Beyond Clonal Hematopoiesis: Somatic Hematopoietic Mutations as Drivers of Cardiovascular Disease and Targets for Precision Therapy

Abstract

Somatic hematopoietic mutations, particularly clonal hematopoiesis of indeterminate potential (CHIP), represent an emerging link between aging, inflammation and cardiovascular disease beyond their established relevance in hematology. This narrative review examines how acquired mutations in hematopoietic stem and progenitor cells contribute to cardiovascular pathogenesis and how this knowledge may inform precision prevention and therapy. Evidence from experimental, clinical and population studies was synthesized with emphasis on clonal expansion, variant allele fraction, gene-specific mechanisms and cardiovascular phenotypes. The reviewed data indicate that driver mutations in DNMT3A, TET2, ASXL1, JAK2, TP53 and PPM1D can promote chronic myeloid inflammation, NLRP3/IL-1β and IL-6 signaling, endothelial dysfunction, atherosclerotic plaque instability, myocardial fibrosis, adverse remodeling, thrombosis, arrhythmias and cardio-oncology complications. The cardiovascular impact of CHIP appears heterogeneous and depends on the mutated gene, clone size, inflammatory phenotype, age, sex, treatment exposures and traditional risk factors. Anti-inflammatory, antithrombotic and mutation-oriented strategies, including IL-1β/NLRP3 blockade and pathway-specific approaches, are promising but remain incompletely validated. Somatic hematopoietic mutations should be considered cardiovascular risk modifiers rather than uniform disease entities. Future studies are needed to define screening thresholds, clinical utility and safety of CHIP-guided risk stratification and targeted therapy.