3.3 Electrical mapping and electrocardiographic studies inex vivo heart preparations
We then explored the effects of HCQ alone and combined with AZM in the whole heart on electrophysiological activation and recovery, their electrocardiographic correlates and the consequent Ca2+ signalling processes reflecting excitation-contraction coupling.
Figure 5A summarises sites of apical stimulation, and multi-electrode array (MEA) and ECG recording in the electrical mapping experiments. Representative left atrial (LA) and left ventricular (LV) isochronal conduction maps (B) obtained in the presence of 0 - 10 µM HCQ revealed a clear reduction of conduction velocity and increased conduction heterogeneities at 10 µM HCQ. Synergistic inhibitory effects on conduction velocity were observed when hearts were treated with the 10 µM HCQ in combination with 10 µM AZM. All these effects were reversed on drug washout (C(i)). 10 µM HCQ significantly decreased conduction velocities of excitation with further decreases in velocity with the 10 µM HCQ and 10 µM AZM combination (C(ii)).
Quantification of the corresponding electrocardiogram (ECG) traces (D(i)) demonstrated that both 10 µM HCQ, and 10 µM HCQ in combination with 10 µM AZM, decreased heart rate (HR)(D(i)), and increased QT interval (D(iii)), PR interval (D(iv)) and QRS duration (D(v)). In particular, AZM when combined with HCQ augmented its effects on HR, and QT and PR interval. Together these results suggested that 10 µM HCQ, and 10 µM HCQ and 10 µM AZM combined, exerted synergistic inhibitory effects on heart rate and conduction, and prolonged cardiac repolarisation.