Impact of atrial fibrillation on the prevalence and characteristics of cytopenia and clonal cytopenia of undetermined significance
C Forner, A Traub, J Vorwerk, L Oelschlaeger, S Hatahet, S S Popescu, N Mateen, E Rawish, J P Wenzel, C Eitel, F Wortmann, N Gebauer, N Von Bubnoff, C Khandanpour, R TilzAbstract
Background
Atrial fibrillation (AF) is the most common arrhythmia in older adults and is associated with substantial morbidity and mortality. Biological mechanisms linking aging to AF remain incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) and its cytopenic variant, clonal cytopenia of undetermined significance (CCUS), are age-related states characterised by the expansion of haematopoietic stem cell clones with somatic mutations. While CHIP has been linked to systemic inflammation, cardiovascular remodelling, and AF, data on CCUS in AF are limited. We investigated associations between cytopenia, CCUS, and AF, including AF subtype and complex supraventricular tachycardias (SVTs).
Purpose
To determine the prevalence of cytopenia and CCUS among AF patients and explore associations with AF type and prognosis.
Methods
We screened 2,083 adults treated at a tertiary rhythmology centre (2021–2025). Patients with unexplained cytopenia (Hb <10 g/dL, leukocytes <2×109/L, or platelets <150×109/L) underwent targeted next-generation sequencing of 159 myeloid genes. CCUS was defined as ≥1 pathogenic or likely pathogenic variant (VAF ≥1%) in a CHIP-associated gene without haematologic malignancy. Analysis included only patients with ≥3 episodes of unexplained cytopenia. Patients were divided into two groups: Group A (AF) and Group B (non-AF).
Results
Among 2,083 included patients, there was no significant difference in the distribution between AF (55.9%) and non-AF patients (44.1%). AF patients were older (median 78 vs. 68 years; p<0.0001) and more often male (64.0% vs. 53.8%; p<0.0001). Unexplained cytopenia was more frequent in AF patients (63.3% vs. 36.7%; p<0.0001), although individual cytopenias did not differ significantly. The prevalence of persistent AF was significantly higher in cytopenic patients (59.2%) than in non-cytopenic patients (48.3%; p=0.0442). Of 51 NGS panels, 25 were positive, including 18 AF and 7 non-AF patients, corresponding to a CCUS prevalence of 51.5% in the cytopenic AF cohort. CCUS positivity was not significantly associated with AF, AF type, complex supraventricular tachycardia (SVT), CHA2DS2-VASc scores, prior ablations, number of mutations, or variant allele frequency (VAF). VAF tended to be higher in AF patients (median 5.0 vs. 2.0; p = 0.056). Although not statistically significant, a trend toward higher rates of complex SVTs and persistent AF was observed among CCUS-positive patients; however, these findings should be interpreted with caution due to the limited sample size.
Conclusion
Consistent with previous findings in CHIP patients, complex SVTs and persistent AF were more prevalent. In our analysis, a similar trend was observed in the cytopenic cohort and among CCUS patients; however, this did not reach statistical significance, likely due to the small sample size. Whether CCUS exerts a stronger arrhythmogenic effect than CHIP remains to be determined in larger studies.Mechanistic link: CCUS and arrhythmia