Atrial fibrillation (AF) is commonly associated with heart failure. A bidirectional relationship exists between the two-AF exacerbates heart failure causing a significant increase in heart failure symptoms, admissions to hospital and cardiovascular death, while pathological remodeling of the atria as a result of heart failure increases the risk of AF. A comprehensive understanding of the pathophysiology of AF is essential if we are to break this vicious circle. In this review, the latest evidence will be presented showing a fundamental role for calcium in both the induction and maintenance of AF. After outlining atrial electrophysiology and calcium handling, the role of calcium-dependent afterdepolarizations and atrial repolarization alternans in triggering AF will be considered. The atrial response to rapid stimulation will be discussed, including the short-term protection from calcium overload in the form of calcium signaling silencing and the eventual progression to diastolic calcium leak causing afterdepolarizations and the development of an electrical substrate that perpetuates AF. The role of calcium in the bidirectional relationship between heart failure and AF will then be covered. The effects of heart failure on atrial calcium handling that promote AF will be reviewed, including effects on both atrial myocytes and the pulmonary veins, before the aspects of AF which exacerbate heart failure are discussed. Finally, the limitations of human and animal studies will be explored allowing contextualization of what are sometimes discordant results.
The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Key Teaching Points•The incidence of atrial arrhythmia is 5%–16% in patients taking Bruton's tyrosine kinase inhibitors, a class of chemotherapeutic agents that is used first line for many hematological malignancies. The main risk factors for developing arrhythmia on treatment are age >65 years, hypertension, prior cardiovascular disease, and a dilated left atrium.•Animal studies have shown ibrutinib leads to off-target kinase inhibition in the myocardium. This leads to increased proinflammatory signaling and impaired cardioprotective mechanisms in the atria, culminating in pathologic remodeling that promotes triggered activity and substrate for reentrant arrhythmias.•A rate control strategy is presently recommended as the first-line treatment option for atrial arrhythmias, with a rhythm control strategy reserved for those who remain symptomatic or develop a rate-related cardiomyopathy. Our case highlights atrial flutter on ibrutinib is amenable to an ablation strategy and should be considered in appropriately selected patients. •The incidence of atrial arrhythmia is 5%–16% in patients taking Bruton's tyrosine kinase inhibitors, a class of chemotherapeutic agents that is used first line for many hematological malignancies. The main risk factors for developing arrhythmia on treatment are age >65 years, hypertension, prior cardiovascular disease, and a dilated left atrium.•Animal studies have shown ibrutinib leads to off-target kinase inhibition in the myocardium. This leads to increased proinflammatory signaling and impaired cardioprotective mechanisms in the atria, culminating in pathologic remodeling that promotes triggered activity and substrate for reentrant arrhythmias.•A rate control strategy is presently recommended as the first-line treatment option for atrial arrhythmias, with a rhythm control strategy reserved for those who remain symptomatic or develop a rate-related cardiomyopathy. Our case highlights atrial flutter on ibrutinib is amenable to an ablation strategy and should be considered in appropriately selected patients.
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