Age- and sex-specific association between clonal hematopoiesis of indeterminate potential and pulmonary hypertension

Background Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related accumulation of somatic mutations in hematopoietic stem cells, and has been implicated in the presence of pulmonary hypertension and all-cause mortality. However, data on age- and sex-specific prognostic implications remain limited, which is critical for guiding preventive strategies. Aims To investigate the effect of age and sex on the association between CHIP and the prognosis of chronic thromboembolic pulmonary hypertension (CTEPH). Methods Patients diagnosed with CTEPH were enrolled from three pulmonary disease centers in China (2006–2021) following established guidelines. CHIP was defined as a variant allele frequency ≥2% in driver genes (e.g., DNMT3A, TET2) via next-generation sequencing. Mortality risks stratified by age (<60 vs. ≥60 years) and sex were analyzed using Cox regression. Results Among 499 CTEPH patients (median age 54 years; 49.7% male; median follow-up 55 months), CHIP mutations were identified in 47 (9.4%) cases, predominantly in DNMT3A, TET2, and RUNX1. CHIP prevalence did not differ significantly between age groups (<60 years: ≥60 years = 8.2% vs. 11.8%, P=0.17) and sex (females: males = 8.4% vs. 11.0%, P=0.33). After adjustment, CHIP was associated with increased mortality in both age groups (<60 years: HR=2.09 [95%CI: 1.03–4.23]; ≥60 years: 3.67 [1.82–7.41]), and both women (2.76, [1.43–5.34]) and men (2.09 [1.13–3.87]) [Figure 1]. The interaction effects by age (PInteraction=0.49) and sex (PInteraction=0.78) were not significant [Figure 2]. Conclusions CHIP in CTEPH patients was associated with a higher risk of mortality, irrespective of age and sex, highlighting the importance of targeted monitoring for CHIP carriers across both age groups and sex.