ADMA, Endothelial Progenitor Cells, and Cardiovascular Risk
To the Editor:
We read with interest the article by Schnabel and colleagues1 exploring the prognostic value of asymmetric dimethylarginine (ADMA) with regard to cardiovascular risk. Baseline serum ADMA levels in patients with coronary artery disease were associated with the primary end point of death from cardiovascular cause or nonfatal myocardial infarction, whereas no relationship was observed with death from other causes. Thus ADMA was identified as an independent risk factor beyond traditional risk factors and novel biomarkers.
Because of its role as an endogenous inhibitor of the endothelial nitric oxide synthase (eNOS), increased ADMA levels likely contribute to the development of endothelial dysfunction and coronary artery disease.2 eNOS is also critically involved in the regulation of endothelial progenitor cells (EPC) and repair of vascular lesions.3 Interestingly, Schmidt-Lucke et al identified an association between reduced levels of circulating EPC and incidence of subsequent cardiovascular events.4 By multivariate analysis, reduced EPC levels were a significant independent predictor of poor prognosis, even after adjustment for traditional cardiovascular risk factors. Unfortunately, neither Schmidt-Lucke et al4 measured ADMA levels in the investigated study cohort, nor did Schnabel et al1 determine circulating EPC. However, the study of Schnabel et al implicates that ADMA may impair endogenous regeneration of diseased blood vessels resulting in progressive development of vascular lesions. Recently, we have shown an inverse correlation between ADMA plasma concentration and circulating EPC levels in patients with coronary artery disease.5 Adjusting for all patient characteristics, these findings were confirmed in multivariate regression analyses. In vitro studies demonstrated the role of ADMA as an endogenous inhibitor of mobilization, differentiation, and function of EPC. Our results therefore bridge the gap between the 2 studies of Schnabel et al1 and Schmidt-Lucke et al.4 Increased cardiovascular risk in patients with high ADMA levels may be explained by low numbers and impaired function of EPC. Identification and development of drugs that effectively reduce ADMA levels would probably lead to a powerful treatment of coronary artery disease by preventing the direct deleterious effects of ADMA to the endothelium and increasing the amount and functional activity of EPC, thus strengthening the self-renewal capacity of endothelium. Such drug candidates may be certain 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which can effectively lower ADMA plasma levels6 and in parallel increase circulating EPC numbers. Further in-depth basic and clinical studies are clearly needed.
This work was supported by the Ernst und Berta Grimmke-Stiftung (to T.T.).
Schnabel R, Blankenberg S, Lubos E, Lackner KJ, Rupprecht HJ, Espinola-Klein C, Jachmann N, Post F, Peetz D, Bickel C, Cambien F, Tiret L, Munzel T. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ Res. 2005; 97: e53–e59.
Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, Imaizumi T. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation. 1999; 99: 1141–1146.
Schmidt-Lucke C, Rossig L, Fichtlscherer S, Vasa M, Britten M, Kamper U, Dimmeler S, Zeiher AM. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation. 2005; 111: 2981–2987.
Thum T, Tsikas T, Stein S, Schultheiss M, Eigenthaler M, Anker SD, Poole-Wilson PA, Ertl G, Bauersachs J. Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. J Am Coll Cardiol. 2005; 46: 1693–1701.