A Potpourri

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 ANP’s 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 won’t fade over time. I’ve 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. I’ve 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. I’ve 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

Yowza, yowza. The cutting edge of AF research, indeed. I'm going to be a while digesting this. Thank you, PC.
Peggy

PC,

A the risk of sounding predictable and a little sycophantic....... most interesting and informative stuff as usual. I'm sure that all here greatly appreciate your continuing efforts to solve the AF puzzle - I know I do.

I'm sure Fran will be most interested in the sentence:

"Vagal LAFers clearly have greater vagal tone and this may be due to compromised ability to remove this secreted glutamate." How can us vagal AFrs compensate for this in addition to avoiding MSG??

Mike F.

PC

Brilliant again. I have suspected for some time that the big P had a hand resetting AF and glutamate toxicity, though I just wasn't sure how. I'm sure you have just explained it.

And as to the ion channels!! Well obviously there is more than just glutamate toxicity - otherwise everyone else on the planet would be suffering AF.

I'm not able to go about looking further into this as i am away from home till Friday, and my own computer has decided to give up the ghost during my move. I've lost some parts of windows and a bit of my hard drive into the bargain. Don't know if its worth fixing.

But I will keep looking in and keeping up to date with whats going on. Especially this.

Keep up the brilliant work.

Fran

Thank you, PC for a very thought provoking post. I was stimulated by the link on autism and did a bit of a search on the hypothalamus and came up with this interesting research. It's quite lengthy, but this bit about the muscarinic receptors was new to me, but more in regards to the M1.

The increase in cholinergic activity in the SHR which most of these observations suggest is mediated at least in part through enhanced density of muscarinic receptors. Muscarinic receptor sites in the SHR are increased as early as 1 wk of age and continue to increase until 11 wk (244). mRNA encoding of five muscarinic receptors in the whole hypothalamus has revealed that there is 40-50% increase in excitatory M1 subtype and a decrease in the inhibitory M4 subtype during the establishment of the hypertension (662). The changes are more pronounced at 12 wk of age. The levels of the other subtypes M2, M3, and M5 in the SHR were not significantly different from the WKY (662). A change in muscarinic receptor density does not occur in renal hypertension (681), but the density is increased in the Dahl salt-sensitive rat (154).
[physrev.physiology.org]

This site has research on hypertension with regards to vasopressin, catecholamines, cholinergics, GABA, serotonin, etc. It's daunting to say the least, for me. It's as if there will never be a real answer to our problem, unless we hit pay dirt, especially when age is related, as there's nothing one can do about that.

I still have a few more of your links to read. Thanks again, for all your hard work, as I know it takes much time and thought.

Richard