田邉 信宏

Heritable pulmonary arterial hypertension (HPAH) is a type of familial pulmonary arterial hypertension, while pulmonary arteriovenous malformations (PAVMs) are abnormal communications between pulmonary arteries and veins that occur frequently in patients with hereditary hemorrhagic telangiectasia (HHT). A 21-year-old woman on continuing medication for HPAH was hospitalized. She had been diagnosed with HPAH at age 4 years and had been receiving epoprostenol infusion from age of 9 years. Although lung perfusion scintigraphy showed a shunt fraction of 18.9% at age of 19 years, the cause of the shunt was unclear. At the time of the present hospitalization, enhanced computed tomography (CT) of the chest and four-dimensional reconstructed images revealed multiple abnormal communications between the peripheral pulmonary arteries and veins. Furthermore, right heart catheterization revealed an elevated mean pulmonary arterial pressure. Wedged angiography of the pulmonary artery of the right lower lobe revealed several PAVMs. Multiple PAVMs and suspected HHT with HPAH was diagnosed. The possibility of PAVMs should be considered even in patients with HPAH. Moreover, evaluation of the shunt fraction by lung perfusion scintigraphy and morphological examination of PAVM by contrast-enhanced CT may facilitate PAVM detection in patients with HPAH.

This study investigated whether dilated bronchial arteries are associated with reperfusion pulmonary edema in patients with chronic thromboembolic pulmonary hypertension. Results showed that the extent of enlarged bronchial arteries was not associated with the development of reperfusion pulmonary edema, whereas the residual pulmonary hypertension had a significant association.

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/cm5, whereas that in the placebo group was 26±180 dyn·s/cm5. Thus, the treatment effect after 17 weeks of selexipag treatment was calculated as -130±189 dyn·s/cm5(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]).

症例は44歳,男性。6年前にアルコール性大腿骨頭壊死のため両側人工股関節置換術の既往あり。4ヵ月前より両側股関節痛および39℃台の弛張熱が出現し,人工股関節部の不安定性が原因と考えられ,人工股関節再置換術の方針となった。術前の胸部X線にて肺野異常陰影を指摘され,胸部CT検査にて肺野びまん性粒状影および左胸水を呈し,喀痰,尿,胸水のTb-CPRが陽性であったことから,肺結核,粟粒結核,結核性胸膜炎と診断された。イソニアジド,リファンビシン,エタンブトール,ピラジナミドによる抗菌化学療法を開始されたが,発熱,股関節痛および血液炎症所見が持続した。造影CT検査にて両側人工股関節感染および右腸腰筋膿瘍が疑われ,右人工股関節置換術を施行された。その後,複数回の洗浄,デブリードマンおよび左人工股関節置換術による外科的加療の追加にて,解熱傾向となり,股関節痛,血液炎症所見および胸部画像所見が改善した。粟粒結核を呈し,抗菌化学療法に治療抵抗性の場合には,全身性に播種性結核病巣が存在する可能性を念頭に精査し,外科的加療などの集学的加療を積極的に検討する必要がある。(著者抄録)

Previous nationwide Japanese data suggested that pulmonary arterial hypertension (PAH) predominantly affects young women. However, the number of elderly patients diagnosed with PAH has been increasing in western countries. There have been no reports on elderly PAH patients in Asian countries. This study aimed to investigate the clinical characteristics of elderly PAH patients in a Japanese cohort. Idiopathic/heritable PAH (I/H-PAH) was included in the national research project on intractable diseases. The patients were required to submit a clinical research form completed by their attending physicians. We analyzed the characteristics of Japanese I/H-PAH using the newly registered forms in 2013 (Study 1, n = 148). Also, we did a retrospective, observational cohort study at Chiba University Hospital (Study 2, n = 42). We compared the characteristics of elderly PAH patients (≥65 years old) with younger patients (<65) in both studies. Study 1 revealed a predominance of males (51% male), better hemodynamics and poorer exercise capacity in the elderly group (n = 72), compared with the younger group (n = 76) in study 1. In Study 2, elderly patients showed a male predominance (63% male), a higher ratio of smokers, a lower % carbon monoxide diffusing capacity, and poorer exercise tolerance. Elderly patients in Study 2 showed less improvement in hemodynamics with therapy. There was no significant difference in disease-specific survival between elderly and younger patients. Japanese elderly patients with I/H-PAH showed poorer exercise capacity and impaired gas exchange, but better pulmonary hemodynamics than younger patients.

The pathogenesis of pulmonary arterial hypertension is closely associated with dysregulated inflammation. Recently, abnormal alterations in gut microbiome composition and function were reported in a pulmonary arterial hypertension experimental animal model. However, it remains unclear whether these alterations are a result or the cause of pulmonary arterial hypertension. The purpose of this study was to investigate whether alterations in the gut microbiome affected the hemodynamics in SU5416/hypoxia rats. We used the SU5416/hypoxia rat model in our study. SU5416/hypoxia rats were treated with a single SU5416 injection (30 mg/kg) and a three-week hypoxia exposure (10% O₂). Three SU5416/hypoxia rats were treated with a combination of four antibiotics (SU5416/hypoxia + ABx group) for four weeks. Another group was exposed to hypoxia (10% O₂) without the SU5416 treatment, and control rats received no treatment. Fecal samples were collected from each animal, and the gut microbiota composition was analyzed by 16S rRNA sequencing. The antibiotic treatment significantly suppressed the vascular remodeling, right ventricular hypertrophy, and increase in the right ventricular systolic pressure in SU5416/hypoxia rats. 16S rRNA sequencing analysis revealed gut microbiota modification in SU5416/hypoxia + ABx group. The Firmicutes-to-Bacteroidetes ratio in SU5416/hypoxia rats was significantly higher than that in control and hypoxia rats. Compared with the control microbiota, 14 bacterial genera, including Bacteroides and Akkermansia, increased, whereas seven bacteria, including Rothia and Prevotellaceae, decreased in abundance in SU5416/hypoxia rats. Antibiotic-induced modification of the gut microbiota suppresses the development of pulmonary arterial hypertension. Dysbiosis may play a causal role in the development and progression of pulmonary arterial hypertension.

This multicenter, prospective, non-interventional study (ClinicalTrials.gov: NCT02117791) evaluated the safety and effectiveness of riociguat for chronic thromboembolic pulmonary hypertension in Japanese clinical practice, registering all patients with chronic thromboembolic pulmonary hypertension treated with riociguat following its launch in Japan in April 2014. Safety was assessed by analyzing the adverse drug reactions. Effectiveness measurements included the assessment of change in World Health Organization functional class, six-minute walk test, and hemodynamics. Overall, 1031 patients were included in the safety analysis with 811 (78.7%) patients in World Health Organization functional class II/III. The mean treatment duration was 591.4 days (median 441.0 days). Adverse drug reactions were reported in 19.5% of patients, the most common being hypotension (5.9%), headache (3.0%), dizziness (1.9%), and gastroesophageal reflux disease (1.5%). Serious adverse drug reactions were reported in 2.1% of patients. Estimated survival was 97.0% at one year, 95.8% at two years, and 94.4% at three years. The effectiveness analysis ( n = 1027) showed significant increases from baseline in six-minute walking distance, and significant reductions from baseline in mean pulmonary arterial pressure and pulmonary vascular resistance. These interim results of riociguat in Japanese patients with chronic thromboembolic pulmonary hypertension demonstrated a safety profile that was generally consistent with those of pivotal clinical studies. The study is ongoing, and will continue to provide insights into the safety and effectiveness of riociguat in real-world practice.

Objective: Macitentan, a novel dual endothelin receptor antagonist, was approved for the treatment of pulmonary arterial hypertension (PAH) in Japan. However, long-term effects in Japanese patients of macitentan are currently unavailable. This study sought to assess the long-term efficacy and safety of macitentan in Japanese patients with PAH.Methods: In this multicenter, open-label, clinical extension study (JapicCTI-121986), efficacy was evaluated based on the change from baseline at 24, 48, 72, 96 and 120-week in the 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. In addition, the time to a hospitalization related to PAH and a morbidity/mortality event was determined. As for safety, the incidence of adverse events and changes in laboratory data and vital signs were assessed.Results: Macitentan was administered at a once-daily dose of 10 mg in 30 PAH patients with a median treatment period of 2.4 years (range, 229-1037 days). The improvements in 6MWD, WHO functional class and NT-pro-BNP at week 24 were maintained throughout the long-term follow-up. Hospitalization related to PAH occurred in 2 patients. Levels of liver enzyme and hemoglobin remained unchanged throughout the study period.Conclusions: This study suggests that the long-term use of macitentan is well tolerated and effective in Japanese patients with PAH. We concluded that macitentan can be a possible approach to reduce morbidity/mortality in Japanese PAH patients.

While the prognosis of idiopathic pulmonary arterial hypertension has improved significantly due to newer medications, lung transplantation remains a critical therapeutic option for severe pulmonary arterial hypertension. Hence, it is essential for patients awaiting lung transplantation to avoid complications, including thrombocytopenia, which may affect their surgical outcomes. Herein we present the case of a 21-year-old woman diagnosed with idiopathic pulmonary arterial hypertension at the age of 15. She developed thrombocytopenia while awaiting lung transplantation. Her medication was switched from epoprostenol to treprostinil, suspecting possible drug-induced thrombocytopenia. Furthermore, she was administered thrombopoietin receptor agonists in view of the possibility of idiopathic thrombocytopenic purpura, along with maximum support for right heart failure. Subsequently, her platelet count increased to >70,000/µL, enabling her to successfully undergo bilateral lung transplantation. Post-bilateral lung transplantation, pulmonary arterial hypertension as well as thrombocytopenia appeared to have resolved. In this case, we suspected that thrombocytopenia could have resulted owing to a combination of pulmonary arterial hypertension, right heart failure, drug interactions, and idiopathic thrombocytopenic purpura. Thrombocytopenia is a very critical condition in patients with pulmonary arterial hypertension, especially those awaiting lung transplantation. Several approaches are known to improve intractable thrombocytopenia in patients with pulmonary arterial hypertension.

The interventricular septum curvature, measured in images of electrocardiogram-gated 320-slice multidetector computed tomography, is reportedly useful and less invasive than right heart catheterization, as it could provide clues regarding pulmonary arterial pressure in patients with chronic thromboembolic pulmonary hypertension. Although pulmonary endarterectomy is an efficient treatment for chronic thromboembolic pulmonary hypertension, the interventricular septum curvature in patients who have received pulmonary endarterectomy has not been evaluated. We evaluated whether the interventricular septum curvature on electrocardiogram-gated 320-slice multidetector computed tomography can predict pulmonary hemodynamics in chronic thromboembolic pulmonary hypertension even after pulmonary endarterectomy. We studied 40 patients with chronic thromboembolic pulmonary hypertension (60.5 ± 9.7 years; 30 females), who underwent pulmonary endarterectomy at Chiba University Hospital between December 2010 and July 2018. To measure the interventricular septum curvature, we prepared left ventricular short-axis tomographic images from 4D images of electrocardiogram-gated 320-slice multidetector computed tomography. We calculated the radius of interventricular septum and determined the interventricular septum curvature in both the systolic and diastolic phases. We compared the interventricular septum curvature with pulmonary hemodynamics measured by right heart catheterization before and after pulmonary endarterectomy. After pulmonary endarterectomy, the correlations of the interventricular septum curvature with mean pulmonary arterial pressure, systolic pulmonary arterial pressure, and pulmonary vascular resistance disappeared, although the interventricular septum curvature was correlated with these pulmonary hemodynamic parameters before pulmonary endarterectomy. Changes in systolic interventricular septum curvature revealed significant correlations with changes in mean pulmonary arterial pressure, systolic pulmonary arterial pressure and pulmonary vascular resistance. Diastolic interventricular septum curvature also showed significant correlations with preoperative pulmonary hemodynamics, but not with postoperative pulmonary hemodynamics. Changes in the interventricular septum curvature after pulmonary endarterectomy could estimate the efficacy of pulmonary endarterectomy, although the interventricular septum curvature after pulmonary endarterectomy showed no significant correlations with pulmonary hemodynamics. Additionally, our findings confirmed that the interventricular septum curvature before pulmonary endarterectomy could be used to evaluate the severity of disease.

BACKGROUND AND OBJECTIVE: The optimal oxygen supplementation needed to avoid tissue hypoxia in patients with pulmonary hypertension (PH) remains unclear. This study aimed to identify the arterial oxygen tension (PaO2 ) level needed to avoid tissue hypoxia which results in a poor prognosis in patients with PH. METHODS: We retrospectively analysed the data for 1571 right heart catheterizations in patients suspected of having PH between 1983 and 2017 at our institution. Examinations were classified according to mean pulmonary arterial pressure (mPAP), cardiac index (CI) and the presence of lung disease, pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH). The PaO2 levels needed to avoid tissue hypoxia were compared in each subgroup. RESULTS: The estimated PaO2 equivalent to a mixed venous oxygen tension (PvO2 ) of 35 mm Hg (tissue hypoxia) was 63.2 mm Hg in all patients, 77.0 mm Hg in those with decreased CI (<2.5 L/min/m2 ) and 57.0 mm Hg in those with preserved CI. Multivariate regression analysis identified mPAP, CI and PaO2 to be independent predictors of extremely low PvO2 . Similar results were observed regardless of the severity of PH or the presence of lung disease, PAH or CTEPH. The PaO2 level needed to avoid tissue hypoxia was higher in patients with mild PH and decreased CI than in those with severe PH and preserved CI (70.2 vs 61.5 mm Hg). CONCLUSION: These findings indicate that a decreased CI rather than increased mPAP induces tissue hypoxia in PH. Patients with PH and decreased CI may need adjustment of oxygen therapy at higher PaO2 levels compared with patients with preserved CI.

Background: The incidence of thromboembolism in patients with cancer is approximately 11%, and the risk of thrombosis in patients with malignant tumors is 6-fold higher than that in healthy persons. Thrombosis not only disrupts the treatment of cancer but also induces deterioration of quality of life (QOL). Knowledge about thrombus treatment is limited, and evidence is scarce. Clarification of the status and safety of venous thromboembolism (VTE) treatment in patients with cancer will contribute to active intervention and improvement of prognosis and QOL. In this study, the therapeutic effects of a non-vitamin K antagonist oral anticoagulant for VTE and the prognosis of cancer after treatment will be examined to establish a therapeutic method for VTE in patients with cancer. Methods and Results: A multicenter, non-interventional, observational study will be conducted in patients with cancer who developed VTE and underwent anticoagulant therapy with rivaroxaban (group A) or warfarin (group B) for 24 weeks. The primary endpoint will be the recurrence/aggravation of symptomatic VTE or occurrence/aggravation of deep vein thrombosis. Registration of 500 patients is needed in order to calculate the 95% confidence interval of the event rate at ±1% precision. Conclusions: The investigation period will run from January 2019 to December 2023 with ongoing selection of patients. Trial registration: no. 5-18-32 (approved 1 August 2018).

Pulmonary capillary hemangiomatosis (PCH) is a very rare and refractory disease characterized by capillary angioproliferation. The updated classification of pulmonary hypertension categorizes PCH into a subgroup of pulmonary arterial hypertension (PAH) alongside pulmonary veno-occlusive disease (PVOD). However, the definitive diagnosis of PCH only with noninvasive tools remains difficult. The aim of this study was to elucidate the radiological and physiological characteristics of PCH. We searched for cases of pathologically confirmed PCH in the English literature published between 2000 and 2018. We identified 26 cases among 39 studies. Then, we extracted and evaluated the relevant clinical information in all cases with available data. On chest computed tomography (CT), ground-glass opacities (GGOs) were observed in 92% of the cases, in which poorly defined nodular pattern was the most common (88%). GGOs in a bat-wing distribution were observed in one case. Septal lines and lymph node enlargement were observed less frequently (each 19%, 12%). Seven cases (27%) had overlapping abnormalities. Diffusing capacity of the lung for carbon monoxide (DLCO) was remarkably decreased. Alveolar hemorrhage by histological findings or bronchoalveolar lavage (BAL) was observed in seven cases. The present study showed that the most characteristic findings of CT in PCH was centrilobular GGOs with a poorly defined nodular pattern, and septal lines and lymph node enlargement were seen less frequently. Alveolar hemorrhage detected by BAL and decreased DLCO may also be helpful to recognize the possibility of PCH like PVOD.

Hepatopulmonary syndrome (HPS) and pulmonary arteriovenous malformation (PAVM) are hypoxemic diseases caused by right-to-left shunting but are rarely concomitant with pulmonary hypertension (PH). A 66-year-old woman with chronic hepatitis C was scheduled to undergo liver transplantation. She was referred to our department for hypoxia and an abnormal shadow in the right lung found on a preoperative examination. She was diagnosed with HPS and a PAVM in the right middle lobe. After liver transplantation, PH temporarily developed, but the pulmonary arterial pressure normalized after coil embolization. Combined HPS and PAVM may cause unique changes in pulmonary hemodynamics during treatment.

Background: The presence of pulmonary hypertension (PH) and treatment with anticoagulant agents could potentially increase the risk for bleeding/hemodynamic complications associated with bronchoscopic procedures. The aim of this study was to assess the safety of diagnostic flexible bronchoscopy (FB) in patients with PH.Methods: A retrospective review of clinical records of patients with echocardiographic evidence of PH (right ventricular systolic pressure [RVSP] > 40 mm Hg) who underwent diagnostic FB between 2004 and 2016 at a single facility in Japan was conducted. Patients with no clinical evidence suggestive of PH who underwent FB during the same period were enrolled as a pairwise-matched control group; factors used in matching included age, sex, and performed procedures.Results: Overall, there were 45 patients in the PH group and 90 patients in the control group. Six (13%) patients in the PH group had severe PH (RVSP > 61 mm Hg). Forceps biopsies and transbronchial needle aspirations were performed in 62% and 13% of patients, respectively, in the PH group, and 58% and 13% of patients, respectively, in the control group. The total incidence of bleeding during FB was not significantly different between the two groups (18% versus 16%; p = 0.742). Vital signs recorded 2 h after FB were also not significantly different between the two groups. There were no episodes of cardiac arrhythmias or deaths associated with the FB procedures.Conclusions: The data suggest that diagnostic FB procedures can be performed safely in patients with echocardiographic evidence of PH. (C) 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

While circulating autoantibodies have been detected in patients with several cardiovascular diseases, such studies have not been performed for chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Here we investigated the production of certain auto-antibodies in CTEPH patients. Initial screening was performed in 5 CTEPH patients and 5 healthy donors (HDs) using a ProtoArray Human Protein Microarray v5.1 containing 9,375 human proteins, and we selected 34 antigens recognized by IgG antibodies more strongly in the sera of CTEPH patients than in the sera of HDs. In subsequent second/third analyses, we validated the auto-antibody level using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) in 96 CTEPH patients and 96 HDs as follows: At the second screening, we used 63 crude peptides derived from those selected 34 antigens and found that the serum levels of autoantibodies for 4 peptides seemed higher in CTEPH patients than in HDs. In third analysis, we used the purified peptides of those selected in second screening and found that serum antibodies against peptides derived from exonuclease 3'-5' domain-containing 2 (EXD2) and phosphorylated adaptor for RNA export (PHAX) were significantly higher in CTEPH patients than in HDs. The serum antibody levels to these antigens were also elevated in PAH patients. The titers against EXD2 peptide decreased after surgical treatment in CTEPH patients. These autoantibodies may be useful as biomarkers of CTEPH and PAH, and further investigations may provide novel insight into the etiology.

BACKGROUND Cytomegalovirus (CMV) pneumonia is common in immunocompromised patients with hematological malignancies. Although the spectrum of illness caused by CMV is well-documented in immunocompromised patients, the clinical course and evolution of lung changes after initiation of antiviral therapy remain unclear. CASE REPORT We present the cases of 3 patients with leukemia who developed CMV pneumonia following cord blood transplantation and who presented with distinctive features on chest computed tomography (CT). In all patients, chest CT showed central peribronchial changes with severe lung volume loss. Furthermore, the patients were refractory to high-dose steroids, and the lung volume loss rapidly progressed, leading to death from respiratory failure. CONCLUSIONS We observed central peribronchial changes with severe lung volume loss after the acute phase in 3 cases of CMV pneumonia. While our diagnosis was made on the basis of exclusion, it is important to bear in mind that lung involvement in CMV pneumonia may be refractory to various treatment modalities and can lead to a fatal clinical course.

Progressive fibrobullous changes in the residual lobes are sometimes observed after lobectomy. Aspergillus osteomyelitis is an uncommon infection that rarely occurs sternally. A 70-year-old man who had undergone lobectomy 12 years earlier was admitted to our hospital for chest pain. He was diagnosed with Aspergillus sternomyelitis based on sternal bone culture after an ultrasound-guided percutaneous needle biopsy. The fibrosis and right residual lung apex volume loss had gradually progressed over 12 years, and therefore, chronic pulmonary aspergillosis (CPA) with direct invasion sternal from the CPA was considered. Aspergillus sternomyelitis can develop from CPA as a late complication of lobectomy.