Direct acute arrhythmic and negative inotropic effects of ibrutinib, but not doxorubicin, in human atrial myocardium

Abstract

Anthracyclines such as doxorubicin are effective antineoplastic agents but are limited by well-known cardiotoxicity. Targeted therapies such as the Bruton tyrosine kinase inhibitor ibrutinib improve oncological outcomes and are generally considered less cardiotoxic with respect to systolic dysfunction. However, clinical studies report a high incidence of atrial arrhythmias during ibrutinib therapy, and the direct acute effects on human multicellular myocardium remain insufficiently characterized.

Our puepose was to determine the acute effects of ibrutinib on contractile function and arrhythmogenicity in human atrial myocardium ex vivo and to assess similar effects with doxorubicin.

Methods

Human right atrial tissue obtained during elective cardiac surgery was studied using an ex-vivo trabecular muscle strip preparation. Contractile activity was recorded during electrical stimulation in an organ bath.To assess arrhythmia susceptibility, strips were exposed to proarrhythmogenic conditions including acetylcholine. In addition, physiological stress was simulated by high-frequency stimulation (5 Hz). Samples were incubated with clinically relevant concentrations of ibrutinib or doxorubicin. Contractile force and arrhythmogenic activity were analyzed before and after high-frequency stimulation. The effects of patient comorbidities (diabetes, obesity, and atrial fibrillation) on arrhythmogenicity were analyzed.

Results

A total of 133 muscle strips from 37 patients were studied. Ibrutinib significantly reduced developed force during steady-state stimulation (Δforce approximately −2 to −5 mN/mm², p = 0.022), indicating impaired contractile reserve, whereas no significant change in force was observed with doxorubicin (p = 0.806). Before high-frequency stimulation, the proportion of muscle strips maintaining regular rhythmic activity was lower with ibrutinib than in control conditions (44.4% vs 66.8%, p = 0.0496), indicating increased baseline arrhythmogenicity. After exposure to proarrhythmogenic stress including 5 Hz stimulation, only 8.9% of strips in the ibrutinib group remained in regular rhythm compared with 21.2% in controls (p = 0.0224), demonstrating increased susceptibility to arrhythmias under physiological stress. Arrhythmias with ibutrinib were predominantly triggered contractions consistent with early or delayed aftercontractions. Doxorubicin did not significantly change arrhythmogenicity either before or after high-frequency stimulation.The influence of comorbidities could not be resolved within the analyzed subgroups.

Conclusion

Ibrutinib induces acute negative inotropy and increases arrhythmogenicity under proarrhythmogenic conditions and physiological stress in human atrial myocardium ex vivo, whereas doxorubicin does not cause significant acute arrhythmogenesis or contractile impairment. These findings support a direct acute proarrhythmic and myocardial depressant effect of BTK inhibition in human myocardium.Arrhythmic contractions