Pulmonary Arterial Hypertension-Specific Therapy for Atrial Septal Defects with Severe Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension-Specific Therapy for Atrial Septal Defects with Severe Pulmonary Arterial Hypertension | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pulmonary Arterial Hypertension-Specific Therapy for Atrial Septal Defects with Severe Pulmonary Arterial Hypertension Sayuri Nakayama, Ryotaro Asano, Akihiro Tsuji, Jin Ueda, Hiroya Hayashi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8754390/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Mar, 2026 Read the published version in Pediatric Cardiology → Version 1 posted 7 You are reading this latest preprint version Abstract Background Pulmonary arterial hypertension (PAH) complicates a subset of patients with atrial septal defects (ASD). Although patients with ASD-PAH and high pulmonary vascular resistance (PVR) generally do not benefit, those who demonstrate a favorable response to PAH-specific therapy, particularly a PVR of < 5 Wood units (WU) post-treatment, may be considered for shunt closure. We aimed to examine the hemodynamic characteristics of patients with severe ASD-PAH who achieved a PVR of < 5 WU with PAH-specific therapy. Methods This retrospective study evaluated 15 patients with severe ASD-PAH (PVR ≥ 5.0 WU) who underwent PAH-specific therapy. The effects of PAH-specific therapy and acute vasoreactivity testing (AVT) were examined. Patients who achieved PVR < 5 WU post-therapy were classified into the low-PVR group, and others into the high-PVR group. Results The PVR significantly decreased from 10.7 ± 5.5 to 7.0 ± 5.2 WU after oral PAH-specific therapy (p < 0.05). The maximum baseline PVR in the low-PVR group (n = 7, 47%) was 9.5 WU. The low-PVR group showed a greater change in PVR during AVT than the high-PVR group (44.9 ± 8.9% vs. 15.4 ± 15.4%, p < 0.01). Conclusions The baseline PVR of 9.5 WU was the upper threshold for achieving PVR < 5.0 WU with oral PAH-specific therapy in severe ASD-PAH. Patients who exhibited a positive response to AVT achieved greater hemodynamic improvement. pulmonary vascular resistance acute vasoreactivity testing pulmonary hypertension Figures Figure 1 Figure 2 Figure 3 Introduction Atrial septal defect (ASD) is the second most common congenital heart disease (CHD) after bicuspid aortic valve [ 1 ]. Pulmonary arterial hypertension (PAH) has been reported in 6–36% of patients with ASD, and its prevalence is steadily increasing among those aged ≥ 30 years [ 2 – 4 ]. Preoperative PAH with elevated pulmonary vascular resistance (PVR) is associated with persistent or recurrent PAH after shunt closure [ 5 ]. Furthermore, PAH that develops after shunt repair has a worse prognosis compared with Eisenmenger syndrome [ 6 , 7 ]. Recent advances in PAH-specific therapy, including prostanoids, endothelin-receptor antagonists, and phosphodiesterase type 5 inhibitors, have led to considerable changes in the treatment of CHD-associated PAH (CHD-PAH) [ 8 , 9 ]. The 2020 European Society of Cardiology (ESC) guidelines for the management of adult CHD indicate that ASD closure may be considered when PVR is < 5.0 Wood units (WU) after PAH-specific therapy in patients with ASD-associated PAH (ASD-PAH) [ 10 ]. Importantly, some studies reported safe ASD closure after successful PAH-specific therapy (known as the “treat and repair” strategy) in patients with severe ASD-PAH with stable post-shunt closure hemodynamics [ 11 – 13 ]. However, the hemodynamic characteristics of patients achieving a PVR < 5 WU after PAH-specific therapy as an indication for ASD closure remain unclear. Furthermore, hemodynamic improvement in PAH-specific therapy is typically limited to patients who have undergone surgical repair. The efficacy of PAH-specific therapy in managing patients with severe ASD-PAH is unclear. Characterizing patients with severe ASD-PAH who achieve a PVR of < 5 WU after PAH-specific therapy may help identify candidates for treatment and repair strategies. Therefore, this study aimed to examine the hemodynamic characteristics of patients with severe ASD-PAH who achieved a PVR of < 5.0 WU with PAH-specific therapy. Methods Study design and population This retrospective study evaluated patients with severe ASD-PAH who were referred to the National Cerebral and Cardiovascular Center in Osaka, Japan, between January 2011 and July 2020. Among the 954 patients with ASD initially identified, 903 patients without suspected pulmonary hypertension based on echocardiography and 4 with other causes of PAH (portopulmonary hypertension, n = 1; chronic thromboembolic pulmonary hypertension, n = 2; and lung disease-related pulmonary hypertension, n = 1) were excluded. Of the remaining 47 patients with suspected pulmonary hypertension, 45 underwent right heart catheterization (RHC), and 21 were diagnosed with ASD-PAH. Among these 21 patients, 17 had severe PAH (PVR ≥ 5.0 WU). Two patients were excluded due to loss to follow-up and lack of data on PAH-specific therapy. Finally, 15 patients with severe ASD-PAH who received PAH-specific therapy were included in the analysis. The patient selection flowchart is shown in Fig. 1 . Clinicodemographic data, including age, sex, ASD morphology, brain natriuretic peptide (BNP) levels, and symptoms at baseline, were collected from electronic medical records. This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Ethics Committee of the National Cerebral and Cardiovascular Center (No. R20075). The committee waived the requirement for informed consent owing to the study's retrospective, observational nature. An “opt-out” approach to consent was approved, and a written explanation for data use was provided on the websites, allowing patients to decline participation without requiring written informed consent. Definition of PAH and clinical evaluations PAH was defined as mean pulmonary arterial pressure (PAP) ≥ 25 mmHg, mean pulmonary arterial wedge pressure ≤ 15 mmHg, and PVR > 3.0 WU based on measurements from hemodynamic variables at the initial RHC [ 14 ]. This definition followed the 2015 ESC/European Respiratory Society guidelines, which were the most recent criteria available when the study was initiated. Although the 2022 ESC/European Respiratory Society guidelines lowered the hemodynamic threshold for PAH diagnosis, the inclusion criteria in this study were set to include patients with severe PAH (PVR ≥ 5.0 WU) and would therefore not be affected by the updated definition. ASD morphology was evaluated using transesophageal echocardiography. PAH symptoms were evaluated using the World Health Organization Functional Classification (WHO-FC). PAH specific therapy PAH-specific therapy includes endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, and prostacyclin analogs (oral and intravenous). Treatment regimens were determined by cardiologists specializing in pulmonary hypertension. Measurement of hemodynamics Hemodynamic parameters, including mean pulmonary capillary wedge pressure, PAP, right atrial pressure, cardiac output, and PVR, were measured using RHC. Cardiac output was determined using the Fick method and corrected for body surface area. An acute vasoreactivity test (AVT) was performed at the initial RHC. In AVT, patients inhaled 100% O 2 and 20 ppm nitric oxide through a mask [ 15 , 16 ]. The effects were observed 10 min after administration. Hemodynamic parameters were measured and calculated before and after inhalation. Follow-up RHC was performed after a median period of 5 months (interquartile range [IQR], 2.0–7.0 months) following initiation or intensification of PAH-specific therapy to evaluate post-treatment hemodynamic changes. Statistical analysis Continuous variables are expressed as means ± standard deviations or medians (IQRs), whereas categorical variables are expressed as numbers and percentages. Patients who achieved a PVR < 5 WU with PAH-specific therapy were classified as the low-PVR group, whereas the remaining patients were classified as the high-PVR group [ 10 ]. Between-group comparisons were performed using the Student’s t-test for normally distributed continuous variables and the Wilcoxon signed-rank test for non-normally distributed continuous or categorical variables. Changes in categorical variables and serial hemodynamic measures from baseline to post-PAH-specific therapy were analyzed using Fisher’s exact and paired t-tests, respectively. The sensitivity, specificity, and accuracy of PVR at baseline and during AVT in predicting response to PAH-specific therapy were determined using receiver operating characteristic (ROC) curve analysis. All statistical analyses were performed using JMP software (version 15; SAS Institute, Cary, NC, USA). Statistical significance was set at p < 0.05. Results Baseline patient characteristics The characteristics of the 15 patients are presented in Table 1 . The mean age at baseline was 49.2 ± 12.7 years, with 14 (93%) patients being female. The median long-axis diameter of ASD was 25.5 mm (IQR, 16.5–31.3 mm). Eight patients had previously received PAH-specific therapy. WHO-FC I, II, and III symptoms were observed in 13%, 60%, and 27% of patients, respectively. None of the patients had WHO-FC IV symptoms. Table 1 Baseline patient characteristics Characteristic All patients (n = 15) Low-PVR group (n = 7) High-PVR group (n = 8) p-value Age, years 49.2 ± 12.7 47.0 ± 12.2 51.1 ± 13.7 0.55 Female, n (%) 14 (93) 7 (100) 7 (88) 0.33 BMI, kg/m 2 20.2 ± 4.0 21.4 ± 4.3 19.1 ± 3.5 0.26 PAH-specific therapy ERA, n (%) PDE5 inhibitors, n (%) Oral prostanoids, n (%) 5 (33) 2 (13) 1 (7) 2 (29) 1 (14) 0 (0) 3 (38) 1 (13) 1 (14) 0.71 0.92 0.27 ASD type Secundum, n (%) CS, n (%) Sinus venosus, n (%) 13 (87) 1 (7) 1 (7) 5 (71) 1 (14) 1 (14) 8 (100) 0 0 0.27 ASD diameter Long axis, mm Average of long and short axis, mm 25.5 (16.5–31.3) 24.0 (16.0–27.5) 31.0 (18.0–39.3) 27.5 (16.5–34.6) 22.5 (14.8–28.8) 17.5 (14.8–25.3) 0.12 0.14 Other malformations – PAPVR (n = 1) Poore – Functional status WHO-FC WHO-FC ≥ III, n (%) 2.1 ± 0.6 4 (27) 2.3 ± 0.2 3 (43) 2.0 ± 0.2 1 (13) 0.41 0.18 BNP, pg/mL 98 (57.3–168.6) 99.6 (52.8–566.1) 97.9 (65.7–123.7) 0.64 sPAP, mmHg 93.7 ± 13.6 85.7 ± 10.4 100.8 ± 12.5 0.03 dPAP, mmHg 34.9 ± 8.6 29.6 ± 2.2 39.5 ± 9.5 0.02 mPAP, mmHg 53.5 ± 9.7 47.9 ± 3.9 58.5 ± 10.7 0.03 PVR, WU 10.7 ± 5.5 7.0 ± 1.3 13.9 ± 5.8 0.01 Qp/Qs 1.53 ± 0.63 1.72 ± 0.51 1.37 ± 0.72 0.31 Qp, L/min 5.06 ± 1.52 6.12 ± 1.14 4.12 ± 1.16 < 0.01 Continuous values are expressed as mean ± SD or median (IQR). Categorical values are expressed as numbers and percentages, and n indicates the number of patients. BMI: body mass index, ERA: endothelin receptor antagonist, PDE5: phosphodiesterase type 5, ASD: atrial septal defect, CS: coronary sinus, PAPVR: partial anomalous pulmonary venous return, WHO-FC: World Health Organization Functional Class, BNP: brain natriuretic peptide, sPAP: systolic pulmonary arterial pressure, dPAP: diastolic pulmonary arterial pressure, mPAP: mean pulmonary arterial pressure, PVR: pulmonary vascular resistance, Qp/Qs: pulmonary to systemic flow ratio, Qp: pulmonary blood flow, Qs: systemic blood flow, SD: standard deviation, IQR: interquartile range, WU: Wood units Among the 15 patients, 7 (47%) achieved a PVR < 5 WU with PAH-specific therapy and were classified as the low-PVR group, whereas the remaining 8 (53%) were classified as the high-PVR group. The maximum baseline PVR in the low-PVR group was 9.5 WU. Partial anomalous pulmonary venous return was detected in a patient in the low-PVR group. Comparisons between the low-PVR and high-PVR groups revealed no significant differences in age (47.0 ± 12.2 vs. 51.1 ± 13.7 years, p = 0.55), ASD diameter (31.0 [IQR, 18.0–39.3] vs. 22.5 [IQR, 14.8–28.8] mm, p = 0.14), and BNP levels (99.6 [IQR, 52.8–566.1] vs. 97.9 [IQR, 65.7–123.7] pg/mL, p = 0.64). WHO-FC I, II, and III symptoms were observed in 14%, 43%, and 43% of patients, respectively, in the low-PVR group, and in 12.5%, 75%, and 12.5% of patients, respectively, in the high-PVR group, with no significant difference (p = 0.38). Changes in hemodynamic parameters after PAH-specific therapy Compared with the high-PVR group, the low-PVR group had significantly lower mean PAP (47.9 ± 3.9 vs. 58.5 ± 10.7 mmHg, p = 0.03), lower PVR (7.0 ± 1.3 vs. 13.9 ± 5.8 WU, p = 0.01), and higher pulmonary blood flow (Qp) (6.12 ± 1.14 vs. 4.12 ± 1.16 L/min, p < 0.01). Hemodynamic data at baseline and after PAH-specific therapy are presented in Supplementary Table 1. All patients received oral PAH-specific therapy. Within a median follow-up period of 5 months (IQR, 2.0–7.0 months), 14 patients (7 patients per group) were treated with endothelin receptor antagonists, all patients received phosphodiesterase type 5 inhibitors, and 13 patients (7 patients in the low-PVR group and 6 patients in the high-PVR group) received oral or inhaled prostanoids (Table 2 ). Table 2 Hemodynamic parameters at baseline and follow-up Case Age Sex PAH‑specific therapy (dose) Baseline mPAP (mm Hg) Baseline PVR (Wood U) AVT % Δ PVR Follow‑up mPAP (mm Hg) Follow‑up PVR (Wood U) Therapy % Δ PVR Low‑PVR group 1 47 F Macitentan 10 mg, Tadalafil 40 mg, Beraprost 240 µg 43 6.53 38.6 34 3.18 51.3 2 38 F Macitentan 10 mg, Tadalafil 40 mg, Beraprost 360 µg 46 5.91 54.8 26 1.74 70.6 3 40 F Ambrisentan 10 mg, Tadalafil 40 mg, Beraprost 120 µg 52 6.72 46.0 44 4.87 27.5 4 35 F Macitentan 10 mg, Tadalafil 40 mg, Selexipag 1.6 mg 44 9.48 33.3 25 4.06 57.2 5 43 F Macitentan 10 mg, Tadalafil 40 mg, Selexipag 2.4 mg 53 8.07 41.4 38 2.75 66.0 6 56 F Macitentan 10 mg, Tadalafil 40 mg, Beraprost 60 µg 47 6.87 N/A 34 1.98 71.1 7 70 F Macitentan 10 mg, Sildenafil 60 mg, Selexipag 1.6 mg 50 5.62 55.2 39 3.23 42.5 High‑PVR group 8 53 F Bosentan 250 mg, Tadalafil 40 mg, Beraprost 120 µg 50 9.87 12.9 46 7.55 23.5 9 73 F Macitentan 10 mg, Tadalafil 40 mg, Beraprost 120 µg 40 14.40 14.8 42 18.0 ‑24.3 10 47 F Macitentan 10 mg, Tadalafil 40 mg, Selexipag 3.2 mg 69 14.90 36.9 45 5.75 61.4 11 32 F Macitentan 10 mg, Tadalafil 40 mg, Beraprost 360 µg 65 12.50 N/A 61 10.0 20.2 12 27 F Macitentan 10 mg, Tadalafil 40 mg, Iloprost (i.t.) 7.5 µg 69 26.52 7.5 56 18.0 32.1 13 34 F Macitentan 10 mg, Tadalafil 40 mg, Beraprost 360 µg 63 14.22 35.6 55 6.75 52.5 14 53 F Tadalafil 40 mg, Selexipag 1.0 mg 63 12.16 ‑1.0 63 9.65 20.7 15 68 M Bosentan 250 mg, Tadalafil 40 mg 49 6.62 1.0 52 7.04 ‑6.3 AVT : acute vasoreactivity test, PVR : pulmonary vascular resistance (Wood units), mPAP : mean pulmonary arterial pressure (mm Hg) Notes 1. %Δ PVR = 100 × [(Baseline PVR – Follow‑up PVR) / Baseline PVR]. 2. Positive values indicate a decrease in PVR; negative values indicate an increase (e.g., Cases 9, 14, 15). 3. “N/A” means the percentage change could not be calculated because the baseline PVR was already very low or the follow‑up measurement was missing. 4. All patients were female, except for Case 15 (male). In the total population, the mean PAP and PVR values significantly decreased from 53.5 ± 9.7 to 44.0 ± 11.8 mmHg (p < 0.001) and from 10.7 ± 5.5 to 7.0 ± 5.2 WU (p < 0.01), respectively, whereas Qp increased from 5.06 ± 1.52 to 7.27 ± 3.22 L/min (p < 0.01). Compared with the high-PVR group, the low-PVR group had a significantly lower mean PAP (34.3 ± 6.9 vs. 58.5 ± 7.7 mmHg, p < 0.01) and PVR (3.2 ± 1.2 vs. 10.3 ± 4.9 WU, p < 0.01) and significantly higher Qp (9.70 ± 2.72 vs. 5.15 ± 1.82 L/min, p < 0.01) after PAH-specific therapy. The mean PAP and PVR were significantly reduced after targeted PAH treatment in the low-PVR group, but not in the high-PVR group (Fig. 2 A, 2 B). The reduction rates in the mean PAP and PVR after targeted PAH treatment were significantly higher in the low-PVR group than in the high-PVR group (mean PAP: 28.7 ± 10.9% vs. 8.7 ± 13.6%, p < 0.001; mean PVR: 55.1 ± 16.1% vs. 22.5 ± 28.1%, p = 0.02). Acute vasoreactivity at baseline AVT was performed in 13 patients (6 in the low-PVR group and 7 in the high-PVR group). There was no significant between-group difference in the change in mean PAP (12.3 ± 3.8% vs. 6.1 ± 9.2%, p = 0.15). However, the reduction rate in PVR during AVT was higher in the low-PVR group than in the high-PVR group (44.9 ± 8.9% vs. 15.4 ± 15.4%, p < 0.01, Fig. 2 C). No adverse events occurred during AVT. Predictors of response to PAH-specific therapy The baseline PVR (cut-off value = 9.5 WU, area under the curve = 0.93) and the change rate in PVR during AVT (cut-off value = 38.6%, area under the curve = 0.95) demonstrated good predictive accuracy (Fig. 3 ). PVR during AVT at cut-off values of 38.6% and 20% revealed sensitivities of 83.3% and 75%, respectively, with both showing 100% specificity. Compared with a PVR change rate of > 38.6% alone, the combination of a baseline PVR of 20% during AVT yielded higher predictive accuracy for response to PAH-specific therapy (100% sensitivity and specificity; Supplemental Fig. 1). Long-term follow-up In the low-PVR group, 6 of 7 patients underwent ASD closure (2 cases using device closure and 4 cases using surgical closure) without fenestration between 3 and 14 months after baseline (Table 3 ). Patients who underwent ASD closure did not experience hospitalization due to heart failure or death, and the improvement in hemodynamics was maintained. Case 7, an older patient who did not undergo ASD closure due to a lack of consent, experienced hospitalization for heart failure followed by death. Conversely, in the high-PVR group, all cases were treated with medication. During the follow-up period, PVR deteriorated in 4 of 8 patients (cases: 10, 11, 12, 13). Furthermore, 4 of the 8 patients (cases 8, 10, 11, and 15) required hospitalization due to heart failure, resulting in one mortality. Table 3 Hemodynamic parameters and prognosis in long-term follow-up Baseline Long-term Follow-up Events Case Age Sex ASD closure (Yes/No) device or surgical closure Time from initial evaluation to ASD closure (months) Duration from baseline to follow-up (months) mPAP (mmHg) PVR (wood unit) 6 MWD (m) Time from baseline to heart failure hospitalization (months) Time from baseline to death (months) Low-PVR group 1 47 F Yes device closure 6 14 14 2.39 600 - - 2 38 F Yes device closure 7 53 14 1.60 525 - - 3 40 F Yes surgical closure 3 48 19 1.75 515 - - 4 35 F Yes surgical closure 10 73 22 3.73 625 - - 5 43 F Yes surgical closure 14 39 6 1.10 490 - - 6 56 F Yes surgical closure 11 70 14 2.00 500 - - 7 70 F No - 19 39 3.20 270 62 88 High-PVR group 8 53 F No - 7 - - 355 164 - 9 73 F No - 83 39 10.1 128 - - 10 47 F No - 76 45 9.50 490 22 - 11 32 F No - 44 66 19.6 - 44 97 12 27 F No - 123 63 23.7 245 - - 13 34 F No - 116 52 12.50 315 - - 14 53 F No - 5 52 7.04 - - - 15 68 M No - 51 47 5.10 340 143 - PVR: pulmonary vascular resistance, mPAP: mean pulmonary arterial pressure, ASD: atrial septal defect, 6MWD: 6-minute walk distance Discussion Main findings The major findings of this study are: (1) 47% of the patients with severe ASD-PAH achieved a PVR of < 5 with oral PAH-specific therapy, (2) a baseline PVR of 9.5 WU was the upper threshold to achieve a PVR of < 5 WU, and (3) patients who achieved a PVR of < 5 WU demonstrated superior acute pulmonary vasoreactivity and better prognosis compared with those who did not (Supplemental Fig. 2). PAH-specific treatment for severe unrepaired ASD-PAH In this study, 47% of patients with severe ASD-PAH achieved a PVR of < 5.0 WU. PAH-specific therapy is reportedly effective for CHD-PAH and Eisenmenger syndrome [ 8 , 9 , 17 , 18 ]. In ASD physiology, PAH is accompanied by high-flow shunting [ 19 ]. These defects should be repaired to reduce Qp; however, residual PAH after shunt closure is a strong risk factor for poor outcomes [ 7 ]. Notably, several studies have reported that PAH treatment and subsequent ASD closure using the treat-and-repair strategy improved hemodynamics and long-term prognosis in patients with severe ASD-PAH [ 11 – 13 ]. According to the ESC guidelines, a PVR of < 5.0 WU should be achieved before ASD closure [ 10 ]. However, the hemodynamic response of patients with severe ASD-PAH to PAH-specific therapy has not yet been investigated in detail. In a study by Bradley et al., shunt repair occurred in only 19/69 (28%) patients with ASD-PAH [ 11 ]. In this multicenter registry study, there were no specific criteria for repair, and medical management was not standardized across the centers. Conversely, our study used a clear criterion of a PVR of < 5.0 WU for ASD closure based on ESC guidelines under the unified management of multidrug therapy at a single institution. Importantly, our findings revealed that almost half of the patients with severe ASD-PAH were candidates for repair, which has important implications for administering PAH drugs when the treat-and-repair strategy is considered. However, a large prospective study is necessary to clarify the efficacy of PAH treatment in patients with severe unrepaired ASD-PAH. Upper PVR threshold to improve a PVR of < 5 WU by PAH-specific therapy In this study, we found that a baseline PVR of 9.5 WU was the upper threshold for improvement to a PVR of < 5 WU when treated with oral PAH-specific therapy in patients with severe ASD-PAH. Patients with severe PVR at baseline did not show marked improvements despite advanced PAH treatment. PAH-specific therapies, which are pulmonary vasodilators, act on vascular smooth muscle to reduce PAP and increase cardiac output. However, their efficacy varies among patients, and PVR on follow-up after medication initiation significantly influences the long-term prognosis of patients with idiopathic PAH [ 20 ]. In particular, PVR reflects blood flow resistance in the pulmonary vascular bed. High PVRs are associated with rapidly progressive pulmonary artery remodeling [ 21 , 22 ]. Therefore, patients with a PVR of ≥ 9.5 WU are assumed to have numerous irreversible lesions, which is a useful factor in stratifying candidate patients for repair. However, further research is needed to establish the association of a baseline PVR of 20% during AVT effectively predicted the response to PAH-specific therapy in patients with severe ASD-PAH, which is consistent with previous findings [ 23 ]. AVT is used to detect treatment responses to calcium channel blockers in patients with idiopathic PAH [ 14 ]. The test involves administering a short-term pulmonary vasodilator agent (e.g., inhaled nitric oxide or aerosolized prostanoids) and measuring the hemodynamic response. A previous study classified patients who experienced a 20% reduction in PVR during AVT as having acute low PVRs to calcium channel blockers [ 24 ]. Furthermore, a positive AVT response reportedly predicts treatment response to pulmonary vasodilators [ 16 ]. Consistently, our study's findings suggest that AVT may be useful for assessing pulmonary vasoreactivity in patients with unrepaired ASD-PAH. However, owing to insufficient evidence, the latest 2020 ESC guidelines do not recommend AVT alone for assessing operability in patients with ASD-PAH [ 10 ]. In this study, AVT was performed solely as a physiological tool to evaluate pulmonary vascular reactivity, not as a determinant of ASD closure. Our results indicated that a PVR change rate of > 20% during AVT might predict the treatment response to PAH-specific therapy. However, further investigation is warranted to clarify the usefulness of the AVT response in identifying patients with unrepaired ASD-PAH eligible for shunt repair. High flow and pulmonary vascular remodeling Notably, patients in the low-PVR group exhibited larger ASD diameters and greater pulmonary blood flow (Qp) at baseline than those in the high-PVR group. This finding might reflect a less advanced stage of pulmonary vascular remodeling, in which left-to-right shunting is preserved, and pulmonary vasoreactivity remains responsive to targeted therapy. Conversely, as pulmonary vascular disease progresses, shunt flow typically decreases because of elevated right-sided pressure and advanced vascular remodeling. In our cohort, baseline Qp was negatively correlated with follow-up PVR, supporting the concept that larger baseline shunts are associated with less severe pulmonary vascular remodeling (Supplemental Fig. 3). However, prolonged exposure to large shunts may accelerate vascular remodeling, underscoring the importance of timely ASD closure when pulmonary hemodynamics permit. Limitations This study had some limitations. First, its retrospective cohort design may have introduced a selection bias. Second, the sample size was limited, reflecting the rarity of severe ASD-PAH, which makes finding enough patients who meet the inclusion criteria difficult. Therefore, our findings should be interpreted with caution and validated in larger multicenter cohorts to enhance external validity. Third, some patients received PAH-specific therapy before the baseline evaluation, which might have influenced the hemodynamic responses. In conclusion, in almost half of the patients with severe ASD-PAH, PVR improved to < 5 WU with PAH-specific therapy. A baseline PVR of 9.5 WU was the upper threshold to achieve a PVR of < 5 WU with oral PAH-specific therapy in patients with severe ASD-PAH. Patients with severe ASD-PAH who achieved a PVR of < 5 WU demonstrated superior acute pulmonary vasoreactivity compared to those who did not. Declarations Competing interest: T. Ogo reports lecture fees from Nippon Shinyaku Co., Ltd. during the conduct of the study and personal fees from Janssen Pharmaceutical K.K., Bayer Yakuhin, Ltd., Nippon Shinyaku Co., Ltd., GlaxoSmithKline K.K., Pfizer Japan Inc., and Mochida Pharmaceutical Co., Ltd., outside the submitted work. The remaining authors declare no conflict of interest. Ethics approval and consent to participate: This study was approved by the Institutional Ethics Committee of the National Cerebral and Cardiovascular Center (No. R20075) and complied with the principles of the Declaration of Helsinki. The committee waived the requirement to obtain informed consent owing to the retrospective observational nature of the study. The use of the “opt-out” consent approach was approved, with a written explanation regarding data usage provided on the websites. Patients were not required to provide written informed consent but were allowed to decline participation. Consent for publication: Not applicable Guarantor T. Ogo takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation Funding: The authors received no specific funding for this work. Author Contribution S. Nakayama, R. Asano, M Hoshiga, and T. Ogo designed the study. A. Tsuji, J. Ueda, H. Hayashi, R. Takano, and S. Fujisaki collected the data. S. Nakayama, R. Asano, and T. Ogo analyzed the data. All the authors participated in the development of the manuscript, provided final approval for submission, and agreed to be accountable for the integrity of this work. Acknowledgments: The authors wish to thank the study group, study staff, and patients. Data Availability The datasets generated and/or analyzed during the current study are not publicly available due to privacy and ethical restrictions but are available from the corresponding author on reasonable request. References Nashat H, Montanaro C, Li W et al (2018) Atrial septal defects and pulmonary arterial hypertension. J Thorac Dis 10(Suppl 24):S2953–s65 Engelfriet P, Meijboom F, Boersma E et al (2008) Repaired and open atrial septal defects type II in adulthood: an epidemiological study of a large European cohort. Int J Cardiol 126(3):379–385 Engelfriet PM, Duffels MG, Möller T et al (2007) Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart 93(6):682–687 Steele PM, Fuster V, Cohen M et al (1987) Isolated atrial septal defect with pulmonary vascular obstructive disease–long-term follow-up and prediction of outcome after surgical correction. Circulation 76(5):1037–1042 D'Alto M, Romeo E, Argiento P et al (2013) Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure. Int J Cardiol 168(4):3797–3801 Kannan BR, Sivasankaran S, Tharakan JA et al (2003) Long-term outcome of patients operated for large ventricular septal defects with increased pulmonary vascular resistance. Indian Heart J 55(2):161–166 Manes A, Palazzini M, Leci E et al (2014) Current era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: a comparison between clinical subgroups. Eur Heart J 35(11):716–724 Dimopoulos K, Inuzuka R, Goletto S et al (2010) Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation 121(1):20–25 Gatzoulis MA, Beghetti M, Galiè N et al (2008) Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 open-label extension study. Int J Cardiol 127(1):27–32 Baumgartner H, De Backer J, Babu-Narayan SV et al (2021) 2020 ESC Guidelines for the management of adult congenital heart disease. Eur Heart J 42(6):563–645 Bradley EA, Ammash N, Martinez SC et al (2019) Treat-to-close: Non-repairable ASD-PAH in the adult: Results from the North American ASD-PAH (NAAP) Multicenter Registry. Int J Cardiol 291:127–133 Kijima Y, Akagi T, Takaya Y et al (2016) Treat and Repair Strategy in Patients With Atrial Septal Defect and Significant Pulmonary Arterial Hypertension. Circ J 80(1):227–234 Takaya Y, Akagi T, Sakamoto I et al (2022) Efficacy of treat-and-repair strategy for atrial septal defect with pulmonary arterial hypertension. Heart 108(5):382–387 Olschewski H, Kovacs G (2015) [ESC guidelines 2015 on pulmonary hypertension]. Herz 40(8):1055–1060 Azeka E, Costa Auler JO Jr., Kajita L et al (2002) Effects of low doses of inhaled nitric oxide combined with oxygen for the evaluation of pulmonary vascular reactivity in patients with pulmonary hypertension. Pediatr Cardiol 23(1):20–26 Hirakawa K, Asano R, Ueda J et al (2024) Calcium channel blockers in patients with pulmonary arterial hypertension receiving PAH-specific treatment. Int J Cardiol 406:132043 Mohammed S, Vijayvergiya R, Malhotra S et al (2021) A randomized, double-blind, placebo-controlled study to evaluate sildenafil, ambrisentan combination therapy in pulmonary hypertension, particularly of Eisenmenger syndrome. Indian Heart J 73(5):633–636 Wals-Rodriguez AJ, Rodriguez-Puras MJ, Garcia-Orta R et al (2022) Pulmonary hypertension in adults with congenital heart disease. Clinical phenotypes and outcomes in the advanced pulmonary vasodilator era. Heart Lung 51:75–81 van der Feen DE, Bartelds B, de Boer RA et al (2017) Pulmonary arterial hypertension in congenital heart disease: translational opportunities to study the reversibility of pulmonary vascular disease. Eur Heart J 38(26):2034–2041 Suzuki S, Asano R, Aoki T et al (2022) Prognostic impact of follow-up pulmonary vascular resistance in pulmonary arterial hypertension. Open Heart. ;9(1) Bush A, Busst CM, Haworth SG et al (1988) Correlations of lung morphology, pulmonary vascular resistance, and outcome in children with congenital heart disease. Br Heart J 59(4):480–485 Heath D, Edwards JE (1958) The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 18(4 Part 1):533–547 Xi SB, Wang SS, Qian MY et al (2019) Predictors of operability in children with severe pulmonary hypertension associated with congenital heart disease. Chin Med J (Engl) 132(7):811–818 Sitbon O, Humbert M, Jaïs X et al (2005) Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111(23):3105–3111 Additional Declarations No competing interests reported. Supplementary Files SupplementalTable1RA2.docx Cite Share Download PDF Status: Published Journal Publication published 26 Mar, 2026 Read the published version in Pediatric Cardiology → Version 1 posted Editorial decision: Revision requested 26 Feb, 2026 Reviews received at journal 17 Feb, 2026 Reviewers agreed at journal 05 Feb, 2026 Reviewers invited by journal 04 Feb, 2026 Editor assigned by journal 03 Feb, 2026 Submission checks completed at journal 03 Feb, 2026 First submitted to journal 01 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8754390","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":586456466,"identity":"0110c69f-421a-411c-bc1e-b2c0af2b662d","order_by":0,"name":"Sayuri Nakayama","email":"","orcid":"","institution":"National Cerebral and Cardiovascular Center","correspondingAuthor":false,"prefix":"","firstName":"Sayuri","middleName":"","lastName":"Nakayama","suffix":""},{"id":586456467,"identity":"b4ce7abe-5afe-4fdb-8469-c042038b935e","order_by":1,"name":"Ryotaro Asano","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYNCCCgkefgTvADFaztjISDaQpIWxLc3GgCizQYC///CzBx/YDvMY325+JvGDoVaOgfEsft0SN9LMDWfwHOYxu3PMTLKH4bgxA8O5BPzW3GAwk+aRAGq5kcMMVH4ssYHhjAFeHfLnj3+T5jEAOmwGsVoMDuQAbUlI4zGQyGF8zMBQQ1iL4Y2cMskZB2x4gJ4yfNhjcMCYjZBf5M4f3ybx8Z+EPf+M5AcHflTUyfFLEAgxdHceZmCTOEOKDgaGOmBU9ZCmZRSMglEwCoY9AAClqkSN8ibZ5AAAAABJRU5ErkJggg==","orcid":"","institution":"National Cerebral and Cardiovascular Center","correspondingAuthor":true,"prefix":"","firstName":"Ryotaro","middleName":"","lastName":"Asano","suffix":""},{"id":586456468,"identity":"b06a2890-92cc-4b88-9466-45b57c67a354","order_by":2,"name":"Akihiro Tsuji","email":"","orcid":"","institution":"National Cerebral and Cardiovascular Center","correspondingAuthor":false,"prefix":"","firstName":"Akihiro","middleName":"","lastName":"Tsuji","suffix":""},{"id":586456469,"identity":"8c19b65c-c513-4269-b7b4-b7f7ec47678c","order_by":3,"name":"Jin Ueda","email":"","orcid":"","institution":"National Cerebral and Cardiovascular Center","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"","lastName":"Ueda","suffix":""},{"id":586456471,"identity":"1df6c807-53c6-44cc-b63c-62b612d762df","order_by":4,"name":"Hiroya Hayashi","email":"","orcid":"","institution":"National Cerebral and Cardiovascular Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroya","middleName":"","lastName":"Hayashi","suffix":""},{"id":586456473,"identity":"39fd7b38-a836-4b9b-b955-81e89db7c183","order_by":5,"name":"Ryo Takano","email":"","orcid":"","institution":"National Cerebral and Cardiovascular Center","correspondingAuthor":false,"prefix":"","firstName":"Ryo","middleName":"","lastName":"Takano","suffix":""},{"id":586456474,"identity":"8c50db54-76a1-486b-b749-04f8d7e8c88b","order_by":6,"name":"Shinya Fujisaki","email":"","orcid":"","institution":"National Cerebral and Cardiovascular Center","correspondingAuthor":false,"prefix":"","firstName":"Shinya","middleName":"","lastName":"Fujisaki","suffix":""},{"id":586456475,"identity":"fa51092e-e143-44c0-acae-048fad73494e","order_by":7,"name":"Masaaki Hoshiga","email":"","orcid":"","institution":"Osaka Medical and Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Masaaki","middleName":"","lastName":"Hoshiga","suffix":""},{"id":586456476,"identity":"09bdd087-a21b-4f6f-9ef1-c2ba1b73ee5c","order_by":8,"name":"Takeshi Ogo","email":"","orcid":"","institution":"National Cerebral and Cardiovascular Center","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Ogo","suffix":""}],"badges":[],"createdAt":"2026-02-01 07:23:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8754390/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8754390/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00246-026-04226-y","type":"published","date":"2026-03-26T16:10:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":102238470,"identity":"af1eac19-f2c4-4815-a29b-f0a2e1ce4192","added_by":"auto","created_at":"2026-02-09 16:40:44","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":176544,"visible":true,"origin":"","legend":"\u003cp\u003ePatient selection flowchart\u003c/p\u003e\n\u003cp\u003ePatients with ASD-PAH who had a PVR of \u0026gt;5.0 WU and no history of shunt repair were retrospectively reviewed.\u003c/p\u003e\n\u003cp\u003eASD: atrial septal defect, PH: pulmonary hypertension, PAH: pulmonary arterial hypertension, PVR: pulmonary vascular resistance, IPAH: idiopathic pulmonary arterial hypertension, PoPH: portopulmonary hypertension, CHD: congenital heart disease, VSD: ventricular septal defect\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8754390/v1/da5f88b99856786839e48b07.jpeg"},{"id":102238454,"identity":"930da266-bc36-43fd-8d06-24da7e59afa7","added_by":"auto","created_at":"2026-02-09 16:40:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":247038,"visible":true,"origin":"","legend":"\u003cp\u003eHemodynamic response to PAH treatment and AVT\u003c/p\u003e\n\u003cp\u003e(A–B) Changes in the mean PAP (A) and PVR (B) after PAH-specific therapy in the low-PVR and high-PVR groups. PAH-specific therapy significantly decreased the mean PAP and PVR in the low-PVR group. (C) PVR during NO challenge in AVT in the low-PVR and high-PVR groups. *p\u0026lt;0.05, **p\u0026lt;0.01, ***p\u0026lt;0.001\u003c/p\u003e\n\u003cp\u003ePAP: pulmonary arterial pressure, PVR: pulmonary vascular resistance, PAH: pulmonary arterial hypertension, AVT: acute vasoreactivity test, PVR: pulmonary vascular resistance,\u003c/p\u003e\n\u003cp\u003eNO: nitric oxide\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8754390/v1/a733c217c5a8cb6979c25b1f.png"},{"id":102238425,"identity":"c7d08931-d61b-440e-8135-4195559fccc1","added_by":"auto","created_at":"2026-02-09 16:40:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":97352,"visible":true,"origin":"","legend":"\u003cp\u003ePredictors for response to PAH-specific therapy treatment\u003c/p\u003e\n\u003cp\u003e(A) Baseline PVR and PVR change rates during AVT in the low- and high-PVR groups. (B) Predictive power by cut-off value. A baseline PVR of \u0026lt; 9.5 WU and a PVR change rate of \u0026gt;20% during AVT have 100% sensitivity, specificity, and accuracy.\u003c/p\u003e\n\u003cp\u003ePAH: pulmonary arterial hypertension, PVR: pulmonary vascular resistance, AVT: acute vasoreactivity test\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8754390/v1/70ce7c06814baf329f0797d2.png"},{"id":105754829,"identity":"efd2305c-8b92-4be0-9372-f719040064be","added_by":"auto","created_at":"2026-03-30 16:22:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1623936,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8754390/v1/1af53829-88c6-4bcb-988c-9e0a29d5486e.pdf"},{"id":102238431,"identity":"9eb86435-069c-42a0-b777-fe36c3340aa0","added_by":"auto","created_at":"2026-02-09 16:40:35","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":15499,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable1RA2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8754390/v1/f7c781759bf8af70cb79cce2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pulmonary Arterial Hypertension-Specific Therapy for Atrial Septal Defects with Severe Pulmonary Arterial Hypertension","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAtrial septal defect (ASD) is the second most common congenital heart disease (CHD) after bicuspid aortic valve [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Pulmonary arterial hypertension (PAH) has been reported in 6\u0026ndash;36% of patients with ASD, and its prevalence is steadily increasing among those aged\u0026thinsp;\u0026ge;\u0026thinsp;30 years [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Preoperative PAH with elevated pulmonary vascular resistance (PVR) is associated with persistent or recurrent PAH after shunt closure [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Furthermore, PAH that develops after shunt repair has a worse prognosis compared with Eisenmenger syndrome [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Recent advances in PAH-specific therapy, including prostanoids, endothelin-receptor antagonists, and phosphodiesterase type 5 inhibitors, have led to considerable changes in the treatment of CHD-associated PAH (CHD-PAH) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The 2020 European Society of Cardiology (ESC) guidelines for the management of adult CHD indicate that ASD closure may be considered when PVR is \u0026lt;\u0026thinsp;5.0 Wood units (WU) after PAH-specific therapy in patients with ASD-associated PAH (ASD-PAH) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eImportantly, some studies reported safe ASD closure after successful PAH-specific therapy (known as the \u0026ldquo;treat and repair\u0026rdquo; strategy) in patients with severe ASD-PAH with stable post-shunt closure hemodynamics [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, the hemodynamic characteristics of patients achieving a PVR\u0026thinsp;\u0026lt;\u0026thinsp;5 WU after PAH-specific therapy as an indication for ASD closure remain unclear. Furthermore, hemodynamic improvement in PAH-specific therapy is typically limited to patients who have undergone surgical repair. The efficacy of PAH-specific therapy in managing patients with severe ASD-PAH is unclear.\u003c/p\u003e \u003cp\u003eCharacterizing patients with severe ASD-PAH who achieve a PVR of \u0026lt;\u0026thinsp;5 WU after PAH-specific therapy may help identify candidates for treatment and repair strategies. Therefore, this study aimed to examine the hemodynamic characteristics of patients with severe ASD-PAH who achieved a PVR of \u0026lt;\u0026thinsp;5.0 WU with PAH-specific therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eThis retrospective study evaluated patients with severe ASD-PAH who were referred to the National Cerebral and Cardiovascular Center in Osaka, Japan, between January 2011 and July 2020. Among the 954 patients with ASD initially identified, 903 patients without suspected pulmonary hypertension based on echocardiography and 4 with other causes of PAH (portopulmonary hypertension, n\u0026thinsp;=\u0026thinsp;1; chronic thromboembolic pulmonary hypertension, n\u0026thinsp;=\u0026thinsp;2; and lung disease-related pulmonary hypertension, n\u0026thinsp;=\u0026thinsp;1) were excluded. Of the remaining 47 patients with suspected pulmonary hypertension, 45 underwent right heart catheterization (RHC), and 21 were diagnosed with ASD-PAH. Among these 21 patients, 17 had severe PAH (PVR\u0026thinsp;\u0026ge;\u0026thinsp;5.0 WU). Two patients were excluded due to loss to follow-up and lack of data on PAH-specific therapy. Finally, 15 patients with severe ASD-PAH who received PAH-specific therapy were included in the analysis. The patient selection flowchart is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Clinicodemographic data, including age, sex, ASD morphology, brain natriuretic peptide (BNP) levels, and symptoms at baseline, were collected from electronic medical records.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Ethics Committee of the National Cerebral and Cardiovascular Center (No. R20075). The committee waived the requirement for informed consent owing to the study's retrospective, observational nature. An \u0026ldquo;opt-out\u0026rdquo; approach to consent was approved, and a written explanation for data use was provided on the websites, allowing patients to decline participation without requiring written informed consent.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDefinition of PAH and clinical evaluations\u003c/h3\u003e\n\u003cp\u003ePAH was defined as mean pulmonary arterial pressure (PAP)\u0026thinsp;\u0026ge;\u0026thinsp;25 mmHg, mean pulmonary arterial wedge pressure\u0026thinsp;\u0026le;\u0026thinsp;15 mmHg, and PVR\u0026thinsp;\u0026gt;\u0026thinsp;3.0 WU based on measurements from hemodynamic variables at the initial RHC [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This definition followed the 2015 ESC/European Respiratory Society guidelines, which were the most recent criteria available when the study was initiated. Although the 2022 ESC/European Respiratory Society guidelines lowered the hemodynamic threshold for PAH diagnosis, the inclusion criteria in this study were set to include patients with severe PAH (PVR\u0026thinsp;\u0026ge;\u0026thinsp;5.0 WU) and would therefore not be affected by the updated definition. ASD morphology was evaluated using transesophageal echocardiography. PAH symptoms were evaluated using the World Health Organization Functional Classification (WHO-FC).\u003c/p\u003e\n\u003ch3\u003ePAH specific therapy\u003c/h3\u003e\n\u003cp\u003ePAH-specific therapy includes endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, and prostacyclin analogs (oral and intravenous). Treatment regimens were determined by cardiologists specializing in pulmonary hypertension.\u003c/p\u003e\n\u003ch3\u003eMeasurement of hemodynamics\u003c/h3\u003e\n\u003cp\u003eHemodynamic parameters, including mean pulmonary capillary wedge pressure, PAP, right atrial pressure, cardiac output, and PVR, were measured using RHC. Cardiac output was determined using the Fick method and corrected for body surface area. An acute vasoreactivity test (AVT) was performed at the initial RHC. In AVT, patients inhaled 100% O\u003csub\u003e2\u003c/sub\u003e and 20 ppm nitric oxide through a mask [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The effects were observed 10 min after administration. Hemodynamic parameters were measured and calculated before and after inhalation. Follow-up RHC was performed after a median period of 5 months (interquartile range [IQR], 2.0\u0026ndash;7.0 months) following initiation or intensification of PAH-specific therapy to evaluate post-treatment hemodynamic changes.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables are expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations or medians (IQRs), whereas categorical variables are expressed as numbers and percentages. Patients who achieved a PVR\u0026thinsp;\u0026lt;\u0026thinsp;5 WU with PAH-specific therapy were classified as the low-PVR group, whereas the remaining patients were classified as the high-PVR group [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Between-group comparisons were performed using the Student\u0026rsquo;s t-test for normally distributed continuous variables and the Wilcoxon signed-rank test for non-normally distributed continuous or categorical variables. Changes in categorical variables and serial hemodynamic measures from baseline to post-PAH-specific therapy were analyzed using Fisher\u0026rsquo;s exact and paired t-tests, respectively. The sensitivity, specificity, and accuracy of PVR at baseline and during AVT in predicting response to PAH-specific therapy were determined using receiver operating characteristic (ROC) curve analysis. All statistical analyses were performed using JMP software (version 15; SAS Institute, Cary, NC, USA). Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eBaseline patient characteristics\u003c/h2\u003e \u003cp\u003eThe characteristics of the 15 patients are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age at baseline was 49.2\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7 years, with 14 (93%) patients being female. The median long-axis diameter of ASD was 25.5 mm (IQR, 16.5\u0026ndash;31.3 mm). Eight patients had previously received PAH-specific therapy. WHO-FC I, II, and III symptoms were observed in 13%, 60%, and 27% of patients, respectively. None of the patients had WHO-FC IV symptoms.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline patient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLow-PVR group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHigh-PVR group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.2\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47.0\u0026thinsp;\u0026plusmn;\u0026thinsp;12.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51.1\u0026thinsp;\u0026plusmn;\u0026thinsp;13.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePAH-specific therapy\u003c/p\u003e \u003cp\u003eERA, n (%)\u003c/p\u003e \u003cp\u003ePDE5 inhibitors, n (%)\u003c/p\u003e \u003cp\u003eOral prostanoids, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (33)\u003c/p\u003e \u003cp\u003e2 (13)\u003c/p\u003e \u003cp\u003e1 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (38)\u003c/p\u003e \u003cp\u003e1 (13)\u003c/p\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003cp\u003e0.92\u003c/p\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASD type\u003c/p\u003e \u003cp\u003eSecundum, n (%)\u003c/p\u003e \u003cp\u003eCS, n (%)\u003c/p\u003e \u003cp\u003eSinus venosus, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (87)\u003c/p\u003e \u003cp\u003e1 (7)\u003c/p\u003e \u003cp\u003e1 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (71)\u003c/p\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003cp\u003e1 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (100)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASD diameter\u003c/p\u003e \u003cp\u003eLong axis, mm\u003c/p\u003e \u003cp\u003eAverage of long and short axis, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.5 (16.5\u0026ndash;31.3)\u003c/p\u003e \u003cp\u003e24.0 (16.0\u0026ndash;27.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.0 (18.0\u0026ndash;39.3)\u003c/p\u003e \u003cp\u003e27.5 (16.5\u0026ndash;34.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.5 (14.8\u0026ndash;28.8)\u003c/p\u003e \u003cp\u003e17.5 (14.8\u0026ndash;25.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther malformations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePAPVR (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePoore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ndash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFunctional status\u003c/p\u003e \u003cp\u003eWHO-FC\u003c/p\u003e \u003cp\u003eWHO-FC\u0026thinsp;\u0026ge;\u0026thinsp;III, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003cp\u003e4 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003cp\u003e3 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003cp\u003e1 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBNP, pg/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98 (57.3\u0026ndash;168.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e99.6 (52.8\u0026ndash;566.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97.9 (65.7\u0026ndash;123.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003esPAP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edPAP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emPAP, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePVR, WU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQp/Qs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQp, L/min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eContinuous values are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (IQR). Categorical values are expressed as numbers and percentages, and n indicates the number of patients.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eBMI: body mass index, ERA: endothelin receptor antagonist, PDE5: phosphodiesterase type 5, ASD: atrial septal defect, CS: coronary sinus, PAPVR: partial anomalous pulmonary venous return, WHO-FC: World Health Organization Functional Class, BNP: brain natriuretic peptide, sPAP: systolic pulmonary arterial pressure, dPAP: diastolic pulmonary arterial pressure, mPAP: mean pulmonary arterial pressure, PVR: pulmonary vascular resistance, Qp/Qs: pulmonary to systemic flow ratio, Qp: pulmonary blood flow, Qs: systemic blood flow, SD: standard deviation, IQR: interquartile range, WU: Wood units\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the 15 patients, 7 (47%) achieved a PVR\u0026thinsp;\u0026lt;\u0026thinsp;5 WU with PAH-specific therapy and were classified as the low-PVR group, whereas the remaining 8 (53%) were classified as the high-PVR group. The maximum baseline PVR in the low-PVR group was 9.5 WU. Partial anomalous pulmonary venous return was detected in a patient in the low-PVR group. Comparisons between the low-PVR and high-PVR groups revealed no significant differences in age (47.0\u0026thinsp;\u0026plusmn;\u0026thinsp;12.2 vs. 51.1\u0026thinsp;\u0026plusmn;\u0026thinsp;13.7 years, p\u0026thinsp;=\u0026thinsp;0.55), ASD diameter (31.0 [IQR, 18.0\u0026ndash;39.3] vs. 22.5 [IQR, 14.8\u0026ndash;28.8] mm, p\u0026thinsp;=\u0026thinsp;0.14), and BNP levels (99.6 [IQR, 52.8\u0026ndash;566.1] vs. 97.9 [IQR, 65.7\u0026ndash;123.7] pg/mL, p\u0026thinsp;=\u0026thinsp;0.64). WHO-FC I, II, and III symptoms were observed in 14%, 43%, and 43% of patients, respectively, in the low-PVR group, and in 12.5%, 75%, and 12.5% of patients, respectively, in the high-PVR group, with no significant difference (p\u0026thinsp;=\u0026thinsp;0.38).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eChanges in hemodynamic parameters after PAH-specific therapy\u003c/h3\u003e\n\u003cp\u003eCompared with the high-PVR group, the low-PVR group had significantly lower mean PAP (47.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9 vs. 58.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.7 mmHg, p\u0026thinsp;=\u0026thinsp;0.03), lower PVR (7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 vs. 13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8 WU, p\u0026thinsp;=\u0026thinsp;0.01), and higher pulmonary blood flow (Qp) (6.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14 vs. 4.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16 L/min, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Hemodynamic data at baseline and after PAH-specific therapy are presented in Supplementary Table\u0026nbsp;1. All patients received oral PAH-specific therapy. Within a median follow-up period of 5 months (IQR, 2.0\u0026ndash;7.0 months), 14 patients (7 patients per group) were treated with endothelin receptor antagonists, all patients received phosphodiesterase type 5 inhibitors, and 13 patients (7 patients in the low-PVR group and 6 patients in the high-PVR group) received oral or inhaled prostanoids (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHemodynamic parameters at baseline and follow-up\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePAH‑specific therapy (dose)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBaseline mPAP (mm Hg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBaseline PVR (Wood U)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAVT % Δ PVR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFollow‑up mPAP (mm Hg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eFollow‑up PVR (Wood U)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTherapy % Δ PVR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow‑PVR group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Tadalafil 40 mg, Beraprost 240 \u0026micro;g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e38.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e51.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Tadalafil 40 mg, Beraprost 360 \u0026micro;g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e54.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e1.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e70.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAmbrisentan 10 mg, Tadalafil 40 mg, Beraprost 120 \u0026micro;g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e46.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e27.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Tadalafil 40 mg, Selexipag 1.6 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e33.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e57.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Tadalafil 40 mg, Selexipag 2.4 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e41.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e2.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e66.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Tadalafil 40 mg, Beraprost 60 \u0026micro;g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003eN/A\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e1.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e71.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Sildenafil 60 mg, Selexipag 1.6 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e55.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e3.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e42.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh‑PVR group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBosentan 250 mg, Tadalafil 40 mg, Beraprost 120 \u0026micro;g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e7.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e23.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Tadalafil 40 mg, Beraprost 120 \u0026micro;g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e14.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e18.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e‑24.3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Tadalafil 40 mg, Selexipag 3.2 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e14.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e36.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e61.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Tadalafil 40 mg, Beraprost 360 \u0026micro;g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003eN/A\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e20.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Tadalafil 40 mg, Iloprost (i.t.) 7.5 \u0026micro;g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e26.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e18.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e32.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacitentan 10 mg, Tadalafil 40 mg, Beraprost 360 \u0026micro;g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e14.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e35.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e6.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e52.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTadalafil 40 mg, Selexipag 1.0 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e‑1.0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e9.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e20.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBosentan 250 mg, Tadalafil 40 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e7.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e‑6.3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003cem\u003eAVT\u003c/em\u003e: acute vasoreactivity test, \u003cem\u003ePVR\u003c/em\u003e: pulmonary vascular resistance (Wood units), \u003cem\u003emPAP\u003c/em\u003e: mean pulmonary arterial pressure (mm Hg)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003cb\u003eNotes\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e1. \u003cb\u003e%Δ PVR\u003c/b\u003e\u0026thinsp;=\u0026thinsp;100 \u0026times; [(Baseline PVR \u0026ndash; Follow‑up PVR) / Baseline PVR].\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e2. Positive values indicate a \u003cem\u003edecrease\u003c/em\u003e in PVR; negative values indicate an \u003cem\u003eincrease\u003c/em\u003e (e.g., Cases 9, 14, 15).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e3. \u0026ldquo;N/A\u0026rdquo; means the percentage change could not be calculated because the baseline PVR was already very low or the follow‑up measurement was missing.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e4. All patients were female, except for Case 15 (male).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the total population, the mean PAP and PVR values significantly decreased from 53.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7 to 44.0\u0026thinsp;\u0026plusmn;\u0026thinsp;11.8 mmHg (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and from 10.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5 to 7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2 WU (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), respectively, whereas Qp increased from 5.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.52 to 7.27\u0026thinsp;\u0026plusmn;\u0026thinsp;3.22 L/min (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Compared with the high-PVR group, the low-PVR group had a significantly lower mean PAP (34.3\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9 vs. 58.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7 mmHg, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and PVR (3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 vs. 10.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9 WU, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and significantly higher Qp (9.70\u0026thinsp;\u0026plusmn;\u0026thinsp;2.72 vs. 5.15\u0026thinsp;\u0026plusmn;\u0026thinsp;1.82 L/min, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) after PAH-specific therapy. The mean PAP and PVR were significantly reduced after targeted PAH treatment in the low-PVR group, but not in the high-PVR group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). The reduction rates in the mean PAP and PVR after targeted PAH treatment were significantly higher in the low-PVR group than in the high-PVR group (mean PAP: 28.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9% vs. 8.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.6%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; mean PVR: 55.1\u0026thinsp;\u0026plusmn;\u0026thinsp;16.1% vs. 22.5\u0026thinsp;\u0026plusmn;\u0026thinsp;28.1%, p\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAcute vasoreactivity at baseline\u003c/h2\u003e \u003cp\u003eAVT was performed in 13 patients (6 in the low-PVR group and 7 in the high-PVR group). There was no significant between-group difference in the change in mean PAP (12.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8% vs. 6.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2%, p\u0026thinsp;=\u0026thinsp;0.15). However, the reduction rate in PVR during AVT was higher in the low-PVR group than in the high-PVR group (44.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9% vs. 15.4\u0026thinsp;\u0026plusmn;\u0026thinsp;15.4%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). No adverse events occurred during AVT.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePredictors of response to PAH-specific therapy\u003c/h2\u003e \u003cp\u003eThe baseline PVR (cut-off value\u0026thinsp;=\u0026thinsp;9.5 WU, area under the curve\u0026thinsp;=\u0026thinsp;0.93) and the change rate in PVR during AVT (cut-off value\u0026thinsp;=\u0026thinsp;38.6%, area under the curve\u0026thinsp;=\u0026thinsp;0.95) demonstrated good predictive accuracy (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). PVR during AVT at cut-off values of 38.6% and 20% revealed sensitivities of 83.3% and 75%, respectively, with both showing 100% specificity. Compared with a PVR change rate of \u0026gt;\u0026thinsp;38.6% alone, the combination of a baseline PVR of \u0026lt;\u0026thinsp;9.5 WU and a PVR change rate of \u0026gt;\u0026thinsp;20% during AVT yielded higher predictive accuracy for response to PAH-specific therapy (100% sensitivity and specificity; Supplemental Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eLong-term follow-up\u003c/h2\u003e \u003cp\u003eIn the low-PVR group, 6 of 7 patients underwent ASD closure (2 cases using device closure and 4 cases using surgical closure) without fenestration between 3 and 14 months after baseline (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Patients who underwent ASD closure did not experience hospitalization due to heart failure or death, and the improvement in hemodynamics was maintained. Case 7, an older patient who did not undergo ASD closure due to a lack of consent, experienced hospitalization for heart failure followed by death. Conversely, in the high-PVR group, all cases were treated with medication. During the follow-up period, PVR deteriorated in 4 of 8 patients (cases: 10, 11, 12, 13). Furthermore, 4 of the 8 patients (cases 8, 10, 11, and 15) required hospitalization due to heart failure, resulting in one mortality.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHemodynamic parameters and prognosis in long-term follow-up\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c11\" namest=\"c8\"\u003e \u003cp\u003eLong-term Follow-up\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e \u003cp\u003eEvents\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eASD closure (Yes/No)\u003c/p\u003e \u003cp\u003edevice or surgical closure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTime from initial evaluation to \u003c/p\u003e \u003cp\u003eASD closure (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDuration from baseline to follow-up (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003emPAP (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePVR (wood unit)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6 MWD (m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eTime from baseline to heart failure hospitalization (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eTime from baseline to death (months)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-PVR group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003edevice closure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003edevice closure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e525\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003esurgical closure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e515\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003esurgical closure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e625\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003esurgical closure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e490\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003esurgical closure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e270\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-PVR group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e355\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e164\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e490\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e19.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e23.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e245\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e12.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e315\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e340\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"13\"\u003ePVR: pulmonary vascular resistance, mPAP: mean pulmonary arterial pressure, ASD: atrial septal defect, 6MWD: 6-minute walk distance\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eMain findings\u003c/h2\u003e \u003cp\u003eThe major findings of this study are: (1) 47% of the patients with severe ASD-PAH achieved a PVR of \u0026lt;\u0026thinsp;5 with oral PAH-specific therapy, (2) a baseline PVR of 9.5 WU was the upper threshold to achieve a PVR of \u0026lt;\u0026thinsp;5 WU, and (3) patients who achieved a PVR of \u0026lt;\u0026thinsp;5 WU demonstrated superior acute pulmonary vasoreactivity and better prognosis compared with those who did not (Supplemental Fig.\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003ePAH-specific treatment for severe unrepaired ASD-PAH\u003c/h2\u003e \u003cp\u003eIn this study, 47% of patients with severe ASD-PAH achieved a PVR of \u0026lt;\u0026thinsp;5.0 WU. PAH-specific therapy is reportedly effective for CHD-PAH and Eisenmenger syndrome [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In ASD physiology, PAH is accompanied by high-flow shunting [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. These defects should be repaired to reduce Qp; however, residual PAH after shunt closure is a strong risk factor for poor outcomes [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Notably, several studies have reported that PAH treatment and subsequent ASD closure using the treat-and-repair strategy improved hemodynamics and long-term prognosis in patients with severe ASD-PAH [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. According to the ESC guidelines, a PVR of \u0026lt;\u0026thinsp;5.0 WU should be achieved before ASD closure [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, the hemodynamic response of patients with severe ASD-PAH to PAH-specific therapy has not yet been investigated in detail. In a study by Bradley et al., shunt repair occurred in only 19/69 (28%) patients with ASD-PAH [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In this multicenter registry study, there were no specific criteria for repair, and medical management was not standardized across the centers. Conversely, our study used a clear criterion of a PVR of \u0026lt;\u0026thinsp;5.0 WU for ASD closure based on ESC guidelines under the unified management of multidrug therapy at a single institution. Importantly, our findings revealed that almost half of the patients with severe ASD-PAH were candidates for repair, which has important implications for administering PAH drugs when the treat-and-repair strategy is considered. However, a large prospective study is necessary to clarify the efficacy of PAH treatment in patients with severe unrepaired ASD-PAH.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eUpper PVR threshold to improve a PVR of \u0026lt;\u0026thinsp;5 WU by PAH-specific therapy\u003c/h2\u003e \u003cp\u003eIn this study, we found that a baseline PVR of 9.5 WU was the upper threshold for improvement to a PVR of \u0026lt;\u0026thinsp;5 WU when treated with oral PAH-specific therapy in patients with severe ASD-PAH. Patients with severe PVR at baseline did not show marked improvements despite advanced PAH treatment. PAH-specific therapies, which are pulmonary vasodilators, act on vascular smooth muscle to reduce PAP and increase cardiac output. However, their efficacy varies among patients, and PVR on follow-up after medication initiation significantly influences the long-term prognosis of patients with idiopathic PAH [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In particular, PVR reflects blood flow resistance in the pulmonary vascular bed. High PVRs are associated with rapidly progressive pulmonary artery remodeling [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, patients with a PVR of \u0026ge;\u0026thinsp;9.5 WU are assumed to have numerous irreversible lesions, which is a useful factor in stratifying candidate patients for repair. However, further research is needed to establish the association of a baseline PVR of \u0026lt;\u0026thinsp;9.5 WU with treatment response in patients with unrepaired ASD-PAH.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eThe effect of the acute vasoreactivity test\u003c/h2\u003e \u003cp\u003eA PVR change rate of \u0026gt;\u0026thinsp;20% during AVT effectively predicted the response to PAH-specific therapy in patients with severe ASD-PAH, which is consistent with previous findings [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. AVT is used to detect treatment responses to calcium channel blockers in patients with idiopathic PAH [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The test involves administering a short-term pulmonary vasodilator agent (e.g., inhaled nitric oxide or aerosolized prostanoids) and measuring the hemodynamic response. A previous study classified patients who experienced a 20% reduction in PVR during AVT as having acute low PVRs to calcium channel blockers [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Furthermore, a positive AVT response reportedly predicts treatment response to pulmonary vasodilators [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Consistently, our study's findings suggest that AVT may be useful for assessing pulmonary vasoreactivity in patients with unrepaired ASD-PAH. However, owing to insufficient evidence, the latest 2020 ESC guidelines do not recommend AVT alone for assessing operability in patients with ASD-PAH [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In this study, AVT was performed solely as a physiological tool to evaluate pulmonary vascular reactivity, not as a determinant of ASD closure. Our results indicated that a PVR change rate of \u0026gt;\u0026thinsp;20% during AVT might predict the treatment response to PAH-specific therapy. However, further investigation is warranted to clarify the usefulness of the AVT response in identifying patients with unrepaired ASD-PAH eligible for shunt repair.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eHigh flow and pulmonary vascular remodeling\u003c/h2\u003e \u003cp\u003eNotably, patients in the low-PVR group exhibited larger ASD diameters and greater pulmonary blood flow (Qp) at baseline than those in the high-PVR group. This finding might reflect a less advanced stage of pulmonary vascular remodeling, in which left-to-right shunting is preserved, and pulmonary vasoreactivity remains responsive to targeted therapy. Conversely, as pulmonary vascular disease progresses, shunt flow typically decreases because of elevated right-sided pressure and advanced vascular remodeling. In our cohort, baseline Qp was negatively correlated with follow-up PVR, supporting the concept that larger baseline shunts are associated with less severe pulmonary vascular remodeling (Supplemental Fig.\u0026nbsp;3). However, prolonged exposure to large shunts may accelerate vascular remodeling, underscoring the importance of timely ASD closure when pulmonary hemodynamics permit.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis study had some limitations. First, its retrospective cohort design may have introduced a selection bias. Second, the sample size was limited, reflecting the rarity of severe ASD-PAH, which makes finding enough patients who meet the inclusion criteria difficult. Therefore, our findings should be interpreted with caution and validated in larger multicenter cohorts to enhance external validity. Third, some patients received PAH-specific therapy before the baseline evaluation, which might have influenced the hemodynamic responses.\u003c/p\u003e \u003cp\u003eIn conclusion, in almost half of the patients with severe ASD-PAH, PVR improved to \u0026lt;\u0026thinsp;5 WU with PAH-specific therapy. A baseline PVR of 9.5 WU was the upper threshold to achieve a PVR of \u0026lt;\u0026thinsp;5 WU with oral PAH-specific therapy in patients with severe ASD-PAH. Patients with severe ASD-PAH who achieved a PVR of \u0026lt;\u0026thinsp;5 WU demonstrated superior acute pulmonary vasoreactivity compared to those who did not.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interest:\u003c/h2\u003e \u003cp\u003eT. Ogo reports lecture fees from Nippon Shinyaku Co., Ltd. during the conduct of the study and personal fees from Janssen Pharmaceutical K.K., Bayer Yakuhin, Ltd., Nippon Shinyaku Co., Ltd., GlaxoSmithKline K.K., Pfizer Japan Inc., and Mochida Pharmaceutical Co., Ltd., outside the submitted work. The remaining authors declare no conflict of interest.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e \u003cp\u003eThis study was approved by the Institutional Ethics Committee of the National Cerebral and Cardiovascular Center (No. R20075) and complied with the principles of the Declaration of Helsinki. The committee waived the requirement to obtain informed consent owing to the retrospective observational nature of the study. The use of the \u0026ldquo;opt-out\u0026rdquo; consent approach was approved, with a written explanation regarding data usage provided on the websites. Patients were not required to provide written informed consent but were allowed to decline participation.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication:\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eGuarantor\u003c/h2\u003e \u003cp\u003eT. Ogo takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThe authors received no specific funding for this work.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eS. Nakayama, R. Asano, M Hoshiga, and T. Ogo designed the study. A. Tsuji, J. Ueda, H. Hayashi, R. Takano, and S. Fujisaki collected the data. S. Nakayama, R. Asano, and T. Ogo analyzed the data. All the authors participated in the development of the manuscript, provided final approval for submission, and agreed to be accountable for the integrity of this work.\u003c/p\u003e\u003ch2\u003eAcknowledgments:\u003c/h2\u003e \u003cp\u003eThe authors wish to thank the study group, study staff, and patients.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to privacy and ethical restrictions but are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNashat H, Montanaro C, Li W et al (2018) Atrial septal defects and pulmonary arterial hypertension. J Thorac Dis 10(Suppl 24):S2953\u0026ndash;s65\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEngelfriet P, Meijboom F, Boersma E et al (2008) Repaired and open atrial septal defects type II in adulthood: an epidemiological study of a large European cohort. Int J Cardiol 126(3):379\u0026ndash;385\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEngelfriet PM, Duffels MG, M\u0026ouml;ller T et al (2007) Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart 93(6):682\u0026ndash;687\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSteele PM, Fuster V, Cohen M et al (1987) Isolated atrial septal defect with pulmonary vascular obstructive disease\u0026ndash;long-term follow-up and prediction of outcome after surgical correction. Circulation 76(5):1037\u0026ndash;1042\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD'Alto M, Romeo E, Argiento P et al (2013) Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure. Int J Cardiol 168(4):3797\u0026ndash;3801\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKannan BR, Sivasankaran S, Tharakan JA et al (2003) Long-term outcome of patients operated for large ventricular septal defects with increased pulmonary vascular resistance. Indian Heart J 55(2):161\u0026ndash;166\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eManes A, Palazzini M, Leci E et al (2014) Current era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: a comparison between clinical subgroups. Eur Heart J 35(11):716\u0026ndash;724\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDimopoulos K, Inuzuka R, Goletto S et al (2010) Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation 121(1):20\u0026ndash;25\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGatzoulis MA, Beghetti M, Gali\u0026egrave; N et al (2008) Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 open-label extension study. Int J Cardiol 127(1):27\u0026ndash;32\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaumgartner H, De Backer J, Babu-Narayan SV et al (2021) 2020 ESC Guidelines for the management of adult congenital heart disease. Eur Heart J 42(6):563\u0026ndash;645\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBradley EA, Ammash N, Martinez SC et al (2019) Treat-to-close: Non-repairable ASD-PAH in the adult: Results from the North American ASD-PAH (NAAP) Multicenter Registry. Int J Cardiol 291:127\u0026ndash;133\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKijima Y, Akagi T, Takaya Y et al (2016) Treat and Repair Strategy in Patients With Atrial Septal Defect and Significant Pulmonary Arterial Hypertension. Circ J 80(1):227\u0026ndash;234\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakaya Y, Akagi T, Sakamoto I et al (2022) Efficacy of treat-and-repair strategy for atrial septal defect with pulmonary arterial hypertension. Heart 108(5):382\u0026ndash;387\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlschewski H, Kovacs G (2015) [ESC guidelines 2015 on pulmonary hypertension]. Herz 40(8):1055\u0026ndash;1060\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzeka E, Costa Auler JO Jr., Kajita L et al (2002) Effects of low doses of inhaled nitric oxide combined with oxygen for the evaluation of pulmonary vascular reactivity in patients with pulmonary hypertension. Pediatr Cardiol 23(1):20\u0026ndash;26\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirakawa K, Asano R, Ueda J et al (2024) Calcium channel blockers in patients with pulmonary arterial hypertension receiving PAH-specific treatment. Int J Cardiol 406:132043\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohammed S, Vijayvergiya R, Malhotra S et al (2021) A randomized, double-blind, placebo-controlled study to evaluate sildenafil, ambrisentan combination therapy in pulmonary hypertension, particularly of Eisenmenger syndrome. Indian Heart J 73(5):633\u0026ndash;636\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWals-Rodriguez AJ, Rodriguez-Puras MJ, Garcia-Orta R et al (2022) Pulmonary hypertension in adults with congenital heart disease. Clinical phenotypes and outcomes in the advanced pulmonary vasodilator era. Heart Lung 51:75\u0026ndash;81\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan der Feen DE, Bartelds B, de Boer RA et al (2017) Pulmonary arterial hypertension in congenital heart disease: translational opportunities to study the reversibility of pulmonary vascular disease. Eur Heart J 38(26):2034\u0026ndash;2041\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuzuki S, Asano R, Aoki T et al (2022) Prognostic impact of follow-up pulmonary vascular resistance in pulmonary arterial hypertension. Open Heart. ;9(1)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBush A, Busst CM, Haworth SG et al (1988) Correlations of lung morphology, pulmonary vascular resistance, and outcome in children with congenital heart disease. Br Heart J 59(4):480\u0026ndash;485\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeath D, Edwards JE (1958) The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 18(4 Part 1):533\u0026ndash;547\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXi SB, Wang SS, Qian MY et al (2019) Predictors of operability in children with severe pulmonary hypertension associated with congenital heart disease. Chin Med J (Engl) 132(7):811\u0026ndash;818\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSitbon O, Humbert M, Ja\u0026iuml;s X et al (2005) Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111(23):3105\u0026ndash;3111\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"pulmonary vascular resistance, acute vasoreactivity testing, pulmonary hypertension","lastPublishedDoi":"10.21203/rs.3.rs-8754390/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8754390/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePulmonary arterial hypertension (PAH) complicates a subset of patients with atrial septal defects (ASD). Although patients with ASD-PAH and high pulmonary vascular resistance (PVR) generally do not benefit, those who demonstrate a favorable response to PAH-specific therapy, particularly a PVR of \u0026lt;\u0026thinsp;5 Wood units (WU) post-treatment, may be considered for shunt closure. We aimed to examine the hemodynamic characteristics of patients with severe ASD-PAH who achieved a PVR of \u0026lt;\u0026thinsp;5 WU with PAH-specific therapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study evaluated 15 patients with severe ASD-PAH (PVR\u0026thinsp;\u0026ge;\u0026thinsp;5.0 WU) who underwent PAH-specific therapy. The effects of PAH-specific therapy and acute vasoreactivity testing (AVT) were examined. Patients who achieved PVR\u0026thinsp;\u0026lt;\u0026thinsp;5 WU post-therapy were classified into the low-PVR group, and others into the high-PVR group.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe PVR significantly decreased from 10.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5 to 7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2 WU after oral PAH-specific therapy (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The maximum baseline PVR in the low-PVR group (n\u0026thinsp;=\u0026thinsp;7, 47%) was 9.5 WU. The low-PVR group showed a greater change in PVR during AVT than the high-PVR group (44.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9% vs. 15.4\u0026thinsp;\u0026plusmn;\u0026thinsp;15.4%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe baseline PVR of 9.5 WU was the upper threshold for achieving PVR\u0026thinsp;\u0026lt;\u0026thinsp;5.0 WU with oral PAH-specific therapy in severe ASD-PAH. Patients who exhibited a positive response to AVT achieved greater hemodynamic improvement.\u003c/p\u003e","manuscriptTitle":"Pulmonary Arterial Hypertension-Specific Therapy for Atrial Septal Defects with Severe Pulmonary Arterial Hypertension","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-09 16:39:40","doi":"10.21203/rs.3.rs-8754390/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-26T14:56:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-17T16:55:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"121747508080239892927748883158740902893","date":"2026-02-05T15:12:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-04T18:31:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-03T13:27:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-03T13:23:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Cardiology","date":"2026-02-01T07:11:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6687be7b-933e-4ad5-88ab-61c655262413","owner":[],"postedDate":"February 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:17:58+00:00","versionOfRecord":{"articleIdentity":"rs-8754390","link":"https://doi.org/10.1007/s00246-026-04226-y","journal":{"identity":"pediatric-cardiology","isVorOnly":false,"title":"Pediatric Cardiology"},"publishedOn":"2026-03-26 16:10:00","publishedOnDateReadable":"March 26th, 2026"},"versionCreatedAt":"2026-02-09 16:39:40","video":"","vorDoi":"10.1007/s00246-026-04226-y","vorDoiUrl":"https://doi.org/10.1007/s00246-026-04226-y","workflowStages":[]},"version":"v1","identity":"rs-8754390","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8754390","identity":"rs-8754390","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}