肺静脈閉塞症／肺毛細血管腫症

PURPOSE OF REVIEW: Systemic sclerosis-associated pulmonary hypertension (SSc-PH) is a heterogeneous, difficult-to-treat condition in which multiple pulmonary hypertension groups frequently overlap. Recent evidence suggests that vascular involvement may contribute to multiple SSc-PH phenotypes. This review highlights recent advances in understanding vascular features and emerging therapeutic strategies beyond vasodilation. RECENT FINDINGS: Pathological and imaging studies demonstrate that vascular remodeling in SSc-PH extends beyond pulmonary arteries to pulmonary veins, capillaries, and coronary microcirculation, consistent with widespread immune-mediated vascular dysfunction. These features are increasingly recognized across various SSc-PH phenotypes: pulmonary arterial hypertension and pulmonary veno-occlusive disease; pulmonary hypertension associated with left heart disease, most commonly heart failure with preserved ejection fraction (PH-HFpEF); and pulmonary hypertension-associated with interstitial lung disease (PH-ILD); each of which is often accompanied by intrinsic right ventricular (RV) dysfunction. Emerging therapies targeting activin signaling, macrophage-vascular crosstalk, B-cell immunity, and endothelial-to-mesenchymal transition require further study but may be essential to identifying disease-modifying approaches across SSc-PH phenotypes. SUMMARY: There is increasing recognition that vascular remodeling across the cardiopulmonary circulation may underlie multiple SSc-PH phenotypes, providing novel insight into SSc-PH disease mechanisms and rationale for the development of therapies targeting vascular remodeling, fibrosis, inflammation, and intrinsic RV dysfunction beyond conventional vasodilator treatment.

BACKGROUND: Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension rarely linked to congenital heart disease (CHD). CASE SUMMARY: An infant with a ventricular septal defect developed pulmonary hypertension. At 3 months, cardiac catheterization showed operable hemodynamics with preserved pulmonary vasoreactivity. Pulmonary artery banding was performed. Despite tadalafil, macitentan, and prostacyclin, pulmonary vascular resistance increased without pulmonary edema. Lung perfusion scintigraphy demonstrated perfusion defects, prompting transplantation. At 2 years and 10 months, he underwent bilateral lung transplantation with intracardiac repair. The explanted lungs demonstrated fibrous intimal thickening of pulmonary venules and hemosiderin deposition, indicating PVOD. DISCUSSION: PVOD may coexist with CHD and mimic CHD-associated pulmonary arterial hypertension, without pulmonary edema during vasodilator therapy. TAKE-HOME MESSAGES: PVOD should be considered in children with CHD developing progressive pulmonary hypertension despite favorable hemodynamics and preserved vasoreactivity. The absence of pulmonary edema during vasodilator therapy does not exclude PVOD.

INTRODUCTION: Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterized by progressive vascular remodeling, with limited understanding of its cellular and molecular mechanisms, particularly in sporadic cases lacking identifiable genetic mutations. We investigated whether patient-derived induced pluripotent stem cells (iPSCs) recapitulate disease-associated cellular phenotypes and transcriptional alterations in sporadic PVOD. METHODS: Integration-free iPSCs were generated from a patient with sporadic PVOD and differentiated toward endothelial and hematopoietic lineages. Endothelial differentiation capacity was assessed by flow cytometry, and transcriptomic profiling was performed using RNA sequencing followed by differential gene expression and gene set enrichment analyses. RESULTS: PVOD-derived iPSCs demonstrated preserved hemangioblast generation but reduced endothelial commitment compared with control cells. Transcriptomic profiling revealed clear segregation between PVOD-derived and control samples by principal component analysis, indicating distinct global gene expression patterns. Differential expression analysis identified genes associated with cellular stress and metabolic regulation, while gene set enrichment analysis demonstrated enrichment of reactive oxygen species and transforming growth factor-β (TGF-β) signaling pathways, consistent with altered stress-related transcriptional programs. DISCUSSION: These findings indicate that iPSCs derived from a patient with sporadic PVOD exhibit altered endothelial differentiation and distinct stress-related transcriptional signatures. This patient-specific iPSC model provides a platform for investigating disease-associated cellular alterations in sporadic PVOD.

TOPIC IMPORTANCE: Pulmonary hypertension (PH) comprises a heterogeneous group of conditions characterized by elevated mean pulmonary artery pressure and is classified into 5 groups according to underlying etiology. Across PH subtypes, pathologic remodeling of the pulmonary microvasculature, including arterioles, capillaries, and venules, drives hemodynamic burden, right ventricular dysfunction, and clinical outcomes. Although certain structural features are conserved, distinct histopathologic patterns shape group-specific pathophysiology, treatment responses, and prognosis. REVIEW FINDINGS: Experimental models (eg, monocrotaline, 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 histologic studies confirm these changes and demonstrate group-specific signatures: venule-predominant remodeling in group 2 PH, dense occlusive venous fibrosis in pulmonary veno-occlusive disease, arterial-dominant lesions in group 1 pulmonary arterial hypertension, and mixed arterial-venous changes in chronic thromboembolic pulmonary hypertension. These structural differences help explain variable therapeutic responses; for example, vasodilators are effective in precapillary arteriolar predominant disease but may precipitate pulmonary edema in venous-predominant PH phenotypes. In chronic thromboembolic pulmonary hypertension, distal arteriolar pathology is a therapeutic target; however, venous remodeling may underlie heterogeneity of outcomes. Emerging noninvasive markers, including echocardiographic indices such as tricuspid annular plane systolic excursion/right ventricular systolic pressure and exercise hemodynamics, may provide physiological surrogates of microvascular disease; however, direct correlations with histopathology remain limited. SUMMARY: Pulmonary vascular remodeling varies substantially across PH groups, with distinct arterial and venous signatures that influence hemodynamics, treatment response, and outcomes. Integrating histopathologic insights with hemodynamic phenotyping and noninvasive assessments may enable earlier detection of pulmonary vascular disease and support more precise, mechanism-directed therapeutic strategies.