Association of clonal hematopoesis and autonomic dysfunction with cardiovacular outcomes in atrial fibrillation

Individuals carrying clonal hematopoiesis of indeterminate potential (CHIP) mutations have an increased risk of cardiovascular disease. Similarly, cardiac autonomic dysfunction is strongly associated with poor prognosis.

This study aimed to investigate the association between CHIP, autonomic dysfunction, and major adverse cardiovascular events (MACE) in patients with atrial fibrillation (AF).

We included patients from the ongoing Swiss-AF cohort study with targeted sequencing for CHIP-related mutations and a digital high-resolution 16-lead resting ECG recording (5-minute duration) for cardiac autonomic function assessment. Deep-targeted sequencing of a panel of 96 CHIP mutations was performed at baseline. Cardiac autonomic function was quantified using periodic repolarization dynamics and dichotomized at 7.5 deg, as previously validated. Multivariable adjusted Cox proportional hazard models were used to investigate the association between CHIP status and autonomic dysfunction with MACE (composite of death, myocardial infarction, stroke/TIA, heart failure or major bleeding).

A total of 1,511 patients (mean age 73±8.5 years, 28% women) were included, with a mean follow-up of 6.1 years. MACE rate was 52.5% in CHIP carriers, 54.1% in patients with autonomic dysfunction, 64% in CHIP carriers with autonomic dysfunction and 36.2% in patients without CHIP and without autonomic dysfunction. In the age- and sex-adjusted model, patients with CHIP had an increased risk of MACE (hazard ratio [HR] 1.11 (95% CI 0.93–1.32, p=0.257), as well as patients with autonomic dysfunction (HR 1.40 (95% CI 1.19–1.65, p<0.001) and CHIP carriers with autonomic dysfunction (HR 1.40 (95% CI 1.06–1.85, p=0.002). After multivariable adjustment, only autonomic dysfunction remained significantly associated with MACE (HR 1.28, 95% CI 1.09–1.51, p=0.003).

In this prospective cohort of patients with AF, CHIP carriers with autonomic dysfunction had the worst prognosis. These findings underscore the prognostic relevance of autonomic function and CHIP mutations in cardiovascular risk assessment in AF.