Clonal Hematopoiesis of Indeterminate Potential in Patients with Chronic Thromboembolic Pulmonary Hypertension

Abstract

AbstractBackgroundThe pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is complex and multifactorial, with growing evidence indicating the involvement of hematologic disorders. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with increased risks of both hematologic malignancies and cardiovascular diseases. The CHIP in patients with CTEPH and its clinical relevance remain undetermined.MethodsWe performed a step-wise calling method on the next-generation sequencing data from 499 CTEPH patients referred to three centers between October 2006 and December 2021 to identify CHIP mutations. We associated CHIP with all-cause mortality in patients with CTEPH. To provide potential mechanistic insights, the associations between CHIP and inflammation characteristics reflected by circulating cytokines and IgG galactosylation, a hallmark of inflammatory state in diseases were also determined.ResultsTotal 51 (10.2%) patients with CTEPH carried at least one CHIP mutation at a variant allele frequency of ≥ 2%, and the most common mutations were amongDNMT3A,RUN1andSTAG2. During a mean follow-up time of 55 months, deaths occurred in 21 patients (42.9%) in the CHIP group and 105 patients (24.3%) in the non-CHIP group, contributing to the 5-year survival rate of 65.3% in the CHIP group and 81.9% in the non-CHIP group (P< 0.001 for log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (HR: 3.447; 95% CI: 1.747 – 6.803;P< 0.001). Besides, patients in the CHIP group showed higher circulating IL-1beta and IL-6 and lower IL-4 and IgG galactosylation compared with the non-CHIP group.ConclusionsCHIP is enriched in CTEPH patients and is associated with a worse prognosis in CTEPH. Mechanically, patients in the CHIP group showed a more severe inflammatory state.Clinical PerspectiveWhat is new?Clonal hematopoiesis of indeterminate potential (CHIP) mutations are enriched in chronic thromboembolic pulmonary hypertension (CTEPH) patients, with most common mutated genes beingDNMT3A,RUN1andSTAG2.CHIP is associated with worse clinical outcomes in CTEPH.CHIP is associated with more severe inflammation state mediated by myeloid as well as lymphoid cells in patients with CTEPH.What are the clinical implications?CHIP might be a risk factor for CTEPH, suggesting a relationship between CTEPH and hematopoietic disorders.CHIP represented an additional disease component in CTEPH that independently impacts prognosis.CHIP might be a potential target for personalized medicine and an indicator of benefit from anti-inflammatory therapies for CTEPH patients.