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Asymmetric, symmetric dimethylarginine predict events in AF with anticoagulation
Asymmetric dimethylarginine and symmetric dimethylarginine were strongly associated with increased mortality in patients with atrial fibrillation who were on anticoagulation, according to a study published in the Journal of the American College of Cardiology.
Elevated levels of asymmetric dimethylarginine were weakly associated with thromboembolic events, whereas elevated levels of symmetric dimethylarginine were linked to bleeding events, according to the study.
ARISTOTLE data
John D. Horowitz, MBBS, PhD, professor of cardiology at University of Adelaide in Australia and director of cardiology and clinical pharmacology at The Queen Elizabeth Hospital in Adelaide, and colleagues analyzed data from 5,004 patients with AF and at least one CHA2DS2-VASc risk factor for stroke from the ARISTOTLE trial. Patients in this trial were assigned warfarin or apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). Bleeding and thromboembolic risk scores were calculated for each patient at randomization.
In this substudy, researchers assessed blood samples to determine asymmetric and symmetric dimethylarginine concentrations. Patients were followed up for a mean of 1.9 years.
Plasma concentrations of asymmetric and symmetric dimethylarginine significantly increased with age, renal impairment, women, congestive HF or permanent AF. These levels also increased as HAS-BLED and CHA2DS2-VASc risk scores increased (P < .001), although they both decreased with diabetes.
After adjusting for treatment and established risk factors, tertile groups of asymmetric dimethylarginine concentrations were linked to death (P < .0001) and stroke/systemic embolism (P = .034). The tertile groups of symmetric dimethylarginine were associated with death and major bleeding (P for both < .001). The C-indices for these outcomes improved when asymmetric and symmetric dimethylarginine were incorporated into HAS-BLED and CHA2DS2-VASc predictive models.
Medication responses
Responses to warfarin or apixaban did not differ based on asymmetric and symmetric dimethylarginine levels.
“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,” Horowitz and colleagues wrote. “Indeed, recent studies in endothelial cells suggest that [asymmetric dimethylarginine] may also increase oxidative stress, via ‘uncoupling’ of [nitric oxide] synthase.”
In a related editorial, John P. Cooke, MD, PhD, Joseph C. “Rusty” Walter and Carole Walter Looke Presidential Distinguished Chair in Cardiovascular Disease Research in the department of cardiovascular sciences and professor of cardiovascular sciences in the Institute for Academic Medicine at Houston Methodist Research Institute, and Roman A. Sukhovershin, MD, PhD, assistant research professor of cardiovascular sciences at the Institute for Academic Medicine and assistant research member at the Research Institute at Houston Methodist, wrote: “Although the mechanism of this relationship is not secure, it likely reflects the relationship between elevated levels of [symmetric dimethylarginine] and impaired renal function. By reducing the clearance of apixaban or warfarin, impaired renal function could increase the risk of bleeding. The findings of Horowitz et al are interesting and justify further studies of the prognostic value of these markers in AF, and the mechanisms by which the methylarginines may be associated with bleeding and thrombosis in AF.” – by Darlene Dobkowski
Disclosures: The ARISTOTLE trial and substudy were funded by Bristol-Myers Squibb and Pfizer. Horowitz, Cooke and Sukhovershin report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.