Pulmonary Hypertension Under the Microscope: What Histopathology Means for Diagnosis and Treatment.

Abstract

Pulmonary hypertension (PH) comprises a heterogeneous group of conditions characterised by elevated mean pulmonary artery pressure and classified into five groups according to underlying aetiology. Across PH subtypes, pathological remodelling of the pulmonary microvasculature, including arterioles, capillaries, and venules, drives hemodynamic burden, right ventricular dysfunction, and clinical outcomes. While certain structural features are conserved, distinct histopathological patterns shape group-specific pathophysiology, treatment responses, and prognosis. Experimental models such as monocrotaline and hypoxia have revealed key mechanisms of medial hypertrophy, distal neomuscularization, intimal fibrosis, and recanalization, but also highlight differences in cellular pathways and vascular compartments involved. Human histological studies confirm these changes and demonstrate group-specific signatures: venule-predominant remodelling in Group 2 PH, dense occlusive venous fibrosis in PVOD, arterial-dominant lesions in Group 1 PAH, and mixed arterial-venous changes in CTEPH. These structural differences help explain variable therapeutic responses; for example, vasodilators are effective in pre-capillary arteriolar predominant disease but may precipitate pulmonary oedema in venous-predominant PH phenotypes. In CTEPH, distal arteriolar pathology is a therapeutic target, though venous remodelling may underlie heterogeneity of outcomes. Emerging non-invasive markers, including echocardiographic indices such as TAPSE/RVSP and exercise hemodynamics, may provide physiological surrogates of microvascular disease, although direct correlations with histopathology remain limited. Pulmonary vascular remodelling varies substantially across PH groups, with distinct arterial and venous signatures that influence hemodynamics, treatment response, and outcomes. Integrating histopathological insights with hemodynamic phenotyping and non-invasive assessments may enable earlier detection of pulmonary vascular disease and support more precise, mechanism-directed therapeutic strategies.