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.

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.

Oral anticoagulants usage in Japanese patients aged 18-74 years with non-valvular atrial fibrillation: a retrospective analysis based on insurance claims data.

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.

After the Dawn　- Balloon Pulmonary Angioplasty for Patients With Chronic Thromboembolic Pulmonary Hypertension.

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.

Effectiveness and Outcome of Pulmonary Arterial Hypertension-Specific Therapy in Japanese Patients With Pulmonary Arterial Hypertension.

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

A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension.

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.

Epoprostenol Therapy for Pulmonary Arterial 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.

Delivery of imatinib-incorporated nanoparticles into lungs suppresses the development of monocrotaline-induced pulmonary arterial hypertension.

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.

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.

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.

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.

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.

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.

PDGF enhances store-operated Ca2+ entry by upregulating STIM1/Orai1 via activation of Akt/mTOR in human pulmonary arterial smooth muscle cells.

Platelet-derived growth factor (PDGF) and its receptor are known to be substantially elevated in lung tissues and pulmonary arterial smooth muscle cells (PASMC) isolated from patients and animals with pulmonary arterial hypertension. PDGF has been shown to phosphorylate and activate Akt and mammalian target of rapamycin (mTOR) in PASMC. In this study, we investigated the role of PDGF-mediated activation of Akt signaling in the regulation of cytosolic Ca(2+) concentration and cell proliferation. PDGF activated the Akt/mTOR pathway and, subsequently, enhanced store-operated Ca(2+) entry (SOCE) and cell proliferation in human PASMC. Inhibition of Akt attenuated the increase in cytosolic Ca(2+) concentration due to both SOCE and PASMC proliferation. This effect correlated with a significant downregulation of stromal interacting molecule (STIM) and Orai, proposed molecular correlates for SOCE in many cell types. The data from this study present a novel pathway for the regulation of Ca(2+) signaling and PASMC proliferation involving activation of Akt in response to upregulated expression of PDGF. Targeting this pathway may lead to the development of a novel therapeutic option for the treatment of pulmonary arterial hypertension.

Safety and efficacy of epoprostenol therapy in pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.

BACKGROUND: Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are rare causes of pulmonary hypertension. There is no proven medical therapy to treat these diseases, and lung transplantation is thought to be the only cure. Administration of vasodilators including epoprostenol sometimes causes massive pulmonary edema and could be fatal in these patients. METHODS AND RESULTS: Eight patients were treated with epoprostenol for 387.3±116.3 days (range, 102-1,063 days), who were finally diagnosed with PVOD or PCH by pathological examination. The maximum dose of epoprostenol given was 55.3±10.7 ng·kg(-1)·min(-1) (range, 21.0-110.5 ng·kg(-1)·min(-1)). With careful management, epoprostenol therapy significantly improved the 6-min walk distance (97.5±39.2 to 329.4±34.6 m, P<0.001) and plasma brain natriuretic peptide levels (381.3±136.8 to 55.2±14.4 pg/ml, P<0.05). The cardiac index significantly increased from 2.1±0.1 to 2.9±0.3 L·min(-1)·m(-2) (P<0.05). However, pulmonary artery pressure and pulmonary vascular resistance were not significantly reduced. For 4 patients, epoprostenol therapy acted as a bridge to lung transplantation. For the other patients who had no chance to undergo lung transplantation, epoprostenol therapy was applied for 528.0±216.6 days and the maximum dose was 63.9±19.0 ng·kg(-1)·min(-1). CONCLUSIONS: This study data suggest that cautious application of epoprostenol can be considered as a therapeutic option in patients with PVOD and PCH.

Acute vasoreactivity testing with nicardipine in patients with pulmonary arterial hypertension.

Acute vasoreactivity testing for patients with pulmonary arterial hypertension (PAH) has been reported to be useful to identify patients with sustained beneficial response to oral calcium-channel blockers (CCBs), but there is a risk of exacerbation during the testing with oral CCBs. Therefore, we developed a testing method utilizing intravenous nicardipine, a short-acting CCB, and examined the safety and usefulness of acute vasoreactivity testing with nicardipine in PAH patients. Acute vasoreactivity testing with nicardipine was performed in 65 PAH patients. Nicardipine was administered by short-time continuous infusion (1 µg·kg⁻¹·min⁻¹ for 5 min and 2 µg·kg⁻¹·min⁻¹ for 5 min) followed by bolus injection (5 µg/kg). Hemodynamic responses were continuously measured using a right heart catheter. Acute responders were defined as patients who showed a decrease in mean pulmonary artery pressure of at least 10 mmHg to an absolute level below 40 mmHg with preserved or increased cardiac output. Two acute responders and sixty-three non-acute responders were identified. There was no hemodynamic instability requiring additional inotropic agents or death during the testing. Acute responders had good responses to long-term oral CCBs. The acute vasoreactivity testing with nicardipine might be safe and useful for identifying CCB responders in PAH patients.

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.

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.