Introduction: 

Unfortunately, presently available proarrhythmia screening tests are not sensitive and specific enough. Recently, we developed a new in vitro proarrhythmia model that is based on reduced repolarization reserve. In our previous study we validated the sensitivity of this model with five reference proarrhythmic drugs. The primary aim of the present study was to validate the specificity of the model. Additionally, we tested the reproducibility of the results and expanded the examination of the specificity of the model.

Methods: 

Isolated, Langendorff perfused rabbit hearts were subjected to 60 min drug perfusion. Repolarization reserve was reduced by the IKs inhibitor HMR1556 in the last 40 min. Catecholamines were added to the perfusate in the last 20 min. The specificity of the model was tested by three clinically proarrhythmia-free drugs: verapamil, lidocaine and metoprolol. The previously tested dofetilide was used again in order to examine the reproducibility of the results. The sensitivity of the model was further examined by quinidine that has a well-known proarrhythmic activity. As a primary endpoint, the incidence of complex arrhythmias (ventricular tachycardia=VT, torsades de pointes=TdP) were determined. We also measured the length of the rate corrected QT (QTc) interval.

Results: 

The negative control drugs (verapamil, lidocaine and metoprolol) significantly shortened the QTc interval and did not evoke arrhythmias in the model. Results with dofetilide did not differ from those gained from our previous validation study; dofetilide significantly lengthened the QTc interval and frequently evoked VT and TdP. Likewise, quinidine significantly lengthened the QTc interval and increased the incidence of VT and TdP.

Conclusion: 

The specificity of our new in vitro proarrhythmia model is high, because negative control drugs have been shown to be safe in the model. The reproducibility of the results has been proven by reproducibly detecting substantial proarrhythmic activity and QTc lengthening effect of dofetilide. Results with the proarrhythmic quinidine confirm our previous conclusion that reduction of repolarization reserve markedly increases the sensitivity of rabbit hearts to proarrhythmic activity of drugs and allows TdP to be regarded as primary endpoint.