Flow Grade-Based Success Rates, Complication Rates, and Balloon Pulmonary Angioplasty Patency for Total Occlusions.

BACKGROUND: The number of successfully recanalized total occlusions affects hemodynamic improvement after balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to clarify the current efficacy, patency, and success rate of BPA for total occlusions. METHODS: Between April 2016 and August 2021, 178 BPAs were performed in 100 patients with CTEPH and total occlusions. The primary success and subsequent patency rates immediately before the second BPA procedure (follow-up) were compared between the segmental and subsegmental groups, based on the flow grade, which was defined as follows: 0, no reperfusion; 1, minimal reperfusion; 2, partial reperfusion; and 3, complete reperfusion. RESULTS: Total occlusions were mainly located in the right lung (70%) and lower lobes (48%). The primary success rate was 88%, with significant improvements in oxygenation, hemodynamic parameters, and 6-minute walk test. The primary flow grade did not differ between groups. However, the proportion of lesions with a flow grade of 2 or 3 at follow-up was significantly higher in the subsegmental group than in the segmental group (84% vs 45%, respectively; P < 0.01). In multivariate analysis, flow grade in the acute phase (odds ratio [OR], 46.9; 95% confidence interval [CI], 12.54-176.78; P < 0.01) and subsegmental lesions (OR, 13.8; 95% CI, 3.24-58.94; P < 0.01) were independently associated with better patency (flow grade of 2 or 3) at follow-up. CONCLUSIONS: Total occlusions can be safely and effectively treated with BPA. BPA for total occlusions may be preferable for subsegmental over segmental lesions.

Rescue balloon pulmonary angioplasty for refractory heart failure in chronic thromboembolic pulmonary hypertension complicated with takotsubo cardiomyopathy.

Balloon pulmonary angioplasty (BPA) seems promising for treating critically ill patients with chronic thromboembolic pulmonary hypertension (CTEPH) because of its less invasive and stepwise nature. However, there are only a few reports on rescue BPA. Herein, we present a case of CTEPH and takotsubo cardiomyopathy in an 82-year-old female. Despite treatment with catecholamines and intra-aortic balloon pumping, low output syndrome due to right heart failure with CTEPH and left heart failure with takotsubo cardiomyopathy did not improve. Therefore, rescue BPA for CTEPH was performed; this immediately improved the patient's hemodynamics. Learning objective: Rescue balloon pulmonary angioplasty (BPA) is an option for critically ill patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) that requires immediate improvement of hemodynamics. BPA strategy initially aimed at partial improvement of pulmonary circulation would be useful in treating CTEPH complicated by refractory right and left heart failure due to coexisting left-sided heart disease.

Antiproliferative effect of selexipag active metabolite MRE-269 on pulmonary arterial smooth muscle cells from patients with chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a group 4 pulmonary hypertension (PH) characterized by nonresolving thromboembolism in the central pulmonary artery and vascular occlusion in the proximal and distal pulmonary artery. Medical therapy is chosen for patients who are ineligible for pulmonary endarterectomy or balloon pulmonary angioplasty or who have symptomatic residual PH after surgery or intervention. Selexipag, an oral prostacyclin receptor agonist and potent vasodilator, was approved for CTEPH in Japan in 2021. To evaluate the pharmacological effect of selexipag on vascular occlusion in CTEPH, we examined how its active metabolite MRE-269 affects platelet-derived growth factor-stimulated pulmonary arterial smooth muscle cells (PASMCs) from CTEPH patients. MRE-269 showed a more potent antiproliferative effect on PASMCs from CTEPH patients than on those from normal subjects. DNA-binding protein inhibitor (ID) genes ID1 and ID3 were found by RNA sequencing and real-time quantitative polymerase chain reaction to be expressed at lower levels in PASMCs from CTEPH patients than in those from normal subjects and were upregulated by MRE-269 treatment. ID1 and ID3 upregulation by MRE-269 was blocked by co-incubation with a prostacyclin receptor antagonist, and ID1 knockdown by small interfering RNA transfection attenuated the antiproliferative effect of MRE-269. ID signaling may be involved in the antiproliferative effect of MRE-269 on PASMCs. This is the first study to demonstrate the pharmacological effects on PASMCs from CTEPH patients of a drug approved for the treatment of CTEPH. Both the vasodilatory and the antiproliferative effect of MRE-269 may contribute to the efficacy of selexipag in CTEPH.

Comparison of the safety and efficacy of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension patients with surgically accessible and inaccessible lesions.

BACKGROUND: Although pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension, not all patients are eligible. While balloon pulmonary angioplasty is an alternative for such patients, its efficacy and safety may differ between patients with and without surgically accessible lesions. METHODS: This study involved 344 patients treated with balloon pulmonary angioplasty who were ineligible for pulmonary endarterectomy. Based on the angiographical lesion location, patients were divided into the surgically accessible (Group 1) and inaccessible (Group 2) groups, and percent changes in hemodynamics and clinical parameters before and after balloon pulmonary angioplasty were investigated. We also conducted survival analyses using Kaplan-Meier analysis. RESULTS: While no differences in baseline characteristics were identified between the groups, balloon pulmonary angioplasty significantly improved hemodynamics in both groups, without any difference regarding the incidence of complications. Meanwhile, the percent changes in the mean pulmonary arterial pressure, pulmonary vascular resistance, 6-min walk distance, right ventricular area index on echocardiography, and the achievement rate of World Health Organization functional class I after balloon pulmonary angioplasty were significantly lower in Group 1 than in Group 2. The cumulative survival rates at 1, 5, and 10 years after balloon pulmonary angioplasty were not significantly different between the two groups (Group 1: 92.5%, 86.1%, 84.3%; and Group 2: 96.5%, 92.9%, 90.1%, respectively). CONCLUSIONS: The outcome of balloon pulmonary angioplasty in inoperable patients with surgically accessible proximal lesions was acceptable; however, further investigations are necessary to clarify the optimal treatment for such patients.

Low incidence of restenosis after successful balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension.

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.

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension concomitant with Klippel-Trenaunay-Weber syndrome.

Klippel-Trenaunay-Weber syndrome (KTWS) is a rare congenital disorder characterized by cutaneous capillary malformations, bone hypertrophy, and multiple venous or lymphatic malformations. KTWS is associated with chronic thromboembolic pulmonary hypertension (CTEPH), presumably due to thromboembolism from multiple vascular malformations. Here, we report the first case series of patients with KTWS-CTEPH who underwent balloon pulmonary angioplasty (BPA). Both patients are alive 20 years and 1 year after the initial diagnosis of CTEPH, respectively, and are stable with improved hemodynamics. BPA may be an effective treatment option for patients with KTWS-CTEPH.

Pulmonary pressure recovery in idiopathic, hereditary and drug and toxin-induced pulmonary arterial hypertension: determinants and clinical impact.

BACKGROUND: Over the past two decades randomized controlled trials of combination treatments for Pulmonary Arterial Hypertension (PAH) have demonstrated improvements of clinical status but only modest reductions in mean pulmonary arterial pressure (mPAP). Recent experiences with upfront combination treatments including parenteral prostacyclins have shown more substantial mPAP reductions, and have provided grounds for reconsiderations of treatment. OBJECTIVES: To evaluate the possibility of achieving mPAP <25 mmHg with current treatments, its determinants and the prognostic impact of mPAP reduction. METHODS: 267 consecutive idiopathic, hereditary and drug and toxin-induced PAH patients treated with targeted therapies from three expert centers were followed with periodic clinical and hemodynamic assessments for survival detection. RESULTS: Fifty-four (20.2%) patients achieved a mPAP <25 mmHg over 58 months (IQR 27-90) of treatment. Determinants of mPAP <25 mmHg were mPAP at diagnosis (HR 0.96, 95C.I. 0.93-0.98, p = 0.002) and an upfront combination strategy (double oral combination: HR 2.3, 95C.I. 1.10-4.76, p = 0.02; one oral plus parenteral prostanoid: HR 3.6, 95C.I. 1.39-9.37, p = 0.008; triple combination employing parenteral prostanoids: HR 12.9, 95C.I. 4.9-33.2, p = 0.0001). Seventy-three patients (27.3%) died. Survival rates were 90%, 79%, 70%, 55%, and 42% at 1, 3, 5, 10, and 15 years, respectively. Mean PAP during follow-up, days from diagnosis to prostanoid initiation and prostanoid maximum dose emerged as independent predictors of survival (Uno-C-index: 0.85). A mPAP ≤35 mmHg during follow-up was identified as the best cutoff value for prediction of survival. CONCLUSIONS: Reduction to a mean PAP ≤ 35 mmHg appears to be a meaningful treatment target in idiopathic, hereditary and drug and toxin-induced pulmonary arterial hypertension.

Balloon pulmonary angioplasty versus riociguat in inoperable chronic thromboembolic pulmonary hypertension (MR BPA): an open-label, randomised controlled trial.

BACKGROUND: Treatment options for patients with chronic thromboembolic pulmonary hypertension ineligible for pulmonary endarterectomy (inoperable CTEPH) include balloon pulmonary angioplasty (BPA) and riociguat. However, these two treatment options have not been compared prospectively. We aimed to compare the safety and efficacy of BPA and riociguat in patients with inoperable CTEPH. METHODS: This open-label, randomised controlled trial was conducted at four high-volume CTEPH centres in Japan. Patients aged 20-80 years with inoperable CTEPH (mean pulmonary arterial pressure ≥25 to <60 mm Hg and pulmonary artery wedge pressure ≤15 mm Hg) and WHO functional class II or III were randomly assigned (1:1) to BPA or riociguat via a computer program located at the registration centre using a minimisation method with biased-coin assignment. In the BPA group, the aim was for BPA to be completed within 4 months of the initial date of the first procedure. BPA was repeated until mean pulmonary arterial pressure decreased to less than 25 mm Hg. The frequency of BPA procedures depended on the difficulty and number of the lesions. In the riociguat group, 1·0 mg riociguat was administered orally thrice daily. When the systolic blood pressure was maintained at 95 mm Hg or higher, the dose was increased by 0·5 mg every 2 weeks up to a maximum of 2·5 mg thrice daily; dose adjustment was completed within 4 months of the date of the first dose. The primary endpoint was change in mean pulmonary arterial pressure from baseline to 12 months, measured in the full analysis set (patients who were enrolled and randomly assigned to one of the study treatments, and had at least one assessment after randomisation). BPA-related complications and indices related to clinical worsening were recorded throughout the study period. Adverse events were recorded throughout the study period and evaluated in the safety analysis set (patients who were enrolled and randomely assigned to one of the study treatments, and had received part of or all the study treatments). This trial is registered in the Japan Registry of Clinical Trials (jRCT; jRCTs031180239) and is completed. FINDINGS: Between Jan 8, 2016, and Oct 31, 2019, 61 patients with inoperable CTEPH were enrolled and randomly assigned to BPA (n=32) or riociguat (n=29). Patients in the BPA group underwent an average of 4·7 (SD 1·6) BPA procedures. In the riociguat group, the mean maintenance dose was 7·0 (SD 1·0) mg/day at 12 months. At 12 months, mean pulmonary arterial pressure had improved by -16·3 (SE 1·6) mm Hg in the BPA group and -7·0 (1·5) mm Hg in the riociguat group (group difference -9·3 mm Hg [95% CI -12·7 to -5·9]; p<0·0001). A case of clinical worsening of pulmonary hypertension occurred in the riociguat group, whereas none occurred in the BPA group. The most common adverse event was haemosputum, haemoptysis, or pulmonary haemorrhage, affecting 14 patients (44%) in the BPA group and one (4%) in the riociguat group. In 147 BPA procedures done in 31 patients, BPA-related complications were observed in 17 procedures (12%) in eight patients (26%). INTERPRETATION: Compared with riociguat, BPA was associated with a greater improvement in mean pulmonary arterial pressure in patients with inoperable CTEPH at 12 months, although procedure-related complications were reported. These findings support BPA as a reasonable option for inoperable CTEPH in centres with experienced BPA operators, with attention to procedure-related complications. FUNDING: Bayer Yakuhin. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Outcome of mean pulmonary arterial pressure-based intensive treatment for patients with pulmonary arterial hypertension.

BACKGROUND: 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. METHOD: From September 2014 to August 2019, 43 consecutive patients with PAH on treatment <3 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 mPAP <40 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. RESULTS: 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). mPAP <40 mmHg at follow-up was the independent predictor of survival. CONCLUSIONS: Lowering mPAP resulted in favorable outcomes in all subsets of PAH patients, making it a therapeutic goal.

Oxygen inhalation can selectively dilate pulmonary arteries in patients with chronic thromboembolic pulmonary hypertension before balloon angioplasty.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (p<0.001) and pulmonary vascular resistance by 0.8 ± 1.8 Wood units (p<0.001). Moreover, the ratio of pulmonary vascular resistance to systemic vascular resistance was significantly reduced by 13.5% (p<0.001). Multivariate regression analysis identified baseline mean PAP (ß = -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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry (No.: UMIN000026882); URL: https://www.umin.ac.jp/ctr/index.htm.

Treatment of Vascular Injury During Balloon Pulmonary Angioplasty in Patients With Chronic Thromboembolic Pulmonary Hypertension.

Background: Treatment strategy for vascular injury during balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) was uncertain. Objectives: This study aimed to identify an optimal therapeutic strategy for vascular injury during BPA in patients with CTEPH. Methods: This study reviewed 207 patients with CTEPH and 956 BPA procedures between November 1, 2012 and November 30, 2015. Patients who were diagnosed with vascular injury during BPA, which was defined as angiographic signs or sudden respiratory and hemodynamic defects were included in this study. The study investigated the safety and efficacy of the hierarchically systematic treatment strategy including gelatin sponge embolization (GSE). Results: More than one-half of the 79 patients and 133 procedures with vascular injury were improved by general treatment with reversal of heparin and high-flow oxygen administration. The investigators performed conventional treatment of proximal vessel occlusion using a guiding or balloon catheter in 47 procedures (35%) in which the culprit vessels could be detected under patients' stable conditions. In 32 procedures (24%) without detected culprit lesions or improvement by conventional treatment, GSE could significantly improve patient condition. The treatment strategy obtained successful bailout in 98% of procedures with vascular injury. No patients who underwent GSE died within 30 days after the treatment. There was no significant difference in cumulative mortality rate (median follow-up: 6.6 years) between groups with or without GSE (15.6% vs 8.2%; adjusted HR: 1.47; 95% CI: 0.25-8.69; P = 0.67). Conclusions: Treatment strategy including GSE would be promising for vascular injury during BPA in patients with CTEPH.

Current strategies for managing chronic thromboembolic pulmonary hypertension: results of the worldwide prospective CTEPH Registry.

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.

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: advances in patient and lesion selection.

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.

High Right Ventricular Afterload during Exercise in Patients with Pulmonary Arterial Hypertension.

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.

Continual Improvement in Pressure Gradient at the Lesion After Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: 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. METHODS: 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. RESULTS: 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, P < 0.001) 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 (r2 = 0.23, P = 0.004) and residual pressure gradient immediately after the initial balloon dilation (r2 = 0.58, P < 0.001). CONCLUSIONS: The 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.

Response to exercise in patients with pulmonary arterial hypertension treated with combination therapy.

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 <25 mmHg in 13 patients. The mPAP increased significantly from 27.9±10.7 to 45.9±16.7 mmHg (p<0.01) during exercise. The cardiac index increased inadequately, and the total pulmonary resistance (TPR) increased significantly from 5.74±3.42 to 6.58±3.82 Wood units (p<0.01). The mPAP/cardiac output (CO) slope was steep (10.0±6.7 mmHg·min·L-1). It significantly correlated with both the minute ventilation/carbon dioxide output slope (r=0.51, p<0.01) and peripheral arterial oxygen saturation/workload slope (r=-0.41, p=0.02). In addition, the mPAP/CO slope correlated significantly with mPAP at rest (r=0.73, p<0.01) and TPR at rest (r=0.64, p<0.01). Even after pulmonary haemodynamics at rest was significantly improved in PAH patients with PAH-specific combination therapy, the mPAP/CO slope was steep and the steep mPAP/CO slope related to decreased ventilatory efficiency and the severity of hypoxaemia. The mPAP/CO slope was steeper in patients with higher mPAP and TPR at rest.

Improvements in French risk stratification score were correlated with reductions in mean pulmonary artery pressure in pulmonary arterial hypertension: a subanalysis of the Japan Pulmonary Hypertension Registry (JAPHR).

BACKGROUND: Since there was no previous report, we analyzed the relationship between French Risk Stratification parameters in pulmonary arterial hypertension (PAH) and mean pulmonary arterial pressures (mPAP) using Japan PH Registry (JAPHR) national-wide cohort. METHODS: We enrolled 108 patients with PAH from JAPHR from previous reported cohort and analyzed the relations between French Risk Stratification scores and hemodynamic improvements. RESULTS: The ratio meeting 0 to 4 French Risk Stratification score was 21.3%, 31.5%, 32.4%, 13.0%, and 1.9% at baseline, and 6.5%, 23.2%, 33.3%, 23.2%, 13.9% at follow-up, respectively. The improvements in the number of criteria met were associated both with mPAP at follow-up (p = 0.03) and with the improvements in mPAP (p < 0.001). CONCLUSION: The improvements in French Risk Stratification may become a marker of improved hemodynamics including mPAP.

Increased levels of platelet-derived microparticles in pulmonary hypertension.

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

3D in vitro Model of Vascular Medial Thickening in Pulmonary Arterial Hypertension.

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.