Abstract
Purpose
Antifibrotics (AF) attenuate the progression of fibrotic interstitial lung disease (ILD), but it is unknown if these drugs affect the progression of pulmonary hypertension (PH) in patients with ILD. We explored whether use of AF therapy was associated with a lower rate of change of mean pulmonary artery pressure (mPAP) in patients with ILD listed for lung transplantation (LTx).
Methods
All LTx recipients at Inova Fairfax Hospital from 2012 to 2023 with a pre-LTx diagnosis of ILD qualified for the analysis. Demographic data, mPAP at the time of LTx listing, intra-operative mPAP during lung transplantation, use of AF and PH therapy, spirometry, and 6-minute walk test data were collated. 153 patients were included the analysis. The mPAP rate of change (mmHg/month) was compared between patients based on the administration of AF in the pre-LTx period.
Results
The mPAP average rate of change was 0.9 mmHg/month for the AF group and 0.7 mmHg/month for the no AF group (p = 0.504). On multivariate analysis, age and the use of PH therapy were associated with mPAP rate of change. After accounting for these factors, AF usage was not associated with mPAP rate of change (p = 0.194). Additionally, AF usage was not found to augment the effects of PH therapy on mPAP change. Age was associated with a faster rate of change of mPAP, and PH therapy was associated with slower rate of change in mPAP.
Conclusion
AF therapy was not associated with a lower rate of change in mPAP in patients with ILD listed for LTx.
Keywords: Pulmonary hypertension, Lung transplantation, Antifibrotics, Pulmonary fibrosis
Background
The antifibrotics (AF) nintedanib, an intracellular tyrosine kinase inhibitor, and pirfenidone, an oral pyridone, attenuate the progression of idiopathic pulmonary fibrosis (IPF) by reducing the annual decline in forced vital capacity (FVC) in patients with IPF on AF therapy [1–3]. Nintedanib has also been shown to mitigate FVC decline in patients with progressive fibrotic interstitial lung disease (ILD), particularly for individuals with fibrotic patterns similar to usual interstitial pneumonia (UIP), indicating that these antifibrotic agents may have potential applications for treating fibrotic lung diseases beyond IPF [4]. However, it is unknown if AF therapy affects the development of pulmonary hypertension (PH) in patients with IPF or other progressive fibrotic ILDs.
PH in the context of significant ILD (PH-ILD) is classified as World Health Organization (WHO) Group 3 PH, and PH in the context of IPF is a significant predictor of mortality [5]. PH is estimated to affect < 10% of initially diagnosed patients with IPF and between 30 and 50% of patients with advanced IPF, with the prevalence being as high as 86% for end-stage IPF cases [6–8]. PH is progressive in IPF cases, with an average increase in mean pulmonary arterial pressure (mPAP) of 1.8 mmHg/year [9]. There is data to suggest that the overall survival of patients with IPF and concomitant PH is worse than the survival of patients with other types of ILD with PH), but there is also data suggesting that survival in patients with PH-ILD is similar across ILD subtypes, and that worsening survival is driven by the severity of PH, rather than by the severity of the ILD [7, 10].
There is emerging data that the antifibrotics improve survival in patients with IPF, but how much of this is due to a delay in the progression of the fibrosis or delay in the development of PH is uncertain. Amelioration of PH in ILD can be due to the effects on the fibrosis or potentially due to the effects of the antifibrotics on the vasculature itself. Indeed, both nintedanib and pirfenidone have been shown to decrease pulmonary vascular smooth muscle cell proliferation, thereby reducing total pulmonary vascular resistance and remodeling in murine models [11, 12], suggesting that AF therapy may have some effect on PH.
Given the relative dearth of treatment options for patients with PH-ILD, the effectiveness of AF in attenuating the progression of fibrosis, and the murine data suggesting additional effects on the pulmonary vasculature, we sought to explore whether AF have any effect on the progression of PH in patients with ILD.
Methods
We performed a retrospective chart review of all LTx recipients at Inova Fairfax Medical Center from 2012 to 2023 who had a pre-LTx diagnosis of ILD. Baseline demographics were recorded including spirometry and 6-minute walk test (6MWT) data. The use of AF therapy at the time of listing and at the time of LTx surgery was also recorded. The use of PH therapy up to 3 weeks before LTx was noted in order to account for confounding effects on PH development. Given the known effects of both venovenous (VV) and venoarterial (VA) extracorporeal membrane oxygenation (ECMO) on both pulmonary and systemic hemodynamics [13, 14], patients on ECMO at the time of LTx were excluded from our study.
We collected both the patients’ initial mPAP at the time of listing (mPAPbaseline) based on listing right heart catheterization (RHC) data, and the patients’ initial intra-operative mPAP at the time of LTx surgery (mPAPfollow−up). PH was defined as a mPAP > 20 mmHg, per the most recent guidelines [15]. To characterize PH development, the mPAP rate of change (mmHg/month) was calculated as the difference between the mPAPfollow−up and the mPAPbaseline divided by the months in between the baseline RHC and the date of LTx. The baseline RHC was performed in the cardiac catheterization laboratory under local anesthesia. The follow-up hemodynamic data was obtained at the time of the lung transplant surgery, but prior to any incisions being made. Pulmonary artery catheters (PAC) are routinely inserted as part of the pre-operative preparation for LTx surgery with the mPAP measurements reported continuously every second. Because cardiac output (CO) and pulmonary capillary wedge pressure (PCWP) were not measured intraoperatively, the pulmonary vascular resistance (PVR) could not be calculated and was therefore not included in our analysis. The average of the first three stable mPAP measurements after the insertion of the PAC were used to determine the mPAPfollow−up. The difference in mPAP corrected for time in months was calculated for each patient. A comparison was performed of the rate of change in mPAP in LTx recipients with ILD who received pre-operative AF therapy versus those who were not treated with anti-fibrotics. A subgroup analysis was performed by repeating this comparison among only those patients with a diagnosis of IPF. The study was approved by the Institutional Review Board at Inova Fairfax Hospital (IRB U21-02-4389).
Statistics
Continuous data are presented as the median and interquartile range (IQR) and compared using the Wilcoxon Rank Sum test. Categorical data are presented as a frequency and percent and compared using Fisher’s exact test. Multivariable generalized linear mixed effects models with random slopes and the inclusion of interaction terms were used to evaluate the effect of AF on the development of PH, accounting for baseline clinical factors such as age, diagnostic group, and PH therapy. All statistical analyses were performed with STATA/SE 17.0 (StataCorp, College Station, TX).
Results
There were 177 patients with ILD who underwent LTx at Inova Fairfax Hospital during the study period (2012–2023). Of these patients, 24 were excluded: 16 received ECMO before LTx surgery and 8 were missing baseline or intra-operative mPAP readings (Fig. 1). Therefore, there were 153 LTx recipients with ILD who formed the study cohort. The demographics of the final cohort at baseline are shown in Appendix Table 1. Notably, the median age was 62, 34% were female, and the median predicted forced vital capacity (FVC) percentage was 45%. Of these patients, 51.0% (N = 78) had idiopathic pulmonary fibrosis (IPF), 15.7% (N = 24) had nonspecific interstitial pneumonia (NSIP), 5.2% (N = 8) had hypersensitivity pneumonitis, 5.2% (N = 8) had rheumatoid disease related ILD, 4.6% (N = 7) had scleroderma related ILD and 18.3% (N = 28) had ILD due to other causes.
Fig. 1.
Consort diagram. (ILD = interstitial lung disease; ECMO = extracorporeal membrane oxidation; AF = antifibrotic; PH = pulmonary hypertension; Rx = medication prescription)
There were 97 patients with PH at baseline (63.4%) and 135 patients (88.2%) with PH at the time of lung transplantation. Of the 56 patients who did not have PH at baseline, 47 developed PH by the time of transplant (83.9%). The median mPAPbaseline and mPAPfollow−up for the entire cohort were 23 mmHg and 28 mmHg, respectively. There were 59 patients (38.6%) on AF therapy and 42 patients (27.5%) on PH therapy during the study period. Among those patients without PH at baseline who developed PH by the time of transplantation, 24/47 (51.1%) received AF. The median time between measurements was 205 days (IQR: 119, 365) for those on AF therapy vs. 188 days (IQR: 66, 443) for those not on AF therapy (p = 0.488). The distribution of the mPAPbaseline and mPAPfollow−up measurements stratified by treatment group is shown in Fig. 2.
Fig. 2.
Distribution of mPAPs at baseline and follow up for each treatment group. (mPAP = mean pulmonary artery pressure)
The AF group had significantly more males (76.3% vs. 59.6%), was significantly older (63 vs. 60 years) and had a higher baseline FVC (47% vs. 43%) and FEV1 (51% vs. 44%) than the no AF group. The AF group had a significantly higher baseline 6MWD (331 vs. 265 m), but the follow up 6MWDs were not significantly different between groups. The AF group was less likely to be on PH therapy during the study period (8/59 [13.6%] vs. 33/94 [35.1%]) and had significantly lower mPAPbaseline (21 vs. 25 mmHg) and mPAPfollow−up (27 vs. 31 mmHg).
The mPAP average rate of change was 0.9 mmHg/month for the AF group and 0.7 mmHg/month for the no AF group (p = 0.504), with the overall distribution shown in Fig. 3. Among only those patients with IPF, the mPAP average rate of change was 1.0 mmHg/month for the AF group and 1.4 mmHg/month for the no AF group (p = 0.388). Notably, there were 37 patients (20.9%) who had a serial drop in their mPAP from baseline, of whom 9 (24.3%) and 20 (54.1%) were treated with AF and PH therapy, respectively. The rate of change of mPAP did not differ based on the ILD diagnosis, baseline spirometric values, DLCO, 6MWD or SpO2 nadir (Appendix Table 2).
Fig. 3.
Distribution of change in mPAP per month. (mPAP = mean pulmonary artery pressure)
For those patients on PH therapy during the study period, the mean mPAPbaseline was 33 mmHg (IQR 27, 43) and the mean mPAPfollow−up was 37 mmHg (IQR 26, 43), with a mean change of 0.1 mmHg/month (IQR 2.1, 0.9). For those patients not on PH therapy, the mean mPAPbaseline was 21 mmHg (IQR 16, 25) and the mean mPAPfollow−up was 27 mmHg (IQR 24, 35), with a mean change of 1.1 mmHg/month (IQR 0.3, 2.6), a higher rate of change than those on PH therapy (p < 0.001). For all patients, the rate of change of mPAP during the study period was significantly higher for those with lower baseline mPAPs (Fig. 4).
Fig. 4.
Rate of change by baseline mPAP, R2 = 0.15, mPAP change = 4.56 − 0.14*Baseline mPAP, β: −0.14 (−0.19, −0.08), Std error: 0.03 p < 0.001. (mPAP = mean pulmonary artery pressure)
A generalized linear mixed effects model was constructed, with variables including age, AF usage, and PH therapy. Using multivariate analysis, age (β: 0.16; 95% CI: 0.02, 0.29, p = 0.023) and the use of PH therapy (β: −3.3; 95% CI: −6.4, −0.27, p = 0.033) were significantly associated with mPAP rate of change. After accounting for these factors, AF usage was not associated with mPAP rate of change (β: −1.78; −4.5, 0.91, p = 0.194), and AF administration did not augment the effects of PH therapy on mPAP change (p = 0.409). Likewise, when the analysis was restricted to those patients with IPF, AF usage was not associated with mPAP rate of change (−1.1; −3.4, 1.3, p = 0.384), and AF administration did not augment the effects of PH therapy on mPAP rate of change (p = 0.151).
Discussion
The use of AF therapy did not appear to significantly affect the rate of change in mPAP in the population of patients with ILD requiring lung transplantation. Additionally, AF usage was not found to augment the effects of PH therapy on mPAP change. Age was associated with a faster mPAP rate of change, and PH therapy was associated with a slower or negative mPAP rate of change.
The increasing prevalence of PH in patients with IPF as the disease progresses suggests that fibroproliferative damage of the lung parenchyma leads to vascular dysfunction that contributes to PH development [6, 8, 16, 17]. As such, we hypothesized that AF therapy would attenuate the increase in mPAP change over time by mitigating the progression of fibrosis in patients with ILD. However, our findings did not support that hypothesis. However, it is gratifying to note that the use of PH therapy did ameliorate the rise in mPAP attesting to the hemodynamic benefit of these agents in patients with ILD. Notably, the prevalence of PH was quite high (88.2%) at the time of transplant, which is indicative that the development of PH in ILD is a marker of end-stage disease.
There are several limitations to this study. The power of the findings is limited by the modest patient sample size. Although we report the first RHC data performed at the time of lung transplant evaluation as “baseline”, these patients had advanced disease and likely had occult PH for a variable period of time prior to this point. The AF and no AF groups had significant differences in baseline age, gender, FVC, FEV1, 6MWD and mPAP. Due to the significant differences in the groups, it is challenging to draw meaningful conclusions from the data, as any differences in outcomes could be related to differences in the baseline parameters. Specifically, our failure to find any significant differences in the change in mPAP during the study period could be due to baseline differences between the groups, rather than the antifibrotic medication. Additionally, we were unable to control for the possibility that patients developed other reasons for a change in their PA pressures during the study period, such as thromboembolic disease or left ventricular diastolic dysfunction. However, patients were monitored very closely pretransplant for the development of any such comorbidities.
The retrospective nature of this study introduced challenges in controlling measurement conditions. The mPAP measurements were recorded under different circumstances: specifically, the mPAPbaseline was measured in the cardiac catheterization lab under local anesthesia, whereas the mPAPfollow−up was measured intraoperatively under general anesthesia. Local anesthesia administration is targeted and doesn’t involve mechanical ventilation, which helps avoid pulmonary pressure elevation. In contrast, the process of general anesthesia (including induction, maintenance, and emergence) has unpredictable effects on pulmonary hemodynamics due to direct medication effects, hypoxemia, body temperature fluctuations, cardiac preload changes, and mechanical ventilation [18]. Ultimately, it is possible that general anesthesia induction agents may have lowered the mPAP readings, resulting in an underestimation of the mPAPfollow−up values. In any event, all patients were subjected to the same circumstances and the difference in the two groups would therefore be negated by this systemic “error”. Despite this, there remains a risk of bias due to the different measurement conditions at baseline and follow up, which may limit the robustness of our conclusions.
The time between mPAP readings varied broadly between patients, necessitating the mPAP change to be reported in mmHg per month. The time between the baseline and follow-up RHC measurements is variable and a “snapshot” in time for each individual patient. Thus, the calculated rate of change might not reflect the rate of change at other points in the patients’ disease course. Unfortunately, CO and PCWP were not obtained in the operating room, thus rendering the PVR incalculable. Indeed, it is conceivable that AF therapy influenced the pulmonary vasculature that impacted the CO more than the mPAP, such that there might have been changes in the PVR that we were unable to ascertain. It is also possible that any effects on the pulmonary vasculature might take longer to emerge than this current analysis allowed. Lastly, results may be skewed by selection bias, as LTx is reserved for end-stage disease only, meaning that findings could differ for IPF or ILD patients with earlier stages of disease [6].
As PH therapy and age were found to correlate significantly with the rate of mPAP change over time, these factors likely confounded the results. Before conclusive statements are made about the therapeutic effectiveness of AF regarding PH development, randomized controlled trials with standardized intervals for mPAP readings and other outcome measurements are necessary. The cohort for analysis should include patients across different severities of disease progression and different age groups. The presence of other treatments, particularly PH therapy, must also be considered as confounding factors. As the development of PH in the context of lung fibrosis is incompletely understood, the presence of other comorbidities related to ILD may also be worth noting. For example, IPF patients have an increased prevalence of thromboembolic disease, coronary artery disease, and sleep-disordered breathing, all of which may affect underlying PH development [17]. As PH development and RV function are also closely intertwined, the presence of RV dysfunction should also be recorded and included as a possible confounding factor for future analysis [8, 17]. Furthermore, we purport that measures or surrogates of the pulmonary vasculature should be considered as endpoints in future antifibrotic studies. While it is not practical or feasible to have baseline and follow-up RHCs in all patients, candidate surrogate measures include centrally adjudicated baseline and follow-up echocardiograms as well as baseline and follow-up NT-proBNPs.
Conclusion
In summary, despite our negative findings, we cannot rule out that AF therapy might influence the pulmonary vasculature either directly or through the amelioration of fibrosis. While not providing a definitive answer about the impact of AF therapy, our analysis has provided further insight into the progressive nature of PH in the context of ILDs. The shortfalls of our current analysis have allowed us to shed light on areas for future research. In any event, AFs play an important role in IPF and progressive fibrotic ILD treatment and we recommend that AF therapy should be continued up to the time of LTx. PH is a common complication associated with ILD and is known to confer a worse prognosis. When patients are listed for lung transplantation, there might not be further consideration to addressing concomitant PH. However, our finding of amelioration of mPAP increases in our ILD cohort underscores the role of approved PH therapies as a “bridge to transplantation” in these patients.
Appendix
Table 1.
Demographics with baseline and follow-up physiologic parameters (N = 153). (IPF = idiopathic pulmonary fibrosis; nsip = nonspecific interstitial pneumonia; hp = hypersensitivity pneumonitis; RA-ILD = rheumatoid disease related interstitial lung disease; fvc = forced vital capacity; FEV1 = forced expiratory volume in 1 s; DLCO=single breath diffusing capacity for carbon monoxide; tlc = total lung capacity.)
| All Patients (N = 153) | No antifibrotic (N = 94) | Antifibrotic (N = 59) | P-value | |
|---|---|---|---|---|
| Demographics | ||||
| Female | 52 (34.0%) | 38 (40.4%) | 14 (23.7%) | 0.037 |
| Age (years) | 62 (55, 66) | 60 (52, 65) | 63 (60, 67) | 0.004 |
| Diagnosis < 0.001 | ||||
| IPF | 78 (51.0%) | 35 (37.2%) | 43 (72.9%) | |
| NSIP | 24 (15.7%) | 20 (21.3%) | 4 (6.8%) | |
| HP | 8 (5.2%) | 6 (6.4%) | 2 (3.4%) | |
| RA-ILD | 8 (5.2%) | 6 (6.4%) | 2 (3.4%) | |
| Scleroderma | 7 (4.6%) | 3 (3.2%) | 4 (6.8%) | |
| Other ILD | 28 (18.3%) | 24 (25.5%) | 4 (6.8%) | |
| Lung function testing | ||||
| FVC, % predicted | 45 (36, 56) | 43 (30, 56) | 47 (41, 56) | 0.031 |
| FEV1, % predicted | 47 (40, 63) | 44 (36, 62) | 51 (44, 63) | 0.017 |
| DLCO, % predicted | 25 (20, 29) | 24 (19, 30) | 28 (20, 29) | 0.667 |
| TLC, % predicted | 37 (32, 49) | 48 (36, 55) | 33 (29, 37) | 0.016 |
| 6MWT distance baseline (m) | 296 (183, 389) | 265 (154, 338) | 331 (253, 451) | 0.001 |
| 6MWT distance follow-up (m) | 282 (175, 338) | 266 (129, 323) | 294 (209, 389) | 0.083 |
| Therapy | ||||
| PH therapy | 42 (27.5%) | 33 (35.1%) | 9 (15.3%) | 0.005 |
| PDE5i | 38 (90.5%) | 29 (87.9%) | 9 (100%) | |
| ERA | 5 (11.9%) | 3 (9.1%) | 2 (22.2%) | |
| Prostacyclin (oral/inhaled) | 1 (2.4%) | 1 (3.0%) | 0 | |
| Prostacyclin (IV) | 14 (33.3%) | 12 (36.4%) | 2 (22.2%) | |
| Hemodynamic measurements | ||||
| mPAP baseline (mmHg): | 23 (18, 28) | 25 (19, 32) | 21 (17, 25) | 0.001 |
| mPAP follow-up (mmHg): | 28 (25, 38) | 31 (26, 40) | 27 (24, 33) | 0.013 |
| mPAP change (mmHg): | 7 (0, 12) | 7 (−2, 13) | 7 (2, 12) | 0.650 |
| Baseline to transplant time (days): | 192 (88, 385) | 188 (66, 443) | 205 (119, 365) | 0.488 |
Table 2.
Factors associated with mPAP rate of change. (IPF = idiopathic pulmonary fibrosis; nsip = nonspecific interstitial pneumonia; fvc = forced vital capacity; FEV1 = forced expiratory volume in 1 s; DLCO=single breath diffusing capacity for carbon monoxide; tlc = total lung capacity; SpO2 = oxygen saturation of peripheral blood; ph = pulmonary hypertension)
| Parameter | Βeta (95% CI) | Standard Error | P-value |
|---|---|---|---|
| Demographics | |||
| Age | 0.18 (0.05, 0.31) | 0.07 | 0.008 |
| Gender (female as reference) | 2.29 (−0.14, 4.71) | 1.24 | 0.064 |
| Diagnosis | |||
| IPF (as reference) | |||
| NSIP | 0.87 (−3.10, 4.85) | 2.03 | 0.667 |
| Other | 0.31 (−2.38, 2.99) | 1.37 | 0.824 |
| Pulmonary function testing (baseline) | |||
| FVC, % predicted | 0.01 (−0.07, 0.08) | 0.04 | 0.941 |
| FEV1, % predicted | 0.02 (−0.05, 0.09) | 0.04 | 0.583 |
| DLCO, % predicted | 0.03 (−0.14, 0.20) | 0.09 | 0.709 |
| TLC, % predicted | 0.04 (−0.09, 0.18) | 0.07 | 0.530 |
| 6-minute walk testing (baseline) | |||
| Distance (m) | −0.01 (−0.01, 0.01) | 0.01 | 0.323 |
| SpO2 Nadir | −0.07 (−0.20, 0.06) | 0.07 | 0.293 |
| Management | |||
| Antifibrotic | −0.08 (−2.46, 2.30) | 1.22 | 0.949 |
| PH therapy | −3.20 (−5.76, −0.64) | 1.31 | 0.014 |
Acknowledgements
Not applicable.
Authors’ contributions
All authors contributed to the study conception and design. Data collection and analysis were performed by Christopher Thomas, Abhimanyu Chandel and Steven Nathan. The first draft of the manuscript was written by Christopher Thomas and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that no funds, grants or other support were received during the preparation of this manuscript.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was approved by the Institutional Review Board (IRB) at Inova Fairfax Hospital (IRB U21-02-4389). Need for informed consent to participate in the study was waived by the IRB.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Richeldi L, Du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071–82. [DOI] [PubMed] [Google Scholar]
- 2.Costabel U, Inoue Y, Richeldi L, Collard HR, Tschoepe I, Stowasser S, et al. Efficacy of nintedanib in idiopathic pulmonary fibrosis across prespecified subgroups in INPULSIS. Am J Respir Crit Care Med. 2016;193(2):178–85. [DOI] [PubMed] [Google Scholar]
- 3.Noble PW, Albera C, Bradford WZ, Costabel U, Du Bois RM, Fagan EA, et al. Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J. 2016;47(1):243–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–27. [DOI] [PubMed] [Google Scholar]
- 5.Rajagopal K, Bryant AJ, Sahay S, Wareing N, Zhou Y, Pandit LM, et al. Idiopathic pulmonary fibrosis and pulmonary hypertension: Heracles meets the hydra. Br J Pharmacol. 2021;178(1):172–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Collum SD, Amione-Guerra J, Cruz-Solbes AS, DiFrancesco A, Hernandez AM, Hanmandlu A, et al. Pulmonary hypertension associated with idiopathic pulmonary fibrosis: current and future perspectives. Can Respir J. 2017;2017:1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Alhamad EH, Cal JG, Alrajhi NN, Alharbi WM. Predictors of mortality in patients with interstitial lung disease-associated pulmonary hypertension. JCM. 2020;9(12):3828. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Nathan SD, Shlobin OA, Ahmad S, Koch J, Barnett SD, Ad N, et al. Serial development of pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Respiration. 2008;76(3):288–94. [DOI] [PubMed] [Google Scholar]
- 9.Teramachi R, Taniguchi H, Kondoh Y, Ando M, Kimura T, Kataoka K, et al. Progression of mean pulmonary arterial pressure in idiopathic pulmonary fibrosis with mild to moderate restriction. Respirology. 2017;22(5):986–90. [DOI] [PubMed] [Google Scholar]
- 10.Price L, Jenkin I, Dimopoulos K, Nathan S, Dawes T, Bax S, McCabe C et al. Survival in patients with pulmonary hypertension associated with fibrotic interstitial lung disease is independent of ILD subtype: A London Study. Am J Respir Crit Care Med. 2025;211:A3281. [DOI] [PMC free article] [PubMed]
- 11.Poble PB, Phan C, Quatremare T, Bordenave J, Thuillet R, Cumont A, et al. Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension. FASEB J. 2019;33(3):3670–9. [DOI] [PubMed] [Google Scholar]
- 12.Huang J, Maier C, Zhang Y, Soare A, Dees C, Beyer C, et al. Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Ann Rheum Dis. 2017;76(11):1941–8. [DOI] [PubMed] [Google Scholar]
- 13.Miranda DR, Van Thiel R, Brodie D, Bakker J. Right ventricular unloading after initiation of venovenous extracorporeal membrane oxygenation. Am J Respir Crit Care Med. 2015;191(3):346–8. [DOI] [PubMed] [Google Scholar]
- 14.Owyang CG, Rippon B, Teran F, Brodie D, Araos J, Burkhoff D et al. Pulmonary Artery Pressures and Mortality during VA ECMO: An ELSO Registry Analysis [Internet]. 2023 [cited 2024 May 4]. Available from: 10.1101/2023.08.08.23293859. [DOI] [PMC free article] [PubMed]
- 15.Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2023;61(1):2200879. [DOI] [PubMed] [Google Scholar]
- 16.Ruffenach G, Hong J, Vaillancourt M, Medzikovic L, Eghbali M. Pulmonary hypertension secondary to pulmonary fibrosis: clinical data, histopathology and molecular insights. Respir Res. 2020;21(1):303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Nathan S, King C. Treatment of pulmonary hypertension in idiopathic pulmonary fibrosis: shortfall in efficacy or trial design? DDDT. 2014;875–885. [DOI] [PMC free article] [PubMed]
- 18.Sarkar MS, Desai PM. Pulmonary hypertension and cardiac anesthesia: anesthesiologist’s perspective. Ann Card Anaesth. 2018;21(2):116–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.