The AFIB Report

Your premier information resource for lone atrial fibrillation



Number 37
MARCH 2004
4th Year


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EDITORIAL

There is emerging evidence that the RAAS (renin angiotensin aldosterone system), or more specifically, angiotensin II and aldosterone may indeed be involved in atrial fibrillation. In this issue we discuss findings indicating that ACE inhibitors and angiotensin II receptor antagonists may help prevent PACs and afib episodes as well as structural and electrical remodeling of the atrium. Both ACE inhibitors and angiotensin II receptor antagonists, unfortunately, have some undesirable side effects and there is also some indication that their beneficial effects on AF may wear off over time.

Also in this issue new evidence that the incidence of AF is increasing rapidly, that time-release propafenone (Rythmol) would appear to be quite effective, that pravastatin (Pravachol) should be avoided by vagal afibbers, and much, much more �.. Read on.

Just a reminder - if you haven't already done so, don't forget to get your copy of my book "Lone Atrial Fibrillation: Towards A Cure" at www.afibbers.org/lafbook.htm - it provides a wealth of information on dealing with LAF.

Yours in sinus rhythm � most of the time :~),
Hans



Long-term success of ablation

TAIPEI, TAIWAN. Taiwanese researchers report that the long-term risk of developing recurring afib after a seemingly successful ablation is quite low. They followed 207 patients who had undergone a successful focal point or pulmonary vein ablation for an average of 30 months. During this time 13 patients (6%) developed renewed afib after 12 months of being afib-free while another 57 patients (28%) developed renewed afib within 12 months of the ablation mostly within the first 6 months. The patients whose afib recurred within the 12 months had more AF focal points and were more likely to have used antiarrhythmic drugs than were the ones whose recurrence happened after 12 months. Of the 13 patients with late recurrence 11 converted spontaneously and 7 had no more episodes even though they did not have a second ablation or used antiarrhythmic drugs. Of the remaining 6, 5 were prescribed propafenone or amiodarone and subsequently had no further episodes; one underwent a second ablation and experienced no further episodes.

The researchers conclude that the incidence of recurrent afib after a year or more following the ablation is quite low and that most patients who do have a very late recurrence do not require antiarrhythmics or a second ablation to prevent further episodes.
Hsieh, MH, et al. Clinical outcome of very late recurrence of atrial fibrillation after catheter ablation of paroxysmal atrial fibrillation. Journal of Cardiovascular Electrophysiology, Vol. 14, June 2003, pp. 598-601

AF episodes after ablation

NEWCASTLE-UPON-TYNE, UNITED KINGDOM. Not all afibbers experience an instant "cure" following pulmonary vein isolation (PVI). British electrophysiologists now report that as many as 30% of successfully ablated PVI patients may experience afib episodes in the 3 months following the ablation, but go on to a complete cure. Their study involved 50 afibbers (20 paroxysmal and 30 persistent) who underwent PVI. Twenty-four (48%) experienced no more episodes during a 9-month follow-up, 10 (20%) experienced episodes during the first 3 months, but then remained afib-free, and the remaining 16 (32%) continued having episodes throughout the follow-up period and were considered to be "failures". Thus the overall success rate was 68% (the same as found in our November 2003 ablation survey).

Patients who experienced an acute cure were less likely to have persistent afib, had less evidence of left atrial structural and electrical abnormalities, and had suffered from afib for a shorter period than had patients who experienced a delayed cure or no cure at all. It is interesting to note that the average left atrial size prior to ablation was 38 mm in the acute cure group, 45 mm in the delayed cure group, and 46 mm in the failure group. Three months after the procedure the corresponding numbers were 37 mm, 42 mm, and 46 mm respectively.
O'Donnell, D, et al. Delayed cure despite early recurrence after pulmonary vein isolation for atrial fibrillation. American Journal of Cardiology, Vol. 91, January 1, 2003, pp. 83-85

Heart rate variability and age

LUBECK, GERMANY. German researchers have just completed a study aimed at determining the association between heart rate variability (HRV), autonomic nervous system modulation, and age and gender. Their study involved 166 healthy men and women between the ages of 20 and 70 years (median age of 40 years) who underwent 24-hour Holter monitoring. Among the highlights of their findings:

  • Normal aging is associated with a continuous decrease of HRV parameters. This decrease is primarily associated with a significant decrease in nighttime parasympathetic (vagal) activity.

  • Women tend to have lower sympathetic (adrenergic) activity than men, but this difference disappears after menopause.

  • Aging is generally associated with a relative baroreceptor impairment leading to higher norepinephrine levels and elevated sympathetic muscle nerve activity.

  • Heart rate decreases continuously at night reaching its lowest level around 3 hours prior to awakening. The decrease is more pronounced in younger persons. The researchers did not observe a significant age-related difference in heart rate during daytime.

Bonnemeier, H, et al. Circadian profile of cardiac autonomic nervous modulation in healthy subjects � differing effects of aging and gender on heart rate variability. Journal of Cardiovascular Electrophysiology, Vol. 14, August 2003, pp. 791- 99

Editor's comment: Although afibbers were not involved in the study the findings would tend to indicate that the initiation of afib episodes between midnight and awakening would be more likely in young persons and would become less likely with age.

Afib and the autonomic nervous system

MATSUMOTO, JAPAN. It is now generally accepted that the autonomic nervous system (ANS) plays an important role in the initiation of paroxysmal (intermittent) atrial fibrillation. It is also known that afib episodes of vagal origin tend to begin at night while those of adrenergic origin tend to begin during the day. Heart rate variability (HRV) studies are useful in measuring ANS activity. It has been found that the low frequency (LF) part of the HRV spectrum indicates the level of activity of the sympathetic (adrenergic) branch of the ANS while the high frequency (HF) part of the spectrum indicates the level of activity of the parasympathetic (vagal) branch of the ANS. The LF/HF ratio is thus an indication of ANS balance.

Japanese researchers recently set out to determine the relationship between the time of afib onset and the autonomic tone (LF and HF levels) before and after the event. Their study included 23 afibbers without structural heart disease. Fourteen of the patients had episodes beginning during the night and 9 had episodes starting during the day. The night-timers were younger (average age of 60 years) and tended to have shorter episodes (average of 4.3 hours) than the day-timers (average age of 71 years; episode duration average of 9.2 hours).

In the night-time group the HF component (vagal activity) increased from 163 msec2 one hour before the episode to 483 msec2 ten minutes before the episode. It returned to 191 msec2 ten minutes after termination of the episode. The changes in the LF component were similar in pattern, but much smaller and there was no change in the LF/HF ratio before or after the event. These data suggest that vagal activity increased before the afib episode and returned to baseline after termination.

In the day-time group the HF (vagal) component did not change before or after the event, but the LF (adrenergic) component increased from 310 msec2 an hour before the event to 496 msec2 ten minutes before the event. Ten minutes after the event the LF component had dropped to 177 msec2, but then gradually returned to baseline. The LF/HF ratio increased gradually from 1.8 an hour prior to the event to 3.2 ten minutes before. Ten minutes after the event the ratio was 1.3. It would appear from these data that in day-time episodes sympathetic (adrenergic) tone increased before the onset of the afib event and was strongly inhibited immediately after the event, although it subsequently returned to base level. The researchers speculate that termination of an adrenergic episode during the day may be associated with inhibition of sympathetic activity.
Tomita, T, et al. Role of autonomic tone in the initiation and termination of paroxysmal atrial fibrillation in patients without structural heart disease. Journal of Cardiovascular Electrophysiology, Vol. 14, June 2003, pp. 559-64

Editor's comment: These findings clearly confirm the close association between changes in the autonomic nervous system and the onset of an afib episode. They also show that regular Holter monitoring records can be used to determine whether an afibber is vagal or adrenergic and thus aid in guiding drug therapy; assuming that the event occurs during the monitoring.

Time-release propafenone proves effective

DURHAM, NORTH CAROLINA. Propafenone (Rythmol) needs to be taken at least three times a day due to its relatively short and patient-dependent elimination half-life (5-17 hours). A new form of sustained release propafenone (propafenone SR) has recently come on the market and a group of American medical researchers now reports on its efficacy. Their study involved 523 patients with atrial fibrillation of which 45-50% had underlying structural heart disease and 50-60% had hypertension. The participants were randomly assigned to one of four protocols � placebo twice daily, 225 mg propafenone SR twice daily, 325 mg propafenone SR twice daily, or 425 mg propafenone SR twice daily. All patients were in sinus rhythm at the start of the trial. The researchers found that patients on placebo went, on average, 41 days before experiencing an afib episode, those on 225 mg twice daily went 112 days, those on 325 mg 291 days, and those on 425 mg more than 300 days without an episode.

The main adverse events were dizziness, taste disturbance, fatigue, constipation, and breathing difficulties. One or more adverse events were experienced by 72% of the members of the placebo group, by 77% in the 225 mg group, 84% in the 325 mg group, and 83% in the 425 mg group. The withdrawal rate from the study was 25% in the 425 mg group and about 13% in the other groups. Propafenone SR did not appear to increase the occurrence of atrial flutter or SVT (supraventricular tachycardia). The researchers conclude that propafenone SR has important and statistically significant antiarrhythmic effects in patients with atrial fibrillation.
Pritchett, ELC, et al. Efficacy and safety of sustained-release propafenone (propafenone SR) for patients with atrial fibrillation. American Journal of Cardiology, Vol. 92, October 15, 2003, pp. 941-46

New guidelines for afib management

PHILADELPHIA, PENNSYLVANIA. The American Academy of Family Physicians and the American College of Physicians have issued their own guidelines for the management of newly detected atrial fibrillation (AF). These guidelines contain six major recommendations:

  1. Rate control rather than rhythm control is the preferred option for most AF patients. Rhythm control may be appropriate in special cases.

  2. AF patients should receive long-term anticoagulation with adjusted-dose warfarin unless they are at low risk for stroke or have contraindications to the use of warfarin.

  3. The following drugs are recommended for rate control � atenolol, metoprolol, diltiazem, and verapamil. Digoxin is considered a second-line agent for rate control.

  4. Both direct-current cardioversion and pharmacological conversion (with ibutilide, flecainide, dofetilide, propafenone or amiodarone) are acceptable options for conversion to sinus rhythm.

  5. Both transesophageal echocardiography (TEE) with short-term anticoagulation followed by early acute cardioversion and post-anticoagulation and delayed cardioversion with pre- and post-anticoagulation are acceptable strategies for electrical cardioversion.

  6. Most patients converted to sinus rhythm should not be placed on rhythm maintenance therapy as the risks (torsades de pointes and other ventricular arrhythmias) outweigh the benefits. In selected patients whose quality of life is compromised by AF the recommended drugs for rhythm control are amiodarone, disopyramide, propafenone and sotalol (in alphabetical order).

Snow, V, et al. Management of newly detected atrial fibrillation: A clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Annals of Internal Medicine, Vol. 139, December 16, 2003, pp. 1018-33

Editor's comment: It is interesting that the guideline authors embrace the CHADS2 risk score for stroke with a score of 0 or 1 not requiring anticoagulation. In this system atrial fibrillation as such has a score of 0. The score is increased by adding 1 point each for recent heart failure, hypertension, diabetes, and age over 75years. A history of stroke or transient ischemic attack requires the addition of 2 points. Thus, according to the CHADS2 scale, most lone afibbers would not benefit from anticoagulation, as the risk of intracranial bleeding (hemorrhagic stroke) with warfarin would outweigh the risk of an ischemic stroke resulting from not being on warfarin.

It is also quite obvious that none of the guideline authors themselves suffer from AF. If they did, they would not so blithely advocate rate control over rhythm control.

Finally, I wonder if the fact that family physicians are now entering the afib arena with their own set of guidelines is an indication that the AF epidemic has reached the point where it can no longer be handled by cardiologists alone.

Incidence of repeat ablation

PHILADELPHIA, PENNSYLVANIA. Most premature atrial complexes (PACs) and indeed atrial fibrillation episodes themselves originate from the area where the pulmonary veins join the left atrium. This observation has fuelled the trend to cure atrial fibrillation by isolating the pulmonary veins from the atrium by the placement of scar tissue (ablation) around the openings of the veins, so as to prevent "rogue" electrical impulses originating from within the veins from reaching the left atrium wall. Some electrophysiologists now routinely isolate all veins during the ablation procedure while others only isolate the veins actually found to generate PACs and AF during the electrophysiology study. The former approach has a higher success rate, but the latter minimizes the risk of subsequent stenosis.

Researchers at the University of Pennsylvania have just released the results of a study designed to determine the reasons for afib recurrence in afibbers who had undergone a seemingly successful pulmonary vein isolation (PVI). Of 226 patients who had undergone a seemingly successful PVI 140 (62%) remained afib-free during the follow-up. Among the remaining 86 patients 31 were able to control their afib with antiarrhythmics while 34 returned for a repeat ablation procedure within an average of 7 months from the original procedure. The researchers found that 61% of the 84 previously isolated pulmonary veins (an average of 2.5 veins per patient) had regained some electrical activity while 39% remained completely isolated. They also identified 50 new trigger points (for PACs and AF), of which, 54% originated from previously isolated veins. The 34 patients were followed for an additional 13 months after their repeat ablation. At the end of the follow-up period 82% were still in sinus rhythm giving an overall success rate of 74% among the original 226 patients.
Gerstenfeld, EP, et al. Incidence and location of focal atrial fibrillation triggers in patients undergoing repeat pulmonary vein isolation. Journal of Cardiovascular Electrophysiology, Vol. 14, July 2003, pp. 685-90

Drugs of little benefit for persistent afibbers

OMAHA, NEBRASKA. About 25% of patients presenting for cardioversion after a first atrial fibrillation (AF) episode have the persistent kind of AF, that is, they do not convert spontaneously within 72 hours. Researchers at Creighton University have just completed a study to determine the effectiveness of rhythm and rate control drugs in maintaining sinus rhythm after a first electrical cardioversion. Their study involved 150 patients with a first persistent afib episode. Fifty of the patients were assigned to receive rhythm control drugs (amiodarone, sotalol, and propafenone primarily) while the remaining 100 were assigned to receive beta or calcium channel blockers. Of particular interest is the fact that 52% of the members of the rhythm control group and 45% of those in the rate control group also received digoxin.

One month after cardioversion 30% of the rhythm control group had relapsed into AF as compared to 41% in the rate control group. All members of the rate control group had relapsed after 36 months, but about 20% of the rhythm control group was still in sinus rhythm 4 years after their initial cardioversion.
Li, H, et al. Comparison of recurrence rates after direct-current cardioversion for new-onset atrial fibrillation patients receiving versus those not receiving rhythm-control drug therapy. American Journal of Cardiology, Vol. 93, January 1, 2004, pp. 45-48

Editor's comment: It is clear that neither rhythm nor rate control drugs are very effective in maintaining sinus rhythm in persistent afibbers. Unfortunately, the design of the trial probably shares a significant proportion of the blame for this. Almost half of all participants were on digoxin, which is now known to worsen AF, especially among vagal afibbers. It is also noteworthy that 90% of the rhythm control drugs used had beta- blocking properties; in other words, would be expected to worsen the situation for vagal afibbers. As for the rate control group, 54% of the drugs used were beta-blockers, which again are detrimental to vagal afibbers. The researchers, as is common, did not distinguish between vagal and adrenergic afibbers, but the trial certainly was, inadvertently I am sure, set up to worsen the situation for any vagal afibbers among the patients.

Vagal afibbers should avoid pravastatin

BOSTON, MASSACHUSETTS. There is some evidence that treatment with statin drugs decreases the incidence of arrhythmias after coronary artery bypass grafting and other procedures involving the heart. Here it should be kept in mind that surgery-induced atrial fibrillation is entirely adrenergic in nature.

A team of American and Korean medical researchers now report that one particular statin drug, pravastatin (Pravachol), has a pronounced effect on the activity of the parasympathetic (vagal) arm of the autonomic nervous system. Their experiment involved 13 women and 8 men between the ages of 34 and 68 years. All participants had high cholesterol levels and were randomized to receive either pravastatin (20 mg/day) or the same dosage of simvastatin (Zocor) for 8 weeks in a single-blind, randomized, crossover study. Lipid profiles and Holter monitor studies were obtained at entry to the trial, at the crossover point, and at the completion of the trial.

Heart rate variability studies clearly showed that pravastatin increased the HF fraction (an indication of vagal activity) during sleep by about 24% with the increase being most pronounced around 3 a.m. Pravastatin therapy also decreased the LF/HF ratio by 31%. The LF/HF (low frequency/high frequency) ratio is a measure of autonomic nervous system balance with a high LF value indicating adrenergic (sympathetic) predominance and a high HF value indicating vagal (parasympathetic) predominance. Simvastatin treatment was not associated with significant changes in heart rate variability parameters.

The researchers also noted that the concentration of heterotrimeric G-protein (G-alpha-i2) in white blood cells (lymphocytes) was significantly increased during pravastatin administration, but not during administration of simvastatin. They speculate that G-alpha-i2 may serve as a molecular marker of the heart's response to parasympathetic stimulation.
Welzig, CM, et al. Lipid lowering by pravastatin increases parasympathetic modulation of heart rate. Circulation, Vol. 108, December 2, 2003, pp. 2743-46

Editor's comment: The practical application of these findings would seem to be that vagal afibbers being treated for high cholesterol levels should avoid pravastatin while adrenergic afibbers may find it helpful.

Economic burden of atrial fibrillation

PARIS, FRANCE. A group of French cardiologists has just completed a study aimed at determining the cost to society of AF. They point out that the incidence of this disorder increased by 300% between 1986 and 1996. It is estimated that over 3.5 million Europeans now suffer from AF.

The study involved 671 AF patients treated by 82 different cardiologists throughout France. The average age of the patients was 69 years, 64% were male, and about 43% suffered from hypertension, 16% from heart failure, 13% from coronary artery disease, and 13% from valvular heart disease. The patients were followed for an average 329 days. During this time 21 patients (3.1%) died and 210 (31.3%) were hospitalized at least once. Anticoagulants (warfarin) were prescribed for 55% of all patients with paroxysmal AF and for 70% of those with persistent or permanent AF. It is interesting that the rate of hemorrhagic stroke (intracranial bleeding) at 0.6% was higher than the rate of ischemic stroke at 0.4%.

The total annual cost of caring for an AF patient was found to be $4500 US. Hospitalizations (for cardioversion, heart failure, and implantation or change of pacemaker) accounted for 52% of the expenditure, drugs accounted for 23%, consultation 9%, further investigations 8%, loss of work 6%, and paramedical procedures 2%. The most important cost drivers were heart failure, coronary artery disease, adverse effects related to the use of amiodarone, hypertension and diabetes. The use of Class I antiarrhythmics such as flecainide or propafenone was not associated with increased costs related to adverse events. The researchers conclude that AF's annual cost to society approaches $13 billion US within the European Union.

American researchers have found that the cost of caring for an AF patient in the USA is about $21,000 US per year. Thus, with about 2 million afibbers in the US, the cost of caring for them for a year would be about $42 billion US �. A major problem indeed!
Le Heuzey, JY, et al. Cost of care distribution in atrial fibrillation patients: the COCAF study. American Heart Journal, Vol. 147, January 2004, pp. 121-26



NEWSBRIEFS

Conduction cells in pulmonary veins.
Researchers at the Cleveland Clinic report that autopsies of the myocardial sleeves of pulmonary veins in five atrial fibrillation patients revealed the presence of P cells, Purkinje cells, and transitional cells similar to those found in the heart's conductive (nodal) tissue. Conductive cells were not found in five control patients without atrial fibrillation. The researchers point out that whether or not these conductive cells are involved in AF still needs to be determined.
Journal of Cardiovascular Electrophysiology, Vol. 14, August 2003, pp.803-09

Seasonal variation in ventricular fibrillation.
German researchers have analyzed data from 308 patients with an implantable cardioverter defibrillator (ICD) over an 11-year period. They found that the ICDs were triggered a total of 233 times to prevent ventricular fibrillation. They observed that the majority of the shock episodes took place in December (40%) while June accounted for only 17% of the ICD triggerings. They conclude that there is a seasonal variation to ventricular fibrillation episodes and speculate that colder temperatures and fewer daylight hours may explain the high incidence in December. American researchers suggest that the use of a light box in the early morning during the winter months, as proposed for the treatment of seasonal affective disorder (SAD) may reduce the incidence of cardiovascular events including ventricular arrhythmias and sudden death.
American Heart Journal, Vol. 146, December 2003, pp. 1061-65, 941-43

Use of medications in atrial fibrillation.
It is estimated that 2.3 million people in the United States now suffer from atrial fibrillation (AF). Of these, 11.8% are classified as lone afibbers that is, afibbers below the age of 65 years with no risk factors for stroke. The number of annual visits to physicians or hospitals relating to AF rose from 2.9 million in 1991 to 4.5 million in 2000. The decade also saw a significant shift in medication use. The use of digoxin (Lanoxin) dropped from 64% to 37% �. A most welcomed trend. Amiodarone (Cordarone) continued to be the most used medication for rhythm control increasing from 0.2% to 6.4% while the use of quinidine declined from 5.0% to 0.0%. The use of Class IC drugs (propafenone and flecainide) increased from 0.5% to 2.9% while the use of beta-blockers and calcium channel blockers remained relatively constant over the decade. Somewhat surprisingly, only 9.8% of the 520 study participants used aspirin for stroke prevention in 2000 as compared to 40% who used warfarin. Warfarin use was particularly high (47.5%) among afibbers aged 80 years or more.
Archives of Internal Medicine, Vol. 164, January 12, 2004, pp. 55-60

Incidence of atrial fibrillation on the increase.
Danish researchers report that the incidence of atrial fibrillation (AF) among Danish men doubled between the period 1976-1978 and the period 1991-1994. They base this conclusion on the incidence of AF observed on electrocardiograms from a random population of about 24,000 patients who had at least three electrocardiograms during the study period. Thus their estimate is likely to be quite conservative, as many afibbers with symptomless paroxysmal (intermittent) AF would have been missed. The researchers found a strong correlation between the observed incidence of AF and male gender, older age, and greater in height. There was also a significant correlation between AF and hypertension and between AF and greater weight in men, and between AF and diabetes in women. The researchers speculate that the association between AF and greater height and weight in men is related to the fact that taller and heavier men tend to have larger left atrial size which, in turn, has been related to an increased risk of AF.
American Journal of Cardiology, Vol. 92, December 15, 2003, pp. 1419-23



RESEARCH REPORT

Atrial Fibrillation and ACE Inhibitors

Earlier this year we explored a possible connection between the renin-angiotensin-aldosterone system (RAAS) and lone atrial fibrillation (The AFIB Report, March 2003 and Virtual Conference Room Sessions 1, 2 and 11). The idea, not supported by any medical evidence at the time, was that an afib episode would be initiated by an excess of aldosterone and terminated when this excess was eliminated through the action of natriuretic peptides released during the episode. Aldosterone is known to have many detrimental effects on the heart and some of them are associated with conditions known to promote LAF:

  • Inflammation and fibrosis of the heart tissue are found in most LAF patients. Aldosterone causes inflammation and fibrosis of the heart tissue by direct action on the MC-receptors in the myocardium. This action is not accompanied by hypertension.

  • Most LAF patients suffer from a systemic inflammation as expressed in abnormally high CRP (C-reactive protein) levels. Aldosterone causes inflammation.

  • Atrial fibrillation is associated with an increased level of reactive oxygen species (ROS) in the heart tissue. Aldosterone causes an increased level.

  • Atrial fibrillation is associated with an imbalance in the ANS. Aldosterone causes such an imbalance, primarily by increasing sympathetic activity.

  • Hypokalemia (low potassium levels) is associated with an increase in PACs, which in turn are associated with an increased risk of LAF episodes. Aldosterone promotes hypokalemia.

  • Hypomagnesemia (low magnesium levels) is associated with an increase in PACs, which in turn are associated with an increased risk of LAF episodes. Aldosterone promotes hypomagnesemia.

Although aldosterone production is primarily initiated by activation of the RAAS, it can also be initiated by ACTH the same hormone that stimulates the secretion of cortisol. A high potassium level or a low sodium level also causes aldosterone secretion to be increased. A magnesium deficiency causes an increase in aldosterone production and subsequent hypokalemia (potassium deficiency). An excess of calcium ions (Ca++) can also increase aldosterone production because excess Ca++ increases the secretion of ACTH.

An excessive production of aldosterone can also be caused by a benign tumour (adenoma) on the adrenal glands or simply by an enlargement (hyperplasia) of the adrenal glands. Hyperplasia itself has been linked to prolonged exposure to stress. Adrenal tumours are fairly common and can be genetically "ordained".

As mentioned previously, aldosterone production is primarily initiated by the renin-angiotensin-aldosterone system. The RAAS is the body's main system for dealing with a decrease in blood pressure that is too great to be handled by the autonomic nervous system alone. The primary purpose of the RAAS is thus to increase blood pressure by preserving (hoarding) sodium and water. The RAAS is normally activated by hypotension caused, for example, by a sudden shift from supine to standing position. The low blood pressure is first sensed by the kidneys, which proceed to secrete a small peptide called renin. Renin is transported to the liver where it helps to produce angiotensin I from a large protein called angiotensinogen. Angiotensin I, in turn, is carried by the blood to the lungs where it is converted into angiotensin II through the action of angiotensin-converting enzyme (ACE).

Angiotensin II is the most potent vasoconstrictor in the body. It causes the blood vessels to constrict and potentiates the sympathetic nervous system resulting in an increase in blood pressure. Angiotensin II also acts on the adrenal glands to produce aldosterone. Aldosterone causes sodium and water to be retained by the kidneys thus increasing the body's fluid content and thereby the blood pressure. The action of the renin- angiotensin part of the RAAS may take seconds to minutes to kick in, but it may take days or even weeks before the full effect of aldosterone is felt.

If there is little medical evidence at the moment that aldosterone is involved in afib, is there any evidence that other parts of the RAAS may be? Indeed there is.

Researchers at the University of Leipzig in Germany recently reported that lone afibbers have significantly more receptors for angiotensin II (subtype I) in the left atrium than do people without LAF. The increase in receptors was apparent in both afibbers with mitral valve prolapse and in those without it. No increase in receptors was found in the right atrium. The researchers conclude that angiotensin II receptor subtype I may play a role in lone atrial fibrillation[1]. The presence of more receptors in afibbers would mean that the level of whatever protein is produced as a result of the angiotensin II molecule docking at its receptor would be elevated. If this protein, or perhaps aldosterone itself, is involved in promoting afib then blocking the subtype I angiotensin II receptor should result in a decrease in afib episodes.

Angiotensin II type 1 receptor (AT1R) antagonists are potent blockers of the receptors. Japanese researchers have found that candesartan (Atacand) significantly shortens afib episodes in dogs and prevents structural remodelling and fibrosis in the atrium[2]. Spanish researchers have found that the AT1R irebesartan (Avapro) allowed afibbers with persistent afib who were electrically cardioverted to stay in sinus rhythm longer after treatment with irebesartan + amiodarone than did patients medicated with amiodarone alone[3].

There is evidence that the AT1R valsartan (Diovan) can actually reduce aldosterone levels. A team of American and Italian researchers treated over 4,000 chronic heart failure patients with valsartan (160 mg twice daily) or placebo and compared plasma aldosterone levels after 24 months. The mean aldosterone level in the placebo group increased by 18.8 pg/mL, but decreased by 23.8 pg/mL in the valsartan group. Thus the mean reduction in aldosterone in the valsartan group compared with the placebo group was 29.3%. The difference between the two groups was most pronounced after just 4 months of treatment[4]. The same group of researchers later concluded that the incidence of new cases of atrial fibrillation among the heart failure patients was significantly lower in the valsartan group than in the placebo group (5.27% versus 7.86% in 23 months of follow-up)[5].

Chinese researchers have found that the AT1R losartan (Cozaar) actually inhibits the production of aldosterone in the myocardium of rats with heart failure[6].

An alternative way of preventing the detrimental effects of angiotensin II is by inhibiting its synthesis as opposed to blocking its uptake (with AT1Rs). Angiotensin-converting enzyme inhibitors (ACE inhibitors) prevent the synthesis of angiotensin II from angiotensin I. There is now some evidence that ACE inhibitors may indeed affect afib episode frequency. Taiwanese researchers recently reported that the ACE inhibitor enalapril (Vasotec) significantly lengthens the afib-free interval following electrical cardioversion of chronic afib when given in combination with amiodarone. After 270 days 74% of the amiodarone + enalapril group was still in sinus rhythm as compared to only 57% in the amiodarone only group[7].

Danish researchers have found that the ACE inhibitor trandolapril (Mavik) decreased the risk of developing atrial fibrillation by over 50% in a group of heart disease patients (left ventricular dysfunction) who had just suffered a heart attack[8]. They point out that ACE inhibition is associated with a reduction in atrial premature beats (PACs), the forerunners of atrial fibrillation, and also tends to prevent enlargement of the left atrium.

Conclusion

Evidence is slowly accumulating to the effect that the RAAS or, perhaps more specifically, angiotensin II and aldosterone may indeed be involved in atrial fibrillation. There is now also emerging evidence that ACE inhibitors and angiotensin II receptor antagonists may act to prevent atrial fibrillation episodes most likely through a reduction in PAC frequency and prevention of structural and electrical remodelling of the atrium. Most research, so far, has involved patients with heart failure or other heart disease, so it is not clear whether the findings are applicable to lone afibbers. However, the observation by the University of Leipzig team that lone afibbers have an abnormally high level of angiotensin II type 1 receptors in the left atrium certainly lends support to the idea that the RAAS is involved in lone afib as well. If this is indeed so then ACE inhibitors or angiotensin II receptor antagonists may prove to be of some benefit in the treatment of LAF, particularly among afibbers with high blood pressure. Both types of drugs, of course, have many undesirable side effects and there are also indications that the effect of some of them, particularly the angiotensin II receptor antagonists may wear off over time[9,10].

The potential benefits of drugs that block aldosterone (mineralo corticoid) receptors rather than angiotensin II receptors should not be overlooked. Spironolactone, a potassium-sparing diuretic, is highly effective in blocking MC-receptors. By doing so, it rebalances the autonomic nervous system (increases parasympathetic activity and decreases sympathetic activity), decreases the risk of stroke, prevents hypokalemia, reduces fibrosis, improves endothelial function, and helps prevent hypertension (by blocking MC-receptors in the brain).

Spironolactone, unfortunately, has several nasty side effects, especially breast enlargement and impotence. It is therefore not likely to be a viable long-term solution for LAF prevention. However, a "cousin" of spironolactone, eplerenone, has recently been developed and shows great promise in initial trials. Eplerenone is significantly more effective than spironolactone and animal experiments have shown that it protects the heart, brain and kidneys, especially against stroke and vascular injury[11]. Eplerenone does not cause breast enlargement or impotence. Could this new drug help prevent episodes? If the hypothesis is correct, it is certainly a very real possibility, but of course only a clinical trial will tell.

In conclusion, the finding of an association between the RAAS and atrial fibrillation opens up exciting new avenues for the use of drugs, other than antiarrhythmics, in the treatment of LAF.

References

  1. Boldt, A, et al. Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease. Journal of the American College of Cardiology, Vol. 42, No. 10, November 19, 2003, pp. 1785-92
  2. Kumagai, K, et al. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. Journal of the American College of Cardiology, Vol. 41, No. 12, June 18, 2003, pp. 2197-2204
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