Chronic thromboembolic pulmonary hypertension: towards an etiology-oriented conceptual framework

Chronic thromboembolic pulmonary hypertension (CTEPH) is traditionally regarded as a late complication of unresolved acute pulmonary embolism. However, this paradigm is challenged by several observations: up to half of patients lack a documented embolic history, distal or microvascular disease is common, and marked geographic differences in treatment strategies exist. While pulmonary endarterectomy (PEA) predominates in Western centers, Japanese programs have advanced balloon pulmonary angioplasty (BPA), particularly for distal disease. These discrepancies suggest that CTEPH represents a biologically heterogeneous condition rather than a post-embolic entity.

We developed an etiology-oriented framework integrating pathogenic mechanisms, vascular lesion distribution, and therapeutic strategies. Using Virchow's triad as a structural lens, dominant disease drivers were mapped to distinct phenotypes within a thrombo-vasculopathic spectrum.

Five mechanistic phenotypes are proposed: (1) thromboembolism-related (Type Ia), characterized by unresolved embolic obstruction and proximal disease; (2) thrombophilia-associated (Type Ib), driven by systemic hypercoagulability; (3) inflammation- or immune-mediated (Type Ic), associated with endothelial injury and vascular remodeling; (4) structural pulmonary arteriopathy-associated (Type II), in which intrinsic arterial abnormalities precede thrombosis; and (5) idiopathic (Type III), without identifiable cause. These phenotypes form a continuum defined by the relative contributions of thrombotic obstruction and intrinsic vascular remodeling. Within this framework, PEA aligns with proximal disease, whereas BPA and medical therapy correspond to distal vasculopathic phenotypes.

CTEPH should be reconsidered as a heterogeneous thrombo-vasculopathic syndrome. An etiology-based framework linking pathobiology, anatomy, and treatment may help explain global practice variation and support phenotype-guided management.