Search

Right ventricular (RV) diastolic stiffness is an independent predictor of survival and is strongly associated with disease severity in patients with precapillary pulmonary hypertension (PH). Therefore, a fully validated echocardiographic method for assessing RV diastolic stiffness needs to be established. This study aimed to compare echocardiography-derived RV diastolic stiffness and invasively measured pressure-volume loop-derived RV diastolic stiffness in patients with precapillary PH. We studied 50 consecutive patients with suspected or confirmed precapillary PH who underwent cardiac catheterization, magnetic resonance imaging, and echocardiography within a 1-week interval. Single-beat RV pressure-volume analysis was performed to determine the gold standard for RV diastolic stiffness. Elevated RV end-diastolic pressure (RVEDP) was defined as RVEDP ≥ 8 mmHg. Using continuous-wave Doppler and M-mode echocardiography, an echocardiographic index of RV diastolic stiffness was calculated as the ratio of the atrial-systolic descent of the pulmonary artery-RV pressure gradient derived from pulmonary regurgitant velocity (PRPGD AC ) to the tricuspid annular plane movement during atrial contraction (TAPM AC ). PRPGD AC /TAPM AC showed significant correlation with β (r = 0.54, p < 0.001) and RVEDP (r = 0.61, p < 0.001). A cut-off value of 0.74 mmHg/mm for PRPGD AC /TAPM AC showed 83% sensitivity and 93% specificity for identifying elevated RVEDP. Multivariate analyses indicated that PRPGD AC /TAPM AC was independently associated with disease severity in patients with precapillary PH, including substantial PH symptoms, stroke volume index, right atrial size, and pressure. PRPGD AC /TAPM AC , based on pulmonary regurgitation velocity waveform analysis, is useful for the noninvasive assessment of RV diastolic stiffness and is associated with prognostic risk factors in precapillary PH., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Precapillary pulmonary hypertension (PH) is characterized by a sustained increase in right ventricular (RV) afterload, impairing systolic function. Two-dimensional (2D) echocardiography is the most performed cardiac imaging tool to assess RV systolic function; however, an accurate evaluation requires expertise. We aimed to develop a fully automated deep learning (DL)-based tool to estimate the RV ejection fraction (RVEF) from 2D echocardiographic videos of apical four-chamber views in patients with precapillary PH., Methods: We identified 85 patients with suspected precapillary PH who underwent cardiac magnetic resonance imaging (MRI) and echocardiography. The data was divided into training (80%) and testing (20%) datasets, and a regression model was constructed using 3D-ResNet50. Accuracy was assessed using five-fold cross validation., Results: The DL model predicted the cardiac MRI-derived RVEF with a mean absolute error of 7.67%. The DL model identified severe RV systolic dysfunction (defined as cardiac MRI-derived RVEF < 37%) with an area under the curve (AUC) of .84, which was comparable to the AUC of RV fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE) measured by experienced sonographers (.87 and .72, respectively). To detect mild RV systolic dysfunction (defined as RVEF ≤ 45%), the AUC from the DL-predicted RVEF also demonstrated a high discriminatory power of .87, comparable to that of FAC (.90), and significantly higher than that of TAPSE (.67)., Conclusion: The fully automated DL-based tool using 2D echocardiography could accurately estimate RVEF and exhibited a diagnostic performance for RV systolic dysfunction comparable to that of human readers., (© 2024 Wiley Periodicals LLC.)

Competing Interests: Disclosures Dr Hosokawa reports personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, and Pfizer, outside the submitted work. Dr Taniguchi reports grants from Janssen Pharmaceutical and Nippon Shinyaku; and personal fees from Janssen Pharmaceutical and Nippon Shinyaku, outside the submitted work. Dr Ikeda reports personal fees from Daiichi-Sankyo, Bayer Yakuhin, and Bristol-Myers Squibb, outside the submitted work. Dr Inami reports personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside the submitted work. Dr Murohara reports a grant and personal fees from Daiichi Sankyo, outside the submitted work. Dr Hatano reports a grant from Japan Agency for Medical Research and Development and personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside the submitted work. Dr Tamura reports grants from Bayer Yakuhin, Nippon Shinyaku, and Mochida Pharmaceutical; and personal fees from Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Janssen Pharmaceutical, outside the submitted work. Dr Yamashita reports a grant from Abbott Vascular Japan; and personal fees from Kaneka Medix, Boston Scientific Japan, Nihon Kohden, Philips Japan, Janssen Pharmaceutical, and Bayer Yakuhin, outside the submitted work. Dr Tsujino reports personal fees from Janssen Pharmaceutical and Nippon Shinyaku; and affiliation with the division supported by endowments from Nippon Shinyaku, Nippon Boehringer Ingelheim, and Mochida Pharmaceutical, outside the submitted work. Dr Yaoita reports personal fees from Bayer Yakuhin and Konica Minolta, outside the submitted work. Dr Minatsuki reports a grant from Fukuda Foundation for Medical Technology, outside the submitted work. Dr Todaka reports a grant from Mochida Pharmaceutical; and personal fee from Bayer Yakuhin, outside the submitted work. Dr Fukuda reports grants from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical; and personal fees from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical, outside the submitted work. Dr Tsutsui reports grants from Mitsubishi Tanabe Pharma, IQVIA Services Japan, MEDINET, Medical Innovation Kyushu, Kowa, Daiichi Sankyo, Johnson & Johnson, NEC, and Nippon Boehringer Ingelheim; personal fees from Novartis Pharma, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Bayer Yakuhin, Kowa, Teijin Pharma, Mitsubishi Tanabe Pharma, Pfizer Japan, Daiichi Sankyo, Novartis Pharma, Janssen Pharmaceutical, Pfizer Japan, Bayer Yakuhin, Otsuka Pharmaceutical, AstraZeneca, and Nippon Rinsho; and is Chairman of Japan Heart Failure Society, outside the submitted work. Dr Abe reports a grant from Konica Minolta and Daiichi Sankyo, outside the submitted work. Drs Watanabe, Yasuda, Kobayakawa, Adachi, and Tatsumi report no conflicts of interest.

Background: Peripheral pulmonary artery stenosis (PPS) refers to stenosis of the pulmonary artery from the trunk to the peripheral arteries. Although paediatric PPS is well described, the clinical characteristics of adult-onset idiopathic PPS have not been established. Our objectives in this study were to characterise the disease profile of adult-onset PPS., Methods: We collected data in Japanese centres. This cohort included patients who underwent pulmonary angiography (PAG) and excluded patients with chronic thromboembolic pulmonary hypertension or Takayasu arteritis. Patient backgrounds, right heart catheterisation (RHC) findings, imaging findings and treatment profiles were collected., Results: 44 patients (median (interquartile range) age 39 (29-57) years; 29 females (65.9%)) with PPS were enrolled from 20 centres. In PAG, stenosis of segmental and peripheral pulmonary arteries was observed in 41 (93.2%) and 36 patients (81.8%), respectively. 35 patients (79.5%) received medications approved for pulmonary arterial hypertension (PAH) and 22 patients (50.0%) received combination therapy. 25 patients (56.8%) underwent transcatheter pulmonary angioplasty. RHC data showed improvements in both mean pulmonary arterial pressure (44 versus 40 mmHg; p<0.001) and pulmonary vascular resistance (760 versus 514 dyn·s·cm -5 ; p<0.001) from baseline to final follow-up. The 3-, 5- and 10-year survival rates of patients with PPS were 97.5% (95% CI 83.5-99.6%), 89.0% (95% CI 68.9-96.4%) and 67.0% (95% CI 41.4-83.3%), respectively., Conclusions: In this study, patients with adult-onset idiopathic PPS presented with segmental and peripheral pulmonary artery stenosis. Although patients had severe pulmonary hypertension at baseline, they showed a favourable treatment response to PAH drugs combined with transcatheter pulmonary angioplasty., Competing Interests: Conflict of interest: All authors have nothing to disclose., (Copyright ©The authors 2023.)

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) results from unresolved thrombotic obstruction of the pulmonary vasculature. Cancer is a known risk factor for CTEPH. This study aimed to determine the impact of cancer on the prevalence, management, and outcomes of patients with CTEPH., Materials and Methods: In this retrospective study involving 99 patients sequentially diagnosed with CTEPH in our hospital, the prevalence of 10 comorbid conditions including a past history of cancer at the time of CTEPH diagnosis were calculated., Results: Among the 99 patients, 17 (17%) had a history of cancer. Breast cancer (n = 6) was the most common cancer type, followed by gastrointestinal cancer (n = 3), uterine cancer (n = 2), and malignant lymphoma (n = 2). Between patients with and without cancer, there were no differences in the demographics, severity of CTEPH, and management; however, the 5-year survival rate was lower for patients with cancer (65%) than for those without (89%). In addition, patients with cancer had significantly worse survival than those without (p = 0.03 by log-rank test). During follow-up, nine patients developed cancer after the diagnosis of CTEPH. Among the 99 patients, 13 died during follow-up, 6 (46%) of whom died of cancer., Conclusions: 17% of our patients with CETPH were diagnosed with cancer, with breast and gastrointestinal tract cancers being the most common. Cancer comorbidity was associated with a poor prognosis and contributed to death in 46% of deceased patients. The impact of cancer on CTEPH should be further evaluated in the future., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) requires lifelong anticoagulation. Long-term outcomes of CTEPH under current anticoagulants are unclear., Objectives: The CTEPH AC registry is a prospective, nationwide cohort study comparing the safety and effectiveness of direct oral anticoagulants (DOACs) and warfarin for CTEPH., Patients/methods: Patients with CTEPH, both tre atment-naïve and on treatment, were eligible for the registry. Inclusion criteria were patients aged ≥20 years and those who were diagnosed with CTEPH according to standard guidelines. Exclusion criteria were not specified. The primary efficacy outcome was a composite morbidity, and mortality outcome comprised all-cause death, rescue reperfusion therapy, initiation of parenteral pulmonary vasodilators, and worsened 6-minute walk distance and WHO functional class. The safety outcome was clinically relevant bleeding, including major bleeding., Results: Nine hundred twenty-seven patients on oral anticoagulants at baseline were analyzed: 481 (52%) used DOACs and 446 (48%) used warfarin. The 1-, 2-, and 3-year rates of composite morbidity and mortality outcome were comparable between the DOAC and warfarin groups (2.6%, 3.1%, and 4.2% vs 3.0%, 4.8%, and 5.9%, respectively; P = .52). The 1-, 2-, and 3-year rates of clinically relevant bleeding were significantly lower in DOACs than in the warfarin group (0.8%, 2.4%, and 2.4% vs 2.5%, 4.8%, and 6.4%, respectively; P = 0.036). Multivariable Cox proportional-hazards regression models revealed lower risk of clinically relevant bleeding in the DOAC group than the warfarin group (hazard ratio: 0.35; 95% CI: 0.13-0.91; P = .032)., Conclusion: This registry demonstrated that under current standard of care, morbidity and mortality events were effectively prevented regardless of anticoagulants, while the clinically relevant bleeding rate was lower when using DOACs compared with warfarin., Competing Interests: Declaration of competing interests K.H. received personal fees from Janssen Pharmaceuticals, Bayer Yakuhin, Nippon Shinyaku, and Pfizer, outside of the submitted work. K.A. received a grant from Konica Minolta and Daiichi Sankyo, outside of the submitted work. Y. Tamura received grants from Bayer Yakuhin, Nippon Shinyaku, and Mochida Pharmaceutical and personal fees from Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Janssen Pharmaceutical, outside of the submitted work. N.N. is member of the board of directors of the Japan Association for Medical Informatics. K. Todaka reports receiving a grant from Mochida Pharmaceutical and received a personal fee from Bayer Yakuhin, outside of the submitted work. Y. Taniguchi received grants from Janssen Pharmaceutical and Nippon Shinyak and received personal fees from Janssen Pharmaceutical and Nippon Shinyaku, outside of the submitted work. T.I. received personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside of the submitted work. I.T. received personal fees from Janssen Pharmaceutical and Nippon Shinyak and is affiliated with the division supported by endowments from Nippon Shinyaku, Nippon Boehringer Ingelheim, and Mochida Pharmaceutical, outside of the submitted work. J.Y. received a grant from Abbott Vascular Japan and received personal fees from Kaneka Medix, Boston Scientific Japan, Nihon Kohden, Philips Japan, Janssen Pharmaceutical, and Bayer Yakuhin, outside of the submitted work. N.I. received personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Bristol-Myers Squibb, outside of the submitted work. H.S. received a grant from Bayer Yakuhin and received personal fees from Actelion Pharmaceuticals Japan, Bayer Yakuhin, and Nippon Shinyaku, outside of the submitted work. T.K. reports receiving personal fees from Kaneka Medix, Abbott Medical Japan, and ACIST Japan, outside of the submitted work. M.H. received personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside of the submitted work. H.O. received grants from Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer Japan, Eisai, GlaxoSmithKline, Mochida Pharmaceutical, Janssen Pharmaceutical, and Nippon Shinyaku, and received consulting fees from Terumo, Japan Lifeline, and Century Medical and personal fees from Bayer Yakuhin, Daiichi Sankyo, Pfizer Japan, and Nippon Shinyaku, outside of the submitted work. Y.F. received grants from Actelion Pharmaceuticals Japan, Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, Pfizer Japa, and personal fees from Actelion Pharmaceuticals Japan, Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, Pfizer Japan, and Bristol-Myers Squibb, outside of the submitted work. N.T. received personal fees from Janssen Pharmaceutical, Bayer Yakuhin, and Nippon Shinyaku, outside of the submitted work. H.M. received grants from Bayer and Nippon Shinyaku; received personal fees from Bayer Yakuhin, Nippon Shinyaku, Mochida Pharmaceutical, Kaneka Medix, and Janssen Pharmaceutical, , outside of the submitted work; is a member of the board of directors or advisory committees for the International CTEPH Association and Japanese Pulmonary Circulation and Pulmonary Hypertension Society; and is a member of the data safety monitoring boards for Janssen Pharmaceutical, United Therapeutics, and Bayer. K. Fukuda received grants from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical, and received personal fees from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical, outside of the submitted work. H.T. received grants from Mitsubishi Tanabe Pharma, IQVIA Services Japan, Medinet, Medical Innovation Kyushu, Kowa, Daiichi Sankyo, Johnson & Johnson, NEC, and Nippon Boehringer Ingelheim; received personal fees from Novartis Pharma, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Bayer Yakuhin, Kowa, Teijin Pharma, Mitsubishi Tanabe Pharma, Pfizer Japan, Daiichi Sankyo, Novartis Pharma, Janssen Pharmaceutical, Pfizer Japan, Bayer Yakuhin, Otsuka Pharmaceutical, AstraZeneca, and Nippon Rinsho, outside the submitted work; and is the chairman of the Japan Heart Failure Society. Soiken Corp accessed and verified the data. The remaining authors K. Funakoshi, S.A., S.M., K. Tatsumi, and T.O. have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Objectives: Systemic sclerosis (SSc) is associated with pulmonary vascular disease and interstitial lung disease, making it difficult to differentiate pulmonary arterial hypertension and pulmonary hypertension (PH) due to lung diseases and/or hypoxia and to decide treatments. We aimed to predict the response to pulmonary vasodilators in patients with SSc and PH., Methods: Eighty-four SSc patients were included with 47 having PH. Chest computed tomography was evaluated using software to calculate the abnormal lung volume (ALV). To define the response to vasodilators, Δ mean pulmonary artery pressure (mPAP)/basal mPAP was used (cut-off value: 10%). The predictive value was evaluated by using the receiver operating characteristic curve., Results: The mean (±standard deviation) value of ALV was 26.8 (±32.2) %. A weak correlation was observed between ALV and forced vital capacity (FVC) (R = -0.46). The predictive value of ALV [area under curve (AUC) = 0.74] was superior to that of FVC (AUC = 0.62) for the response to vasodilators. No hemodynamic parameters differed between patients with high and low ALV, whereas survival was worse in high ALV., Conclusions: Quantitative chest computed tomography well predicted the response to vasodilators in patients with SSc and PH. Our results suggest its utility in differentiating the dominance of pulmonary vascular disease or interstitial lung disease., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB) facilitates the diagnosis of various respiratory diseases. The safety of performing EBUS-guided TBB in patients with a finding of pulmonary hypertension (PH) is controversial. Little is known about the relationship between the risk of bleeding associated with EBUS-guided TBB in the presence of PH suspected on echocardiography or chest CT., Methods: To assess the risk of bleeding associated with EBUS-guided TBB in patients with presumed PH per echocardiography or chest CT, we retrospectively reviewed the medical records of 314 consecutive patients who underwent EBUS-guided TBB using a guide sheath (GS), as well as echocardiography and chest CT. Bleeding complication was defined as over one minute of suctioning; repeated wedging of the bronchoscope; instillation of cold saline, diluted vasoactive substances, or thrombin due to persistent bleeding. Findings of suspected PH were defined as peak tricuspid regurgitation velocity (TRV) > 2.8 m/s on echocardiography or pulmonary artery to aorta ratio (PA:A ratio) > 0.9 on chest CT., Results: In total, 35 (11.1%) patients developed bleeding, and all cases were managed safely. Furthermore, 17 (5.4%) and 59 (18.8%) patients were suspected to have PH based on echocardiography and chest CT, respectively. Among the patients suspected to have PH on echocardiography, five (5/17 = 29.4%) patients developed bleeding. Among the patients suspected to have PH on chest CT, 11 (11/59 = 18.6%) patients developed bleeding. Univariate analysis revealed that long diameter (≥ 30 mm) of the lesion, lesion location (the biopsy site was inner than the segmental bronchus), bronchoscopic diagnosis of malignancy, and additional biopsy were potential predictive factors for bleeding. The finding of suspected PH on echocardiography correlated significantly with bleeding (p = 0.03). On multivariate analysis, long diameter (≥ 30 mm) of the lesion (p = .021) and findings of suspected PH on echocardiography (p = .049) were significantly associated with bleeding., Conclusion: All cases of bleeding in the present study were managed safely. The risk of bleeding is moderately elevated when PH is suspected by echocardiography in patients undergoing EBUS-guided TBB using a GS., (© 2022. The Author(s).)

Aims: Although the left ventricular (LV) dysfunction in pre-capillary pulmonary hypertension (PH) has been recently recognized, the mechanism of LV dysfunction in this entity is not completely understood. We thus aimed to elucidate the determinants of intraventricular pressure difference (IVPD), a measure of LV suction, in pre-capillary PH., Methods and Results: Right heart catheterization and echocardiography were performed in 86 consecutive patients with pre-capillary PH (57 ± 18 years, 85% female). IVPD was determined using colour M-mode Doppler to integrate the Euler equation. In overall, IVPD was reduced compared to previously reported value in normal subjects. In univariable analyses, QRS duration (P = 0.028), LV ejection fraction (P = 0.006), right ventricular (RV) end-diastolic area (P < 0.001), tricuspid annular plane systolic excursion (P = 0.004), and LV early-diastolic eccentricity index (P = 0.009) were associated with IVPD. In the multivariable analyses, RV end-diastolic area and LV eccentricity index independently determined the IVPD., Conclusion: Aberrant ventricular interdependence caused by RV enlargement could impair the LV suction. This study first applied echocardiographic IVPD, a reliable marker of LV diastolic suction, to investigate the mechanism of LV diastolic dysfunction in pre-capillary PH., Competing Interests: Conflict of interest: none declared., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: A few studies have focused on the cause of death from different types of pulmonary hypertension (PH). This study aimed to systematically analyze the primary and secondary causes of death and compare the profiles between different PH groups., Methods: The contribution of PH to death was assessed in precapillary PH (i.e., group 1 [pulmonary arterial hypertension], group 3 [PH associated with lung disease], and group 4 [chronic thromboembolic PH]) using specific criteria; death was classified into three categories: PH death (death due to PH only), PH-related death, and PH-unrelated death. Disorders other than PH that contributed to death were analyzed, and mortality profiles were compared between groups., Results: Eighty deceased patients with PH were examined (group 1, n = 28; group 3, n = 39; and group 4, n = 13). The contribution of PH to death was significantly different between the three groups. "PH death" was most common in group 1 (61%), "PH-related death" in group 3 (56%), and "PH-related death" and "PH-unrelated death" in group 4 (38% for both). The highest contributing factor to death other than PH was respiratory failure in group 3 and malignant disease in group 4., Conclusions: Significant variations in the causes of death were observed in groups 1, 3, and 4 PH patients. In addition to PH, respiratory failure and malignant disease significantly contributed to death in group 3 and group 4 PH, respectively. Understanding the precise death cause may be important in achieving better outcomes in PH patients., Competing Interests: Conflict of Interest Ichizo Tsujino, Takahiro Sato, and Satoshi Konno received research funding from Nihon Shinyaku Co Ltd. Nippon Boehringer Ingelheim Co., Ltd. and Mochida Pharmaceutical Co., Ltd. IY reports grants from KAKENHI, AMED, and Health, Labour and Welfare Policy Research Grants, research fund by Nihon Medi-Physics, and speaker fees from Chugai Pharmaceutical Co, AstraZeneca plt, Japan Tabacco Pharamaceutical Division, and Nippon Shinyaku Co, not related to the submitted work., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remain limited. Selexipag, an oral selective IP prostacyclin receptor agonist approved for pulmonary arterial hypertension, is a potential treatment option for CTEPH., Methods: In this multicentre, randomised, double-blind, placebo-controlled study, 78 Japanese patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and/or balloon pulmonary angioplasty were randomly assigned to receive placebo or selexipag. The primary end-point was the change in pulmonary vascular resistance (PVR) from baseline to week 20. Secondary end-points were changes in other haemodynamic parameters: 6-min walk distance (6MWD), Borg dyspnoea scale score, World Health Organization (WHO) functional class, EuroQol five-dimension five-level tool and N-terminal pro-brain natriuretic peptide., Results: The change in PVR was -98.2±111.3 dyn·s·cm -5 and -4.6±163.6 dyn·s·cm -5 in the selexipag and placebo groups, respectively (mean difference -93.5 dyn·s·cm -5 ; 95% CI -156.8 to -30.3; p=0.006). The changes in cardiac index (p<0.001) and Borg dyspnoea scale score (p=0.036) were also significantly improved over placebo. 6MWD and WHO functional class were not significantly improved. The common adverse events in the selexipag group corresponded to those generally observed following administration of a prostacyclin analogue., Conclusion: Selexipag significantly improved PVR and other haemodynamic variables in patients with CTEPH, although exercise capacity remained unchanged. Further large-scale investigation is necessary to prove the role of selexipag in CTEPH., Competing Interests: Conflict of interest: Nippon Shinyaku Co., Ltd, provided grants for this study group. T. Ogo reports personal fees from Nippon Shinyaku Co., Ltd, during the conduct of the study; personal fees from Janssen Pharmaceutical K.K., Bayer Yakuhin, Ltd, Nippon Shinyaku Co., Ltd, GlaxoSmithKline K.K., Pfizer Japan Inc., and Mochida Pharmaceutical Co., Ltd, outside the submitted work. H. Shimokawahara reports grants from Kaneka Corporation, Bayer Taiwan Co., Ltd, Bayer Yakuhin, Ltd, Daiichi Sankyo Company, Ltd, Japan Lifeline Co., Ltd, Actelion Pharmaceuticals Ltd, Pfizer Inc., and Mochida Pharmaceutical Co., Ltd, outside the submitted work. H. Kinoshita reports grants and personal fees from Nippon Shinyaku Co., Ltd, during the conduct of the study; personal fees from Janssen Pharmaceutical K.K., Nippon Shinyaku Co., Ltd, and Bayer Yakuhin, Ltd, outside the submitted work. S. Sakao reports personal fees from Actelion Pharmaceuticals Ltd, Bayer Yakuhin, Ltd, Daiichi Sankyo Company, Ltd, and Pfizer Japan Inc., grants from the Ministry of Health, Labour, and Welfare of Japan (number 27280401), and Grant-in-Aid for Scientific Research B from the Japan Society for the Promotion of Science (JSPS) (number JP18H03664), outside the submitted work. K. Abe reports grants from Mochida Pharmaceutical Co., Ltd, and Daiichi Sankyo Healthcare Co., Ltd, outside the submitted work. H. Maki reports grants from Bayer Yakuhin, Ltd, and Mochida Pharmaceutical Co., Ltd, outside the submitted work. T. Sugano reports personal fees from Janssen Pharmaceutical K.K., Bayer Holding Ltd, Mochida Pharmaceutical Co., Ltd, Daiichi Sankyo Company, Ltd, Takeda Pharmaceutical Company Ltd, Amgen Inc., Otsuka Pharmaceutical Co., Ltd, Novartis Pharma K.K., and Nippon Shinyaku Co., Ltd, outside the submitted work. I. Tsujino reports grants from Actelion Pharmaceuticals Japan Ltd, Mochida Pharmaceutical Co., Ltd, and Nippon Boehringer Ingelheim Co., Ltd, personal fees from Bayer Yakuhin, Ltd, Janssen Pharmaceutical K.K., Pfizer Japan Inc., and Nippon Shinyaku Co., Ltd, outside the submitted work. N. Tanabe reports personal fees from Nippon Shinyaku Co., Ltd, during the conduct of the study; personal fees from Nippon Shinyaku Co., Ltd, Bayer AG, and Janssen Pharmaceutical K.K., outside the submitted work. K. Tatsumi reports personal fees from Nippon Shinyaku Co., Ltd, Janssen Pharmaceutical K.K., and Actelion Pharmaceuticals Ltd, during the conduct of the study. S. Matoba, H. Motoki, N. Takama, J. Ako, Y. Ikeda, S. Joho, T. Saeki and K. Yoshioka, have no conflicts of interest outside the submitted work. N. Shiota, S. Tanaka and C. Yamamoto are employees of Nippon Shinyaku Co., Ltd., (Copyright ©The authors 2022.)

Objectives: Systemic sclerosis associated pulmonary arterial hypertension (SSc-PAH) is of clinical significance owing to its poor outcome. One of the explanations for the outcome is the co-presence of left heart disease (LHD). The aim of this study is to assess LHD phenotype in patients with SSc and pulmonary hypertension (PH)., Methods: This study included consecutive patients with SSc who underwent right heart catheterisation to diagnose PAH. Heart failure with preserved ejection fraction (HFpEF) was evaluated according to the recommendation of 6th WSPH and to the Framingham criteria., Results: In total, 76 patients were enrolled in this study. Of them, 42 had PH (mPAP >20 mmHg) with a normal left ventricle ejection fraction (≥50%). Among the 42 patients, four and three patients were classified "HFpEF not excluded" and "HFpEF confirmed" whereas 10 had a clinical diagnosis of HFpEF according to 6th WSPH and Framingham criteria, respectively. These differences were due mainly to relatively low PAWP (<13 mmHg). By a combination of ROC curve and logistic regression analyses, left atrial dimension and left ventricular end-diastolic volume index assessed with echocardiography and cardiac MRI, respectively, had significantly higher predictive values for detecting the complication of HFpEF rather than PAWP., Conclusions: Morphological evaluation using echocardiography and cardiac MRI, compared with haemodynamic evaluation by PAWP, may better reflect the copresence of LHD phenotype in patients with SSc and PH. Our data would also indicate a limited elevation of PAWP in patients with SSc, PH and HFpEF.

Background: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis., Methods and results: Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI., Conclusions: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.

Background: Selexipag is an oral prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. This study examined its efficacy and safety in Japanese patients with non-operated or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH)., Methods and results: This Phase II study was a randomized, double-blind, placebo-controlled parallel-group comparison. The primary endpoint was a change in pulmonary vascular resistance (PVR) from baseline to week 17. The main analysis involved a per-protocol set group of 28 subjects. The change in PVR (mean±SD) after 17 weeks of treatment in the selexipag group was -104±191 dyn·s/cm 5 , whereas that in the placebo group was 26±180 dyn·s/cm 5 . Thus, the treatment effect after 17 weeks of selexipag treatment was calculated as -130±189 dyn·s/cm 5 (P=0.1553). Although the primary endpoint was not met, for the group not concomitantly using a pulmonary vasodilator the PVR in the selexipag group was significantly decreased compared with placebo group (P=0.0364). The selexipag group also showed improvement in total pulmonary resistance and cardiac index., Conclusions: Selexipag treatment improved pulmonary hemodynamics in Japanese patients with CTEPH, but PVR did not show a significant difference between the selexipag and placebo groups. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111667]).

Objectives: Pulmonary hypertension (PH) in patients with CTD is a heterogeneous condition affected by left heart disease, chronic lung disease and thromboembolism as well as pulmonary vascular disease. Recent studies using cardiac magnetic resonance (CMR) have shown that right ventricular dysfunction is predictive for mortality in patients with PH, but limited to pulmonary arterial hypertension. This study aimed to analyse prognostic factors in PH-CTD., Methods: This retrospective analysis comprised 84 CTD patients, including SSc, who underwent both CMR and right heart catheterization from 2008 to 2018. Demographics, laboratory findings, and haemodynamic and morphological parameters were extracted. The prognostic value of each parameter was evaluated by multivariate analysis using covariables derived from propensity score to control confounding factors., Results: Of 84 patients, 65 had right heart catheterization-confirmed PH (54 pulmonary arterial hypertension, 11 non-pulmonary arterial hypertension). Nine out of these PH patients died during a median follow-up period of 25 months. In 65 patients with PH, right ventricular end-diastolic dimension index (RVEDDI) evaluated by CMR was independently associated with mortality (hazard ratio 1.24; 95% CI: 1.08-1.46; P = 0.003). In a receiver operating characteristic analysis, RVEDDI highly predicted mortality, with area under the curve of 0.87. The 0.5-2-year follow-up data revealed that RVEDDI in both survivors and non-survivors did not significantly change over the clinical course, leading to the possibility that an early determination of RVEDDI could predict the prognosis., Conclusion: RVEDDI simply evaluated by CMR could serve as a significant predictor of mortality in PH-CTD. A further validation cohort study is needed to confirm its usability., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Early intervention in pulmonary arterial hypertension associated with systemic sclerosis (SSc) may improve its prognosis. We aimed to establish an algorithm to detect mean pulmonary artery pressure (mPAP) > 20 mmHg using non-invasive examinations in SSc patients by modifying the DETECT algorithm. This study included SSc patients who underwent right heart catheterization (RHC) in our hospital during 2010-2018. Following variables were assessed for performance to predict mPAP ≥ 25 mmHg or > 20 mmHg; anti-centromere or U1-RNP antibody, plasma BNP level, serum urate level, right axis deviation, forced vital capacity (FVC)/diffusing capacity for carbon monoxide (DLCO) ratio, and tricuspid regurgitation velocity. Of 58 patients enrolled in this study, 24 had mPAP of ≥ 25 mmHg and 9 had mPAP of 21-24 mmHg. Among variables tested, only FVC/DLCO elevated similarly in patients with mPAP of ≥ 25 mmHg (median 2.5) and those with mPAP of 21-24 mmHg (median 2.5) compared to those with mPAP of ≤ 20 mmHg (median 1.5). Given the particularly good correlation between DLCO and mPAP of > 20 mmHg, each variable was weighted according to its odds ratio and the total weighted score was calculated. The total weighted score exhibited a good predictive performance for mPAP of > 20 mmHg with its sensitivity of 87.5% and specificity of 92%. Among conventional risk factors for PAH, decreased DLCO may predict mPAP > 20 mmHg with priority in SSc patients. Weighting DLCO may improve the performance of screening algorithm for early SSc-PAH.

Background: Balloon pulmonary angioplasty (BPA) has been performed for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or residual pulmonary hypertension after pulmonary endarterectomy (PEA). We performed a systematic review to assess the efficacy and safety of BPA, especially compared to medical treatment or PEA., Methods: We reviewed all studies investigating pre- and post-treatment pulmonary hemodynamics, mortality, or complications from three electronic databases (PubMed, Cochrane Library, Japan Medical Abstracts Society) prior to February 2017. From 26 studies retrieved, we selected 13 studies (493 patients): the 10 most recent ones including complete data from each institution, one study of residual pulmonary hypertension, and two studies comparing BPA with medical treatment or PEA., Results: No randomized controlled or prospective controlled studies comparing BPA with medical treatment or PEA were reported. The early mortality of BPA ranged from 0% to 14.3%; lung injury occurred in 7.0% to 31.4% (average sessions, 2.5-6.6). Mean pulmonary arterial pressure decreased from 39.4-56 to 20.9-36 mm Hg, and the 6-min walk distance increased from 191-405 to 359-501 m. The 2-year mortality of 80 patients undergoing BPA was significantly lower compared to 68 patients receiving medical treatment (1.3% vs. 13.2%); the risk ratio was 0.14 (95% confidence interval: 0.03-0.76). No significant difference was observed in the 2-year mortality between BPA (n=97) and PEA (n=63) patients., Conclusions: This systematic review suggests that BPA improves hemodynamics, has acceptable early mortality, and may improve long-term survival compared with medical treatment in inoperable CTEPH patients., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: The trend of the initial treatment strategy for pulmonary arterial hypertension (PAH) has changed from monotherapies to upfront combination therapies. This study analyzed treatments and outcomes in Japanese patients with PAH, using data from the Japan PH Registry (JAPHR), which is the first organized multicenter registry for PAH in Japan.Methods and Results:We studied 189 consecutive patients (108 treatment-naïve and 81 background therapy patients) with PAH in 8 pulmonary hypertension (PH) centers enrolled from April 2008 to March 2013. We performed retrospective survival analyses and analyzed the association between upfront combination and hemodynamic improvement, adjusting for baseline NYHA classification status. Among the 189 patients, 1-, 2-, and 3-year survival rates were 97.0% (95% CI: 92.1-98.4), 92.6% (95% CI: 87.0-95.9), and 88.2% (95% CI: 81.3-92.7), respectively. In the treatment-naïve cohort, 33% of the patients received upfront combination therapy. In this cohort, 1-, 2-, and 3-year survival rates were 97.6% (95% CI: 90.6-99.4), 97.6% (95% CI: 90.6-99.4), and 95.7% (95% CI: 86.9-98.6), respectively. Patients on upfront combination therapy were 5.27-fold more likely to show hemodynamic improvement at the first follow-up compared with monotherapy (95% CI: 2.68-10.36)., Conclusions: According to JAPHR data, initial upfront combination therapy is associated with improvement in hemodynamic status.

Background: Serial assessment of right ventricular ejection fraction (RVEF) predicts the clinical outcome of patients with pulmonary hypertension (PH). Cardiac magnetic resonance imaging (CMRI) enables RVEF monitoring, but its applicability is limited in clinical practice. This study aimed to examine the correlation between changes in CMRI-derived RVEF with those in echocardiographic indices in patients with precapillary PH., Methods: CMRI and echocardiographic indices of RV systolic function were evaluated at baseline and follow-up in 54 consecutive patients with precapillary PH (pulmonary arterial hypertension (PAH), n = 23; non-PAH, n = 31). During follow-up, medical treatment was optimized according to the guidelines for PH. Using CMRI-derived RVEF as the gold standard, we examined the accuracy of five echocardiographic indices by correlation analysis and receiver operating characteristic (ROC) analysis and by calculating sensitivity, specificity, and positive and negative predictive values., Results: After an average period of 9.5 months, CMRI-derived RVEF improved from 30.2% ± 10.6% at baseline to 41.4% ± 11.3% at follow-up. These changes significantly correlated with those in the five echocardiographic indices, i.e., %RV fractional shortening (r = 0.27), %RV area change (r = 0.46), tricuspid annular plane systolic excursion (TAPSE) (r = 0.84), RV myocardial performance index (RVMPI) (r = -0.72), and systolic lateral tricuspid annular motion velocity (TVlat) (r = 0.66). Of these indices, %RV area change, TAPSE, and TVlat significantly correlated with those of CMRI-derived RVEF in both PAH and non-PAH subgroups. ROC analysis showed that improvement in echocardiographic indices predicted a pre-specified improvement in CMRI-derived RVEF (>2.9%), with TAPSE and TVlat showing better accuracy over the other three indices., Conclusions: Echocardiographic indices modestly correlate with the changes in CMRI-derived RVEF in precapillary PH patients. Comparison among the five echocardiographic indices revealed that TAPSE and TVlat provide better accuracy than %RV fractional shortening, %RV area change, and RVMPI.

Background: Few studies have addressed the value of combining computed tomography-derived pulmonary vasculature metrics for the diagnosis and haemodynamic evaluation of pulmonary arterial hypertension (PAH)., Materials and Methods: We measured three computed tomography parameters for the pulmonary artery, peripheral vessels, and pulmonary veins: the ratio of the diameter of the pulmonary artery to the aorta (PA/Ao), the cross-sectional area of small pulmonary vessels <5mm 2 as a percentage of total lung area (%CSA <5 ), and the diameter of the right inferior pulmonary vein (PVD). The measured quantities were compared between patients with PAH (n=45) and control subjects (n=56), and their diagnostic performance and associations with PAH-related clinical indices, including right heart catheterization measurements, were examined., Results: PA/Ao and %CSA <5 were significantly higher in patients with PAH than in controls. Receiver-operating characteristic curve analysis for ability to diagnose PAH showed a high area under the curve (AUC) for PA/Ao (0.95) and modest AUCs for %CSA <5 (0.75) and PVD (0.56). PA/Ao correlated positively with mean pulmonary arterial pressure and PVD correlated negatively with pulmonary vascular resistance. The %CSA <5 correlated negatively with mean pulmonary arterial pressure and pulmonary vascular resistance and positively with cardiac index. Notably, the PA/Ao and PVD values divided by %CSA <5 correlated better with right heart catheterization indices than the non-divided values., Conclusion: PA/Ao, %CSA <5 , and PVD are useful non-invasive pulmonary vasculature metrics, both alone and in combination, for diagnosis and haemodynamic assessment of PAH., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Balloon pulmonary angioplasty (BPA) is an alternative therapy for patients with chronic thromboembolic pulmonary hypertension who are ineligible for pulmonary endarterectomy-the standard therapy. Currently, most reported results of BPA are from relatively small cohorts treated at single centers. The present study evaluated the safety and efficacy of BPA for chronic thromboembolic pulmonary hypertension based on a multicenter registry., Methods and Results: A total of 308 patients (62 men and 246 women; mean age, 61 years) underwent 1408 procedures at 7 institutions in Japan. Data were retrospectively reviewed to evaluate clinical outcome and complications. Hemodynamics were significantly improved in 249 patients in whom BPA was terminated, most often because of improvement in mean pulmonary arterial pressure or symptomatic improvement after 1154 procedures. In 196 patients who underwent follow-up right heart catheterization, improvement of hemodynamic parameters was maintained. Mean pulmonary arterial pressure decreased from 43.2±11.0 to 24.3±6.4 mm Hg after final BPA and 22.5±5.4 mm Hg at follow-up, with significant reduction of concomitant use of pulmonary hypertension-targeted therapy and oxygen supplementation. Complications occurred in 511 (36.3%), including pulmonary injury (17.8%), hemoptysis (14.0%), and pulmonary artery perforation (2.9%). Twelve patients (3.9%) died during follow-up, including 8 patients who died within 30 days after BPA. The leading causes of death were right heart failure, multiorgan failure, and sepsis. Overall survival was 96.8% (95% confidence interval, 93.7%-98.4%) at 1 and 2 years and 94.5% (95% confidence interval, 89.3%-97.3%) at 3 years, respectively, after the initial BPA procedure for all 308 patients., Conclusions: This multicenter registry suggested improved hemodynamic results after BPA. Complication rates were high, but overall survival was comparable with pulmonary endarterectomy. BPA may be an important therapeutic option in patients with chronic thromboembolic pulmonary hypertension., (© 2017 American Heart Association, Inc.)

We investigated the serum haptoglobin levels in patients with pulmonary arterial hypertension (PAH) based on the hypothesis that haptoglobin levels would reflect subclinical hemolysis due to microangiopathy in pulmonary arterioles.This cross-sectional study included 3 groups of patients attending Hokkaido University Hospital: PAH, chronic thromboembolic pulmonary hypertension (CTEPH), and connective tissue diseases (CTD) without PAH (CTD-non-PAH) group. Serum haptoglobin levels were measured by standardized turbidimetric immunoassay in all patients. Demographic data, laboratory results, right heart catheter, and echocardiographic findings were extracted from the medical records. Decreased haptoglobin levels were defined as below 19 mg/dL based on the 95th percentile of healthy controls.Thirty-five patients in PAH group including 11 with idiopathic PAH (IPAH) and 24 with CTD-associated PAH (CTD-PAH), 27 in CTEPH group, and 32 in CTD-non-PAH group were analyzed. Serum haptoglobin levels in PAH group (median 66 mg/dL) were significantly lower than those in CTEPH group (median 94 mg/dL, P = .03) and CTD-non-PAH group (median 79 mg/dL, P = .03). The prevalence of decreased haptoglobin levels was 26% in PAH group, 15% in CTEPH group, and 6% in CTD-non-PAH group. Serum haptoglobin levels had a significant negative correlation (r = -0.66, P < .001) with mean pulmonary artery pressure in PAH group, particularly in CTD-PAH subgroup (r = -0.74, P < .001), but no correlation in IPAH subgroup (r = -0.52, P = .13) and in CTEPH group (r = -0.17, P = .41). Follow-up cases of CTD-PAH showed lowering pulmonary artery pressure led to normalizing serum haptoglobin levels.Serum haptoglobin levels decreased in PAH patients and inversely correlated with pulmonary artery pressure in CTD-PAH patients, suggesting their potential as a surrogate marker for CTD-PAH.

Objectives: Pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc) has a poor prognosis compared to PAH associated with other connective tissue diseases (CTD). The objective of this study was to examine the difference in hemodynamic state between SSc-PAH and other CTD-PAH by performing cardiac magnetic resonance (CMR) imaging., Methods: A single center retrospective analysis was conducted comprising 40 consecutive CTD patients who underwent right heart catheterization and CMR at the same period from January 2010 to October 2015., Results: Thirty-two patients had pre-capillary pulmonary hypertension. Of these, 15 had SSc and 17 had other CTD. CMR measurements, particularly the ratio of right to left end-diastolic volume (RVEDV/LVEDV), correlated well with mean pulmonary arterial pressure (mPAP). Conversely, RVEDV/LVEDV and mPAP correlated differently in SSc and non-SSc patients. In SSc patients, the ratio of RVEDV/LVEDV to mPAP was significantly higher compared to non-SSc patients. In the follow-up study, 2 SSc patients exhibited increased RVEDV/LVEDV in spite of decreased mPAP following treatment. Kaplan-Meier analysis revealed poor prognosis of patients with increased RVEDV/LVEDV following treatment., Conclusions: Our data indicated that altered bi-ventricular interplay detected at CMR may represent SSc-related cardiac involvement and reflect poor prognosis of SSc-PAH.

Background and Objective: Pulmonary hypertension (PH) is often associated with respiratory diseases, but only a small number of patients present with severe PH defined as mean pulmonary arterial pressure ≥ 35 mm Hg. We here conducted a multicenter, retrospective study of patients with severe PH associated with respiratory diseases (R-PH) to reveal their demographics, treatment, prognosis and determinants of prognosis., Methods: From 101 patients with severe R-PH collected by postal survey at the first stage, 70 patients with four major diseases (chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis with emphysema (CPFE), interstitial pneumonia associated with connective tissue disease (CTD-IP), interstitial pneumonia (IP)) and normal pulmonary arterial wedge pressure were studied for clinical characteristics, treatment and prognosis., Results: Three-year survival rates were 50% for COPD (n = 18), 35.7% for IP (n = 19) and 68.1% for CTD-IP (n = 20), and the 2-year survival rate for CPFE (n = 13) was only 22.6%. Eighty-one per cent of patients had been treated with pharmacotherapy specific for pulmonary arterial hypertension. Those patients who had received phosphodiesterase-5 inhibitors (PDE-5I) displayed significantly better survival from the date of diagnosis than those who had not (3-year survival: 61.8% vs 20.0% P < 0.0001), especially in the IP, CTD-IP and CPFE groups. Multivariate analysis also revealed that treatment with PDE-5I was a positive prognostic factor., Conclusions: We here demonstrated the dismal prognosis of patients with severe R-PH. The remarkably better survival in those patients who had received PDE-5I warrants and facilitates future prospective randomized studies in this particular population., (© 2015 Asian Pacific Society of Respirology.)

Background: Symptoms and signs and indices of right heart function are predictors of clinical outcomes in patients with pulmonary hypertension (PH). However, the significance of right atrial (RA) indices has not been sufficiently investigated. We investigated whether RA parameters predict outcomes in patients with pre-capillary PH., Methods: Study subjects were 68 patients with pre-capillary PH. RA size and function (systolic, reservoir, and conduit functions) were evaluated by cardiac magnetic resonance imaging., Results: During the mean follow-up period of 24 months, 16 of 68 patients experienced clinical worsening (CW), defined as hospitalization because of right heart failure, lung transplantation, or PH-related death. Kaplan-Meier and log-rank test showed that World Health Organization functional class, pericardial effusion, increased brain natriuretic peptide concentration, reduced right ventricular ejection fraction (RVEF), increased minimum RA volume index, and decreased RA reservoir volume were associated with CW-free survival. The combination of RVEF and RA reservoir function was a better predictor of CW-free survival. In univariate Cox hazard proportional analysis, CW was associated with the RA reservoir volume index (hazard ratio [HR] = 0.80). In multivariate analysis, CW was associated with World Health Organization functional class (HR = 4.3), RA minimum volume index (HR = 1.07), and RA reservoir volume index (HR = 0.73)., Conclusions: RA volume and reservoir function and their combined use with RVEF are novel predictors of CW in patients with pre-capillary PH., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Purpose: The right ventricle (RV) has a high capacity to adapt to pressure or volume overload before failing. However, the mechanisms of RV adaptation, in particular RV energetics, in patients with pulmonary hypertension (PH) are still not well understood. We aimed to evaluate RV energetics including RV oxidative metabolism, power and efficiency to adapt to increasing pressure overload in patients with PH using (11)C-acetate PET., Methods: In this prospective study, 27 patients with WHO functional class II/III PH (mean pulmonary arterial pressure 39.8 ± 13.5 mmHg) and 9 healthy individuals underwent (11)C-acetate PET. (11)C-acetate PET was used to simultaneously measure oxidative metabolism (k mono) for the left ventricle (LV) and RV. LV and RV efficiency were also calculated., Results: The RV ejection fraction in PH patients was lower than in controls (p = 0.0054). There was no statistically significant difference in LV k mono (p = 0.09). In contrast, PH patients showed higher RV k mono than did controls (0.050 ± 0.009 min(-1) vs. 0.030 ± 0.006 min(-1), p < 0.0001). PH patients exhibited significantly increased RV power (p < 0.001) and hence increased RV efficiency compared to controls (0.40 ± 0.14 vs. 0.017 ± 0.12 mmHg·mL·min/g, p = 0.001)., Conclusion: The RV oxidative metabolic rate was increased in patients with PH. Patients with WHO functional class II/III PH also had increased RV power and efficiency. These findings may indicate a myocardial energetics adaptation response to increasing pulmonary arterial pressure.

Background: Pulmonary hypertension (PH) often correlates with respiratory disease severity. Right heart catheterization (RHC) is recommended for the definitive diagnosis of PH associated with respiratory disease (R-PH). However, no previous studies have evaluated the perceived necessity for pulmonologists to use RHC for R-PH diagnosis, or the management of R-PH in Japan., Methods: Questionnaires were mailed to 855 institutions, approved by the Japanese Respiratory Society. Questions included the prevalence and necessity of RHC and other methods in R-PH diagnosis, and current trends in the treatment of R-PH., Results: Questionnaires were returned from 289 institutions (34%). Patients with R-PH were examined by pulmonologists in 89% of institutions; some pulmonologists performed echocardiography (15%) and some RHC (13%). Echocardiography was used to diagnose R-PH in 99% of institutions and RHC was used in 36%. RHC was considered in cases of suspected PH in 49% of institutions and prior to initiation of pulmonary arterial hypertension (PAH)-specific therapy in 57%. Of patients diagnosed with R-PH, 47% were treated with ambulatory oxygen therapy. Furthermore, 98 of 145 institutions used PAH-specific therapy to treat R-PH. Of the 1355 patients who underwent RHC as a part of PH evaluation, 29% were confirmed to have PH, and 8% had severe PH with a mean pulmonary arterial pressure of ≥35mmHg., Conclusions: The current diagnostic and treatment modalities for R-PH in Japan were evaluated. Although few pulmonologists perform RHC for R-PH diagnosis in Japan, more than half consider using RHC for patients before initiating PAH-specific therapy., (© 2013 Published by The Japanese Respiratory Society on behalf of The Japanese Respiratory Society.)

Severe pulmonary hypertension (PH) often develops in patients with pulmonary Langerhans cell histiocytosis (PLCH). Supplemental oxygen treatment is often used, whereas pulmonary arterial hypertension-specific vasodilators are generally considered hazardous because of the possible development of pulmonary edema and deterioration of hypoxia. In the present report, we herein describe a PLCH patient with severe PH in whom sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, substantially improved the pulmonary hemodynamics before lung transplantation. An immunohistochemical study of the resected lung revealed positive staining for PDE5 on the diseased pulmonary arteries. These observations suggest that sildenafil can be a promising therapeutic option for PH in patients with PLCH.

The present study examined whether tricuspid annular plane systolic excursion (TAPSE) can simply predict right ventricular ejection fraction (RVEF) in patients with pulmonary hypertension (PH). The TAPSE cut-off value to predict reduced RVEF was also evaluated. The association between TAPSE and cardiac magnetic resonance imaging (CMRI)-derived RVEF was examined in 53 PH patients. The accuracy of the prediction equation to calculate RVEF using TAPSE was also evaluated. In PH patients, TAPSE was strongly correlated with CMRI-derived RVEF in PH patients (r = 0.86, p < 0.0001). We then examined the accuracy of the two equations: the original regression equation (RVEF = 2.01 × TAPSE + 0.6) and the simplified prediction equation (RVEF = 2 × TAPSE). Bland-Altman plot showed that the mean difference ± limits of agreement was 0.0 ± 10.6 for the original equation and -0.6 ± 10.6 for the simplified equation. Intraclass correlation coefficient was 0.84 for the original and 0.82 for the simplified equation. Normal RVEF was considered to be ≥40% based on the data from 53 matched controls, and the best TAPSE cut-off value to determine reduced RVEF (<40%) was calculated to be 19.7 mm (sensitivity 88.9%, specificity 84.6%). A simple equation of RVEF = 2 × TAPSE enables easy prediction of RVEF using TAPSE, an easily measurable M-mode index of echocardiography. TAPSE of 19.7 mm predicts reduced RVEF in PH patients with clinically acceptable sensitivity and specificity.

Background: Few studies have focused on right atrial (RA) structure and function in pulmonary hypertension (PH). We sought to evaluate RA volume and phasic function using cardiac magnetic resonance (CMR), and to examine their clinical relevance in PH., Methods: We prospectively studied 50 PH patients and 21 control subjects. RA volume and indices of phasic function (reservoir volume, ejection fraction [EF], and conduit volume) were evaluated by CMR., Results: Maximum RA volume index was significantly higher in PH patients (56 [44-70] ml/m(2)) than in controls (40 [30-48] ml/m(2)) (p<0.001). Reservoir volume index was significantly lower in PH than in controls (p<0.001), but conduit volume index was higher in PH than in controls (p=0.008). RA EF was similar when comparing the two groups (p=0.925). Interestingly, RA EF was increased in PH patients with WHO functional class III patients as compared with controls (p<0.001) but was reduced in advanced PH patients with WHO functional class IV (p<0.01). Maximum RA volume and RA EF significantly correlated with pulmonary hemodynamic indices, atrial and brain natriuretic hormone levels, and CMR-derived right ventricular indices. By contrast, RA reservoir volume correlated with cardiac index and 6-minute walk distance., Conclusions: PH is associated with increased size, decreased reservoir function, and increased conduit function of the right atrium. RA systolic function indicated by RA EF increases in patients with mild to moderate PH but decreases in patients with advanced PH. Varying associations between RA indices and conventional PH indices suggest their unique role in the management of PH., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: This study investigated the major clinical determinants of late gadolinium enhancement (LGE) at ventricular insertion points (VIPs) commonly seen in patients with pulmonary hypertension (PH)., Methods: Forty-six consecutive PH patients (mean pulmonary artery pressure ≥25 mmHg at rest) and 21 matched controls were examined. Right ventricular (RV) morphology, function and LGE mass volume at VIPs were assessed by cardiac magnetic resonance (CMR). Radial motion of the left ventricular (LV) wall and interventricular septum (IVS) was assessed by speckle-tracking echocardiography. Paradoxical IVS motion index was then calculated. Univariate and multivariate regression analysis were conducted to characterize the relationship between LGE volume at VIPs and PH-related clinical indices, including the paradoxical IVS motion index., Results: Mean pulmonary arterial pressure (MPAP) of PH patients was 38±9 mmHg. LGE at VIPs was observed in 42 of 46 PH patients, and the LGE volume was 2.02 mL (0.47-2.99 mL). Significant correlations with LGE volume at VIPs were observed for MPAP (r = 0.50) and CMR-derived parameters [RV mass index (r = 0.53), RV end-diastolic volume index (r = 0.53), RV ejection fraction (r = -0.56), and paradoxical IVS motion index (r = 0.77)]. In multiple regression analysis, paradoxical IVS motion index alone significantly predicted LGE volume at VIPs (p<0.001)., Conclusions: LGE at VIPs seen in patients with PH appears to reflect altered IVS motion rather than elevated RV pressure or remodeling. Long-term studies would be of benefit to characterize the clinical relevance of LGE at VIPs.

The aim of this study was to explore whether the regional peak longitudinal (LS) and circumferential strains (CS) at the right ventricular (RV) free wall could be used to identify global RV dysfunction in relation to RV ejection fraction (RVEF) and plasma concentration of brain natriuretic peptide (BNP) in pulmonary hypertension (PH). A total of 37 consecutive patients diagnosed with PH and 13 healthy control subjects were included. Fast strain encoded and routine cine MRI was performed. The LS and CS at three RV levels were quantified and their relations with RVEF and BNP were investigated. Receiver operating characteristic (ROC) analysis was employed to assess the diagnostic utility of strain encoded MRI for the detection of low RVEF. Significant correlations with LS were observed for RVEF and BNP. Compared to CS, LS showed better correlation with RVEF. The mid-ventricular level of RV was the most sensitive site for evaluation of RV dysfunction. According to our ROC analysis, LS showed higher sensitivity and specificity to detect low RVEF. Compared to CS, LS showed stronger correlations with RVEF and BNP and could be a good detector of RV dysfunction in PH.

Background: The accuracy of echocardiographic parameters of right ventricular (RV) function has not been sufficiently validated in patients with pulmonary hypertension (PH). The aim of this study was to evaluate whether echocardiographic measurements reliably reflect RV systolic function in PH using cardiac magnetic resonance imaging (CMRI)-derived RV ejection fraction (RVEF) as a gold standard., Methods: A total of 37 consecutive patients with PH, 20 with pulmonary arterial hypertension, 12 with chronic thromboembolic PH, and five others, were prospectively studied. All patients underwent echocardiography, CMRI, and right-heart catheterization within a 1-week interval. Associations between five echocardiography-derived parameters of RV systolic function and CMRI-derived RVEF were evaluated., Results: All five echocardiography-derived parameters were significantly correlated with CMRI-derived RVEF (percentage RV fractional shortening: r = 0.48, P = .0011; percentage RV area change: r = 0.40, P = .0083; tricuspid annular plane systolic excursion [TAPSE]: r = 0.86, P < .0001; RV myocardial performance index: r = -0.59, P < .0001; and systolic lateral tricuspid annular motion velocity: r = 0.63, P < .0001). Compared with the other indices, TAPSE exhibited the highest correlation coefficient. Of the five echocardiographic measurements, only TAPSE significantly predicted CMRI-derived RVEF in multiple regression analysis (P < .0001). Intraobserver and interobserver reproducibility was favorable for all five indices and was particularly high for TAPSE and systolic lateral tricuspid annular motion velocity., Conclusions: Echocardiographic measurements are promising noninvasive indices of RV systolic function in patients with PH. In particular, TAPSE is superior to other indices in accuracy., (Copyright © 2012 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a life-threatening complication in connective tissue diseases (CTD). It remains controversial whether immunosuppressive therapy is useful for PAH associated with CTD (PAH-CTD). The Dana Point algorithm does not refer such treatments in patients with PAH-CTD due to the lack of evidence. However, some case reports have shown the potential efficacy of immunosuppression for PAH-CTD. Here we report five cases of PAH-CTD treated with corticosteroids and discuss the current management of PAH-CTD with immunosuppressive agents. Our cases consisted of three active systemic lupus erythematosus (SLE), a quiescent SLE and an active polymyositis. WHO functional classes at baseline were class III in three cases and class II in two. Median follow-up period was 44 (28-92) weeks. PAH was diagnosed by right heart catheterization in all cases (median pulmonary arterial pressure was 45 (29-49) mmHg). All patients received 1 mg/kg of prednisolone (PSL) for 2-4 weeks, followed by appropriate dose reduction. Methylprednisolone pulse therapy was performed in patients resistant to the high dosage of PSL. Four patients received vasodilators in combination. The therapy as above improved WHO functional class 4 weeks after the initiation of PSL in all the patients. Two patients required dose increase or additional administration of vasodilators due to the dose reduction of PSL. Corticosteroid therapy may be effective for PAH-CTD at least in the short term, even in low general activity of CTD or moderate PAH. Our experience suggests that corticosteroid therapy, by itself or in conjunction with standard vasodilators, is effective for PAH-CTD patients.

A 45-year-old man, who had been diagnosed with primary pulmonary hypertension (PPH) 8 years before, was referred to our hospital because of short breath and lower-limb edema. Findings of chest X-ray, electrocardiogram, and cardiac ultrasound showed right atrial and ventricular dilatation/hypertrophy that were compatible with advanced PPH. Chest enhanced computed tomography (CT), however, unexpectedly showed that contrast in the main pulmonary artery was diluted by blood flow from the descending aorta. On electrocardiography-synchronized CT, the arterial duct connecting the main pulmonary artery and descending aorta was clearly delineated. As a result, the long-standing diagnosis of PPH was corrected to secondary pulmonary arterial hypertension caused by patent ductus arteriosus, thanks to the "reverse" enhancement on CT.

Background: Oral prostacyclin analogs can improve the prognosis of patients with mild to moderate pulmonary arterial hypertension (PAH), but because they often provoke adverse effects, such as flushing and dizziness, administering the optimal dose can be difficult., Methods and Results: In the present study, a novel long-acting oral beraprost (TRK-100STP: 0-360 mug/day for 12 weeks) was administered to 4 patients with mild to moderate PAH. The patients tolerated the drug well with mild adverse manifestations and negligible effects on the systemic circulation. In contrast, pulmonary vascular resistance decreased by 27+/-12% and the 6-min walk test distance increased by 11+/-11%., Conclusions: TRK-100STP is a novel option in the medical management of patients with PAH.

The patient investigated was a 43-year-old woman with primary pulmonary hypertension (PPH) and refractory protein-losing enteropathy (PLE). She underwent living-donor lobar lung transplantation (LDLLT), which led to remarkable improvement in both pulmonary hypertension and PLE. Although there have been no reports, to our knowledge, that have demonstrated PLE as a complication of PPH, the present case clearly shows how PLE could complicate PPH. In addition, and more importantly, hypo-proteinemia due to PLE should not necessarily be an exclusion criterion for lung transplantation when PPH is involved, because it could markedly improve after transplantation.

Although sildenafil, an oral phosphodiesterase type-5 inhibitor, may offer benefits in the pharmacological management of pulmonary hypertension (PH), safety and effectiveness have not been studied during coadministration with beraprost, an oral prostacyclin analogue. To address this issue, we administered oral beraprost (40 microg) on day 1 and beraprost (40 microg) plus sildenafil (25 mg) on days 2 to 6 patients with moderate to severe PH. Although sildenafil plus beraprost produced transient flushing in 2 of 6 patients, systemic hemodynamics and arterial and venous gas analyses were similar in comparisons between the 2 treatment groups. In contrast, sildenafil plus beraprost therapy resulted in a 2.2-fold greater reduction in mean pulmonary arterial pressure and a 1.6-fold greater reduction in pulmonary vascular resistance compared with beraprost alone, and reductions in these parameters persisted longer with combination therapy than with beraprost alone. Addition of oral sildenafil to beraprost appears to represent a safe and effective therapeutic option, at least in the acute phase, for patients with pulmonary hypertension.