Inhibition of Putative Ibrutinib Targets Promotes Atrial Fibrillation, Conduction Blocks, and Proarrhythmic...

The mechanism by which ibrutinib, a Bruton's tyrosine kinase inhibitor, can elevate the risk of arrhythmias is not fully elucidated. In this study, we explored how inhibition of off-target kinases can contribute to this phenomenon.

We performed a Mendelian randomization analysis to examine the causal associations between genetically proxied inhibition of six putative ibrutinib drug targets (ErbB2/HER2, CSK, JAK3, TEC, BLK, and PLCG2) and the atrial fibrillation (AF) risk, proarrhythmic ECG indices, and cardiometabolic traits and diseases. Inverse-variance weighted random-effects models and Wald ratio were used to examine the associations between genetically proxied inhibition of these drug targets and the risk of outcomes. Colocalization analyses were employed to examine the robustness of the causally significant findings. ELISAs were used to measure ErbB2 levels in intracardiac plasma samples.

Genetically proxied ErbB2 inhibition was associated with an increased AF risk, higher P wave terminal force, and prolonged QTc interval. Patients with AF had significantly higher intracardiac ErbB2 levels compared with patients with paroxysmal supraventricular tachycardia. CSK inhibition prolonged the QRS duration, decreased the QTc interval, and was potentially linked to conduction blocks. PLCG2 inhibition led to decreased P wave terminal force, shorter QTc interval, and increased risk of left bundle branch block. BLK inhibition shortened the QTc interval and was also associated with atrioventricular block.

The off-target effects and downstream targets of ibrutinib, including CSK, PLCG2, ERBB2, TEC, and BLK, may lead to cardiac electrical homeostasis imbalances and lethal cardiovascular diseases. Using drugs that inhibit these targets should be given extra caution.