Clonal hematopoiesis is linked to increased risks of all-cause mortality, cardiovascular death, and bleeding complications in patients with atrial fibrillation

Importance Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with several cardiovascular diseases. However, its relationship with cardiovascular outcomes in individuals with atrial fibrillation (AF) is not yet well understood. Objective To examine associations of CHIP mutations with all-cause mortality and cardiovascular outcome in a prospective AF cohort. Design, Setting, and Participants Prospective, multicenter cohort study of AF patients from the Swiss-AF study who underwent targeted sequencing for CHIP-related mutations, and standardized clinical assessment between June 1, 2010, and June 13, 2024. Exposure Deep-targeted sequencing (96 CHIP mutations, 500× coverage) was performed at baseline. Three CHIP carrier patterns were compared: any CHIP carrier, DNMT3A mutation carriers, and non-DNMT3A mutation carriers (CHIP mutations other than DNMT3A). Main Outcomes and Measures Cardiovascular outcomes such as mortality, stroke, myocardial infarction, heart failure events and AF burden were assessed during the up to 14 years of follow up (Mean/Median follow up of 7.3/7.5 years). Associations between CHIP and outcomes were assessed using multivariable adjusted logistic and linear regression models and competing risk models. Exclusion criteria included inability to give informed consent, a history of malignancies and secondary forms of AF attributable to reversible causes, such as infection or perioperative AF. Results A total of 3018 AF patients (mean [SD] age 70.6 [± 10.2] years; 28.2% women) were included. CHIP mutations were present in 593 (19,6 %) patients, with epigenetic regulator genes DNMT3A (284, 47.9%) and TET2 (167, 28.2%) being most commonly affected. At baseline, CHIP carriers were characterized by older age, higher BMI, and an increased prevalence of diabetes, coronary heart disease (CHD), and chronic kidney disease (CKD). A history of heart failure was more common among CHIP carriers, who also demonstrated a higher proportion of patients with permanent atrial fibrillation. Compared to non-carriers, CHIP carriers underwent fewer pulmonary vein isolations (PVIs) and received less Type Ic antiarrhythmic therapy. Additionally, they exhibited elevated high-sensitivity C-reactive protein (hsCRP) levels and a greater use of diuretics. In a follow-up analysis adjusted for age, sex, relevant risk factors, comorbidities and mortality as competing event where appropriate, CHIP carriers exhibited significantly higher cardiovascular mortality, as well as increased rates of bleeding events. Patients younger than 75 years had a significantly higher HR for heart failure events during follow up. However, no significant differences were observed in the rate of AF progression or amount of heart failure events between CHIP carriers and non-carriers. Conclusions and Relevance CHIP is associated with higher cardiovascular mortality and bleeding events in patients with AF.