BPA has been extensively developed in recent years to offer an option for patients with CTEPH who are ineligible for PEA, the gold standard in managing this condition. This procedure has become a safe and effective strategy for normalizing the mPAP, thus enhancing vital prognosis. However, improving the QOL by withdrawing HOT after achieving sufficient oxygenation should also be a central goal. Several interventional cardiology units worldwide have incorporated BPA in the past few decades and although most reports support its effectiveness, concerns about its risks still exist.

Our results seem to corroborate the concepts expressed in the recent clinical consensus statement of the ESC Working Group on Pulmonary Circulation and Right Ventricular Function, [13] where it was recognized that the hemodynamic positive outcomes reported in a multicenter registry from Japan [14] tended to surpass those reported by the European registries of Poland, [15] France, [16] and Germany, [17] probably because Japanese interventionists have refined the surgical technique for at least 10 years since 2001, developing a more cautious, stepwise approach using 0.014-in. guidewires. However, intrinsic differences between European and Japanese patients with CTEPH have also been reported. There are relevant differences in baseline parameters (e.g., C-reactive protein and fibrinogen concentrations, and red thrombus incidence was higher in European patients). In addition, there were more women than men among patients with CTEPH undergoing BPA in Japan, generally elderly women with less deep vein thrombosis, fewer acute embolic episodes, better cardiac function, and lower arterial oxygen tension [13]. Also, the extended concurrent use of pulmonary vasodilators in Japan may be a relevant factor for better clinical outcomes [13]. In line with the results of the Japanese multicenter registry [14], which included data from seven Japanese institutions performing BPA since 2004, we managed to reduce the mPAP of our patients by ~ 16 mmHg (43% of the baseline value, 47% in the Japanese multicenter registry) and reach an absolute mPAP value of < 25 mmHg. It is worth mentioning that whereas age, sex, and most comorbidities were similarly represented in our cohort and those of the Japanese multicenter registry, our patients had a higher incidence of prior acute pulmonary embolism, mental illness, and malignant tumors. In addition, we succeeded in reducing the PVR and BNP levels and enhancing the 6 MWD and SaO2. Corroborating the improved oxygenation levels in our BPA-treated patients, we detected significant discontinuation rates of both HOT and riociguat, which may be linked to the return to normal mPAP levels in many patients.

Regarding complication rates, although lung injury and hemoptysis were somewhat higher than those reported in the Japanese multicenter registry, severe complications requiring intubation were more infrequent (< 1% vs. 5.5%). A meta-analysis from 2021 showed that reperfusion pulmonary edema/injury and pulmonary vascular injury occurred in 25% and 16% of cases, respectively [18].

As a catheter-based procedure, BPA success largely relies on the operators’ technical proficiency, which, in turn, depends on their expertise and experience. The longitudinal sub-analysis presented here suggests that the Japanese BPA technique is so refined that even from the beginning of our learning curve, which began in 2012, we succeeded in decreasing the mPAP to normal levels in most patients, attaining an improved prognosis, a goal that other countries could not achieve yet, as deduced from data reported by 12 European countries (Denmark, Poland, France, Greece, UK, Germany, Spain, Austria, Netherlands, Belgium, Norway, and the Czech Republic) plus the US [13]. Nevertheless, as already indicated, the wider use of pulmonary vasodilators in patients with CTEPH in Japan compared with other countries may have contributed to the higher success of BPA. The procedures performed by more experienced operators at our hospital during the later sub-period (cohort 2) were associated with higher rates of HOT discontinuation and, therefore, improved QOL. A trend towards a lower incidence of severe complications was also observed.

Previous studies indicate that BPA has a steep learning curve. It has been proposed that more than 50 operations must be performed to achieve stable surgical results [19]. In this study, significant improvements in measurable hemodynamic parameters were observed in both cohorts; however, less severe complications were observed in the later cohort. Hong et al. [20] conducted a similar longitudinal analysis, dividing 194 BPA sessions into four groups, and found that the operation time and mean time to dilate one blood vessel decreased steadily, whereas the number of dilated blood vessels per BPA session increased progressively after performing the first 50 procedures. However, consistent with our findings, these authors did not find a significant difference in the degree of change in the mPAP and PVR values when comparing earlier and later procedures.

Nevertheless, because CTEPH is a rare condition, it may be reasonable to centralize BPA procedures in high-volume CTEPH centers to perform a statistically relevant number of BPA sessions, thus allowing intensive operator training, which is expected to reduce the incidence of procedure-related complications. In this sense, Jevnikar et al. [21] expressed a similar concept in a recent publication. BPA conducted by more experienced operators is expected to result in improved patient prognosis and better QOL.

There is consensus on the existence of an unavoidable learning curve for BPA, for which most experienced centers usually show significant reductions in the frequency of adverse events in more recently treated patients [22]. For instance, the complication rate fell from 11.2 to 7.7% when comparing the first 1006 sessions with the most recent 562 sessions in the French Reference Centre for Pulmonary Hypertension [16].

In this CTEPH case series, the degree of improvement in mPAP and PVR in the second sub-period was not significantly different from that in the first sub-period. This lack of difference may be because of sufficient reductions in mPAP and PVR obtained since the implementation of BPA at our hospital in 2012. Conversely, other countries have reported modest improvements in mPAP, even at expert centers. The Department of Cardiology at YCUH, which provides a refined BPA procedure following the Japanese style, managed to reduce mPAP to normal levels from the early stage of its learning curve (2012–2015) and allowed normalization of SaO2 in the later stage (2015–2018).

The available data indicate sustained hemodynamic benefits and high survival (98.9% at 1, 2, and 3 years) after BPA in Japan [23]. For this reason, BPA has become the strategy of choice for managing patients with inoperable CTEPH in Japan.

In line with the significant progress in SaO2, the withdrawal rate of HOT significantly increased in cohort 2 compared with that in cohort 1. Considering that the normalization of pressure precedes the normalization of oxygenation, the effects of BPA may be comprehensively accomplished later in the treatment.

The longitudinal sub-analysis demonstrated that the BPA procedure applied at our hospital was sufficiently refined to result in relevant reductions in mPAP and a low incidence of complications since the beginning of the learning curve. Interestingly, we detected a significant difference in favor of the later period for oxygenation parameters (higher SaO2 and HOT discontinuation rates) and less severe complications. In other countries, such as France, there were significant differences between stages of the learning curve regarding mPAP change but little or no significant difference concerning oxygenation or complication rates [7, 16]. For instance, in the study carried out by Piliero et al. in France between May 2013 and February 2020, changes in hemodynamic parameters were greater in the ‘recent period’ (April 2017–February 2020) compared with the ‘initial period’ (May 2013-March 2017): mPAP and PVR decreased by − 37% (vs. − 22%) and − 53% (vs. − 38%), respectively, but the complication rates were not significantly different (5.7% vs. 9.3%) [7].

The rise in pulmonary artery pressure is considered a late event: mPAP is said to increase after 2/3 of the pulmonary artery is obstructed [24]. Therefore, if BPA sessions manage to unblock only 1/3 of the diseased pulmonary artery, mPAP will probably decrease to normal levels, but SaO2 will not recover adequately. Therefore, it is important to achieve complete repair of diseased pulmonary arteries through a refined BPA procedure, such as that of the Japanese style, to recover not only normal mPAP but also normal SaO2 and better QOL.

One important aspect to note is that in cohort 1, sufficient performance—such as an adequate reduction in mPAP—might have been achieved due to the procedures being performed by CVIT-certified specialists who were already highly skilled in catheter interventions. However, in cohort 2, further improvements were observed, including enhanced FC, improved SaO2, withdrawal from HOT, and a reduction in severe complications. These additional improvements suggest that the enhanced outcomes may be attributed to the learning curve effect, reflecting the continuous refinement of technique and increased operator experience over time.

Our findings corroborate that BPA, a minimally invasive intervention, is an effective strategy to treat patients with inoperable CTEPH and improve their QOL. However, there are several points that should be considered while interpreting the findings. It was a single-center study with a retrospective design covering a limited number of patients and BPA sessions.

Another limitation of this study is the procedural transition in the BPA method over time. Beginning in 2016, our institution gradually shifted from the traditional BPA approach—where a small number of branches were treated with a large balloon in the first session—to the more recent Staged Dilatation Strategy. The latter involves dilating multiple branches with a small balloon in the initial session and completing the procedure with a larger balloon in subsequent sessions. However, since the data in this study extend only until 2018, the impact of this procedural transition on the results is likely minimal. Additionally, the findings of this study may not be fully applicable to physicians who are not yet proficient in catheter-based interventions.

In line with nationwide trends, BPA techniques at our institution have evolved over time. As a result, the outcomes of this study may reflect not only the operators’ learning curves but also the overall maturation of BPA treatment in Japan. Considering current treatment strategies as of 2024, it may be possible that even less experienced operators can achieve favorable outcomes if BPA is performed under appropriate guidance. Given that CTEPH is a rare disease, to further improve oxygenation and minimize severe complications, it may be beneficial to refer target patients to specialized centers with experienced BPA teams.