Decreased diastolic calcium concentrations in patients with persistent versus paroxysmal atrial fibrillation

Background Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia and is associated with heart failure, thromboembolism and premature mortality. With aging populations and rising comorbidities, AF incidence and prevalence continue to increase. At the cellular level, AF is characterized by disrupted Ca2+ handling in cardiomyocytes, promoting ectopic activity and arrhythmogenic triggers. Disease progression is heterogeneous but commonly involves transition from paroxysmal AF (pAF) to persistent AF (persAF). This process is driven by altered Ca2+ signaling and structural remodeling, increasing AF burden. Purpose Comparative human data on intracellular Ca2+transients in pAF and persAF are limited. This study aimed to investigate potential differences in intracellular Ca2+ dynamics in isolated atrial cardiomyocytes (aCMs) from patients with pAF and persAF. Methods Left atrial appendages were collected from patients diagnosed with pAF or persAF undergoing heart valve repair and/or coronary artery bypass surgery. ACMs were isolated by enzymatic digestion. Intracellular Ca2+ and sarcomere shortening were assessed simultaneously under basal conditions and during β-adrenergic stimulation with isoprenaline. Atrial structural remodelling was investigated histologically, and expression of key Ca2+ dynamics proteins was quantified by immunoblotting. Results Atrial tissue samples from 28 patients with pAF (n=13) or persAF (n=15) were analysed (median age 66 years; 21.4% female). At inclusion, 92.3% pAF and 53.3% persAF patients were in sinus rhythm. The median CHA2DS2-VASc-Score was 2, and patients received anticoagulants (92.9%), rate control medication (89.3%), and Ca2+ channel blockers (28.6%). These baseline characteristics did not differ between groups significantly. Histology demonstrated atrial-specific slender aCMs with central nuclei in all samples. Compared with pAF, aCMs from persAF patients tended to be less aligned, more branched, and longer, indicating a more pronounced structural remodelling. Basal diastolic Ca2+ levels were significantly lower in aCMs from persAF patients. At the same time, Ca2+ reuptake was delayed in persAF vs pAF aCMs. Isoprenaline increased intracellular Ca2+ dynamics in both groups. However, differences between groups disappeared, suggesting an increased β-adrenergic effect in persAF. Protein expression levels of Cav1.2, sarcoplasmic reticulum Ca2+-ATPase 2a, and phospholamban remained largely unaltered. Conclusion To our knowledge, this is the first study comparing intracellular Ca2+ dynamics in human aCMs isolated from left atrial appendages of patients with pAF and persAF. AF progression was associated with aCM hypertrophy, reduced diastolic Ca2+ levels, and enhanced β-adrenergic excitability. A change in Ca2+ dynamics during AF progression should be further investigated, as it may necessitate distinct therapeutic strategies for AF treatment.