- Open Access
Gasometric gradients between blood obtained from the pulmonary artery wedge and pulmonary artery positions in pulmonary arterial hypertension
© The Author(s). 2019
- Received: 18 June 2018
- Accepted: 20 December 2018
- Published: 8 January 2019
Little is known on the pulmonary gradients of oxyhemoglobin, carboxyhemoglobin and methemoglobin in pulmonary arterial hypertension (PAH). We sought to determine these gradients in group 1 PAH and assess their association with disease severity and survival.
During right heart catheterization (RHC) we obtained blood from pulmonary artery (PA) and pulmonary artery wedge (PAW) positions and used co-oximetry to test their gasometric differences.
We included a total of 130 patients, 65 had group 1 PAH, 40 had pulmonary hypertension (PH) from groups 2–5 and 25 had no PH during RHC. In all groups, PAW blood had higher pH, carboxyhemoglobin and lactate as well as lower pCO2 than PA blood. In group 1 PAH (age 58 ± 15 years, 72% females), methemoglobin in the PAW was lower than in the PA blood (0.83% ± 0.43 vs 0.95% ± 0.50, p = 0.03) and was directly associated with the degree of change in pulmonary vascular resistance (R = 0.35, p = 0.02) during inhaled nitric oxide test. Oxyhemoglobin in PA (HR (95%CI): 0.90 (0.82–0.99), p = 0.04) and PAW (HR (95%CI): 0.91 (0.84–0.98), p = 0.003) blood was associated with adjusted survival in PAH.
Marked differences were observed in the gasometric determinations between PAW and PA blood. The pulmonary gradient of methemoglobin was lower in PAH patients compared to controls and a higher PAW blood methemoglobin was associated with a more pronounced pulmonary vascular response to inhaled nitric oxide. Pulmonary artery and PAW oxyhemoglobin tracked with disease severity and survival in PAH.
- Blood gas analysis
- Pulmonary hypertension
Pulmonary arterial hypertension (PAH) is a condition characterized by progressive narrowing of the small pulmonary arteries that if left untreated leads to right heart failure and death . This pre-capillary involvement results in a distinct hemodynamic profile characterized by a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and pulmonary vascular resistance (PVR) > 3 Wood units . During the last three decades, the understanding of the pathobiology of PAH has markedly improved; however, there remains a need to determine whether certain gasometric alterations play a role in the pathogenesis of PAH.
The lungs oxygenate the blood and remove the carbon dioxide (CO2) generated by metabolic processes. It remains unknown how the lungs of patients with PAH process carboxyhemoglobin (COHb) and methemoglobin (metHb); which are compounds potentially involved in the pathogenesis of the disease [3–6]. Endogenously, carbon monoxide (CO) is produced by the catabolism of heme by heme oxygenase . Carbon monoxide is in part produced in the lungs [8, 9] where it may act as a pulmonary vasodilator . Methemoglobin results from the oxidation of the hemoglobin iron to a ferric (Fe+++) state, a reaction that occurs when oxyhemoglobin reacts with nitric oxide (NO) ; therefore levels of metHb may track with levels of NO, a potent vasodilator implicated in the pathogenesis of PAH .
Subjects and study design
This cross-sectional study was approved by the Cleveland Clinic institutional review board (study number: 06–245 and 14–1069). Written informed consent was waived given the retrospective nature of the study. We included consecutive patients who underwent RHC either to a) diagnose pulmonary hypertension (PH) or b) manage patients with prior diagnosis of PH. Right heart catheterizations were performed between December 2012 and April 2015.
We carefully assessed each patient to determine the etiology of PH based on the Fifth World Symposium classification . Group 1 PH includes the idiopathic and heritable forms, PH associated with drugs, toxins, connective tissue and congenital heart diseases, portal hypertension, HIV infection and schistosomiasis. Group 2, 3, 4 and 5 includes PH due to left heart disease, lung disease/hypoxia, chronic thromboembolic disease and multifactorial mechanisms, respectively. For the purpose of this study, patients were divided into three groups: a) patients with PAH (PH group 1), 2) patients with PH groups 2–5, and 3) age- and gender-matched subjects without evidence of resting PH on RHC (mPAP < 25 mmHg). Patients without PH underwent RHC due to elevated right ventricular systolic pressure on echocardiography. Patients were excluded (n = 50) if the PAW blood could not be obtained during RHC or if it showed an SO2 < 90%, suggestive of an inadequate balloon wedging with leakage of deoxygenated blood from the proximal (before the balloon) to the distal (after the balloon) aspect of the PA catheter.
Right heart catheterization
Subjects underwent RHC in the outpatient setting by a single operator (A.R.T.). All RHC were done under local anesthesia using 5 mL of 2% lidocaine. We continued or started oxygen (O2) supplementation in patients in whom the resting pulse oxygen saturation (SpO2) was < 90%. We maintained the same O2 flow during all the study measurements. In the supine position and with the transducer located in the mid-thoracic line (4th intercostal space), we measured the right atrial (RA) pressure, mean PAP and PAWP at end-expiration. We determined cardiac output (CO) by thermodilution. We calculated the cardiac index (CO / body surface area), the transpulmonary pressure gradient (TPG: mean PAP - PAWP), diastolic pulmonary gradient (DPG: diastolic PAP – PAWP) and PVR (TPG / CO). When appropriate, we performed a pulmonary vasodilator challenge using inhaled NO at 40 ppm for 5 min .
Pulmonary artery and PAW blood were obtained immediately after fluoroscopic site confirmation and obtaining an adequate waveform. The tip of the pulmonary artery catheter was located in West zone 3 . Ten mL of blood were discarded from each site before a sample was collected in a blood gas syringe. Blood gas samples were immediately analyzed using the ABL 800 Flex analyzer (Radiometer, Copenhagen, Denmark) which uses co-oximetry and provide determinations of COHb, metHb, Hb and lactate.
We collected data regarding demographics, use of PAH-specific medications and smoking status (current smoker was defined as a person who smoked tobacco in the last 30 days). We determined the severity of PH by using the New York Heart Association (NYHA) functional class, plasma N- terminal pro-B type natriuretic peptide (NT-proBNP), distance walked in the six-minute walk test (6MWD), RV size and function on echocardiography and hemodynamic determinations during RHC. Right ventricular function was determined both subjectively by visual inspection and objectively by the tricuspid annular plane systolic excursion (TAPSE) . We also recorded the diffusion lung capacity for carbon monoxide corrected for Hb (DLCOc) .
Continuous data are presented as mean ± standard deviation (SD) or median (interquartile range (IQR)) as appropriate. Categorical data are summarized as discrete values and percentages (n (%)). Continuous and categorical variables were compared across the groups using analysis of variance (ANOVA) and Chi-square, respectively. Paired data were contrasted with paired t test or Friedman test as appropriate. Associations were tested using the Pearson correlation test. Survival analysis was performed with Cox proportional hazards model adjusted by age, gender and other pre-specified variables. The starting point for the survival analyses was the date of the gasometric determinations. Patients were censored at the time of lung transplantation and followed until death or end of the study in January 2018. Cox proportional hazards model results are expressed as hazard ratios (HR) with the corresponding 95% confidence intervals (CI). All p values are two-tailed and a value of < 0.05 was considered significant. The statistical analyses were performed using the statistical package IBM SPSS, version 20 (IBM; Armonk, New York) and MedCalc, version 14.12.0 (Ostend, Belgium).
We included a total of 130 patients, of whom 65 had group 1 PAH, 40 had PH from groups 2–5 and 25 had no PH during RHC. Of the patients with PAH, 38 (58%) had idiopathic or heritable PAH, 17 (26%) had PAH associated with connective tissue diseases, 5 (8%) had porto-pulmonary hypertension and 5 (8%) had PAH due to other etiologies. Patients with non-group 1 PH belonged to PH groups 2 (n = 20, 50%), 3 (n = 10, 25%), 4 (n = 5, 12.5%) and 5 (n = 5, 12.5%). All patients without PH (n = 25, 19%) had an elevated RVSP (≥ 40 mmHg) and associated diseases such as scleroderma, cirrhosis, interstitial lung disease, obstructive sleep apnea or suggestion of left ventricular diastolic dysfunction by echocardiogram.
Baseline patient characteristics
Group 1 pulmonary arterial hypertension
Groups 2–5 pulmonary hypertension
P (ANOVA / Chi square)
58 ± 15
59 ± 20
54 ± 20
Female gender, n (%)
NYHA functional class, n (%)
Supplemental O2, n (%)
FiO2 in patients on supplemental O2 (%)
42 ± 22
35 ± 16
29 ± 3
2084 ± 3247
2087 ± 2737
180 ± 153
310 ± 129
317 ± 106
343 ± 130
DLCOc (% predicted)
54 ± 15
51 ± 28
60 ± 26
1.90 ± 0.62
1.81 ± 0.62
2.68 ± 0.80
RVSP (mm Hg)
73 ± 26
63 ± 22
50 ± 18
RA pressure (mmHg)
8 ± 6
9 ± 5
4 ± 3
42 ± 14
37 ± 10
17 ± 5
10 ± 5
15 ± 6
8 ± 3
32 ± 13
23 ± 10
9 ± 3
3.0 ± 0.9
2.7 ± 0.8
3.2 ± 0.7
PVR (Wood units)
6.7 ± 4.2
5.0 ± 3.5
1.5 ± 0.8
Gasometric determinations (PA)
7.41 ± 0.03
7.39 ± 0.04
7.40 ± 0.03
41.8 ± 5.7
47.7 ± 8.5
44.6 ± 4.6
68.1 ± 7.6
66.6 ± 9.7
72.4 ± 5.9
1.6 ± 1.1
1.6 ± 0.9
1.4 ± 1.0
1.0 ± 0.5
0.9 ± 0.4
0.8 ± 0.4
Lactic acid (mmoL/L)
0.8 ± 0.4
1.1 ± 0.5
1.0 ± 0.4
Gasometric determinations (PAW)
7.54 ± 0.08
7.49 ± 0.10
7.49 ± 0.08
27.1 ± 8.2
34.0 ± 10.6
32.3 ± 7.4
93.6 ± 5.4
92.0 ± 7.0
93.4 ± 3.6
1.8 ± 1.2
1.7 ± 1.1
1.6 ± 1.0
0.8 ± 0.4
0.8 ± 0.4
0.9 ± 0.4
Lactic acid (mmoL/L)
0.9 ± 0.4
1.2 ± 0.6
1.1 ± 0.5
Comparison of PAW and PA blood in patients with group 1 PAH
Comparison of pulmonary artery wedge and mixed venous blood in pulmonary arterial hypertension patients (n = 63)
Pulmonary artery wedge blood
Mixed venous blood
95% CI of the difference
P (paired T test)
7.53 ± 0.08
7.40 ± 0.03
0.11 to 0.15
27.1 ± 8.2
41.9 ± 5.7
−16.42 to − 13.10
104.4 ± 53.5
39.6 ± 4.7
51.40 to 78.30
pO2 a (mmHg)
82.5 ± 24.9
40.1 ± 4.8
38.01 to 50.96
22.3 ± 4.0
25.7 ± 3.3
− 3.83 to − 2.96
93.6 ± 5.4
68.3 ± 7.3
22.95 to 27.61
O2Hb a (%)
92.7 ± 6.5
70.5 ± 6.3
19.11 to 25.28
1.76 ± 1.18
1.59 ± 1.1
0.06 to 0.26
COHb b (%)
1.52 ± 0.79
1.33 ± 0.61
0.07 to 0.24
0.83 ± 0.43
0.95 ± 0.50
− 0.23 to − 0.01
12.7 ± 2.4
12.8 ± 2.3
− 0.29 to + 0.07
0.94 ± 0.35
0.82 ± 0.36
0.08 to 0.15
Comparison of PAW and PA blood gradients among study groups
Differences between pulmonary artery wedge and mixed venous blood in the three groups of patients
Group 1 pulmonary arterial hypertension
Groups 2–5 pulmonary hypertension
P (ANOVA / Chi square)
0.13 ± 0.07
0.10 ± 0.09
0.09 ± 0.06
− 14.7 ± 6.6
−14.2 ± 8.0
−12 ± 6.0
64.9 ± 53.4
58.0 ± 47.4
42.7 ± 27.0
pO2 a (mmHg)
42.5 ± 24.7
36.4 ± 21.3
40.9 ± 26.5
− 3.4 ± 1.7
−3.0 ± 1.4
− 2.9 ± 1.3
25.3 ± 9.3
23.7 ± 9.6
21.0 ± 6.3
O2Hb a (%)
22.2 ± 9.0
25.1 ± 6.7
21.9 ± 6.1
0.16 ± 0.40
0.09 ± 0.41
0.21 ± 0.53
COHb b (%)
0.17 ± 0.41
0.09 ± 0.42
0.22 ± 0.56
−0.12 ± 0.42
−0.11 ± 0.43
0.12 ± 0.27
− 0.11 ± 0.74
−0.19 ± 0.50
0.10 ± 0.61
0.12 ± 0.13
0.10 ± 0.14
0.06 ± 0.08
Association between blood gases, gradients and disease severity in group 1 PAH patients
The gradient of O2Hb between PAW and PA was directly associated with RA pressure (R: 0.34, p = 0.006), PVR (R: 0.35, p = 0.006) and NT-proBNP (R: 0.36, p = 0.03) and inversely associated with CI (R: − 0.43, p < 0.001) and TAPSE (R: -0.32, p = 0.013). Other gasometric gradients were not significantly associated with markers of disease severity.
Response to inhaled NO challenge and gasometric determinations in group 1 PAH patients
In group 1 PAH patients: the PVR decreased a mean of 16.3% ± 16.9% (n = 45). The percentage drop in PVR was inversely associated with Hb (R = − 0.34, p = 0.02) and directly associated with metHb (R = 0.35, p = 0.02) and O2Hb (R = 0.321, p = 0.03) in the PAW blood.
Relationship between blood determinations, gradients and survival in PH patients
The median (IQR) follow-up for patients with type 1 PAH was 41 (22–51) months, with a 2-year survival of 78%. When adjusted for age and gender, variables associated with mortality in group 1 PAH included: PA O2Hb (HR (95%CI): 0.87 (0.81–0.94), p = 0.001) and PAW O2Hb (HR (95%CI): 0.93 (0.87–0.98), p = 0.01). Pulmonary artery O2Hb was associated with mortality even when adjusted by supplemental oxygen therapy (HR (95%CI): 0.89 (0.82–0.96), p = 0.003) and adding PVR, 6MWD and number of PAH-specific therapies (HR (95%CI):0.90 (0.82–0.99), p = 0.04). Pulmonary artery wedge O2Hb continued to be a significant predictor when adjusted by supplemental oxygen therapy (HR (95%CI): 0.89 (0.83–0.96), p = 0.001), PA O2Hb (HR (95%CI): 0.88 (0.82–0.95), p = 0.001), and adding PVR, 6MWD and number of PAH-specific therapies (HR (95%CI):0.91 (0.84–0.98), p = 0.003). Methemoglobin or COHb levels measured in the PA or PAW, or their pulmonary gradients, did not predict survival.
In the present study we reported results on gasometric gradients between PAW and PA blood and compared findings in patients with group 1 PAH, PH groups 2–5 and age- and gender-matched disease controls. In all groups, we noted that the PAW blood showed higher pH, COHb and lactate compared to the PA blood. Interestingly, the level of metHb was lower in PAW blood than in PA blood in patients with PH, in contrast to higher levels in the PAW blood in patients without PH. In patients with group 1 PAH, we noted that a higher PAW metHb was associated with a more pronounced PVR drop during inhaled nitric oxide challenge. In patients with group 1 PAH, a lower PA and PAW O2Hb levels were independently associated with worse survival.
As shown by others [19, 20], the pH was higher in the PAW blood compared to the PA blood, in association with a lower pCO2. This pH gradient was more pronounced in patients with PAH than the other 2 groups of patients. Patients with PAH tend to have lower arterial pCO2 [28, 29] given an increase in the respiratory drive, an effect that becomes more evident in the PAW blood. Interestingly, the levels of lactate were higher in the PAW than PA blood suggesting lung production, as seen in other diseases such as acute respiratory distress syndrome [14, 30, 31]. We speculate that the differences in PAW blood are due to a) double lung passage of blood, initially from the PA through the alveolar capillaries and pulmonary veins to the left atrium, and then backwards from the left atrium through the pulmonary veins and alveolar capillaries to the PA catheter, leading to longer exposure to alveolar gas and intensification of the lung processes (Fig. 1) and/or b) prolonged exposure of the PAW blood to alveolar gases, given the temporal immobility of blood in a functional portion of the lung.
Nitric oxide is a potent vasodilator  that plays an important role in the pathogenesis of PH . The reaction with O2Hb is one of the catabolic pathways for NO, a process that generates nitrate and metHb . Naples et al. showed that venous metHb correlated with the levels of NO in the plasma of asthmatic patients . In our study, we showed that blood metHb levels are lower in the PAW compared to PA position in PH patients; in contrast, we found higher levels of metHb in PAW position in patients without PH. These findings insinuate a reduced production or an enhanced metabolism of metHb in the lung of PH patients. Interestingly, in PAH patients, a higher metHb in PAW blood was associated with a more pronounced decline in PVR during inhaled NO challenge, suggesting a greater diffusion of NO, a healthier pulmonary vasculature and/or an earlier stage of the disease in these patients. Further investigations may determine whether the level of metHb in the PAW position is associated with the response to PH-medications that target the nitric oxide pathway.
Carboxyhemoglobin is produced endogenously during the oxidation of heme compounds by heme oxygenase . The carbon monoxide released from this catabolic reaction has vasodilatory , anti-inflammatory  and anti-proliferative properties . Hypoxia transiently increases expression of heme oxygenase [38, 39]. The increased expression of heme oxygenase prevented the development of PH induced by hypoxia [38, 39] a mechanism that may involve the antiproliferative action of carbon monoxide . In the present study, we found that COHb is higher in the PAW compared to PA blood in all groups of patients, suggesting pulmonary production and systemic metabolism of carbon monoxide. A finding consistent with prior studies which showed positive arteriovenous COHb difference, with higher COHb in arterial compared to venous blood [8, 34, 40].
Analysis of survival in group 1 PAH patients showed that PA and PAW O2Hb adjusted by age, gender, use of supplemental oxygen, PVR and 6MWD are independent predictors of long-term survival. The association between PA O2Hb and survival was expected given previous research [41, 42]. The association between PAW blood O2Hb and survival is novel and consistent with our prior study showing that hypoxemia (determined by pulse oximetry) in patients with idiopathic and heritable PAH is associated with worse survival .
Our study has limitations: a) retrospective analysis, b) even though the gasometric differences of metHb are small and might not be clinically significant, they provide an insight on the complex physiological processes involving nitric oxide and c) although patients had a detailed smoking history, surreptitious smoking or other environmental exposure that increased carbon monoxide could not be ruled out. Smoking may affect the pulmonary endothelium, leading to pulmonary vascular remodeling and PH, even in the absence of hypoxemia and destructive emphysematous lung disease [44–48]. Despite these limitations, our study is the first to assess the gasometric gradients between PAW and PA blood in patients with PAH.
Pulmonary artery wedge blood samples had higher pH and lower pCO2 than PA, suggesting that PAW blood was exposed to alveolar gas for a longer period of time. Methemoglobin levels were lower in the PAW than PA blood in patients with PAH and a higher PAW metHb was associated with a more pronounced pulmonary vascular response to inhaled NO. Pulmonary artery and PAW O2Hb tracked with disease severity and survival in PAH patients.
A.R.T is supported by NIH grant # R01HL130307. M.K.A was supported by the Egyptian Ministry of Higher Education and Scientific Research Scholarship program grant.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
The authors have no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
GK Participated in the design of the study, data collection, statistical analysis, interpretation of the results, writing and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. MA Participated in the design of the study, data collection, interpretation of the results, writing and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. MDF Participated in the data collection, interpretation of the results and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. WD Participated in the data collection, interpretation of the results and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. RAD Participated in the design of the study, interpretation of the results and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. ART Participated in the design of the study, data collection, statistical analysis, interpretation of the results, writing and critical revision of the manuscript for important intellectual content and final approval of the manuscript submitted. ART is the guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article.
Ethics approval and consent to participate
This study was approved by the Cleveland Clinic institutional review board (study number: 06–245 and 14–1069). Written informed consent was waived given the retrospective nature of the study.
Ghaleb Khirfan MD: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
Mostafa K. Ahmed MD: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
Michael D. Faulx MD: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
Wael Dakkak MD: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
Raed A. Dweik MD: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
Adriano R. Tonelli MD: The author has no significant conflicts of interest with any companies or organization whose products or services may be discussed in this article.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Tonelli AR, Arelli V, Minai OA, Newman J, Bair N, Heresi GA, Dweik RA. Causes and circumstances of death in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;188:365–9.View ArticlePubMedGoogle Scholar
- Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D42–50.View ArticleGoogle Scholar
- Pabalan MJ, Nayak SP, Ryan RM, Kumar VH, Lakshminrusimha S. Methemoglobin to cumulative nitric oxide ratio and response to inhaled nitric oxide in PPHN. J Perinatol. 2009;29:698–701.View ArticleGoogle Scholar
- Morita T, Perrella MA, Lee ME, Kourembanas S. Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP. Proc Natl Acad Sci U S A. 1995;92:1475–9.View ArticlePubMedGoogle Scholar
- Morita T, Mitsialis SA, Koike H, Liu Y, Kourembanas S. Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells. J Biol Chem. 1997;272:32804–9.View ArticleGoogle Scholar
- Kourembanas S. Hypoxia and carbon monoxide in the vasculature. Antioxid Redox Signal. 2002;4:291–9.View ArticleGoogle Scholar
- Montellano PR. The mechanism of heme oxygenase. Curr Opin Chem Biol. 2000;4:221–7.View ArticleGoogle Scholar
- Meyer J, Prien T, Van Aken H, Bone HG, Waurick R, Theilmeier G, Booke M. Arterio-venous carboxyhemoglobin difference suggests carbon monoxide production by human lungs. Biochem Biophys Res Commun. 1998;244:230–2.View ArticleGoogle Scholar
- Scharte M, Bone HG, Van Aken H, Meyer J. Increased carbon monoxide in exhaled air of critically ill patients. Biochem Biophys Res Commun. 2000;267:423–6.View ArticleGoogle Scholar
- Dubuis E, Gautier M, Melin A, Rebocho M, Girardin C, Bonnet P, Vandier C. Chronic carbon monoxide enhanced IbTx-sensitive currents in rat resistance pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2002;283:L120–9.View ArticleGoogle Scholar
- Privat C, Lantoine F, Bedioui F, Millanvoye van Brussel E, Devynck J, Devynck MA. Nitric oxide production by endothelial cells: comparison of three methods of quantification. Life Sci. 1997;61:1193–202.View ArticleGoogle Scholar
- Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:214–21.View ArticleGoogle Scholar
- Johnson ML, Emhoff CA, Horning MA, Brooks GA. Transpulmonary lactate shuttle. Am J Physiol Regul Integr Comp Physiol. 2012;302:R143–9.View ArticleGoogle Scholar
- De Backer D, Creteur J, Zhang H, Norrenberg M, Vincent JL. Lactate production by the lungs in acute lung injury. Am J Respir Crit Care Med. 1997;156:1099–104.View ArticleGoogle Scholar
- Bendjelid K, Treggiari MM, Romand JA. Transpulmonary lactate gradient after hypothermic cardiopulmonary bypass. Intensive Care Med. 2004;30:817–21.View ArticleGoogle Scholar
- Wang TL, Hsu KL, Chiang FT, Tseng CD, Tseng YZ. Anaerobic metabolism in patients undergoing intra-aortic balloon counterpulsation for cardiogenic shock. J Formos Med Assoc. 1995;94:379–85.Google Scholar
- Inoue T, Sakai Y, Morooka S, Hayashi T, Takayanagi K, Yamaguchi H, Takabatake Y. Venoarterial carbon dioxide tension gradient in acute heart failure. Cardiology. 1993;82:383–7.View ArticleGoogle Scholar
- Harris P, Bailey T, Bateman M, Fitzgerald MG, Gloster J, Harris EA, Donald KW. Lactate, pyruvate, glucose, and free fatty acid in mixed venous and arterial blood. J Appl Physiol. 1963;18:933–6.View ArticleGoogle Scholar
- Williams WH Jr, Olsen GN, Allen WG, Yergin BM. Use of blood gas values to estimate the source of blood withdrawn from a wedged flow-directed catheter in critically ill patients. Crit Care Med. 1982;10:636–40.View ArticleGoogle Scholar
- Brewster H, McIlroy MB. Blood gas tensions and pH of pulmonary “wedge” samples in patients with heart disease. J Appl Physiol. 1973;34:413–6.View ArticleGoogle Scholar
- Safian RD, Come SE, Kadin M, Lorell BH. Use of pulmonary capillary wedge aspirates for the antemortem diagnosis of pulmonary microvascular tumor. Catheter Cardiovasc Diagn. 1989;17:112–5.View ArticleGoogle Scholar
- Tonelli AR, Mubarak KK, Li N, Carrie R, Alnuaimat H. Effect of balloon inflation volume on pulmonary artery occlusion pressure in patients with and without pulmonary hypertension. Chest. 2011;139:115–21.View ArticleGoogle Scholar
- Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34–41.View ArticleGoogle Scholar
- Tonelli AR, Alnuaimat H, Mubarak K. Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension. Respir Med. 2010;104:481–96.View ArticleGoogle Scholar
- West JB, Dollery CT. Distribution of blood flow and the pressure-flow relations of the whole lung. J Appl Physiol. 1965;20:175–83.View ArticleGoogle Scholar
- Ahmed M, Dweik RA, Tonelli AR. What is the best approach to a high systolic pulmonary artery pressure on echocardiography? Cleve Clin J Med. 2016;83:256–60.View ArticleGoogle Scholar
- Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26:720–35.View ArticleGoogle Scholar
- Hoeper M, Pletz M, Golpon H, Welte T. Prognostic value of blood gas analyses in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2007;29:944–50.View ArticleGoogle Scholar
- Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107:216–23.View ArticleGoogle Scholar
- Douzinas EE, Tsidemiadou PD, Pitaridis MT, Andrianakis I, Bobota-Chloraki A, Katsouyanni K, Sfyras D, Malagari K, Roussos C. The regional production of cytokines and lactate in sepsis-related multiple organ failure. Am J Respir Crit Care Med. 1997;155:53–9.View ArticleGoogle Scholar
- Brown SD, Clark C, Gutierrez G. Pulmonary lactate release in patients with sepsis and the adult respiratory distress syndrome. J Crit Care. 1996;11:2–8.View ArticleGoogle Scholar
- Zapol WM, Rimar S, Gillis N, Marletta M, Bosken CH. Nitric oxide and the lung. Am J Respir Crit Care Med. 1994;149:1375–80.View ArticleGoogle Scholar
- Gow AJ, Luchsinger BP, Pawloski JR, Singel DJ, Stamler JS. The oxyhemoglobin reaction of nitric oxide. Proc Natl Acad Sci U S A. 1999;96:9027–32.View ArticlePubMedGoogle Scholar
- Naples R, Laskowski D, McCarthy K, Mattox E, Comhair SA, Erzurum SC. Carboxyhemoglobin and methemoglobin in asthma. Lung. 2015;193:183–7.View ArticlePubMedGoogle Scholar
- Tenhunen R, Marver HS, Schmid R. Microsomal heme oxygenase. Characterization of the enzyme. J Biol Chem. 1969;244:6388–94.Google Scholar
- Furchgott RF, Jothianandan D. Endothelium-dependent and -independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels. 1991;28:52–61.Google Scholar
- Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000;6:422–8.View ArticleGoogle Scholar
- Liang OD, Mitsialis SA, Chang MS, Vergadi E, Lee C, Aslam M, Fernandez-Gonzalez A, Liu X, Baveja R, Kourembanas S. Mesenchymal stromal cells expressing heme oxygenase-1 reverse pulmonary hypertension. Stem Cells. 2011;29:99–107.View ArticlePubMedGoogle Scholar
- Christou H, Morita T, Hsieh CM, Koike H, Arkonac B, Perrella MA, Kourembanas S. Prevention of hypoxia-induced pulmonary hypertension by enhancement of endogenous heme oxygenase-1 in the rat. Circ Res. 2000;86:1224–9.View ArticleGoogle Scholar
- Yasuda H, Sasaki T, Yamaya M, Ebihara S, Maruyama M, Kanda A, Sasaki H. Increased arteriovenous carboxyhemoglobin differences in patients with inflammatory pulmonary diseases. Chest. 2004;125:2160–8.View ArticleGoogle Scholar
- Sandoval J, Bauerle O, Palomar A, Gomez A, Martinez-Guerra ML, Beltran M, Guerrero ML. Survival in primary pulmonary hypertension. Validation of a prognostic equation. Circulation. 1994;89:1733–44.View ArticleGoogle Scholar
- Wensel R, Opitz CF, Anker SD, Winkler J, Hoffken G, Kleber FX, Sharma R, Hummel M, Hetzer R, Ewert R. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation. 2002;106:319–24.View ArticleGoogle Scholar
- Khirfan G, Naal T, Abuhalimeh B, Newman J, Heresi GA, Dweik RA, Tonelli AR. Hypoxemia in patients with idiopathic or heritable pulmonary arterial hypertension. PLoS One. 2018;13:e0191869.View ArticlePubMedGoogle Scholar
- Wright JL, Levy RD, Churg A. Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment. Thorax. 2005;60:605–9.View ArticlePubMedGoogle Scholar
- Wright JL, Churg A. Effect of long-term cigarette smoke exposure on pulmonary vascular structure and function in the Guinea pig. Exp Lung Res. 1991;17:997–1009.View ArticleGoogle Scholar
- Peinado VI, Pizarro S, Barbera JA. Pulmonary vascular involvement in COPD. Am J Respir Crit Care Med. 2008;134:808–14.Google Scholar
- Ferrer E, Peinado VI, Diez M, Carrasco JL, Musri MM, Martinez A, Rodriguez-Roisin R, Barbera JA. Effects of cigarette smoke on endothelial function of pulmonary arteries in the Guinea pig. Respir Res. 2009;10:76.View ArticlePubMedGoogle Scholar
- Barbera JA, Peinado VI, Santos S. Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J. 2003;21:892–905.View ArticlePubMedGoogle Scholar