Search

Mean pulmonary arterial pressure (mPAP) has not been recognized as a therapeutic target for pulmonary arterial hypertension (PAH). However, previous reports demonstrated that the survival of patients with some types of pulmonary hypertension was associated with mPAP. Therefore, we treated all subsets of PAH patients with the aim of lowering mPAP and evaluated the efficacy of the treatment algorithm.From September 2014 to August 2019, 43 consecutive patients with PAH on treatment3 months on referral were enrolled in this study. They were treated according to our treatment algorithm mainly based on World Health Organization functional class, mPAP, and percent predicted diffusing capacity of the lung for carbon monoxide. The therapeutic goal was the achievement of mPAP40 mmHg at follow-up. We evaluated clinical parameters, survival rate, and its determinants. Survival analyses were conducted using the Kaplan-Meier method and the relationship between all-cause death and selected variables was analyzed using the Cox proportional hazards model for mortality.mPAP significantly improved at the last follow-up [45 (35-55) mmHg to 24 (19-30) mmHg, p 0.05], and the therapeutic goal was achieved in 37 patients (86%). The 5-year survival rate of all patients was 90.7%. The survival rate of patients who achieved the therapeutic goal (3- and 5-year survival: 97.3%) was significantly better than that of the patients who did not achieve the therapeutic goal (3-year survival: 50.0%, p 0.05). The 5-year survival rates of the patients were the same among different treatment regimens (p = 0.985). mPAP40 mmHg at follow-up was the independent predictor of survival.Lowering mPAP resulted in favorable outcomes in all subsets of PAH patients, making it a therapeutic goal.

Balloon pulmonary angioplasty (BPA) is now a treatment option for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, the incidence of restenosis and long-term changes in vessel diameters in pulmonary arteries after BPA are unknown. The present study investigated the incidence of restenosis by measuring changes in vessel diameter after BPA. We reviewed 58 patients (168 lesions) with CTEPH who underwent single dilation for the target lesion (type A/B/C lesions) during BPA procedure followed by selective pulmonary angiography more than 6 months after the final BPA procedure. The outcomes of BPA were assessed in terms of pulmonary artery diameters. In a median follow-up of 1.9 (1.2-2.7) years, restenosis occurred in only one case with a type C lesion after BPA (0.6%). In type A/B lesions, the minimal lumen diameter was significantly enlarged at follow-up after BPA [3.48 (2.59-4.34) to 4.22 (3.31-4.90) mm]. In type C lesions, the minimal lumen diameter was unchanged at follow-up after BPA [3.15 (1.96-3.64) to 3.28 (2.38-4.61) mm]. The present results revealed that restenosis after BPA rarely occurs in type A/B/C lesions. Minimal lumen diameters for type A/B lesions continually increased and those for type C lesions did not decrease. Stent implantation in type A/B/C lesions would be unnecessary after BPA.

Pulmonary injury is a major complication of balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH). Lung injury after BPA can be exacerbated by a high mean pulmonary arterial pressure (PAP). Although oxygen inhalation is expected to lower mean PAP in patients with CTEPH, no relevant investigation has been conducted.Consecutive patients with CTEPH who underwent BPA were enrolled in this study. We evaluated the hemodynamics using right heart catheterization while breathing ambient air and with administration of 5 L/min oxygen for 10 min.This study included 52 consecutive patients with CTEPH, of whom 23 (44%) were treated with specific pulmonary vasodilators. Exposure to oxygen was well tolerated. Oxygen administration significantly decreased mean PAP by 3.8 ± 3.2 mmHg (p0.001) and pulmonary vascular resistance by 0.8 ± 1.8 Wood units (p0.001). Moreover, the ratio of pulmonary vascular resistance to systemic vascular resistance was significantly reduced by 13.5% (p0.001). Multivariate regression analysis identified baseline mean PAP (β = -0.427, p = 0.006) as the only significant predictor of decreased mean PAP under oxygen administration. No significant difference in oxygen effect on mean PAP was found between patients with and without vasodilators.In patients with CTEPH, 5 L/min supplemental oxygen inhalation could decrease mean PAP significantly by selective pulmonary artery dilatation, regardless of the usage of vasodilators, and thus could be helpful to maximize the safety of BPA.UMIN Clinical Trials Registry (No.: UMIN000026882); URL: https://www.umin.ac.jp/ctr/index.htm.

Lung injury is a serious complication of balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH). Selecting a smaller balloon might minimize the occurrence of lung injury; however, it could also increase the risk of restenosis.We analyzed the first target lesions in the initial BPA procedure in 34 consecutive patients with CTEPH. We measured proximal pressure with a guiding catheter and distal pressure with a pressure wire. We retrospectively investigated pressure gradients at the lesions before and immediately after the initial dilation with a smaller balloon and before the second procedure.The proximal pressure decreased, and the distal pressure increased immediately after the initial balloon dilation. The pressure gradient at the lesion diminished significantly by the second procedure (from 26.4 ± 10.7 to 18.2 ± 9.9 mm Hg, P0.001) without serious complications. The residual pressure gradient had further diminished (to 9.8 ± 6.5 mm Hg, P = 0.02) until the second procedure. The reduction in pressure gradient at the lesion from immediately after the initial balloon dilation to the second procedure was positively correlated with both the baseline mean pulmonary arterial pressure (rThe residual pressure gradient at the lesion diminished continually after dilation with a smaller balloon. This strategy could decrease pulmonary arterial pressure safely. It would be reasonable to dilate the lesions sequentially in 2 procedures.

Purpose of review Balloon pulmonary angioplasty (BPA) has been performed worldwide for patients who are ineligible for pulmonary endarterectomy (PEA). However, the technical details of BPA have not been standardized, and no international consensus regarding patient and lesion selection for BPA has been reached. Evidence for the combination of BPA with PEA or medical therapy is also lacking. This review highlights recent progress in BPA in terms of patient and lesion selection and the current procedural approach for BPA, including combination treatment. Recent findings The indications for BPA have expanded with recent reports describing the improved safety and efficacy of BPA. Because lesions are generally present in all segmental and subsegmental pulmonary arteries, it is recommended to treat all the lesions to achieve desirable hemodynamic improvement. Selective pulmonary angiography is the gold standard for lesion selection in modern BPA aimed at total revascularization. Despite the lack of randomized controlled studies, combination treatment with BPA may be well tolerated and effective. Summary BPA, alone or in combination with PEA or medical therapy, may be a treatment option for patients who are not candidates for monotreatment of PEA. However, further investigation is required to standardize patient and lesion selection for BPA.

Background Pulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH) therapy and balloon pulmonary angioplasty (BPA) are currently accepted therapies for chronic thromboembolic pulmonary hypertension (CTEPH). This international CTEPH Registry identifies clinical characteristics of patients, diagnostic algorithms and treatment decisions in a global context. Methods 1010 newly diagnosed consecutive patients were included in the registry between February 2015 and September 2016. Diagnosis was confirmed by right heart catheterisation, ventilation–perfusion lung scan, computerised pulmonary angiography and/or invasive pulmonary angiography after at least 3 months on anticoagulation. Results Overall, 649 patients (64.3%) were considered for PEA, 193 (19.1%) for BPA, 20 (2.0%) for both PEA and BPA, and 148 (14.7%) for PAH therapy only. Reasons for PEA inoperability were technical inaccessibility (n=235), comorbidities (n=63) and patient refusal (n=44). In Europe and America and other countries (AAO), 72% of patients were deemed suitable for PEA, whereas in Japan, 70% of patients were offered BPA as first choice. Sex was evenly balanced, except in Japan where 75% of patients were female. A history of acute pulmonary embolism was reported for 65.6% of patients. At least one PAH therapy was initiated in 35.8% of patients (26.2% of PEA candidates, 54.5% of BPA candidates and 54.1% of those not eligible for either PEA or BPA). At the time of analysis, 39 patients (3.9%) had died of pulmonary hypertension-related causes (3.5% after PEA and 1.8% after BPA). Conclusions The registry revealed noticeable differences in patient characteristics (rates of pulmonary embolism and sex) and therapeutic approaches in Japan compared with Europe and AAO., There are distinct regional differences in the management of CTEPH patients but globally, the proportion of patients managed by PEA remains stable, independently of the new established treatment options of PAH therapies and BPA https://bit.ly/3zEXxkv

Background Oral anticoagulants use has increased rapidly, internationally. Here we look at risks and benefits, based on Japanese data, of therapy with low risk non-valvular atrial fibrillation patients. Objectives Using a health insurance claims data set we assessed: (i) oral anticoagulants usage in Japan, and (ii) efficacy and safety of dabigatran compared with warfarin, in Japanese patients with non-valvular atrial fibrillation, aged 18–74 years. Methods We identified 4380 non-valvular atrial fibrillation patients treated with anticoagulants between 1 January 2005, and 28 February 2014, and estimated the adjusted hazard ratio for stroke or systemic embolism, and any hemorrhagic event (Cox proportional hazards regression model with stabilized inverse probability treatment weighting). Results The data included 101 989 anticoagulant prescriptions for 4380 patients, of which direct oral anticoagulants increased to 40.0% of the total by the end of the study. After applying exclusion criteria, 1536 new non-valvular atrial fibrillation patients were identified, including 1071 treated with warfarin and 465 with dabigatran. Mean ages were 56.11 ± 9.70 years for warfarin, and 55.80 ± 9.65 years for dabigatran. The adjusted hazard ratio (95% confidence interval), comparing dabigatran with warfarin, was 0.48 (0.25–0.91) for stroke or systemic embolism, and 0.91 (0.60–1.39) for any hemorrhage including intracranial and gastrointestinal. Conclusions Number of patients prescribed direct oral anticoagulants steadily increased, and incidence of all-cause bleeding related to dabigatran was similar to warfarin, in our study population of younger non-valvular atrial fibrillation patients. Dabigatran, compared with warfarin, generally reduced risk of all-cause stroke and systemic embolism.

Back ground: Ventilator-associated pneumonia (VAP) is a common nocosomial infection in intensive care unit (ICU). Local microbiological surveillance of pathogens and resistance patterns for early-onset VAP (EOVAP) and late-onset VAP (LOVAP) will help to choose appropriate empiric antibiotics. Objective: To compare the multi-drug resistant (MDR) pathogens, treatment outcomes, and factors associated with hospital mortality of VAP. Method: A cross-sectional study between 1 January 2015 and 31 December 2017 at Srinagarind hospital, Khon Kaen University was conducted. The demographic data, causative pathogens, hospital length of stay (LOS), ICU LOS, mechanical ventilator (MV) days, and hospital mortality were retrospectively reviewed. Results: One hundred and ninety patients were enrolled; 42 (22%) were EOVAP and 148 (78%) were LOVAP. Acinetobacter baummanii was the most common pathogen in both groups (50 % EOVAP vs 52.7% LOVAP). MDR pathogens were significant greater in LOVAP (81.8 %) than EOVAP (61.9%) (p = 0.007). The EOVAP had a significantly better ICU LOS (median 20.0 (11.0, 30.0) vs. 26.5 (17.0, 43.0) days), hospital LOS (median 26.5 (15.0, 44.0) vs. 35.5 (24.0, 56.0) days) shorter MV days (14.0 (10.0, 29.0) vs. 23.0 (14.0, 35.5) days) and lower hospital mortality (11.9 % VS 27.7%) than LOVAP ( p < 0.05). The factor associated with hospital mortality was having simplified acute physiology score (SAP) ≥ 40 with an adjusted odds ratio (aOR) of 2.22 (95%CI, 1.08-4.54, p = 0.02). Conclusion: LOVAP had significantly higher MDR pathogens, MV days, ICU LOS, hospital LOS and hospital mortality than EOVAP. A broad-spectrum antibiotic to cover MDR pathogens should be considered in LOVAP. The factor associated with hospital mortality of VAP was a SAPII score ≥ 40.

Pulmonary arterial hypertension (PAH)-specific combination therapy improves pulmonary haemodynamics at rest in patients with PAH; nevertheless, exertional dyspnoea remains. We investigated pulmonary haemodynamic response to exercise, and the relationship to ventilatory efficiency and hypoxaemia in patients with PAH treated with combination therapy. 32 clinically stable patients with PAH undergoing combination therapy underwent cardiopulmonary exercise testing with right heart catheterisation. Haemodynamic impairment was moderate to severe before treatment. However, after treatment it was significantly improved, and the mean pulmonary arterial pressure (mPAP) at rest was, Even after pulmonary haemodynamics at rest are improved in PAH patients with combination therapy, pulmonary haemodynamic response to exercise is abnormal, and related to abnormal respiratory response and the severity of hypoxaemia https://bit.ly/2HGS0TX

Thrombosis and coagulation abnormalities are thought to be involved in disease progression of pulmonary hypertension. Platelet-derived microparticles (PDMP) are released from platelets following stimulation and have recently been demonstrated to play an important role in pathogenesis of various diseases. This study aimed to evaluate PDMP levels in patients with pulmonary hypertension.Our cross-sectional study enrolled a total of 113 participants including 73 patients with pulmonary hypertension and 40 participants to serve as a control group. PDMP levels were measured using a PDMP ELISA kit, which detects glycoproteins CD42a and CD42b. Clinical parameters, including exercise capacity and hemodynamic parameters, were collected, and the relationship to PDMP levels were evaluated.PDMP levels were significantly higher in patients than in participants in the control group (23.2 ± 39.4 U/mL and 7.8 ± 3.6 U/mL, respectively, P 0.05). PDMP levels in patients with chronic thromboembolic pulmonary hypertension were correlated with right atrial pressure and cardiac index. PDMP levels were higher in male patients with idiopathic pulmonary arterial hypertension. Furthermore, patients administered a higher dose of epoprostenol had a tendency for lower PDMP levels.The data suggest that PDMP levels are increased in patients with pulmonary hypertension. Further study is needed to understand the mechanism and impact of PDMP on disease progression.

In pulmonary arterial hypertension (PAH), excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) causes vascular medial thickening. Medial thickening is a histopathological hallmark of pulmonary vascular remodeling, the central disease process driving PAH progression. Pulmonary vascular remodeling causes stenosis and/or obstruction of small pulmonary arteries. This leads to increased pulmonary vascular resistance, elevated pulmonary arterial pressure, and ultimately right heart failure. To improve the survival of PAH patients, which remains at approximately 60% at 3 years after diagnosis, the development of novel PAH-targeted drugs is desired. To this end, a detailed understanding of the mechanisms underlying excessive PASMC proliferation and the medial thickening that ensues is necessary. However, a lack of in vitro models that recapitulate medial thickening impedes our deeper understanding of the pathogenetic mechanisms involved. In the present study, we applied 3-dimensional (3D) cell culture technology to develop a novel in vitro model of the pulmonary artery medial layer using human PAH patient-derived PASMCs. The addition of platelet-derived growth factor (PDGF)-BB, a mitogen known to promote excessive PASMC proliferation in PAH, resulted in increased thickness of the 3D-PAH media tissues. Conversely, administration of the PDGF receptor inhibitor imatinib or other clinical PAH drugs inhibited this medial thickening-inducing effect of PDGF-BB. Altogether, by using 3D cell culture technology, we report the generation of an in vitro model of medial thickening in PAH, which had hitherto not been successfully modeled in vitro. This model is potentially useful for assessing the ability of candidate PAH drugs to suppress medial thickening.

Pulmonary arterial hypertension (PAH) is a progressive disease with increased pulmonary vascular resistance and pulmonary arterial pressure. Progress in research to develop PAH drugs over the past ...

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.

The right ventricle (RV) is more sensitive to an increase in afterload than the left ventricle (LV), and RV afterload during exercise increases more easily than LV afterload. Pulmonary arterial hypertension (PAH)-specific therapy has improved pulmonary hemodynamics at rest; however, the pulmonary hemodynamic response to exercise is still abnormal in most patients with PAH. In these patients, RV afterload during exercise could be higher, resulting in a greater increase in RV wall stress. Recently, an increasing number of studies have indicated the short-term efficacy of exercise training. However, considering the potential risk of promoting myocardial maladaptive remodeling, even low-intensity repetitive exercise training could lead to long-term clinical deterioration. Further studies investigating the long-term effects on the RV and pulmonary vasculature are warranted. Although the indications for exercise training for patients with PAH have been expanding, exercise training may be associated with various risks. Training programs along with risk stratification based on the pulmonary hemodynamic response to exercise may enhance the safety of patients with PAH.

Idiopathic/heritable pulmonary arterial hypertension has a poor prognosis despite the available therapeutic options. Survival of Japanese patients with this disease entity has not been reported in the multicenter setting. A retrospective study of 141 patients with idiopathic/heritable pulmonary arterial hypertension treated at 3 pulmonary hypertension centers in Japan from 1992 to 2012 investigated survival and determinants of survival. Mean survival time from treatment initiation was 14.7 ± 0.8 years (95% confidence interval, 13.1 to 16.3 years) and the 1-, 3-, 5-, and 10-year survival rates were 97.9%, 92.1%, 85.8%, and 69.5%, respectively. Patients showed significant improvement in exercise capacity and hemodynamics after treatment. Patients with 6-minute walk distance >372 m, mean pulmonary arterial pressure ≤46 mm Hg, and cardiac index >2.5 L/min/m 2 at follow-up had a significantly better prognosis. Most patients (99.2%) were receiving pulmonary hypertension-targeted drugs at follow-up. Use of endothelin receptor antagonists and intravenous epoprostenol were related to survival in the univariate analysis. Among the patients who were on intravenous epoprostenol therapy, those with endothelin receptor antagonists had a significantly better prognosis, whereas patients on warfarin had a significantly worse prognosis. In conclusion, survival of Japanese patients with idiopathic/heritable pulmonary arterial hypertension in this study was good, showing improvement in hemodynamic parameters supported by pulmonary hypertension-targeted drugs.

Background Intravenous epoprostenol is an effective treatment for idiopathic and heritable pulmonary arterial hypertension. We aimed to clarify factors that determine the survival of patients with severe pulmonary hypertension who received epoprostenol treatment. Methods This is a retrospective observational study consisting of 46 patients with idiopathic and heritable pulmonary arterial hypertension in World Health Organization (WHO) functional class III or IV and undergoing intravenous epoprostenol treatment. We compared the following factors between survivors and non-survivors: clinical characteristics, exercise capacity, hemodynamics, interval between diagnosis and treatment initiation, concomitant pulmonary arterial hypertension-targeted drugs, maximum dose of epoprostenol, and the speed of up-titration. We defined a rapid increase group as those receiving epoprostenol ≥20 ng/kg/min at 3 months and ≥45 ng/kg/min at 1 year of treatment. Results Thirty-two patients (70%) survived and 14 patients died during an average follow-up period of 2100 days. Mean pulmonary artery pressure, concomitant pulmonary arterial hypertension-targeted drugs, and the maximum epoprostenol dose were comparable between the two subsets of patients. WHO functional class III was more common than class IV, and the 6-min walking distance was longer in the survivor than the non-survivor group. The survivors typically showed a rapid increase in epoprostenol dose during the first year of treatment. This rapid increase group was associated with a continuous reduction in mean pulmonary artery pressure during the follow-up period, whereas the slow increase group showed no reduction in mean pulmonary artery pressure after 6 months of treatment. The 9.5-year survival rate was also significantly better in the rapid increase group compared with the slow increase group (100% vs. 64%, p = 0.022). Conclusions In idiopathic and heritable pulmonary arterial hypertension patients, a rapid increase in epoprostenol dose soon after the initiation of treatment seems to be important to achieve a continuous reduction in mean pulmonary artery pressure and to improve survival.

There is an urgent need to develop novel in-vitro models to mimic the disease conditions in pulmonary hypertension (PH). We developed a microfluidic cell culture device for PH studies that withstood high shear stress. Techniques were also developed for cell recovery from the microchannel and mRNA isolation from the collected cells. Using this device, we found that shear stress caused a 7.5-fold increase in the transcription levels of a PH-related molecule, Cyclin D1.

A microfluidic cell stretch device was developed to investigate the effects of stretching stress on pulmonary artery smooth muscle cell (PASMC) proliferation in pulmonary arterial hypertension (PAH). The microfluidic device harbors upper cell culture and lower control channels, separated by a stretchable poly(dimethylsiloxane) membrane that acts as a cell culture substrate. The lower channel inlet was connected to a vacuum pump via a digital switch-controlled solenoid valve. For cyclic stretch at heartbeat frequency (80 bpm), the open or close time for each valve was set to 0.38 s. Proliferation of normal PASMCs and those obtained from patients was enhanced by the circumferential stretching stimulation. This is the first report showing patient cells increased in number by stretching stress. These results are consistent with the abnormal proliferation observed in PAH. Circumferential stretch stress was applied to the cells without increasing the pressure inside the microchannel. Our data may suggest that the stretch stress itself promotes cell proliferation in PAH.

Background: Balloon pulmonary angioplasty (BPA) has become an alternative treatment for inoperable patients with chronic thromboembolic pulmonary hypertension. Lung injury (LI) is a major complication of BPA and may attenuate the benefits of BPA. Therefore, we conducted a retrospective study to evaluate the association between patient and procedural characteristics and LI in patients with chronic thromboembolic pulmonary hypertension. Methods and Results: We reviewed 76 patients with chronic thromboembolic pulmonary hypertension who underwent BPA and multidetector computed tomography scanning pre- and post-BPA procedures. We performed BPA on 1247 vessels during 297 BPA procedures and reviewed 594 multidetector computed tomography scans. By comparing pre- and post-BPA multidetector computed tomography images, we diagnosed LI as follows: newly appeared ground-glass opacity, consolidation, and pleural effusion. LI was detected using multidetector computed tomography scans during 138 procedures (47%), and mechanical ventilation was required during 40 procedures (13%). Angiographic findings of extravasation with or without simultaneous clinical symptoms (BPA-related vascular injury) occurred during 50 procedures (17%). In mixed-effect logistic regression models, the BPA-related vascular injury was an independent predictor of LI after BPA, odds ratio, 20.1 (6.43–63.1). High mean pulmonary artery pressure before BPA procedure and BPA-related vascular injury were independent predictors of mechanical ventilation after BPA, odds ratio, 1.13 (1.03–1.24) and 10.8 (3.77–30.9), respectively. Conclusions: Vascular injury during BPA could be a triggering factor of LI after BPA, and its severity could be exacerbated by a high pulmonary artery pressure.

In the past 5 years, balloon pulmonary angioplasty (BPA) for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are deemed inoperable has undergone significant refinement. As a result, the procedure is now used worldwide and has become a promising therapeutic option for those patients. However, pulmonary endarterectomy remains the gold standard treatment for patients with CTEPH because the techniques and strategies for BPA are not yet unified. The best therapeutic option for each patient should be determined based on discussion among a multidisciplinary team of experts. For BPA to become an established treatment for CTEPH, further data are needed. This review summarizes the techniques and strategies of BPA at present and discusses the future development of the procedure.

Objective This study was conducted to evaluate the safety and efficacy of a new more thermostable Flolan (epoprostenol) solution prepared with the reformulated pH 12.0 diluent in Japanese patients with pulmonary arterial hypertension (PAH) receiving higher doses of Flolan than those typically administered in Western countries. Methods This open-label, single-arm study was conducted in 10 Japanese PAH patients. During the run-in period, patients were intravenously infused with Flolan (45 ng/kg/min or higher doses) solution prepared with the existing pH 10.5 diluent. The patients were then switched to a new more thermostable Flolan solution prepared with the reformulated pH 12.0 diluent and observed for a 4-week treatment period. As a primary endpoint, safety after switching to the new Flolan solution was evaluated. Secondary endpoints included hemodynamics and the necessity for dose adjustment of Flolan in these patients. Results All 10 patients completed the study period. Observed adverse events were nausea and hepatic function abnormal in 1 patient each, and both events were mild. No patients required dose adjustment due to the change from baseline in mean pulmonary artery pressure (mPAP) measured 3 hrs after switching to Flolan solution prepared with the reformulated diluent. No major changes from baseline in mPAP, pulmonary vascular resistance, or right atrial pressure were observed at 24 hrs and at 4 weeks after switching to the Flolan solution prepared with pH 12.0 diluent. Although some patients showed increases in cardiac output (CO) from baseline at 24 hrs and 4 weeks, no patients required dose reduction as a result of an increase in CO. Conclusion Neither safety/efficacy concerns nor any dose adjustments of Flolan after switching to a more thermostable Flolan solution prepared with the reformulated pH 12.0 diluent could be required in Japanese patients with PAH receiving higher doses of Flolan. Trial registration ClinicalTrials.gov Identifier: NCT02705807

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.

Pulmonary arterial hypertension (PAH) is characterized by elevation of pulmonary artery pressure caused by pulmonary vasoconstriction and vascular remodeling, which leads to right heart failure and death. Epoprostenol (prostaglandin I2) has a potent short-acting vasodilator property, and intravenous continuous epoprostenol is therefore used for treatment of PAH. Here we review evidence for the usefulness of intravenous continuous epoprostenol therapy in patients with PAH. Epoprostenol therapy is effective in idiopathic PAH patients and in patients with PAH associated with connective tissue disease, portal hypertension or congenital heart diseases, but it is not effective in patients with pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. High-dose epoprostenol therapy markedly improved hemodynamics in some patients with PAH, possibly due to reverse remodeling of pulmonary arteries. This therapy has several side effects and complications such as headache, hypotension and catheter-related infections. Intravenous continuous epoprostenol is an effective treatment, but there are still some problems to be resolved.

The release of endogenous prostacyclin (PGI2) is depressed in patients with pulmonary arterial hypertension (PAH). PGI2 replacement therapy by epoprostenol infusion is one of the best treatments available for PAH. Here, we provide an overview of the current clinical data for epoprostenol. Epoprostenol treatment improves symptoms, exercise capacity, and hemodynamics, and is the only treatment that has been shown to reduce mortality in patients with idiopathic PAH (IPAH) in randomized clinical trials. We have reported that high-dose epoprostenol therapy (>40 ng/kg/min) also results in marked hemodynamic improvement in some patients with IPAH. High-dose epoprostenol has a pro-apoptotic effect on PAH-PASMCs via the IP receptor and upregulation of Fas ligand (FasL) in vitro. However, long-term intravenous administration of epoprostenol is sometimes associated with catheter-related infections and leads to considerable inconvenience for the patient. In the future, the development of new routes of administration or the development of powerful PGI2 analogs, IP-receptor agonists, and gene and cell-based therapy enhancing PGI2 production with new routes of administration is required.

Platelet-derived growth factor (PDGF) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Imatinib, a PDGF-receptor tyrosine kinase inhibitor, improved hemodynamics, but serious side effects and drug discontinuation are common when treating PAH. A drug delivery system using nanoparticles (NPs) enables the reduction of side effects while maintaining the effects of the drug. We examined the efficacy of imatinib-incorporated NPs (Ima-NPs) in a rat model and in human PAH-pulmonary arterial smooth muscle cells (PASMCs). Rats received a single intratracheal administration of PBS, FITC-NPs, or Ima-NPs immediately after monocrotaline injection. Three weeks after monocrotaline injection, intratracheal administration of Ima-NPs suppressed the development of pulmonary hypertension, small pulmonary artery remodeling, and right ventricular hypertrophy in the rat model of monocrotaline-induced PAH. We also examined the effects of imatinib and Ima-NPs on PDGF-induced proliferation of human PAH-PASMCs by (3)H-thymidine incorporation. Imatinib and Ima-NPs significantly inhibited proliferation after 24 hours of treatment. Ima-NPs significantly inhibited proliferation compared with imatinib at 24 hours after removal of these drugs. Delivery of Ima-NPs into lungs suppressed the development of MCT-induced PAH by sustained antiproliferative effects on PAS-MCs.

AimsIdiopathic/heritable pulmonary arterial hypertension (I/HPAH) carries a poor prognosis despite the therapeutic options available. Patient survival from Western countries has been reported, but data from Asia are scarce.Main methodsWe retrospectively reviewed 56 patients with I/HPAH treated at a single referral center in Japan. Survival analyses were conducted using the Kaplan–Meier method with the log-rank test. Variables associated with survival were determined using a Cox proportional hazard model.Key findingsThere were 41 women (73%) and the mean age at the diagnosis was 32±17years. Mean survival time from the diagnosis was 14.9±0.8years (95% CI, 13.4–16.4years), with 1-, 2-, 3-, 5- and 10-year survival rates of 98, 96, 96, 96 and 78%, respectively. In patients who underwent follow-up right-heart catheterization >3months after initial catheterization, mean pulmonary arterial pressure (mPAP) was decreased significantly from 63±15 to 35±10mmHg with an improved cardiac index. Patients with high levels of brain natriuretic peptide (BNP) or low oxygen saturation at baseline showed worse survival. At follow-up, 98% of patients were on PAH-targeted drugs. WHO functional classes I and II, mPAP 2.5L/min/m2, BNP 347m at follow-up were predictors of good prognosis in the univariate analysis.SignificanceThe study revealed a long-term survival of Japanese patients with I/HPAH. Hemodynamic parameters improved significantly after treatment, which might be related to high prescription rates of PAH-targeted drugs. Multicenter studies are needed to reveal the prognostic factors for I/HPAH.

Background Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are rare causes of pulmonary hypertension. Although diagnosis is based on pathological findings, an early diagnosis is crucial because of poor prognosis compared to other types of pulmonary hypertension. Furthermore, vasodilators may cause fatal pulmonary edema in patients with PVOD/PCH. This study aimed to identify specific characteristics for patients with PVOD/PCH to clinically diagnose PVOD/PCH. Methods Clinical data were obtained at baseline and were compared between 19 patients with PVOD/PCH and 55 patients with idiopathic/heritable pulmonary arterial hypertension. Receiver operating characteristic analyses were used to determine characteristics specific for patients with PVOD/PCH and a scoring system to diagnose PVOD/PCH was developed. Results Patients with PVOD/PCH had a smoking history and were predominantly male. Six-minute walk distance was significantly lower and oxygen desaturation was severe during the walk. Diffusion capacity of carbon monoxide was significantly low. Radiological findings included ground glass opacity on chest high-resolution computed tomography (CT) in all patients with PVOD/PCH, and thickened septal lines in 90% of the patients. Lung perfusion scintigraphy showed defect in >70% of the patients. Pulmonary edema after initiation of vasodilation therapy was frequently observed in PVOD/PCH patients. Based on these results, we identified nine important clinical characteristics and a novel scoring system was designed to clinically diagnose PVOD/PCH: male sex, smoking history, 6-minute walk distance Conclusions Our novel prediction rule for diagnosing PVOD/PCH may offer an early clinical diagnosis of these diseases.

Background— Balloon pulmonary angioplasty (BPA) has become an alternative therapy for patients with chronic thromboembolic pulmonary hypertension who are ineligible for pulmonary endarterectomy. We retrospectively investigated intravascular ultrasound measurements to elucidate how the lumen enlarges immediately after BPA. Methods and Results— A total of 326 lesions in 71 patients with chronic thromboembolic pulmonary hypertension were analyzed. The cross-sectional areas (CSAs) of the external elastic membrane and lumen measured by intravascular ultrasound before and after BPA were assessed for each lesion type (type A, ring-like stenosis lesions; type B, web lesions; type C, subtotal occlusion lesions). Comparing the lesion types, the proportion of the area occupied by fibrous tissue was smallest in the type A lesions and largest in the type C lesions. The mean lesion lumen CSA was increased after BPA because of an increase in external elastic membrane CSA (from 23.2±12.9 to 27.2±14.3 mm 2 ; P 2 ; P r 2 =0.762; P Conclusions— Lumen enlargement immediately after BPA was obtained by the overall vessel expansion induced by a stretch of the arterial wall. In addition, the amount of fibrous tissue depended on each lesion type. Thus, it might be beneficial to change the balloon size to correspond with the lesion type.

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-naive 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-naive 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 Pulmonary arterial hypertension (PAH) is a severe lung disease with only few effective treatments available. Familial cases of PAH are usually recognized as an autosomal dominant disease, but incomplete penetrance of the disease makes it difficult to identify pathogenic variants in accordance with a Mendelian pattern of inheritance. Methods To elucidate the complex genetic basis of PAH, we obtained whole exome- or genome-sequencing data of 17 subjects from 9 families with heritable PAH and applied gene-based association analysis with 9 index patients and 300 PAH-free controls. Results A burden of rare variants in BMPR2 significantly contributed to the risk of the disease (p = 6.0 × 10−8). Eight of nine families carried four previously reported single nucleotide variants and four novel insertion/deletion variants in the gene. One of the novel variants was a large 6.5 kilobase-deletion. In the remaining one family, the patient carried a pathogenic variant in a member of potassium channels, KCNK3, which was the first replicative finding of channelopathy in an Asian population. Conclusions The variety of rare pathogenic variants suggests that gene-based association analysis using genome-wide sequencing data from increased number of samples is essential to tracing the genetic heterogeneity and developing an appropriate panel for genetic testing. Electronic supplementary material The online version of this article (doi:10.1186/s12890-017-0400-z) contains supplementary material, which is available to authorized users.

To improve efficacy and safety of balloon pulmonary angioplasty, accumulation of experience and knowledge is needed http://ow.ly/lVSj30bFFNh

Background Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are categorized as Group 1′ in the clinical classification of pulmonary hypertension. No medical therapy has been proven to be effective in patients with PVOD/PCH. Imatinib is a molecular targeted drug and was expected to be effective in patients with pulmonary arterial hypertension. We evaluated its efficacy and safety in patients with PVOD/PCH. Methods In the present observational study, 9 patients with PVOD/PCH received imatinib. Clinical data including exercise capacity and hemodynamics at baseline and at follow-up were compared. Survival rate of patients treated with imatinib was compared to those of 7 patients who did not treated with imatinib. Results Imatinib was prescribed at doses of 100–400 mg/day and was well-tolerated. At follow-up, World Health Organization functional class and brain natriuretic peptide levels significantly improved. Mean pulmonary arterial pressure was significantly reduced (from 56.8 ± 8.3 to 43.7 ± 9.0 mmHg) with preserved cardiac index. Patients were treated with imatinib for 797.2 ± 487.0 days. Seven patients (77.8%) died and 2 patients (22.2%) underwent lung transplantation. Mean survival time in patients treated with imatinib therapy was 1493.7 ± 196.3 days (95% confidence interval, 1108.9–1878.5 days), significantly longer than those without imatinib treatment (713.0 ± 258.1 days, log-rank test, P = 0.04). Conclusions Imatinib improved exercise capacity, hemodynamics and survival in patients with PVOD/PCH. In patients with PVOD/PCH, who have no effective medical therapy available, imatinib might function as a bridge to lung transplantation, and may become a potential therapeutic option to improve their survival.