Integrated clinical and genetic phenotyping in newly diagnosed pulmonary hypertension: comparative insights across IPAH, CTD-APAH, and CTEPH

Background

The ESC/ERS classification of pul­monary hypertension (PH) is based on distinct clinical phenotypes, which however often overlap significantly in clinical practice. While registries like COMPERA and ASPIRE provide robust hemodynamic comparisons, there remains a paucity of data integrating deep genetic and clinical phenotyping across the spectrum of incident PH in a prospective cohort of consecutive patients.

Purpose

The prospective SPH-RESP study aims to provide a comparison of phenotypic and genotypic characteristics of consecutive, newly diagnosed cases with idiopathic pulmonary arterial hypertension (IPAH), connective tissue disease–associated PAH (CTD-APAH), and chronic thromboembolic PH (CTEPH).

Methods

Consecutive, newly diagnosed patients with IPAH, CTD-APAH, and CTEPH referred for right heart catheterization at a single PAH center between October 1, 2021, and November 15, 2025 were included. Clinical, laboratory, echocardiographic, and hemodynamic data were analyzed across groups. Within each group, 10 patients underwent PAH gene-panel testing; selection was random in the IPAH group, whereas CTD-APAH and CTEPH patients were chosen to achieve age matching with the IPAH cohort. None had a known family history of PAH.

Results

IPAH patients were younger than CTD-APAH and CTEPH patients, and exhibited the most severe pulmonary vascular disease, with higher mean pulmonary artery pressure and pulmonary vascular resistance, and lower cardiac index. Right atrial area was also larger in IPAH, indicating more advanced right-sided remodeling. CTEPH showed intermediate hemodynamic impairment, while CTD-APAH displayed comparatively milder pulmonary pressures but a predominance of WHO functional class III symptoms. Comorbidity burden differed modestly, with diabetes being more frequent in IPAH, see Table 1.

Across all etiologies, genetically tested patients were younger, had fewer comorbidities, and better renal function than non-tested patients. The PAH gene-panel did not identify any known pathogenic or likely pathogenic variants. One IPAH patient carried a heterozygous ATP13A3 splice-region variant of uncertain significance (c.3313+4A>G), absent from population databases and predicted to affect RNA splicing. Although ATP13A3 loss-of-function variants are enriched in PAH cohorts, heterozygous variants typically demonstrate incomplete penetrance; therefore, the clinical significance of this finding remains uncertain.

Conclusions

IPAH demonstrated the most severe hemodynamic impairment, CTEPH showed intermediate severity, and CTD-APAH exhibited milder pulmonary pressures but more substantial functional limitation. The absence of known PAH-pathogenic genetic variants in this cohort underscores the limited diagnostic yield of broad gene-panel testing in routine clinical populations and the need for larger studies to clarify the genetic contribution to PH.For image description, please refer to the figure legend and surrounding text.