ASSESSMENT OF ASYMMETRIC DIMETHYLARGININE IN PATIENTS WITH PULMONARY HYPERTENSION
https://doi.org/10.18705/1607-419X-2014-20-1-45-52
Abstract
Objective. Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide inhibitor. Increased level ADMA may contribute to endothelial dysfunction in patients with pulmonary hypertension (PH). The aim of the study was to assess the possible link between ADMA and basic determinants of PH severity.
Design and methods. We examined 56 patients with PH (mean age 42,8 ± 14,5 years, 19 males): idiopathic pulmonary arterial hypertension was diagnosed in 32 subjects, 7 subjects had corrected congenital heart disease, 7 subjects had scleroderma, and 11 — inoperable chronic thromboembolic pulmonary hypertension, and 12 healthy subjects formed control group (41,8 ± 10,3 years, 3 males). Serum ADMA by ELISA method, serum NT pro-BNP (Elecsys) and uric acid levels were determined. Echocardiography, 6-minute walking test (6MWT), right heart catheterization and cardiopulmonary exercise testing (CPX) were performed.
Results. The symptoms of II functional class (FC) WHO were present in 23 % patients, III FC — in 59 % patients and IV FC — in 13 % patients, 6MWT was decreased (362 ± 97 m) and NT-proBNP level was elevated (1833 ± 2176 pg/ml). Serum ADMA level in patients with PH were elevated in comparison with healthy controls (0,68 ± 0,25 vs 0,35 ± 0,12 µmol/l? p < 0,05). ADMA levels correlated with such prognostic markers as NT-proBNP (r = 0,44? p = 0,0008), mean right atrium pressure (r = 0,31? p < 0,05) and stroke volume LV (r = -0,34? p = 0,01). Serum ADMA was negatively correlated with 6MWT distance (r = -0,37? p = 0,004), work load by CPX (r = -0,42? p = 0,02).
Conclusions. Serum ADMA level is elevated in patients with PH and correlates with prognostic markers. Also ADMA level predicts exercise intolerance. We assume that ADMA is a marker of endothelial dysfunction, and could be used for the assessment of PH severity.
About the Authors
A. V. KazimliRussian Federation
Corresponding author: Federal Almazov Medical Research Centre, 2 Akkuratov st., St Petersburg, Russia, 197341. E-mail: kazimli_aygun@yahoo.com (Aigun V. Kazimli, MD, a Researcher at the Scientiic Department of Cardiomyopathies at Federal Almazov Medical Research Centre).
N. S. Goncharova
Russian Federation
A. V. Berezina
Russian Federation
A. V. Naymushin
Russian Federation
O. M. Moiseeva
Russian Federation
References
1. Sibal L., Agarwal S.C., Home P.D. et al. The role of asymmetric dimethylarginine (adma) in endothelial dysfunction and cardiovascular disease // Curr. Cardiol. Rev. — 2010. — Vol. 6, № 2. — P. 82–90.
2. Boger R.H., Sullivan L.M., Schwedhelm E. et al. Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community // Circulation. — 2009. — Vol. 119, № 12. — P. 1592–1600.
3. Cooke J.P. Asymmetrical dimethylarginine. A novel marker? // Circulation. — 2004. — Vol. 109. — P. 1813–1818.
4. Жлоба А.А. Асимметричный диметиларгинин в качестве медиатора и маркера развития эндотелиальной дисфункции // Артериальная гипертензия. — 2007. — T. 13, № 2. — C. 119–127. /
5. Warwick G., Thomas P.S., Yates D.H. Biomarkers in pulmonary hypertension // Eur. Respir. J. — 2008. — Vol. 32, № 2. — P. 503–512.
6. Boger R.H., Bode-Boger S.M., Szuba A. et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia // Circulation. — 1998. — Vol. 98, № 18. — P. 1842–1847.
7. Miyazaki H., Matsuoka H., Cooke J.P. et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis // Circulation. — 1999. — Vol. 99, № 9. — P. 1141–1146.
8. Surdacki A., Nowicki M., Sandmann J. et al. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension // J. Cardiovasc. Pharmacol. — 1999. — Vol. 33, № 4. — P. 652–658.
9. Abbasi F., Asagmi T., Cooke J.P. et al. Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus // Am. J. Cardiol. — 2001. — Vol. 88, № 101. — P. 1201–1203.
10. Boger R.H., Zoccali C. ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease // Atheroscler. Suppl. — 2003. — Vol. 4, № 4. — P. 23–28.
11. Stuhlinger M.C., Oka R.K., Graf E.E. et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine // Circulation. — 2003. — Vol. 108, № 8. — P. 933–938.
12. Valkonen V.P., Paiva H., Salonen J.T. et al. Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine // Lancet. — 2001. — Vol. 358, № 9299. — P. 2127–2128.
13. Meinitzer A., Seelhorst U., Wellnitz B. et al. Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the Ludwigshafen Risk and Cardiovascular Health study) // Clin. Chem. — 2007. — Vol. 53, № 2. — P. 273–283.
14. Cooper C.J., Landzberg M.J., Anderson T.J. et al. Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans // Circulation. — 1996. — Vol. 93, № 2. — P. 266–271.
15. Millatt L.J., Whitley G.S., Li D. et al. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension // Circulation. — 2003. — Vol. 108, № 12. — P. 1493–1498.
16. Skoro-Sajer N., Mittermayer F., Panzenboeck A. et al. Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension // Am. J. Respir. Crit. Care. Med. — 2007. — Vol. 176, № 11. — P. 1154–1160.
17. Kielstein J.T., Bode-Boger S.M., Hesse G. et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hyper-tension // Arterioscler. Thromb. Vasc. Biol. — 2005. — Vol. 25, № 7. — P. 1414–1418.
18. Dimitroulas T., Giannakoulas G., Sfetsios T. et al. Asymmetrical dimethylarginine in systemic sclerosis-related pulmonary arterial hypertension // Rheumatology (Oxford). — 2008. — Vol. 47, № 11. — P. 1682–1685.
19. Gorenlo M., Zheng C., Werle E. et al. Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension // J. Cardiovasc. Pharmacol. — 2001. — Vol. 37, № 4. — P.489–492.
20. Haider D.G., Bucek R.A., Reiter M. et al. The cardiovascular risk marker asymmetrical dimethylarginine is not affected by venous thromboembolism // Transl. Res. 2006. — Vol. 148, № 1. — P. 26–29.
21. Galie`N., Hoeper M.M., Humbert M. et al. Guidelines for the diagnosis and treatment of pulmonary hypertension // Eur. Heart. J. — 2009. — Vol. 30, № 20. — P. 2493–2537.
22. Rudski L.G., Lai W.W., Ailalo J. et al. Guidelines for the echocardiographic assessment of the right heart in adults // J. Am. Soc. Echocardiogr. — 2010. — Vol. 23, № 7. — P. 685–713.
23. Brooks D., Solway S., Gibbons W.J. Guidelines for the six-minute walk test // Am. J. Respir. Crit. Care. Med. — 2002. — Vol. 166, № 1. — P. 111–117.
24. Moncada S., Palmer R.M., Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology // Pharmacol. Rev. — 1991. — Vol. 43, № 2. — P. 109–142.
25. Giaid A., Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension // N. Engl. J. Med. — 1995. — Vol. 333, № 4. — P. 214–221.
26. Kielstein J.T., Impraim B., Simmel S. et al. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans // Circulation. — 2004. — Vol. 109, № 2. — P. 172–177.
27. Roberts J.D., Foria P.R. Diagnosis and assessment of pulmonary vascular disease by Doppler echocardiography // Pulm. Circ. — 2011. — Vol. 1, № 2. — P. 160–181.
28. Stamm J.A., Risbano M.G., Mathier M.A. Overview of current therapeutic approaches for pulmonary hypertension // Pulm. Circ. — 2011. — Vol. 1, № 2. — P. 138–159.
29. Arena R., Guazzi M., Myers J. et al. Cardiopulmonary exercise testing in the assessment of pulmonary hypertension // Expert Rev. Resp. Med. — 2011 — Vol. 5, № 2. — P. 281–293.
30. Ohnishi M., Wada A., Tsutamoto T. et al. Endothelin stimulates an endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, in experimental heart failure // Clin. Sci. (Lond). — 2002. — Vol. 103, Suppl. 48. — Р. 241–244.
31. Leiper J.M., Santa Maria J., Chubb A. et al. Identiication of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deimnases // Biochem. J. — 1999. — Vol. 343, Pt. 1 — P. 209–214.
32. Родионов Р.Н., Блохин И.О., Галагудза М.М. и др. Асимметричный диметиларгинин и его роль в этиологии и патогенезе сердечно-сосудистых заболеваний // Артериальная ги- пертензия. — 2008. — Т. 14, № 4. — С. 306–314. / Rodionov R.N., Blokhin I.O., Galagoudza M.M. et al. Asymmetric dimethylarginine and its role in etiology and pathogenesis of cardiovascular diseases // Arterial Hypertension [Arterialnaya Gipertenziya]. — 2008. — Vol. 14, № 4. — Р. 306–314 [Russian].
33. Dayoub H., Achan V., Adimoolam S. et al Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis. Genetic and physiological evidence // Circulation. — 2003. — Vol. 108, № 24. — P. 3042–3047.
34. Pullamsetti S., Kiss L., Ghofrani H.A. et al. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension // FASEB J. — 2005. — Vol. 19, № 9. — P. 1175–1777.
Review
For citations:
Kazimli A.V., Goncharova N.S., Berezina A.V., Naymushin A.V., Moiseeva O.M. ASSESSMENT OF ASYMMETRIC DIMETHYLARGININE IN PATIENTS WITH PULMONARY HYPERTENSION. "Arterial’naya Gipertenziya" ("Arterial Hypertension"). 2014;20(1):45-52. (In Russ.) https://doi.org/10.18705/1607-419X-2014-20-1-45-52