Skip to main content

Advertisement

SpringerLink
Log in

Elevated Homocysteine and Asymmetric Dimethyl Arginine Levels in Pulmonary Hypertension Associated With Congenital Heart Disease

  • Original Article
  • Published:
Pediatric Cardiology Aims and scope Submit manuscript

Abstract

Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality among patients with congenital heart disease (CHD). This study was designed to determine biomarker levels in patients with PAH associated with CHD (PAH–CHD) and CHD patients without PAH and to investigate the relationship of these potential biomarkers with hemodynamic findings. In this prospective single-center study, patients with CHD were analyzed according to the presence or absence of PAH and compared with healthy control subjects. Cardiac catheterization and echocardiographs were performed. Plasma homocysteine, asymmetric dimethyl arginine (ADMA), and nitric oxide (NO) levels were determined by enzyme-linked immunosorbent assay. Homocysteine and ADMA levels were higher in the PAH–CHD group (n = 30) than among CHD patients with left-to-right shunting but no PAH (n = 20; P < 0.001) and healthy control subjects (n = 20; P < 0.001). There was no difference in NO levels. Cyanotic PAH–CHD patients had significantly higher homocysteine than acyanotic patients in the same group. No correlation was shown between echocardiographic/hemodynamic parameters and homocysteine, ADMA, and NO levels. Homocysteine and ADMA levels are increased in patients with PAH–CHD. These parameters have the potential to be used as biomarkers in the diagnosis and follow-up evaluation of patients with PAH–CHD. However, large, multicentered prospective studies are required to facilitate routine use of these biologic markers in the clinical setting.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Arroliga AC, Sandur S, Jacobsen DW, Tewari S, Mustafa M, Mascha EJ, Robinson K (2003) Association between hyperhomocysteinemia and primary pulmonary hypertension. Respir Med 97:825–829

    Article  PubMed  Google Scholar 

  2. Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, Gaine S (2004) Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 43:40–47

    Article  Google Scholar 

  3. Böger RH (2006) Asymmetric dimethylarginine (ADMA): a novel risk marker in cardiovascular medicine and beyond. Ann Med 38:126–136

    Article  PubMed  Google Scholar 

  4. Chatterjee A, Black SM, Catravas JD (2008) Endothelial nitric oxide (NO) and its pathophysiologic regulation. Vasc Pharmacol 49:134–140

    Article  CAS  Google Scholar 

  5. Dayal S, Lentz SR (2005) ADMA and hyperhomocysteinemia. Vasc Med 10:27–33

    Article  Google Scholar 

  6. Galiè N, Torbicki A, Barst R, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, ESC Committee for Practice Guidelines (2009) Guidelines for the diagnosis and treatment of pulmonary hypertension: the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 30:2493–2537

    Article  PubMed  Google Scholar 

  7. Giaid A (1998) Nitric oxide and endothelin-1 in pulmonary hypertension. Chest 114:208–212

    Article  Google Scholar 

  8. Gorenflo M, Zheng C, Werle E, Fiehn W, Ulmer HE (2001) Plasma levels of asymmetrical dimethyl-l-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol 37:489–492

    Article  PubMed  CAS  Google Scholar 

  9. Haworth SG (2006) The management of children with congenital heart disease. In: Beghetti M, Barst RJ, Naeije R, Rubin LJ (eds) Pulmonary arterial hypertension related to congenital heart disease, 1st edn. Elsevier, Amsterdam, pp 129–141

    Google Scholar 

  10. Humbert M, Sitbon O, Simonneau G (2004) Treatment of pulmonary arterial hypertension. N Engl J Med 351:1425–1436

    Article  PubMed  CAS  Google Scholar 

  11. Ikemoto Y, Teraguchi M, Takaya J, Nogi S, Kobayashi Y (1998) Plasma levels of nitric oxide products and endothelin in pulmonary hypertension with congenital heart disease. Acta Paediatr 87:715–716

    Article  PubMed  CAS  Google Scholar 

  12. Kaneko FT, Arroliga AC, Dweik RA, Comhair SA, Laskowski D, Oppedisano R, Thomassen MJ, Erzurum SC (1998) Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med 158:917–923

    PubMed  CAS  Google Scholar 

  13. Kari JA, Donald AE, Vallance DT, Bruckdorfer KR, Leone A, Mullen MJ, Bunce T, Dorado B, Deanfield JE, Rees L (1997) Physiology and biochemistry of endothelial function in children with chronic renal failure. Kidney Int 52:468–472

    Article  PubMed  CAS  Google Scholar 

  14. Kielstein JT, Bode-Böger SM, Hesse G, Martens-Lobenhoffer J, Takacs A, Fliser D, Hoeper MM (2005) Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 25:1414–1418

    Article  PubMed  CAS  Google Scholar 

  15. Kotake F, Kobayashi J, Sonada M, Komoda T (2000) Nitric oxide-related compounds in patients with congenital heart defects and pulmonary hypertension. Pediatr Int 42:249–254

    Article  PubMed  CAS  Google Scholar 

  16. Kulik TJ (1992) Pulmonary hypertension. In: Fyler DC (ed) Nadas’ pediatric cardiology. Hanley & Belfus Inc., Philadelphia, pp 83–100

    Google Scholar 

  17. LaFarge CG, Miettinen OS (1970) The estimation of oxygen consumption. Cardiovasc Res 4:23–30

    Article  PubMed  CAS  Google Scholar 

  18. Lentz SR, Rodionov RN, Dayal S (2003) Hyperhomocysteinemia, endothelial dysfunction, and cardiovascular risk: the potential role of ADMA. Atheroscler Suppl 4:61–65

    Article  PubMed  CAS  Google Scholar 

  19. Millatt LJ, Whitley GS, Li D, Leiper JM, Siragy HM, Carey RM, Johns RA (2003) Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation 108:1493–1498

    Article  PubMed  CAS  Google Scholar 

  20. Nihill MR (1995) Clinical management of patients with pulmonary hypertension. In: Emmanouilides GC, Riemenschneider TA, Al-len HD, Gutgesell HP (eds) Heart disease in infants, children, and adolescents, 5th edn. Williams & Wilkins, Baltimore, pp 1695–1711

    Google Scholar 

  21. Özerol IH, Pac FA, Ozerol E, Ege E, Yologlu S, Temel I, Pac M (2004) Plasma endothelin-1, homocysteine, and serum nitric oxide values in patients with left-to-right shunt. Indian Heart J 56:653–657

    PubMed  Google Scholar 

  22. Siekmeier R, Grammer T, März W (2008) Role of oxidants, nitric oxide, and asymmetric dimethylarginine in endothelial function. J Cardiovasc Pharmacol Ther 13:279–297

    Article  PubMed  CAS  Google Scholar 

  23. Simonneau G, Robbins I, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R (2009) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 54:43–54

    Article  Google Scholar 

  24. Skoro-Sajer N, Mittermayer F, Panzenboeck A, Bonderman D, Sadushi R, Hitsch R, Jakowitsch J, Klepetko W, Kneussl MP, Wolzt M, Lang IM (2007) Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 176:1154–1160

    Article  PubMed  CAS  Google Scholar 

  25. Takaya J, Teraguchi M, Nogi S, Ikemoto Y, Kobayashi Y (1998) Relation between plasma nitrate and mean pulmonary arterial pressure in ventricular septal defect. Arch Dis Child 79:498–501

    Article  PubMed  CAS  Google Scholar 

  26. Tsikas D, Boger RH, Sandmann J, Bode-Böger SM, Frölich JC (2000) Endogenous nitric oxide synthase inhibitors are responsible for the l-arginine paradox. FEBS Lett 478:1–3

    Article  PubMed  CAS  Google Scholar 

  27. Tulloh RMR (2005) Congenital heart disease in relation to pulmonary hypertension in paediatric practice. Paediatr Respir Rev 6:174–180

    Article  PubMed  Google Scholar 

  28. Tutar E (2008) Konjenital kalp hastalarında pulmoner vasküler yatak ve pulmoner vasküler obstrüktif hastalık: farklı tipler, güncel yaklaşımlar. Turk Klin J Cardiol Spec Top 1:60–76

    Google Scholar 

  29. Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J (1997) Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 272:17012–17017

    Article  PubMed  CAS  Google Scholar 

  30. Vargo TA (1998) Cardiac catheterization: hemodynamic measurements. In: Garson A, Bricker JT, Fisher DJ, Neish SR (eds) The science and practice of pediatric cardiology, 2nd edn. Lippincott Williams & Wilkins, Baltimore, pp 961–993

    Google Scholar 

  31. Warwick G, Thomas PS, Yates DH (2008) Biomarkers in pulmonary hypertension. Eur Respir J 32:503–512

    Article  PubMed  CAS  Google Scholar 

  32. Wernovsky G (2001) Transposition of the great arteries. In: Allen HD, Gutgesell HP, Clark EB, Driscoll DJ (eds) Heart disease in infants, children, and adolescents, 6th edn. Williams & Wilkins, Baltimore, pp 1027–1084

    Google Scholar 

  33. Zighetti ML, Cattaneo M, Falcon CR, Lombardi R, Harari S, Savoritto S, Mannucci PM (1997) Absence of hyperhomocysteinemia in ten patients with primary pulmonary hypertension. Thromb Res 85:279–282

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Elements Communications for medical writing assistance during the preparation of this manuscript, funded by Actelion Pharmaceuticals Ltd.

Author information

Authors and Affiliations

  1. Department of Pediatric Cardiology, Kirikkale University Medical School, Fabrikalar Mahallesi, Sağlık Sokak, 71100, Kirikkale, Turkey

    Cihat Sanli

  2. Department of Pediatric Cardiology, Gazi University Medical School, Ankara, Turkey

    Deniz Oguz, Rana Olgunturk, Fatma Sedef Tunaoglu, Serdar Kula & Ayhan Cevik

  3. Department of Biochemistry, Gazi University Medical School, Ankara, Turkey

    Hatice Pasaoglu & Ozlem Gulbahar

Authors
  1. Cihat Sanli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deniz Oguz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rana Olgunturk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fatma Sedef Tunaoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Serdar Kula
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hatice Pasaoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ozlem Gulbahar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ayhan Cevik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cihat Sanli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sanli, C., Oguz, D., Olgunturk, R. et al. Elevated Homocysteine and Asymmetric Dimethyl Arginine Levels in Pulmonary Hypertension Associated With Congenital Heart Disease. Pediatr Cardiol 33, 1323–1331 (2012). https://doi.org/10.1007/s00246-012-0321-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00246-012-0321-9

Keywords

Search

Navigation