ANP, Baroreflex, Ion Channels, Fever, Vagal Tone and Disopyramide
Part I. (ANP and the Baroreflex)
There has been considerable speculation that something builds up to initiate an episode of AF and this buildup is rectified by the episode and finally terminated. This seems to lead to a repeating cycle with a specific episode duration and interval between episodes that is unique for each individual?
When this question was first raised to my knowledge in the BB, ANP was unofficially nominated as a likely suspect. Hans further highlighted this discussion in the first Session of the CR now in the Proceedings (http://www.afibbers.org/conference/session1.pdf), both of which were created to stimulate its continuing dialogue and examination.
AF stimulates the secretion of ANP. Previously I was fixated on the intracellular K imbalance (known trigger for AF) and ANPs ability to correct this by directly blocking the activity of aldosterone, which causes absorption of Na at the expense of K excretion. Perhaps there is another mechanism through which ANP affects AF.
I have recently discovered that baroreceptor mediated reflex bradycardic responses are markedly enhanced by ANP (http://www.ans.org.au/ans2001/317W.pdf).
The afferent pathway of the baroreflex ends in the nucleus tractus solitarius (NTS - see previous BB post on glutamate - [
www.yourhealthbase.com] and previous CR posts on glutamate - [
www.afibbers.org]).
Therefore, ANP should result in a constant release of glutamate from the NTS for the duration of the episode.
Perhaps this results in the depletion of neuron stores of glutamate. Termination of AF might occur when this depletion has reached some threshhold level, at which point autonomic balance swings toward the sympathetic. Post episode HRV supports this interpretation. The gradual return of HRV to normal suggests that glutamate stores within the NTS may be gradually replenished such that the usual autonomic balance is restored. In the time period before the next episode not only do glutamate stores in the neuron gradually increase but also there may be a gradual increase of secreted glutamate within the synaptic space. Vagal LAFers clearly have greater vagal tone and this may be due to compromised ability to remove this secreted glutamate. This could be due to either a polymorphism for glutamate decarboxylase, Vitamin B6 and/or magnesium deficiency, etc., (see previous post in CR, Session 4 - [
www.afibbers.org]).
Given the circumventricular location of the NTS (see [
webteach.mccs.uky.edu]
for an actual photo demonstrating how close the NTS is to the fourth ventricle), sensitivity to MSG/free glutamates (Chinese Restaurant Syndrome) would seem to support the above interpretation.
In summary, vagal LAFers may have a threshhold for glutamate degradation/removal. Once this threshhold is exceeded, vagal tone increases and persists. AF then is triggered. During the episode this situation is only exacerbated by even more secretion of glutamate into the synaptic space. This is a nonproblem since AF is already underway. At some point glutamate stores within the neuron are depleted. AF terminates with this balance of power shift toward the sympathetic. It terminates because this causes an increase in cardiac conduction velocity, increase in HR, etc. The atria are not able to support the existence of the required six wavelets of Moe. Immediately after the episode ends intraneuronal glutamate stores are gradually replenished. And the cycle starts anew.
Part II. (Ion Channels)
There has been much discussion in the recent medical literature on ion channelopathies. Examples include Brugada Syndrome and Long QT (Segment) Syndrome. These are rare disorders involving mutations in the DNA that regulate electrical activity via ion channels. In long QT syndrome one or more of the K channels are closed inappropriately.
In familial AF they are inappropriately open, as reported on this BB by Carol and Kerry back in July of this year at [
www.hon.ch].
Shortly thereafter Dave McCarthy reported an article on tarantula venom stopping AF at [
www.heartinfo.com]
This too works via ion channel activity.
Then there was some discussion about the experimental drug RSD 1235. RSD1235 selectively blocks ion channels that are known to be active during episodes of atrial fibrillation.
[
www.cardiome.com]
And finally Richard furnished a nice link explaining the mechanism behind vagal tone in the heart. [
clapham.tch.harvard.edu]
Here again, a potassium channel, specifically IKACh is responsible for any change in vagal tone.
As suggested many months ago by Fran and Erling, ion channels appear to be the final common pathway in the genesis of LAF, at least for the vagal variety. Stress in adrenergic LAF may initiate episodes through the hypothalamus (hypothalamus-pituitary axis or HPA) and its effect on ion channels as well.
Part III. Fever and Vagal Tone
I once posted that I thought I experienced fewer PACs and AF appeared to be less likely when I was febrile. This was the experience of another LAFer, as detailed at through the Cleveland Clinic Forum at
[
www.medhelp.org]
Exactly how does this work?
Thermoregulation is governed by the hypothalamus, especially the anterior hypothalamus. See p. 1 at [
www.rug.nl] for a nice diagram of how the hypothalamus and NTS control vagal tone.
The likelihood of sleep onset
is actually minimal at the time when the circadian rhythm in brain temperature peaks. In fact, sleep onset probability increases on the falling limb of the circadian core temperature rhythm.
[
www.rau.edu.uy]
This is basically stating that as the sun sets, core temperature decreases and sleepiness increases.
Similarly HRV increases (with the approach of bedtime) on the falling limb of the circadian core temperature rhythm.
Thus, an increase in core temperature, i.e., fever, is associated with a decrease in HRV, at least wrt time, if not wrt cause.
This may be the mechanism by which any inclination toward vagal LAF might be thwarted during a fever.
Again the mechanism of action is via potassium ion channels.
Part IV. Disopyramide
These muscarinic (M2) receptors controlling the most recently described potassium ion channel IKACh are located on the surface of atrial heart muscle cells, but are also present on smooth muscle in the eye (ciliary muscle), GI tract, urinary bladder and salivary glands in the mouth. Disopyramide (Norpace, Rythmodan) is a muscarinic M2 antagonist, i.e., IKACh (and hyperpolarization) is inhibited, intracellular K+ are maintained, depolarization is enhanced, AERP lengthens (HR increases and HRV decreases). In blocking these M2 receptors, disopyramide causes vagolysis, blurred vision, constipation, urinary retention and dry mouth.
I have struggled, as have many of you, finding a behavior/med protocol that works and wont fade over time. Ive tried all manner of vitamins and supplements and have basically given up on all but magnesium. This is not to say that there are not many other benefits to be realized from them. For me, AF is not one of them. Ive tried several antiarrhythmics, mostly flecainide and disopyramide. I think I might have finally found a regimen that works. So far, 125 mg disopyramide at 6AM, 9AM, noon, 3PM, 5PM, 6PM and 9PM seems to work. It has a half life of 5-6 hours with peak levels in just under 2 hours. I ramp up the dosage in the evening to counteract the looming vagal tone of the night.
The side effects are quite tolerable. In fact the constipation is nicely countered by the laxative effects of the hydrated magnesium. Ive learned to be a little more patient in the loo wrt #1. The dry mouth is less bothersome than the seasonal allergies that are now a thing of the past.
If you have refractory vagal LAF, you might approach your MD about this. Recommended dosage is 600-800mg/d. This regimen totals 875mg/d.
Although PACs are still present on my monitor, I never feel them, unlike previously.
Hopefully this effect of disopyramide will last until ablation techniques are sufficiently advanced.
PC v54