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MC van de Veerdonk, T Kind, JT Marcus, G-J Mauritz, MW Heymans, H-J Bogaard, A Boonstra, KMJ Marques, N Westerhof, A Vonk-Noordegraaf (2011)
Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy, 58
K Strimmer (2008)
fdrtool: a versatile R package for estimating local and tail area-based false discovery rates, 24
( Brener MI, Masoumi A, Ng VG, Tello K, Bastos MB, Cornwell WK 3rd, Hsu S, Tedford RJ, Lurz P, Rommel K-P, Kresoja K-P, Nagueh SF, Kanwar MK, Kapur NK, Hiremath G, Sarraf M, Van Den Enden AJM, Van Mieghem NM, Heerdt PM, Hahn RT, Kodali SK, Sayer GT, Uriel N, Burkhoff D. Invasive right ventricular pressure-volume analysis: basic principles, clinical applications, and practical recommendations. Circ Heart Fail 15: e009101, 2022. doi:10.1161/CIRCHEARTFAILURE.121.009101.34963308)
Brener MI, Masoumi A, Ng VG, Tello K, Bastos MB, Cornwell WK 3rd, Hsu S, Tedford RJ, Lurz P, Rommel K-P, Kresoja K-P, Nagueh SF, Kanwar MK, Kapur NK, Hiremath G, Sarraf M, Van Den Enden AJM, Van Mieghem NM, Heerdt PM, Hahn RT, Kodali SK, Sayer GT, Uriel N, Burkhoff D. Invasive right ventricular pressure-volume analysis: basic principles, clinical applications, and practical recommendations. Circ Heart Fail 15: e009101, 2022. doi:10.1161/CIRCHEARTFAILURE.121.009101.34963308Brener MI, Masoumi A, Ng VG, Tello K, Bastos MB, Cornwell WK 3rd, Hsu S, Tedford RJ, Lurz P, Rommel K-P, Kresoja K-P, Nagueh SF, Kanwar MK, Kapur NK, Hiremath G, Sarraf M, Van Den Enden AJM, Van Mieghem NM, Heerdt PM, Hahn RT, Kodali SK, Sayer GT, Uriel N, Burkhoff D. Invasive right ventricular pressure-volume analysis: basic principles, clinical applications, and practical recommendations. Circ Heart Fail 15: e009101, 2022. doi:10.1161/CIRCHEARTFAILURE.121.009101.34963308, Brener MI, Masoumi A, Ng VG, Tello K, Bastos MB, Cornwell WK 3rd, Hsu S, Tedford RJ, Lurz P, Rommel K-P, Kresoja K-P, Nagueh SF, Kanwar MK, Kapur NK, Hiremath G, Sarraf M, Van Den Enden AJM, Van Mieghem NM, Heerdt PM, Hahn RT, Kodali SK, Sayer GT, Uriel N, Burkhoff D. Invasive right ventricular pressure-volume analysis: basic principles, clinical applications, and practical recommendations. Circ Heart Fail 15: e009101, 2022. doi:10.1161/CIRCHEARTFAILURE.121.009101.34963308
GD Lewis, D Ngo, AR Hemnes, L Farrell, C Domos, PP Pappagianopoulos, BP Dhakal, A Souza, X Shi, ME Pugh, A Beloiartsev, S Sinha, CB Clish, RE Gerszten (2016)
Metabolic profiling of right ventricular-pulmonary vascular function reveals circulating biomarkers of pulmonary hypertension, 67
CC Kao, SH Wedes, JW Hsu, KM Bohren, SAA Comhair, F Jahoor, SC Erzurum (2015)
Arginine metabolic endotypes in pulmonary arterial hypertension, 5
CG Ireland, RL Damico, TM Kolb, SC Mathai, M Mukherjee, SL Zimmerman, AA Shah, FM Wigley, BA Houston, PM Hassoun, DA Kass, RJ Tedford, S Hsu (2021)
Exercise right ventricular ejection fraction predicts right ventricular contractile reserve, 40
( Ireland CG, Damico RL, Kolb TM, Mathai SC, Mukherjee M, Zimmerman SL, Shah AA, Wigley FM, Houston BA, Hassoun PM, Kass DA, Tedford RJ, Hsu S. Exercise right ventricular ejection fraction predicts right ventricular contractile reserve. J Heart Lung Transplant 40: 504–512, 2021. doi:10.1016/j.healun.2021.02.005.33752973)
Ireland CG, Damico RL, Kolb TM, Mathai SC, Mukherjee M, Zimmerman SL, Shah AA, Wigley FM, Houston BA, Hassoun PM, Kass DA, Tedford RJ, Hsu S. Exercise right ventricular ejection fraction predicts right ventricular contractile reserve. J Heart Lung Transplant 40: 504–512, 2021. doi:10.1016/j.healun.2021.02.005.33752973Ireland CG, Damico RL, Kolb TM, Mathai SC, Mukherjee M, Zimmerman SL, Shah AA, Wigley FM, Houston BA, Hassoun PM, Kass DA, Tedford RJ, Hsu S. Exercise right ventricular ejection fraction predicts right ventricular contractile reserve. J Heart Lung Transplant 40: 504–512, 2021. doi:10.1016/j.healun.2021.02.005.33752973, Ireland CG, Damico RL, Kolb TM, Mathai SC, Mukherjee M, Zimmerman SL, Shah AA, Wigley FM, Houston BA, Hassoun PM, Kass DA, Tedford RJ, Hsu S. Exercise right ventricular ejection fraction predicts right ventricular contractile reserve. J Heart Lung Transplant 40: 504–512, 2021. doi:10.1016/j.healun.2021.02.005.33752973
( Melhem NJ, Chajadine M, Gomez I, Howangyin K-Y, Bouvet M, Knosp C, Sun Y, Rouanet M, Laurans L, Cazorla O, Lemitre M, Vilar J, Mallat Z, Tedgui A, Ait-Oufella H, Hulot J-S, Callebert J, Launay J-M, Fauconnier J, Silvestre J-S, Taleb S. Endothelial cell indoleamine 2, 3-dioxygenase 1 alters cardiac function after myocardial infarction through kynurenine. Circulation 143: 566–580, 2021. doi:10.1161/CIRCULATIONAHA.120.050301.33272024)
Melhem NJ, Chajadine M, Gomez I, Howangyin K-Y, Bouvet M, Knosp C, Sun Y, Rouanet M, Laurans L, Cazorla O, Lemitre M, Vilar J, Mallat Z, Tedgui A, Ait-Oufella H, Hulot J-S, Callebert J, Launay J-M, Fauconnier J, Silvestre J-S, Taleb S. Endothelial cell indoleamine 2, 3-dioxygenase 1 alters cardiac function after myocardial infarction through kynurenine. Circulation 143: 566–580, 2021. doi:10.1161/CIRCULATIONAHA.120.050301.33272024Melhem NJ, Chajadine M, Gomez I, Howangyin K-Y, Bouvet M, Knosp C, Sun Y, Rouanet M, Laurans L, Cazorla O, Lemitre M, Vilar J, Mallat Z, Tedgui A, Ait-Oufella H, Hulot J-S, Callebert J, Launay J-M, Fauconnier J, Silvestre J-S, Taleb S. Endothelial cell indoleamine 2, 3-dioxygenase 1 alters cardiac function after myocardial infarction through kynurenine. Circulation 143: 566–580, 2021. doi:10.1161/CIRCULATIONAHA.120.050301.33272024, Melhem NJ, Chajadine M, Gomez I, Howangyin K-Y, Bouvet M, Knosp C, Sun Y, Rouanet M, Laurans L, Cazorla O, Lemitre M, Vilar J, Mallat Z, Tedgui A, Ait-Oufella H, Hulot J-S, Callebert J, Launay J-M, Fauconnier J, Silvestre J-S, Taleb S. Endothelial cell indoleamine 2, 3-dioxygenase 1 alters cardiac function after myocardial infarction through kynurenine. Circulation 143: 566–580, 2021. doi:10.1161/CIRCULATIONAHA.120.050301.33272024
D Schranner, G Kastenmüller, M Schönfelder, W Römisch-Margl, H Wackerhage (2020)
Metabolite concentration changes in humans after a bout of exercise: a systematic review of exercise metabolomics studies, 6
( Lahm T, Douglas IS, Archer SL, Bogaard HJ, Chesler NC, Haddad F, Hemnes AR, Kawut SM, Kline JA, Kolb TM, Mathai SC, Mercier O, Michelakis ED, Naeije R, Tuder RM, Ventetuolo CE, Vieillard-Baron A, Voelkel NF, Vonk-Noordegraaf A, Hassoun PM; American Thoracic Society Assembly on Pulmonary Circulation. Assessment of right ventricular function in the research setting: knowledge gaps and pathways forward. an official American Thoracic Society Research Statement. Am J Respir Crit Care Med 198: e15–e43, 2018. doi:10.1164/rccm.201806-1160ST.30109950)
Lahm T, Douglas IS, Archer SL, Bogaard HJ, Chesler NC, Haddad F, Hemnes AR, Kawut SM, Kline JA, Kolb TM, Mathai SC, Mercier O, Michelakis ED, Naeije R, Tuder RM, Ventetuolo CE, Vieillard-Baron A, Voelkel NF, Vonk-Noordegraaf A, Hassoun PM; American Thoracic Society Assembly on Pulmonary Circulation. Assessment of right ventricular function in the research setting: knowledge gaps and pathways forward. an official American Thoracic Society Research Statement. Am J Respir Crit Care Med 198: e15–e43, 2018. doi:10.1164/rccm.201806-1160ST.30109950Lahm T, Douglas IS, Archer SL, Bogaard HJ, Chesler NC, Haddad F, Hemnes AR, Kawut SM, Kline JA, Kolb TM, Mathai SC, Mercier O, Michelakis ED, Naeije R, Tuder RM, Ventetuolo CE, Vieillard-Baron A, Voelkel NF, Vonk-Noordegraaf A, Hassoun PM; American Thoracic Society Assembly on Pulmonary Circulation. Assessment of right ventricular function in the research setting: knowledge gaps and pathways forward. an official American Thoracic Society Research Statement. Am J Respir Crit Care Med 198: e15–e43, 2018. doi:10.1164/rccm.201806-1160ST.30109950, Lahm T, Douglas IS, Archer SL, Bogaard HJ, Chesler NC, Haddad F, Hemnes AR, Kawut SM, Kline JA, Kolb TM, Mathai SC, Mercier O, Michelakis ED, Naeije R, Tuder RM, Ventetuolo CE, Vieillard-Baron A, Voelkel NF, Vonk-Noordegraaf A, Hassoun PM; American Thoracic Society Assembly on Pulmonary Circulation. Assessment of right ventricular function in the research setting: knowledge gaps and pathways forward. an official American Thoracic Society Research Statement. Am J Respir Crit Care Med 198: e15–e43, 2018. doi:10.1164/rccm.201806-1160ST.30109950
A Vonk Noordegraaf, KM Chin, F Haddad, PM Hassoun, AR Hemnes, SR Hopkins, SM Kawut, D Langleben, J Lumens, R Naeije (2019)
Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update, 53
( Donoho D, Jin J. Higher criticism thresholding: optimal feature selection when useful features are rare and weak. Proc Natl Acad Sci USA 105: 14790–14795, 2008. doi:10.1073/pnas.0807471105.18815365)
Donoho D, Jin J. Higher criticism thresholding: optimal feature selection when useful features are rare and weak. Proc Natl Acad Sci USA 105: 14790–14795, 2008. doi:10.1073/pnas.0807471105.18815365Donoho D, Jin J. Higher criticism thresholding: optimal feature selection when useful features are rare and weak. Proc Natl Acad Sci USA 105: 14790–14795, 2008. doi:10.1073/pnas.0807471105.18815365, Donoho D, Jin J. Higher criticism thresholding: optimal feature selection when useful features are rare and weak. Proc Natl Acad Sci USA 105: 14790–14795, 2008. doi:10.1073/pnas.0807471105.18815365
S Hsu, BA Houston, E Tampakakis, AC Bacher, PS Rhodes, SC Mathai, RL Damico, TM Kolb, LK Hummers, AA Shah, Z McMahan, CP Corona-Villalobos, SL Zimmerman, FM Wigley, PM Hassoun, DA Kass, RJ Tedford (2016)
Right ventricular functional reserve in pulmonary arterial hypertension, 133
( Lewis GD, Ngo D, Hemnes AR, Farrell L, Domos C, Pappagianopoulos PP, Dhakal BP, Souza A, Shi X, Pugh ME, Beloiartsev A, Sinha S, Clish CB, Gerszten RE. Metabolic profiling of right ventricular-pulmonary vascular function reveals circulating biomarkers of pulmonary hypertension. J Am Coll Cardiol 67: 174–189, 2016. doi:10.1016/j.jacc.2015.10.072.26791065)
Lewis GD, Ngo D, Hemnes AR, Farrell L, Domos C, Pappagianopoulos PP, Dhakal BP, Souza A, Shi X, Pugh ME, Beloiartsev A, Sinha S, Clish CB, Gerszten RE. Metabolic profiling of right ventricular-pulmonary vascular function reveals circulating biomarkers of pulmonary hypertension. J Am Coll Cardiol 67: 174–189, 2016. doi:10.1016/j.jacc.2015.10.072.26791065Lewis GD, Ngo D, Hemnes AR, Farrell L, Domos C, Pappagianopoulos PP, Dhakal BP, Souza A, Shi X, Pugh ME, Beloiartsev A, Sinha S, Clish CB, Gerszten RE. Metabolic profiling of right ventricular-pulmonary vascular function reveals circulating biomarkers of pulmonary hypertension. J Am Coll Cardiol 67: 174–189, 2016. doi:10.1016/j.jacc.2015.10.072.26791065, Lewis GD, Ngo D, Hemnes AR, Farrell L, Domos C, Pappagianopoulos PP, Dhakal BP, Souza A, Shi X, Pugh ME, Beloiartsev A, Sinha S, Clish CB, Gerszten RE. Metabolic profiling of right ventricular-pulmonary vascular function reveals circulating biomarkers of pulmonary hypertension. J Am Coll Cardiol 67: 174–189, 2016. doi:10.1016/j.jacc.2015.10.072.26791065
A Boucly, J Weatherald, L Savale, X Jaïs, V Cottin, G Prevot, F Picard, P de Groote, M Jevnikar, E Bergot, A Chaouat, C Chabanne, A Bourdin, F Parent, D Montani, G Simonneau, M Humbert, O Sitbon (2017)
Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension, 50
( Ghosh S, Gupta M, Xu W, Mavrakis DA, Janocha AJ, Comhair SAA, Haque MM, Stuehr DJ, Yu J, Polgar P, Naga Prasad SV, Erzurum SC. Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 310: L1199–L1205, 2016. doi:10.1152/ajplung.00092.2016.27130529)
Ghosh S, Gupta M, Xu W, Mavrakis DA, Janocha AJ, Comhair SAA, Haque MM, Stuehr DJ, Yu J, Polgar P, Naga Prasad SV, Erzurum SC. Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 310: L1199–L1205, 2016. doi:10.1152/ajplung.00092.2016.27130529Ghosh S, Gupta M, Xu W, Mavrakis DA, Janocha AJ, Comhair SAA, Haque MM, Stuehr DJ, Yu J, Polgar P, Naga Prasad SV, Erzurum SC. Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 310: L1199–L1205, 2016. doi:10.1152/ajplung.00092.2016.27130529, Ghosh S, Gupta M, Xu W, Mavrakis DA, Janocha AJ, Comhair SAA, Haque MM, Stuehr DJ, Yu J, Polgar P, Naga Prasad SV, Erzurum SC. Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 310: L1199–L1205, 2016. doi:10.1152/ajplung.00092.2016.27130529
( Svedjeholm R, Ekroth R, Joachimsson PO, Ronquist G, Svensson S, Tydén H. Myocardial uptake of amino acids and other substrates in relation to myocardial oxygen consumption four hours after cardiac operations. J Thorac Cardiovasc Surg 101: 688–694, 1991. doi:10.1016/S0022-5223(19)36700-5. 2008107)
Svedjeholm R, Ekroth R, Joachimsson PO, Ronquist G, Svensson S, Tydén H. Myocardial uptake of amino acids and other substrates in relation to myocardial oxygen consumption four hours after cardiac operations. J Thorac Cardiovasc Surg 101: 688–694, 1991. doi:10.1016/S0022-5223(19)36700-5. 2008107Svedjeholm R, Ekroth R, Joachimsson PO, Ronquist G, Svensson S, Tydén H. Myocardial uptake of amino acids and other substrates in relation to myocardial oxygen consumption four hours after cardiac operations. J Thorac Cardiovasc Surg 101: 688–694, 1991. doi:10.1016/S0022-5223(19)36700-5. 2008107, Svedjeholm R, Ekroth R, Joachimsson PO, Ronquist G, Svensson S, Tydén H. Myocardial uptake of amino acids and other substrates in relation to myocardial oxygen consumption four hours after cardiac operations. J Thorac Cardiovasc Surg 101: 688–694, 1991. doi:10.1016/S0022-5223(19)36700-5. 2008107
N Nagaya, M Uematsu, T Satoh, S Kyotani, F Sakamaki, N Nakanishi, M Yamagishi, T Kunieda, K Miyatake (1999)
Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension, 160
( Cai Z, Tian S, Klein T, Tu L, Geenen LW, Koudstaal T, van den Bosch AE, de Rijke YB, Reiss IKM, Boersma E, van der Ley C, Van Faassen M, Kema I, Duncker DJ, Boomars KA, Tran-Lundmark K, Guignabert C, Merkus D. Kynurenine metabolites predict survival in pulmonary arterial hypertension: a role for IL-6/IL-6Rα. Sci Rep 12: 12326, 2022. doi:10.1038/s41598-022-15039-3.35853948)
Cai Z, Tian S, Klein T, Tu L, Geenen LW, Koudstaal T, van den Bosch AE, de Rijke YB, Reiss IKM, Boersma E, van der Ley C, Van Faassen M, Kema I, Duncker DJ, Boomars KA, Tran-Lundmark K, Guignabert C, Merkus D. Kynurenine metabolites predict survival in pulmonary arterial hypertension: a role for IL-6/IL-6Rα. Sci Rep 12: 12326, 2022. doi:10.1038/s41598-022-15039-3.35853948Cai Z, Tian S, Klein T, Tu L, Geenen LW, Koudstaal T, van den Bosch AE, de Rijke YB, Reiss IKM, Boersma E, van der Ley C, Van Faassen M, Kema I, Duncker DJ, Boomars KA, Tran-Lundmark K, Guignabert C, Merkus D. Kynurenine metabolites predict survival in pulmonary arterial hypertension: a role for IL-6/IL-6Rα. Sci Rep 12: 12326, 2022. doi:10.1038/s41598-022-15039-3.35853948, Cai Z, Tian S, Klein T, Tu L, Geenen LW, Koudstaal T, van den Bosch AE, de Rijke YB, Reiss IKM, Boersma E, van der Ley C, Van Faassen M, Kema I, Duncker DJ, Boomars KA, Tran-Lundmark K, Guignabert C, Merkus D. Kynurenine metabolites predict survival in pulmonary arterial hypertension: a role for IL-6/IL-6Rα. Sci Rep 12: 12326, 2022. doi:10.1038/s41598-022-15039-3.35853948
N Nagaya, M Uematsu, H Oya, N Sato, F Sakamaki, S Kyotani, K Ueno, N Nakanishi, M Yamagishi, K Miyatake (2001)
Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension, 163
MI Brener, A Masoumi, VG Ng, K Tello, MB Bastos, WK Cornwell, S Hsu, RJ Tedford, P Lurz, K-P Rommel, K-P Kresoja, SF Nagueh, MK Kanwar, NK Kapur, G Hiremath, M Sarraf, AJM Van Den Enden, NM Van Mieghem, PM Heerdt, RT Hahn, SK Kodali, GT Sayer, N Uriel, D Burkhoff (2022)
Invasive right ventricular pressure-volume analysis: basic principles, clinical applications, and practical recommendations, 15
( Mathai SC, Bueso M, Hummers LK, Boyce D, Lechtzin N, Le Pavec J, Campo A, Champion HC, Housten T, Forfia PR, Zaiman AL, Wigley FM, Girgis RE, Hassoun PM. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J 35: 95–104, 2010. doi:10.1183/09031936.00074309.19643943)
Mathai SC, Bueso M, Hummers LK, Boyce D, Lechtzin N, Le Pavec J, Campo A, Champion HC, Housten T, Forfia PR, Zaiman AL, Wigley FM, Girgis RE, Hassoun PM. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J 35: 95–104, 2010. doi:10.1183/09031936.00074309.19643943Mathai SC, Bueso M, Hummers LK, Boyce D, Lechtzin N, Le Pavec J, Campo A, Champion HC, Housten T, Forfia PR, Zaiman AL, Wigley FM, Girgis RE, Hassoun PM. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J 35: 95–104, 2010. doi:10.1183/09031936.00074309.19643943, Mathai SC, Bueso M, Hummers LK, Boyce D, Lechtzin N, Le Pavec J, Campo A, Champion HC, Housten T, Forfia PR, Zaiman AL, Wigley FM, Girgis RE, Hassoun PM. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J 35: 95–104, 2010. doi:10.1183/09031936.00074309.19643943
( Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen SL, Vichinsky EP, Morris SM Jr, Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 294: 81–90, 2005. doi:10.1001/jama.294.1.81.15998894)
Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen SL, Vichinsky EP, Morris SM Jr, Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 294: 81–90, 2005. doi:10.1001/jama.294.1.81.15998894Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen SL, Vichinsky EP, Morris SM Jr, Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 294: 81–90, 2005. doi:10.1001/jama.294.1.81.15998894, Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen SL, Vichinsky EP, Morris SM Jr, Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 294: 81–90, 2005. doi:10.1001/jama.294.1.81.15998894
( Tedford RJ, Mudd JO, Girgis RE, Mathai SC, Zaiman AL, Housten-Harris T, Boyce D, Kelemen BW, Bacher AC, Shah AA, Hummers LK, Wigley FM, Russell SD, Saggar R, Saggar R, Maughan WL, Hassoun PM, Kass DA. Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circ Heart Fail 6: 953–963, 2013. doi:10.1161/CIRCHEARTFAILURE.112.000008.23797369)
Tedford RJ, Mudd JO, Girgis RE, Mathai SC, Zaiman AL, Housten-Harris T, Boyce D, Kelemen BW, Bacher AC, Shah AA, Hummers LK, Wigley FM, Russell SD, Saggar R, Saggar R, Maughan WL, Hassoun PM, Kass DA. Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circ Heart Fail 6: 953–963, 2013. doi:10.1161/CIRCHEARTFAILURE.112.000008.23797369Tedford RJ, Mudd JO, Girgis RE, Mathai SC, Zaiman AL, Housten-Harris T, Boyce D, Kelemen BW, Bacher AC, Shah AA, Hummers LK, Wigley FM, Russell SD, Saggar R, Saggar R, Maughan WL, Hassoun PM, Kass DA. Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circ Heart Fail 6: 953–963, 2013. doi:10.1161/CIRCHEARTFAILURE.112.000008.23797369, Tedford RJ, Mudd JO, Girgis RE, Mathai SC, Zaiman AL, Housten-Harris T, Boyce D, Kelemen BW, Bacher AC, Shah AA, Hummers LK, Wigley FM, Russell SD, Saggar R, Saggar R, Maughan WL, Hassoun PM, Kass DA. Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension. Circ Heart Fail 6: 953–963, 2013. doi:10.1161/CIRCHEARTFAILURE.112.000008.23797369
Y Tanada, T Shioi, T Kato, A Kawamoto, J Okuda, T Kimura (2015)
Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats, 137
( Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA, Howard LS, Kiely DG, Peacock AJ, Pepke-Zaba J, Toshner MR, Wort SJ, Gibbs JSR, Lawrie A, Gräf S, Morrell NW, Wilkins MR. Plasma metabolomics implicates modified transfer RNAs and altered bioenergetics in the outcomes of pulmonary arterial hypertension. Circulation 135: 460–475, 2017. doi:10.1161/CIRCULATIONAHA.116.024602.27881557)
Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA, Howard LS, Kiely DG, Peacock AJ, Pepke-Zaba J, Toshner MR, Wort SJ, Gibbs JSR, Lawrie A, Gräf S, Morrell NW, Wilkins MR. Plasma metabolomics implicates modified transfer RNAs and altered bioenergetics in the outcomes of pulmonary arterial hypertension. Circulation 135: 460–475, 2017. doi:10.1161/CIRCULATIONAHA.116.024602.27881557Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA, Howard LS, Kiely DG, Peacock AJ, Pepke-Zaba J, Toshner MR, Wort SJ, Gibbs JSR, Lawrie A, Gräf S, Morrell NW, Wilkins MR. Plasma metabolomics implicates modified transfer RNAs and altered bioenergetics in the outcomes of pulmonary arterial hypertension. Circulation 135: 460–475, 2017. doi:10.1161/CIRCULATIONAHA.116.024602.27881557, Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA, Howard LS, Kiely DG, Peacock AJ, Pepke-Zaba J, Toshner MR, Wort SJ, Gibbs JSR, Lawrie A, Gräf S, Morrell NW, Wilkins MR. Plasma metabolomics implicates modified transfer RNAs and altered bioenergetics in the outcomes of pulmonary arterial hypertension. Circulation 135: 460–475, 2017. doi:10.1161/CIRCULATIONAHA.116.024602.27881557
CR Morris, GJ Kato, M Poljakovic, X Wang, WC Blackwelder, V Sachdev, SL Hazen, EP Vichinsky, SM Morris, MT Gladwin (2005)
Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease, 294
( Galiè 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 MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Esp Cardiol (Engl Ed) 69: 177, 2016. doi:10.1016/j.rec.2016.01.002.26837729)
Galiè 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 MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Esp Cardiol (Engl Ed) 69: 177, 2016. doi:10.1016/j.rec.2016.01.002.26837729Galiè 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 MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Esp Cardiol (Engl Ed) 69: 177, 2016. doi:10.1016/j.rec.2016.01.002.26837729, Galiè 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 MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Esp Cardiol (Engl Ed) 69: 177, 2016. doi:10.1016/j.rec.2016.01.002.26837729
( Tanada Y, Shioi T, Kato T, Kawamoto A, Okuda J, Kimura T. Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats. Life Sci 137: 20–27, 2015. doi:10.1016/j.lfs.2015.06.021.26141987)
Tanada Y, Shioi T, Kato T, Kawamoto A, Okuda J, Kimura T. Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats. Life Sci 137: 20–27, 2015. doi:10.1016/j.lfs.2015.06.021.26141987Tanada Y, Shioi T, Kato T, Kawamoto A, Okuda J, Kimura T. Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats. Life Sci 137: 20–27, 2015. doi:10.1016/j.lfs.2015.06.021.26141987, Tanada Y, Shioi T, Kato T, Kawamoto A, Okuda J, Kimura T. Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats. Life Sci 137: 20–27, 2015. doi:10.1016/j.lfs.2015.06.021.26141987
NJ Melhem, M Chajadine, I Gomez, K-Y Howangyin, M Bouvet, C Knosp, Y Sun, M Rouanet, L Laurans, O Cazorla, M Lemitre, J Vilar, Z Mallat, A Tedgui, H Ait-Oufella, J-S Hulot, J Callebert, J-M Launay, J Fauconnier, J-S Silvestre, S Taleb (2021)
Endothelial cell indoleamine 2, 3-dioxygenase 1 alters cardiac function after myocardial infarction through kynurenine, 143
( Chun H, Keleş S. Sparse partial least squares regression for simultaneous dimension reduction and variable selection. J R Stat Soc Series B Stat Methodol 72: 3–25, 2010. doi:10.1111/j.1467-9868.2009.00723.x.20107611)
Chun H, Keleş S. Sparse partial least squares regression for simultaneous dimension reduction and variable selection. J R Stat Soc Series B Stat Methodol 72: 3–25, 2010. doi:10.1111/j.1467-9868.2009.00723.x.20107611Chun H, Keleş S. Sparse partial least squares regression for simultaneous dimension reduction and variable selection. J R Stat Soc Series B Stat Methodol 72: 3–25, 2010. doi:10.1111/j.1467-9868.2009.00723.x.20107611, Chun H, Keleş S. Sparse partial least squares regression for simultaneous dimension reduction and variable selection. J R Stat Soc Series B Stat Methodol 72: 3–25, 2010. doi:10.1111/j.1467-9868.2009.00723.x.20107611
Z Cai, S Tian, T Klein, L Tu, LW Geenen, T Koudstaal, AE van den Bosch, YB de Rijke, IKM Reiss, E Boersma, C van der Ley, M Van Faassen, I Kema, DJ Duncker, KA Boomars, K Tran-Lundmark, C Guignabert, D Merkus (2022)
Kynurenine metabolites predict survival in pulmonary arterial hypertension: a role for IL-6/IL-6Rα, 12
( Boucly A, Weatherald J, Savale L, Jaïs X, Cottin V, Prevot G, Picard F, de Groote P, Jevnikar M, Bergot E, Chaouat A, Chabanne C, Bourdin A, Parent F, Montani D, Simonneau G, Humbert M, Sitbon O. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J 50: 1700889, 2017.doi:10.1183/13993003.00889-2017. 28775050)
Boucly A, Weatherald J, Savale L, Jaïs X, Cottin V, Prevot G, Picard F, de Groote P, Jevnikar M, Bergot E, Chaouat A, Chabanne C, Bourdin A, Parent F, Montani D, Simonneau G, Humbert M, Sitbon O. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J 50: 1700889, 2017.doi:10.1183/13993003.00889-2017. 28775050Boucly A, Weatherald J, Savale L, Jaïs X, Cottin V, Prevot G, Picard F, de Groote P, Jevnikar M, Bergot E, Chaouat A, Chabanne C, Bourdin A, Parent F, Montani D, Simonneau G, Humbert M, Sitbon O. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J 50: 1700889, 2017.doi:10.1183/13993003.00889-2017. 28775050, Boucly A, Weatherald J, Savale L, Jaïs X, Cottin V, Prevot G, Picard F, de Groote P, Jevnikar M, Bergot E, Chaouat A, Chabanne C, Bourdin A, Parent F, Montani D, Simonneau G, Humbert M, Sitbon O. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J 50: 1700889, 2017.doi:10.1183/13993003.00889-2017. 28775050
( Fijalkowska A, Kurzyna M, Torbicki A, Szewczyk G, Florczyk M, Pruszczyk P, Szturmowicz M. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 129: 1313–1321, 2006. doi:10.1378/chest.129.5.1313.16685024)
Fijalkowska A, Kurzyna M, Torbicki A, Szewczyk G, Florczyk M, Pruszczyk P, Szturmowicz M. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 129: 1313–1321, 2006. doi:10.1378/chest.129.5.1313.16685024Fijalkowska A, Kurzyna M, Torbicki A, Szewczyk G, Florczyk M, Pruszczyk P, Szturmowicz M. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 129: 1313–1321, 2006. doi:10.1378/chest.129.5.1313.16685024, Fijalkowska A, Kurzyna M, Torbicki A, Szewczyk G, Florczyk M, Pruszczyk P, Szturmowicz M. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 129: 1313–1321, 2006. doi:10.1378/chest.129.5.1313.16685024
( Chong J, Xia J. MetaboAnalystR: an R package for flexible and reproducible analysis of metabolomics data. Bioinformatics 34: 4313–4314, 2018. doi:10.1093/bioinformatics/bty528.29955821)
Chong J, Xia J. MetaboAnalystR: an R package for flexible and reproducible analysis of metabolomics data. Bioinformatics 34: 4313–4314, 2018. doi:10.1093/bioinformatics/bty528.29955821Chong J, Xia J. MetaboAnalystR: an R package for flexible and reproducible analysis of metabolomics data. Bioinformatics 34: 4313–4314, 2018. doi:10.1093/bioinformatics/bty528.29955821, Chong J, Xia J. MetaboAnalystR: an R package for flexible and reproducible analysis of metabolomics data. Bioinformatics 34: 4313–4314, 2018. doi:10.1093/bioinformatics/bty528.29955821
( Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn J-Y, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui W-J, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133: 2038–2049, 2016. doi:10.1161/CIRCULATIONAHA.115.020226.27059949)
Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn J-Y, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui W-J, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133: 2038–2049, 2016. doi:10.1161/CIRCULATIONAHA.115.020226.27059949Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn J-Y, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui W-J, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133: 2038–2049, 2016. doi:10.1161/CIRCULATIONAHA.115.020226.27059949, Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, Jeyaraj D, Youn J-Y, Ren S, Liu Y, Rau CD, Shah S, Ilkayeva O, Gui W-J, William NS, Wynn RM, Newgard CB, Cai H, Xiao X, Chuang DT, Schulze PC, Lynch C, Jain MK, Wang Y. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133: 2038–2049, 2016. doi:10.1161/CIRCULATIONAHA.115.020226.27059949
SC Mathai, M Bueso, LK Hummers, D Boyce, N Lechtzin, J Le Pavec, A Campo, HC Champion, T Housten, PR Forfia, AL Zaiman, FM Wigley, RE Girgis, PM Hassoun (2010)
Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension, 35
( Hsu S, Houston BA, Tampakakis E, Bacher AC, Rhodes PS, Mathai SC, Damico RL, Kolb TM, Hummers LK, Shah AA, McMahan Z, Corona-Villalobos CP, Zimmerman SL, Wigley FM, Hassoun PM, Kass DA, Tedford RJ. Right ventricular functional reserve in pulmonary arterial hypertension. Circulation 133: 2413–2422, 2016. doi:10.1161/CIRCULATIONAHA.116.022082.27169739)
Hsu S, Houston BA, Tampakakis E, Bacher AC, Rhodes PS, Mathai SC, Damico RL, Kolb TM, Hummers LK, Shah AA, McMahan Z, Corona-Villalobos CP, Zimmerman SL, Wigley FM, Hassoun PM, Kass DA, Tedford RJ. Right ventricular functional reserve in pulmonary arterial hypertension. Circulation 133: 2413–2422, 2016. doi:10.1161/CIRCULATIONAHA.116.022082.27169739Hsu S, Houston BA, Tampakakis E, Bacher AC, Rhodes PS, Mathai SC, Damico RL, Kolb TM, Hummers LK, Shah AA, McMahan Z, Corona-Villalobos CP, Zimmerman SL, Wigley FM, Hassoun PM, Kass DA, Tedford RJ. Right ventricular functional reserve in pulmonary arterial hypertension. Circulation 133: 2413–2422, 2016. doi:10.1161/CIRCULATIONAHA.116.022082.27169739, Hsu S, Houston BA, Tampakakis E, Bacher AC, Rhodes PS, Mathai SC, Damico RL, Kolb TM, Hummers LK, Shah AA, McMahan Z, Corona-Villalobos CP, Zimmerman SL, Wigley FM, Hassoun PM, Kass DA, Tedford RJ. Right ventricular functional reserve in pulmonary arterial hypertension. Circulation 133: 2413–2422, 2016. doi:10.1161/CIRCULATIONAHA.116.022082.27169739
( Vonk Noordegraaf A, Chin KM, Haddad F, Hassoun PM, Hemnes AR, Hopkins SR, Kawut SM, Langleben D, Lumens J, Naeije R. Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update. Eur Respir J 53: 1801900, 2019.doi:10.1183/13993003.01900-2018. 30545976)
Vonk Noordegraaf A, Chin KM, Haddad F, Hassoun PM, Hemnes AR, Hopkins SR, Kawut SM, Langleben D, Lumens J, Naeije R. Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update. Eur Respir J 53: 1801900, 2019.doi:10.1183/13993003.01900-2018. 30545976Vonk Noordegraaf A, Chin KM, Haddad F, Hassoun PM, Hemnes AR, Hopkins SR, Kawut SM, Langleben D, Lumens J, Naeije R. Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update. Eur Respir J 53: 1801900, 2019.doi:10.1183/13993003.01900-2018. 30545976, Vonk Noordegraaf A, Chin KM, Haddad F, Hassoun PM, Hemnes AR, Hopkins SR, Kawut SM, Langleben D, Lumens J, Naeije R. Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update. Eur Respir J 53: 1801900, 2019.doi:10.1183/13993003.01900-2018. 30545976
A Vonk-Noordegraaf, F Haddad, KM Chin, PR Forfia, SM Kawut, J Lumens, R Naeije, J Newman, RJ Oudiz, S Provencher, A Torbicki, NF Voelkel, PM Hassoun (2013)
Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology, 62
RJ Tedford, JO Mudd, RE Girgis, SC Mathai, AL Zaiman, T Housten-Harris, D Boyce, BW Kelemen, AC Bacher, AA Shah, LK Hummers, FM Wigley, SD Russell, R Saggar, R Saggar, WL Maughan, PM Hassoun, DA Kass (2013)
Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension, 6
T Lahm, IS Douglas, SL Archer, HJ Bogaard, NC Chesler, F Haddad, AR Hemnes, SM Kawut, JA Kline, TM Kolb, SC Mathai, O Mercier, ED Michelakis, R Naeije, RM Tuder, CE Ventetuolo, A Vieillard-Baron, NF Voelkel, A Vonk-Noordegraaf, PM Hassoun (2018)
Assessment of right ventricular function in the research setting: knowledge gaps and pathways forward. an official American Thoracic Society Research Statement, 198
( Chung L, Fairchild RM, Furst DE, Li S, Alkassab F, Bolster MB, Csuka ME, Derk CT, Domsic RT, Fischer A, Frech TM, Gomberg-Maitland M, Gordon JK, Hinchcliff M, Hsu V, Hummers LK, Khanna D, Medsger TAJ, Molitor JA, Preston IR, Schiopu E, Shapiro L, Hant F, Silver R, Simms R, Varga J, Steen VD, Zamanian RT. Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry. Clin Exp Rheumatol 35: 106–113, 2017. 27908301)
Chung L, Fairchild RM, Furst DE, Li S, Alkassab F, Bolster MB, Csuka ME, Derk CT, Domsic RT, Fischer A, Frech TM, Gomberg-Maitland M, Gordon JK, Hinchcliff M, Hsu V, Hummers LK, Khanna D, Medsger TAJ, Molitor JA, Preston IR, Schiopu E, Shapiro L, Hant F, Silver R, Simms R, Varga J, Steen VD, Zamanian RT. Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry. Clin Exp Rheumatol 35: 106–113, 2017. 27908301Chung L, Fairchild RM, Furst DE, Li S, Alkassab F, Bolster MB, Csuka ME, Derk CT, Domsic RT, Fischer A, Frech TM, Gomberg-Maitland M, Gordon JK, Hinchcliff M, Hsu V, Hummers LK, Khanna D, Medsger TAJ, Molitor JA, Preston IR, Schiopu E, Shapiro L, Hant F, Silver R, Simms R, Varga J, Steen VD, Zamanian RT. Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry. Clin Exp Rheumatol 35: 106–113, 2017. 27908301, Chung L, Fairchild RM, Furst DE, Li S, Alkassab F, Bolster MB, Csuka ME, Derk CT, Domsic RT, Fischer A, Frech TM, Gomberg-Maitland M, Gordon JK, Hinchcliff M, Hsu V, Hummers LK, Khanna D, Medsger TAJ, Molitor JA, Preston IR, Schiopu E, Shapiro L, Hant F, Silver R, Simms R, Varga J, Steen VD, Zamanian RT. Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry. Clin Exp Rheumatol 35: 106–113, 2017. 27908301
( Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, Yamagishi M, Kunieda T, Miyatake K. Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 160: 487–492, 1999. doi:10.1164/ajrccm.160.2.9812078.10430718)
Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, Yamagishi M, Kunieda T, Miyatake K. Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 160: 487–492, 1999. doi:10.1164/ajrccm.160.2.9812078.10430718Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, Yamagishi M, Kunieda T, Miyatake K. Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 160: 487–492, 1999. doi:10.1164/ajrccm.160.2.9812078.10430718, Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, Yamagishi M, Kunieda T, Miyatake K. Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 160: 487–492, 1999. doi:10.1164/ajrccm.160.2.9812078.10430718
R Svedjeholm, R Ekroth, PO Joachimsson, G Ronquist, S Svensson, H Tydén (1991)
Myocardial uptake of amino acids and other substrates in relation to myocardial oxygen consumption four hours after cardiac operations, 101
S Ghosh, M Gupta, W Xu, DA Mavrakis, AJ Janocha, SAA Comhair, MM Haque, DJ Stuehr, J Yu, P Polgar, SV Naga Prasad, SC Erzurum (2016)
Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension, 310
( van de Veerdonk MC, Kind T, Marcus JT, Mauritz G-J, Heymans MW, Bogaard H-J, Boonstra A, Marques KMJ, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 58: 2511–2519, 2011. doi:10.1016/j.jacc.2011.06.068.22133851)
van de Veerdonk MC, Kind T, Marcus JT, Mauritz G-J, Heymans MW, Bogaard H-J, Boonstra A, Marques KMJ, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 58: 2511–2519, 2011. doi:10.1016/j.jacc.2011.06.068.22133851van de Veerdonk MC, Kind T, Marcus JT, Mauritz G-J, Heymans MW, Bogaard H-J, Boonstra A, Marques KMJ, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 58: 2511–2519, 2011. doi:10.1016/j.jacc.2011.06.068.22133851, van de Veerdonk MC, Kind T, Marcus JT, Mauritz G-J, Heymans MW, Bogaard H-J, Boonstra A, Marques KMJ, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 58: 2511–2519, 2011. doi:10.1016/j.jacc.2011.06.068.22133851
MB Brown, A Kempf, CM Collins, GM Long, M Owens, S Gupta, Y Hellman, V Wong, M Farber, T Lahm (2018)
A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension: a pilot study, 8
S Hsu, CE Simpson, BA Houston, A Wand, T Sato, TM Kolb, SC Mathai, DA Kass, PM Hassoun, RL Damico, RJ Tedford (2020)
Multi-beat right ventricular-arterial coupling predicts clinical worsening in pulmonary arterial hypertension, 9
( Schranner D, Kastenmüller G, Schönfelder M, Römisch-Margl W, Wackerhage H. Metabolite concentration changes in humans after a bout of exercise: a systematic review of exercise metabolomics studies. Sports Med Open 6: 11, 2020. doi:10.1186/s40798-020-0238-4.32040782)
Schranner D, Kastenmüller G, Schönfelder M, Römisch-Margl W, Wackerhage H. Metabolite concentration changes in humans after a bout of exercise: a systematic review of exercise metabolomics studies. Sports Med Open 6: 11, 2020. doi:10.1186/s40798-020-0238-4.32040782Schranner D, Kastenmüller G, Schönfelder M, Römisch-Margl W, Wackerhage H. Metabolite concentration changes in humans after a bout of exercise: a systematic review of exercise metabolomics studies. Sports Med Open 6: 11, 2020. doi:10.1186/s40798-020-0238-4.32040782, Schranner D, Kastenmüller G, Schönfelder M, Römisch-Margl W, Wackerhage H. Metabolite concentration changes in humans after a bout of exercise: a systematic review of exercise metabolomics studies. Sports Med Open 6: 11, 2020. doi:10.1186/s40798-020-0238-4.32040782
L Chung, RM Fairchild, DE Furst, S Li, F Alkassab, MB Bolster, ME Csuka, CT Derk, RT Domsic, A Fischer, TM Frech, M Gomberg-Maitland, JK Gordon, M Hinchcliff, V Hsu, LK Hummers, D Khanna, TAJ Medsger, JA Molitor, IR Preston, E Schiopu, L Shapiro, F Hant, R Silver, R Simms, J Varga, VD Steen, RT Zamanian (2017)
Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry, 35
J Chong, J Xia (2018)
MetaboAnalystR: an R package for flexible and reproducible analysis of metabolomics data, 34
N Galiè, M Humbert, J-L Vachiery, S Gibbs, I Lang, A Torbicki, G Simonneau, A Peacock, A Vonk Noordegraaf, M Beghetti, A Ghofrani, MA Gomez Sanchez, G Hansmann, W Klepetko, P Lancellotti, M Matucci, T McDonagh, LA Pierard, PT Trindade, M Zompatori, M Hoeper (2016)
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension, 69
CE Simpson, RL Damico, L Hummers, RM Khair, TM Kolb, PM Hassoun, SC Mathai (2019)
Serum uric acid as a marker of disease risk, severity, and survival in systemic sclerosis-related pulmonary arterial hypertension, 9
( Kao CC, Wedes SH, Hsu JW, Bohren KM, Comhair SAA, Jahoor F, Erzurum SC. Arginine metabolic endotypes in pulmonary arterial hypertension. Pulm Circ 5: 124–134, 2015. doi:10.1086/679720.25992277)
Kao CC, Wedes SH, Hsu JW, Bohren KM, Comhair SAA, Jahoor F, Erzurum SC. Arginine metabolic endotypes in pulmonary arterial hypertension. Pulm Circ 5: 124–134, 2015. doi:10.1086/679720.25992277Kao CC, Wedes SH, Hsu JW, Bohren KM, Comhair SAA, Jahoor F, Erzurum SC. Arginine metabolic endotypes in pulmonary arterial hypertension. Pulm Circ 5: 124–134, 2015. doi:10.1086/679720.25992277, Kao CC, Wedes SH, Hsu JW, Bohren KM, Comhair SAA, Jahoor F, Erzurum SC. Arginine metabolic endotypes in pulmonary arterial hypertension. Pulm Circ 5: 124–134, 2015. doi:10.1086/679720.25992277
A Fijalkowska, M Kurzyna, A Torbicki, G Szewczyk, M Florczyk, P Pruszczyk, M Szturmowicz (2006)
Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension, 129
CE Simpson, RL Damico, PM Hassoun, LJ Martin, J Yang, MK Nies, RD Vaidya, S Brandal, MW Pauciulo, ED Austin, DD Ivy, WC Nichols, AD Everett (2020)
Noninvasive prognostic biomarkers for left heart failure as predictors of survival in pulmonary arterial hypertension, 157
CJ Rhodes, P Ghataorhe, J Wharton, KC Rue-Albrecht, C Hadinnapola, G Watson, M Bleda, M Haimel, G Coghlan, PA Corris, LS Howard, DG Kiely, AJ Peacock, J Pepke-Zaba, MR Toshner, SJ Wort, JSR Gibbs, A Lawrie, S Gräf, NW Morrell, MR Wilkins (2017)
Plasma metabolomics implicates modified transfer RNAs and altered bioenergetics in the outcomes of pulmonary arterial hypertension, 135
( Simpson CE, Damico RL, Hummers L, Khair RM, Kolb TM, Hassoun PM, Mathai SC. Serum uric acid as a marker of disease risk, severity, and survival in systemic sclerosis-related pulmonary arterial hypertension. Pulm Circ 9: 2045894019859477, 2019. doi:10.1177/2045894019859477.31384431)
Simpson CE, Damico RL, Hummers L, Khair RM, Kolb TM, Hassoun PM, Mathai SC. Serum uric acid as a marker of disease risk, severity, and survival in systemic sclerosis-related pulmonary arterial hypertension. Pulm Circ 9: 2045894019859477, 2019. doi:10.1177/2045894019859477.31384431Simpson CE, Damico RL, Hummers L, Khair RM, Kolb TM, Hassoun PM, Mathai SC. Serum uric acid as a marker of disease risk, severity, and survival in systemic sclerosis-related pulmonary arterial hypertension. Pulm Circ 9: 2045894019859477, 2019. doi:10.1177/2045894019859477.31384431, Simpson CE, Damico RL, Hummers L, Khair RM, Kolb TM, Hassoun PM, Mathai SC. Serum uric acid as a marker of disease risk, severity, and survival in systemic sclerosis-related pulmonary arterial hypertension. Pulm Circ 9: 2045894019859477, 2019. doi:10.1177/2045894019859477.31384431
H Chun, S Keleş (2010)
Sparse partial least squares regression for simultaneous dimension reduction and variable selection, 72
( Strimmer K. fdrtool: a versatile R package for estimating local and tail area-based false discovery rates. Bioinformatics 24: 1461–1462, 2008. doi:10.1093/bioinformatics/btn209.18441000)
Strimmer K. fdrtool: a versatile R package for estimating local and tail area-based false discovery rates. Bioinformatics 24: 1461–1462, 2008. doi:10.1093/bioinformatics/btn209.18441000Strimmer K. fdrtool: a versatile R package for estimating local and tail area-based false discovery rates. Bioinformatics 24: 1461–1462, 2008. doi:10.1093/bioinformatics/btn209.18441000, Strimmer K. fdrtool: a versatile R package for estimating local and tail area-based false discovery rates. Bioinformatics 24: 1461–1462, 2008. doi:10.1093/bioinformatics/btn209.18441000
D Donoho, J Jin (2008)
Higher criticism thresholding: optimal feature selection when useful features are rare and weak, 105
H Sun, KC Olson, C Gao, DA Prosdocimo, M Zhou, Z Wang, D Jeyaraj, J-Y Youn, S Ren, Y Liu, CD Rau, S Shah, O Ilkayeva, W-J Gui, NS William, RM Wynn, CB Newgard, H Cai, X Xiao, DT Chuang, PC Schulze, C Lynch, MK Jain, Y Wang (2016)
Catabolic defect of branched-chain amino acids promotes heart failure, 133
( Brown MB, Kempf A, Collins CM, Long GM, Owens M, Gupta S, Hellman Y, Wong V, Farber M, Lahm T. A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension: a pilot study. Pulm Circ 8: 2045893217743966, 2018. doi:10.1177/2045893217743966.29199900)
Brown MB, Kempf A, Collins CM, Long GM, Owens M, Gupta S, Hellman Y, Wong V, Farber M, Lahm T. A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension: a pilot study. Pulm Circ 8: 2045893217743966, 2018. doi:10.1177/2045893217743966.29199900Brown MB, Kempf A, Collins CM, Long GM, Owens M, Gupta S, Hellman Y, Wong V, Farber M, Lahm T. A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension: a pilot study. Pulm Circ 8: 2045893217743966, 2018. doi:10.1177/2045893217743966.29199900, Brown MB, Kempf A, Collins CM, Long GM, Owens M, Gupta S, Hellman Y, Wong V, Farber M, Lahm T. A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension: a pilot study. Pulm Circ 8: 2045893217743966, 2018. doi:10.1177/2045893217743966.29199900
29 Background: Right ventricular (RV) adaptation is the principal determinant of outcomes in pulmonary 30 arterial hypertension (PAH), however RV function is challenging to assess. RV responses to 31 hemodynamic stressors are particularly difficult to interrogate without invasive testing. This study 32 sought to identify metabolomic markers of in vivo right ventricular function and exercise performance in 33 PAH. 34 Methods: Consecutive subjects with PAH (n=23) underwent rest and exercise right heart catheterization 35 with multi‐beat pressure volume loop analysis. Pulmonary arterial blood was collected at rest and during 36 exercise. Mass spectrometry‐based targeted metabolomics were performed, and metabolic associations 37 with hemodynamics and comprehensive measures of RV function were determined using sparse partial 38 least squares regression. Metabolite profiles were compared to NT‐proBNP measurements for accuracy 39 in modeling ventriculo‐arterial parameters. 40 Results: Thirteen metabolites changed in abundance with exercise, including metabolites reflecting 41 increased arginine bioavailability, precursors of catecholamine and nucleotide synthesis, and branched 42 chain amino acids. Higher resting arginine bioavailability predicted more favorable exercise 43 hemodynamics and pressure‐flow relationships. Subjects with more severe PAH augmented arginine 44 bioavailability with exercise to a greater extent than subjects with less severe PAH. We identified 45 relationships between kynurenine pathway metabolism and impaired ventriculo‐arterial coupling, worse 46 RV diastolic function, lower RV contractility, diminished RV contractility with exercise, and RV dilation 47 with exercise. Metabolite profiles outperformed NT‐proBNP in modeling RV contractility, diastolic 48 function, and exercise performance. 49 Conclusions: Specific metabolite profiles correspond to RV functional measurements only obtainable via 50 invasive pressure‐volume loop analysis and predict RV responses to exercise. Metabolic profiling may 51 inform discovery of RV functional biomarkers. 52 53 New & Noteworthy 54 55 In this cohort of PAH patients, we investigate metabolomic associations with comprehensive right 56 ventricular (RV) functional measurements derived from multi‐beat RV pressure‐volume loop analysis. 57 Our results show that tryptophan metabolism, particularly the kynurenine pathway, is linked to intrinsic 58 RV function and PAH pathobiology. Findings also highlight the importance of arginine bioavailability in 59 the cardiopulmonary system's response to exercise stress. Metabolite profiles selected via unbiased 60 analysis outperformed NT‐proBNP in predicting load‐independent measures of RV function at rest and 61 cardiopulmonary system performance under stress. Overall, this work suggests the potential for select 62 metabolites to function as disease‐specific biomarkers, offers insights into PAH pathobiology, and 63 informs discovery of potentially targetable RV‐centric pathways. 64 65 Supplemental material available at: 66 https://doi.org/10.6084/m9.figshare.22263364 67 68 69 Introduction 70 The status of the right ventricle (RV) is the major determinant of survival in pulmonary arterial 1‐3 71 hypertension (PAH). Reliable surrogates of RV function would be valuable for predicting disease 72 trajectory and assisting clinical management decisions, particularly if these markers are dynamic such 73 that they vary as the RV changes. The N‐terminal prohormone of B‐type natriuretic peptide (NT‐ 74 proBNP), the current clinical gold standard biomarker, is reflective of myocyte stretch and secreted by 4‐8 75 ventricular cardiomyocytes. As such, NT‐proBNP is well‐positioned to reflect pressure and volume 76 loads presented to the ventricle, but it is perhaps less well‐suited to reflect comprehensive RV function, 77 particularly load‐independent metrics such as contractility, ventricular relaxation, or measures of 78 functional reserve (e.g., what will happen when the cardiopulmonary system is stressed). 79 PAH is characterized by dysregulated metabolism in the pulmonary vasculature and at the 9, 10 80 whole‐body level, and metabolomics can be used to characterize RV‐PA dysfunction. However, 81 previous studies have examined metabolite associations with hemodynamics and the pressure‐flow 9, 82 relationship, which are determined by characteristics of the pulmonary circulation, rather than the RV. 83 Cardiac‐specific contributions to the cardiopulmonary unit can be characterized by examining 3, 11 84 pressure‐volume relationships in the RV (PV loops). Invasive RV PV loops allow for gold‐standard 85 assessments of intrinsic RV contractility (end‐systolic elastance, or Ees), ventricular diastolic function, 12‐14 86 and stroke work. Relating ventricular contractile function to effective arterial elastance (Ea), a 87 lumped parameter reflective of afterload also derived from the PV loop, allows an assessment of how 12, 15 88 well contractile function is matched to afterload, a concept known as RV‐PA coupling (Ees/Ea). 89 When PV loops are measured at rest and with exercise, changes in RV contractility and chamber dilation 13, 16 90 illustrate RV functional reserve in vivo. 91 The present study leverages targeted metabolomics to examine metabolic associations with rest 92 and exercise hemodynamics, including PV loops at rest and with exercise, in a cohort of patients with 93 PAH. Because exercise poses a stressor to the cardiopulmonary system that prompts PAH symptoms and 94 can “unmask” occult pulmonary vascular disease, we sampled pulmonary arterial blood for 95 metabolomics both at rest and during exercise. We sought to identify metabolic profiles that closely 96 reflect RV functional parameters obtainable with PV loops and/or with exercise, hypothesizing that such 97 profiles could outperform NT‐proBNP in predicting RV function and exercise hemodynamics in PAH, and 98 secondarily reveal fundamentals of underlying disease pathobiology. 99 Methods 100 Cohort 101 Recruitment occurred at a single tertiary‐care center through referrals for diagnosis or 102 management of PAH. The study protocol was approved by the Johns Hopkins Institutional Review Board, 103 and all patients gave informed consent. Patients underwent cardiac magnetic resonance imaging (MRI), 104 transthoracic echocardiography, right heart catheterization (RHC), and invasive RV PV loop analysis on 105 the same day. Thereafter, patients were longitudinally followed for clinical worsening, which was 106 defined by any one of: ≥ 10% decline in 6‐minute walk distance, worsening World Health Organization 107 (WHO) functional class, PAH therapy escalation >3 months after index RHC, RV failure hospitalization, or 108 lung transplant or death. 109 Hemodynamic Assessment 110 Patients underwent standard RHC with an 8 French internal jugular introducer sheath, which 111 was then exchanged for dual‐entry 9 French sheath for placement of 5 French PV conductance catheter 112 and 4 French PA wedge catheter. The PV catheter was maintained in place during exertion, and peak 113 exercise was defined as symptom‐limited maximum effort with at least stage 2 (25 Watts, 4 minutes) 114 exertion using supine cycle ergometry during RHC. Serum samples were collected from the pulmonary 115 artery during rest and exercise. Multi‐beat PV loops were constructed based on simultaneous 12, 13 116 measurements of pressure and volume at different loading conditions, as previously described. PV 117 loops were analyzed to derive ventriculo‐arterial measurements including Ees and Ea, with the ratio of 118 elastances calculated as Ees/Ea. Tau, a load‐independent time constant of RV relaxation, was also 119 calculated. Supplemental Figure 1 in the Online Supplement outlines and describes the key ventriculo‐ 120 arterial variables that were evaluated for metabolomic associations. 121 PAH was diagnosed by a mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, pulmonary 122 vascular resistance (PVR) ≥ 3 Wood units, and pulmonary artery wedge pressure (PAWP) ≤ 15 mm Hg 123 during RHC, which was the consensus definition at the time of cohort enrollment. 124 Targeted Metabolomics 125 Multiplexed liquid chromatography‐mass spectrometry‐based targeted metabolomics were 126 performed on patient plasma samples at the Johns Hopkins Molecular Determinants Core at All 127 Children’s Hospital. All samples were obtained under fasting conditions. After standard sample 128 preparation, high pressure liquid chromatography was accomplished using a Shimadzu HPLC comprised 129 of a SIL‐30ACMP 6‐MTP autosampler and Nexera LC‐30AD HPLC Pumps (Shimadzu, Kyoto, Japan). 130 Chromatographic separation was performed using a pentafluorophenylpropyl column. Mass 131 spectrometry was performed using a triple quadrupole (QQQ) mass spectrometer (Shimadzu, LCMS‐ 132 8060, Kyoto, Japan) equipped with an electrospray ionization source used in both positive and negative 133 mode. Each batch of samples was run with a system suitability quality control, which was created from 134 commercially available plasma. Two hundred and forty‐one compounds plus 18 heavy standards were 135 measured. Chromatographic integration was performed using LabSolutions Insight (Version 3.5, 136 Shimadzu, Kyoto, Japan). 137 Statistical Analysis 138 Paired t‐tests were completed to assess for metabolite abundances that changed significantly 139 from rest to exercise. Associations between metabolites and RV‐PA clinical variables were examined 140 using sparse partial least squares regression (sPLS) with the spls package for R. The optimal tuning 141 parameter was selected by 10‐fold cross validation. Metabolite and clinical data were re‐scaled by 142 mean‐centering and dividing by the standard deviation of each variable in order to implement sPLS and 143 to facilitate interpretation and comparison. Pre‐exercise, post‐exercise, and the difference in pre‐ and 144 post‐exercise (delta exercise) metabolite measures were analyzed separately, and we fit a separate 145 model for each cardiopulmonary measure. Logistic regression was used to examine metabolite 146 associations with clinical outcomes. Significant metabolite predictors of clinical outcomes were selected 19, 20 147 by harsh criticism thresholding with the fdrtool package for R. Model accuracy comparisons between 148 metabolites and NT‐proBNP were performed using the area under receiver operating characteristics 149 curves (AUC) for binary outcome variables with the ROCit package for R, and R‐squared between 150 observed and predicted outcomes for continuous variables. Pathway enrichment analysis and pathway 151 topology analysis were performed to contextualize metabolomics results at the metabolic pathway 152 level, and pathway impact values were calculated using the MetaboAnalystR package for R. All 153 analyses were performed using R Statistical Software (v4.1.2; R Core Team 2021). 154 Results 155 Our PAH cohort (n=23) was predominantly female (83%) and predominantly white (83%) (Table 156 1). In general, subjects had mild‐to‐moderate disease, with median mPAP of 33 mmHg and PVR of 4.7 157 Wood Units. Median right ventricular ejection fraction (RVEF) assessed by cardiac MRI was preserved at 158 50% (interquartile range 39‐57%), however the median RV‐PA coupling ratio was less than 1.0 at 0.66 159 (IQR 0.45‐0.99) implying decoupling of RV contractility from afterload. Sixteen subjects had systemic 160 sclerosis‐associated PAH (SSc‐PAH), and 7 subjects had idiopathic PAH (IPAH). 161 Rest‐Exercise Differences 162 In subjects with PAH, 13 metabolite features had significantly different circulating 163 concentrations with exercise compared to rest measurements (Table 2 and Figure 1). Alanine and the 164 branched chain amino acids (BCAA) leucine and isoleucine increased in concentration with exercise, 165 along with phenylalanine, a catecholamine precursor; inosine, a precursor of nucleotide synthesis; and 166 N‐acetylated forms of leucine and asparagine. Measures of arginine bioavailability, including arg/orn 167 and GABR, increased with exercise, whereas ornithine, a product of the urea cycle, decreased. 168 There were significant associations between increases in circulating BCAAs with exercise and 169 clinical variables reflective of greater disease severity in PAH. For all ventriculo‐arterial parameters, delta 170 metabolite associations are provided in Supplemental Table S1. Greater delta valine was associated with 171 higher PVR at rest; greater delta leucine was associated with higher mPAP both at rest and with 172 exercise. Increases in arginine bioavailability with exercise were associated with higher PVR and lower 173 CO with exercise, though not with rest hemodynamics. 174 Exercise‐induced increases in circulating uridine, a pyrimidine nucleoside found only in RNA (not 175 present in DNA) that is essential for flux through the pentose phosphate pathway, were associated with 176 multiple cardiopulmonary measurements, including adverse exercise hemodynamics (higher mPAP, PVR 177 and lower CO with exercise), worse RV diastolic function (lower Tau), and steeper pulmonary pressure‐ 178 flow relationships. 179 Rest Metabolite Associations 180 Metabolic features of the kynurenine pathway, the major route for tryptophan catabolism in 181 humans, were inversely associated with several important measures of RV function, including Ees, 182 Ees/Ea, and RV functional reserve (delta Ees) in vivo. All pre‐exercise metabolite associations with 183 clinical parameters are provided in Supplemental Table S2, and a heatmap of the top 25 rest metabolite‐ 184 phenotype associations is presented in Figure 2a. Rest kynurenine was robustly associated with Tau, a 185 measure of RV diastolic function, such that each standard deviation increase in kynurenine 186 concentration was associated with one standard deviation lower Tau (beta coefficient ‐0.99, 95% CI ‐ 187 1.12 ‐ ‐0.69). In addition to kynurenine itself, its ratio to tryptophan, kyn/trp, a surrogate for kynurenine 188 pathway enzymatic activity, was significantly associated with worse RV‐PA coupling (Ees/Ea ‐0.44, 95% 189 CI ‐0.41 ‐ ‐0.05), lower RV contractility, (Ees ‐0.11, 95% CI ‐0.13 – ‐0.01), reduced contractility with 190 exercise (dEes ‐0.080, 95% CI ‐0.117 ‐ ‐0.005), and RV dilation with exercise (dEDV 0.105, 95% CI 0.017 – 191 0.126). Higher resting kynurenine concentrations were also associated with adverse resting pulmonary 192 hemodynamics (mPAP and PVR). 193 Conversely, indole pathway metabolism, an alternative route for tryptophan catabolism, was 194 associated with better RV function and lower pulmonary pressures: higher indolepyruvate was 195 significantly associated with better RV diastolic function (Tau 0.195, 95% CI 0.094‐0.561) and lower 196 mPAP both at rest (‐0.479, 95% CI ‐0.653 ‐ ‐0.284) and with exercise (‐0.423, 95% CI ‐0.487 ‐ ‐0.096). 197 Higher resting N‐acetylasparagine, one of the metabolites that significantly increased in abundance with 198 exercise, was associated with lower pulmonary pressures and better RV function. 199 Metabolic features of arginine bioavailability measured at rest predicted exercise 200 hemodynamics and pulmonary pressure‐flow relationships with exercise. While exercise‐induced 201 increases in arginine bioavailability were associated with higher exercise PVR and steeper multi‐point 202 mPAP/CO slopes, greater arginine bioavailability measured during the rest state predicted lower 203 exercise PVR and less steep multi‐point mPAP/CO slopes, indicative of more favorable pulmonary 204 vascular responses to exercise. Importantly, in sensitivity analyses, associations between arginine 205 bioavailability and ventriculo‐arterial parameters persisted with adjustment for PDE5 inhibitors. 206 Exercise Metabolite Associations 207 Higher kynurenine pathway metabolites measured post‐exercise were associated with various 208 hemodynamic measures: higher post‐exercise kynurenine was associated with higher resting RAP 209 (0.298, 95% CI 0.025 – 0.328), mPAP (0.314, 95% CI 0.045‐0.340), and PVR (0.691, 95% CI 0.175‐0.930). 210 In general, magnitudes of association for post‐exercise kynurenine were greater than those for 211 kynurenine measured at rest. Higher kynurenine post‐exercise was significantly associated with lower 212 VO2 max. All post‐exercise metabolite associations are shown in Supplemental Table S3, and a heatmap 213 of the top 25 exercise metabolite‐phenotype associations is presented in Figure 2b. 214 Given the known impacts of pulmonary vasodilators on key metabolic pathways, we performed 215 sensitivity analyses adjusting sPLS models for PAH‐specific therapies. Heatmaps depicting top 216 metabolite‐phenotype associations (at both rest and exercise) are shown in Supplemental Figures 3a 217 and 3b. Results of these analyses confirmed the robustness of key metabolite‐phenotype associations, 218 particularly those involving arginine‐NO and kynurenine pathway metabolism. 219 Clinically Relevant Dichotomies 220 To ground our analyses in clinical relevance, we next dichotomized PAH subjects according to 221 whether they possessed 1) decoupled versus preserved Ees/Ea (as a comprehensive measure of RV 222 functional adaptation), and 2) did or did not experience a clinical worsening event during the follow‐up 223 period. We used a clinically validated cut‐point of Ees/Ea <0.65 to signify RV‐PA uncoupling. Subjects 224 with a coupling ratio <0.65 tended to have higher kynurenine pathway metabolites; higher 1‐ 225 methylnicotinamide, an NAD metabolite; and higher methionine sulfoxide, a marker of oxidative stress 226 (Figure 3a). Subjects who experienced clinical worsening tended to have higher uric acid, lower histidine, 227 and greater increases in inosine with exercise (Figure 3b). 228 Comparisons with NT‐proBNP 2 229 The R statistic was used to evaluate the accuracy of metabolite models, compared to NT‐ 230 proBNP, for predicting ventriculo‐arterial parameters. In regression modeling, R describes the 231 proportion of variance in a dependent variable (in this case, a ventriculo‐arterial measurement) that is 232 accounted for by an explanatory variable (in this case, selected metabolites or NT‐proBNP). Pre‐ and 233 post‐exercise metabolites selected by sPLS models outperformed NT‐proBNP in predicting RV exercise 234 performance in vivo. NT‐proBNP was not informative in explaining variation in dEes (change in RV 235 contractility with exercise) or dEDV (change in RV dilation with exercise) within the cohort (R 0.00). For 236 both dEes and dEDV, post‐exercise metabolites outperformed rest metabolites: pre‐exercise 237 metabolites explained 29% of variance and post‐exercise metabolites explained 53% of variance for 238 dEes, while pre‐exercise metabolites explained 56% of variance and post‐exercise metabolites explained 239 88% of variance for dEDV (Figures 4a and 4b). Metabolite combinations for all models depicted in Figure 240 4 are shown in Supplemental Tables 1b, 2b, and 3b. 241 Resting NT‐proBNP accounted for the variation present in the relaxation measurement Tau very 242 poorly, with only 7% of variance explained, while resting metabolites selected by sPLS accounted for 243 61% of variance in Tau, and exercise metabolites accounted for 52% of variance. Similarly, resting NT‐ 244 proBNP did not explain variation in the load‐independent RV contractility metric Ees (R 2%), whereas 245 resting metabolites explained 51% of the variance present, and post‐exercise metabolites explained 59% 246 of the variance present. Metabolites did not outperform NT‐proBNP in accounting for the variation 247 present in the coupling metric Ees/Ea, which relates contractility to afterload (R for NT‐proBNP, rest 248 metabolites, and post‐exercise metabolites 20%, 27%, and 21%, respectively) (Figures 4c and 4d). 249 Resting NT‐proBNP performed better in modeling pulmonary pressures, explaining 26% of the 250 variance in resting mPAP and 30% of the variance in exercise mPAP. However, metabolites selected by 251 sPLS models provided better model accuracy, with rest metabolites explaining 81% of the variance in 252 resting mPAP, and metabolites measured post‐exercise explaining 90% of the variance in exercise mPAP. 253 Similarly, resting NT‐proBNP explained 35% of the variance in resting CO, and 22% of the variance in CO 254 at exercise. Pre‐exercise metabolites selected by sPLS models explained 67% of the variance in CO at 255 rest, while post‐exercise metabolites selected by sPLS explained 87% of the variance in exercise CO 256 (Figures 4e and 4f). Metabolites also outperformed NT‐proBNP in explaining variation in PVR at rest and 257 with exercise (Table 3). 258 Over an average of 6.3 years of observation, 15 patients experienced a clinical worsening event; 259 9 patients died. A combination of lower histidine (OR 3.62, 95% CI 1.11‐19.17) and higher uric acid levels 260 (OR 2.12, 95% CI 0.65 – 9.43) was associated with greater odds of experiencing clinical worsening, and 261 this combination outperformed NT‐proBNP for predicting clinical worsening in the cohort (AUC 0.84 for 262 metabolites versus 0.64 for NT‐proBNP) (Figure 5). 263 Pathway Analysis 264 The plots in Figure 6 depict metabolic pathway analysis for models that explained a high 265 proportion of variability (R >80%) for our hemodynamic and RV functional variables of interest. 2 2 266 Metabolites that explained a high proportion of variation in mPAP at rest (R 81%) and with exercise (R 267 90%) were enriched for over‐represented tryptophan metabolism, with relatively large pathway impact 268 scores >0.1 (Figures 6a). Metabolic pathways significantly over‐represented in other highly predictive 269 models (e.g., for CO and change in RV dilation with exercise) included arginine biosynthesis and 270 metabolism, BCAA biosynthesis and degradation, purine and pyrimidine metabolism, and aminoacyl‐ 271 tRNA biosynthesis (Figure 6b). 272 Discussion 273 To our knowledge, this study represents the first investigation of metabolomic associations with 274 comprehensive RV functional measurements only obtainable via multi‐beat RV PV loop analysis, 275 allowing identification of metabolite profiles associated with RV adaptation to increasing afterload, 276 measures of intrinsic RV function such as relaxation and contractility, and measures of RV exercise 277 performance in vivo. Our findings show that tryptophan metabolism is linked with multiple measures of 278 intrinsic RV function, with robust inverse relationships existing between kynurenine and RV diastolic 279 function and kynurenine and RV‐PA coupling. Our findings also point to the importance of arginine 280 bioavailability in the cardiopulmonary unit’s response to the stress of exercise. In most instances, 281 metabolite profiles selected by sPLS models outperformed NT‐proBNP, particularly for prediction of 282 measures that are load‐independent or reflect the performance of the cardiopulmonary system under 283 stress. 284 Aberrant tryptophan metabolism was implicated by our metabolomic pathway analyses, and 285 kynurenine pathway metabolites were more accurate than NT‐proBNP in predicting pulmonary 286 pressures in our PAH cohort. These results add to a growing body of both clinical and preclinical 287 evidence implicating the kynurenine pathway of tryptophan metabolism as relevant to PAH 288 pathobiology. Lewis et al. identified strong associations between tryptophan metabolites, including 289 kynurenine, and adverse hemodynamics in human subjects with RV‐pulmonary vascular dysfunction. 290 More recently, Cai et al. demonstrated kynurenine pathway metabolites are associated with survival and 291 with response to therapy in PAH. Preclinical data suggest kynurenine pathway metabolism may have 292 cardiac‐specific effects: in mice, simulation of myocardial infarction (MI) by left coronary ligation induces 293 generation of kynurenine via indoleamine 2, 3‐dioxygenase (IDO), an enzyme that catalyzes conversion 294 of tryptophan to kynurenine. After MI, genetic deletion of endothelial IDO limited cardiac injury, 295 resulting in improved cardiomyocyte contractility and less adverse ventricular remodeling. Conversely, 296 kynurenine supplementation precipitated cardiomyocyte apoptosis. Taken together, these 297 observations localize kynurenine pathway metabolism to the cardiopulmonary circuit. 298 In our cohort, arginine bioavailability proved dynamic with exercise and appeared important to 299 adaptive hemodynamic responses and pulmonary pressure‐flow relationships. Higher resting arginine 300 bioavailability was associated with a more favorable hemodynamic profile. With exercise, subjects with 301 more severe hemodynamics augmented arginine bioavailability to a greater extent than subjects with 302 more favorable hemodynamics, suggesting that such augmentation may be compensatory. Arginine is 303 the substrate for synthesis of nitric oxide (NO), which is crucial to vascular homeostasis and effects 304 vasodilation. Patients with PAH and other forms of pulmonary hypertension have reduced arginine 24, 25 305 bioavailability compared to healthy controls, and arginine conversion to urea (via arginase) is known 306 to be inversely associated with mPAP measurements. Moreover, NO production from arginine by 307 vascular endothelium in PAH is compromised by inactivated endothelial NO synthase in pulmonary 308 artery endothelial cells. Compensatory increases in arginine bioavailability with exertion might 309 function as a counterbalance to these known deficits. 310 Prior work has suggested that distinct arginine metabolic endotypes exist in PAH, such that 311 some patients have high arginase activity and decreased NO synthesis, while others have low arginase 312 activity. Relationships between clinical phenotypes and endogenous arginine biosynthesis have not 313 been similarly studied in PAH. However, our results lend credence to small clinical studies that have 314 previously demonstrated improvements in exercise performance with L‐arginine supplementation. One 315 small proof‐of‐concept study demonstrated improvements in six‐minute walking distance, V02 max, and 316 heart rate recovery when subjects with PAH adhered to a prescribed light exercise regimen along with L‐ 317 arginine supplementation (6,000 mg/day). Another small randomized placebo‐controlled trial showed 318 improvements in V02 max and reductions in mPAP and PVR in precapillary pulmonary hypertension 319 patients randomized to L‐arginine supplementation. 320 Purine and pyrimidine modified nucleosides and other metabolites have been previously 9, 10 321 associated with phenotypes and outcomes in PAH, and we re‐demonstrate this in the present study. 29 30 322 Uric acid has been associated with survival in both IPAH and SSc‐PAH and is a predictor of clinical 323 worsening in the current study. In our cohort, inosine levels dynamically increased with exercise, and 324 exercise‐induced increases in uridine were associated with adverse hemodynamics and RV function. It 325 remains unclear whether over‐represented purine/pyrimidine metabolism represents hyperproliferation 326 and increased cell turnover in disease, abnormal pentose phosphate metabolism, or, as other authors 327 have postulated, post‐translational modification of tRNAs required for translation of disease‐specific 328 proteins. Our pathway analyses, which implicate aminoacyl‐tRNA biosynthesis in metabolite profiles 329 that robustly predict exercise responses, align best with the latter hypothesis. 330 In our cohort, increased circulating BCAAs with exercise were associated with more severe PAH. 331 While increased alanine concentrations are generally observed with exercise, increases in BCAAs with 332 exercise are not demonstrated in healthy subjects. In a systematic review and meta‐analysis of 27 333 human exercise metabolomics studies, leucine and isoleucine concentrations in the blood significantly 334 decreased within 30 minutes of a bout of exercise, in contrast to our results in PAH. One early 335 investigation of myocardial amino acid metabolism following cardiac surgery detected increased net 336 uptake of BCAAs and glutamate post‐operatively that was directly correlated with myocardial oxygen 337 consumption. BCAAs are elevated in the myocardium of mice and humans with heart failure, and BCAA 338 catabolic defects have been demonstrated. Supplementation of BCAAs has been shown to improve 339 ventricular contractility in the failing mouse heart. In the context of these prior studies, our results add 340 to a collection of observations suggesting a mismatch between myocardial AA availability and utilization 341 may contribute to experimental and human heart failure. The provisioning of increased AA during stress 342 states, as seen in post‐ischemic cardiac surgery patients and in our PAH patients, might serve an 343 adaptive function, though this is speculative. Future mechanistic work is needed to clarify the cellular 344 sources and fates of AAs that increase or decrease with exercise in PAH. 345 In addition to offering pathobiologic insights, our findings underscore the potential for select 346 metabolites to function as disease‐specific biomarkers. Metabolite combinations outperformed NT‐ 347 proBNP, the current clinical gold standard marker, for predicting most hemodynamic and RV functional 348 variables. Improvements in model accuracy were most robust for prediction of variables associated with 349 intrinsic RV function, such as relaxation and contractility, and RV exercise performance. Kynurenine 350 pathway features were among those consistently selected into metabolite models that improved 351 predictive accuracy. Further research is needed to validate selected metabolites as RV‐specific 352 biomarkers, including studies that absolutely quantify metabolite abundance and examine statistical 353 discrimination rigorously, but these initial results suggest that identification of molecules that are 354 pathobiologically related to disease‐specific variables may result in improved biomarker calibration. 355 This study has important limitations, including its modest sample size and lack of a suitable 356 validation cohort. These limitations, though, are inherent to a study design that leverages difficult to 357 perform RV PV loops in subjects with a rare disease. PV loop analysis is a strength of the study, allowing 358 examination of relationships between varied aspects of metabolism and comprehensive RV function. 359 SSc‐PAH subjects predominate within our cohort, which reflects referral patterns at our center. Because 360 we are under‐powered to examine subtype‐specific metabolite associations, we cannot be certain that 361 the associations in our cohort generalize to all PAH. Finally, while we are able to demonstrate novel 362 associations with these analyses, future studies are needed to elucidate the mechanistic functions of 363 metabolic pathways implicated here. 364 In conclusion, specific metabolite profiles predict various aspects of RV‐PA function. Future work 365 is needed to conduct broader‐based metabolic profiling in larger, phenotypically rich cohorts, and to 366 integrate metabolite profiles with other ‐omics layers. Such profiling has the potential to deepen our 367 pathobiologic understanding of PAH, identify targetable pathways, and inform discovery of biomarkers 368 that report on RV‐centric features of disease. 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 Acknowledgements 386 This project was supported by the Johns Hopkins School of Medicine Biostatistics, Epidemiology and 387 Data Management (BEAD) Core. Additionally, the authors wish to acknowledge Dr. Tijana Tuhy for 388 design assistance with this manuscript’s graphical abstract, created with BioRender.com. 389 Sources of Funding 390 NIH/NHLBI K23HL153781 (C.E.S.), R01HL114910 (P.M.H.), U01HL125175‐03S1 (P.M.H., S.C.M.), 391 R01HL132153 (R.L.D., P.M.H.), K08HL132055 (K.S.), K23HL146889 (S.H.) 392 New Investigator Award from the Scleroderma Foundation (C.E.S.) 393 Disclosures 394 The authors report no conflicts of interest related to the present work. Dr. Tedford reports general 395 disclosures to include consulting relationships with Medtronic, Abbott, Aria CV Inc., Acceleron/Merck, 396 Alleviant, CareDx, Cytokinetics, Itamar, Edwards LifeSciences, Eidos Therapeutics, Lexicon 397 Pharmaceuticals, and Gradient. Dr. Tedford is the national principal investigator for the RIGHT‐FLOW 398 clinical trial (Edwards), serves on steering committee for Merck, Edwards, and Abbott as well as a 399 research advisory board for Abiomed. He also does hemodynamic core lab work for Merck. Dr. Mathai 400 reports fees from Actelion, United Therapeutics, Janssen, MSD, and Clinical Viewpoints, has served on 401 an Advisory Board for Bayer, and reports a leadership/fiduciary role with the Patient Centered 402 Outcomes Research Institute, all unrelated to the current work. Dr. Hassoun serves on a scientific 403 steering board for MSD, an activity unrelated to the current work. 404 405 406 407 408 References 409 410 1. van de Veerdonk MC, Kind T, Marcus JT, et al. Progressive right ventricular dysfunction in 411 patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 2011; 58: 2511‐ 412 2519. DOI: 10.1016/j.jacc.2011.06.068. 413 2. Vonk‐Noordegraaf A, Haddad F, Chin KM, et al. Right heart adaptation to pulmonary arterial 414 hypertension: physiology and pathobiology. J Am Coll Cardiol 2013; 62: D22‐33. DOI: 415 10.1016/j.jacc.2013.10.027. 416 3. Lahm T, Douglas IS, Archer SL, et al. Assessment of Right Ventricular Function in the Research 417 Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research 418 Statement. Am J Respir Crit Care Med 2018; 198: e15‐e43. 2018/08/16. DOI: 10.1164/rccm.201806‐ 419 1160ST. 420 4. Simpson CE, Damico RL, Hassoun PM, et al. Noninvasive prognostic biomarkers for left heart 421 failure as predictors of survival in pulmonary arterial hypertension. Chest 2020 2020/01/29. DOI: 422 10.1016/j.chest.2019.12.037. 423 5. Chung L, Fairchild RM, Furst DE, et al. Utility of B‐type natriuretic peptides in the assessment of 424 patients with systemic sclerosis‐associated pulmonary hypertension in the PHAROS registry. Clin Exp 425 Rheumatol 2017; 35 Suppl 106: 106‐113. 2016/12/03. 426 6. Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation 427 in pulmonary arterial hypertension. Eur Respir J 2017; 50 2017/08/05. DOI: 10.1183/13993003.00889‐ 428 2017. 429 7. Mathai SC, Bueso M, Hummers LK, et al. Disproportionate elevation of N‐terminal pro‐brain 430 natriuretic peptide in scleroderma‐related pulmonary hypertension. Eur Respir J 2010; 35: 95‐104. DOI: 431 10.1183/09031936.00074309. 432 8. Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N‐terminal brain natriuretic peptide as a 433 prognostic parameter in patients with pulmonary hypertension. Chest 2006; 129: 1313‐1321. DOI: 434 10.1378/chest.129.5.1313. 435 9. Lewis GD, Ngo D, Hemnes AR, et al. Metabolic Profiling of Right Ventricular‐Pulmonary Vascular 436 Function Reveals Circulating Biomarkers of Pulmonary Hypertension. J Am Coll Cardiol 2016; 67: 174‐ 437 189. DOI: 10.1016/j.jacc.2015.10.072. 438 10. Rhodes CJ, Ghataorhe P, Wharton J, et al. Plasma Metabolomics Implicates Modified Transfer 439 RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension. Circulation 2017; 440 135: 460‐475. 2016/11/25. DOI: 10.1161/CIRCULATIONAHA.116.024602. 441 11. Vonk Noordegraaf A, Chin KM, Haddad F, et al. Pathophysiology of the right ventricle and of the 442 pulmonary circulation in pulmonary hypertension: an update. Eur Respir J 2019; 53 2018/12/14. DOI: 443 10.1183/13993003.01900‐2018. 444 12. Hsu S, Simpson CE, Houston BA, et al. Multi‐Beat Right Ventricular‐Arterial Coupling Predicts 445 Clinical Worsening in Pulmonary Arterial Hypertension. J Am Heart Assoc 2020; 9: e016031. 2020/05/10. 446 DOI: 10.1161/JAHA.119.016031. 447 13. Hsu S, Houston BA, Tampakakis E, et al. Right Ventricular Functional Reserve in Pulmonary 448 Arterial Hypertension. Circulation 2016; 133: 2413‐2422. DOI: 10.1161/CIRCULATIONAHA.116.022082. 449 14. Tedford RJ, Mudd JO, Girgis RE, et al. Right ventricular dysfunction in systemic sclerosis‐ 450 associated pulmonary arterial hypertension. Circ Heart Fail 2013; 6: 953‐963. DOI: 451 10.1161/CIRCHEARTFAILURE.112.000008. 452 15. Brener MI, Masoumi A, Ng VG, et al. Invasive Right Ventricular Pressure‐Volume Analysis: Basic 453 Principles, Clinical Applications, and Practical Recommendations. Circ Heart Fail 2022; 15: e009101. 454 2021/12/30. DOI: 10.1161/CIRCHEARTFAILURE.121.009101. 455 16. Ireland CG, Damico RL, Kolb TM, et al. Exercise right ventricular ejection fraction predicts right 456 ventricular contractile reserve. J Heart Lung Transplant 2021; 40: 504‐512. 2021/03/24. DOI: 457 10.1016/j.healun.2021.02.005. 458 17. Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the Diagnosis and 459 Treatment of Pulmonary Hypertension. Rev Esp Cardiol (Engl Ed) 2016; 69: 177. DOI: 460 10.1016/j.rec.2016.01.002. 461 18. Chun H and Keles S. Sparse partial least squares regression for simultaneous dimension 462 reduction and variable selection. J R Stat Soc Series B Stat Methodol 2010; 72: 3‐25. 2010/01/29. DOI: 463 10.1111/j.1467‐9868.2009.00723.x. 464 19. Donoho D and Jin J. Higher criticism thresholding: Optimal feature selection when useful 465 features are rare and weak. Proc Natl Acad Sci U S A 2008; 105: 14790‐14795. 2008/09/26. DOI: 466 10.1073/pnas.0807471105. 467 20. Strimmer K. fdrtool: a versatile R package for estimating local and tail area‐based false discovery 468 rates. Bioinformatics 2008; 24: 1461‐1462. 2008/04/29. DOI: 10.1093/bioinformatics/btn209. 469 21. Chong J and Xia J. MetaboAnalystR: an R package for flexible and reproducible analysis of 470 metabolomics data. Bioinformatics 2018; 34: 4313‐4314. 2018/06/30. DOI: 471 10.1093/bioinformatics/bty528. 472 22. Cai Z, Tian S, Klein T, et al. Kynurenine metabolites predict survival in pulmonary arterial 473 hypertension: A role for IL‐6/IL‐6Ralpha. Sci Rep 2022; 12: 12326. 2022/07/20. DOI: 10.1038/s41598‐ 474 022‐15039‐3. 475 23. Melhem NJ, Chajadine M, Gomez I, et al. Endothelial Cell Indoleamine 2, 3‐Dioxygenase 1 Alters 476 Cardiac Function After Myocardial Infarction Through Kynurenine. Circulation 2021; 143: 566‐580. 477 2020/12/05. DOI: 10.1161/CIRCULATIONAHA.120.050301. 478 24. Kao CC, Wedes SH, Hsu JW, et al. Arginine metabolic endotypes in pulmonary arterial 479 hypertension. Pulm Circ 2015; 5: 124‐134. 2015/05/21. DOI: 10.1086/679720. 480 25. Morris CR, Kato GJ, Poljakovic M, et al. Dysregulated arginine metabolism, hemolysis‐associated 481 pulmonary hypertension, and mortality in sickle cell disease. JAMA 2005; 294: 81‐90. 2005/07/07. DOI: 482 10.1001/jama.294.1.81. 483 26. Ghosh S, Gupta M, Xu W, et al. Phosphorylation inactivation of endothelial nitric oxide synthesis 484 in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2016; 310: L1199‐1205. 485 2016/05/01. DOI: 10.1152/ajplung.00092.2016. 486 27. Brown MB, Kempf A, Collins CM, et al. A prescribed walking regimen plus arginine 487 supplementation improves function and quality of life for patients with pulmonary arterial hypertension: 488 a pilot study. Pulm Circ 2018; 8: 2045893217743966. 2017/12/05. DOI: 10.1177/2045893217743966. 489 28. Nagaya N, Uematsu M, Oya H, et al. Short‐term oral administration of L‐arginine improves 490 hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir 491 Crit Care Med 2001; 163: 887‐891. 2001/04/03. DOI: 10.1164/ajrccm.163.4.2007116. 492 29. Nagaya N, Uematsu M, Satoh T, et al. Serum uric acid levels correlate with the severity and the 493 mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 1999; 160: 487‐492. DOI: 494 10.1164/ajrccm.160.2.9812078. 495 30. Simpson CE, Damico RL, Hummers L, et al. Serum uric acid as a marker of disease risk, severity, 496 and survival in systemic sclerosis‐related pulmonary arterial hypertension. Pulm Circ 2019; 9: 497 2045894019859477. 2019/08/07. DOI: 10.1177/2045894019859477. 498 31. Schranner D, Kastenmuller G, Schonfelder M, et al. Metabolite Concentration Changes in 499 Humans After a Bout of Exercise: a Systematic Review of Exercise Metabolomics Studies. Sports Med 500 Open 2020; 6: 11. 2020/02/11. DOI: 10.1186/s40798‐020‐0238‐4. 501 32. Svedjeholm R, Ekroth R, Joachimsson PO, et al. Myocardial uptake of amino acids and other 502 substrates in relation to myocardial oxygen consumption four hours after cardiac operations. J Thorac 503 Cardiovasc Surg 1991; 101: 688‐694. 1991/04/01. 504 33. Sun H, Olson KC, Gao C, et al. Catabolic Defect of Branched‐Chain Amino Acids Promotes Heart 505 Failure. Circulation 2016; 133: 2038‐2049. 2016/04/10. DOI: 10.1161/CIRCULATIONAHA.115.020226. 506 34. Tanada Y, Shioi T, Kato T, et al. Branched‐chain amino acids ameliorate heart failure with cardiac 507 cachexia in rats. Life Sci 2015; 137: 20‐27. 2015/07/05. DOI: 10.1016/j.lfs.2015.06.021. 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 Figure Legends 531 Figure 1. Box plots depicting abundance of metabolites that significantly increase (a) or decrease (b) th 532 post‐exercise compared to pre‐exercise. The center line denotes the median value (50 percentile) and th th 533 upper and lower hinges denote 75 and 25 percentiles of data respectively. Upper and lower fences th th 534 denote 1.5 times the 75 percentile and 25 percentile respectively. Individual data points beyond 535 upper and lower fences are presented as dots. 536 Figure 2. Heatmaps depicting the top 25 unadjusted rest (a) and exercise (b) metabolite associations 537 with ventriculo‐arterial parameters. Parameters are listed along the y‐axis, and individual metabolites 538 are shown on the x‐axis. The red‐blue color scale represents the value of the z‐scored coefficient, which 539 reflects the mean standard deviation change for each ventriculo‐arterial parameter per one standard 540 deviation increase in metabolite. Red colors correspond to lower values, and blue colors correspond to 541 higher values, as per the color key. Dendrograms reflect hierarchical clustering that orders rows and 542 columns by similarity of associations. 543 Figure 3. Volcano plots showing the magnitude (x‐axis) and significance (y‐axis) of metabolite fold‐ 544 change differences in subjects with decoupled versus preserved Ees/Ea (a) and with versus without 545 clinical worsening (b). Dots represent individual metabolite features. Features increased in subjects with 546 decoupled Ees/Ea (a) or clinical worsening (b) are shown with red dots, while features decreased are 547 shown with blue dots. The lower horizontal line indicates borderline statistical significance at α=0.20. 548 The upper horizontal line indicates statistical significance at α=0.05. 549 Figure 4. Model fit for sparse PLS models utilizing NT‐proBNP, pre‐exercise metabolites, and post‐ 550 exercise metabolites as explanatory variables to predict ventriculo‐arterial parameters as dependent 551 variables: dEDV and dEes (a and b); Ees and Tau (c and d); and rest and exercise mPAP (e and f). Actual 552 values in the data (x‐axis) are plotted against the values predicted by the models (y‐axis). R values are 553 rounded to two decimal places. 554 Figure 5. Receiver operating characteristics curves for logistic regression models of clinical worsening. 555 Area under the curve for NT‐proBNP (gray curve) and metabolites selected by logistic regression (black 556 curve) are shown. Sensitivity (true positive rate) is plotted on the y‐axis, and 1‐specificity (false positive 557 rate) is plotted on the x‐axis. 558 Figure 6. Pathway enrichment and topology analysis for sPLS models with R greater than 80%. Pathway 559 impact is plotted on the x‐axis, and significance is plotted on the x‐axis. Point sizes are proportionate to 560 pathway impact. Point colors reflect p‐values from largest (blue) to smallest (red). The KEGG pathway 561 database was used as a reference metabolome. The solid horizontal line indicates statistical significance 562 at α=0.05. The dashed horizontal line indicates statistical significance at α=0.10. 563 564 565 566 567 Table 1. Demographics and Clinical Characteristics Variable Median (IQR) or n (%), as appropriate Age, years 61.00 (47.00, 66.00] Sex (% female) Female 19 (82.6%) Male 4 (17.4%) Race (% white) White 19 (82.6%) non-White 4 (17.4%) Subtype (% IPAH vs SScPAH) IPAH 7 (30.4%) SScPAH 16 (69.6%) WHO FC, n I/II/III 1 1 (4.3%) 2 11 (47.8%) 3 11 (47.8%) pro-BNP, pg/dL 326.00 (116.00, 681.50] Cr, mg/dL 0.90 (0.80, 1.00] RAP, mmHg 7.00 (3.50, 10.00] meanPAP, mmHg 33.00 (27.00, 47.00] PAWP, mmHg 10.00 (6.00, 12.00] CO, L/min 4.60 (4.20, 5.33] PVR, Wood units 4.67 (2.86, 8.39] VO2 peak, mL/kg/min 10.50 (8.97, 12.43] RER 0.93 (0.89, 1.00] Ees (RV contractility) 0.52 (0.43, 0.69] Ea (RV afterload) 0.69 (0.52, 1.08] Ees/Ea (RV-PA coupling) 0.66 (0.45, 0.99] RVEF, % 49.62 (38.53, 56.88] Tau Suga 32.28 (24.27, 37.66] RV end diastolic volume, mL 177.63 (132.70, 196.95] meanPAP at 25W, mmHg 48.00 (39.00, 64.00] PAWP at 25W, mmHg 15.00 (9.00, 20.00] CO at 25W, L/min 9.30 (6.97, 10.00] PVR at 25W, Wood units 5.12 (3.56, 7.87] mPAP/CO multi-point slope 4.64 (1.51, 7.01] PAWP/CO multi-point slope 0.87 (0.03, 2.41] Taking PDE5 inhibitor Yes 13 (56.5%) No 10 (43.5%) Taking ERA Yes 17 (73.9%) No 6 (26.1%) Taking prostanoid Yes 0 (0.0%) No 23 (100.0%) Abbreviations: IQR: interquartile range; IPAH: idiopathic pulmonary arterial hypertension; SSc-PAH: systemic sclerosis-associated pulmonary arterial hypertension; WHO: World Health Organization; FC: functional classification; pro-BNP: brain-type natriuretic peptide pro-hormone; Cr: creatinine; RAP: right atrial pressure; meanPAP: mean pulmonary arterial pressure; PAWP: pulmonary artery wedge pressure; CO: cardiac output; PVR: pulmonary vascular resistance; VO2 peak: maximum oxygen uptake; RER: respiratory equivalence ratio; Ees: end- systolic elastance; Ea: end-arterial elastance; RVEF: right ventricular ejection fraction; PDE5 inhibitor: phosphodiesterase-5 inhibitor; ERA: endothelin receptor antagonist Table 2. Significant Paired Rest-Exercise Differences in Metabolite Abundance Metabolite Feature Class Pathway Fold- log2 (FC) p-value change (FC) Alanine Amino acid Alanine and aspartate 1.1936 0.2553 0.0004 metabolism Arg/Orn Amino acid Urea cycle 1.1909 0.2520 0.0006 Leucine Amino acid BCAA metabolism 1.0886 0.1225 0.0035 GABR Amino acid Urea cycle 1.1699 0.2264 0.0043 Ornithine Amino acid Urea cycle 0.9259 -0.1111 0.0067 Methionine Amino acid Methionine, Cysteine, 1.0891 0.1231 0.0135 SAM and Taurine Metabolism N-alpha-Acetylasparagine Amino acid Alanine and aspartate 1.1272 0.1727 0.0163 metabolism Isoleucine Amino acid BCAA metabolism 1.0731 0.1018 0.0214 3-Aminoisobutanoic acid Amino acid Pyrimidine metabolism 1.1605 0.2147 0.0254 Serine Amino acid Glycine, Serine and 0.9452 -0.0814 0.0384 Threonine Metabolism Inosine Nucleotide Purine Metabolism 1.7256 0.7871 0.0415 N-Acetylleucine Amino Acid BCAA metabolism 1.0845 0.1171 0.0415 Phenylalanine Phenylalanine 1.0560 0.07861 0.0484 Amino Acid Metabolism Table 3. Model Accuracy Comparisons: proportion of variance for each parameter explained by selected metabolite combinations versus NT-proBNP Parameter pre-exercise metabolite post-exercise metabolite NT-proBNP R 2 2 profile R profile R Exercise mPAP 0.93 0.90 0.30 Rest PAWP 0.90 0.08 0.06 Rest mPAP 0.81 0.81 0.26 Exercise PVR 0.75 0.61 0.57 Rest PVR 0.74 0.63 0.43 PCWP/CO 0.69 0.74 0.61 Rest CO 0.67 0.58 0.35 TauSuga 0.61 0.52 0.07 RER 0.59 0.39 0.13 dEDV 0.56 0.88 0.00 Ees 0.51 0.59 0.02 Peak VO2 0.50 0.38 0.18 Ve/VO2 0.42 0.48 0.29 mPAP/CO 0.37 0.53 0.53 Exercise PAWP 0.37 0.02 0.24 dEes 0.29 0.53 0.00 Ees/Ea 0.27 0.21 0.20 Exercise CO 0.05 0.87 0.22 See Table 1 for abbreviations. Figure 1a Figure 1b Figure 2a Figure 2b Figure 3a Figure 3b A Figures 4a and 4b C Figures 4c and 4d E Figures 4e and 4f Figure 5 A Figures 6a and 6b C Figures 6c and 6d Specific metabolomic profiles associate with discrete aspects of right ventricular-pulmonary arterial function Aberrant tryptophan metabolism is linked with intrinsic RV function measured with multi-beat pressure-volume loop analysis, and resting arginine bioavailability predicts RV-PA responses to exercise
AJP Lung Cellular and Molecular Physiology – The American Physiological Society
Published: Jun 1, 2023
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