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

Background The 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. Methods We 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. Results Total 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 among DNMT3A, RUN1 and STAG2. 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. Conclusions CHIP 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018), National Key Research and Development Program of China (2022YFC2703902), National Natural Science Foundation of China (82241020)?and National High Level Hospital Clinical Research Funding (2022-PUMCH-B-099 and 2022-PUMCH-A-200). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics review boards of the Shanghai Pulmonary Hospital, FuWai Hospital and Peking Union Medical College Hospital I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data supporting the results of the paper is provided in the manuscript. Other data underlying this article will be shared on reasonable requests to the corresponding authors.