From Columbia University, New York, NY.
Correspondence to J. Thomas Bigger, Jr, MD, Columbia University PH 103-D, 630 W 168th St, New York, NY 10032. E-mail jtb2{at}columbia.edu
In
this issue of Circulation, Benjamin et
al1 provide evidence from the Framingham cohort
that atrial fibrillation (AF) increases the mortality rate and that
this association persists when adjusted for age, hypertension, smoking,
diabetes, electrocardiographic left ventricular
hypertrophy, myocardial infarction, congestive heart
failure, valvular heart disease, and stroke or transient
ischemic attack. The current analysis showed that of
the 5209 residents of Framingham who originally enrolled in this
population study, 621 developed AF during follow-up. Participants who
developed AF were more likely to have hypertension, a smoking habit,
electrocardiographic left ventricular
hypertrophy, myocardial infarction, congestive heart
failure, valvular heart disease, and stroke or transient
ischemic attack at baseline. Echocardiographic
left atrial dimension was not available for analysis. The
age-adjusted odds ratios for death with AF were 2.4 for men and 3.5 for
women. After adjusting for risk factor status at each biennial
examination, the odds ratios for death were 1.5 for men and 1.9 for
women. Much of the excess death attributable to AF occurred soon after
diagnosis of AF, but after the first 30-day mortality experience was
excluded, there was still a significant association of AF with death
during follow-up. There was no interaction between age and AF for death
during follow-up; ie, AF increased the likelihood of dying at all
ages.
There was a significant interaction between AF and sex with
respect to mortality; the presence of AF substantially decreased the
survival advantage women usually have over men. The morbidity of
patients with AF is well known. The present study documents an
independent mortality burden for AF as well. This finding extends
previous studies2 3 and motivates the renaissance
of research in AF that is currently underway.
The high incidence of AF (more than 2 million Americans), particularly
in elderly men,2 and the morbidity and mortality
associated with AF3 4 provide strong motivation
to determine the mechanisms of AF and to prevent and treat AF.
However, the article by Benjamin et al1 leaves
some epidemiological questions unanswered. The Framingham sample did
not permit a meaningful examination of the relationship between race
and the incidence of AF or outcome of patients with AF. AF has been
classified as paroxysmal, persistent, or permanent and has also been
classified by its association with cardiac diseases or
metabolic disorders.5 In the
Framingham study, AF was not classified, so we cannot know from that
study whether different categories of AF have a different
prognosis.
The Framingham study presented in this issue of
Circulation (Benjamin et al1) compares
causes of death in patients with AF with age- and sex-matched control
subjects. The causes of death potentially could guide further inquiry
and suggest hypotheses about useful interventions. AF-associated deaths
probably are caused by heart failure, stroke, and adverse drug effects,
eg, ventricular arrhythmias or hemorrhage.
Table 4 in the Framingham report (Reference 11 ) indicates that the
distribution of causes of death for the AF patients was similar to that
of matched control patients without AF. At face value, this finding
suggests that AF increases the probability of death without changing
the mode of death. However, if the causes of death were examined more
closely, additional meaningful findings might be uncovered.
The effects of treatment on outcomes are hard to delineate in a
longitudinal observational study because sicker patients are more
likely to be treated. Nevertheless, a study of treatment patterns,
especially with anticoagulants, drugs used for control of
ventricular rate, and antiarrhythmic drugs could highlight
issues that warrant further study. This information may well be
available in the Framingham files.
We know that AF is associated with morbidity and mortality, but we do
not know enough about the risk-to-benefit ratio of therapies under
evaluation for patients with AF. Placebo-controlled trials with
warfarin have shown a substantial reduction in stroke
rates.6 7 The risk-to-benefit ratio of the many
new therapies can only be determined from controlled clinical trials
after they have shown promise in mechanistic and pilot studies.
The magnitude of the AF problem ensures funding of discovery and
development of diagnostic and therapeutic modalities.
Improved knowledge of how AF is initiated and perpetuated will direct
and correct the direction of inquiry. A wonderful example is research
by Allessie's group (Wijffels and colleagues8,9)
showing that the electrical properties of the atria change rapidly in
the first hours and days of AF; ie, the atrial effective refractory
period shortens dramatically, and its dependence on atrial cycle length
is substantially reduced. These findings have been confirmed, and this
important new knowledge has prompted new treatment strategies. Thanks
to Allessie's research there is even hope that sinus rhythm can be
restored in patients with permanent AF.10 There
is some preliminary evidence that this surprising outcome can be
obtained with implanted atrial cardioverters. As time goes on after
implantation of atrial cardioverters, periods of sinus rhythm last
longer, and the intervals between shocks
increase.11
Current therapeutic developments encompass new antiarrhythmic drugs,
several pacemaker strategies, AV node ablation and rate responsive
pacing, implantable atrial defibrillators, and surgical or catheter
ablation procedures to restore and permanently maintain sinus rhythm.
As these treatment modalities are refined, each of them is likely to
benefit some patients who suffer from AF. To me, it seems that catheter
ablation has the furthest to go but potentially the most to offer.
A simple catheter ablation procedure in the lower right atrium restores
sinus rhythm in nearly all cases of atrial
flutter.12 Catheter ablation already has had
significant impact on rate control in AF. Catheter ablation of the
specific targets in the right atrium can produce complete AV block (a
rate-responsive pacemaker is required)13 14 or
decrease the ventricular rate in AF without producing AV
block.15 These procedures can achieve rate
control after drugs fail. The benefits of ablation-induced rate control
include marked improvement in symptoms and a substantial increase in
left ventricular ejection
fraction.13 14 15 AF continues after these
procedures, so the need for anticoagulant therapy continues.
Surgery or catheter ablation of AF can restore sinus rhythm. To develop
catheter ablation of AF as a mainstream therapy will require that a
long list of problems be solved. The targets for ablation must be
defined. Rarely, a simple target can be identified. Rare cases of AF
have been demonstrated to be focal and easily
ablated.16 Most often, AF is a complex reentrant
rhythm with several circulating wave fronts. Surgical ablation using a
complex maze operation has a high probability of
success.17 Simpler surgical procedures that focus
on the posterior left atrium are successful
also.18 There is already substantial evidence
that there are critical targets for catheter ablation in the common
forms of AF. The posterior left atrium is one critical zone for AF
ablation to restore sinus rhythm.19 It is likely
that some ablation targets for AF will be in inaccessible locations and
will benefit from better imaging and catheter guidance systems. CT,
intracardiac echocardiography, and magnetic methods
are being explored as imaging techniques to support catheter ablation.
Better catheter-steering systems or preformed catheters that seek the
ablation targets are being evaluated now, and computerized mapping
systems continue to improve. Better energy sources or application
strategies for ablation will also help to bring catheter ablation of AF
into the mainstream.
Only after catheter ablation becomes successful for most cases of AF
and becomes relatively quick and efficient can we better evaluate
whether conversion of AF to sinus or atrial paced rhythm will
substantially reduce stroke, heart failure, hospitalization, and death.
Also, controlled trials can determine how much conversion of AF to
sinus or atrial paced rhythm will improve symptoms, exercise capacity,
and functional status. If we can achieve permanent sinus or atrial
paced rhythm, we have reason to hope that outcomes will improve. The
benefits of sinus rhythm to reduce the morbidity and mortality should
be quantified by controlled clinical trials. If we are not careful
about the strategy for research on AF, these trials may never be done,
because at some point they will be deemed unethical. Hopefully, the
National Heart, Lung, and Blood Institute will take responsibility for
conducting and monitoring the critical research pathways for AF so that
a coherent picture of the risks, benefits, and costs will be made
available.
Beyond finding effective treatments for AF, it should be possible to
prevent AF. The Cardiovascular Health
Study2 and the Framingham
study1 have shown that some of the risk factors
for AF are subject to control, eg, systolic blood pressure,
blood glucose, and valvular heart disease. Importantly, the
Cardiovascular Health Study showed, in a prospective
study, the very strong relationship between left atrial enlargement and
the incidence of AF during follow-up. That study made it clear that the
left atrial enlargement preceded the development of AF and strongly
suggests that control of the conditions that lead to left atrial
enlargement will decrease the development of AF. Successful treatment
of risk factors could prevent the development of left
ventricular hypertrophy and left atrial
enlargement and thereby prevent AF. In this regard, in randomized
trials of antihypertensive therapy that sought to prevent or to obtain
regression of left ventricular hypertrophy, AF
could be considered to have been an outcome of those pathological
conditions. Presumably, there should be less AF in groups treated with
antihypertensive drugs, especially in those that showed regression of
left ventricular hypertrophy and smaller left
atrial size. Already, it has been shown that long-term treatment of
hypertension with certain drugs causes a reduction in left atrial
size.20
The relationship between left atrial enlargement and incidence of AF
was so strong in the Cardiovascular Health
Study2 that it would be reasonable to plan and
conduct prophylaxis trials in patients with substantially enlarged left
atria who have yet to develop AF. ß-Blockade and anticoagulation
would be candidates for prophylaxis trials. Epidemiological studies
have already shown that ß-blocker use is associated with a large
decrease in the incidence of AF.2 This finding is
impressive since the expectation in an epidemiological study is that
ß-blockers would be associated with an increase in AF because
ß-blocker use is an indicator of hypertension, angina pectoris,
myocardial infarction, and hyperthyroidism. An inverse association
between ß-blocker use and AF must have overcome the indicator effect
for disease.
Although the best strategies for management of AF and the
diagnostic and therapeutic critical pathways have yet to be
defined, new knowledge is accumulating at an impressive rate, and
patients already benefit substantially from the effort.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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© 1998 American Heart Association, Inc.
Editorial
Epidemiological and Mechanistic Studies of Atrial Fibrillation as a Basis for Treatment Strategies
Key Words: Editorials • fibrillation, atrial • prevention • hypertension • catheter ablation • stroke
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