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Published in: Respiratory Research 1/2022

Open Access 01-12-2022 | Positron Emission Tomography | Research

Perfusion imaging heterogeneity during NO inhalation distinguishes pulmonary arterial hypertension (PAH) from healthy subjects and has potential as an imaging biomarker

Authors: Tilo Winkler, Puja Kohli, Vanessa J. Kelly, Ekaterina G. Kehl, Alison S. Witkin, Josanna M. Rodriguez-Lopez, Kathryn A. Hibbert, Mamary T. Kone, David M. Systrom, Aaron B. Waxman, Jose G. Venegas, Richard N. Channick, R. Scott Harris

Published in: Respiratory Research | Issue 1/2022

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Abstract

Background

Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient’s response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects.

Methods

We studied 5 controls and 4 subjects with PAH using HRCT and 13NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV2Qtotal) and its components in the vertical (CV2Qvgrad) and cranio-caudal (CV2Qzgrad) directions, and the residual heterogeneity (CV2Qr), were assessed at baseline and while breathing oxygen and nitric oxide (O2 + iNO). The length scale spectrum of CV2Qr was determined from 10 to 110 mm, and the response of regional perfusion to O2 + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Qvgrad) were derived from perfusion images, and ventilation-perfusion distributions from images of 13NN washout kinetics.

Results

O2 + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O2 + iNO, CV2Qvgrad was significantly higher in controls than in PAH (0.08 (0.055–0.10) vs. 6.7 × 10–3 (2 × 10–4–0.02), p < 0.001) with a considerable gap between groups. Qvgrad and CV2Qtotal showed smaller differences: − 7.3 vs. − 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV2Qvgrad had the largest effect size among the primary parameters during O2 + iNO. CV2Qr, and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant.

Conclusions

Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.
Literature
2.
go back to reference Halliday SJ, Hemnes AR, Robbins IM, Pugh ME, Zhao DX, Piana RN, et al. Prognostic value of acute vasodilator response in pulmonary arterial hypertension: beyond the “classic” responders. J Heart Lung Transplant Off Publ Int Soc Heart Transplant. 2015;34:312–8.CrossRef Halliday SJ, Hemnes AR, Robbins IM, Pugh ME, Zhao DX, Piana RN, et al. Prognostic value of acute vasodilator response in pulmonary arterial hypertension: beyond the “classic” responders. J Heart Lung Transplant Off Publ Int Soc Heart Transplant. 2015;34:312–8.CrossRef
3.
go back to reference Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46:903–75.PubMedCrossRef Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46:903–75.PubMedCrossRef
4.
go back to reference Malhotra R, Hess D, Lewis GD, Bloch KD, Waxman AB, Semigran MJ. Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension. Pulm Circ. 2011;1:250–8.PubMedPubMedCentralCrossRef Malhotra R, Hess D, Lewis GD, Bloch KD, Waxman AB, Semigran MJ. Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension. Pulm Circ. 2011;1:250–8.PubMedPubMedCentralCrossRef
5.
go back to reference Musch G, Layfield JDH, Harris RS, Melo MFV, Winkler T, Callahan RJ, et al. Topographical distribution of pulmonary perfusion and ventilation, assessed by PET in supine and prone humans. J Appl Physiol. 2002;93:1841–51.PubMedCrossRef Musch G, Layfield JDH, Harris RS, Melo MFV, Winkler T, Callahan RJ, et al. Topographical distribution of pulmonary perfusion and ventilation, assessed by PET in supine and prone humans. J Appl Physiol. 2002;93:1841–51.PubMedCrossRef
6.
go back to reference Prisk GK, Yamada K, Henderson AC, Arai TJ, Levin DL, Buxton RB, et al. Pulmonary perfusion in the prone and supine postures in the normal human lung. J Appl Physiol. 2007;103:883–94.PubMedCrossRef Prisk GK, Yamada K, Henderson AC, Arai TJ, Levin DL, Buxton RB, et al. Pulmonary perfusion in the prone and supine postures in the normal human lung. J Appl Physiol. 2007;103:883–94.PubMedCrossRef
7.
go back to reference Hopkins SR, Henderson AC, Levin DL, Yamada K, Arai T, Buxton RB, et al. Vertical gradients in regional lung density and perfusion in the supine human lung: the Slinky effect. J Appl Physiol. 2007;103:240–8.PubMedCrossRef Hopkins SR, Henderson AC, Levin DL, Yamada K, Arai T, Buxton RB, et al. Vertical gradients in regional lung density and perfusion in the supine human lung: the Slinky effect. J Appl Physiol. 2007;103:240–8.PubMedCrossRef
8.
go back to reference Burrowes KS, Hunter PJ, Tawhai MH. Investigation of the relative effects of vascular branching structure and gravity on pulmonary arterial blood flow heterogeneity via an image-based computational model. Acad Radiol. 2005;12:1464–74.PubMedCrossRef Burrowes KS, Hunter PJ, Tawhai MH. Investigation of the relative effects of vascular branching structure and gravity on pulmonary arterial blood flow heterogeneity via an image-based computational model. Acad Radiol. 2005;12:1464–74.PubMedCrossRef
9.
go back to reference Hlastala MP, Glenny RW. Vascular structure determines pulmonary blood flow distribution. Physiol Am Physiol Soc. 1999;14:182–6. Hlastala MP, Glenny RW. Vascular structure determines pulmonary blood flow distribution. Physiol Am Physiol Soc. 1999;14:182–6.
10.
go back to reference Nelson TR, West BJ, Goldberger AL. The fractal lung: universal and species-related scaling patterns. Experientia. 1990;46:251–4.PubMedCrossRef Nelson TR, West BJ, Goldberger AL. The fractal lung: universal and species-related scaling patterns. Experientia. 1990;46:251–4.PubMedCrossRef
11.
go back to reference Cool CD, Stewart JS, Werahera P, Miller GJ, Williams RL, Voelkel NF, et al. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Am J Pathol. 1999;155:411–9.PubMedPubMedCentralCrossRef Cool CD, Stewart JS, Werahera P, Miller GJ, Williams RL, Voelkel NF, et al. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Am J Pathol. 1999;155:411–9.PubMedPubMedCentralCrossRef
12.
go back to reference Kohli P, Kelly VJ, Kehl EG, Rodriguez-Lopez J, Hibbert KA, Kone M, et al. Perfusion imaging distinguishes exercise pulmonary arterial hypertension at rest. Am J Respir Crit Care Med. 2019;199:1438–41.PubMedPubMedCentralCrossRef Kohli P, Kelly VJ, Kehl EG, Rodriguez-Lopez J, Hibbert KA, Kone M, et al. Perfusion imaging distinguishes exercise pulmonary arterial hypertension at rest. Am J Respir Crit Care Med. 2019;199:1438–41.PubMedPubMedCentralCrossRef
13.
go back to reference Horn M, Hooper W, Brach B, Ashburn W, Moser K. Postural changes in pulmonary blood flow in pulmonary hypertension: a noninvasive technique using ventilation-perfusion scans. Circulation. 1982;66:621–6.PubMedCrossRef Horn M, Hooper W, Brach B, Ashburn W, Moser K. Postural changes in pulmonary blood flow in pulmonary hypertension: a noninvasive technique using ventilation-perfusion scans. Circulation. 1982;66:621–6.PubMedCrossRef
14.
go back to reference Lau EM, Bailey DL, Bailey EA, Torzillo PJ, Roach PJ, Schembri GP, et al. Pulmonary hypertension leads to a loss of gravity dependent redistribution of regional lung perfusion: a SPECT/CT study. Heart Br Card Soc. 2014;100:47–53. Lau EM, Bailey DL, Bailey EA, Torzillo PJ, Roach PJ, Schembri GP, et al. Pulmonary hypertension leads to a loss of gravity dependent redistribution of regional lung perfusion: a SPECT/CT study. Heart Br Card Soc. 2014;100:47–53.
15.
go back to reference Lefebvre B, Kyheng M, Giordano J, Lamblin N, de Groote P, Fertin M, et al. Dual-energy CT lung perfusion characteristics in pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD/PCH): preliminary experience in 63 patients. Eur Radiol. 2022;32:4574–86.PubMedCrossRef Lefebvre B, Kyheng M, Giordano J, Lamblin N, de Groote P, Fertin M, et al. Dual-energy CT lung perfusion characteristics in pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis (PVOD/PCH): preliminary experience in 63 patients. Eur Radiol. 2022;32:4574–86.PubMedCrossRef
16.
go back to reference Giordano J, Khung S, Duhamel A, Hossein-Foucher C, Bellèvre D, Lamblin N, et al. Lung perfusion characteristics in pulmonary arterial hypertension (PAH) and peripheral forms of chronic thromboembolic pulmonary hypertension (pCTEPH): dual-energy CT experience in 31 patients. Eur Radiol. 2017;27:1631–9.PubMedCrossRef Giordano J, Khung S, Duhamel A, Hossein-Foucher C, Bellèvre D, Lamblin N, et al. Lung perfusion characteristics in pulmonary arterial hypertension (PAH) and peripheral forms of chronic thromboembolic pulmonary hypertension (pCTEPH): dual-energy CT experience in 31 patients. Eur Radiol. 2017;27:1631–9.PubMedCrossRef
17.
go back to reference Wollmer P, Rozkovec A, Rhodes CG, Allan RM, Maseri A. Regional pulmonary blood volume in patients with abnormal blood pressure or flow in the pulmonary circulation. Eur Heart J. 1984;5:924–31.PubMedCrossRef Wollmer P, Rozkovec A, Rhodes CG, Allan RM, Maseri A. Regional pulmonary blood volume in patients with abnormal blood pressure or flow in the pulmonary circulation. Eur Heart J. 1984;5:924–31.PubMedCrossRef
18.
go back to reference Hovnanian ALD, Costa ELV, Hoette S, Fernandes CJCS, Jardim CVP, Dias BA, et al. Electrical impedance tomography in pulmonary arterial hypertension. PLoS ONE. 2021;16:e0248214.PubMedPubMedCentralCrossRef Hovnanian ALD, Costa ELV, Hoette S, Fernandes CJCS, Jardim CVP, Dias BA, et al. Electrical impedance tomography in pulmonary arterial hypertension. PLoS ONE. 2021;16:e0248214.PubMedPubMedCentralCrossRef
19.
go back to reference Jones AT, Hansell DM, Evans TW. Quantifying pulmonary perfusion in primary pulmonary hypertension using electron-beam computed tomography. Eur Respir J. 2004;23:202–7.PubMedCrossRef Jones AT, Hansell DM, Evans TW. Quantifying pulmonary perfusion in primary pulmonary hypertension using electron-beam computed tomography. Eur Respir J. 2004;23:202–7.PubMedCrossRef
20.
go back to reference Lau EMT, Humbert M, Celermajer DS. Early detection of pulmonary arterial hypertension. Nat Rev Cardiol. 2015;12:143–55.PubMedCrossRef Lau EMT, Humbert M, Celermajer DS. Early detection of pulmonary arterial hypertension. Nat Rev Cardiol. 2015;12:143–55.PubMedCrossRef
21.
go back to reference Asadi AK, Sá RC, Kim NH, Theilmann RJ, Hopkins SR, Buxton RB, et al. Inhaled nitric oxide alters the distribution of blood flow in the healthy human lung, suggesting active hypoxic pulmonary vasoconstriction in normoxia. J Appl Physiol. 2015;118:331–43.PubMedCrossRef Asadi AK, Sá RC, Kim NH, Theilmann RJ, Hopkins SR, Buxton RB, et al. Inhaled nitric oxide alters the distribution of blood flow in the healthy human lung, suggesting active hypoxic pulmonary vasoconstriction in normoxia. J Appl Physiol. 2015;118:331–43.PubMedCrossRef
22.
go back to reference Vidal Melo MF, Layfield D, Harris RS, O’Neill K, Musch G, Richter T, et al. Quantification of regional ventilation-perfusion ratios with PET. J Nucl Med. 2003;44:1982–91.PubMed Vidal Melo MF, Layfield D, Harris RS, O’Neill K, Musch G, Richter T, et al. Quantification of regional ventilation-perfusion ratios with PET. J Nucl Med. 2003;44:1982–91.PubMed
23.
go back to reference Wellman TJ, Winkler T, Costa ELV, Musch G, Harris RS, Venegas JG, et al. Effect of regional lung inflation on ventilation heterogeneity at different length scales during mechanical ventilation of normal sheep lungs. J Appl Physiol. 2012;113:947–57.PubMedPubMedCentralCrossRef Wellman TJ, Winkler T, Costa ELV, Musch G, Harris RS, Venegas JG, et al. Effect of regional lung inflation on ventilation heterogeneity at different length scales during mechanical ventilation of normal sheep lungs. J Appl Physiol. 2012;113:947–57.PubMedPubMedCentralCrossRef
24.
go back to reference Harris RS, Winkler T, Tgavalekos N, Musch G, Melo MFV, Schroeder T, et al. Regional pulmonary perfusion, inflation, and ventilation defects in bronchoconstricted patients with asthma. Am J Respir Crit Care Med. 2006;174:245–53.PubMedPubMedCentralCrossRef Harris RS, Winkler T, Tgavalekos N, Musch G, Melo MFV, Schroeder T, et al. Regional pulmonary perfusion, inflation, and ventilation defects in bronchoconstricted patients with asthma. Am J Respir Crit Care Med. 2006;174:245–53.PubMedPubMedCentralCrossRef
25.
go back to reference Vidal Melo MF, Winkler T, Harris RS, Musch G, Greene RE, Venegas JG. Spatial heterogeneity of lung perfusion assessed with 13N PET as a vascular biomarker in chronic obstructive pulmonary disease. J Nucl Med. 2010;51:57–65.PubMedCrossRef Vidal Melo MF, Winkler T, Harris RS, Musch G, Greene RE, Venegas JG. Spatial heterogeneity of lung perfusion assessed with 13N PET as a vascular biomarker in chronic obstructive pulmonary disease. J Nucl Med. 2010;51:57–65.PubMedCrossRef
26.
go back to reference Kelly VJ, Hibbert KA, Kohli P, Kone M, Greenblatt EE, Venegas JG, et al. Hypoxic pulmonary vasoconstriction does not explain all regional perfusion redistribution in asthma. Am J Respir Crit Care Med. 2017;196:834–44.PubMedPubMedCentralCrossRef Kelly VJ, Hibbert KA, Kohli P, Kone M, Greenblatt EE, Venegas JG, et al. Hypoxic pulmonary vasoconstriction does not explain all regional perfusion redistribution in asthma. Am J Respir Crit Care Med. 2017;196:834–44.PubMedPubMedCentralCrossRef
27.
go back to reference Winkler T, Melo MFV, Degani-Costa LH, Harris RS, Correia JA, Musch G, et al. Estimation of noise-free variance to measure heterogeneity. PLoS ONE. 2015;10: e0123417.PubMedPubMedCentralCrossRef Winkler T, Melo MFV, Degani-Costa LH, Harris RS, Correia JA, Musch G, et al. Estimation of noise-free variance to measure heterogeneity. PLoS ONE. 2015;10: e0123417.PubMedPubMedCentralCrossRef
28.
go back to reference Motta-Ribeiro G, Winkler T, Hashimoto S, Vidal Melo MF. Spatial heterogeneity of lung strain and aeration and regional inflammation during early lung injury assessed with PET/CT. Acad Radiol. 2019;26:313–25.PubMedCrossRef Motta-Ribeiro G, Winkler T, Hashimoto S, Vidal Melo MF. Spatial heterogeneity of lung strain and aeration and regional inflammation during early lung injury assessed with PET/CT. Acad Radiol. 2019;26:313–25.PubMedCrossRef
29.
go back to reference Motta-Ribeiro GC, Hashimoto S, Winkler T, Baron RM, Grogg K, Paula LFSC, et al. Deterioration of regional lung strain and inflammation during early lung injury. Am J Respir Crit Care Med. 2018;198:891–902.PubMedPubMedCentralCrossRef Motta-Ribeiro GC, Hashimoto S, Winkler T, Baron RM, Grogg K, Paula LFSC, et al. Deterioration of regional lung strain and inflammation during early lung injury. Am J Respir Crit Care Med. 2018;198:891–902.PubMedPubMedCentralCrossRef
32.
go back to reference West JB, Dollery CT. Distribution of blood flow and ventilation-perfusion ratio in the lung, measured with radioactive CO2. J Appl Physiol. 1960;15:405–10.PubMedCrossRef West JB, Dollery CT. Distribution of blood flow and ventilation-perfusion ratio in the lung, measured with radioactive CO2. J Appl Physiol. 1960;15:405–10.PubMedCrossRef
33.
go back to reference Lai-Fook SJ. A continuum mechanics analysis of pulmonary vascular interdependence in isolated dog lobes. J Appl Physiol. 1979;46:419–29.PubMedCrossRef Lai-Fook SJ. A continuum mechanics analysis of pulmonary vascular interdependence in isolated dog lobes. J Appl Physiol. 1979;46:419–29.PubMedCrossRef
34.
go back to reference Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43:S25-32.CrossRef Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43:S25-32.CrossRef
35.
go back to reference Barst RJ, Gibbs JSR, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S78-84.PubMedPubMedCentralCrossRef Barst RJ, Gibbs JSR, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S78-84.PubMedPubMedCentralCrossRef
36.
go back to reference Tuder RM, Stacher E, Robinson J, Kumar R, Graham BB. Pathology of pulmonary hypertension. Clin Chest Med. 2013;34:639–50.PubMedCrossRef Tuder RM, Stacher E, Robinson J, Kumar R, Graham BB. Pathology of pulmonary hypertension. Clin Chest Med. 2013;34:639–50.PubMedCrossRef
37.
go back to reference Rol N, Timmer EM, Faes TJC, Vonk Noordegraaf A, Grünberg K, Bogaard H-J, et al. Vascular narrowing in pulmonary arterial hypertension is heterogeneous: rethinking resistance. Physiol Rep. 2017;5:e13159.PubMedPubMedCentralCrossRef Rol N, Timmer EM, Faes TJC, Vonk Noordegraaf A, Grünberg K, Bogaard H-J, et al. Vascular narrowing in pulmonary arterial hypertension is heterogeneous: rethinking resistance. Physiol Rep. 2017;5:e13159.PubMedPubMedCentralCrossRef
38.
go back to reference Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:261–72.PubMedPubMedCentralCrossRef Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:261–72.PubMedPubMedCentralCrossRef
39.
go back to reference Arai TJ, Henderson AC, Dubowitz DJ, Levin DL, Friedman PJ, Buxton RB, et al. Hypoxic pulmonary vasoconstriction does not contribute to pulmonary blood flow heterogeneity in normoxia in normal supine humans. J Appl Physiol. 2009;106:1057–64.PubMedCrossRef Arai TJ, Henderson AC, Dubowitz DJ, Levin DL, Friedman PJ, Buxton RB, et al. Hypoxic pulmonary vasoconstriction does not contribute to pulmonary blood flow heterogeneity in normoxia in normal supine humans. J Appl Physiol. 2009;106:1057–64.PubMedCrossRef
40.
go back to reference Hughes M, West JB. Point:Counterpoint: gravity is/is not the major factor determining the distribution of blood flow in the human lung. J Appl Physiol. 2008;104:1531–3.PubMedCrossRef Hughes M, West JB. Point:Counterpoint: gravity is/is not the major factor determining the distribution of blood flow in the human lung. J Appl Physiol. 2008;104:1531–3.PubMedCrossRef
41.
go back to reference Glenny R. Counterpoint: gravity is not the major factor determining the distribution of blood flow in the healthy human lung. J Appl Physiol. 2008;104:1533–5.PubMedCrossRef Glenny R. Counterpoint: gravity is not the major factor determining the distribution of blood flow in the healthy human lung. J Appl Physiol. 2008;104:1533–5.PubMedCrossRef
42.
go back to reference Henderson AC, Sá RC, Theilmann RJ, Buxton RB, Prisk GK, Hopkins SR. The gravitational distribution of ventilation-perfusion ratio is more uniform in prone than supine posture in the normal human lung. J Appl Physiol. 2013;115:313–24.PubMedPubMedCentralCrossRef Henderson AC, Sá RC, Theilmann RJ, Buxton RB, Prisk GK, Hopkins SR. The gravitational distribution of ventilation-perfusion ratio is more uniform in prone than supine posture in the normal human lung. J Appl Physiol. 2013;115:313–24.PubMedPubMedCentralCrossRef
43.
go back to reference Barberà JA, Roger N, Roca J, Rodriguez-Roisin R, Rovira I, Higenbottam TW. Worsening of pulmonary gas exchange with nitric oxide inhalation in chronic obstructive pulmonary disease. Lancet. 1996;347:436–40.PubMedCrossRef Barberà JA, Roger N, Roca J, Rodriguez-Roisin R, Rovira I, Higenbottam TW. Worsening of pulmonary gas exchange with nitric oxide inhalation in chronic obstructive pulmonary disease. Lancet. 1996;347:436–40.PubMedCrossRef
44.
go back to reference Katayama Y, Higenbottam TW, DiazdeAtauri MJ, Cremona G, Akamine S, Barbera JA, et al. Inhaled nitric oxide and arterial oxygen tension in patients with chronic obstructive pulmonary disease and severe pulmonary hypertension. Thorax. 1997;52:120–4.PubMedPubMedCentralCrossRef Katayama Y, Higenbottam TW, DiazdeAtauri MJ, Cremona G, Akamine S, Barbera JA, et al. Inhaled nitric oxide and arterial oxygen tension in patients with chronic obstructive pulmonary disease and severe pulmonary hypertension. Thorax. 1997;52:120–4.PubMedPubMedCentralCrossRef
45.
go back to reference Cardús J, Burgos F, Diaz O, Roca J, Barberá JA, Marrades RM, et al. Increase in pulmonary ventilation-perfusion inequality with age in healthy individuals. Am J Respir Crit Care Med. 1997;156:648–53.PubMedCrossRef Cardús J, Burgos F, Diaz O, Roca J, Barberá JA, Marrades RM, et al. Increase in pulmonary ventilation-perfusion inequality with age in healthy individuals. Am J Respir Crit Care Med. 1997;156:648–53.PubMedCrossRef
46.
go back to reference Sá RC, Henderson AC, Simonson T, Arai TJ, Wagner H, Theilmann RJ, et al. Measurement of the distribution of ventilation-perfusion ratios in the human lung with proton MRI: comparison with the multiple inert-gas elimination technique. J Appl Physiol Bethesda Md. 1985;2017(123):136–46. Sá RC, Henderson AC, Simonson T, Arai TJ, Wagner H, Theilmann RJ, et al. Measurement of the distribution of ventilation-perfusion ratios in the human lung with proton MRI: comparison with the multiple inert-gas elimination technique. J Appl Physiol Bethesda Md. 1985;2017(123):136–46.
47.
go back to reference Kretzschmar M, Schilling T, Vogt A, Rothen HU, Borges JB, Hachenberg T, et al. Multiple inert gas elimination technique by micropore membrane inlet mass spectrometry—a comparison with reference gas chromatography. J Appl Physiol. 2013;115:1107–18.PubMedCrossRef Kretzschmar M, Schilling T, Vogt A, Rothen HU, Borges JB, Hachenberg T, et al. Multiple inert gas elimination technique by micropore membrane inlet mass spectrometry—a comparison with reference gas chromatography. J Appl Physiol. 2013;115:1107–18.PubMedCrossRef
48.
go back to reference Vidal Melo MF, Harris RS, Layfield JDH, Venegas JG. Topographic basis of bimodal ventilation-perfusion distributions during bronchoconstriction in sheep. Am J Respir Crit Care Med. 2005;171:714–21.CrossRef Vidal Melo MF, Harris RS, Layfield JDH, Venegas JG. Topographic basis of bimodal ventilation-perfusion distributions during bronchoconstriction in sheep. Am J Respir Crit Care Med. 2005;171:714–21.CrossRef
49.
go back to reference Bratel T, Lagerstrand L, Brodin L-A, Nowak J, Randmaa I. Ventilation-perfusion relationships in pulmonary arterial hypertension: effect of intravenous and inhaled prostacyclin treatment. Respir Physiol Neurobiol. 2007;158:59–69.PubMedCrossRef Bratel T, Lagerstrand L, Brodin L-A, Nowak J, Randmaa I. Ventilation-perfusion relationships in pulmonary arterial hypertension: effect of intravenous and inhaled prostacyclin treatment. Respir Physiol Neurobiol. 2007;158:59–69.PubMedCrossRef
50.
go back to reference Dantzker DR, Bower JS. Mechanisms of gas exchange abnormality in patients with chronic obliterative pulmonary vascular disease. J Clin Invest. 1979;64:1050–5.PubMedPubMedCentralCrossRef Dantzker DR, Bower JS. Mechanisms of gas exchange abnormality in patients with chronic obliterative pulmonary vascular disease. J Clin Invest. 1979;64:1050–5.PubMedPubMedCentralCrossRef
51.
go back to reference Mélot C, Naeije R, Mols P, Vandenbossche JL, Denolin H. Effects of nifedipine on ventilation/perfusion matching in primary pulmonary hypertension. Chest. 1983;83:203–7.PubMedCrossRef Mélot C, Naeije R, Mols P, Vandenbossche JL, Denolin H. Effects of nifedipine on ventilation/perfusion matching in primary pulmonary hypertension. Chest. 1983;83:203–7.PubMedCrossRef
52.
go back to reference Voswinckel R, Reichenberger F, Gall H, Schmehl T, Gessler T, Schermuly RT, et al. Metered dose inhaler delivery of treprostinil for the treatment of pulmonary hypertension. Pulm Pharmacol Ther. 2009;22:50–6.PubMedCrossRef Voswinckel R, Reichenberger F, Gall H, Schmehl T, Gessler T, Schermuly RT, et al. Metered dose inhaler delivery of treprostinil for the treatment of pulmonary hypertension. Pulm Pharmacol Ther. 2009;22:50–6.PubMedCrossRef
53.
go back to reference Nickander J, Themudo R, Sigfridsson A, Xue H, Kellman P, Ugander M. Females have higher myocardial perfusion, blood volume and extracellular volume compared to males—an adenosine stress cardiovascular magnetic resonance study. Sci Rep. 2020;10:10380.PubMedPubMedCentralCrossRef Nickander J, Themudo R, Sigfridsson A, Xue H, Kellman P, Ugander M. Females have higher myocardial perfusion, blood volume and extracellular volume compared to males—an adenosine stress cardiovascular magnetic resonance study. Sci Rep. 2020;10:10380.PubMedPubMedCentralCrossRef
54.
go back to reference Kozu K, Sugimura K, Aoki T, Tatebe S, Yamamoto S, Yaoita N, et al. Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension. Heart Vessels. 2018;33:939–47.PubMedCrossRef Kozu K, Sugimura K, Aoki T, Tatebe S, Yamamoto S, Yaoita N, et al. Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension. Heart Vessels. 2018;33:939–47.PubMedCrossRef
Metadata
Title
Perfusion imaging heterogeneity during NO inhalation distinguishes pulmonary arterial hypertension (PAH) from healthy subjects and has potential as an imaging biomarker
Authors
Tilo Winkler
Puja Kohli
Vanessa J. Kelly
Ekaterina G. Kehl
Alison S. Witkin
Josanna M. Rodriguez-Lopez
Kathryn A. Hibbert
Mamary T. Kone
David M. Systrom
Aaron B. Waxman
Jose G. Venegas
Richard N. Channick
R. Scott Harris
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2022
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-022-02239-8

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The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.