Background: Clonal hematopoiesis (CH) is characterized by the expansion of the hematopoietic stem/progenitor pool in the setting of somatic mutations in the absence of evident myeloid neoplasm. In addition to the heightened risk of myeloid neoplasm, CH of indeterminate potential (CHIP) also confers an increased risk for multi-system non-hematologic complications, including cardiovascular disease, liver disease, osteoporosis, and kidney disease. DNMT3A, TET2, and ASXL1 (DTA) mutations confer an approximately 2-fold increased risk for heart disease, presumably related to a hyperinflammatory phenotype. We have recently defined the natural history of patients with canonical CH mutations with regard to risk of progression to myeloid neoplasm (Br J Haematol 2024), but the differential impact of CH mutations with regard to incident cardiovascular disease remains to be explored in multidisciplinary CHIP Clinics.

Methods: We identified patients from the UMass CHIP Clinic (www.umassmed.edu/chip-clinic) and from the UMass Research Information Core diagnosed with CHIP or clonal cytopenia of undetermined significance (CCUS) between 2014-2025. A total of 134 patients met the International Consensus Classification definition for CHIP or CCUS, with aberrations spanning 31 genes known to be implicated in myeloid neoplasm. Among these 134 patients, 88 (65.7%) were within the evaluable range of age 40-79 years for risk assessment using the 10-year Atherosclerotic Cardiovascular Disease (ASCVD) model. We stratified these 88 patients into those who had only DTA mutations without other mutations (“sole DTA,” n = 24) and those who had did not have purely DTA mutations (“non-sole DTA,” n = 64) to assess the differential impact of these clusters on ASCVD risk. A negative control dataset included 22 healthy persons with morphologically normal bone marrow results and without mutations.

Results: Median age for healthy, sole DTA, and non-sole DTA groups was 67.1 years, 68.2 years, and 69.0 years, respectively (single-factor ANOVA p = 0.73).The 10-year ASCVD risk in the non-sole DTA group was significantly higher compared to healthy controls (29.6% vs. 19.1%, p = 0.028). There was no difference in 10-year ASCVD risk for sole DTA vs. non-sole DTA groups (25.0% vs. 29.6%, p = 0.26). We then assessed the impact of optimization of cardiovascular risk factors (including systolic blood pressure, high-density lipoprotein, smoking, and diabetes mellitus) on the 10-year ASCVD risk. The mean risk reduction (“delta”) was significantly higher in the non-sole DTA group vs. healthy controls (18.2% ± 1.8% vs. 12.1% ± 2.9%, p = 0.047). There was no difference in the delta with optimization of risk factors for the sole DTA vs. non-sole DTA groups (15.2% vs. 18.2%, p = 0.18). We then performed subgroup analysis of ASCVD risk for each individual DTA mutation. Patients with DNMT3A-mutant CH (n = 22) had significantly lower ASCVD risk compared to non-DNMT3A-mutant CH (n = 66) (23.1% ± 3.3% vs. 30.1% ± 2.2%, respectively, p = 0.043). There was no difference in 10-year ASCVD risk for TET2-mutant CH vs. non-TET2-mutant CH (30.7% ± 3.9% vs. 27.4% ± 2.2%, p = 0.23). There was also no difference in risk for ASXL1-mutant CH vs. non-ASXL1-mutant CH (39.8% ± 10.9% vs. 27.5% ± 1.9%, p = 0.16).

Conclusion: Patients with CH involving non-DTA mutations had significantly higher 10-year ASCVD risk compared to healthy controls. These patients also had a significantly greater potential for ASCVD risk reduction with optimization of risk factors. Given that cardiovascular disease remains the leading cause of mortality worldwide, ASCVD risk reduction in this subgroup of patients may be a high-value proposition across CHIP clinics globally with the potential to improvement population health metrics. The findings of this study merit interventional clinical trials aimed at risk mitigation for CH-associated non-hematologic comorbidities identified in multidisciplinary CHIP clinics.

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2025
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