Abstract
Background
Balloon pulmonary angioplasty (BPA) is an established therapy for chronic thromboembolic pulmonary hypertension (CTEPH), but its optimal lesion-specific endpoint remains unclear. This study aimed to clarify the optimal endpoint for pressure-guided BPA (PG-BPA) based on the distal pulmonary artery pressure waveform (Pd-WF).
Methods and Results
We retrospectively analyzed 23 patients with CTEPH who underwent 118 PG-BPA sessions involving 424 lesions. The pressure ratio (PR; i.e., the distal-to-proximal mean pulmonary artery pressure ratio) and Pd-WF were evaluated for each lesion. Complete arterialization of the Pd-WF (Pd-CA), defined as a distal-to-proximal pulse pressure ratio >0.5, was used as the physiological endpoint. PR improved significantly from a median of 0.52 (interquartile range [IQR] 0.39–0.66) to 0.80 (IQR 0.73–0.89) after balloon dilatation (P<0.001), and Pd-CA was achieved in 63.9% of lesions. Significant decreases were seen in both mean pulmonary artery pressure (median 34 [IQR 26–50] to 19 [IQR 18–25] mmHg) and pulmonary vascular resistance (median 8.3 (IQR 5.6–13.6) to 2.7 (IQR 2.1–4.0 Wood units; both P<0.0001). The number of lesions achieving Pd-CA correlated with the percentage reduction in pulmonary vascular resistance (r=−0.52, P=0.011). Receiver operating characteristic analysis identified a PR cut-off value of 0.77 for predicting Pd-CA (area under the curve 0.86; P<0.0001).
Conclusions
Pd-CA may represent an optimal physiological endpoint for PG-BPA and enable lesion-level optimization beyond angiographic assessment alone.
Key Words: Balloon pulmonary angioplasty, Chronic thromboembolic pulmonary hypertension, Complete arterialization of distal pulmonary artery pressure waveform, Distal pulmonary artery pressure waveform, Pressure ratio
Central Figure.
Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by organized thrombi in the pulmonary arteries, and its prognosis is poor without appropriate treatment.1 Although pulmonary endarterectomy was the only curative treatment for CTEPH, approximately 40% of patients were not candidates for pulmonary endarterectomy because of comorbidities and thrombus distribution.2 Recently, balloon pulmonary angioplasty (BPA), a less invasive catheter interventional therapy, has become the standard treatment for inoperable CTEPH, achieving substantial improvements in hemodynamics and oxygenation.3–5 Excellent prognosis after BPA was reported in a Japanese multicenter registry.6 However, approximately 75% of patients do not achieve sufficient symptomatic improvement,7 and exercise-induced pulmonary hypertension persists in nearly half the patients despite hemodynamic normalization after BPA.8,9 To address these issues, CTEPH treatments, including BPA, need to be further optimized.
To date, most BPA procedures have been performed under angiographic guidance. Although pulmonary blood flow can be quantified using angiography-based pulmonary flow grade (PFG), this is a subjective assessment that depends on the quality of the angiographic image.10 Ideally, a more objective evaluation is needed of optimal balloon dilatation for each lesion during BPA. Pressure-wire-guided BPA has been reported as an objective measure of the pressure ratio (PR), defined as the ratio of distal pressure (Pd) to proximal pressure (Pa) across the lesion.11 In this report, because PR is closely related to pulmonary blood flow as evaluated by PFG, the PR target after balloon dilatation was set at 0.80. However, the optimal PR cut-off value based on objective physiological indices rather than angiographic findings remains unclear.
The pressure waveform in the distal pulmonary artery (Pd-WF) differs before and after balloon dilatation (Figure 1). In addition, the Pd-WF was arterialized after adequate PR, and PFG was achieved through optimal balloon dilatation.12 These observations suggest that complete arterialization of the Pd-WF (Pd-CA) is required to obtain sufficient pulmonary blood perfusion. Therefore, we hypothesized that Pd-CA could serve as a physiological endpoint for BPA and conducted this study to determine the optimal endpoint based on Pd-CA.
Figure 1.
Representative images of pressure-guided balloon pulmonary angioplasty and definitions of the distal pulmonary artery pressure waveform (Pd-WF). (A) Subtotal lesion of the subsegmental pulmonary artery before balloon dilatation (red arrow). The pulmonary flow grade (PFG) is 0 and the pressure ratio (PR) is 0.28. The Pd-WF is wedge type (Pd-W); that is, a flat or atrial waveform with clear a and v waves (blue waveform in the red square). (B) After dilatation using a 2.5-mm balloon catheter (red arrow). The PFG and PR improved to Grade 2 and 0.54, respectively. The Pd-WF shows incomplete arterialization (Pd-IA), namely an incomplete arterial waveform with a distal-to-proximal pulse pressure ratio (PPPd/PPPa) ≤0.5 (blue waveform in the red square). (C) After dilatation using a 6.0-mm balloon catheter (red arrow). The PFG and PR improved to Grade 3 and 0.77, respectively. The Pd-WF shows complete arterialization (Pd-CA); that is, a complete arterial waveform with PPPd/PPPa >0.5 (blue waveform in the red square).
Methods
Patient Enrollment and CTEPH Diagnosis
BPA was performed on 28 patients with CTEPH between April 2018 and December 2023 at Toho University Sakura Medical Center. Of these patients, 23 who underwent pressure-guided BPA (PG-BPA) in all sessions were enrolled in this study, and their clinical data were collected retrospectively. CTEPH was defined as follows: mean pulmonary artery pressure (mPAP) ≥20 mmHg; pulmonary artery wedge pressure (PAWP) <15 mmHg; and organized thrombi detected on contrast-enhanced computed tomography or pulmonary angiography and multiple perfusion defects detected by lung perfusion scintigraphy.13 All patients were diagnosed with CTEPH after at least 3 months of anticoagulant therapy. Other types of pulmonary hypertension were ruled out using blood tests, echocardiography, pulmonary function tests, systemic computed tomography, and right heart catheterization (RHC).
Pressure-Guided BPA
All BPA procedures were performed through the common femoral or internal jugular veins. Before BPA, RHC was performed using a 6-Fr wedge-pressure catheter. The zero reference point was set at the mid-thoracic line. PAWP, mPAP, and mean right atrial pressure were measured at end-expiration. Cardiac output (CO) and the cardiac index (CI) were measured using the Fick method, and the pulmonary vascular resistance (PVR) was calculated. After RHC, an 8-Fr flex sheath was inserted into the main pulmonary artery. Each target vessel was selected using a 7- or 6-Fr guiding catheter. After selective pulmonary angiography, a 0.014-inch guidewire was advanced through the target lesion. For pressure measurement, a pressure catheter was advanced into the distal pulmonary artery over the guidewire, or the guidewire was exchanged for a pressure wire using a microcatheter. Subsequently, Pa and Pd were measured, and PR was calculated. Before balloon dilatation, the pressure catheter or pressure wire was pulled back to detect the lesion location, defined as the point of the pressure gradient. According to angiographic vessel diameter and pressure measurement, each lesion was dilated using an appropriate-sized balloon catheter (1.2–7.0 mm). Balloon dilatation was performed until the PR reached 0.80 whenever possible or blood flow improved to PFG 3. When mPAP before BPA was >35 mmHg, smaller balloon catheters were used so that the Pd did not exceed 35 mmHg to prevent BPA-related complications.11 Additional balloon dilatation for these lesions was performed if a PR of 0.80 could not be achieved in later sessions, when the patient’s mPAP was <35 mmHg. For each BPA session, the fluoroscopic exposure time and contrast medium dose were limited to 60 min and 200 mL, respectively. BPA sessions were continued until mPAP was <20 mmHg or until sufficient improvement of clinical symptoms, such as to World Health Organization functional class I or II.
Evaluation of Pd-WF
All pressure measurements were performed using a pressure catheter or wire. Before these devices were advanced across the lesions, the pressure sensor was positioned at the tip of the guiding catheter and pressure equalization was performed. Subsequently, the devices were advanced into the distal part of the pulmonary artery, and Pa and Pd were measured. Pa was measured at the tip of the guiding catheter, and Pd was measured at the distal pulmonary artery using the pressure catheter or wire. The PR was calculated as Pd/Pa. Simultaneously, Pd-WFs were recorded. The PR (Pd/Pa) and Pd-WF were measured before and after dilatation whenever possible.
Pd-WFs can be classified into 3 types (Figure 1): wedge (Pd-W), incomplete arterialization (Pd-IA), and complete arterialization (Pd-CA). Pd-W was defined as an atrial waveform with clear a and v waves or as a flat waveform without these waves (Figure 1A), Pd-IA was defined as an incomplete arterial waveform with a Pd to Pa pulse pressure ratio (PPPd/PPPa) of ≤0.5 (Figure 1B), and Pd-CA was defined as a complete arterial waveform with a PPPd/PPPa >0.5 (Figure 1C). These definitions are based on the observation that the median PPPd/PPPa after balloon dilatation in the present study was 0.58. To facilitate visual discrimination based on waveform morphology, Pd-CA was defined as a PPPd/PPPa >0.5.
Timing of Clinical Data Collection
Data on patient characteristics were collected at the time of CTEPH diagnosis (i.e., before BPA). Hemodynamic parameters measured by RHC and clinical parameters such as WHO functional class, B-type natriuretic peptide (BNP), and 6-minute walk distance (6MWD) were collected at the time of CTEPH diagnosis and during the chronic post-BPA phase (3–12 months after BPA). Pressure data, evaluated using a pressure catheter or pressure wire in each lesion, were collected during all BPA sessions.
Statistical Analysis
Continuous variables are expressed as median with interquartile range (IQR). Categorical variables are expressed as numbers and percentages. Data before and after BPA were compared using the Wilcoxon test for continuous variables and the χ2 test for categorical variables. Comparisons among the 3 groups were made using the Kruskal–Wallis test, followed by post hoc Wilcoxon rank-sum tests with adjustment for multiple comparisons. Spearman’s correlation coefficient was used to evaluate correlations between data. In lesion-level analyses, mixed-effects models with patient-level random effects were also used to account for the clustering of multiple lesions within the same patient. Multivariable linear regression analysis was used to evaluate whether the association between achieving Pd-CA and hemodynamic improvement was independent of potential confounders. The percentage reduction in PVR was used as the dependent variable, and pulmonary vasodilator use, baseline PVR, and the number of lesions in which Pd-CA was achieved were included as covariates. Receiver operating characteristic (ROC) curve analysis was used to determine the PR cut-off value for predicting the achievement of Pd-CA. Statistical significance was set at P<0.05. Statistical analyses were performed using JMP software version 14.2 (SAS Institute, Cary, NC, USA).
Ethical Considerations
This study was approved by the Ethics Committee of Toho University Sakura Medical Center (S24043_S23071) and was performed in accordance with the Declaration of Helsinki. Patients were given the opportunity to opt-out of the study on the institution’s website.
Results
Study Population and Lesion Selection
The study flowchart is shown in Figure 2. In all, 23 patients with CTEPH who underwent PG-BPA were enrolled in the study, and data for 118 PG-BPA sessions and 460 lesions were analyzed. Pressure data were not obtained for 36 lesions; thus, pressure data were available for 424 lesions. Of these lesions, 393 with pressure data obtained before and after balloon dilatation were included in the lesion-level analysis. In addition, 389 lesions with post-dilatation pressure data, after excluding 35 lesions that represented initial procedures in the sequential dilatation method, were included in the patient-level analysis.
Figure 2.
Study flowchart. CTEPH, chronic thromboembolic pulmonary hypertension; PG-BPA, pressure-guided balloon pulmonary angioplasty.
Patient Characteristics
Patient characteristics are summarized in Table 1. The median age was 76 years (IQR 65–80 years), and 65.2% of patients were female. Eighteen (73.9%), 1 (4.3%), and 3 (13.0%) patients had a history of acute pulmonary embolism, coagulopathy, and active cancer, respectively. The median number of BPA sessions was 5 (IQR 4–6). Home oxygen therapy was required for 14 (60.9%) patients. Warfarin was administered to 10 (43.5%) patients, whereas 13 (56.5%) patients were administered direct oral anticoagulants. Regarding selective pulmonary vasodilators, riociguat was administered to 16 (69.6%) patients and selexipag was administered to 2 (8.7%) patients before BPA.
Table 1.
Characteristics of Patients With Chronic Thromboembolic Pulmonary Hypertension (n=23)
| Age (years) | 76 [65–80] |
| Female sex | 15 (65.2) |
| History of APTE | 18 (73.9) |
| Coagulopathy | 1 (4.3) |
| Active cancer | 3 (13.0) |
| Total no. BPA sessions per patient | 5 [4–6] |
| HOT | 14 (60.9) |
| Warfarin | 10 (43.5) |
| DOAC | 13 (56.5) |
| Selective pulmonary vasodilators | |
| Riociguat | 16 (69.6) |
| Selexipag | 2 (8.7) |
Data are presented as the median [interquartile range] or n (%). APTE, acute pulmonary thromboembolism; BPA, balloon pulmonary angioplasty; DOAC, direct oral anticoagulant; HOT, home oxygen therapy.
PG-BPA Findings
The PG-BPA findings for each lesion are presented in Table 2. After balloon dilatation, PFG improved significantly (P<0.0001) from Grade 1 (IQR 1–2) to Grade 3 (IQR 3–3). PR also improved significantly (P<0.0001) from 0.51 (0.39–0.66) to 0.80 (0.73–0.89). These improvements remained significant in mixed-effects models accounting for patient-level clustering (PR: β=0.28, P<0.0001; PFG: β=1.56, P<0.0001). Before dilatation, 262 (66.2%), 107 (27.2%), and 24 (6.1%) lesions were classified as Pd-W, Pd-IA, and Pd-CA, respectively, compared with 4 (1.0%), 138 (35.1%), and 251 (63.9%) lesions, respectively, after dilatation. The median total number of lesions treated per patient was 17 (IQR 12–22), and the median total number of lesions per patient in which Pd-CA was achieved after dilatation was 11 (IQR 8–15). The median percentage of lesions achieving post-dilatation Pd-CA per patient was 75.0% (IQR 58.8–83.3%).
Table 2.
Pressure-Guided Balloon Pulmonary Angioplasty Findings at the Lesion and Patient Levels
| Lesion-level PG-BPA data (n=393) | |||
|---|---|---|---|
| Predilatation | Post-dilatation | P value | |
| PFG | 1 [1–2] | 3 [3–3] | <0.0001 |
| PR | 0.52 [0.39–0.66] | 0.80 [0.73–0.89] | <0.0001 |
| Pd-WF | |||
| Pd-W | 262 (66.7) | 4 (1.0) | |
| Pd-IA | 107 (27.2) | 138 (35.1) | |
| Pd-CA | 24 (6.1) | 251 (63.9) | |
| Patient-level PG-BPA data (n=23) | |||
| Total no. lesions treated per patient | 17 [12–22] | ||
| Total no. lesions that achieved Pd-CA per patient | 11 [8–15] | ||
| % Lesions that achieved Pd-CA per patient | 75.0 [58.8–83.3] | ||
Unless indicated otherwise, data are presented as the median [interquartile range] or n (%). Data were compared using Wilcoxon or Chi-squared tests. Pd, distal pulmonary artery pressure; Pd-CA, complete Pd arterialization; Pd-IA, incomplete Pd arterialization; Pd-W, wedge-type Pd waveform; Pd-WF, Pd pressure waveform; PFG, pulmonary flow grade; PG-BPA, pressure-guided balloon pulmonary angioplasty; PR, pressure ratio.
The locations and characteristics of the treated lesions are detailed in Supplementary Table 1. In all, 460 lesions were treated, of which 424 (92.2%) were treated under pressure guidance. Of these lesions, 264 (57.4%) were in the right lung and 196 (42.6%) were in the left lung. There were166 (36.1%), 126 (27.4%), and 168 (36.5%) lesions in the upper, middle, lingual, and lower lobes, respectively, and 3 (0.7%), 200 (43.5%), and 257 (55.9%) lesions located in the lobar, segmental, and subsegmental pulmonary arteries, respectively. According to angiographic lesion classification,14 there were 52 (11.3%) Type A (ring-like stenosis) lesions, 375 (81.5%) Type B (web) lesions, 24 (5.2%) Type C (subtotal) lesions, 9 (2.0%) Type D (total occlusion) lesions, and 0 (0%) Type E (tortuous) lesions.
Symptomatic complications occurred in 5 (4.2%) sessions. All complications were caused by wire perforation and were accompanied by hemoptysis. Oxygen supplementation was required in all patients, and one patient required non-invasive positive-pressure ventilation. There were no cases of reperfusion pulmonary edema or periprocedural death.
Changes in Hemodynamic and Clinical Parameters After PG-BPA
The changes in hemodynamic and clinical parameters after PG-BPA are presented in Table 3. Significantly decreases were seen in both mPAP (from 34 [IQR 26–50] to 19 [IQR 18–25] mmHg) and PVR (from 8.3 [5.6–13.6] to 2.7 [2.1–4.0] Wood units) after BPA. CO and CI also improved significantly. Before BPA, approximately 65% of patients had severe clinical symptoms, defined as WHO Class III or IV; however, no patients remained in WHO Class III or IV after BPA, and all patients were classified as WHO Class I or II (12 [52.2%] and 11 [47.8%], respectively). BNP levels and 6MWD also improved significantly after BPA.
Table 3.
Changes in Hemodynamic and Clinical Parameter After PG-BPA in Patients With Chronic Thromboembolic Pulmonary Hypertension (n=23)
| Before BPA | After BPAA | P value | |
|---|---|---|---|
| PAWP (mmHg) | 9 [7–11] | 9 [7–12] | 0.50 |
| mPAP (mmHg) | 34 [26–50] | 19 [18–25] | <0.0001 |
| mRAP (mmHg) | 5 [4–7] | 5 [4–7] | 0.12 |
| PVR (Wood units) | 8.3 [5.6–13.6] | 2.7 [2.1–4.0] | <0.0001 |
| CO (L/min) | 2.9 [2.3–3.6] | 3.9 [3.0–4.5] | 0.002 |
| CI (L/min/m2) | 1.8 [1.6–2.4] | 2.5 [2.2–2.6] | 0.002 |
| WHO functional class | |||
| Class I | 0 (0) | 12 (52.2) | |
| Class II | 8 (34.8) | 11 (47.8) | |
| Class III | 14 (60.9) | 0 (0) | |
| Class IV | 1 (4.3) | 0 (0) | |
| BNP (pg/mL) | 50.7 [21.7–207] | 22.1 [10.6–41.6] | 0.0007 |
| 6MWD (m) | 330 [286–382] | 386.5 [329–429.25] | 0.0001 |
Unless indicated otherwise, data are presented as the median [interquartile range] or n (%). Data were compared between groups using the Wilcoxon test. AThe median follow-up duration after BPA was 6 months (interquartile range 3–8 months). 6 MWD, 6-minute walk distance; BNP, B-type natriuretic peptide; CI, cardiac index; CO, cardiac output; mPAP, mean pulmonary artery pressure; mRAP, mean right atrial pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; WHO, World Health Organization. Other abbreviations as in Tables 1,2.
Correlations Between Changes in Hemodynamic Parameters and Pd-CA After BPA
Figure 3 shows correlations between relative changes in the hemodynamic parameters and the number of lesions in which Pd-CA was achieved after BPA. Relative changes in mPAP (∆mPAP) and CO (∆CO) were not significantly correlated with the number of lesions in which Pd-CA was achieved (Figure 3A,B), whereas changes in PVR (∆PVR) were significantly negatively correlated with the number of lesions in which Pd-CA was achieved (r=−0.52, P=0.011; Figure 3C). In a multivariable linear regression analysis, the number of lesions in which Pd-CA was achieved remained independently associated with a greater reduction in PVR (β=−2.53, P=0.0005), after adjustment for pulmonary vasodilator use and baseline PVR (Supplementary Table 2). Pulmonary vasodilator use was also significantly associated with ∆PVR (β=−25.5, P=0.0075).
Figure 3.
Correlations between the number of lesions achieving complete arterialization of distal pulmonary artery pressure (Pd-CA) and changes in hemodynamic parameters: (A) mean arterial pressure (mPAP), (B) cardiac output (CO), and (C) pulmonary vascular resistance (PVR).
Relationships Between PFG, PR, and Pd-WF
Figure 4A shows a significant positive correlation between the PR and PFG grades (r=0.73, P<0.0001). The association between PR and PFG also remained significant in a mixed-effects model accounting for patient-level clustering (β=0.16, P<0.0001).
Figure 4.
Relationships among pulmonary flow grade (PFG), pressure ratio (PR), and distal pulmonary artery pressure waveform (Pd-WF). (A,B) Relationships between PR and PFG (A) and Pd-WF (B). The boxes show the interquartile range, with the median value indicated by the horizontal line; whiskers show the range. *P<0.0001. (C) Distribution of PFG according to Pd-WF. Comparisons among 3 groups were made using the Kruskal–Wallis test, followed by post hoc Wilcoxon rank-sum tests with adjustment for multiple comparisons. Pd-CA, complete arterialization of distal pulmonary artery pressure; Pd-IA, incomplete arterialization of distal pulmonary artery pressure.
Figure 4B shows the relationship between PR and Pd-WF. Lesions classified as Pd-W had the lowest PR values (median 0.44; IQR 0.33–0.55), whereas PR values for lesions classified as Pd-CA (median 0.85; IQR 0.79–0.92) were significantly higher than those classified as Pd-W and Pd-IA (median 0.69; IQR 0.61–0.75; P<0.0001). In a mixed-effects model accounting for patient-level clustering, PR differed significantly across Pd-WF categories (P<0.0001), with higher values in Pd-IA and Pd-CA than in Pd-W (β=0.25 and 0.41, respectively; both P<0.0001).
Figure 4C shows the distribution of PFG according to the Pd-WF. Approximately 75% of lesions classified as Pd-W had PFG 0 or 1. In contrast, nearly half the lesions classified as Pd-IA achieved PFG 3. Among lesions classified as Pd-CA, PFG 3 was achieved in approximately 85%.
Figure 5 shows the ROC analysis of PR for predicting Pd-CA. The optimal cut-off value of PR for predicting Pd-CA was 0.77, with an area under the curve of 0.86, sensitivity of 86.3%, and specificity of 70.6% (P<0.0001).
Figure 5.
Receiver operating characteristic (ROC) analysis for predicting complete arterialization of the distal pulmonary artery pressure waveform. The optimal pressure ratio cut-off value was 0.77, with an area under the curve of 0.86, sensitivity of 86.3%, and specificity of 70.6%.
Discussion
In this study we retrospectively analyzed data on PG-BPA, including Pd-WFs. The main findings of this study are that lesions achieving Pd-CA exhibited higher PR and PFGs than lesions with other types of Pd-WFs, the number of lesions achieving Pd-CA was significantly associated with a greater reduction in PVR, and the optimal PR cut-off value for predicting Pd-CA was 0.77. Collectively, these findings suggest that Pd-CA may serve as an optimal and objective endpoint for BPA based on physiological assessments.
Efficacy and Safety of PG-BPA
Inami et al. reported that PG-BPA improved treatment efficacy and markedly reduced BPA-related complications, including reperfusion lung edema.11 In their study, the optimal endpoints were defined as a PR >0.80 to achieve PFG 3 and Pd <35 mmHg to avoid complications.11 In addition, Satoh et al. reported that a PR of 0.70 represented the optimal endpoint based on 2-dimensional lung perfusion angiography.15 In that report, lower rates of residual pulmonary hypertension after BPA and fewer complications were observed compared with angiography-guided BPA.15 In the present study, PG-BPA was performed using a procedural strategy similar to that reported by Inami et al.11 and resulted in excellent hemodynamic improvement and a low incidence of symptomatic complications. These findings confirm that PG-BPA has a favorable efficacy and safety profile. However, these endpoints are largely derived from angiographic findings; therefore, the development of physiology-based indices is warranted. In this context, Pd-CA analysis may provide a complementary physiological dimension that directly reflects the effective distal perfusion beyond angiography alone.
Pd-CA as a Physiological Index
In this study, Pd-CA was defined as PPPd/PPPa >0.5, which served as the primary physiological endpoint of BPA based on the Pd-WF analysis. Pd-CA is a quantitative index that can be easily identified via visual assessment. In addition, Pd-CA exhibited higher PR and PFG than the other Pd-WFs. These findings indicated that Pd-CA exhibited adequate pulmonary blood flow. However, it should be noted that although post-dilatation Pd-WF was classified as Pd-IA, approximately half these lesions achieved PFG 3, indicating that angiographic improvement does not necessarily correspond to physiological recovery. This discrepancy suggests that relying on angiographic appearance alone may be insufficient to fully assess improvement in pulmonary blood flow. Although angiography primarily reflects macroscopic contrast flow, Pd-WF analysis can provide additional functional information, including distal vascular resistance and microvascular impairment. Therefore, performing BPA with Pd-CA as a guiding index may be useful for optimizing lesion-level treatments. In this context, Pd-CA may offer incremental value by capturing lesion-level hemodynamic recovery beyond angiographic findings.
Relationship Between Pd-CA Achievement and Hemodynamics
In this study, the number of lesions in which Pd-CA was achieved was significantly associated with the reduction in PVR. This suggests that Pd-CA-guided BPA may contribute to improvement of the pulmonary circulation, including the microcirculation. Given that a substantial proportion of patients were receiving pulmonary vasodilators, the potential confounding effect of pharmacotherapy is an important consideration. However, in the present study, the number of lesions in which Pd-CA was achieved remained independently associated with hemodynamic improvement even after adjustment for pulmonary vasodilator use and baseline PVR. These findings suggest that lesion-level optimization contributes to PVR reduction beyond the effects of pharmacological therapy.
Mizoguchi et al.16 reported that an increased number of dilated lesions was associated with a reduction in mPAP; however, the relationship with PVR was not addressed in their study. In the study of Satoh et al.,15 BPA guided by a PR >0.70 resulted in greater improvements in mPAP and PVR compared with angiography-guided BPA. Together with the present study, these results suggest that dilating a greater number of lesions using Pd-CA as a physiological endpoint may lead to more favorable hemodynamic improvement. In the present study, although the number of lesions in which Pd-CA was achieved was associated with the degree of PVR reduction, it was not significantly associated with reductions in mPAP. A plausible explanation for this discrepancy is that mPAP is influenced by both distal PVR and CO. In our cohort, BPA resulted in improvements in CO and reductions in PVR, which may have attenuated the decrease in mPAP, thereby obscuring its association with the number of lesions in which Pd-CA was achieved.
Optimal Endpoint Based on Pd-CA
In the present study, the median patient-level rate of achieving Pd-CA was 75%, suggesting that achieving Pd-CA in a large proportion of lesions was associated with favorable hemodynamic improvement. The optimal PR cut-off value for predicting Pd-CA was 0.77. In previous studies, the lesion-level target PR values based on angiographic findings were reported to be 0.70 or 0.80,11,15 which are generally comparable to the results of the present study. However, PR reflects the magnitude of pressure recovery, whereas Pd-CA is defined based on distal pressure waveform morphology and may capture additional physiological information, including distal vascular resistance and microvascular function. As discussed above, in addition to achieving sufficient PR improvement, Pd-CA allows adequate blood flow to be restored at the level of each pulmonary artery lesion. Therefore, BPA guided by physiological indices, including Pd-CA, may be useful for optimizing lesion-level treatment; however, these findings should be considered hypothesis-generating and require prospective multicenter validation, including comparisons with angiography-guided or other imaging-based strategies,17 to establish Pd-CA as a reliable procedural endpoint.
Study Limitations
This study has several limitations. First, this was a single-center retrospective observational study with a relatively small sample size, which may limit the generalizability of the findings. Larger prospective multicenter studies are required to validate the clinical utility of Pd-CA as a physiological endpoint of BPA. In addition, the retrospective design and procedural heterogeneity across sessions may introduce unmeasured bias; however, standardized procedures and objective physiological parameters may mitigate this limitation.
Second, Pd-CA was defined using a PPPd/PPPa cutoff value of >0.5, which was derived from the distribution of post-dilatation Pd-WFs in the present cohort and was selected to facilitate visual discrimination. Although this threshold demonstrated physiological and clinical relevance, it remains to be empirically determined and may require refinement and external validation. To assess the robustness of this definition, sensitivity analyses were performed using alternative thresholds (PPPd/PPPa >0.4 and >0.6). The association between the number of lesions in which Pd-CA was achieved and the percentage reduction in PVR was preserved at a lower threshold (>0.4) but attenuated at a higher threshold (>0.6), likely due to reduced statistical power. These findings suggest that the observed relationship is not dependent on a single cut-off value but is maintained across a physiologically plausible range (Supplementary Table 3).
Third, pulmonary vasodilators were administered to approximately 70% of patients. Pd-CA achievement was significantly associated with a reduction in PVR, and this association remained significant after adjustment for pulmonary vasodilator use and baseline PVR; however, a residual confounding effect of pharmacotherapy cannot be completely excluded.
Finally, this study did not directly compare Pd-CA-guided BPA with angiographically or other imaging-guided BPA strategies, nor did it directly assess clinically meaningful outcomes. Future comparative studies are warranted to determine whether Pd-CA-guided optimization translates into superior long-term clinical outcomes.
Conclusions
Pd-CA may be an optimal physiological endpoint for PG-BPA. The number of lesions in which Pd-CA was achieved was significantly associated with the reduction in PVR, and a PR cut-off value of 0.77 optimally predicted Pd-CA. These findings suggest that Pd-CA-guided BPA may enable more effective lesion-level optimization than angiographic assessment alone.
Disclosures
The authors have no conflicts of interest to declare.
IRB Information
This study was approved by the Ethics Committee of Toho University Sakura Medical Center (S24043_S23071).
Supplementary Files
Supplementary Table 1. Supplementary Table 2. Supplementary Table 3.
Acknowledgments
The authors thank the staff of the Division of Cardiovascular Medicine and the catheterization laboratory at Toho University Sakura Medical Center for their valuable support. During the preparation of this manuscript, the authors used ChatGPT (OpenAI) and Editage (www.editage.jp) for English language editing and to improve grammar and readability. The authors reviewed and approved all content and take full responsibility for the manuscript.
Funding Statement
Sources of Funding: None.
Data Availability
Not applicable.
References
- 1. Riedel M, Stanek V, Widimsky J, Prerovsky I.. Long-term follow-up of patients with pulmonary thromboembolism: Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982; 81: 151–158, doi:10.1378/chest.81.2.151. [DOI] [PubMed] [Google Scholar]
- 2. Pepke-Zaba J, Delcroix M, Lang I, Mayer E, Jansa P, Ambroz D, et al.. Chronic thromboembolic pulmonary hypertension (CTEPH): Results from an international prospective registry. Circulation 2011; 124: 1973–1981, doi:10.1161/CIRCULATIONAHA.110.015008. [DOI] [PubMed] [Google Scholar]
- 3. Ikeda N.. Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. Cardiovasc Interv Ther 2020; 35: 130–141, doi:10.1007/s12928-019-00637-2. [DOI] [PubMed] [Google Scholar]
- 4. Fujii S, Nagayoshi S, Matsumoto T, Miyamoto T, Ogawa K, Yoshimura M.. Spontaneous hemodynamic improvement after balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension is observed within a short term after balloon pulmonary angioplasty. Cardiovasc Interv Ther 2024; 39: 302–313, doi:10.1007/s12928-024-00987-6. [DOI] [PubMed] [Google Scholar]
- 5. Komura N, Sugano T, Ono F, Nakayama M, Suzuki T, Kawaura N, et al.. Effect of balloon pulmonary angioplasty on chronic thromboembolic pulmonary hypertension: An assessment of the learning curve in a Japanese university hospital. Cardiovasc Interv Ther 2025; 40: 389–399, doi:10.1007/s12928-024-01076-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Masaki K, Hosokawa K, Funakoshi K, Taniguchi Y, Adachi S, Inami T, et al.. Outcomes of chronic thromboembolic pulmonary hypertension after balloon pulmonary angioplasty and pulmonary endarterectomy. JACC Asia 2024; 4: 577–589, doi:10.1016/j.jacasi.2024.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Ikeda N, Masaki K, Hosokawa K, Funakoshi K, Taniguchi Y, Adachi S, et al.. Insights into balloon pulmonary angioplasty and the WHO functional class of chronic thromboembolic pulmonary hypertension patients: Findings from the CTEPH AC registry. Cardiovasc Interv Ther 2025; 40: 689–700, doi:10.1007/s12928-025-01095-9. [DOI] [PubMed] [Google Scholar]
- 8. Kikuchi H, Goda A, Takeuchi K, Inami T, Kohno T, Sakata K, et al.. Exercise intolerance in chronic thromboembolic pulmonary hypertension after pulmonary angioplasty. Eur Respir J 2020; 56: 1901982, doi:10.1183/13993003.01982-2019. [DOI] [PubMed] [Google Scholar]
- 9. Suzuki T, Iwahashi N, Abe T, Komura N, Abe M, Konishi M, et al.. Clinical usefulness of passive leg lifting during right heart catheterization for diagnosing exercise-induced pulmonary hypertension: A pilot study. Circ J 2026; 90: 228–231, doi:10.1253/circj.CJ-25-0515. [DOI] [PubMed] [Google Scholar]
- 10. Inami T, Kataoka M, Shimura N, Ishiguro H, Yanagisawa R, Taguchi H, et al.. Pulmonary Edema Predictive Scoring Index (PEPSI), a new index to predict risk of reperfusion pulmonary edema and improvement of hemodynamics in percutaneous transluminal pulmonary angioplasty. JACC Cardiovasc Interv 2013; 6: 725–736, doi:10.1016/j.jcin.2013.03.009. [DOI] [PubMed] [Google Scholar]
- 11. Inami T, Kataoka M, Shimura N, Ishiguro H, Yanagisawa R, Fukuda K, et al.. Pressure-wire-guided percutaneous transluminal pulmonary angioplasty: A breakthrough in catheter-interventional therapy for chronic thromboembolic pulmonary hypertension. JACC Cardiovasc Interv 2014; 7: 1297–1306, doi:10.1016/j.jcin.2014.06.010. [DOI] [PubMed] [Google Scholar]
- 12. Sato S, Ito T, Todani S, Nonaka S, Mikamo H, Shimizu K.. Chronic thromboembolic pulmonary hypertension and iodine allergy successfully treated using gadolinium contrast and pressure catheter. Cardiovasc Interv Ther 2025; 40: 451–453, doi:10.1007/s12928-024-01047-9. [DOI] [PubMed] [Google Scholar]
- 13. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RM, Brida M, et al.. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: Developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG). Eur Heart J 2022; 43: 3618–3731, doi:10.1093/eurheartj/ehac237.36017548 [Google Scholar]
- 14. Kawakami T, Ogawa A, Miyaji K, Mizoguchi H, Shimokawahara H, Naito T, et al.. Novel angiographic classification of vascular lesions in chronic thromboembolic pulmonary hypertension based on selective angiography and results of balloon pulmonary angioplasty. Circ Cardiovasc Interv 2016; 9: e003318, doi:10.1161/CIRCINTERVENTIONS.115.003318. [DOI] [PubMed] [Google Scholar]
- 15. Satoh T, Yaoita N, Higuchi S, Nochioka K, Yamamoto S, Sato H, et al.. Improving balloon pulmonary angioplasty through target endpoint optimization using a pressure catheter and angiographic lung perfusion. JACC Cardiovasc Interv 2024; 17: 2394–2407, doi:10.1016/j.jcin.2024.08.045. [DOI] [PubMed] [Google Scholar]
- 16. Mizoguchi H, Ogawa A, Munemasa M, Mikouchi H, Ito H, Matsubara H.. Refined balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension. Circ Cardiovasc Interv 2012; 5: 748–755. [DOI] [PubMed] [Google Scholar]
- 17. Avci BK, Seyahi E, Polat F, Kolak Z, Yalman H, Atahan E, et al.. Role of optical coherence tomography in vasculitis-associated pulmonary hypertension and chronic thromboembolic pulmonary hypertension. Circ J 2024; 88: 1620–1628, doi:10.1253/circj.CJ-24-0254. [DOI] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Supplementary Table 1. Supplementary Table 2. Supplementary Table 3.
Data Availability Statement
Not applicable.