Download In Patients With Chronic Atrial Fibrillation and Left Ventricular

In Patients With Chronic Atrial
Fibrillation and Left Ventricular Systolic
Dysfunction, Restoration of Sinus
Rhythm Confers Substantial Benefit*
José Azpitarte, FESC; Oscar Baún, MD; Eduardo Moreno, MD;
Rocı́o Garcı́a-Orta, MD; Jesús Sánchez-Ramos, MD; and Luis Tercedor, MD
Study objectives: To evaluate the benefit of sinus rhythm (SR) restoration in patients with chronic
controlled atrial fibrillation (AF) and left ventricular systolic dysfunction (LVSD).
Design: Prospective case-control study on the short-term outcome (6 to 9 months) of clinical and
echocardiographic variables following attempted cardioversion.
Setting: Outpatient clinic of a university hospital.
Patients: Fifteen men and 5 women, ranging in age from 40 to 76 years, who had chronic
controlled (mean [ⴞ SD] ventricular rate, 82 ⴞ 10 beats/min) AF and left ventricular fractional
shortening (LVFS) of < 28% at baseline. Control was provided by retrospective paired echocardiographic examinations of six AF patients, plus the study cases with potentially unsuccessful
cardioversion or early recurrence of AF.
Interventions: Attempt to restore SR with amiodarone or electrical countershock.
Measurements and results: Conversion was attained in 17 patients, but AF recurred early in 4
patients, 3 of whom had proven ischemic LVSD. In the 13 patients with sustained SR, LVFS
increased from 20 ⴞ 4% to 31 ⴞ 6% (p < 0.0001). In contrast, no changes were detected in the
control group (n ⴝ 13). This improvement was paralleled by decreases in left ventricular (LV)
end-diastolic dimension (from 55 ⴞ 7 to 51 ⴞ 6 mm; p ⴝ 0.014), LV mass (from 181 ⴞ 28 to
159 ⴞ 37 g; p ⴝ 0.015), and left atrial diameter (from 45 ⴞ 9 mm to 42 ⴞ 7; p ⴝ 0.003). A marked
decrease in heart rate (from 82 ⴞ 9 to 64 ⴞ 5 beats/min; p < 0.0001) and a reduction in New York
Heart Association functional class (from 2.3 ⴞ 0.9 to 1.2 ⴞ 0.4; p ⴝ 0.0007) also were observed in
patients with sustained SR but not among subjects in the control group.
Conclusions: Even when adequate control of the ventricular rate has been achieved, the LV
function of patients with chronic AF greatly improves after restoration and maintenance of SR.
(CHEST 2001; 120:132–138)
Key words: amiodarone; atrial fibrillation; case-control study; electrical countershock; heart failure; left ventricular
dysfunction
Abbreviations: ACE ⫽ angiotensin-converting enzyme; AF ⫽ atrial fibrillation; LA ⫽ left atrium; LV ⫽ left ventricle,
ventricular; LVEDD ⫽ left ventricular end-diastolic dimension; LVFS ⫽ left ventricular fractional shortening;
LVM ⫽ left ventricular mass; LVS ⫽ left ventricular systolic; LVSD ⫽ left ventricular systolic dysfunction; SR ⫽ sinus
rhythm
many as 30% of patients with heart failure have
A sbeen
reported to have concomitant atrial fibrillation (AF).1 In this setting, AF traditionally has been
regarded as a mere epiphenomenon, ie, as an innocent bystander of the underlying myocardial disease.
However, some reports2–5 have documented cases of
*From the Division of Cardiology, Virgen de las Nieves University Hospital, Granada, Spain.
Manuscript received April 11, 2000; revision accepted January
29, 2001.
Correspondence to: José Azpitarte, MD, Division of Cardiology,
Virgen de las Nieves University Hospital, Av de las Fuerzas
Armadas 2, 18014 Granada, Spain; e-mail: [email protected]
complete resolution of congestive heart failure after
conversion to sinus rhythm (SR). Despite the relevance of this fact, which was first reported ⬎ 60
years ago,2 it has been largely ignored in clinical
practice, perhaps because few studies6 –10 have, to
our knowledge, addressed this issue in a prospective
and comprehensive way. There is also a concern
about whether the best therapeutic approach to
these patients is to restore SR or simply to adequately control the ventricular rate. Thus, to gain
deeper insight into the potential benefit of restoring
SR, we conducted a prospective study on patients
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Clinical Investigations
who had echocardiographic left ventricular systolic
dysfunction (LVSD) and a controlled ventricular rate
before attempted cardioversion.
Materials and Methods
Study Patients
One hundred forty-seven consecutive patients with chronic AF
were evaluated in the outpatient clinic of our institution and
submitted to an echocardiographic examination after a period of
pharmacologic treatment aimed at controlling the ventricular
heart rate (Fig 1). Among the group of 99 patients who underwent a high-quality M-mode echocardiogram, 20 patients (15
men and 5 women) with left ventricular fractional shortening
(LVFS) of ⬍ 28% constituted the basis of the study.
History, physical examination, ECG, and chest radiograph
were performed before the echocardiography in every case. The
mean (⫾ SD) age of the patients was 61 ⫾ 10 years (range, 40 to
76 years). LVSD was considered to be of ischemic origin because
of typical angina (one patient, also with an aortic mechanic
prosthesis) or history of myocardial infarction (five patients). In
the other 14 patients, a definite origin of LVSD could not be
established, although nonsevere hypertension was present in 5
patients and 1 patient had undergone an aortic valve replacement. The mean duration of AF, for the 16 patients in whom it
could be determined, was 12 ⫾ 9 months (range, 3 to 65
months).
Prior to baseline echocardiography and the attempted cardioversion, all patients received anticoagulation therapy and were
treated by digoxin as a first-line therapy for ventricular rate
control. The adequacy of the ventricular response, and therefore
the need for additional drug therapy, was judged in the usual
clinical manner through fortnightly examinations at the outpatient clinic. As a result, 19 of 20 patients received another of the
following drugs: low dose of amiodarone, 200 mg daily (9
patients); atenolol (4 patients); diltiazem (2 patients); and verapamil (4 patients). In order to evaluate more accurately the
ventricular rate control achieved, a 24-h Holter recording was
performed in each patient at the time of the echocardiography.
Seventeen patients were also receiving angiotensin-converting
enzyme (ACE) inhibitor therapy, and 9 patients were receiving
furosemide therapy. After the drug treatment, 2 patients were
New York Heart Association functional class I, 12 patients were
class II, 4 patients were class III, and 2 patients were class IV.
After the baseline echocardiogram, an ACE inhibitor drug was
added to the treatment of three patients who were not already
receiving it. The reversion of AF was attempted by an oral
loading dose of amiodarone (1g daily until a total dose of 100
mg/kg of weight) followed by a maintenance dose (200 mg daily)
in the nine patients who were already receiving it for ventricular
rate control. If this therapy was unsuccessful, patients underwent
synchronized direct-current external shock, as did those not
treated by amiodarone. Following the index cardioversion, all
patients who attained SR were placed on low-dose amiodarone
therapy. Conversely, amiodarone was withdrawn and replaced by
bisoprolol in those patients who did not attain conversion.
Finally, patients not receiving amiodarone therapy before failed
conversion remained with or were changed to ␤-blocker therapy
if they previously were taking a calcium channel blocker. The
study was approved by the Ethics Committee of the Virgen de las
Nieves University Hospital, and written informed consent was
obtained from all of the participants.
Echocardiography
Figure 1. Flow diagram showing the enrollment of patients,
their outcomes following cardioversion, and the final composition
of the two compared groups. On the left, 13 patients who had
sustained SR after conversion. On the right, seven patients with
unsuccesful cardioversion (n ⫽ 3) or early recurrence of AF
(n ⫽ 4), plus six historical control subjects in chronic AF. LVFS
of ⬍ 28% in a high-quality M-mode echocardiogram was a
requisite for inclusion. Furthermore, a focus on ventricular rate
control was made before echocardiographic examination of the
study patients. FS ⫽ fractional shortening.
A two-dimensionally guided M-mode echocardiogram (model
XP 128; Acuson; Mountain View, CA) was performed in each
patient by one expert cardiologist. Only recorded echocardiograms that demonstrated optimal visualization of left ventricular
(LV) interfaces were used. Measurements for M-mode-guided
calculation were taken just below the tip of the mitral valve and
were averaged from three cardiac cycles with a preceding RR
interval between 750 and 950 ms. LV end-diastolic dimension
(LVEDD), LV end-systolic dimension (LVESD), septal thickness
(ST), posterior wall thickness (PWT), and left atrial (LA) diameter
were measured according to the guidelines of the American Society
of Echocardiography.11 LVFS (%), a measure of LV systolic (LVS)
function, was calculated as follows: (LVEDD ⫺ LVESD) ⫼
LVEDD. LV mass (LVM), according to Devereux et al,12 was
estimated as follows: 1.04 ([ST ⫹ PWT ⫹ LVEDD3] ⫺
LVEDD3) ⫻ 0.8 ⫹ 0.6. To avoid interreader differences, all
the echocardiographic measurements were done by the same
author (E.M.).
The first examination was performed prior to cardioversion, at
a mean of 68 ⫾ 12 days (range, 44 to 92 days) after the beginning
of the ventricular rate control therapy. The second examination
took place between 6 and 9 months after the index cardioversion.
Although every patient in the study provided their own control,
we used, for external control purposes, paired echocardiographic
examinations performed at least 6 months apart on six patients
with chronic AF and LVFS values of ⬍ 28% who were randomly
selected from our echocardiographic archives. At the time of the
echocardiography, all the control subjects were receiving digoxin
therapy plus one additional drug (four patients were receiving
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133
atenolol, one patient was receiving bisoprolol, and one patient
was receiving verapamil), and five patients also received ACE
inhibitor therapy. For the purposes of comparison, it was planned
to form a group, adding patients with potential failed conversion
or early recurrence of AF to the six control examinations.
Statistical Analysis
Values are expressed as mean ⫾ SD. The Student’s t test was
used to detect baseline differences between the patients and the
control subjects. The same test, for paired data, was used to
detect changes after attempted cardioversion in the study patients, and between the first and second examination in the
external control group. Comparisons between percentages were
made with Fisher’s Exact Test. AF-free survival curves were
calculated using the Kaplan-Meier method, and the log-rank test
was used for curves comparison. p Values ⬍ 0.05 were defined as
statistically significant. Statistical analyses were performed with
statistical software (GraphPad Prism, version 2.0; GraphPad
Software; San Diego, CA).
Results
Attainment and Maintenance of SR
SR was obtained in 17 patients, 6 by amiodarone
therapy and 11 by electrical cardioversion. Two of
three patients who were resistant to electrical therapy had LVSD of ischemic origin. Early recurrence
of AF occurred in four patients. Thus, two groups of
13 cases each were available for comparison (Fig 1).
Three of the four patients who returned early to AF
had ischemic LVSD. The other 13 patients (12 of
whom had nonischemic LVSD) were in SR at the
time of the second examination. In 12 of these
patients, SR has been maintained from the last
recording to the date of writing, representing a mean
follow-up of 12 ⫾ 7 months. In the remaining patient, who also had ischemic LVSD in addition to an
aortic mechanic prosthesis, the AF recurred at
month 14 of observation. One patient had a transient
episode of AF related to acute pneumonia 14 months
after cardioversion. The proportion of patients who
were free of AF recurrence was 92% in patients with
nonischemic LVSD, whereas none of the four patients with ischemic LVSD were free of recurrence
(p ⫽ 0.0009 [Fig 2]).
Changes in LV Function
There was no significant difference between the
baseline echocardiographic data of patients who
remained in SR and those of patients who persisted
in or returned to AF (Table 1). After 6 months, the
LVFS increased from 20 ⫾ 4 to 31 ⫾ 6%
(p ⬍ 0.0001) in the 13 patients who were in SR at
this time. By contrast, no changes were noted in the
group of 13 patients who were in AF at the follow-up
(Table 1). Figure 3 shows the individual evolution of
Figure 2. The proportion of patients remaining free of recurrent
AF after successful conversion. Freedom was significantly higher
in patients with nonischemic LVSD (p ⫽ 0.0009 [log-rank test]).
The number of patients in each group is shown in parentheses.
the LVFS values. Whereas LVFS increased in all
patients who had sustained SR, this outcome was
rarely observed in patients who were in AF at the
second examination. As a consequence, 10 of the 13
patients with SR were at or above the level of 28% at
the second examination, whereas this behavior was
noted in only 2 of the 13 patients with persisting or
recurring AF (p ⫽ 0.005). LVEDD (baseline, 55 ⫾ 7
mm; repeat examination, 51 ⫾ 6 mm; p ⫽ 0.014),
LVM (baseline, 181 ⫾ 28 g; repeat examination,
159 ⫾ 37 g; p ⫽ 0.015), and LA diameter (baseline,
45 ⫾ 9 mm; repeat examination, 42 ⫾ 7 mm;
p ⫽ 0.03) only decreased in the patients with sustained SR.
Changes in Ventricular Heart Rate and Functional
Class
At baseline, the mean ventricular rate of AF (24-h
Holter monitoring) was 82 ⫾ 9 beats/min. After 6
months, the mean heart rate of the 13 patients with
sustained SR had decreased to 64 ⫾ 5 beats/min
(p ⬍ 0.0001; Table 1). In spite of these heart rate
changes, and because of bias in the cycle selection,
the mean RR intervals from which the echocardiographic measures were derived did not differ between before and after cardioversion. The ventricular response of the seven patients with failed
conversion or AF recurrence was similar at the first
and second examination. Concerning symptomatic
evaluation, an improvement in New York Heart
Association class (2.3 ⫾ 0.9 at baseline vs 1.2 ⫾ 0.4
at follow-up; p ⫽ 0.0007) was observed in the patients with sustained SR but not in the seven patients
with unsuccessful conversion or AF recurrence
(2.3 ⫾ 0.5 at baseline vs 2.6 ⫾ 0.5 at the second
examination; p ⫽ 0.36).
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Clinical Investigations
Table 1—Outcome of Echocardiographic and Ventricular Rate Measurements*
Sustained SR (n ⫽ 13)
Persistence or Recurrence of AF
(n ⫽ 13)
Variable
Baseline
Follow-up
Baseline
Follow-up
RR intervals, ms
LVFS, %
LVEDD, mm
LVM, g
LAD, mm
Ventricular rate, beats/min
816 ⫾ 57
20 ⫾ 4
55 ⫾ 7
181 ⫾ 28
45 ⫾ 9
82 ⫾ 9
848 ⫾ 42
31 ⫾ 6†
51 ⫾ 6‡
159 ⫾ 37§
42 ⫾ 7㛳
64 ⫾ 5†
828 ⫾ 59
20 ⫾ 5
57 ⫾ 8
201 ⫾ 47
46 ⫾ 5
84 ⫾ 10#
820 ⫾ 50
19 ⫾ 7
56 ⫾ 7
192 ⫾ 32
48 ⫾ 4¶
80 ⫾ 16#
*Values are given as mean ⫾ SD. LAD ⫽ left atrial diameter.
†p ⬍ 0.0001 vs baseline.
‡p ⫽ 0.014 vs baseline.
§p ⫽ 0.015 vs baseline.
㛳p ⫽ 0.003 vs baseline.
¶p ⫽ 0.04 vs baseline.
#n ⫽ 7.
Discussion
To date, research into the outcome of LV function
after conversion to SR in patients with AF and LVSD
has been sparse.6 –10 There is also reasonable doubt
as to whether the restoration of SR is the best
therapy for these patients or whether similar benefits
can be obtained by a simple ventricular rate control.
With this in mind, we designed a study using Mmode two-dimensionally guided echocardiography
and prospectively enrolled a population that had
LVFS of ⬍ 28% before cardioversion. Prior to the
echocardiographic examination, we focused on controlling the ventricular rate response in order to
Figure 3. Extent of increase in LVFS over time. Solid boxes
connected by lines indicate individual data points for each
patient, at baseline and after 6 to 9 months. Solid boxes with
deviation bars indicate mean pooled data at each time point. A
universal improvement can be observed in patients who were in
SR at the second evaluation (left), whereas this kind of response
was only occasionally seen in control subjects (right). The number
of patients in each group is shown in parentheses.
segregate the possible improvements in LV function
intrinsic to the restoration of SR from those induced
by a sustained lower ventricular rate. In other words,
we wanted to investigate whether a gain in LV
function can be achieved even after an adequate
control of the ventricular rate has been obtained.
Major Findings
The main study outcome is that, despite previous
good control of the ventricular rate, LVS function
was greatly improved in patients with restored and
sustained SR. In contrast, no changes were detected
in those patients who returned to or persisted in AF
during the echocardiographic follow-up. In addition,
reductions in LVEDD, LVM, and LA diameter were
observed only in patients with sustained SR.
It is generally accepted that atrial systole improves
LV performance by means of the Frank-Starling
mechanism, ie, by increasing LV preload (the enddiastolic fiber length).13 In an experimental model,
Linderer et al14 observed that AF causes an upward
shift in the end-diastolic pressure-diameter relationship (ie, the end-diastolic volume becomes smaller at
a given end-diastolic pressure). According to the
Frank-Starling law, this smaller LV end-diastolic
volume results in a smaller stroke volume (a downward shift of the conventional ventricular function
curve). Interestingly, the opening of the pericardium
shifts the end-diastolic pressure-diameter relationship downward and the stroke volume-end-diastolic
diameter relation upward; thus, it counters the effect
of the withdrawal of the atrial contribution on these
curves. Therefore, the primary reaction (an upward
shift in the end-diastolic pressure-diameter relationship) on this sequence of events was thought to be
caused by an unemptied atrium that compromised
the pericardial volume.14
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135
According to these experimental data, the following changes can be expected with the restoration of
SR: (1) a better emptying of the LA at LV enddiastole, and thus a removal of the restraining pericardial force; (2) a downward shift in the enddiastolic pressure-diameter relationship; (3) and an
improvement (upward shift) of the ventricular function curve. These favorable hemodynamic changes,
rather than an improved myocardial intrinsic contractility, may account for the reported improvement
in exercise performance after successful cardioversion.10,15,16
In the present study, a decrease rather than an
increase in the LVEDD was observed in patients
with sustained SR. This finding, suggesting that the
improvement in LV function was likely due to a
better myocardial contractility and not to the FrankStarling mechanism, was apparently in conflict with
the above-mentioned experimental results. However, the following large differences between the two
studies must be pointed out: in the acute experimental work, the data were obtained from animals with
normal LV values,14 whereas our patients had
chronic AF and marked LVSD. In our view, it is
possible that in the chronic setting a remodeling of
the LV with regression of the dilation might have
occurred after several months of the improved ventricular efficiency afforded by sustained SR.
The Link between AF and LVSD
Despite the small number of patients enrolled in the
study, a striking difference was observed in the attainment and maintenance of SR between patients with
proven ischemic LVSD and those with LVSD of presumably nonischemic origin. This finding should be
taken with reservation because it emerged from an a
posteriori analysis. In addition, it should be taken into
account that we used only clinical criteria to distinguish
between ischemic and nonischemic LVSD. Nevertheless, this finding suggests that AF-LVSD concomitance
encompasses a wide physiopathologic spectrum. At one
end, AF is a mere epiphenomenon of a profound
alteration in LV function (ie, LVSD of ischemic origin),
so that a high recurrence rate is likely as long as the
primary cause of LVSD persists. However, at the other
end of the spectrum, the arrhythmia may be a primary
phenomenon that induces insidious myocardial dysfunction, with no expectation of recurrences because of
the ensuing improvement in LVS function. Evidently,
intermediate situations also can occur when AF is not
the primary cause of the LVSD but can contribute to it.
Low-dose dobutamine stress echocardiography was
proposed to distinguish between idiopathic LVSD
with secondary arrhythmia and tachycardia-induced
LVSD,17 in order to predict the recovery of LV func-
tion after the restoration of SR. Our study does not
contain these kind of data, but the universal improvement of LV function observed among the nonischemic
patients suggests that AF-induced LVSD is far more
widespread than is currently understood.
To Simply Control Ventricular Rate or to Attempt
Conversion to SR?
Reduction of the heart rate is thought to be the
principal mechanism implicated in the improvement
of LV function.18,19 Tachycardia is an inefficient,
energy-wasting mechanism of ventricular contraction,20 and an experimental model of tachycardiainduced heart failure has been studied extensively.21,22 Its clinical counterpart, tachycardia-induced
cardiomyopathy, was first described in patients with
incessant atrial tachycardia.23 Concerning AF, the
best examples of the regression of heart failure have
been reported in patients with noncontrolled ventricular responses.4,5 In the present study, we tried to
demonstrate that the restoration of SR can improve
LV function even after an adequate ventricular
response has been achieved. The mean ventricular
rate at rest achieved in our patients was well below
the range considered to be a good control.24 Despite
this, LV function was greatly improved after conversion. There was no difference between before and
after cardioversion in the mean RR intervals preceding the cycles from which the echocardiographic
measures were taken, which obviously was due to a
bias in the selection of cycles. However, it was also
evident that the ventricular rate estimated by 24-h
Holter recording was significantly lower in SR. Thus,
it was not feasible to differentiate between the
improvement intrinsic to SR restoration and that
achieved by the additional sustained reduction in
heart rate provided by SR per se.
While our study was not able to distinguish the
origin of improvements, it seems clear that SR is
more physiologic and must always be attempted. The
achievement of SR not only restores atrial function
but also suppresses the variation in RR intervals that
adversely affects LV function, regardless of the
ventricular rate.25,26 In addition, the heart rate is
more stable because the sinus node is much less
influenced by sympathetic drive than is the atrioventricular conduction.27 Alternatively, if SR cannot be
achieved and an adequate ventricular rate is difficult
to obtain, atrioventricular junction ablation and permanent ventricular pacing have been proposed to
improve LV function.28,29 However, another study30
was unable to show any benefit of this therapy in
terms of improving cardiac performance.
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Clinical Investigations
Limitations of the Study
The present study has some limitations that deserve consideration. First, for ethical reasons, it was
not a randomized study, and the group constituted
for comparison purposes was partially retrospective.
Second, the number of patients enrolled was small.
Third, the evaluation of symptoms was not performed in a blinded fashion. The estimation of LV
function in patients with AF is problematic due to
changes from beat to beat. To minimize this difficulty, we selected for M-mode measurement three
cycles with predefined RR intervals that were similar. Evidently, M-mode has limitations in evaluating
global LV function; however, it is an adequate tool
for intrapatient follow-up comparison. In addition, to
avoid interreader differences, all of the echocardiographic measurements were performed by the same
author.
The most important limitation of the study was the
inability to exclude other factors that can improve LV
function. For instance, several drugs prescribed for
our patients, such as digoxin,31 ACE inhibitors,32 amiodarone,33 or ␤-blockers,34 can improve LV performance. However, most patients were taking these
drugs before the baseline data were obtained. We
cannot rule out the possibility that hidden and reversible conditions played some role in the good outcomes
of patients with LVSD, such as concealed alcoholism
followed by total abstinence,35 subclinical myocarditis,36 or simply a better control of hypertension.
Clinical Implications
Despite these reservations, we think that the
results obtained from the intrapatient comparisons
are sufficiently impressive to spell out a clear message on the clinical approach to AF in the setting of
LVSD. The independently worse prognosis conferred by AF has been documented.37 The increased
risk of embolism is well appreciated,38 but the
importance of AF in the progression of heart failure39,40 is poorly understood. Furthermore, there is
increasing evidence that patients with heart failure
who convert to SR have a lower mortality rate than
those who do not.41 All these data, along with our
results, suggest that a more vigorous approach to
cardioversion should be adopted in patients with AF
and LVSD, especially when the latter has no clear
origin.
In conclusion, patients with chronic AF and LVSD
of nonischemic origin receive considerable mediumterm benefits from SR restoration, even when an
adequate control of the ventricular rate has been
achieved. This finding is of major clinical relevance
and should be tested in a larger population.
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