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.