Hetzel Institute, Adelaide, Australia).
Determination of ADMA and SDMA concentrations utilized derivatization with AccQ-Flor to generate stable fluorescent derivatives, which were assayed by high-performance liquid chromatography (22). The coefficients of variability for replicate estimates were 7% for both ADMA and SDMA concentrations.
Demographics and other variables among the patients participating in the ADMA/SDMA substudy were summarized by using median values and 25th/75th percentile values for continuous variables and frequencies for categorical variables. Differences across biomarker tertile groups were compared using the chi-square test for categorical variables and analysis of variance for continuous variables.
Multivariable linear regression with natural logarithm of the ADMA/SDMA level as response variable and categorized baseline characteristics as independent variables was used to investigate the independent effect of each variable. Model-adjusted estimates were consequently presented as geometric means, and differences between groups as ratios of geometric means.
Efficacy analyses included all patients participating in the substudy and all events from randomization until efficacy cutoff date. Bleeding analyses were on-treatment, including all patients who received at least 1 dose of the study drug and all events within 2 days after the last dose of study drug.
Outcomes in relation to ADMA and SDMA in tertile groups and as continuous variables were evaluated both in simple and in multivariable Cox proportional hazards models. Multivariable analyses included established clinical risk factors (age, sex, hypertension, diabetes mellitus, congestive heart failure, previous stroke, systemic embolus, or transient ischemic attack, creatinine clearance, history of clinical relevant bleeding, and treatment with antiplatelet or nonsteroidal anti-inflammatory agent at randomization) and randomized treatment.
The increased discriminative value of ADMA and SDMA was assessed by estimating the C-indices for models with and without these measures. In addition to the multivariable models, models including the CHA2DS2-VASc score or HAS-BLED score and randomized treatment were analyzed. The HAS-BLED score was calculated excluding labile International Normalized Ratio.
Interactions with randomized treatment were evaluated by adding interaction terms to Cox proportion hazards models including randomized treatment and ADMA or SDMA. Kaplan-Meier estimates of the cumulative hazard rate were calculated and plotted. All event rates were reported per 100 patient-years of follow-up. A 2-sided p value of <0.05 was considered statistically significant, and there were no adjustments for multiple comparisons because the analyses were exploratory. All statistical analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, North Carolina).
The patients in this substudy were representative of the characteristics of the entire ARISTOTLE study cohort, with the exceptions that relatively few patients from outside Europe or North America were included and that the incidence of thromboembolism was lower in the substudy patients (Online Table 1). Median plasma ADMA concentration was 0.608 μmol at baseline, with tertile group ranges of <0.567, 0.567 to 0.653, and >0.653 μmol/l. Median SDMA concentration was 0.560 μmol/l, with tertile group ranges of <0.505, 0.505 to 0.632, and >0.632 μmol/l. There was a direct correlation (r = 0.47; p < 0.0001) between ADMA and SDMA concentrations.
As shown in Tables 1 and 2, ADMA concentrations increased significantly with age, were greater in females than males, were inversely related to creatinine clearance, and tended to be elevated in the presence of heart failure and persistent/permanent AF. However, not all components of the CHADS2 and CHA2DS2-VASc incidences were directly related to ADMA concentrations: ADMA concentrations tended to be lower in diabetic patients, whereas a prior diagnosis of hypertension was not significantly associated with ADMA concentrations.
SDMA concentrations (Tables 1 and 2) also increased with age, but were greater in males than females. As with ADMA, SDMA levels were inversely related to creatinine clearance, and were significantly elevated in the presence of heart failure. Diabetes was associated with significantly lower SDMA levels, whereas a history of hypertension was associated with significant elevation of SDMA levels. Previous myocardial infarction was strongly associated with elevated SDMA levels, as was prior stroke.
The results of these individual associations were that ADMA and SDMA levels tended to increase with both CHADS2 and CHA2DS2-VASc scores, as well as with HAS-BLED scores (p < 0.001 for all).
During the course of the study, stroke or systemic embolism occurred in 136 patients (1.12%/year), in the evaluated subset, ISTH major hemorrhage in 262 patients (2.43%/year), and 471 (3.77/year) died. The rates of these outcomes were similar to those occurring within the entire ARISTOTLE cohort. The associations between plasma ADMA and SDMA concentration tertile groups on major outcomes in the ARISTOTLE trial are summarized in Figures 1, 2⇓⇓, and 3 and Table 3. These risk- and treatment-adjusted models indicate that increasing tertile groups of ADMA concentrations were predictive of stroke/systemic embolism rates, whereas SDMA concentrations were strongly and directly predictive of risk of major bleeds. Both ADMA and SDMA concentrations were directly related to risk of both total and cardiovascular death, whereas neither ADMA nor SDMA concentrations significantly predicted risk of acute myocardial infarction.
Adjustment of ADMA associations for variability in SDMA somewhat attenuated associations with stroke/systemic embolism (p = 0.069), total death (p = 0.025), and cardiovascular death (p = 0.023). However, adjustment of SDMA associations for ADMA did not affect tertile group associations with major bleeding (p = 0.0006), total death (p = 0.002), and cardiovascular death (p = 0.0012).
The impact on C-index values of addition of ADMA and SDMA levels to models including randomized treatment and CHA2DS2-VASc or HAS-BLED scores, is summarized in Table 4. Both ADMA and SDMA increased the C-index for total mortality, cardiovascular death and for major bleeding. Neither ADMA nor SDMA levels predicted differential responses to warfarin compared with those to apixaban (Figures 4 and 5).
The main findings of this study, summarized in the “Message and Clinical Context” presentation (Online Appendix), are:
1. Both plasma ADMA and SDMA concentrations are directly correlated with age, female sex, and heart failure, and also with CHADS2, CHA2DS2-VASc, and HAS-BLED scores.
2. On multivariable analysis, elevated levels of ADMA, but not of SDMA, are associated with the risk of stroke/systemic embolism, whereas SDMA, but not ADMA, is associated with the risk for major bleeding.
3. Both ADMA and SDMA levels are associated with total and cardiovascular mortality even in the presence of information from clinical risk indicators.
To date, identification of risk factors for stroke and systemic embolism, major bleeding, and mortality in patients with chronic AF treated with oral anticoagulation has been derived primarily from a number of clinical studies, which retrospectively have identified a number of clinically based factors (7,8). On the other hand, many of the key variables included among these risk factors are known to be associated with endothelial dysfunction (23), a condition associated first and foremost with impaired NO signaling, whether due to reduced NO generation or to increased “scavenging” of NO by superoxide anion. In a recently reported study (24), it was found that the occurrence of AF in the general population was associated with elevation of plasma ADMA concentrations. This ARISTOTLE substudy was designed to test the hypothesis that elevated plasma ADMA and SDMA concentrations might represent independent biochemical risk factors for CVA, major hemorrhage, and mortality thereby contributing to the predictive value of the clinical parameters in current empiric scoring methods.
The results of the study demonstrated that both plasma ADMA and SDMA concentrations correlated significantly and directly with CHADS2 and CHA2DS2-VASc scores. These correlations were driven primarily by strong direct correlations with some, but not all, of the clinical parameters in these scores. For example, there was an inverse correlation with the presence of diabetes mellitus. These findings are consistent with those of previous investigators, who have found that in general, ADMA levels are not elevated in diabetes (25,26). Therefore, ADMA and SDMA concentrations do not represent the sole biochemical bases for the relationships between the CHADS2 and CHA2DS2-VASc scores and thromboembolic outcomes in AF.
On the other hand, even when adjusting for the important clinical risk factors, the plasma ADMA concentration was independently associated with the risk for stroke and systemic embolism, whereas the SDMA concentration was independently associated with the risk of major hemorrhage; and finally, both markers were associated with cardiovascular and total mortality. Thus, both ADMA and SDMA plasma concentrations represent interesting biomarkers furthering understanding of the causes of thrombotic and bleeding events in patients with AF during anticoagulant therapy. The apparently negative data regarding association between ADMA concentrations and risk of AMI are somewhat limited by the relatively small numbers of AMI cases.
Although plasma ADMA concentrations may not be precisely representative of local tissue concentrations, there is strong evidence that changes in plasma ADMA concentrations correlate with variability in activation of NOS, and that plasma ADMA concentration can therefore be regarded as a biochemical measure of endothelial dysfunction (25,27,28). ADMA is cleared by a combination of renal excretion and by metabolism. Dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that plays a primary role in ADMA metabolism, is inhibited by oxidative stress (29), and there is evidence that MPO, an enzyme of leukocyte origin that has been implicated in the pathogenesis of AF, may inactivate DDAH (9). Determination of concentrations and activity of both DDAH and MPO might have helped to further delineate the precise mechanism(s) whereby ADMA concentrations modulate outcomes in chronic AF. In the absence of such evaluations, the mechanistic construct outlined in the Central Illustration remains somewhat putative. It is thus possible that elevation of ADMA levels may result in part from MPO release. On the other hand, there is no general agreement as to the precise mechanism(s) of interaction between ADMA and NOS, and specifically to what extent ADMA may act simply by reducing NO formation as distinct from inducing NOS “uncoupling” (30). The observed association between ADMA levels and the risk of stroke might be a corollary to the concept that ADMA concentrations represent an independent index of thrombotic risk in coronary disease (16,17,31), where small increases in ADMA concentrations seem to correspond to substantial increments in event rates (31).
In this study, SDMA concentration was not independently associated with stroke, but was independently associated with both ISTH major bleeding and cardiac and total death. These data extend the limited previous information on SDMA as a prognostic marker. In a previous smaller study of AF patients, SDMA, rather than ADMA, levels were found to be independently associated with the combined endpoint of ischemic stroke and cardiac death (32). SDMA levels also appear to be predictive of mortality after stroke (33). Furthermore, SDMA has been shown previously to represent a risk marker for all-cause mortality in the KAROLA (Langzeitfolge der Kardiologischeschen Anschlussheilbehandlung) (34) and Dallas Heart (35) studies, and to predict the extent of coronary calcification in the general population. The strength of the association between SDMA levels and outcomes in the current study is all the more remarkable because of the ongoing controversy related to the biological actions of SDMA. Indeed, it has been suggested that SDMA may be biologically inert (36) and that plasma SDMA levels may essentially represent measures of renal dysfunction (37,38). However, in the current dataset, the prognostic implications of SDMA levels were evaluated after correcting for variability in renal function. Furthermore, SDMA appears to be more than just a weak, indirect, NOS inhibitor (37). It may increase oxidative stress and thus act as an NO “scavenger.” SDMA appears to exert proinflammatory effects (39), and even though these have not been extensively defined to date, the current data suggest that these effects may be relevant to the clinical course of AF. Similarly, a recent study in patients with chronic renal disease (40) demonstrated an association between elevation of SDMA levels and impairment of flow-mediated dilatation.
Our study, therefore, shows that plasma concentrations of both ADMA and SDMA are independently associated with the risk of adverse events in anticoagulated patients with AF after adjusting for clinical risk factors. It remains to be determined whether either ADMA or SDMA levels might maintain independent associations and eventually represent clinically useful biomarkers in comparison or conjunction with other established biomarkers for outcomes in AF (41,42). It must be noted that the observed association between ADMA concentrations and risk of thromboembolism, although statistically significant, is relatively weak, suggesting involvement of other mechanisms in risk. Still, the present findings emphasize that both endothelial dysfunction and inflammatory activation affect both pathogenesis, as well as stroke and bleeding outcomes in anticoagulated patients with AF. Indeed, recent studies in endothelial cells suggest that ADMA may also increase oxidative stress, via “uncoupling” of NO synthase (30,43).
The main limitations of this study relate to the pathophysiological implications of the findings, rather than to the predictive utility of ADMA/SDMA concentrations in patients with AF. As indicated earlier, the investigation did not include full delineation of the biochemical mechanisms of action of ADMA and SDMA in this circumstance. Furthermore, it was not possible within this study design to determine whether the observed associations with cardiovascular endpoints reflect causative effects of ADMA and SDMA.
In anticoagulated patients with AF, elevated ADMA levels are associated with thromboembolic events (although this is not a strong association), elevated SDMA levels with bleeding events, and both associated with increased mortality. These findings suggest that disturbances of NO function modulate both thrombotic and hemorrhagic risk in anticoagulated patients with AF.
COMPETENCY IN MEDICAL KNOWLEDGE: Risk factors for thromboembolism in patients with AF are associated with endothelial dysfunction and inflammation. Plasma concentrations of both ADMA and SDMA correlate with the risk of stroke and bleeding, supporting a role for nitric oxide deficiency in the pathogenesis of these events.
TRANSLATIONAL OUTLOOK: Further studies are needed to determine the clinical utility of measuring ADMA and SDMA concentrations to improve risk stratification and guide clinical decision making in patients with AF.
Editorial assistance was provided by Ebba Bergman, PhD, and Sanne Carlsson, BA, BSc, at UCR, Sweden, with funds from Bristol-Myers Squibb and Pfizer.
The ARISTOTLE trial and this substudy were funded by Bristol-Myers Squibb and Pfizer Inc. Dr. De Caterina has received institutional grant support from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo; honoraria and lecture fees from Bristol-Myers Squibb/Pfizer; consulting fees and honoraria from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Merck, and Novartis; and has served as a steering committee member for Bristol-Myers Squibb/Pfizer. Dr. Alexander has received institutional research grants from Bristol-Myers Squibb, Merck, Pfizer, Boehringer Ingelheim, CSL Behring, National Institutes of Health, Regado Biosciences, Sanofi, Tenax Therapeutics, and Vivus Pharmaceuticals; and consulting fees and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Ortho-McNeil-Janssen, Pfizer, Portola Pharmaceuticals, Regado Biosciences, and Sohmalution. Dr. Andersson has received an institutional research grant from Bristol-Myers Squibb/Pfizer. Dr. Lopes has received institutional grant support from Bristol-Myers Squibb and GlaxoSmithKline; consulting fees from Bayer, Boehringer Ingelheim, and Pfizer; and honoraria from Merck and Portola. Dr. Steg has received institutional research grants from Merck, Sanofi, and Servier; honoraria and nonfinancial support from AstraZeneca, Sanofi, and Servier; and honoraria from Amarin, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Medtronic, Janssen, The Medicines Company, CSL-Behring, Regeneron, and GlaxoSmithKline; and is a stockholder in Aterovax. Dr. Hylek has served as an advisory board member for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb Daiichi-Sankyo, Janssen, Medtronic, and Pfizer; and has received symposium lecture fees from Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb. Dr. Mohan is a former employee of Bristol-Myers Squibb. Dr. Hanna is an employee of and has stock ownership in Bristol-Myers Squibb. Dr. Granger has received research grants from GlaxoSmithKline, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Sanofi, Takeda, The Medicines Company, Janssen, Bayer, Medtronics Foundation, Merck & Co., and Armetheon; and personal fees from GlaxoSmithKline, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Sanofi, Takeda, The Medicines Company, Janssen, Bayer, Hoffmann-La Roche, Eli Lilly, AstraZeneca, Daiichi-Sankyo, Ross Medical Corporation, Salix Pharmaceuticals, Gilead, and Medtronic. Prof. Wallentin has received institutional research grants from AstraZeneca, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, GlaxoSmithKline, Merck & Co., and Roche; consultancy fees from GlaxoSmithKline, Abbott, AstraZeneca, Bristol-Myers Squibb/Pfizer, and Boehringer Ingelheim; lecture fees and travel support from GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb/Pfizer, and Boehringer Ingelheim; honoraria from GlaxoSmithKline; and holds 2 patents involving GDF-15. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- asymmetric dimethylarginine
- atrial fibrillation
- cerebrovascular accident
- International Society on Thrombosis and Haemostasis
- nitric oxide
- nitric oxide synthase
- symmetric dimethylarginine
- Received April 28, 2016.
- Revision received April 17, 2018.
- Accepted May 10, 2018.
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