Atrial Anti-Arrhythmic Effects of Heptanol in Langendorff-Perfused Mouse Hearts

Abstract

Acute effects of heptanol (0.1 to 2 mM) on atrial electrophysiology were explored in Langendorff-perfused mouse hearts. Left atrial bipolar electrogram or monophasic action potential recordings were obtained during right atrial stimulation. Regular pacing at 8 Hz elicited atrial activity in 11 out of 11 hearts without inducing atrial arrhythmias. Programmed electrical stimulation using a S1S2 protocol provoked atrial tachy-arrhythmias in 9 of 17 hearts. In the initially arrhythmic group, 2 mM heptanol exerted anti-arrhythmic effects (Fisher's exact test, P < 0.05) and increased atrial effective refractory period (ERP) from 26.0 ± 1.9 to 57.1 ± 2.5 ms (ANOVA, P < 0.001) despite increasing activation latency from 18.7 ± 1.1 to 28.9 ± 2.1 ms (P < 0.001) and leaving action potential duration at 90% repolarization (APD90) unaltered (25.6 ± 1.2 vs. 27.2 ± 1.2 ms; P > 0.05), which led to increases in ERP/latency ratio from 1.4 ± 0.1 to 2.1 ± 0.2 and ERP/APD90 ratio from 1.0 ± 0.1 to 2.1 ± 0.2 (P < 0.001). In contrast, in the initially non-arrhythmic group, heptanol did not alter arrhythmogenicity, increased AERP from 47.3 ± 5.3 to 54.5 ± 3.1 ms (P < 0.05) and activation latency from 23.7 ± 2.2 to 31.3 ± 2.5 ms and did not alter APD90 (24.1 ± 1.2 vs. 25.0 ± 2.3 ms; P > 0.05), leaving both AERP/latency ratio (2.1 ± 0.3 vs. 1.9 ± 0.2; P > 0.05) and ERP/APD90 ratio (2.0 ± 0.2 vs. 2.1 ± 0.1; P > 0.05) unaltered. Lower heptanol concentrations (0.1, 0.5 and 1 mM) did not alter arrhythmogenicity or the above parameters. The present findings contrast with known ventricular pro-arrhythmic effects of heptanol associated with decreased ERP/latency ratio, despite increased ERP/APD ratio observed in both the atria and ventricles.

Fig 1

Simultaneous left atrial bipolar electrogram (BEG) (top trace) and left ventricular monophasic action potential (MAP) (bottom trace) recordings obtained before (a, control) and after the introduction (b) of 2 mM heptanol, and 15 minutes after its removal from the perfusing solution (c, wash out) during regular 8 Hz pacing. Atrial and ventricular deflections were labelled “A” and “V”, respectively. Activation latency (d) and CV (e) obtained before and after introduction of 2 mM heptanol, and 15 minutes after its removal (n = 11 in all cases). Activation latency was significantly increased (asterisks, ANOVA, P < 0.001) and therefore CV was significantly decreased (asterisks, P < 0.01) by 2 mM heptanol. The effects of heptanol were reversible as both activation latency and CV recovered to their control values after its removal from the perfusing solution (daggers, P > 0.05).

Fig 2

Simultaneous atrial BEG and ventricular MAP recordings obtained from a representative heart that showed provoked atrial tachy-arrhythmias during programmed electrical stimulation (PES) (a) before introduction of heptanol (top panel). Atrial and ventricular deflections were labelled “A” and “V” respectively, and the train of atrial tachy-arrhythmias was labelled “AT”. Recordings obtained after introduction of 2 mM heptanol showed that AT could not be provoked during PES (middle panel). Recordings obtained 15 minutes after removal of 2 mM heptanol from the perfusing solution showing the return of atrial tachy-arrhythmias (bottom panel). Simultaneous atrial BEG and ventricular MAP recordings obtained from a representative heart that did not show AT during PES (b) before introduction of 2 mM heptanol (top panel). Recordings obtained seconds after its introduction (middle panel) and 15 minutes after its removal (bottom panel) showed no change in atrial arrhythmogenicity. Incidence of atrial arrhythmias (c): heptanol (2 mM) exerted significant anti-arrhythmic effects (asterisks, Fisher’s exact test, P < 0.001) that were reversed upon its removal (daggers, comparison between 2 mM and washout, P < 0.001).

Fig 3. Monophasic action potential (MAP) recordings obtained from the arrhythmic (a) and non-arrhythmic hearts (b) during regular 8 Hz pacing before (top panel) and after introduction of 2 mM heptanol (middle panel) and after its removal from the perfusing solution (bottom panel).

Fig 4

In the arrhythmic group, 2 mM heptanol increased activation latency (a, asterisks, ANOVA, P < 0.001, n = 9) and therefore decreased the corresponding CV (b; P < 0.01; n = 9) and increased atrial effective refractory period (AERP) (c, P < 0.001; n = 9) without altering APD₉₀ (d, P > 0.05, n = 5). In the non-arrhythmic group, 2 mM heptanol also increased activation latency (e, P < 0.05, n = 8), decreased CV (f, P < 0.05, n = 8) and increased AERP (g, P < 0.05, n = 8) without altering APD₉₀ (h, P > 0.05, n = 5). All values recovered to control values after removal of heptanol from the perfusing solution (P > 0.05).

Fig 5. Derived parameters.

Heptanol (2 mM) increased excitation wavelength (a, asterisks, ANOVA, P < 0.01) and AERP/APD₉₀ ratio (b, P < 0.001) in the arrhythmic group, but did not alter either parameter in the non-arrhythmic group (c and d, P > 0.05). All values recovered to control values after removal of heptanol from the perfusing solution (P > 0.05).