Clinical Management and Outcomes of Patients With Portopulmonary Hypertension Enrolled in the Japanese Multicenter Registry

Abstract

Background: Portopulmonary hypertension (PoPH) is one of the major underlying causes of pulmonary arterial hypertension (PAH). However, PoPH, especially treatment strategies, has been poorly studied. Therefore, this study evaluated current treatments for PoPH, their efficacy, and clinical outcomes of patients with PoPH.

Methods and Results: Clinical data were collected for patients with PoPH who were enrolled in the Japan Pulmonary Hypertension Registry between 2008 and 2021. Hemodynamic changes, functional class, and clinical outcomes were compared between patients with PoPH treated with monotherapy and those treated with combination therapies. Clinical data were analyzed for 62 patients with PoPH, including 25 treatment-naïve patients, from 21 centers in Japan. In more than half the patients, PAH-specific therapy improved the New York Heart Association functional class by at least one class. The 3- and 5-year survival rates of these patients were 88.5% (95% confidence interval [CI] 76.0–94.7) and 80.2% (95% CI 64.8–89.3), respectively. Forty-one (66.1%) patients received combination therapy. Compared with patients who had received monotherapy, the mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac index were significantly improved in patients who had undergone combination therapies.

Conclusions: Combination therapy was commonly used in patients with PoPH with a favorable prognosis. Combination therapies resulted in significant hemodynamic improvement without an increased risk of side effects.

Portopulmonary hypertension (PoPH), classified as a subgroup of Group 1 in clinical classifications of pulmonary hypertension (PH), is pulmonary arterial hypertension (PAH) associated with portal hypertension.¹ PAH is a progressive disease; however, clinical evidence shows improved prognosis with the widespread application of combination therapies.^2,3 Although PoPH is a major component accounting for 5–16% of PAH, randomized control trials investigating prognostic improvements in patients who undergo PAH-specific therapies have excluded those with PoPH.^3–5 This is because patients with PoPH have comorbid liver diseases, thus raising concerns of more easily induced side effects such as a higher rate of liver injury⁶ and poor prognosis.⁷ Therefore, evidence for PAH-specific treatments of PoPH is limited, with only 1 randomized controlled trial, the PORTICO trial,⁸ having established evidence for the treatment of PoPH with macitentan. Initial monotherapy should be considered for treating patients with PoPH because evidence is lacking for the treatment of these patients with combination or upfront combination therapies.^9,10 Therefore, it is important to evaluate the effectiveness of PAH-specific therapies, especially combination therapies, in treating patients with PoPH using real-world data.

The Japan Pulmonary Hypertension Registry (JAPHR) was established to collect data for patients with PH visiting PH centers in Japan. In this study, these data were used to evaluate current treatment patterns and clinical events for patients with PoPH in Japan, as well as changes in hemodynamic and clinical parameters associated with PAH-specific therapy. In addition, we compared differences in clinical events and hemodynamic changes between patients with PoPH undergoing combination therapy and those receiving monotherapy.

Methods

Study Participants

The JAPHR network was established using a grant from the Japanese government. This network has currently enrolled more than 1,000 patients with PAH in the database. In this study, we evaluated all patients with PoPH who were recruited between April 2008 and November 2021 at each center. PoPH was defined as mean pulmonary arterial pressure (PAP) ≥25 mmHg at rest, a pulmonary artery wedge pressure (PAWP) ≤15 mmHg, and pulmonary vascular resistance (PVR) >3 Wood units (measured by right heart catheterization) with portal hypertension.

Evaluation and Definition of Clinical Variables

We collected data from the web-based data registration system on patient characteristics, including age, sex, dates of diagnosis and final follow-up, World Health Organization (WHO) functional class, 6-min walk distance (6MWD), hemodynamics, laboratory data, and medication for PAH. Data for all patients treated at participating centers were consecutively entered in the registry.

Combination therapy was defined as treatment with ≥2 PAH-specific drugs administered simultaneously during the follow-up period. Baseline data were collected at the time of the first right heart catheterization at each center. Patients were followed up at least every 12 months, or whenever a major clinical event, such as death or transplantation, occurred. Out-of-range data or missing values were automatically queried by the system upon data entry, thus improving data quality control. The treatment-naïve cohort was defined as patients undergoing their first right heart catheterization at the participating center before and after treatment.

Discontinuation of pulmonary vasodilators due to the development of side effects or exacerbation of PH was determined by each physician in participating centers.

Ethics Approval

This study conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the ethics committees of Kyoto University Graduate School and Faculty of Medicine (Approval no. R1919-13) and International University of Health and Welfare (Approval no. 5-16-23). The institutional review boards of all participating centers approved the study design. All participants provided written informed consent.

This study has been registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000026680).

Statistical Analysis

Continuous variables that were not normally distributed are presented as median values with the interquartile range (IQR). Categorical variables are presented as counts and percentages. The distribution of continuous variables between groups was compared using the Mann-Whitney U test. The Wilcoxon signed-rank test was used to compare pre- and post-treatment measurements in the treatment-naïve cohort, as well as baseline and final follow-up data in the total cohort. Fisher’s exact test was used to compare proportions of categorical variables between groups. Kaplan-Meier curves were used to represent survival from all-cause death. Time to event was considered the time from diagnosis to all-cause death. Two-sided P<0.05 was considered significant for all statistical tests. Statistical analyses were performed using R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline Characteristics and Treatment Profiles

There were 1,022 patients enrolled in the JAPHR as Group 1 in clinical classifications of PH. We identified 64 consecutive patients with PoPH enrolled in the registry from 24 PH centers. Two patients who did not receive PAH-specific treatment were excluded (Figure 1), leaving 62 patients (median age 51 years; 37 women) in the present study. Of these patients, 25 were categorized as treatment naïve.

Figure 1.

Flow diagram showing the recruitment of patients with portopulmonary hypertension (PoPH). JAPHR, Japan Pulmonary Hypertension Registry; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension.

The baseline characteristics of patients in both the total and treatment-naïve cohorts are presented in Table 1. Treatment details at the time of the final follow-up are presented in Supplementary Table 1. In the total cohort, 41 (66.1%) patients received combination therapy, 11 of whom were treated with triple combination therapy. The ratio of patients receiving combination therapy was similar (68.0%) in the treatment-naïve cohort. An endothelin-receptor antagonist was the most frequently used PAH-specific drug, followed by drugs targeting the nitric oxide pathway.

Table 1. Baseline Characteristics of Study Participants

	Total cohort (n=62)	Treatment-naïve cohort (n=25)
Age (years)	61 [41–60]	55 [43–59]
Female sex	37 (59.7)	16 (64.0)
Height (m)	1.64 [1.55–168.8]	1.57 [1.54–1.66]
Body weight (kg)	64 [53–74]	62 [52–77]
WHO functional class
I	6 (9.7)	1 (4.0)
II	28 (45.2)	9 (36.0)
III	25 (40.3)	12 (48.0)
IV	3 (4.8)	3 (12.0)
BNP (pg/mL)	60 [21–209]	79 [37–347]
Bilirubin (mg/dL)	1.4 [1.0–2.2]	2.1 [1.4–2.8]
Creatinine (mg/dL)	0.70 [0.63–0.94]	0.69 [0.62–0.75]
Uric acid (mg/dL)	5.7 [4.6–7.2]	6.9 [4.3–7.6]
6MWD (m)	380 [308–455]	350 [298–392]

Values are expressed as the median [interquartile range] or n (%). 6MWD, 6-min walk distance; BNP, B-type natriuretic peptide; WHO, World Health Organization.

Changes in Clinical Parameters in the Total Cohort

The median observation period from diagnosis to the last follow-up was 1,466 days (IQR 390–1,746) days. Table 2 presents hemodynamics and clinical parameters for patients in the total cohort at the time of their enrollment in the registry and at the last follow-up. During the follow-up period, hemodynamic improvement was observed in the total cohort. Both mean PAP and PVR decreased significantly, and the cardiac index and 6MWD increased significantly. There was no significant worsening of PAWP or mean right atrial pressure. The percentage of patients with WHO functional class I and II increased from 54.9% to 69.7%, and an improvement in WHO functional class by one or more classes was observed in 29% of patients (Table 3).

Table 2. Changes in Hemodynamics and Clinical Parameters of Patients in the Total Cohort

	Median difference	Study entry	Final follow-up	P value
Mean PAP (mmHg)	−6 [−14, 1]	38 [32, 44]	32 [26, 39]	<0.001
PAWP (mmHg)	1 [−3, 3]	9 [7, 11]	10 [7, 12]	0.56
Mean RAP (mmHg)	0 [−3, 2]	5 [4, 8]	6 [4, 8]	0.70
PVR (dyn·s·cm−5)	−191 [−336, −34]	465 [326, 587]	264 [189, 372]	<0.001
Cardiac index (L/min/m2)	0.60 [−0.38, 1.53]	3.00 [2.47, 3.80]	3.90 [3.20, 4.50]	0.039
SvO2 (%)	1 [−2, 7]	75 [68, 75]	74 [71, 77]	0.071
6MWD	25 [3, 68]	380 [308, 455]	410 [349, 480]	0.039
BNP (pg/mL)	−15 [−146, 15]	60 [21, 209]	40 [24, 72]	0.039
WHO functional class				0.044
I	–	6 (9.7)	10 (17.9)	–
II	–	28 (45.2)	29 (51.8)	–
III	–	25 (40.3)	16 (28.6)	–
IV	–	3 (4.8)	1 (1.8)	–

Unless indicated otherwise, values are expressed as the median [interquartile range] or n (%). PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RAP, right arterial pressure; SvO₂, mixed venous oxygen saturation. Other abbreviations as in Table 1.

Table 3. Clinical Events in the Total and Treatment-Naïve Cohorts

	Total	Monotherapy	Combination therapy	P value
Total cohort
No. patients	62	21	41
Death	13 (21.0)	4 (19.0)	9 (22.0)	0.99
Clinical PH worsening	6 (9.7)	1 (4.8)	5 (12.2)	0.66
PAH-specific drug discontinuation due to side effects	6 (9.7)	0 (0.0)	6 (14.6)	0.16
Improved WHO functional class	18 (29.0)	5 (23.8)	13 (31.7)	0.99
Treatment-naïve cohort
No. patients	25	8	17
Death	6 (24.0)	2 (25.0)	4 (23.5)	0.99
Clinical PH worsening	3 (12.0)	0 (0.0)	3 (17.6)	0.53
PAH-specific drug discontinuation due to side effects	4 (16.0)	0 (0.0)	4 (23.5)	0.27
Improved WHO functional class	13 (52.0)	4 (50.0)	9 (52.0)	0.99

Unless indicated otherwise, values are expressed as n (%). PAH, pulmonary arterial hypertension; PH, pulmonary hypertension. Other abbreviations as in Table 1.

Death, PH exacerbation, and PAH-specific drug discontinuation due to side effects were observed in 21.0%, 9.7%, and 9.7% of patients with PoPH, respectively, during the follow-up period. Of the 13 patients who died, 8 had liver-related deaths, including hepatocellular carcinoma. Based on Kaplan-Meier curves, survival in patients with PoPH at 1, 3, 5, and 10 years was 94.7% (95% confidence interval [CI] 84.5–98.3%), 88.5% (95% CI 76.0–94.7%), 80.2% (95% CI 64.8–89.3%), and 63.6% (95% CI 43.3–78.2%), respectively (Figure 2).

Figure 2.

Kaplan-Meier survival curves for patients with portopulmonary hypertension (PoPH) over a 10-year course from the time of diagnosis, where the day of PoPH diagnosis is designated as Day 0.

Comparison of Monotherapy and Combination Therapy in PoPH Patients

Hemodynamic changes in patients in the total and treatment-naïve cohorts are presented in Table 4. Details of the monotherapy and combination therapy groups are presented in Supplementary Table 2. Baseline hemodynamics in the total cohort were generally similar between the combination and monotherapy groups; in the treatment-naïve cohort, baseline PVR tended to be higher (P=0.050) and cardiac index lower (P=0.12) in the combination therapy than monotherapy group. Mean PAP, PVR, and cardiac index were significantly improved in the combination therapy group of the total cohort. Hemodynamic changes in the monotherapy group showed a tendency towards improvement, although the difference was not statistically significant. In the treatment-naïve cohort, patients in both the monotherapy and combination therapy groups showed significant improvements in the mean PAP and cardiac index. However, significant reductions in PVR were observed only in the combination therapy group. Moreover, among treatment-naïve patients, those who received combination therapy showed significant improvements in PVR (before and after treatment) compared with those in the monotherapy group (median −341 [IQR −729, −279] vs. −189 [IQR −329, −137] dyn·s·cm⁻⁵, respectively; P=0.023; Table 4). The clinical outcomes of monotherapy and combination therapy are presented in Table 3. There were no significant differences in death, PH worsening, PAH-specific drug discontinuation due to side effects, or WHO functional class improvement between the 2 groups for either the total cohort or the treatment-naïve cohort.

Table 4. Changes in Hemodynamics and Clinical Parameters of Patients in the Total and Treatment-Naïve Cohorts After the Initiation of Therapy

	Monotherapy			Combination therapy			P value** (mono- vs. combination therapy)
	Study entry	Final follow-up	P value*	Study entry	Final follow-up	P value*
Total cohort (N=62)
No. patients	21			41
Mean PAP (mmHg)	37 [32–43]	32 [27–40]	0.058	38 [32–44]	32 [24–37]	<0.01	0.78
PAWP (mmHg)	9 [7–12]	11 [7–12]	0.67	9 [7–11]	10 [7–12]	0.67	0.90
Mean RAP (mmHg)	6 [4–12]	5 [3–8]	0.94	5 [4–8]	6 [4–7]	0.73	0.94
PVR (dyn·s·cm−5)	461 [385–521]	301 [150–375]	0.11	469 [310–614]	264 [195–363]	<0.001	0.43
Cardiac index (L/min/m2)	3.00 [2.38–3.65]	3.65 [3.23–4.08]	0.99	3.00 [2.50–3.80]	3.90 [3.20–4.50]	0.015	0.38
SvO2 (%)	72 [66–74]	74 [72–77]	0.80	72 [68–75]	74 [70–79]	0.045	0.16
6MWD	399 [295–445]	438 [401–481]	0.13	370 [308–455]	402 [340–480]	0.20	0.081
BNP (pg/mL)	74 [22–312]	64 [33–211]	0.31	60 [22–164]	34 [19–51]	0.10	0.60
WHO functional class			0.12			0.16	–
I	2 (9.5)	5 (29.4)	–	4 (9.8)	5 (12.8)	–	–
II	11 (52.4)	8 (47.1)	–	17 (41.5)	21 (53.8)	–	–
III	7 (33.3)	4 (23.5)	–	18 (43.9)	12 (30.8)	–	–
IV	1 (4.8)	0 (0.0)	–	2 (4.9)	1 (2.6)	–	–
Treatment-naïve cohort (N=25)
No. patients	8			17
Mean PAP (mmHg)	41 [35–48]	32 [28–37]	0.035	42 [35–51]	28 [26–33]	<0.01	0.34
PAWP (mmHg)	9 [7–11]	10 [6–11]	0.67	9 [7–12]	11 [8–12]	0.67	0.45
Mean RAP (mmHg)	6 [4–9]	5 [3–7]	0.94	6 [4–10]	6 [5–8]	0.73	0.91
PVR (dyn·s·cm−5)	464 [392–530]	301 [171–428]	0.078	614 [513–891]	245 [188–281]	<0.001	0.023
Cardiac index (L/min/m2)	3.60 [2.63–4.25]	3.35 [3.18–4.35]	<0.01	2.50 [2.20–2.90]	4.10 [3.70–4.70]	<0.001	0.085
SvO2 (%)	73 [70–74]	74 [71–76]	0.78	68 [63–72]	74 [72–80]	<0.01	0.017
6MWD	370 [340–418]	438 [401–481]	0.13	335 [223–370]	370 [342–408]	0.12	0.28
BNP (pg/mL)	35 [18–179]	33 [29–122]	0.50	85 [53–347]	45 [24–70]	0.052	1
WHO functional class			0.089			<0.01	–
I	0 (0.0)	3 (37.5)	–	1 (5.9)	3 (17.6)	–	–
II	4 (50.0)	2 (25.0)	–	5 (29.4)	11 (64.7)	–	–
III	3 (37.5)	3 (37.5)	–	9 (52.9)	3 (17.6)	–	–
IV	1 (12.5)	0 (0.0)	–	2 (5.9)	0 (0.0)	–	–

Unless indicated otherwise, values are expressed as median [interquartile range] or n (%). *Wilcoxon signed rank test for paired data (pre- and post-treatment measurements). **Mann-Whitney U test for differences between pre- and post-treatment. Abbreviations as in Tables 1,2.

Discussion

In this study we investigated the current treatment plan for patients with PoPH in Japan. The study revealed the following important findings: (1) the combination therapy was used in approximately two-thirds of patients; (2) there were hemodynamic improvements (e.g., a decrease in mean PAP and PVR) with combination therapy; and (3) there was no significant increase in death or PAH-specific treatment-related side effects after the administration of combination therapy. According to these results, combination therapy with careful monitoring for the side effects of PAH-specific drugs may be considered in patients with PoPH.

Combination therapy for patients with PoPH was suggested to be effective in improving hemodynamics. In the present study, hemodynamics (e.g., mean PAP, PVR, and cardiac index) were improved in patients who received combination therapy, both in the total cohort and in the treatment-naïve cohort. In the French Pulmonary Hypertension Registry, PVR was significantly lower, especially in the combination therapy group, and mean PAP and cardiac index also improved significantly.¹¹ These results are consistent with those of the present study. At the molecular level, the left portal vein shunt allows blood-containing vasoactive substances to bypass the liver and avoid hepatic metabolism. These vasoactive substances cause vasodilation and a decrease in PVR. Furthermore, the high cardiac output due to a reduced PVR caused by shunting also results in PH.^12,13 Given these facts, further high cardiac output may be a concern with concomitant PAH-specific therapy; however, no significant increase in right atrial pressure or PAWP was observed in patients enrolled in the present study. These results are similar to those reported in some previous studies.^8,14

There were no obvious problems suggested in this study with combination therapy for PoPH. Drug clearance is reduced in patients with PoPH, and there is strong concern about potential side effects of PAH-specific therapies.¹⁵ However, in the present study, no significant difference was observed in the frequency of death or adverse effects from PAH-specific therapy between patients who had undergone monotherapy and those receiving combination therapy for PoPH. The PORTICO trial, which was limited to patients with PoPH, also reported no safety concerns with the treatment using macitentan.⁸ In a Japanese report of patients with PoPH in 2012–2013, drugs targeting the nitric oxide pathway were used more frequently than endothelin-receptor antagonists.¹⁶ Conversely, an endothelin-receptor antagonist was the most commonly used PAH-specific drug in the present study because some recent prospective studies revealed the effectiveness of endothelin-receptor antagonists in the treatment of patients with PoPH.^8,14 As per the findings of these studies, PAH-specific drug use, especially in combination therapies, is expected to be safe if the drug and dosages are carefully selected.

The mortality rate of patients with PoPH in Japan has been reported to be low.¹⁶ In this study, the 3- and 5-year survival rates were as high as 88.5% and 80.2%, respectively. However, in a study conducted among patients enrolled in the French Pulmonary Hypertension Registry, the 3- and 5-year survival rates were low, at 69% and 51%, respectively.¹¹ There are several reports on the survival rates of patients with PoPH, with 5-year survival rates ranging from 35% to 68%.^5,17–19 There are 2 potential explanations for differences in the reported survival rates of patients with PoPH. The first is differences in treatment strategies for PoPH. In the present study, 66.1% of PoPH patients received combination therapy, whereas very few patients in the French (15.7%) and Spanish (10.1%) registries received combination therapy.^11,19 Furthermore, triple combination therapy was used in 17.7% patients in the present study, compared with a rate of 0.8% in other studies.^11,19 The French registry included 26% patients who had not undergone PAH-specific therapy,¹¹ whereas in the present study all patients underwent PAH-specific therapy. Continuous intravenous prostanoid infusion was also reported in 2.5% of patients enrolled in the French registry,¹¹ compared with 9.7% of patients in the present study. Continuous intravenous epoprostenol therapy at a mean dose of 40 ng/kg/min was also reportedly used for patients with PAH enrolled in the Japanese registry.³ Such aggressive high-dose continuous parenteral prostacyclin therapy may also have been used in patients with PoPH. This aggressive treatment may have been the reason for the lack of a significant difference in survival rates between patients with idiopathic PAH and those with PoPH enrolled in the Japanese registry, despite the very favorable 3-year survival rate of 100% in patients with idiopathic PAH.^3,16 Although PoPH is considered one of the diseases for which monotherapy is effective,¹ it may be reasonable to consider combination therapy for patients with PoPH. Another reason for the difference in survival rates is the difference in background diseases associated with PoPH; the low incidence of PoPH and its sparse and inconsistent clinical features may account for the differences in reported mortality.²⁰ In patients with PoPH, liver-related deaths are common,^18,19 and Child-Pugh Stage C is associated with a poor prognosis.^11,17 In the French registry of PoPH, alcoholic cirrhosis was common (58.1% of patients), and 33.3% and 9.9% of patients had Child-Pugh Stage B and C, respectively.¹¹ The Child-Pugh stage is associated with survival rate. In addition, the median Model for End-Stage Liver Disease (MELD) score was identified as an independent prognostic predictor for patients with PoPH.¹¹ The MELD score has been reported to be significantly associated with waitlist mortality in patients with PoPH.²¹ Although the severity of liver diseases in patients enrolled in the present study was relatively mild, the JAPHR did not collect information on the causative disease or Child-Pugh classification and MELD score of patients with PoPH. However, in reports from Japan, approximately 90% of patients with PoPH showed no cirrhosis or Child-Pugh Stage A, suggesting that the severity of liver disease in patients with PoPH in Japan may be mild.¹⁶

Study Limitations

This study has several limitations, as follows: (1) although we used multicenter data, the number of cases was small; (2) because this was a multicenter study, treatment strategies for PoPH may have differed between centers; (3) patients for whom PAH-specific therapy was initiated were enrolled in the registry, and that may have led to selection bias; and (4) the lack of data on the causative disease of PoPH and the severity of liver disease precludes analysis that takes into account liver diseases.

Conclusions

Combination therapy was aggressively used in the treatment of patients with PoPH in Japan, leading to a high survival rate. Patients receiving combination therapies showed hemodynamic improvement, and PAH-specific drug discontinuations due to side effects were not frequently observed compared with patients who received monotherapy.

Acknowledgments

The authors express their gratitude to all the participants and staff involved in this study, especially Rika Takeyasu and Ayako Igi for data management.

Sources of Funding

This research was supported by the Japan Agency for Medical Research and Development (AMED) under Grant no. JP21ek0109567 h0001.

Disclosures

Yuichi Tamura has received remuneration from Janssen and Daiichi Sankyo; research funds from Mochida; and is affiliated with the Pulmonary Hypertension Center, which is supported by an endowment from Nippon Shinyaku. Y. Taniguchi has received research grants from Janssen Pharmaceuticals and Nippon Shinyaku. I.T. has received remuneration from Nippon Shinyaku and Janssen; and is affiliated with the Division of Respiratory and Cardiovascular Innovative Research, which is supported by endowments from Nippon Shinyaku, Nippon Boehringer Ingelheim, and Mochida. H.M. has received remuneration from Janssen, Bayer, Nippon Shinyaku, Kaneka Medix, and Mochida; and research funds from Nippon Shinyaku. Y.S. has received remuneration from Bayer Yakuhin and Daiichi-Sankyo; and research funds from Kimura Memorial Heart Foundation. S.A. has received remuneration from Bayer Yakuhin and Nippon Shinyaku. K.A. has received research funds from Mochida Pharmaceutical and Daiichi Sankyo. M.H. has received remuneration from Janssen, Bayer, and Nippon Shinyaku; and is affiliated with the Department of Therapeutic Strategy for Heart Failure, which is supported by an endowment from Mochida, Nippon Shinyaku, and Janssen. S.I. has received remuneration from Janssen Pharmaceutical, Nippon Shinyaku, and Bayer Yakuhin. K.S. has received remuneration from Bayer Yakuhin, Sanofi, Otsuka Pharmaceutical, Novartis Pharma, and Janssen Pharmaceutical. H.K. has received consultation fees from Mitsubishi-Tanabe Pharma and EP Croit, as well as speaker fees from Chugai Pharmaceutical and Johnson and Johnson, and is affiliated with the Department of Health Quality Assessment at The University of Tokyo, a social collaboration department supported by the National Clinical Database, Johnson & Johnson, Nipro Corporation, and Intuitive Surgical Sarl. K.T. has received remuneration from Janssen. K.K. is a member of Circulation Reports’ Editorial Board. The remaining authors have no conflicts of interest to declare.

IRB Information

This study was approved by the ethics committees of Kyoto University Graduate School and Faculty of Medicine and International University of Health and Welfare (Approval no. R1919-13 and 5-16-23, respectively).

Appendix

The investigators involved in the Japan Pulmonary Hypertension Registry (JAPHR) study are listed below:

• Kenichi Hirata (Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine)

• Takahiro Sato, Junichi Nakamura (Division of Respiratory and Cardiovascular Innovative Research, Faculty of Medicine, Hokkaido University)

• Toru Satoh, Hanako Kikuchi, and Kaori Takeuchi (Department of Cardiovascular Medicine, Kyorin University School of Medicine)

• Nobuhiro Tanabe, Seiichiro Sakao, Toshihiko Sugiura, Akira Naito, Ayumi Sekine, Rika Suda, and Akiko Moriya (Department of Respirology, Graduate School of Medicine, Chiba University)

• Yoshihiro Fukumoto, Nobuhiro Tahara (Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine)

• Toyoaki Murohara, Takahisa Kondo, Yoshihisa Nakano, Masahiro Yoshida, Kenichiro Yasuda, Itsumure Nishiyama, Miku Hirose, and Takeshi Adachi (Department of Cardiology, Nagoya University Hospital)

• Kazuya Hosokawa (Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences)

• Hiroaki Kitaoka (Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University)

• Yuki Ueno, Koji Maemura (Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences)

• Masataka Sata (Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences)

• Masayuki Takamura, Hirofumi Okada, and Chiaki Goten (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences)

• Koichi Sugimoto (Department of Cardiovascular Medicine, Fukushima Medical University)

• Yoshito Ogihara, Toru Sato (Department of Cardiology and Nephrology, Mie University Graduate School of Medicine)

• Sintaro Nakano (Department of Cardiology, Saitama Medical University International Medical Center)

• Yuichiro Minami (Department of Cardiology, Tokyo Women’s Medical University)

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circrep.CR-22-0098

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