Evaluation of the impact of pulmonary circulation, particularly pulmonary vascular resistance, in patients with idiopathic pulmonary fibrosis: an exploratory study

Abstract

Background

Idiopathic pulmonary fibrosis (IPF) is a progressive disease often complicated by pulmonary hypertension (PH), leading to a worse prognosis. In this study, we use the term “secondary PH” to refer to PH that develops as a complication of IPF (i.e., IPF-PH), and “the ERPE (Exercise-Responsive PAP Elevation) group, defined as patients without resting PH but with potential PAP elevation during exertion, indicating early pulmonary vascular stress.” This study aimed to evaluate the impact of pulmonary vascular resistance (PVR) on the clinical course, activities of daily living (ADL), and exercise tolerance in IPF patients. Additionally, we sought to determine whether PVR influences prognosis within a short-term period of just two years.

Methods

This exploratory single-center study was conducted as an interim analysis of a prospective trial targeting patients with IPF complicated by secondary PH or ERPE. The analysis included 49 IPF patients who received conventional IPF management without pulmonary arterial hypertension (PAH)-specific therapies and completed a two-year follow-up. Pulmonary circulation parameters, including PVR and pulmonary artery pressure (PAP), were assessed via right heart catheterization. Lung function, ADL, and exercise tolerance were also evaluated. Statistical analyses were performed to assess the association between PVR and prognosis.

Results

Higher PVR was significantly associated with poorer prognosis and worsening restrictive lung impairment. PVR correlated with modified Medical Research Council (mMRC) scores (Spearman’s ρ = 0.47, p = 0.0007) and 6-minute walk distance (Spearman’s ρ = -0.41, p = 0.0042). Proportional hazard analysis identified PVR as a significant predictor of overall survival (hazard ratio [HR]: 1.28, 95% confidence interval [CI]: 1.0055–1.53, p = 0.013). PVR also strongly correlated with maximum exercise tolerance (Spearman’s ρ = -0.60, p < 0.0001). Importantly, even within the short two-year follow-up, elevated PVR significantly impacted both home-stay survival (HR: 1.20, 95% CI: 1.0072–1.41, p = 0.032) and overall survival, underscoring its predictive value over a short time frame.

Conclusions

PVR is associated with prognosis, ADL, and exercise tolerance in IPF patients. Importantly, even within a short two-year period, PVR was significantly linked to clinical outcomes. While causality cannot be established, our findings suggest that PVR may serve as a potentially useful early prognostic marker. Regular PVR monitoring could provide valuable insights into disease progression and may support earlier therapeutic interventions to improve outcomes.

Trial registration

This study is registered in the UMIN Clinical Trials Registry (UMIN000055468). Trial registration at 10/09/2024. Retrospectively registered.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12890-025-03837-0.

Background

Idiopathic pulmonary fibrosis (IPF) is a progressive disease that leads to impaired lung function, dyspnea, and poor prognosis. As the disease advances, pulmonary hypertension (PH) frequently develops and is recognized as an independent prognostic factor in IPF patients [1–10]. Rising pulmonary artery pressure (PAP) reflects irreversible vascular remodeling, often indicating delayed treatment, as significant vascular damage has typically occurred by the time PAP is elevated [11]. Additionally, right ventricular strain may begin before a measurable rise in PAP, suggesting the importance of detecting early changes in pulmonary circulation [12–14].

An analysis of interstitial lung disease patients undergoing right heart catheterization (RHC) showed that even mildly elevated pulmonary vascular resistance (PVR > 2 Wood Units) at diagnosis is associated with increased mortality [15]. Factors such as endothelin, which is known to play a role in pulmonary arterial hypertension (PAH), are also implicated in the development of PH in diseases like IPF and COPD [16–18]. Based on these findings, we hypothesize that pulmonary circulation—particularly PVR—has a significant, independent impact on prognosis, activities of daily living (ADL), and exercise tolerance in IPF patients.

As PVR increases, PAP is expected to rise correspondingly. To explore the impact of pulmonary circulation on ADL, activity, and prognosis in IPF patients, we are conducting a prospective study (UMIN ID: UMIN000042159). This study includes IPF patients with PH or those showing Exercise-Responsive PAP Elevation (ERPE), defined as mPAP > 30 mmHg during exertion, indicating potential PH exposure in daily life.

In this exploratory clinical analysis, conducted as part of the interim analysis of the clinical trial, we focused on the group receiving conventional IPF treatment without ERA administration. Specifically, we analyzed data with a particular focus on PVR in addition to PAP. The objective of this analysis was to examine the correlation between pulmonary circulation parameters, particularly PVR, and prognosis, ADL, and activity in IPF patients.

The results of this study, even within the relatively short two-year monitoring period, suggest that PVR, the primary focus of our analysis, is strongly associated not only with prognosis, ADL, and activity but also with maximal exercise tolerance assessed using a treadmill. Unlike the six-minute walk test, which is influenced by patient-determined walking speeds, treadmill-based assessments provide a more precise measure of exercise capacity. These findings, encompassing IPF patients with a wide range of PAP conditions—from the ERPE group, defined as patients without resting PH but with potential PAP elevation during exertion, indicating early pulmonary vascular stress to less severe PH and severe PH—underscore the potential importance of PVR as a key indicator, and we present these results as a valuable contribution to understanding IPF and PH progression.

Materials and methods

A summary of the classification and enrollment process is shown in Fig. 1.

Fig. 1.

Flowchart for grouping of patients included in the final analysis. This diagram outlines the classification process of patients with chronic fibrotic IIP who were screened by HRCT and stratified using RHC results. Patients were grouped into severe PH (n = 4), less severe PH (n = 21), and ERPE (n = 24), based on mPAP and mPAWP. Abbreviations: PH, pulmonary hypertension; ERPE, Exercise-Responsive PAP Elevation; RHC, right heart catheterization; mPAP, mean pulmonary artery pressure; mPAWP, mean pulmonary arterial wedge pressure; IPF, idiopathic pulmonary fibrosis; IIP, idiopathic interstitial pneumonia

Study design and methods

This exploratory analysis was conducted as part of an interim evaluation of a prospective study (UMIN ID: UMIN000042159) involving patients with IPF complicated by secondary PH or ERPE.

The analysis focused on patients who had completed a two-year follow-up without receiving pulmonary arterial hypertension (PAH)-specific therapies, and evaluated the impact of pulmonary vascular resistance (PVR) alongside pulmonary artery pressure (PAP).

Primary outcomes

To investigate the relationship between pulmonary circulation parameters, including pulmonary vascular resistance (PVR), and the prognosis in patients with idiopathic pulmonary fibrosis (IPF).

In this study, “prognosis” was defined as two distinct clinical outcomes over a two-year period: (1) overall survival and (2) home-stay survival, which is defined as the duration a patient was able to live at home without requiring admission to a long-term care facility or hospital-based permanent care.

Secondary outcomes

To investigate the correlation between pulmonary circulation parameters, including pulmonary vascular resistance (PVR), and activities such as activities of daily living (ADL) and maximum exercise tolerance in patients with idiopathic pulmonary fibrosis (IPF).

Target patient population

As part of the interim analysis of an ongoing prospective study (UMIN ID: UMIN000042159), this exploratory study was conducted in patients with IPF complicated by secondary ERPE or PH classified as WHO functional class II, III, or IV. Eligible patients were those who received conventional management for lung disease without PAH-specific therapies between October 2020 and September 2022, and who completed a two-year follow-up.

Inclusion was conditional on meeting all eligibility criteria and having no exclusion criteria.

Inclusion criteria

1. Patients aged 20 years old or older (both sexes).

2. Patients diagnosed at our hospital as having IPF (WHO functional class II, III, or IV) who did not exhibit hypoxia either at rest or during the 6-minute walk test (6MWT), including those on long-term oxygen therapy (LTOT) whose PaO₂ was maintained at ≥ 60 mmHg while on oxygen therapy. This inclusion criterion was designed to exclude cases in which decreased ADL and dyspnea in daily life might be attributable to hypoxia, and to minimize the influence of hypoxic pulmonary vasoconstriction (HPV) as a confounding cause of pulmonary hypertension.

3. Patients with stable IPF who had not required any change in treatment during the three months prior to study entry—defined as those with completely organized honeycomb lung based on high-resolution computed tomography (CT), diagnosed as having chronic IPF, and not requiring urgent initiation of any therapy known to provide definite improvement in IPF—or patients who presented to our hospital for the first time with progressive respiratory failure and had not received any medical treatment for IPF within the three months preceding their visit.

   • *Excluding those whose progressive respiratory failure required no treatment for IPF itself and those who had an increased LTOT dose as a minimum requirement for progressive respiratory failure.

4. Patients with eePAP or clinically significant PH, defined as having a PAWP ≤ 15 mmHg, mPAP < 25 mmHg at rest, and mPAP ≥ 30 mmHg during exertion, and/or mPAP ≥ 25 mmHg at rest.

5. Inpatients and outpatients.

6. Patients who provided written informed consent to participate in this study.

Exclusion criteria

1. Patients who had received any drug specific for PAH (e.g., phosphodiestetrase type 5 [PDE-5] inhibitors, endothelin receptor antagonists, or prostaglandin analogs) prior to their enrollment.

2. Patients with any disease that could cause right heart overload.

3. Patients with hypoxia during 6MWT (PaO₂ < 60 mmHg)*.

   • * Excluded were those whose hypoxia (PaO₂ < 60 mmHg) had been corrected with LTOT (i.e., those in whom LTOT is in place to ensure PaO2 > 60 mmHg both at rest and during 6MWT, who were deemed equivalent to IPF patients receiving routine therapy in clinical practice to allow them to be monitored for changes in their condition, prognosis and functional capacity for ADL).

4. Women who were pregnant or might have been pregnant, and who were lactating.

5. Other patients judged by the investigator to be ineligible for this study (e.g., those with any disease or condition other than IPF that might affect their ADL, such as arrhythmia, LV failure, pulmonary thromboembolism, connective tissue diseases, intervertebral disc herniation, as they were confirmed by history taking, physical examination, chest x-ray, echocardiography (ECG), lung perfusion scintigraphy, and measurements of various parameters conducted during the run-in period).

Grouping of patients

The classification of patients into each PH severity group is summarized in Fig. 1.

This analysis targeted patients from our ongoing study with minimal IPF activity at diagnosis, confirmed by chronic fibrosing interstitial pneumonia (f-IIP) on high-resolution CT, and included right heart catheterization (RHC) to evaluate right heart function for symptom assessment.

According to the current diagnostic criteria, exercise-induced pulmonary hypertension (exercise-PH) is diagnosed by confirming an mPAP/cardiac output (CO) slope of > 3 mmHg/L/min during exercise. However, diagnosing exercise-induced PH is not straightforward. In this study, we interpreted patients with an mPAP < 25 mmHg and mPAWP ≤ 15 mmHg, but with an mPAP ≥ 30 mmHg during straining, as potentially developing pulmonary hypertension during daily life. Although these patients were not strictly classified as having exercise-induced PH, they were regarded as having exercise-induced elevation of pulmonary artery pressure (eePAP) in this study. Among them, those with an mPAP below 20 mmHg were classified into the ERPE group.

Although the current diagnostic criteria define PH as a resting mPAP > 20 mmHg, this analysis used data from an ongoing study originally designed prior to the guideline revision. In that protocol, patients were assigned to the PH group if they had a resting mPAP ≥ 25 mmHg, or if their resting mPAP was between 20 and 25 mmHg and mPAP ≥ 30 mmHg was observed during straining.

Based on these data, we classified patients as having less severe PH if they had a resting mPAP between 20 and 35 mmHg and mPAWP ≤ 15 mmHg, and as having severe PH if they had mPAP ≥ 35 mmHg with mPAWP ≤ 15 mmHg. This stratification reflects the structure of the original data and forms the analytical basis of the present study.

The aim of this study was to assess the extent to which PH, ranging from ERPE to mild and severe PH secondary to IPF, impacts the clinical course of IPF patients. Furthermore, this study aimed to emphasize the importance of early evaluation of conditions leading to PH and to explore the potential utility of future research on early therapeutic intervention for such conditions.

Target sample size

To perform factor analysis on the primary outcomes of this study—home-stay survival (the duration a patient can remain at home before requiring permanent institutional care) and overall survival—at least 10 events per factor were estimated to be necessary.

In our previous study, we evaluated the two-year prognosis of patients with IPF who had a mPAP of ≥ 20 mmHg but < 25 mmHg and also showed effort-induced mPAP (mPAPOE) ≥ 30 mmHg, which we defined as exercise-induced elevation of pulmonary artery pressure (eePAP) in the present study. We also assessed patients with PH in the range of 25 mmHg ≤ mPAP < 35 mmHg. Among these patients, 8 of 12 experienced events for home-stay survival, and 7 experienced events for overall survival.

Based on these findings, it was estimated that approximately half of the IPF patients with mPAP between 20 and 25 mmHg and eePAP, or with mPAP between 25 and 35 mmHg, would experience an event. Therefore, a minimum of 20 patients was required for analysis. Assuming that patients with mPAP < 25 mmHg but with eePAP would comprise approximately half of the cohort, the necessary sample size was increased to 40. Accounting for protocol deviations, a total of 50 patients were enrolled. After excluding protocol deviations, at least 40 patients were expected to be available for two-year prognostic analysis, with more than 10 events anticipated.

Accordingly, the analysis was conducted once the number of patients who had completed the two-year follow-up in the ongoing prospective trial (UMIN ID: UMIN000042159) exceeded 50. These patients had IPF with secondary PH or exhibited exertional PAP > 30 mmHg and had received conventional IPF management without PAH-specific therapies. The final analysis included more than 40 patients, among whom over 10 events were recorded.

Evaluation parameters

Hemodynamics

ECG examinations, complete two-dimensional, pulsed-wave, color-flow echocardiography, and Doppler measurements were conducted using the Toshiba ultrasound system Xario (TOSHIBA MEDICAL SYSTEMS CORPORATION, Tochigi, Japan) as previously described [12–14, 19–29] during the run-in period* (See supplementary document for parameters).

Right heart catheterization (RHC) was also performed during the run-in period*. Hemodynamic parameters, including systolic PAP (SPAP), diastolic PAP (DPAP), mean PAP (mPAP), systolic pulmonary artery wedge pressure (SPAWP), diastolic PAWP (DPAWP), mean PAWP (mPAWP), systolic right ventricular pressure (SRVP), diastolic RVP (DRVP), mean RVP (mRVP), systolic right atrial pressure (SRAP), diastolic RAP (DRAP), mean RAP (mRAP), cardiac output (CO), and cardiac index (CI), as well as PVR, were measured with the patient in the supine position via the internal jugular vein.

CO was measured by the thermodilution method.

In addition, mixed venous blood gas analysis was performed.

Survival analysis

Home-stay survival; Duration of being able to live at home before requiring permanent facility care, and overall survival were determined by the duration of survival from week 0 (start of assessment). Even for those unable to undergo the periodic assessments due to change of their attending physician, etc., this survival analysis was continued by contacting the patient’s current physician to have his/her survival status confirmed. Patients were censored from Home-stay survival if they could no longer continue ambulatory treatment and were admitted to another hospital or if they could no longer present to our hospital for progression of respiratory failure.

Other parameters

Pulmonary function tests (PFT) were carried out during the run-in period* and performed as deemed appropriate thereafter (see supplementary document for parameters).

ADL assessments, including exercise tolerance tests [30–32], were conducted during the run-in period* (see supplementary document for details on parameters). For patients receiving long-term oxygen therapy (LTOT) to ensure adequate oxygen intake during the 6-minute walk test (6MWT) — which was considered equivalent to routine therapy for IPF patients in clinical practice — treadmill exercise tests (TMET) were performed with LTOT in place to monitor changes in their condition, prognosis, and functional capacity for ADL.

Arterial blood gas (ABG), arterial plasma lactate, and N-terminal (NT)-proBNP levels were measured during the run-in period and were performed as deemed appropriate thereafter** [33] (see supplementary document for parameters).

Hematology, biochemistry, and urinalysis were performed during the run-in period* and performed as deemed appropriate thereafter.

*Run-in period: Within 2 weeks after written informed consent was obtained from each patient.

Periodic assessments that were not performed in patients as planned, based on the attending physician’s judgment, were considered acceptable unless the patient met any discontinuation criteria (e.g., pneumonia) (see supplementary document for parameters).

Concomitant drugs and therapies

(see supplementary document for Concomitant drugs and therapies).

Study period

Patients who were enrolled between October 2020 and September 2022 and had completed a two-year follow-up were included in the analysis.

Statistical analysis

Data were expressed as mean ± standard deviation (SD). Changes in individual outcome measures from baseline were compared and analyzed. Paired data were analyzed using the Mann–Whitney U test. Trends over time were analyzed using the least squares method.

To evaluate the impact of various factors on prognostic events, a Cox proportional hazards model was applied. All statistical analyses were performed using JMP version 14.2 (SAS Institute Inc., Cary, NC). A two-sided P value of < 0.05 was considered statistically significant.

Results

Patients

This report summarizes an exploratory study of IPF patients with pulmonary hypertension (PH) and/or exercise-induced elevation of PAP (eePAP) who completed a two-year follow-up. Between October 2020 and September 2022, 52 IPF outpatients meeting the entry criteria were enrolled. All had chronic fibrotic idiopathic interstitial pneumonia (IIP) confirmed by high-resolution CT showing honeycomb lung with basal subpleural predominance.

A summary of patient inclusion and group classification is presented in Fig. 1.

Of the 52 patients, 3 were excluded: 1 with pre-existing aplastic anemia (less severe PH group), 1 with a myocardial infarction (the ERPE group), and 1 who died from acute respiratory failure, both during the run-in period. The remaining 49 patients were included in the analysis: 4 with severe PH, 21 with less severe PH, and 24 with ERPE. The analysis met target sample size requirements.

Although the severe PH group had only 4 patients, limiting evaluations, they were older and had lower height, weight, ADL, and exercise tolerance compared to other groups (Table 1). Demographics such as height, weight, age, and sex were similar between the less severe PH and the ERPE groups. These clinical characteristics are detailed in Table 1.

Table 1.

Baseline clinical characteristics of IPF patients stratified by PH severity

	All	Severe PH	Less severe PH	ERPE	P value of Severe vs Less severe PH, Less severe PH vs ERPE, Severe PH vs ERPE
No. (male/female)	49(36/13)	4(0/4)	21(19/2)	24(17/7)	0.0001* 0.14 0.0072*
Age (y.o.)	69.27± 6.89	73.00± 5.83	68.62± 7.74	69.21± 6.30	0.37 0.95 0.37
Height (cm)	161.09±10.17	151.25±14.68	163.76±8.95	160.50±9.67	0.081 0.19 0.21
Weight (kg)	60.08±12.25	49.23±11.50	62.18±13.78	60.15±10.39	0.12 0.84 0.13
ADL including exercise tolerance test
mMRC grade 0/1/2/3/4 (n)	0/17/10/14/8	0/0/0/0/4	0/5/4/9/3	0/12/6/5/1	0.0066* 0.15 <0.0001*
6min walk	310.28	131.24	290.81	358.36	0.0812
distance (m)	±139.56	±177.12	±118.18	±125.68	0.077 0.041*
Treadmil exercise test (METs)	4.40±2.44	1.18±0.21	3.85±2.02	5.39±2.38	0.0019* 0.018* 0.0014*
Right heart catheter
mPAP (mmHg)	21.00±8.64	39.25±4.79	25.43±3.75	14.08±3.84	0.0018* <0.0001* 0.0015*
mPAWP (mmHg)	6.69±3.76	10.00±4.55	7.65±3.67	5.33±3.23	0.31 0.047* 0.051
mRVP (mmHg)	12.51±4.69	14.75±8.26	14.38±4.79	10.50±2.96	0.50 0.0019* 0.37
mRAP (mmHg)	3.27±2.63	4.50±5.74	3.38±2.29	2.96±2.27	0.97 0.56 0.92
CO (L/min)	5.15±1.65	3.60±0.27	5.79±2.06	4.84±1.05	0.010* 0.14 0.0085*
CI (L/min/m2)	3.27±1.40	2.56±0.35	3.75±1.93	2.96±0.65	0.049* 0.056 0.29
PVR (wood)	3.13±2.15	8.18±1.86	3.54±1.67	1.92±0.84	0.0038* 0.0008* 0.0016*
PVRI (wood)	4.95±3.11	11.52±2.71	5.80±2.56	3.11±1.32	0.0076* 0.0002* 0.0016*
Pulmonary function test
%VC (%)	77.43±22.29	67.93±24.65	70.85±20.12	84.67±22.52	0.76 0.053 0.28
FVC (L)	2.34±0.81	1.79±1.34	2.28±0.69	2.47±0.84	0.32 0.44 0.24
%DLco(%)	42.36±27.36	15.57±6.93	32.92±24.50	54.06±26.19	0.17 0.0032* 0.0091*
ECG
ET (msec)	286.05±44.85	234.00±27.46	283.68±31.24	296.71±51.10	0.016* 0.46 0.018*
PAAcT (msec)	100.54±26.87	99.00±61.48	94.65±16.39	105.71±26.49	0.29 0.18 0.26
ICT (msec)	14.41±18.84	8.75±10.31	14.25±21.33	15.48±18.12	0.78 0.37 0.49
IRT (msec)	55.82±47.42	76.25±72.41	59.83±45.50	49.08±45.47	0.94 0.35 0.43
ICT+IRT (msec)	72.37±57.57	85.00±70.24	83.66±56.05	60.84±57.08	0.94 0.11 0.54
TEI index	0.28±0.25	0.38±0.31	0.30±0.24	0.24±0.26	0.70 0.20 0.49
TAPSE(cm)	2.41±1.22	3.47±4.29	2.39±0.52	2.24±0.43	0.14 0.33 0.13
Aortic Blood data at rest
pH	7.42±0.024	7.42±0.027	7.42±0.022	7.42±0.027	0.94 0.61 0.81
PaO2 (mmHg)	80.51±15.68	65.00±25.15	76.79±10.57	86.72±15.36	0.39 0.017* 0.12
Aortic oxygen saturation (%)	95.50±1.85	95.00±2.59	94.95±1.95	96.07±1.52	0.87 0.056 0.39
NT-proBNP (pg/ml)	361.57±1319.93	3040.75±3786.86	124.47±117.45	65.76±37.43	0.012* 0.16 0.0018*

Data are presented as mean ± standard deviation or number (%)

PH Pulmonary hypertension, PAP Pulmonary artery pressure, PV Pulmonary vascular resistance, mPAP mean PAP, ERPE Exercise-Responsive PAP Elevation, mPAWP mean pulmonary artery wedge pressure, mRVP mean right ventricular pressure, mRAP mean right atrial pressure, CO Cardiac output, CI Cardiac index, ADL Activities of Daily Living, TMET Treadmill exercise tests, MET Maximum exercise tolerance, PaO₂ Partial pressure of oxygen in arterial blood, ECG Echocardiography, ET Right ventricular ejection time, ICT Right ventricular isovolumetric contraction time, IRT Right ventricular isovolumetric relaxation time, TEI index right ventricular total ejection isovolumetric index, TAPSE Tricuspid annular plane systolic excursion, FVC Forced vital capacity, %VC Percent vital capacity/predicted vital capacity, %DLco Percent diffusing capacity for carbon monoxide / predicted, mMRC modified Medical Research Council

*P value for Wilcoxon signed-rank test to assess the difference between patients in the severe vs. less severe PH group (upper row), less severe vs. the ERPE group (middle row), and severe vs. the ERPE group (lower row)

Regarding concomitant pharmacologic therapies, antifibrotic agents were administered only to two patients in the severe PH group; both received nintedanib. No patients in the less severe PH or the ERPE groups received antifibrotic therapy. As for diuretic use, all four patients in the severe PH group received furosemide (two received 20 mg/day, and two received 30 mg/day). In the less severe PH group, four patients were prescribed furosemide (20 mg/day), and in the ERPE group, two patients received furosemide at the same dosage. These medications were administered according to the clinical judgment of the attending physicians.

Clinical course and adverse event

Of the 49 patients, 21 experienced ADL decline due to worsening conditions, including dyspnea on exertion, leading to hospitalization and permanent facility care. Among them, 16 died. Adverse events are summarized in Table 2.

Table 2.

Clinical course and adverse events during 2-Year Follow-Up in IPF patients stratified by PH severity

	All	Severe PH	Less severe PH	ERPE	P-value for comparing event occurrence rates Severe vs Less severe PH Less severe PH vs ERPE Severe PH vs ERPE (P-value for comparing time to event occurrence)
Hospitalization resulting in lifelong inability to live at home (Home-stay survival days for those with hospitalization-event occurrence only)	21  (320.48± 245.07)	3 (335.00±279.85)	11 (377.09±253.49)	7 (225.29±224.59)	0.60 (0.64) 0.14 (0.16) 0.12 (0.73)
Death (Survival days for those with death-event occurrence only)	16 (381.94± 235.64)	3 (346.33± 292.34)	7 (437.57±236.63)	6 (334.83± 239.68)	0.27 (0.57) 0.74 (0.43) 0.047* (0.80)
Other	7 (Cerebral infarction: 1 Fracture due to fall: 1 Hepatitis:1 Pneumonia: 2 Myocardial infarction: 1 Depression: 1)	0	2 (Cerebral infarction: 1 Depression: 1)	5 (Fracture due to fall: 1 Hepatitis:1 Pneumonia: 2 Myocardial infarction: 1)	N.A

Data presented as mean ± SD

Values indicate number of events unless otherwise noted

PH Pulmonary hypertension, IPF Idiopathic pulmonary fibrosis, ERPE Exercise-Responsive PAP Elevation, ADL Activities of daily living

*P value for Wilcoxon signed-rank test to assess the difference between two groups in all possible group combinations

In the ERPE group, events included 1 myocardial infarction (day 577), 1 fall with fracture (day 450), 2 pneumonias (days 24, 438), 1 hepatitis (day 438), and 2 hospital transfers due to relocation (days 518, 700).

In the less severe PH group, there was 1 case of depression (day 262) and 1 cerebral infarction (day 180). Evaluation parameters were recorded until each event.

Home-stay survival and overall survival (Table 2, Fig. 2a–d)

Fig. 2.

Prognostic analysis using Cox proportional hazards models. a 2-year Home-stay survival curve for all patients over two years. b 2-year Home-stay survival curves stratified by PH severity group. c 2-year Overall survival curve for all patients over two years. d 2-year Overall survival curves stratified by PH severity group. Cox proportional hazard analysis was used to evaluate %VC, %DLco, mean PAP, and PVR as predictors of prognosis. Estimated mean durations are shown in the Results section. Abbreviations:%VC, percent vital capacity; %DLco, diffusing capacity for carbon monoxide; mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance

Among the 49 IPF patients included in the analysis, 21 required permanent facility care within the 2-year follow-up period (severe PH: 3, less severe PH: 11, ERPE: 7). The mean duration from enrollment to this event (home-stay survival) was 320.48 ± 245.07 days. Stratified by group, the mean durations were 335.00 ± 279.85 days for severe PH, 377.09 ± 253.49 days for less severe PH, and 225.29 ± 224.59 days for ERPE.

The estimated mean 2-year home-stay survival durations for all patients were 533.38 ± 39.68 days overall, 398.50 ± 138.64 days for the severe PH group, 525.20 ± 59.17 days for the less severe PH group, and 504.77 ± 53.09 days for the ERPE group. No significant hazard ratios were observed between the less severe and the ERPE groups in Cox proportional hazard models.

These results are shown in Fig. 2a and b.

Sixteen patients died during the 2-year observation period (severe PH: 3, less severe PH: 7, ERPE: 6). The mean survival time among deceased patients was 381.94 ± 235.64 days (346.33 ± 292.34 for severe PH, 437.57 ± 236.63 for less severe PH, and 334.83 ± 239.68 for ERPE). Estimated 2-year overall survival durations were 594.06 ± 33.86 days overall, with 413.50 ± 142.26 for severe PH, 606.58 ± 50.27 for less severe PH, and 573.21 ± 45.47 for ERPE. No statistically significant differences were observed among the three groups (Fig. 2c and d).

Findings from right heart catheterization

Given the small sample size, data from the severe PH group should be considered reference values, with no definitive conclusions. However, all indicators, including mPAP, suggested greater right heart strain in this group compared to the others. In contrast, no significant differences in CO or CI were observed between the less severe and the ERPE groups, but mPAP and PVR showed significant differences (see Table 1).

Additional parameters

As shown in Table 1, the severe PH group results should be treated as reference due to the small sample size (four patients), limiting definitive conclusions. However, this group tended to be older, with lower height, weight, ADL, and exercise tolerance compared to the others.

No significant differences were found in the 6MWT or mMRC scale, but maximum exercise tolerance, measured by the treadmill exercise test, differed significantly between groups.

Pulmonary function tests showed no significant differences in restrictive lung dysfunction indicators, but %DLco significantly differed between the ERPE group and the two PH groups.

Correlation between evaluated parameters and ADL, exercise tolerance, and prognosis

Analysis of all patients showed significant correlations between the mMRC scale and pulmonary function, including %VC (Spearman’s ρ = − 0.69, p < 0.0001) and FVC (ρ = − 0.53, p = 0.0001). Similarly, 6MWD correlated with %VC (ρ = 0.64, p < 0.0001) and FVC (ρ = 0.56, p < 0.0001). Maximum exercise tolerance (MET) also correlated with %VC (ρ = 0.40, p = 0.0064) and FVC (ρ = 0.45, p = 0.0017) (Fig. 3a).

Fig. 3.

Correlation between evaluated parameters and ADL/exercise tolerance. a Correlation between pulmonary function (%VC, FVC) and activity scales (mMRC, 6MWD, MET). b Correlation between mPAP/PVR and activity parameters. Spearman’s correlation coefficient was used. Color of points represents PH severity as in Fig. 2. Abbreviations: mMRC, modified Medical Research Council scale; 6MWD, 6-minute walk distance; MET, maximal exercise tolerance; FVC, forced vital capacity

PVR showed significant correlations with mMRC (ρ = 0.47, p = 0.0007), 6MWD (ρ = − 0.41, p = 0.0042), and MET (ρ = − 0.60, p < 0.0001), with similar trends observed for mPAP (Fig. 3b).

%VC and FVC did not significantly correlate with mPAP but did correlate with PVR: %VC (ρ = − 0.31, p = 0.031) and FVC (ρ = − 0.34, p = 0.020) (Supplementary Fig. 3).

%DLco was significantly inversely correlated with PVR in the total cohort (ρ = − 0.58, p < 0.0001), but not within subgroups (ERPE: ρ = − 0.30, p = 0.10; less severe PH: ρ = − 0.30, p = 0.19) (Supplementary Fig. 4).

For prognostic analyses, proportional hazard analysis identified %VC (HR: 0.98, p = 0.024), %DLco (HR: 0.97, p = 0.0067), mean PAP (HR: 1.05, p = 0.042), and PVR (HR: 1.20, p = 0.032) as significant factors for home-stay survival (Fig. 2a). FVC was not significant (HR: 0.80, p = 0.45).

For overall survival, %VC (HR: 0.97, p = 0.027), %DLco (HR: 0.97, p = 0.0062), mean PAP (HR: 1.066, p = 0.025), and PVR (HR: 1.28, p = 0.013) were significant (Fig. 2c), while FVC was not (HR: 0.70, p = 0.31).

Correlation between evaluated parameters and ADL, exercise tolerance, and prognosis

In the full cohort analysis, the mMRC scale showed significant inverse correlations with %VC (ρ = − 0.69, p < 0.0001) and FVC (ρ = − 0.53, p = 0.0001). Likewise, 6MWD was positively correlated with %VC (ρ = 0.64, p < 0.0001) and FVC (ρ = 0.56, p < 0.0001). MET also showed moderate correlations with %VC (ρ = 0.40, p = 0.0064) and FVC (ρ = 0.45, p = 0.0017) (Fig. 3a).

PVR was significantly correlated with mMRC (ρ = 0.47, p = 0.0007), 6MWD (ρ = − 0.41, p = 0.0042), and MET (ρ = − 0.60, p < 0.0001), with similar findings for mPAP (Fig. 3b).

While %VC and FVC did not significantly correlate with mPAP, both were significantly correlated with PVR (%VC: ρ = − 0.31, p = 0.031; FVC: ρ = − 0.34, p = 0.020) (Supplementary Fig. 3).

%DLco was inversely correlated with PVR in the total cohort (ρ = − 0.58, p < 0.0001). However, subgroup analyses for the ERPE and less severe PH groups did not reach statistical significance (ERPE: ρ = − 0.30, p = 0.10; less severe PH: ρ = − 0.30, p = 0.19) (Supplementary Fig. 4).

In an additional analysis restricted to the ERPE group (mPAP < 20 mmHg), MET was significantly correlated with PVR (ρ = − 0.49, p = 0.015), but not with mPAP (ρ = − 0.31, p = 0.14) (Supplementary Fig. 5).

In Cox proportional hazard analysis for home-stay survival, significant predictors included %VC (HR: 0.98, p = 0.024), %DLco (HR: 0.97, p = 0.0067), mean PAP (HR: 1.05, p = 0.042), and PVR (HR: 1.20, p = 0.032). FVC was not significant (HR: 0.80, p = 0.45).

For overall survival, %VC (HR: 0.97, p = 0.027), %DLco (HR: 0.97, p = 0.0062), mean PAP (HR: 1.066, p = 0.025), and PVR (HR: 1.28, p = 0.013) were also significant, while FVC was not (HR: 0.70, p = 0.31) (Fig. 2a and c).

Discussion

Many patients with IPF experience a rapid increase in PAP as the disease progresses [7], and the presence of PH has been shown to be associated with poor prognosis [7]. While pirfenidone and nintedanib are available as treatments to slow the progression of fibrosis, these therapies are not expected to improve the overall prognosis of IPF [34]. Furthermore, for patients with fully developed honeycomb lungs, treatment is often limited to symptomatic management with long-term oxygen therapy (LTOT) to alleviate the progression of respiratory failure.

PH is recognized as a prognostic factor in IPF; however, frequent and precise evaluation of PAP using RHC is rarely performed due to its invasive nature. Furthermore, although inhaled treprostinil has recently become available as a therapeutic option for pulmonary hypertension associated with interstitial lung diseases including IPF, overall treatment options for secondary elevation of PAP in IPF remain limited. In clinical practice, effective interventions are often initiated only after PH is strongly suspected or confirmed, which may contribute to the scarcity of clinical data and the difficulty in early-stage management. As a result, in clinical practice, accurate assessment and confirmation of PAP are often only undertaken when PH is strongly suspected, and the need for treatment becomes relatively urgent. This practice may contribute to the limited accumulation of clinical data on secondary PAP elevation in IPF.

The pulmonary circulation system is characterized by high compliance, with the thickness of the right ventricular free wall being only about one-third that of the left ventricular wall, allowing for significant expansion. During increased pulmonary blood flow, such as during exercise, the pulmonary vessels readily expand, resulting in passive dilation. Due to the abundant reserve capacity of the pulmonary vascular bed, it is believed that pulmonary artery pressure does not increase at rest until the functional vascular bed is reduced to approximately one-third, even in the presence of organic narrowing of the pulmonary arteries [11].

Based on this understanding, if the critical importance of investigating the pathophysiological processes leading to PAP elevation before its clinical suspicion can be further validated, it may open new perspectives for managing IPF patients. Proactively performing RHC prior to a marked rise in PAP could provide valuable insights into the pathophysiology of the pulmonary vascular bed and the often subtle progression of IPF and PH. This approach could be recognized as a more meaningful strategy for early and precise detection using RHC. Furthermore, evaluating the pathophysiology before PAP elevation is suspected and implementing even earlier therapeutic interventions targeting the pulmonary vasculature could contribute to improving the prognosis of both IPF patients and those with secondary PH associated with IPF.

Supporting this perspective, a recent analysis of patients diagnosed with interstitial lung disease who underwent right heart catheterization demonstrated that even a slight elevation in PVR (PVR > 2 Wood Units) at the time of initial diagnosis was associated with increased mortality rates [15].

While prior studies have demonstrated the prognostic value of PVR in IPF, including in large retrospective cohorts [35, 36], our study expands this understanding by showing that even patients without overt PH—and those with PVR ≤ 2 Wood Units—exhibited early adverse outcomes associated with elevated PVR over a two-year period. These results provide compelling support for the proactive incorporation of right heart catheterization into routine clinical practice for IPF, even before PH becomes clinically apparent. Early evaluation of PVR and other hemodynamic parameters may facilitate timely risk stratification and serve as a foundation for future prospective investigations aimed at optimizing IPF management.

In this study, we focused on pulmonary circulation indicators such as PVR, as well as respiratory function tests, to analyze and compare the prognosis, ADL, and activity of IPF patients with less severe PH, severe PH, and ERPE (a condition where PAP increases during daily activities but does not yet meet the diagnostic criteria for PH). Patients were monitored over a limited period of two years. The aim of this analysis was not to establish specific cutoff values for PVR, but rather to explore whether the gradual worsening of pulmonary hemodynamics is associated not only with declines in ADL and activity but also with deterioration in prognosis as early as two years ahead.

The results of this study indicate that the small sample size of the severe PH group made independent evaluation challenging, and the data should be considered as reference values. However, an analysis of IPF patients spanning a wide range of PAP conditions—from ERPE to less severe PH and severe PH—revealed that both PVR and PAP were significantly correlated with patient prognosis and ADL, even within the relatively short two-year monitoring period. The observation of such correlations, despite the limited monitoring duration, suggests that the pathophysiology of the pulmonary vascular bed is more strongly, closely, and critically associated with the progression of IPF than previously appreciated. Among these, PVR demonstrated the strongest correlation with patient prognosis, ADL, and activity capacity, underscoring its potential significance as a key factor in IPF management.

A limitation of this study is the lack of data from IPF patients who neither exhibit PH nor demonstrate exercise-induced PAP elevation, in addition to those with PH or potential PAP elevation during daily activities. Additionally, although the functional impact of PVR could be further explored by stratifying patients based on WHO functional class, the present study used data obtained from a prospective trial that included only patients with WHO functional class II or higher. Functional status was recorded using mMRC grades as shown in Table 1. However, subgrouping based on mMRC grade was not feasible due to the limited number of patients in each grade category. However, due to the invasive nature of RHC, it is particularly challenging to design and conduct studies involving this procedure in patients without suspected PH. Additionally, expanding the sample size to enable a more comprehensive analysis of prognostic factors and ensuring a sufficient number of events for robust prognostic evaluation represent further areas for improvement in future research.

The results of this study suggest that PVR, which is believed to reflect the entire progression of PAP changes from ERPE to severe PH, is strongly associated not only with the prognosis as early as two years ahead, ADL, and activity levels of IPF patients but also with maximal exercise tolerance assessed using a treadmill. Unlike the six-minute walk test, which is influenced by patient-determined walking speeds, treadmill-based assessments provide a more precise and objective measure of exercise capacity. These findings underscore the importance of the relationship between PVR and maximal exercise tolerance, which has been rarely investigated in previous studies.

Indicators of restrictive lung dysfunction, which reflect the parenchymal respiratory impairment in IPF, were also significantly correlated with patients’ ADL, activity levels, and home-stay survival.

A significant correlation was observed between indicators of restrictive lung dysfunction and PVR; however, no significant correlation was found between these indicators and PAP. In the progression of IPF, PAP may correlate with indicators of restrictive lung dysfunction up to a certain stage, or it may begin to correlate at a later stage. The results of this study also suggest that PVR may more accurately reflect the impact of parenchymal lung damage. However, the possibility that there are stages where PVR does not correlate with these indicators cannot be excluded.

Consistent with the Results section, even in patients not meeting PH criteria, PVR remained a key correlate of reduced exercise tolerance, underscoring its role as an early indicator of pulmonary circulatory impairment. This suggests that PVR may reflect early changes in pulmonary circulation before PH becomes clinically apparent.

Furthermore, %DLco was inversely correlated with PVR in the overall population, although this relationship was not statistically significant within individual subgroups. In our analysis, %DLco was also identified as a significant prognostic factor for both overall survival and home-stay survival over a two-year period. However, since %DLco may be affected by various clinical factors such as disease activity, comorbidities, and treatment regimens, its interpretation as a prognostic biomarker may be more complex. In contrast, PVR demonstrated not only a strong correlation with prognosis but also consistency across multiple outcome parameters, suggesting that it may serve as a more stable and sensitive indicator for short-term prognosis in IPF, especially for evaluating early pulmonary vascular involvement.

These findings suggest that PVR may already influence the pathophysiology of IPF at an early stage, before detectable elevation of PAP.

Furthermore, it has been reported that the development of PH in IPF may involve factors related to pulmonary arterial hypertension (PAH), such as endothelin, in addition to parenchymal damage [16–18]. The mechanisms underlying the development of PH in IPF patients are complex and not yet fully understood.

Conclusions

In the future, proactively evaluating PVR and other indicators of right heart strain in IPF patients, even before PH is suspected, may help in understanding the disease pathology and establishing timely clinical management strategies. Although studies investigating the relationship between RHC data and prognosis, ADL, and activity in IPF patients, including those without PH, remain challenging, the findings of this study may serve as a valuable foundation for further research in IPF patient care.

While causality cannot be established due to the observational and exploratory nature of this study, our findings suggest that PVR may serve as a potentially useful early prognostic marker. These results support the need for further prospective validation.

Abbreviations

IPF

Idiopathic Pulmonary Fibrosis

PH

Pulmonary hypertension

PAP

Pulmonary artery pressure

PVR

Pulmonary vascular resistance

SPAP

Systolic PAP

DPAP

Diastolic PAP

mPAP

Mean PAP

PAWP

Pulmonary artery wedge pressure

SPAWP

Systolic pulmonary artery wedge pressure

DPAWP

Diastolic PAWP

mPAWP

Mean PAWP

RVP

Right ventricular pressure

SRVP

Systolic right ventricular pressure

DRVP

Diastolic RVP

mRVP

Mean RVP

RAP

Right atrial pressure

SRAP

Systolic RAP

DRAP

Diastolic RAP

mRAP

Mean RAP

CO

Cardiac output

CI

Cardiac index

eePAP

Exercise-induced elevation of PAP

ADL

Activities of Daily Living

6MWT

6-minute walk test

6MWD

6mineuts walk distance

TMET

Treadmill exercise tests

MET

Maximum exercise tolerance

RHC

Right heart catheterization

HPV

Hypoxic pulmonary vasoconstriction

PaO₂

Partial pressure of oxygen in arterial blood

LTOT

Long-term oxygen therapy

CT

Computed tomography

ECG

Echocardiography

PFT

Pulmonary function tests

FEV1

Forced expiratory volume in 1 second

FVC

Forced vital capacity

%VC

Percent vital capacity/predicted vital capacity

%DLco

Percent diffusing capacity for carbon monoxide / predicted

mMRC

Modified Medical Research Council

Authors’ contributions

YT: wrote the main manuscript text, and Conception and design of the study, analysis, and interpretation of data.KO, SK, TT, AM, NT, KK: Conception and design of the study, interpretation of data.KK, MS: Conception and design of the study, data interpretation, drafting, and critical revisions of the manuscript.The final version of the manuscript has been reviewed and approved by all authors.All authors read and approved the final manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

The datasets generated and/or analyzed during the current study will be made available after the publication of the paper at [https://center6.umin.ac.jp/cgi-bin/ctr_e/ctr_view.cgi?recptno=R000063381] upon reasonable request from the corresponding author.

Declarations

Ethics approval and consent to participate

An informed consent form describing the following items was prepared. Consent had to be obtained in writing (see supplementary data on procedures regarding informed consent; supplementary information regarding compensation in case of trial-related injury or death and supplementary information regarding medical expenses). The study protocol was approved by the Ethics Committee of Nippon Medical School. All patients provided their informed consent in writing prior to their participation in this study, and the study was performed in accordance with the ethical standards of the Declaration of Helsinki (2013).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.