Findings from LAFS II � Part 3
A. Effect of Antiarrhythmic Drugs
Second, I have compiled and evaluated 211 responses regarding the effectiveness of individual drugs by the 115 respondents who had tried them. Most afibbers have tried several drugs thus there are many more individual responses than there are actual respondents.
I believe this subjective evaluation of drug effectiveness is extremely revealing and worthwhile. The individual afibber is, by far, the best judge of what works and what doesn't. If a drug reduces the frequency or duration of episodes without significant side effects then the afibber will declare it a success and be keen to continue on it. If, on the other hand, the drug does not produce noticeable benefits or has horrendous side effects then the afibber trying it will get off it and declare it a failure.
Before we get into the actual evaluation it may be worthwhile to just briefly recap the properties and mode of action of the drugs evaluated.
How They Work
Antiarrhythmic drugs are divided into 4 classes depending on their mode of action. To understand how they work let us take a brief look at the modus operandi of an individual muscle cell (myocyte) in the heart. The membranes of myocytes act as small pumps that pump sodium, potassium and, to a lesser extent, calcium and magnesium ions in and out of the cells. When the cell is at rest the concentration of potassium is high inside the cell and the concentration of sodium is high outside the cell. At certain times the ion channels which allow entry of sodium into the cell open and sodium ions rush into the cell causing it to generate an electric charge (depolarization) and contract. The contractions proceed from cell to cell making the whole muscle fiber contract and ultimately making the whole atria contract.
Potassium leaks out of the cell during the depolarization period, but as soon as the depolarization is over it begins to flow back into the cell during what is called the rest or refractory period. Atrial fibrillation is characterized by a total lack of refractory periods. Calcium and magnesium ions follow the sodium and potassium ions respectively, but at a slower rate. Thus sodium and calcium are "excitatory" ions while potassium and magnesium can be viewed as "calming" ions. This underscores the importance of having adequate intracellular levels of both potassium and magnesium and also explains why a magnesium infusion often halts AF. It is likely that a potassium infusion would have a similar effect, but it would be far too dangerous because of the much faster action of potassium ions.
The rate of the fibrillating heart can be slowed by partially blocking the ion channels that allow the influx of sodium or calcium or the outflow of potassium. Antiarrhythmic drugs owe their effectiveness to their capability to block ion channels. Class I drugs such as quinidine, disopyramide, flecainide and propafenone primarily block the sodium channels, but also have some potassium blocking effect. Class III drugs such as sotalol, amiodarone and dofetilide primarily block the potassium channels and class IV drugs such as verapamil and diltiazem block the inward movement of calcium. Class II drugs, the so-called beta-blockers, have no direct effect on the heart cells, but slow the heart rate by blunting the stimulatory effects of norepinephrine and the sympathetic nervous system.
Beta-blockers such as atenolol and propranolol, and antiarrhythmics like flecainide, propafenone, sotalol, amiodarone, verapamil, and diltiazem are the drugs most often prescribed for LAF. Digoxin (Lanoxin) used to be widely used, but has now been totally discredited. Several clinical trials have shown that it can lengthen attacks and even cause the LAF to become chronic. Verapamil and diltiazem are useful in lowering the heart rate during an attack, but do not prevent attacks or speed up the conversion to sinus rhythm. Flecainide is useful in converting afib to sinus rhythm and somewhat useful in preventing attacks. It does, however, have some rather nasty side effects including sudden death. It, like other antiarrhythmic drugs, can also cause arrhythmias.
It is easy to see why drugs like flecainide have serious side effects. Their action is not limited to the atria. They also slow down the action of the ventricles � sometimes with disastrous results. Propafenone is somewhat similar to flecainide; however, it also has slight beta-blocking properties making it a poor choice for afibbers with vagal LAF. Sotalol is not effective in converting to normal sinus rhythm, but supposedly has some preventive action. It also has beta- blocking properties. Amiodarone is used in patients with serious ventricular arrhythmias and is generally not recommended for LAF due to its potentially devastating adverse effects.
Use Versus Episode Frequency and Duration
Eighty-seven (59%) of the paroxysmal afibbers were currently using a pharmaceutical drug to ward off or shorten episodes while 61 (41%) were not taking any such drugs. The average number of episodes over a six-month period was 11 for drug takers and 8 for non-drug takers; this difference was not statistically significant.
The average duration of an episode was 9 hours for both drug takers and non-drug takers and there was no significant difference in the total time spent in fibrillation over the six-month survey period (79 hours versus 75 hours).
There were no differences between drug takers and non-drug takers as far as average age, gender distribution or total years of LAF. The finding that, overall, afibbers who take antiarrhythmics are no better off than afibbers who do not is indeed surprising; however, it should be kept firmly in mind that none of the drugs prescribed for LAF have been specifically developed to deal with this condition and, as a matter of fact, some of them are not even approved for the treatment of paroxysmal atrial fibrillation as such. So essentially whenever a LAF patient is prescribed an antiarrhythmic it is a trial and error procedure � there is no guarantee of success. This is compounded by the fact that many afibbers are clearly receiving the wrong drugs for their particular condition. This is particularly pronounced among vagal afibbers.
Drugs in Vagal LAF
A closer look at the collected data shows that the seeming overall lack of effect of drugs is actually caused by the fact that some drug takers are on drugs that are clearly contraindicated for their condition while others are on drugs that are beneficial. There is ample evidence that vagal afibbers should not take digoxin (Lanoxin), beta-blockers or antiarrhythmics with beta-blocking properties as these drugs are known to markedly worsen their condition. Yet, of the 48 vagal afibbers on drugs 24 (50%) were on beta-blockers or drugs with beta-blocking properties. These people had an average of 9 episodes lasting 12 hours over the six-month survey period. In comparison, vagal afibbers on the drugs best suited for them flecainide (Tambocor) or disopyramide (Norpace, Rythmodan) had 17 episodes lasting an average of only 4 hours over the survey period. Vagal afibbers on contraindicated drugs spent an average of 106 hours in afib over the period as compared to 41 hours for those on flecainide or disopyramide and 116 hours for those taking no drugs at all. The number of afibbers having no episodes at all was 7 (41%) in the flecainide/disopyramide group, 3 (12%) in the beta-blocking group, 1 (17%) in the group on a variety of other drugs, and 7 (24%) in the group taking no drugs.
The conclusion from this data is that vagal afibbers who cannot tolerate flecainide or disopyramide are better off taking no drugs at all.
Drugs in Adrenergic LAF
Drugs in Mixed LAF
Drugs in Chronic LAF
In conclusion, the data collected in the survey does not support the assumption that treatment with antiarrhythmics is generally beneficial to people with lone atrial fibrillation. There are clearly cases where afibbers have been helped by these drugs, e.g. flecainide or disopyramide for vagal afibbers, but in general terms they do not seem to be helpful and, in many cases, are clearly detrimental. It would appear to be up to each individual, in cooperation with his or her physician, to find the right drug or to forego antiarrhythmics altogether. Remember that LAF is not life- threatening, but antiarrhythmics can be. The best and safest approach for many afibbers may well be to just take verapamil or diltiazem during an episode to keep the heart rate under control.
B. Subjective Evaluation of Drug Performance
Metoprolol (Toprol, Lopressor)
Other beta-blockers (bisoprolol, propranolol)
Amiodarone (Cordarone, Pacerone)
Disopyramide (Norpace, Rythmodan)
Sotalol (Betapace, Sotacor)
Diltiazem (Cardizem, Tiazac)
Three afibbers had tried a combination of propafenone and beta-blockers. One adrenergic afibber had found a combination of 150 mg propafenone and 50 mg metoprolol twice a day to be beneficial. The other 2 found no benefits.
One mixed afibber had found a combination of 25 mg metoprolol and .125 mg digoxin daily to be of benefit.
Drugs for conversion only
Although the above conclusions are based on subjective evaluations by 115 afibbers they are in remarkably good agreement with clinical experience and with the conclusions reached by relating actual episode severity to drug use. I believe these conclusions can be used as guidelines if you want to try a drug to reduce the number or duration of LAF episodes. Bear in mind though that both flecainide and disopyramide are very powerful and should only be used by afibbers with structurally sound hearts; they also tend to lose their effectiveness over time.
Finally, do keep in mind that 40% of all afibbers participating in our survey use no drugs to
prevent episodes and, on aggregate, have no more episodes than do afibbers on drugs. Whether
or not drugs help is clearly a highly individual matter and much experimentation will likely be
required to find the optimum one for you � if indeed there is one.
We have now followed up on the recently performed procedures and can report that we have heard from 4 of the afibbers who underwent ablation therapy late last year or early this year. Three of the procedures were completely successful and one was not. This brings the final score to:
The successful procedures were done at the Cleveland Clinic (3), Presbyterian Hospital (1), Duke Medical Center (1), and Virginia Mason in Seattle (1).
That's it for our now. In the next issue we will discuss the benefits of supplements and
Stress (emotional or physical) is the single-most common trigger for afib episodes. It is particularly significant for adrenergic and mixed afibbers with over 90% of adrenergic and 56% of mixed afibbers listing emotional or work-related stress as an important trigger.
Stress is the body's response to an event that upsets its normal balance (homeostasis). Stressors can be physical, emotional, chemical or biological. Examples of physical stressors are vigorous exercise, trauma, exposure to cold, and surgery. The most common chemical stressor, apart from adverse drug and food reactions, is hypoglycemia (low blood sugar). Emotional stressors run the gamut from anxiety to depression, fear of flying, an exam or other difficult mental task, fear of demotion or loss of job, marriage break-up, loss of a loved one, moving house, etc. In short, it can be anything that taxes you emotionally or gives you a gut feeling that something is not right. Bacterial and viral infections and fever are the most common biological stressors[2-5]. Stress can be acute, like when you face a mugger in a dark alley or chronic, like when you have to deal with an unreasonable boss every day.
The Body's Reaction to Stress
While it is clear that the fight or flight reaction caused by adrenaline release can be life-saving it is not entirely clear why the release of cortisol would help protect against the effects of long-term stress. There are two major physiological effects of cortisol release � a rise in blood glucose levels and an anti-inflammatory effect. Release of adrenaline also causes a rise in glucose levels. This is of particular importance when it comes to rapidly reversing the effects of hypoglycemia (low blood sugar).
The Glucose Connection
Blood levels of glucose are controlled within narrow limits by the counter-regulatory actions of insulin and glucagon (also produced in the pancreas). Insulin is released in response to a carbohydrate meal and glucagon (and some insulin) is released in response to a protein meal. If glucose levels fall too low in between meals glucagon will act on the glycogen stored in the liver and muscles and initiate the release of glucose into the blood stream. However, if only high carbohydrate meals are consumed there may not be enough glucagon to do the job and the body will then alert the back-up system. This causes the release of cortisol or, in extreme cases, adrenaline in order to bring the glucose levels up by converting glycogen stored in the liver. In other words, cortisol can be released not only by exposure to a stressor, but also directly in response to low glucose levels caused by an inadequate glucagon supply.
When it comes to glucose the brain is a very strict taskmaster indeed. It will not tolerate low glucose levels for very long before it hits the "panic button". It is also clear that the brain is pro- active, that is, it reacts to any stressor by demanding more glucose as a precaution. This demand is met by the release of stress hormones.
The Ins and Outs of Cortisol
Cortisol levels, in non-stress conditions, are normally tightly controlled and follow a predictable diurnal pattern with levels being highest just after awakening and declining during the day to reach their lowest level during the night. Both excessively high and excessively low cortisol levels can have devastating effects. Addison's disease is the result of a cortisol deficiency whereas Cushing's disease is associated with consistently excessive levels. Adrenal exhaustion is seen after prolonged exposure to stress[2,3,5].
High cortisol levels have also been implicated in irritable bowel syndrome, anorexia, and osteoporosis[7-10]. It is interesting that women with a history of childhood abuse are extremely sensitive to stress in later life and release much greater amounts of ACTH than do women who have experienced a normal childhood. This could indicate that the body is trying to get the adrenals to produce cortisol (by releasing ACTH) but that they are too exhausted to respond. Although only women were evaluated in this study another study found that children of both sexes who had experienced a traumatic childhood (family fights or abandonment) had consistently higher cortisol levels than did children in more harmonious families. These higher than normal childhood cortisol levels could lead to adrenal exhaustion and the inability to cope with stress in later life[12,13].
While there is ample evidence that high adrenaline levels can trigger and sustain atrial fibrillation there is practically none concerning the association between cortisol levels and AF. In searching the more than 11 million articles in MEDLINE I only came up with one dealing with the subject. This was published in the Russian heart journal "Kardiologiia" in 1975. The researchers concluded that there is a distinct increase in cortisol excretion during an AF episode. Could cortisol be triggering or sustaining atrial fibrillation? I have not come across any evidence to suggest this, not because it isn't so, but strictly because nobody seems to have looked into this possibility.
Clearly more research is required in this field and one good first step would be for a number of afibbers to obtain a salivary cortisol profile to see whether it is abnormal during sinus rhythm. I am having mine tested shortly and will let you know the results. In the meantime, I am endeavouring to keep my cortisol levels under control.
Managing Cortisol Levels
It is interesting that some afibbers have been able to, at least partially, prevent episodes by dietary changes. One of the approaches involved eating a lot of chicken (mainly protein and fat); this may be helpful in keeping cortisol under control, but is probably not desirable for the long term. Other afibbers have found a correlation between episodes and saliva or urine acidity (pH) and have noted improvement by adjusting the diet to produce a more alkaline environment. A more alkaline environment is known to be associated with lower cortisol levels, but much more research is required to determine the optimum pH and how to achieve and maintain it.
Could dietary adjustments help control atrial fibrillation through cortisol control? There certainly are some tantalizing indications that it could, but more research is obviously required.
Another fairly simple way to manage cortisol levels is by going easy on the exercise. There is growing evidence that marathon running and other vigorous, sustained activities really are not beneficial and this applies doubly to afibbers. Any exercise lasting more than about 40 minutes sharply elevates cortisol levels and increases oxidative stress to the point that it becomes counterproductive[18,19]. Dr. Kenneth Cooper, MD, the "father of aerobics", has reached the conclusion that too much exercise may actually increase the risk of developing medical problems. It can also put a serious damper on your sex life by decreasing testosterone levels. Most health experts now agree that one or two brisk 30-minute walks a day is the optimum exercise for staying healthy[20,21].
Several supplements have been found useful in keeping stress and cortisol levels under control. Among them vitamin C, the B vitamin complex, and phosphatidylserine[22-24].
Smoking and alcohol consumption both increase cortisol levels so should be avoided[25,26]. Meditation, visualization, deep breathing, listening to relaxing music, and especially, laughing a lot are all excellent ways of keeping cortisol levels under control as is having a warm, but not hot, bath (100-102 degrees F). As a matter of fact, using any of these methods to stop the initial adrenaline rush occurring at the beginning of an afib episode and then following up with a brisk walk to "burn-off" any remaining excess adrenaline and noradrenaline (norepinephrine) may well be an effective way of speeding conversion to sinus rhythm.
Can Cortisol Levels be Too Low?
Indeed it could, excessively low cortisol levels may indicate adrenal exhaustion and result in increased ACTH excretion and an excessive reaction to short-term stress � not a good thing for afibbers. Researchers at the University of Minnesota recently found that adverse conditions that produced frequent elevated cortisol levels in childhood may contribute to low levels in adulthood and that these low levels may make the adult hypersensitive to stress. They conclude that lower than expected cortisol values should not necessarily be relegated to the file drawer because they contradict the current dogma that stress is only associated with high levels of cortisol.
Low cortisol levels or adrenal exhaustion have been associated with such diverse conditions as chronic fatigue syndrome, fibromyalgia, and rheumatoid arthritis[29-31]. Could lower than normal cortisol levels be a trigger for AF episodes? I am not aware of any research into this, but it is clearly a possibility. It is also a possibility that abnormal cortisol levels may affect adrenergic and vagal afibbers differently and that excessive ACTH or CHR levels could play a role in initiating or sustaining afib, but again, to my knowledge nobody has ever looked into this.
You may wish to wait for my results before proceeding, but if you do decide to have a cortisol/DHEA profile done (when in normal sinus rhythm) I would suggest that you ask your physician to order the "Adrenocortex Stress Profile" from the Great Smokies Diagnostic Laboratory in Asheville, NC. It will be much easier to compare results if we all use the same test and laboratory. Great Smokies has a good reputation for accuracy and reliability. You can find out more about the test at http://www.gsdl.com/assessments/adrenocortex/.
The AFIB REPORT is published monthly by Hans R. Larsen MSc ChE
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Copyright © 2002 by Hans R. Larsen
The AFIB REPORT does not provide medical advice. Do not attempt self- diagnosis or self-medication based on our reports. Please consult your health-care provider if you wish to follow up on the information presented.