J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://jocmr.elmerjournals.com

Original Article

Volume 17, Number 3, March 2025, pages 153-163

Oral Pulmonary Arterial Hypertension-Targeted Therapy in Patients With Pulmonary Hypertension due to Interstitial Lung Disease

Figure 1. Patient screening. CHD: congenital heart disease; CHF: congestive heart failure; CT: computed tomography; CTD: connective tissue disease; CTEPH: chronic thromboembolic pulmonary hypertension; FVC: forced vital capacity; ILA: interstitial lung abnormality; ILD: interstitial lung disease; PAH: pulmonary arterial hypertension; PH: pulmonary hypertension; PoPH: portopulmonary hypertension; TLC: total lung capacity; WSPH: World Symposium of Pulmonary Hypertension.

Figure 2. Association between PAH-targeted therapy and hemodynamics. ERA: endothelin receptor antagonist; mPAP: mean pulmonary arterial pressure; mRAP: mean right atrial pressure; PCWP: pulmonary capillary wedge pressure; PDE5-I: phosphodiesterase-5 inhibitor; PVR: pulmonary vascular resistance.

Figure 3. Association between PAH-targeted therapy and NT-proBNP (a), exercise parameters (b1-3), PFTs (c1-4) and functional class (d). DLCO: diffusion limitation of carbon monoxide; ERA: endothelin receptor antagonist; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; METs: metabolic equivalents of task; NT-proBNP: N-terminal pro-B-type natriuretic peptide; PDE5-I: phosphodiesterase-5 inhibitor; TLC: total lung capacity; WHO FC: World Health Organization functional class.

**Table 1.** Baseline Patient Characteristics
Characteristic	Baseline (N = 37)
Data are presented as mean ± SD, median (IQR), or n (%), as appropriate. ^aDesquamative interstitial pneumonia, organizing pneumonia, or unclassifiable ILD. ^bThese patients met criteria for combined pulmonary fibrosis and emphysema (CPFE), as defined by the 2022 ATS/ERS/JRS/ALAT Research Statement. ACEIs/ARBs: angiotensin-converting enzyme inhibitors/angiotensin receptor blockers; BMI: body mass index; DLCO: diffusion limitation of carbon monoxide; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; ILD: interstitial lung disease; IQR: interquartile range; METs: metabolic equivalents of task; mPAP: mean pulmonary arterial pressure; mRAP: mean right atrial pressure; NSIP: nonspecific interstitial pneumonia; NT-proBNP: N-terminal pro-B-type natriuretic peptide; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; SD: standard deviation; SLE: systemic lupus erythematosus; TLC: total lung capacity; UIP: usual interstitial pneumonia; WHO: World Health Organization.
Age (years)	60.22 ± 10.54
Female	29 (78.4)
BMI (kg/m²)	28.98 ± 6.87
Race
African-American	20 (54.1)
Caucasian	15 (40.5)
Asian	1 (2.7)
Hispanic	1 (2.7)
Subtype of ILD
Connective tissue disease associated-ILD	27 (73.0)
Idiopathic pulmonary fibrosis	4 (10.8)
Hypersensitivity pneumonitis	2 (5.4)
Unclassifiable	2 (5.4)
Idiopathic NSIP	1 (2.7)
Smoking-related ILD	1 (2.7)
Imaging pattern
Definite/probable UIP	17 (45.9)
NSIP	14 (37.8)
Other^a	6 (16.2)
Pulmonary function test
TLC (% predicted)	68.9 ± 20.2
FVC (% predicted)	59.9 ± 15.7
FEV₁ (% predicted)	63 ± 16.2
DLCO (% predicted)	34.5 ± 15.3
Comorbidities
Connective tissue disease	27 (73.0)
Systemic sclerosis	11 (29.7)
Mixed connective tissue disease	4 (10.8)
Rheumatoid arthritis	4 (10.8)
Polymyositis/dermatomyositis	3 (8.1)
SLE/SLE overlap syndrome	2 (5.4)
Undifferentiated connective tissue disease	2 (5.4)
Sjogren’s syndrome	1 (2.7)
Hypertension	19 (51.4)
Obesity (BMI ≥ 30 kg/m²)	15 (40.5)
Heart failure with preserved ejection fraction	12 (32.4)
Chronic obstructive pulmonary disease^b	7 (18.9)
Obstructive sleep apnea	7 (18.9)
Atrial fibrillation	7 (18.9)
Diabetes mellites	7 (18.9)
Venous thromboembolism	6 (16.2)
Chronic kidney disease	5(13.5)
Heart failure with reduced ejection fraction	2 (5.4)
Medications
Diuretics	25 (67.6)
Aspirin	12 (32.4)
Beta-blockers	11 (29.7)
ACEIs/ARBs	8 (21.6)
Calcium channel blockers
Dihydropyridines	10 (27.0)
Non-dihydropyridines	4 (10.8)
Warfarin/DOACs	7 (18.9)
Labs (n = 30)
NT-proBNP (pg/mL)	1,498 (675 - 3,208)
Pulmonary hemodynamics (n = 33)
mRAP (mm Hg)	9.4 ± 4.2
mPAP (mm Hg)	44.5 ± 10.5
PCWP (mm Hg)	12.0 ± 3.3
Cardiac output (L/min)	3.8 ± 1.1
Cardiac index (L/min/m²)	2.1 ± 0.6
PVR (Wood units)	8.9 ± 4.0
6-min walk test or treadmill
Walk time (s), n = 7	335.8 ± 119.7
Walk distance (m), n = 10	233.4 ± 87.0
METs, n = 6	5.10 ± 1.05
WHO functional class (n = 31)
II	6 (19.4)
III	21 (67.7)
IV	4 (12.9)

Table 1. Baseline Patient Characteristics

Characteristic

Baseline (N = 37)

Data are presented as mean ± SD, median (IQR), or n (%), as appropriate. ^aDesquamative interstitial pneumonia, organizing pneumonia, or unclassifiable ILD. ^bThese patients met criteria for combined pulmonary fibrosis and emphysema (CPFE), as defined by the 2022 ATS/ERS/JRS/ALAT Research Statement. ACEIs/ARBs: angiotensin-converting enzyme inhibitors/angiotensin receptor blockers; BMI: body mass index; DLCO: diffusion limitation of carbon monoxide; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; ILD: interstitial lung disease; IQR: interquartile range; METs: metabolic equivalents of task; mPAP: mean pulmonary arterial pressure; mRAP: mean right atrial pressure; NSIP: nonspecific interstitial pneumonia; NT-proBNP: N-terminal pro-B-type natriuretic peptide; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; SD: standard deviation; SLE: systemic lupus erythematosus; TLC: total lung capacity; UIP: usual interstitial pneumonia; WHO: World Health Organization.

Age (years)

60.22 ± 10.54

Female

29 (78.4)

BMI (kg/m²)

28.98 ± 6.87

Race

African-American

20 (54.1)

Caucasian

15 (40.5)

Asian

1 (2.7)

Hispanic

1 (2.7)

Subtype of ILD

Connective tissue disease associated-ILD

27 (73.0)

Idiopathic pulmonary fibrosis

4 (10.8)

Hypersensitivity pneumonitis

2 (5.4)

Unclassifiable

2 (5.4)

Idiopathic NSIP

1 (2.7)

Smoking-related ILD

1 (2.7)

Imaging pattern

Definite/probable UIP

17 (45.9)

NSIP

14 (37.8)

Other^a

6 (16.2)

Pulmonary function test

TLC (% predicted)

68.9 ± 20.2

FVC (% predicted)

59.9 ± 15.7

FEV₁ (% predicted)

63 ± 16.2

DLCO (% predicted)

34.5 ± 15.3

Comorbidities

Connective tissue disease

27 (73.0)

Systemic sclerosis

11 (29.7)

Mixed connective tissue disease

4 (10.8)

Rheumatoid arthritis

4 (10.8)

Polymyositis/dermatomyositis

3 (8.1)

SLE/SLE overlap syndrome

2 (5.4)

Undifferentiated connective tissue disease

2 (5.4)

Sjogren’s syndrome

1 (2.7)

Hypertension

19 (51.4)

Obesity (BMI ≥ 30 kg/m²)

15 (40.5)

Heart failure with preserved ejection fraction

12 (32.4)

Chronic obstructive pulmonary disease^b

7 (18.9)

Obstructive sleep apnea

7 (18.9)

Atrial fibrillation

7 (18.9)

Diabetes mellites

7 (18.9)

Venous thromboembolism

6 (16.2)

Chronic kidney disease

5(13.5)

Heart failure with reduced ejection fraction

2 (5.4)

Medications

Diuretics

25 (67.6)

Aspirin

12 (32.4)

Beta-blockers

11 (29.7)

ACEIs/ARBs

8 (21.6)

Calcium channel blockers

Dihydropyridines

10 (27.0)

Non-dihydropyridines

4 (10.8)

Warfarin/DOACs

7 (18.9)

Labs (n = 30)

NT-proBNP (pg/mL)

1,498 (675 - 3,208)

Pulmonary hemodynamics (n = 33)

mRAP (mm Hg)

9.4 ± 4.2

mPAP (mm Hg)

44.5 ± 10.5

PCWP (mm Hg)

12.0 ± 3.3

Cardiac output (L/min)

3.8 ± 1.1

Cardiac index (L/min/m²)

2.1 ± 0.6

PVR (Wood units)

8.9 ± 4.0

6-min walk test or treadmill

Walk time (s), n = 7

335.8 ± 119.7

Walk distance (m), n = 10

233.4 ± 87.0

METs, n = 6

5.10 ± 1.05

WHO functional class (n = 31)

6 (19.4)

III

21 (67.7)

4 (12.9)

**Table 2.** Distribution of Pulmonary Arterial Hypertension-Targeted Therapy
Medications	n (%)
ERA: endothelin receptor antagonist; IV: intravenous; PDE5-I: phosphodiesterase-5 inhibitor.
Monotherapy
PDE5-I (sildenafil = 17, tadalafil = 2)	19 (51.4)
ERA (bosentan = 4)	4 (10.8)
Prostanoid (IV treprostinil = 3, IV epoprostenol = 1)	4 (10.8)
Dual therapy
PDE5-I + ERA (sildenafil + bosentan = 1, sildenafil + ambrisentan = 2, tadalafil + ambrisentan = 6)	9 (24.3)
Triple therapy
Tadalafil + ambrisentan + IV treprostinil	1 (2.7)

Table 2. Distribution of Pulmonary Arterial Hypertension-Targeted Therapy

Medications

n (%)

ERA: endothelin receptor antagonist; IV: intravenous; PDE5-I: phosphodiesterase-5 inhibitor.

Monotherapy

PDE5-I (sildenafil = 17, tadalafil = 2)

19 (51.4)

ERA (bosentan = 4)

4 (10.8)

Prostanoid (IV treprostinil = 3, IV epoprostenol = 1)

4 (10.8)

Dual therapy

PDE5-I + ERA (sildenafil + bosentan = 1, sildenafil + ambrisentan = 2, tadalafil + ambrisentan = 6)

9 (24.3)

Triple therapy

Tadalafil + ambrisentan + IV treprostinil

1 (2.7)

**Table 3.** Pulmonary Hemodynamics, Laboratory Data, and Functional Parameters in Patients With Measurements Both Before and After Treatment With Pulmonary Arterial Hypertension-Targeted Therapy
Endpoint	n	Baseline	Follow-up	P value*
Data are presented as mean ± SD, median (IQR), or n (%) as appropriate. *Calculated using paired t-test or related-samples Wilcoxon signed rank test as appropriate. DLCO: diffusion limitation of carbon monoxide; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; IQR: interquartile range; METs: metabolic equivalents of task; mPAP: mean pulmonary arterial pressure; mRAP: mean right atrial pressure; NT-proBNP: N-terminal pro-B-type natriuretic peptide; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; SD: standard deviation; TLC: total lung capacity; WHO: World Health Organization.
Pulmonary hemodynamics			At 46 (25 - 89) weeks
mRAP (mm Hg)	14	9.93 ± 7.75	6.71 ± 4.08	0.099
mPAP (mm Hg)	16	44.13 ± 10.87	38.81 ± 12.62	0.026
PCWP (mm Hg)	12	11.83 ± 3.01	10.67 ± 6.69	0.653
Cardiac output (L/min)	13	4.25 ± 1.31	5.17 ± 1.07	0.014
Cardiac index (L/min/m²)	11	2.11 ± 0.69	2.67 ± 0.65	0.018
PVR (Wood units)	13	8.38 ± 3.76	4.50 ± 2.13	< 0.001
Labs
NT-proBNP (pg/mL)	26	1,421 (675 - 2,709)	At 18 (13.5 - 36) weeks, 842 (295 - 2,329)	0.045
6-min walk test or treadmill			At 32 (25 - 73) weeks
Walk time (s)	4	384 ± 126.52	504.50 ± 83.07	0.069
Walk distance (m)	8	228.62 ± 97.99	263.12 ± 101.75	0.164
METs	3	4.13 ± 1.03	5.33 ± 0.58	0.102
WHO functional class	29		At 30 (14 - 34) weeks
II		6 (20.69%)	2 (6.90%)	1.000
III		19 (65.52%)	27 (93.10%)
IV		4 (13.79%)	0 (0%)
Pulmonary function test			At 43 (15 - 101) weeks
TLC (% predicted)	18	72.11 ± 20.82	72.83 ± 23.80	0.815
FVC (% predicted)	25	61.92 ± 16.89	60.00 ± 18.89	0.357
FEV₁ (% predicted)	25	64.96 ± 17.39	63.76 ± 17.06	0.500
DLCO (% predicted)	18	33.78 ± 14.92	30.72 ± 16.33	0.550

Table 3. Pulmonary Hemodynamics, Laboratory Data, and Functional Parameters in Patients With Measurements Both Before and After Treatment With Pulmonary Arterial Hypertension-Targeted Therapy

Endpoint

Baseline

Follow-up

P value*

Data are presented as mean ± SD, median (IQR), or n (%) as appropriate. *Calculated using paired t-test or related-samples Wilcoxon signed rank test as appropriate. DLCO: diffusion limitation of carbon monoxide; FEV₁: forced expiratory volume in one second; FVC: forced vital capacity; IQR: interquartile range; METs: metabolic equivalents of task; mPAP: mean pulmonary arterial pressure; mRAP: mean right atrial pressure; NT-proBNP: N-terminal pro-B-type natriuretic peptide; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; SD: standard deviation; TLC: total lung capacity; WHO: World Health Organization.

Pulmonary hemodynamics

At 46 (25 - 89) weeks

mRAP (mm Hg)

9.93 ± 7.75

6.71 ± 4.08

0.099

mPAP (mm Hg)

44.13 ± 10.87

38.81 ± 12.62

0.026

PCWP (mm Hg)

11.83 ± 3.01

10.67 ± 6.69

0.653

Cardiac output (L/min)

4.25 ± 1.31

5.17 ± 1.07

0.014

Cardiac index (L/min/m²)

2.11 ± 0.69

2.67 ± 0.65

0.018

PVR (Wood units)

8.38 ± 3.76

4.50 ± 2.13

< 0.001

Labs

NT-proBNP (pg/mL)

1,421 (675 - 2,709)

At 18 (13.5 - 36) weeks, 842 (295 - 2,329)

0.045

6-min walk test or treadmill

At 32 (25 - 73) weeks

Walk time (s)

384 ± 126.52

504.50 ± 83.07

0.069

Walk distance (m)

228.62 ± 97.99

263.12 ± 101.75

0.164

METs

4.13 ± 1.03

5.33 ± 0.58

0.102

WHO functional class

At 30 (14 - 34) weeks

6 (20.69%)

2 (6.90%)

1.000

III

19 (65.52%)

27 (93.10%)

4 (13.79%)

0 (0%)

Pulmonary function test

At 43 (15 - 101) weeks

TLC (% predicted)

72.11 ± 20.82

72.83 ± 23.80

0.815

FVC (% predicted)

61.92 ± 16.89

60.00 ± 18.89

0.357

FEV₁ (% predicted)

64.96 ± 17.39

63.76 ± 17.06

0.500

DLCO (% predicted)

33.78 ± 14.92

30.72 ± 16.33

0.550