Introduction: Ibrutinib is rapidly becoming the treatment of choice for many B-cell malignancies, but its proarrhythmic effects may limit its widespread use. Ibrutinib recipients are at 4-fold increased risk of developing atrial fibrillation (AF) as compared with other chemotherapeutic agents. GWAS have consistently identified an AF risk locus on chromosome 4q25. The nearest gene, Pitx2c, has been implicated in the development of the pulmonary vein myocardium.
Hypothesis: To elucidate the underlying molecular mechanisms by which ibrutinib increases susceptibility to AF using a heterozygous Pitx2c+/- mouse model and human induced pluripotent stem cell (hiPSC)-derived atrial-like cardiomyocytes (CMs).Methods: We performed transesophageal rapid pacing (TErP) in B6s and two groups of transgenic Pitx2c+/- mice, control and ibrutinib-treated, to assess AF inducibility and burden. HiPSC-derived atrial-like CMs, generated by a novel enriching protocol with retinoic acid, were exposed to ibrutinib for 48 hours. We then recorded action potential duration (APD90) and the late Na current (INa-L) before and after ibrutinib exposure.
Results:Pitx2c+/- mice showed greater incidence of AF compared to B6s after TErP (Fig. 1A). AF burden in ibrutinib-treated mice was increased vs. controls with the number of days of treatment (Fig. 1B). When hiPSC-derived atrial-like CMs were exposed to ibrutinib, both the APD90 (Fig. 1C: 138ms vs 49ms) and the INa-L (Fig. 1D: % of peak INa: 2.46% vs 0.61%) were markedly prolonged.
Conclusions: We showed that Pitx2c+/- mice not only have easily inducible AF but when exposed to ibrutinib the AF burden is markedly increased. Ibrutinib exposed hiPSC atrial-like CMs prolong the APD90, an effect in part mediated by enhanced INa-L. Thus one potential mechanism by which ibrutinib increases susceptibility to AF is by modulation of INa-L.