Clonal haematopoiesis of indeterminate potential (CHIP) is the clonal expansion of haematopoietic cells caused by somatic mutations. This phenomenon has been shown to increase with age and to be associated with inflammation and atherosclerosis. A new study published in JAMA Cardiology now links CHIP with poor prognosis in chronic heart failure (HF) of ischaemic origin.

Bone-marrow-derived mononuclear cells were obtained from 200 patients with chronic HF and analysed by deep targeted amplicon sequencing to detect the presence of CHIP. A total of 47 mutations with a variant allele fraction ≥0.02 were found in 38 of the patients (18.5%). The somatic mutations most commonly occurred in DNMT3A (14 patients), TET2 (nine patients), KDM6A (four patients) and BCOR (three patients).

DNMT3A and TET2 encode proteins involved in DNA methylation and demethylation, which exert epigenetic control on gene expression. Functionally, these two proteins are important regulators of inflammation by augmenting monocyte adhesion and macrophage activity. Patients with either DNMT3A or TET2 mutations had significantly worse long-term clinical outcomes than patients who were not CHIP carriers. The presence of DNMT3A or TET2 mutations was independently associated with an increased risk of death or hospitalization for HF (HR 2.1, 95% CI 1.1–4.0, P = 0.02). Of note, a significant dose–response association was reported between variant allele fraction and clinical outcome.

The investigators speculate that identifying patients with HF who are CHIP carriers could inform a precision-medicine approach. For example, antioxidants might be used to activate remaining wild-type TET2 in patients with TET2 mutations.