Electrophysiological Profile of Different Antiviral Therapies in a Rabbit Whole-Heart Model

Abstract

Antiviral therapies for treatment of COVID-19 may be associated with significant proarrhythmic potential. In the present study, the potential cardiotoxic side effects of these therapies were evaluated using a Langendorff model of the isolated rabbit heart. 51 hearts of female rabbits were retrogradely perfused, employing a Langendorff-setup. Eight catheters were placed endo- and epicardially to perform an electrophysiology study, thus obtaining cycle length-dependent action potential duration at 90% of repolarization (APD₉₀), QT intervals and dispersion of repolarization. After generating baseline data, the hearts were assigned to four groups: In group 1 (HXC), hearts were treated with 1 µM hydroxychloroquine. Thereafter, 3 µM hydroxychloroquine were infused additionally. Group 2 (HXC + AZI) was perfused with 3 µM hydroxychloroquine followed by 150 µM azithromycin. In group 3 (LOP) the hearts were perfused with 3 µM lopinavir followed by 5 µM and 10 µM lopinavir. Group 4 (REM) was perfused with 1 µM remdesivir followed by 5 µM and 10 µM remdesivir. Hydroxychloroquine- and azithromycin-based therapies have a significant proarrhythmic potential mediated by action potential prolongation and an increase in dispersion. Lopinavir and remdesivir showed overall significantly less pronounced changes in electrophysiology. In accordance with the reported bradycardic events under remdesivir, it significantly reduced the rate of the ventricular escape rhythm.

Keywords: Anitviral; Arrhythmia; Azithromycin; Hydroxychloroquine; Long QT syndrome; Lopinavir; Remdesivir; Sudden cardiac death.

Fig. 1

Representative example of ventricular tachycardia arising from programmed ventricular stimulation (arrows).

Fig. 2

A Cycle length-dependent action potential durations (APD₉₀) and B QT intervals under baseline conditions (empty circles) and after treatment with 1 µM (green square), 3 µM (dark green triangle) hydroxychloroquine (HXC). C Overall APD₉₀ and D QT interval. Concentration-dependent effect of hydroxychloroquine on E spatial dispersion of repolarization, F effective refractory period (ERP), G post-repolarization refractoriness (PRR) and H ventricular escape rate. I Number of ventricular tachycardia (VT)/ fibrillation (VF) induced by programmed ventricular stimulation (* = p<0.05).

Fig. 3

A Cycle length-dependent action potential durations (APD₉₀) and B QT intervals under baseline conditions (empty circles) and after treatment with 3 µM hydroxychloroquine (HXC) (green square) and additional perfusion with 150 µM (yellow triangle) azithromycin (AZI). C Overall APD₉₀ and D QT interval. Effect of hydroxychloroquine and azithromycin on E spatial dispersion of repolarization, F effective refractory period (ERP), G post-repolarization refractoriness (PRR) and H ventricular escape rate. I Number of ventricular tachycardia (VT)/ fibrillation (VF) induced by programmed ventricular stimulation (* = p<0.05).

Fig. 4

A Cycle length-dependent action potential durations (APD₉₀) and B QT intervals under baseline conditions (empty circles) and after treatment with 3 µM (pink square), 5 µM (red triangle) and 10µM (red square) lopinavir (LOP). C Overall APD₉₀ and D QT interval. Concentration-dependent effect of lopinavir on E spatial dispersion of repolarization, F effective refractory period (ERP), G post-repolarization refractoriness (PRR) and H ventricular escape rate. I Number of ventricular tachycardia (VT)/ fibrillation (VF) induced by programmed ventricular stimulation (* = p<0.05).

Fig. 5

A Cycle length-dependent action potential durations (APD₉₀) and B QT intervals under baseline conditions (empty circles) and after treatment with 1 µM (light blue square), 5 µM (blue triangle) and 10µM (dark blue square) remdesivir (REM). C Overall APD₉₀ and D QT interval. Concentration-dependent effect of remdesivir on E spatial dispersion of repolarization, F effective refractory period (ERP), G post-repolarization refractoriness (PRR) and H ventricular escape rate. I Number of ventricular tachycardia (VT)/ fibrillation (VF) induced by programmed ventricular stimulation (* = p<0.05).