The Immunological Consequences of Clonal Hematopoiesis in Heart Failure

Inflammation is increasingly recognized as a central driver of heart failure (HF), particularly in older adults, yet the underlying immune mechanisms remain diverse and incompletely understood. Clonal hematopoiesis (CH), defined by the expansion of somatically mutated hematopoietic clones, has emerged as a risk factor for the development of numerous age-related diseases including HF. Experimental and clinical evidence suggests that mutant clones carrying driver gene mutations promote a pro-inflammatory immune cell phenotype that contributes to cardiac injury, remodeling and adverse outcomes. Notably, CH has been implicated in HF across diverse etiologies, including both HFrEF and HFpEF, highlighting its broad impact on a vast array of HF syndromes. More recently, it has been discovered that hematopoietic loss of the Y chromosome (LOY) also contributes to HF. LOY appears to shift macrophages toward a fibrotic and away from a pro-inflammatory phenotype, contrasting with that observed for driver gene mutations and suggesting that different somatic alterations contribute to HF via divergent mechanisms. In this review, we examine the clinical and experimental associations between CH and HF. We also explore how CH may drive age-related immune heterogeneity in HF and highlight its potential to be leveraged for personalized interventions in patients with HF.