Introduction: 

Vanoxerine is a piperazine derivate, initially developed for the treatment of cocaine-withdrawal symptoms. While previous studies showed an effect on multiple cardiac ion channels, vanoxerine was successfully tested for the treatment of atrial fibrillation. However, significant QT prolongation and the occurrence of proarrhythmia raised serious safety concerns while the electrophysiological mechanisms remained mainly undetected. Therefore, aim of this study was to investigate the effects of vanoxerine on cardiac electrophysiology in a sensitive whole-heart model. 

Methods: 

Eight hearts of New Zealand White rabbits were retrogradely perfused employing a Langendorff-setup. Eight catheters were placed endo- and epicardially, thereby recording monophasic action potentials. Hearts were paced at seven different cycle lengths (300-900ms), thus obtaining cycle-length dependent action potential duration at 90% of repolarization (APD₉₀), QT interval, dispersion of repolarization, effective refractory period (ERP) and post-repolarization-refractoriness (PRR) as difference of ERP and APD₉₀ (PRR: ERP-APD₉₀). In addition, burst pacing was utilized to assess ventricular vulnerability. Thereafter, bradycardic AV-blocked hearts were perfused with a hypokalemic solution to enhance the occurrence of triggered activity (early afterdepolarizations and torsade de pointes). After generating baseline data, the hearts were perfused with increasing doses of vanoxerine 0.2µM, 0.5µM and 1.0µM while the protocol was repeated.

Results: 

Perfusion with vanoxerine led to a dose-dependent shortening of the APD₉₀ (baseline: 150 ± 29 ms; 0.2µM: 149 ± 22 ms (p<0.05); 0,5 µM: 142 ± 23 ms (p=ns); 1.0µM: 133 ± 22 ms) while the QT interval was mostly unaltered. Due to a slight prolongation of the ERP under 0.2µM vanoxerine (baseline: 177 ± 39 ms; 0.2µM: 186 ± 39 ms (p<0.05)) vanoxerine 0.2µM led to a slightly prolonged PRR (baseline: 38 ± 42 ms; 0.2µM 61 ± 45 ms (p=ns)) while dispersion of repolarization remained unchanged (baseline: 53 ± 29 ms; 0.2µM: 47 ± 15 ms) Meanwhile, 0.2µM vanoxerine reduced arrhythmia susceptibility compared to baseline conditions (baseline-inducibility: 62,5%, 0.2µM: 50% / number of events: baseline: 25; 0.2µM: 20). Increasing doses of vanoxerine resulted in a shortened PRR (0.5µM: 37 ± 42 ms (p=ns); 1,0 µM: 50 ± 27 ms (p=ns)) and an increased dispersion of repolarization especially with 1µM vanoxerine (0.5µM: 47 ± 17 ms, p=ns; 1.0µM: 68 ± 24 ms (p<0.05)). This resulted in an increased inducibility of ventricular tachycardias (0.5µM: 75%; 1.0µM: 75%). 

Conclusion:

The electrophysiological safety profile of vanoxerine appears to be complex. While lower doses of vanoxerine seem to reduce ventricular arrhythmia susceptibility by reducing dispersion of repolarization and prolonging the PRR, higher doses of vanoxerine raise inducibility of ventricular tachycardia in the setting of an increased dispersion of repolarization and a shortened PRR.