Experimental evidence for proarrhythmic effects of non-steroidal anti-inflammatory drugs in a sensitive whole-heart model

Background

Previous studies have raised serious concerns on cardiovascular safety of widely prescribed non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, the aim of this study was to characterize the electrophysiological effects of certain NSAIDs in an established whole heart model of proarrhythmia.

Methods and results

38 hearts of New Zealand White rabbits were harvested, retrogradely perfused employing a Langendorff setup, and electrophysiology studies were performed to investigate action potential duration at 90% of repolarization (APD₉₀ ), QT intervals, and effective refractory period (ERP). After generating baseline data, hearts were perfused with ibuprofen (group 1, n=12; 10μM and 30μM), indomethacin (group 2, n=13; 10μM and 20μM), and diclofenac (group 3, n=13; 10μM and 20μM), respectively, and the pacing protocols were repeated for each concentration. In all groups, perfusion with the NSAIDs resulted in a significant and reproducible shortening of APD₉₀ and QT interval. In all groups, the arrhythmia susceptibility was significantly raised as occurrence of monomorphic ventricular tachycardia under programmed ventricular stimulation was significantly increased under perfusion with ibuprofen, indomethacin and diclofenac in all concentrations.

Conclusion

The perfusion with ibuprofen, indomethacin, and diclofenac in commonly used doses raised the arrhythmia susceptibility in an established rabbit whole-heart model while APD shortening and shortened ERP seem to be crucial for arrhythmogenesis.