Clonal Cytopenias of Undetermined Significance and Cardiovascular Disease: Inflammatory Mechanisms, Risk Stratification, and Clinical Outcomes

Clonal cytopenia of undetermined significance (CCUS) is defined by persistent, unexplained cytopenias accompanied by somatic mutations characteristic of clonal hematopoiesis, in the absence of morphologic criteria for myeloid malignancy. While traditionally viewed as a hematologic precursor state, emerging evidence indicates that CCUS represents a systemic inflammatory disorder with important cardiovascular relevance. Mutant myeloid clones associated with CCUS promote chronic low-grade inflammation, dysregulated cytokine signaling, and inflammasome activation, processes that contribute to endothelial dysfunction, accelerated atherosclerosis, and adverse myocardial remodeling. In parallel, anemia and other cytopenias commonly observed in CCUS independently exacerbate cardiovascular stress by increasing myocardial oxygen demand, worsening heart failure outcomes, and complicating antithrombotic and invasive management in patients with coronary artery disease. CCUS frequently overlaps with aging-related syndromes such as frailty and multimorbidity, further amplifying cardiovascular risk and influencing prognosis. As molecular testing becomes increasingly integrated into clinical practice, cardiologists will encounter CCUS with greater frequency across a range of cardiovascular settings. This review synthesizes contemporary evidence linking CCUS to cardiovascular disease, highlights mechanisms relevant to cardiology, and outlines practical considerations for cardiovascular risk assessment and interdisciplinary management, while identifying key gaps for future cardio-hematology research.