ExperimentalIbrutinib promotes atrial fibrillation by inducing structural remodeling and calcium dysregulation in the atrium
Introduction
Ibrutinib is a novel antitumor oral drug that irreversibly inhibits Bruton tyrosine kinase (BTK) and is mainly used to treat refractory chronic lymphocytic leukemia (CLL).1 Because it significantly improves progression-free and overall survival rates, ibrutinib is considered the most significant breakthrough drug for treatment of CLL.2, 3 Although ibrutinib is generally well tolerated, ibrutinib-related atrial fibrillation (AF) is often reported. The incidence of new-onset AF is approximately 5%–9%, and AF occurs primarily 3–8 months after ibrutinib treatment was started, especially in elderly patients.4, 5 AF management in patients treated with ibrutinib is challenging because of the intrinsic bleeding propensity of these patients; moreover, half of the patients discontinue ibrutinib treatment or reduce the dose of ibrutinib.6, 7
It is widely recognized that the therapeutic mechanism underlying ibrutinib’s effects involves the irreversible inhibition of BTK. McMullen et al8 reported that ibrutinib inhibited PI3K-AKT activity in cultured neonatal cardiomyocytes, which suggested that ibrutinib-induced AF may involve inhibition of the BTK-PI3K-AKT signaling pathway, although there is disagreement over this issue. More recently, Tuomi et al9 reported that acute or short-term (14 days) ibrutinib administration induced AF in a dose-dependent manner in young mice, suggesting that “off-target” effects of ibrutinib may be responsible for the development of AF. Overall, the arrhythmogenic mechanisms underlying ibrutinib’s effects remain unclear. Because age is an independent risk factor for ibrutinib-induced AF and AF occurs after several months of treatment with ibrutinib, in the present study we developed a novel model of AF induction with 1 month of oral administration of ibrutinib in elderly mice and explored the underlying arrhythmogenic mechanisms in this model.
Section snippets
Animal
C57Bl/6 mice (weight 30–36 g; mean age 24 months) were purchased from the Animal Centre of Capital Medical University, Beijing, China. All experimental procedures were approved by the Animal Care and Use Committee of Capital Medical University and were performed in compliance with the Guide for the Care and Use of Laboratory Animals proposed by the Institute of Animal Resources and published by the National Institutes of Health.
Establishment of ibrutinib-induced AF mouse model
Mice in the ibrutinib group were administered ibrutinib 25 mg/kg/d
Ibrutinib enhanced susceptibility to AF
To test whether ibrutinib enhanced susceptibility to AF, electrocardiogram was recorded and intraesophageal burst pacing was performed in the ibrutinib and control groups. At baseline, no episodes of atrial arrhythmia were observed in either group, and there was no significant difference in surface electrocardiograms between the 2 groups (Figure 1A). Compared with controls, episodes of pacing-induced AF were observed more frequently in the ibrutinib group (27.8% vs 77.8%) (Figures 1B and 1D).
Discussion
In the present study, we demonstrated that aged mice have an increased susceptibility to AF after oral administration of ibrutinib (25 mg/kg/d) for 4 weeks. Ibrutinib markedly increased fibrotic remodeling in the atrium and predisposed atrial myocytes to spontaneous Ca2+ release from SR. Thus, our data suggest that ibrutinib enhances triggering events and increases the vulnerability of substrates for development of AF.
Accumulating evidence indicates that ibrutinib is an independent risk factor
Conclusion
In the present study, we demonstrated that 4 weeks of ibrutinib administration promoted susceptibility to AF in aged mice. The arrhythmogenic mechanisms underlying this effect were associated with structural remodeling and Ca2+, suggesting that ibrutinib not only provides a vulnerable substrate but also enhances triggers for the genesis and perpetuation of AF. Enhanced CaMKII activity likely is responsible for the cardiotoxicity of ibrutinib, suggesting that inhibiting CaMKII could be a
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Cited by (0)
This study was supported by a grant from the National Natural Science Foundation of China (No. 81530016, 81670291, 81770318, and 81870244) and the Beijing Natural Science Foundation (No. 7152049). All authors have reported that they have no conflicts relevant to the contents of this paper to disclose.