The Dana Point clinical classification of pulmonary hypertension (4th World Symposium, 2008) deleted the proximal/distal subcategories of chronic thromboembolic pulmonary hypertension (CTEPH) precisely because no consensus definitions existed, leaving operability for pulmonary endarterectomy (PEA) as an expert-center judgement. This problem - the surviving, still-open core of the six-part research agenda enumerated in that classification report - asks for (i) consensus, anatomy-based definitions that reproducibly distinguish surgically accessible (proximal) from inaccessible (distal) chronic thromboembolic disease on standard imaging, and (ii) operability criteria that generalize across centers, so that operability verdicts and the allocation among PEA, balloon pulmonary angioplasty (BPA), and medical therapy are reproducible and predict post-operative outcome, including the borderline cases where expert centers currently disagree. As of 2026 the gap is demonstrably open: operability verdicts are overturned at expert evaluation in up to half of referrals, guidelines recommend multidisciplinary assessment on the basis of expert consensus rather than validated criteria, and no validated multicenter criteria set has been published.

Background

Pulmonary hypertension (PH) is elevated blood pressure in the pulmonary circulation, confirmed by right heart catheterization (direct pressure measurement via a catheter floated through the right heart into the pulmonary artery). Chronic thromboembolic pulmonary hypertension (CTEPH) is the fourth clinical group of PH: persistent obstruction of pulmonary arteries by organized, fibrotic thrombotic material left over from incompletely resolved pulmonary embolism, typically accompanied by a secondary small-vessel (microvascular) arteriopathy resembling that of pulmonary arterial hypertension. The two components - mechanical obstruction and microvascular disease - jointly determine pulmonary vascular resistance (PVR), the afterload faced by the right ventricle.

CTEPH is the only potentially curable form of PH. Pulmonary endarterectomy (PEA, also called pulmonary thromboendarterectomy) is the surgical removal of the organized material from the pulmonary arterial tree under cardiopulmonary bypass and deep hypothermic circulatory arrest; at experienced centers perioperative mortality is around 2% and pulmonary pressures can normalize. Balloon pulmonary angioplasty (BPA) - percutaneous catheter dilation of obstructed segmental and subsegmental arteries - became established during the 2010s for patients judged inoperable or with residual PH after PEA, and riociguat is the only drug approved for inoperable or persistent CTEPH.

"Operability" denotes the decision that a patient's obstruction is surgically accessible and that the patient will tolerate and benefit from PEA rather than BPA and/or medical therapy. The 4th World Symposium on Pulmonary Hypertension (Dana Point, 2008) removed the proximal/distal subcategories of CTEPH from the clinical classification because "there is no consensus among experts about the definitions of proximal and distal CTEPH", noting that operability "may be quite unclear, and it may vary depending on individual centers", and left operability as a judgement of expert centers weighing the location of obstruction, the correlation between hemodynamic severity and the angiographic obstruction burden, comorbidities, patient preference, and surgeon experience (Simonneau et al. 2009). Later classification updates kept a single CTEPH category and introduced chronic thromboembolic pulmonary disease (CTEPD) for the same obstruction pattern without PH (Simonneau et al. 2019).

The gap has not closed; it has become more consequential. The CHEST-1 trial of riociguat in "inoperable" CTEPH had to introduce central adjudication by experienced surgeons because local operability verdicts diverged, and "lack of standardized assessment of pulmonary endarterectomy eligibility risks suboptimal treatment" (Jenkins et al. 2016). Contemporary reviews describe operability assessment as "subjective and dependent on surgical and center expertise" and list the accuracy of preoperative prediction, the contribution of small-vessel disease to residual PH, and borderline cases among the field's unanswered questions (Yang et al. 2023; Verbelen et al. 2022). In a global cross-sectional survey of 353 physicians, up to 50% of respondents evaluating referred patients concluded a different operability status than the referring center (Kopeć et al. 2024). The 2022 ESC/ERS guidelines recommend assessment of operability by an expert multidisciplinary team (class IC) - a recommendation explicitly based on symposium conclusions "rather than on any new published evidence" (Humbert et al. 2022; Kim et al. 2024). With PEA, BPA, medical therapy, and combined approaches now all available, "operability assessment and patient selection remain the Achilles' heel" of CTEPH care (Kim et al. 2024); the ongoing GO-CTEPH trial randomizes technically operable patients between PEA and BPA, and single-country "practical operability frameworks" are still being proposed rather than validated (Nishiyama et al. 2025).

Problem Statement

Close the definitional and decisional gap that the Dana Point classification left open for CTEPH: (1) establish consensus, anatomy-based definitions of proximal versus distal chronic thromboembolic disease - specified reproducibly on standard imaging (conventional or selective pulmonary angiography, CT pulmonary angiography) at the segmental arterial level - so that the anatomical accessibility of disease is no longer center-dependent; and (2) derive and validate operability criteria for pulmonary endarterectomy that generalize across centers, incorporating the decision factors the source enumerated (location and surgical accessibility of the obstruction, the correlation between obstruction burden and catheter-measured hemodynamic severity - the imprint of small-vessel disease - and comorbidities, but not patient preference and surgeon experience, which vary with the patient and the treating team and so cannot ground criteria that generalize across centers), such that operability verdicts and the resulting allocation among pulmonary endarterectomy, balloon pulmonary angioplasty, and medical therapy are reproducible across centers and predict post-operative outcome, including for the borderline cases of disproportion between imaging-visible obstruction and hemodynamic severity where expert centers currently disagree. The two parts are jointly posed: absent prospectively collected multi-center outcome data, their resolution is a fully specified, evidence-grounded proposal for each part together with the validation design by which the definitions' reproducibility and the criteria's cross-center reproducibility and outcome-predictiveness would be established.

References

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