Riluzole reduces the incidence of cardiac arrhythmias immediately post coronary artery occlusion S'M

1
Riluzole reduces the incidence of cardiac
arrhythmias immediately post coronary artery
occlusion S.M. Weiss, I. Forgie, P.W. Gage
(dec.), W.B. Cowden Division of Molecular
Bioscience, The John Curtin School of Medical
Research, The Australian National University,
Acton, ACT, Australia
Figure 2 Time course of arrhythmic
episodes
Time post occlusion (minutes) legend
CONTROL RILUZOLE
Introduction

• Persistent sodium channels in cardiac cell
  membranes are known to open under hypoxic
  conditions. We hypothesized that the subsequent
  cellular influx of sodium could produce cellular
  depolarization which could lead to automatic or
  triggered arrhythmias. Furthermore, with
  sufficient influx of sodium, the sodium-calcium
  exchanger could reverse thus overloading the
  affected cells with calcium and subsequently
  producing a substrate for re-entrant arrhythmias.

Average no. of episodes per animal
The effect of riluzole on the incidence of
arrhythmias (shown by phase) is demonstrated in
Figure 3.
Aim
Figure 3 Number of arrhythmic episodes per
phase
Time post occlusion (phase) legend CONTROL
RILUZOLE
To test in an animal model of acute myocardial
infarction (AMI) whether riluzole, a drug for
treating amyotrophic lateral sclerosis (ALS) (Lou
Gehrig's disease) with suspected persistent
sodium channel blocking activity, reduces the
incidence of early arrhythmias arising from AMIs.
Average no. of episodes per animal
Method
16 pigs (MF, 20-35 kg) were sedated with
stresnil (1-2 mg/kg im), anaesthetised with
thiopentone sodium (10-15 mg/kg iv) and
maintained under general anaesthesia with a
mixture of isoflurane (0.5 2) in oxygen.
Artificial ventilation was maintained at a volume
of 15 ml/kg and a rate of 12 breaths per minute.
An intravenous saline drip was maintained for
intra-operative hydration. Blood pressure (BP)
and a lead II electrocardiogram (ECG) were
monitored, digitised and recorded. Riluzole (8
mg/kg) was administered to 6 of the pigs by
single bolus intra-peritoneal injection. The
remaining 10 pigs served as controls. Following a
mid-sternotomy and dissection of the pericardium,
the left anterior descending coronary artery
(LAD) was completely occluded mid-way along its
length by ligation approximately fifty minutes
after the administration of riluzole. The LAD was
not reperfused and remained occluded for the
duration of each experiment (3 hours).
Arrhythmias were classified into the groups PVCs
(single and multiple PVCs, bigeminy, trigeminy
quadrigeminy), non-sustained arrhythmias
(episodes of ventricular tachycardia (VT) and/or
ventricular fibrillation (VF) which
self-terminated within 15 seconds of
commencement) and sustained or lethal arrhythmias
(episodes of VT and/or VF which ran for more than
15 seconds). Sustained arrhythmias were
terminated using epicardial cardioversion or
defibrillation (5 30 J). Statistical
significance was determined using 2-tailed
unpaired Students t-tests.
Riluzole did not alter the R-R interval, the P-R
interval, the QRS interval, the QT interval or
the QTc interval when compared with the control
group.
Key observations

• riluzole did not alter the number of animals
  developing PVCs though it did reduce the number
  of animals developing bi-, tri- quadrigeminy
  beats
• riluzole halved the number of animals which
  developed non-sustained arrhythmias
• riluzole halved the number of animals which
  developed sustained arrhythmias
• the pigs in this study exhibited a similar time
  course of arrhythmias post coronary artery
  occlusion to humans
• the anti-arrhythmic effect of riluzole was time
  dependent and became more pronounced late in
  phase 1b and during phase 2
• riluzole significantly reduced the incidence of
  all types of arrhythmias during phase 2
• riluzole greatly reduced the incidence of
  sustained (lethal) arrhythmias during all 3
  phases
• riluzole did not alter any of the ECG intervals
  RR, PR, QRS, QT or QTc

Results
Discussion
The position of the occlusion was comparable
between the groups with the proportion of
ischaemic to overall length of the LAD being 52
3 in the control group and 57 5 in the
riluzole group. All of the animals in the control
group developed both non-sustained and sustained
arrhythmias. Conversely, only half of the animals
in the riluzole group developed any non-sustained
and/or sustained arrhythmias (see Figure 1).
As yet, there is no confirmed relationship
between sodium influx through persistent sodium
channels and the incidence of cardiac
arrhythmias. Furthermore, there is no evidence
yet that riluzole blocks persistent sodium
channels in cardiac cell membranes. However,
given the striking results shown above, it is
clear that riluzole significantly reduced the
incidence of all types of cardiac arrhythmias
subsequent to induced AMIs. As the reduction in
incidence was time-dependent, these results
suggest that the action of riluzole was greater
as the tissue became increasingly hypoxic and
hence that riluzole may have acted as a
persistent sodium channel blocker in these
experiments. Of greatest significance is that
riluzole reduced the incidence of sustained
(lethal) arrhythmias by (on average) 58 in phase
1a, 86 in phase 1b and 90 in phase 2 compared
with the control group.
Conclusion
This study suggests that riluzole may be
clinically effective in reducing the incidence of
early arrhythmias, in particular lethal
arrhythmias, arising from myocardial ischaemia.
Moreover, this study suggests that riluzole may
be clinically effective in reducing the incidence
of sudden cardiac death associated with early AMI
and that this effect may be due to persistent
sodium channel blockade.
As with humans, arrhythmias occurred in phases
with phase 1a arrhythmias occurring in the first
15 minutes, phase 1b occurring between 15 and 60
minutes, and phase 2 occurring between 60 and 180
minutes following occlusion (see Figure 2).