Key result
Vascular IPAH phenotype achieves greater 6MWD gains than cardiometabolic phenotype but shows similar 5-year survival.
Why the study?
Idiopathic pulmonary arterial hypertension is characterized by significant clinical heterogeneity, prompting an investigation into whether machine learning-based cluster analysis can identify distinct patient phenotypes with differing therapeutic responses and long-term survival.
Does machine learning-based clustering into vascular versus cardiometabolic phenotypes predict differences in therapeutic response and long-term survival in patients with idiopathic pulmonary arterial hypertension?
Cohort (n=297)
Does machine learning-based clustering into vascular versus cardiometabolic phenotypes predict differences in therapeutic response and long-term survival in patients with idiopathic pulmonary arterial hypertension?
Machine learning clustering stratifies IPAH patients into a younger vascular phenotype with better functional and neurohumoral therapy response and an older cardiometabolic phenotype, though both groups experience similar 5-year mortality.
No survival difference between phenotypes; leaves open whether clustering informs prognosis or therapy in idiopathic PAH.
Objective Idiopathic pulmonary arterial hypertension (IPAH) is characterized by significant clinical heterogeneity. This study aimed to identify distinct patient phenotypes using machine learning-based cluster analysis and to evaluate their differences in therapeutic response and long-term survival. Methods A total of 297 patients with IPAH were analyzed. Hierarchical agglomerative clustering was performed based on baseline demographics, invasive hemodynamics, and comorbidities. Longitudinal changes in 6-minute walk distance (6MWD), NT-proBNP, multiparametric risk scores and echocardiographic parameters (PASP, TAPSE/PASP) were evaluated over 12 months. Results Two distinct clusters were identified. Cluster 1 (n=198; "Vascular Phenotype") comprised younger patients (median age 40 years) with low comorbidity burden but severe hemodynamic impairment. Cluster 2 (n=99; "Cardiometabolic Phenotype") consisted of older patients (median age 65 years) with a high prevalence of obesity (78%), diabetes (73%), and hypertension (57%). Female predominance was significantly higher in Cluster 2 (p=0.012). While WHO Functional Class, ESC/ERS, REVEAL 2.0, REVEAL 2.0 lite, and FPHN risk status were comparable, Cluster 1 exhibited significantly lower TAPSE, S’, and TAPSE/PASP ratio, alongside a higher rate of pericardial effusion compared to Cluster 2 (p<0.001 for all). Furthermore, Cluster 1 was associated with lower LVEDP (p=0.032) and cardiac index (p<0.001), but higher mean pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary-to-systemic vascular resistance ratio (p<0.001 for all). Triple combination therapies were more frequently utilized in Cluster 1 (41.6% vs. 25.5%, p=0.048). Median follow-up was 763 (227-1993) days. Cluster 1 showed a greater increase in 6MWD (median 75m vs. 42m, p<0.001) and significantly lower NT-proBNP levels at final assessment (median 55 vs. 145 pg/mL, p=0.017). Despite these phenotypic differences, five-year survival was similar between groups (Log-rank p=0.452). Neither unadjusted (HR: 0.868; 95% CI: 0.60–1.26, p=0.452) nor adjusted (HR: 0.711; 95% CI: 0.47–1.07, p=0.099) Cox regression analyses showed a significant mortality difference. Conclusion IPAH patients can be phenotypically stratified into a "classic" vascular group and a "cardiometabolic" group. Although the first group demonstrates a more robust functional and neurohumoral response to PAH therapy, the similar survival rates suggest that mortality is driven by hemodynamic severity in the younger vascular phenotype group versus metabolic frailty in the older comorbid group.
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Kaymaz et al. (2026) conducted a cohort in Idiopathic pulmonary arterial hypertension (IPAH) (n=297). Vascular phenotype (Cluster 1) vs. Cardiometabolic phenotype (Cluster 2) was evaluated on Five-year survival / mortality (HR 0.711, 95% CI 0.47-1.07, p=0.099). The vascular IPAH phenotype had greater 6MWD gains (75m vs 42m, p<0.001) than the cardiometabolic phenotype, but similar 5-year survival (adjusted HR 0.711; 95% CI 0.47-1.07; p=0.099).
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