Homoarginine predicts mortality in treatment-naive patients with pulmonary arterial hypertension.
- 1Department of Cardiovascular Medicine, University of Oxford, United Kingdom; DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e.V.), Partner Site Hamburg/Kiel/Lübeck, Germany; Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. Electronic address: [email protected]
- 2INSERM CIC1406, Clinical Pharmacology Department, University Hospital, Grenoble, France; Inserm U1042, Université Grenoble Alpes, France.
- 3DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e.V.), Partner Site Hamburg/Kiel/Lübeck, Germany; Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
- 4Centre de Référence de l’Hypertension Pulmonaire Sévère’ Pulmonology and Respiratory Intensive Care Department, Antoine Béclère Hospital, AP-HP, Clamart, France; INSERM U999, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France; University Paris-Sud, Kremlin-Bicêtre, France.
Pulmonary arterial hypertension (PAH) is a rare progressive disease with a 3-year mortality rate of approx. 45% in incident patients. The prostacyclin, endothelin-1 (ET-1), and nitric oxide (NO) pathways are validated therapeutic targets, however the underlying pathomechanisms are not yet fully understood. In the present study, we investigated metabolites of the NO pathway (e.g. l-arginine, asymmetric dimethylarginine (ADMA), and homoarginine), which are potentially involved in the pathophysiology of PAH.
Newly diagnosed, treatment-naïve incident PAH patients were recruited from six centers and followed for three years. In longitudinal analyses we investigated the prognostic potential of these markers. Cross-sectional analysis was later used to study associations between prognostic relevant markers and clinical phenotypes of PAH.
Among 108 enrolled patients (53 ± 17 years, mean ± SD), 76 had idiopathic (i)PAH. Kaplan–Meier survival analysis and adjusted Cox proportional hazard models identified homoarginine as an independent predictor of mortality (HR:0.51, CI:0.28–0.94 for PAH and HR:0.41 CI:0.19–0.88 for iPAH), but not l-arginine or ADMA. Homoarginine was lower in 27 patients who died during the follow-up, i.e. 1.26 ± 0.48 vs. 1.64 ± 0.69 μmol/L, P < 0.01. In Pearson’s correlation analysis homoarginine correlated with 6-minute walking distance (r = 0.31), cardiac output (r = 0.23), right atrial pressure (r = −0.21), big ET-1 (r = −0.31), and NT-proBNP (r = −0.21; P < 0.05 for all).
Homoarginine was found an independent predictor for mortality in newly diagnosed PAH and iPAH patients. Further experimental studies are necessary to elucidate the involvement of homoarginine in the pathophysiology of PAH and its potential role as a therapeutic option for these patients.
Homoarginine, Hypertension, Pulmonary, Survival
Homoarginine predicts mortality in treatment-naive patients with pulmonary arterial Hypertension (published in “Int J Cardiol.2016 Aug;217:12-15”)
Narrowing of blood vessels from the lung circulatory system precedes an increase in pulmonary arterial pressure, a disease known as pulmonary arterial hypertension (PAH). Patients suffer from dispnoe, right heart dysfunction, and signs of obstruction. Prognosis of PAH is poor and the severity and progression of disease is evaluated based on the functional status quantified by the NYHA class, 6-min walking distance, and hemodynamic parameters.
In our multicenter, prospective, prognostic, and single blinded study we included untreated patients with newly diagnosed PAH. The study started in November 2003 and run for two years, with a 3 year follow-up for each patient. The main goal of the study was to test the prognostic relevance of baseline biomarker concentrations (i.e. isoprostanes, big endothelin-1, arginine metabolites, high sensitivity CRP, NT-Pro-BNP, and cardiac troponin T) in these patients. Correlation analysis was performed to study the link between plasma and urinary biomarkers and NYHA class, 6-min walking distance, and hemodynamic parameters. Moreover, applying multivariable Cox regression models, we tested the predictive value of these biomarkers for the combined end point of the study, i.e. death from any cause and pulmonary or cardiopulmonary transplantation.
Interestingly, we only identified two prognostic biomarkers in this treatment-naïve cohort: isoprostanes1 and homoarginine2. Isoprostanes are isomers of prostaglandins, among them thromboxane A2 and prostacyclin, which are known to be involved in the pathophysiology of several circulatory disease by activating their distinct receptors. Recently, selexipag, a prostacyclin-receptor agonist, was the first oral selective agonist of this drug class shown to be beneficial in the treatment of PAH.3 Homoarginine is an arginine analogue involved in nitric oxide (NO) metabolism. NO downstream signaling has been targeted for many years in patients with PAH by stimulating soluble guanylyl cyclase or inhibiting phosphodiesterase 4, e.g. riociguat4 and tadalafil5. However, the precise underlying molecular mechanism of homoarginine remains elusive and in the future it has to be established whether homoarginine is more a biomarker or potential mediator in the pathophysiology of PAH. Homoarginine is a constituent of pea pules and readily absorbed after oral ingestion. Another source of homoarginine is the metabolic conversion from arginine by arginine:glycine amidinotransferase (AGAT; EC 18.104.22.168) mainly expressed in the liver and kidney. Most recently, we were able to show that homoarginine can be orally supplemented in humans, is well tolerated and increases plasma concentrations several fold.6
In summary, we tested biomarkers that provide additional prognostic information in PAH on top of established functional and hemodynamic parameters. We identified a new biomarker, i.e. homoarginine, that is related to the pathophysiology of PAH and moreover which might be suitable as a novel therapeutic option through dietary supplementation of homoarginine in PAH patients.
- Cracowski JL, Degano B, Chabot F, Labarere J, Schwedhelm E, Monneret D, Iuliano L, Schwebel C, Chaouat A, Reynaud-Gaubert M, Faure P, Maas R, Renversez JC, Cracowski C, Sitbon O, Yaici A, Simonneau G, Humbert M. Independent association of urinary f2-isoprostanes with survival in pulmonary arterial hypertension. Chest. 2012;142:869-876
- Atzler D, Cracowski JL, Cordts K, Böger RH, Humbert M, Schwedhelm E. Homoarginine predicts mortality in treatment-naive patients with pulmonary arterial hypertension. International journal of cardiology. 2016;217:12-15
- Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galie N, Ghofrani HA, Hoeper MM, Lang IM, Preiss R, Rubin LJ, Di Scala L, Tapson V, Adzerikho I, Liu J, Moiseeva O, Zeng X, Simonneau G, McLaughlin VV, Investigators G. Selexipag for the treatment of pulmonary arterial hypertension. The New England journal of medicine. 2015;373:2522-2533
- Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ, Group P-S. Riociguat for the treatment of pulmonary arterial hypertension. The New England journal of medicine. 2013;369:330-340
- Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, White RJ, Chan M, Beardsworth A, Frumkin L, Barst RJ, Pulmonary Arterial H, Response to Tadalafil Study G. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894-2903
- Atzler D, Schonhoff M, Cordts K, Ortland I, Hoppe J, Hummel FC, Gerloff C, Jaehde U, Jagodzinski A, Böger RH, Choe CU, Schwedhelm E. Oral supplementation with l-homoarginine in young volunteers. British journal of clinical pharmacology. 2016; doi: 10.1111/bcp.13068.