Journal of the American College of Cardiology
Potential Treatment Influences and Mechanisms Related to Asymmetric Dimethylarginine Control in Heart Failure
Author + information
- Scott S. Billecke, PhD⁎ (scott.billecke{at}beaumont.edu),
- Louis G. D'Alecy, PhD and
- Pamela A. Marcovitz, MD
- ↵⁎Department of Cardiology, Ministrelli Women's Heart Center, Beaumont Health System, 3601 W. Thirteen Mile Road, Royal Oak, Michigan 48073
We found the fascinating work presented by Shao et al. (1) to be particularly compelling, as it highlights the physiological impact—and potential clinical importance—of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and dimethylarginine dimethylaminohydrolases (DDAHs) in patients with congestive heart failure. Ongoing research has provided ample evidence for the prognostic value of ADMA in the setting of cardiovascular disease, and the enormous breadth of disorders with endothelial dysfunction as a central component suggests a prominent role for ADMA in vascular disease progression. By scrutinizing ADMA production and metabolism paralleling vascular dysfunction with subsequent heart failure, Shao et al. underscore the role of arginine dysregulation and elevated ADMA in cardiovascular disease.
There are a few observations in their study (1), however, that warrant further scrutiny. The authors report a significant treatment difference between those with congestive heart failure and those with advanced decompensated heart failure; the former exhibits high angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) use (92%), whereas the frequency of ACEI/ARB use was significantly less in the advanced decompensated heart failure group (61%) (p < 0.0001). This difference might affect interpretation of the ADMA findings, because ACEI/ARBs decrease circulating ADMA levels (2). Moreover, these medications may affect DDAH expression and/or activity (3). Shao et al. also reported higher DDAH-1 expression in hearts from patients who had heart failure but did not have elevated systolic pulmonary artery pressure compared with controls and heart failure patients who did have elevated systolic pulmonary artery pressure, suggesting a successful compensatory effect of DDAH-1 up-regulation. It may be interesting to evaluate ACEI/ARB treatment differences among these groups.
In addition, the authors (1) note the importance of both ADMA production and elimination in controlling ADMA and conclude, on the basis of DDAH and protein arginine methyltransferase expression patterns, that reduced elimination is likely responsible for the observed elevated ADMA levels. Although this hypothesis may ultimately be true, it is worth noting that proteolysis is necessary for ADMA release and, hence, accumulation. It has been noted that high concentrations of protein-incorporated ADMA are present in, and proteolytically released from, erythrocytes (4). Because high protein turnover may yield greater ADMA release and because heart failure is associated with cachexia, it might be reasonable to consider protein turnover when evaluating ADMA dysregulation in congestive heart failure.
- American College of Cardiology Foundation
