Biomarkers in Pulmonary Vascular Disease: Gauging Response to Therapy
2017; Elsevier BV; Volume: 120; Issue: 8 Linguagem: Inglês
10.1016/j.amjcard.2017.06.014
ISSN1879-1913
Autores Tópico(s)Nitric Oxide and Endothelin Effects
ResumoBiomarkers are increasingly being investigated in the treatment of pulmonary vascular disease. In particular, the signaling pathways targeted by therapies for pulmonary arterial hypertension provide biomarkers that potentially can be used to guide therapy and to assess clinical response as an alternative to invasive procedures such as right-sided cardiac catheterization. Moreover, the growing use of combination therapy for both the initial and subsequent treatment of pulmonary arterial hypertension highlights the need for biomarkers in this treatment approach. Currently approved therapies for pulmonary arterial hypertension target 3 major signaling pathways: the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, the endothelin pathway, and the prostacyclin pathway. Although the main biomarker used in practice and evaluated in clinical trials is N-terminal pro-brain natriuretic peptide, other putative biomarkers include the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine, NO metabolites including S-nitrosothiols and nitrite, exhaled NO, endothelins, cyclic guanosine monophosphate, cyclic adenosine monophosphate, and atrial natriuretic peptide. This review describes accessible biomarkers, related to the actual molecules targeted by current therapies, for measuring and predicting response to the individual pulmonary arterial hypertension treatment classes as well as combination therapy. Biomarkers are increasingly being investigated in the treatment of pulmonary vascular disease. In particular, the signaling pathways targeted by therapies for pulmonary arterial hypertension provide biomarkers that potentially can be used to guide therapy and to assess clinical response as an alternative to invasive procedures such as right-sided cardiac catheterization. Moreover, the growing use of combination therapy for both the initial and subsequent treatment of pulmonary arterial hypertension highlights the need for biomarkers in this treatment approach. Currently approved therapies for pulmonary arterial hypertension target 3 major signaling pathways: the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, the endothelin pathway, and the prostacyclin pathway. Although the main biomarker used in practice and evaluated in clinical trials is N-terminal pro-brain natriuretic peptide, other putative biomarkers include the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine, NO metabolites including S-nitrosothiols and nitrite, exhaled NO, endothelins, cyclic guanosine monophosphate, cyclic adenosine monophosphate, and atrial natriuretic peptide. This review describes accessible biomarkers, related to the actual molecules targeted by current therapies, for measuring and predicting response to the individual pulmonary arterial hypertension treatment classes as well as combination therapy. There has been a growing focus on the use of biomarkers as an alternative or adjunct to invasive procedures, such as right-sided cardiac catheterization, for assessing and guiding response to therapy for pulmonary arterial hypertension (PAH) and other pulmonary vascular diseases. The signaling pathways targeted by PAH therapies—including the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cyclic GMP or cGMP) pathway, the endothelin pathway, and the prostacyclin pathway1Galiè N. Corris P.A. Frost A. Girgis R.E. Granton J. Jing Z.C. Klepetko W. McGoon M.D. McLaughlin V.V. Preston I.R. Rubin L.J. Sandoval J. Seeger W. Keogh A. Updated treatment algorithm of pulmonary arterial hypertension.J Am Coll Cardiol. 2013; 62: D60-D72Crossref PubMed Scopus (548) Google Scholar—provide potential biomarkers that are currently being investigated.2Al-Naamani N. Preston I.R. Biomarkers and other methods for assessing patient progress.in: Maron B.A. Zamanian R.T. Waxman A.B. Pulmonary Hypertension: Basic Science to Clinical Medicine. Springer, 2015Google Scholar In this review and elsewhere, we focus on biomarkers emanating from these treatment-related signaling pathways; for broader reviews of biomarkers in PAH we refer the reader to another recent review.3Swaminathan A.C. Dusek A.C. McMahon T.J. Treatment-related biomarkers in pulmonary hypertension.Am J Respir Cell Mol Biol. 2015; 52: 663-673Crossref PubMed Scopus (24) Google Scholar Moreover, a combination therapy approach for PAH is gaining greater acceptance for both the initial and subsequent treatment of PAH,1Galiè N. Corris P.A. Frost A. Girgis R.E. Granton J. Jing Z.C. Klepetko W. McGoon M.D. McLaughlin V.V. Preston I.R. Rubin L.J. Sandoval J. Seeger W. Keogh A. Updated treatment algorithm of pulmonary arterial hypertension.J Am Coll Cardiol. 2013; 62: D60-D72Crossref PubMed Scopus (548) Google Scholar, 4Galiè N. Humbert M. Vachiery J.L. Gibbs S. Lang I. Torbicki A. Simonneau G. Peacock A. Vonk Noordegraaf A. Beghetti M. Ghofrani A. Gomez Sanchez M.A. Hansmann G. Klepetko W. Lancellotti P. Matucci M. McDonagh T. Pierard L.A. Trindade P.T. Zompatori M. Hoeper M. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).Eur Respir J. 2015; 46 (Erratum in: Eur Respir J 2015;46(6):1855–1856): 903-975Crossref PubMed Scopus (2055) Google Scholar and biomarkers for response to combination therapies may be the most relevant as the treatment of PAH continues to evolve. This review provides an overview of noninvasive biomarkers for the pathways targeted by current PAH therapies, with an emphasis on the use of biomarkers to assess response to combination therapy. After the identification of NO as the "endothelium-derived relaxing factor,"5Ignarro L.J. Buga G.M. Wood K.S. Byrns R.E. Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.Proc Natl Acad Sci USA. 1987; 84: 9265-9269Crossref PubMed Scopus (4329) Google Scholar its role in the pathophysiology of PAH has been well established. Nitric oxide synthase (NOS) generates NO endogenously from l-arginine using tetrahydrobiopterin and other cofactors.6Pollock J.S. Förstermann U. Mitchell J.A. Warner T.D. Schmidt H.H. Nakane M. Murad F. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells.Proc Natl Acad Sci USA. 1991; 88: 10480-10484Crossref PubMed Scopus (894) Google Scholar NO, in turn, binds to the heme moiety and activates sGC, which catalyzes the conversion of guanosine-5′-triphosphate to cGMP.7Arnold W.P. Mittal C.K. Katsuki S. Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations.Proc Natl Acad Sci USA. 1977; 74: 3203-3207Crossref PubMed Scopus (1194) Google Scholar Through the production of cGMP, sGC can exert many physiological effects such as mediating vascular smooth muscle tone and motility, phototransduction, and maintaining fluid and electrolyte homeostasis. Downstream effects also include vascular smooth muscle relaxation and vasodilation.7Arnold W.P. Mittal C.K. Katsuki S. Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations.Proc Natl Acad Sci USA. 1977; 74: 3203-3207Crossref PubMed Scopus (1194) Google Scholar, 8Ignarro L.J. Byrns R.E. Wood K.S. Endothelium-dependent modulation of cGMP levels and intrinsic smooth muscle tone in isolated bovine intrapulmonary artery and vein.Circ Res. 1987; 60: 82-92Crossref PubMed Scopus (137) Google Scholar To do this, cGMP acts directly with downstream effectors such as the family of cGMP-dependent protein kinases, cyclic nucleotide-gated channels, and cGMP-regulated phosphodiesterases (PDEs).9Lucas K.A. Pitari G.M. Kazerounian S. Ruiz-Stewart I. Park J. Schulz S. Chepenik K.P. Waldman S.A. Guanylyl cyclases and signaling by cyclic GMP.Pharmacol Rev. 2000; 52: 375-414PubMed Google Scholar The sGC activity increases more than 200-fold in response to NO.10Lee Y.C. Martin E. Murad F. Human recombinant soluble guanylyl cyclase: expression, purification, and regulation.Proc Natl Acad Sci USA. 2000; 97: 10763-10768Crossref PubMed Scopus (121) Google Scholar This signal is quickly removed by the action of PDE5A enzyme. However, for sGC activation and downstream signaling to occur, there must be at least some level of bioactive NO produced to bind to target. In conditions of NO deficiency, this pathway is not activated at all or is severely compromised. This ubiquitous pathway is present in all endothelial cells along the entire cardiovascular system, including the pulmonary vasculature. In addition to signaling via sGC and cGMP, NO can be converted into more durable S-nitrosothiols (SNOs), in which the cysteine residue of proteins or peptides bind an NO derivative reversibly. SNOs play important roles in cardiovascular and pulmonary physiology, in part through the regulation of protein function.11Foster M.W. Hess D.T. Stamler J.S. Protein S-nitrosylation in health and disease: a current perspective.Trends Mol Med. 2009; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar, 12Gaston B. Singel D. Doctor A. Stamler J.S. S-nitrosothiol signaling in respiratory biology.Am J Respir Crit Care Med. 2006; 173: 1186-1193Crossref PubMed Scopus (189) Google Scholar, 13McMahon T.J. Moon R.E. Luschinger B.P. Carraway M.S. Stone A.E. Stolp B.W. Gow A.J. Pawloski J.R. Watke P. Singel D.J. Piantadosi C.A. Stamler J.S. Nitric oxide in the human respiratory cycle.Nat Med. 2002; 8: 711-717Crossref PubMed Scopus (405) Google Scholar, 14Lima B. Forrester M.T. Hess D.T. Stamler J.S. S-nitrosylation in cardiovascular signaling.Circ Res. 2010; 106: 633-646Crossref PubMed Scopus (407) Google Scholar In a study of patients with advanced PAH, the ability of red blood cells (RBCs) to relax blood vessels in hypoxia was deficient, and RBC S-nitrosohemoglobin (SNO-Hb), in which RBC hemoglobin carries an SNO group reversibly,15Sonveaux P. Lobysheva I.I. Feron O. McMahon T.J. Transport and peripheral bioactivities of nitrogen oxides carried by red blood cell hemoglobin: role in oxygen delivery.Physiology (Bethesda). 2007; 22: 97-112Crossref PubMed Scopus (56) Google Scholar was depressed.16McMahon T.J. Ahearn G.S. Moya M.P. Gow A.J. Huang Y.C. Luchsinger B.P. Nudelman R. Yan Y. Krichman A.D. Bashore T.M. Califf R.M. Singel D.J. Piantadosi C.A. Tapson V.F. Stamler J.S. A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension.Proc Natl Acad Sci USA. 2005; 102: 14801-14806Crossref PubMed Scopus (109) Google Scholar When these patients inhaled the SNO-donating gas ethyl nitrite, pulmonary hemodynamics (pulmonary arterial pressure [PAP] and pulmonary vascular resistance [PVR]) improved significantly in concert with improved RBC-associated vasoactivity and RBC SNOs.16McMahon T.J. Ahearn G.S. Moya M.P. Gow A.J. Huang Y.C. Luchsinger B.P. Nudelman R. Yan Y. Krichman A.D. Bashore T.M. Califf R.M. Singel D.J. Piantadosi C.A. Tapson V.F. Stamler J.S. A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension.Proc Natl Acad Sci USA. 2005; 102: 14801-14806Crossref PubMed Scopus (109) Google Scholar These results suggest that SNO-Hb may serve as a clinically relevant biomarker and that SNO repletion strategies are of interest in PAH. Certain analogs of l-arginine inhibit NOS and include the endogenous inhibitors NG-monomethyl-l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine.17Leiper J. Vallance P. Biological significance of endogenous methylarginines that inhibit nitric oxide synthases.Cardiovasc Res. 1999; 43: 542-548Crossref PubMed Scopus (418) Google Scholar ADMA, the most clinically significant endogenous NOS inhibitor, is produced mainly in the lung18Bulau P. Zakrzewicz D. Kitowska K. Leiper J. Gunther A. Grimminger F. Eickelberg O. Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA.Am J Physiol Lung Cell Mol Physiol. 2007; 292: L18-L24Crossref PubMed Scopus (108) Google Scholar and is upregulated in the lungs and plasma of patients with PAH.19Pullamsetti S. Kiss L. Ghofrani H.A. Voswinckel R. Haredza P. Klepetko W. Aigner C. Fink L. Muyal J.P. Weissmann N. Grimminger F. Seeger W. Schermuly R.T. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension.FASEB J. 2005; 19: 1175-1177Crossref PubMed Scopus (159) Google Scholar, 20Kielstein J.T. Bode-Böger S.M. Hesse G. Martens-Lobenhoffer J. Takacs A. Fliser D. Hoeper M.M. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension.Arterioscler Thromb Vasc Biol. 2005; 25: 1414-1418Crossref PubMed Scopus (186) Google Scholar, 21Skoro-Sajer N. Mittermayer F. Panzenboeck A. Bonderman D. Sadushi R. Hitsch R. Jakowitsch J. Klepetko W. Kneussl M.P. Wolzt M. Lang I.M. Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension.Am J Respir Crit Care Med. 2007; 176: 1154-1160Crossref PubMed Scopus (94) Google Scholar In a study in patients with PAH (n = 57), mean plasma ADMA levels were higher than those in controls (n = 22; 0.53 vs 0.36 µmol/L; p <0.001) and showed a significant positive correlation with right atrial pressure (RAP) and a significant negative correlation with mixed-venous oxygen saturation (SvO2), stroke volume, cardiac index (CI), mean arterial blood pressure, and survival.18Bulau P. Zakrzewicz D. Kitowska K. Leiper J. Gunther A. Grimminger F. Eickelberg O. Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA.Am J Physiol Lung Cell Mol Physiol. 2007; 292: L18-L24Crossref PubMed Scopus (108) Google Scholar Similar results were seen in patients with chronic thromboembolic pulmonary hypertension (CTEPH; n = 135): significantly higher mean plasma ADMA levels versus controls (n = 40; 0.62 vs 0.51 µmol/L; p = 0.0002); a significant positive correlation with mean pulmonary arterial pressure (mPAP), RAP, and PVR; and a significant negative correlation with cardiac output, CI, and SvO2.19Pullamsetti S. Kiss L. Ghofrani H.A. Voswinckel R. Haredza P. Klepetko W. Aigner C. Fink L. Muyal J.P. Weissmann N. Grimminger F. Seeger W. Schermuly R.T. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension.FASEB J. 2005; 19: 1175-1177Crossref PubMed Scopus (159) Google Scholar ADMA levels also predicted survival in patients with CTEPH (p <0.0001).21Skoro-Sajer N. Mittermayer F. Panzenboeck A. Bonderman D. Sadushi R. Hitsch R. Jakowitsch J. Klepetko W. Kneussl M.P. Wolzt M. Lang I.M. Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension.Am J Respir Crit Care Med. 2007; 176: 1154-1160Crossref PubMed Scopus (94) Google Scholar Although ADMA levels provide prognostic information and correlate with hemodynamics, additional studies are needed to determine their utility in assessing response to treatment. NO undergoes oxidation to form the nitrogen oxide (NOx) metabolites nitrite (NO2−) and nitrate (NO3−), which can be detected in bronchoalveolar lavage fluid and circulating in the blood.22Dweik R.A. Laskowski D. Abu-Soud H.M. Kaneko F. Hutte R. Stuehr D.J. Erzurum S.C. Nitric oxide synthesis in the lung. Regulation by oxygen through a kinetic mechanism.J Clin Invest. 1998; 101: 660-666Crossref PubMed Scopus (260) Google Scholar, 23Kaneko F.T. Arroliga A.C. Dweik R.A. Comhair S.A. Laskowski D. Oppedisano R. Thomassen M.J. Erzurum S.C. Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension.Am J Respir Crit Care Med. 1998; 158: 917-923Crossref PubMed Scopus (188) Google Scholar, 24Archer S.L. Djaballah K. Humbert M. Weir K.E. Fartoukh M. Dall'ava-Santucci J. Mercier J.C. Simonneau G. Dinh-Xuan A.T. Nitric oxide deficiency in fenfluramine- and dexfenfluramine-induced pulmonary hypertension.Am J Respir Crit Care Med. 1998; 158: 1061-1067Crossref PubMed Scopus (92) Google Scholar, 25Ibrahim Y.I. Ninnis J.R. Hopper A.O. Deming D.D. Zhang A.X. Herring J.L. Sowers L.C. McMahon T.J. Power G.G. Blood A.B. Inhaled nitric oxide therapy increases blood nitrite, nitrate, and S-nitrosohemoglobin concentrations in infants with pulmonary hypertension.J Pediatr. 2012; 160: 245-251Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Several studies evaluating circulating NOx have failed to show a significant difference between patients with PAH and controls.24Archer S.L. Djaballah K. Humbert M. Weir K.E. Fartoukh M. Dall'ava-Santucci J. Mercier J.C. Simonneau G. Dinh-Xuan A.T. Nitric oxide deficiency in fenfluramine- and dexfenfluramine-induced pulmonary hypertension.Am J Respir Crit Care Med. 1998; 158: 1061-1067Crossref PubMed Scopus (92) Google Scholar, 25Ibrahim Y.I. Ninnis J.R. Hopper A.O. Deming D.D. Zhang A.X. Herring J.L. Sowers L.C. McMahon T.J. Power G.G. Blood A.B. Inhaled nitric oxide therapy increases blood nitrite, nitrate, and S-nitrosohemoglobin concentrations in infants with pulmonary hypertension.J Pediatr. 2012; 160: 245-251Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 26Girgis R.E. Champion H.C. Diette G.B. Johns R.A. Permutt S. Sylvester J.T. Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy.Am J Respir Crit Care Med. 2005; 172: 352-357Crossref PubMed Scopus (108) Google Scholar Urinary NOx, however, was found to be significantly lower in patients with PAH (n = 9) compared with controls (n = 12; 42 vs 62 µM/mM creatinine; p = 0.04).24Archer S.L. Djaballah K. Humbert M. Weir K.E. Fartoukh M. Dall'ava-Santucci J. Mercier J.C. Simonneau G. Dinh-Xuan A.T. Nitric oxide deficiency in fenfluramine- and dexfenfluramine-induced pulmonary hypertension.Am J Respir Crit Care Med. 1998; 158: 1061-1067Crossref PubMed Scopus (92) Google Scholar Patients in this study were on a diet restricted in nitrite and nitrate, as dietary intake may affect plasma and urinary levels of NOx.26Girgis R.E. Champion H.C. Diette G.B. Johns R.A. Permutt S. Sylvester J.T. Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy.Am J Respir Crit Care Med. 2005; 172: 352-357Crossref PubMed Scopus (108) Google Scholar, 27Bryan N.S. Grisham M.B. Methods to detect nitric oxide and its metabolites in biological samples.Free Radic Biol Med. 2007; 43: 645-657Crossref PubMed Scopus (615) Google Scholar NO produced endogenously in the lung regulates airway function, directly or indirectly, and can be measured noninvasively in exhaled breath.28American Thoracic Society; European Respiratory Society ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.Am J Respir Crit Care Med. 2005; 171: 912-930Crossref PubMed Scopus (2810) Google Scholar, 29Dweik R.A. Boggs P.B. Erzurum S.C. Irvin C.G. Leigh M.W. Lundberg J.O. Olin A.C. Plummer A.L. Taylor D.R. American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical ApplicationsAn official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications.Am J Respir Crit Care Med. 2011; 184: 602-615Crossref PubMed Scopus (1796) Google Scholar Airway inflammation such as in asthma results in an increased immune response and upregulation of inducible nitric oxide synthase. This acute overproduction of NO can result in increases in exhaled NO due to extravascular production of NO. Measurement of changes in the fractional NO concentration in expired breath (FENO) aids in evaluating and predicting an asthma patient's response to anti-inflammatory therapy, as an adjunct to established clinical and laboratory assessments of asthma. However, baseline levels of exhaled NO have been shown to be significantly lower in patients with PAH than in controls,29Dweik R.A. Boggs P.B. Erzurum S.C. Irvin C.G. Leigh M.W. Lundberg J.O. Olin A.C. Plummer A.L. Taylor D.R. American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical ApplicationsAn official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications.Am J Respir Crit Care Med. 2011; 184: 602-615Crossref PubMed Scopus (1796) Google Scholar, 30Kharitonov S.A. Cailes J.B. Black C.M. du Bois R.M. Barnes P.J. Decreased nitric oxide in the exhaled air of patients with systemic sclerosis with pulmonary hypertension.Thorax. 1997; 52: 1051-1055Crossref PubMed Scopus (133) Google Scholar although this did not hold true in all studies.24Archer S.L. Djaballah K. Humbert M. Weir K.E. Fartoukh M. Dall'ava-Santucci J. Mercier J.C. Simonneau G. Dinh-Xuan A.T. Nitric oxide deficiency in fenfluramine- and dexfenfluramine-induced pulmonary hypertension.Am J Respir Crit Care Med. 1998; 158: 1061-1067Crossref PubMed Scopus (92) Google Scholar, 31Forrest I.A. Small T. Corris P.A. Effect of nebulized epoprostenol (prostacyclin) on exhaled nitric oxide in patients with pulmonary hypertension due to congenital heart disease and in normal controls.Clin Sci (Lond). 1999; 97: 99-102Crossref PubMed Scopus (25) Google Scholar, 32Riley M.S. Pórszász J. Miranda J. Engelen M.P. Brundage B. Wasserman K. Exhaled nitric oxide during exercise in primary pulmonary hypertension and pulmonary fibrosis.Chest. 1997; 111: 44-50Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar One would expect lower vascular endothelial NO production in patients with PAH, and the inability to generate NO leads to impaired vasodilation and therefore elevated chronic tone on vessels and development of PAH with remodeling. In a prospective study of 17 patients with PAH who were initiating treatment, lower FENO at study entry was correlated with a lower decrease in PAP over the course of the study among the 12 patients who survived the study and was also correlated with longer time since diagnosis33Machado R.F. Londhe Nerkar M.V. Dweik R.A. Hammel J. Janocha A. Pyle J. Laskowski D. Jennings C. Arroliga A.C. Erzurum S.C. Nitric oxide and pulmonary arterial pressures in pulmonary hypertension.Free Radic Biol Med. 2004; 37: 1010-1017Crossref PubMed Scopus (61) Google Scholar In addition, FENO significantly increased during the study in patients who survived but did not significantly change in patients who died, potentially indicating response to therapy.33Machado R.F. Londhe Nerkar M.V. Dweik R.A. Hammel J. Janocha A. Pyle J. Laskowski D. Jennings C. Arroliga A.C. Erzurum S.C. Nitric oxide and pulmonary arterial pressures in pulmonary hypertension.Free Radic Biol Med. 2004; 37: 1010-1017Crossref PubMed Scopus (61) Google Scholar Utilization of exhaled NO in PAH patients will have to consider any underlying or incident pulmonary inflammation that may be contributing to extravascular NO production and discriminate from vascular production of NO and its derivatives. It is not clear at this time how intravascular production of NO translates to what can be detected in exhaled breath. Because the cause of PAH is related to loss of pulmonary intravascular NO production, specific determination of exhaled NO and how it relates to this specific vascular function is necessary. sGC, the enzyme that catalyzes the synthesis of cGMP in response to NO binding, leads to increased levels of cGMP and vasorelaxation.34Stasch J.P. Pacher P. Evgenov O.V. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease.Circulation. 2011; 123: 2263-2273Crossref PubMed Scopus (401) Google Scholar Riociguat, an sGC stimulator, is the first agent in this class to be approved and is indicated for the treatment of PAH and CTEPH.1Galiè N. Corris P.A. Frost A. Girgis R.E. Granton J. Jing Z.C. Klepetko W. McGoon M.D. McLaughlin V.V. Preston I.R. Rubin L.J. Sandoval J. Seeger W. Keogh A. Updated treatment algorithm of pulmonary arterial hypertension.J Am Coll Cardiol. 2013; 62: D60-D72Crossref PubMed Scopus (548) Google Scholar It has a dual mechanism of action in which it increases the sensitivity of sGC to NO and also stimulates sGC independently of NO.1Galiè N. Corris P.A. Frost A. Girgis R.E. Granton J. Jing Z.C. Klepetko W. McGoon M.D. McLaughlin V.V. Preston I.R. Rubin L.J. Sandoval J. Seeger W. Keogh A. Updated treatment algorithm of pulmonary arterial hypertension.J Am Coll Cardiol. 2013; 62: D60-D72Crossref PubMed Scopus (548) Google Scholar The pivotal clinical trials of riociguat included N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels as a secondary end point.35Ghofrani H.A. Galiè N. Grimminger F. Grünig E. Humbert M. Jing Z.C. Keogh A.M. Langleben D. Kilama M.O. Fritsch A. Neuser D. Rubin L.J. PATENT-1 Study GroupRiociguat for the treatment of pulmonary arterial hypertension.N Engl J Med. 2013; 369: 330-340Crossref PubMed Scopus (937) Google Scholar, 36Ghofrani H.A. D'Armini A.M. Grimminger F. Hoeper M.M. Jansa P. Kim N.H. Mayer E. Simonneau G. Wilkins M.R. Fritsch A. Neuser D. Weimann G. Wang C. CHEST-1 Study GroupRiociguat for the treatment of chronic thromboembolic pulmonary hypertension.N Engl J Med. 2013; 369: 319-329Crossref PubMed Scopus (932) Google Scholar In the phase 3 Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1) in patients with PAH (n = 443), patients who received riociguat (2.5-mg maximum dose TID) had significantly lower NT-proBNP levels at week 12 than patients who received placebo (least-squares mean difference: −432 pg/ml; p <0.001).35Ghofrani H.A. Galiè N. Grimminger F. Grünig E. Humbert M. Jing Z.C. Keogh A.M. Langleben D. Kilama M.O. Fritsch A. Neuser D. Rubin L.J. PATENT-1 Study GroupRiociguat for the treatment of pulmonary arterial hypertension.N Engl J Med. 2013; 369: 330-340Crossref PubMed Scopus (937) Google Scholar Similar results were seen in the phase 3 Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (CHEST-1) of riociguat versus placebo in patients with recurrent or inoperable CTEPH (n = 261) at 16 weeks (least-squares mean difference: −444 pg/ml; p <0.001).36Ghofrani H.A. D'Armini A.M. Grimminger F. Hoeper M.M. Jansa P. Kim N.H. Mayer E. Simonneau G. Wilkins M.R. Fritsch A. Neuser D. Weimann G. Wang C. CHEST-1 Study GroupRiociguat for the treatment of chronic thromboembolic pulmonary hypertension.N Engl J Med. 2013; 369: 319-329Crossref PubMed Scopus (932) Google Scholar The decreases in NT-proBNP from baseline with riociguat were maintained for up to a year in the PATENT-2 and CHEST-2 extensions and were comparable for patients who were switched from placebo to riociguat for the extension studies.37Rubin L.J. Galiè N. Grimminger F. Grünig E. Humbert M. Jing Z.C. Keogh A. Langleben D. Fritsch A. Menezes F. Davie N. Ghofrani H.A. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2).Eur Respir J. 2015; 45: 1303-1313Crossref PubMed Scopus (143) Google Scholar, 38Simonneau G. D'Armini A.M. Ghofrani H.A. Grimminger F. Hoeper M.M. Jansa P. Kim N.H. Wang C. Wilkins M.R. Fritsch A. Davie N. Colorado P. Mayer E. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2).Eur Respir J. 2015; 45: 1293-1302Crossref PubMed Scopus (201) Google Scholar Consistent with the NT-proBNP data, PATENT-1 and CHEST-1 also showed a significant benefit versus placebo in the primary end points (change from baseline in 6-min walk distance [6MWD] at weeks 12 and 16, respectively).35Ghofrani H.A. Galiè N. Grimminger F. Grünig E. Humbert M. Jing Z.C. Keogh A.M. Langleben D. Kilama M.O. Fritsch A. Neuser D. Rubin L.J. PATENT-1 Study GroupRiociguat for the treatment of pulmonary arterial hypertension.N Engl J Med. 2013; 369: 330-340Crossref PubMed Scopus (937) Google Scholar, 36Ghofrani H.A. D'Armini A.M. Grimminger F. Hoeper M.M. Jansa P. Kim N.H. Mayer E. Simonneau G. Wilkins M.R. Fritsch A. Neuser D. Weimann G. Wang C. CHEST-1 Study GroupRiociguat for the treatment of chronic thromboembolic pulmonary hypertension.N Engl J Med. 2013; 369: 319-329Crossref PubMed Scopus (932) Google Scholar PDE5 hydrolyzes cGMP formed from the NO-sGC-cGMP pathway.39Kass D.A. Champion H.C. Beavo J.A. Phosphodiesterase type 5: expanding roles in cardiovascular regulation.Circ Res. 2007; 101: 1084-1095Crossref PubMed Scopus (162) Google Scholar Inhibition of PDE5 leads to increased levels of cGMP, which stimulates cGMP-dependent protein kinase.39Kass D.A. Champion H.C. Beavo J.A. Phosphodiesterase type 5: expanding roles in cardiovascular regulation.Circ Res. 2007; 101: 1084-1095Crossref PubMed Scopus (162) Google Scholar PDE5 activity is upregulated in pulmonary vascular smooth muscle in PAH, and inhibition of PDE5 results in vasodilation.40Hanson K.A. Ziegler J.W. Rybalkin S.D. Miller J.W. Abman S.H. Clarke W.R. Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity.Am J Physiol. 1998; 275: L931-L941PubMed Google Scholar, 41Michelakis E.D. Tymchak W. Noga M. Webster L. Wu X.C. Lien D. Wang S.H. Modry D. Archer S.L. Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension.Circu
Referência(s)