From the Division of Cardiology, Department of Medicine, National
Yang-Ming University, School of Medicine, Veterans General Hospital-Taipei,
Taiwan, ROC.
Correspondence to Shih-Ann Chen, MD, Division of Cardiology, Department of Medicine, Veterans General Hospital-Taipei, 201 Sec 2. Shih-Pai Road, Taipei, Taiwan, ROC. E-mail sachen{at}vghtpe.gov.tw
Methods and Results—The study population consisted of 36 patients
(mean age, 53±17 years) with clinically documented typical atrial
flutter. A 20-pole "halo" catheter was positioned around the
tricuspid annulus. Incremental pacing was performed to measure the
conduction velocity along the isthmus and lateral wall, and
extrastimulation was performed to evaluate atrial refractory period in
the baseline state and after intravenous infusion of
ibutilide, propafenone, and amiodarone. Efficacy of these drugs
in conversion of typical atrial flutter and patterns of termination
were also determined. Ibutilide significantly increased the atrial
refractory period and decreased conduction velocity in the isthmus at
short pacing cycle length. It terminated atrial flutter in 8 (67%) of
12 patients after prolongation of flutter cycle length due to increase
(86±19%) of conduction time in the isthmus. Propafenone predominantly
decreased conduction velocity with use dependency and significantly
increased atrial refractory period, but it only converted atrial
flutter in 4 (33%) of 12 patients. Amiodarone had fewer
effects on atrial refractory period and conduction velocity than did
ibutilide and propafenone, and it terminated atrial flutter in only 4
(33%) of 12 patients. Termination of typical atrial flutter was due to
failure of wave front propagation through the isthmus, which occurred
with cycle length oscillation, abruptly without variability
of cycle length, or after premature activation of the reentrant
circuit.
Conclusions—Ibutilide, with a unique increase in atrial
refractoriness, was more effective in conversion of atrial flutter than
were propafenone and amiodarone.
Catheter Positions
Baseline Electrophysiologic Study
Intracardiac bipolar electrograms were displayed
simultaneously with ECG leads V1, II,
III, and aVF on a multichannel oscilloscopic recorder (CardioLab
System, Prucka Engineering, Inc) and were recorded on paper at a
speed of 100 or 200 mm/s. The filter was set from 30 to 500 Hz.
The onset of activation electrograms was measured when the first rapid
deflection crosses the baseline with an angle >45
degrees.6 In the left anterior oblique (LAO)
view, the electrode pairs located in the medial sites of the right
atrium–inferior vena cava junction were considered located
within the isthmus; those located in the lateral sites of the right
atrium–inferior vena cava junction were considered located
within the lateral wall. Therefore the relevant conduction velocity
could be calculated by measuring the respective activation time and
distance between two end-dipoles within the isthmus and lateral
wall.18 The method for measuring activation time
during atrial flutter was the same as that during atrial pacing. In Fig 1B
Pharmacologic Study
Definitions
Statistical Analysis
Effective Refractory Period
Termination of Typical Atrial Flutter
Group 2 Patients
Effective Refractory Period
Termination of Typical Atrial Flutter
Group 3 Patients
Effective Refractory Period
Termination of Typical Atrial Flutter
Comparisons Among Groups 1, 2, and 3
Electropharmacologic Effects of Ibutilide, Propafenone, and
Amiodarone
Propafenone is a class IC antiarrhythmia drug that has weak
ß-adrenergic antagonist
properties.28 Recently, Duan et
al29 found that propafenone blocked the transient
outward, delayed rectifier and inward rectifier potassium currents in
rabbit atrial myocytes. In the canine Y-shaped incision model, Spinelli
and Hoffman12 reported that propafenone
terminated atrial flutter in 6 of 6 dogs; termination was preceded by
marked increases in the flutter cycle length as a result of marked
slowing of conduction velocity and less prolongation of atrial
refractory period. In the present study, propafenone produced
use-dependent decrease of conduction velocity in the isthmus and free
wall and increased atrial refractory period by 15% to 29%. It
markedly prolonged the flutter cycle length due to a predominant
increase of activation time in the low right atrial isthmus.
The primary effects of intravenous amiodarone
include depression of sinus rhythm and AV node conduction by blocking
ß-adrenergic receptors and calcium channels, slowing
intraventricular conduction by blocking sodium
channels, and slight prolongation of atrial and ventricular
refractory period by inhibiting potassium
channels.30 31 32 Platou and
Refsum33 reported that intravenous
amiodarone could convert rapid pacing-induced atrial flutter to
sinus rhythm by increasing atrial refractoriness in 5 of 5 dogs. In the
present study, amiodarone prolonged atrial refractory
period to a lesser extent (10% to 18%) than did ibutilide and
propafenone. Furthermore, it only decreased isthmus conduction velocity
at 250-ms pacing cycle length with borderline significance and did not
significantly change conduction velocity in the free wall at any pacing
cycle length. Thus the cycle length of typical atrial flutter was only
slightly prolonged.
Possible Mechanisms of Termination of Typical Atrial Flutter by
Antiarrhythmia Drugs
In the present study, conversion of atrial flutter by ibutilide was
characterized mainly by increased cycle length variability. Guo et
al35 have suggested that ibutilide may induce
transient beat-to-beat changes in action potential duration and atrial
refractoriness and produce unstable oscillations in the
reentrant circuit. Presumably during these oscillating cycles of
reentry, tissues are excited, depolarized, and begin to repolarize but
recover to different levels of full excitability, depending on the
previous cycle length.36 37 38 Finally,
oscillations between two consecutive cycle lengths are such
that the arriving reentrant impulse collides with longer refractory
isthmus tissues that have not recovered, and block
occurs.36 37 38 In the absence of complete
elimination of the excitable gap,39 a possible
explanation for abrupt termination of atrial flutter without cycle
length variability by ibutilide and amiodarone would be a
reduced safety factor for conduction resulting from decreased atrial
excitability or encroachment of the reentrant wave front on the
relative refractory period of sites with markedly prolonged
refractoriness, as suggested by Cha et al27 and
Restivo et al.40 Termination of atrial flutter
after premature activation of the reentrant circuit by ibutilide and
amiodarone requires either failure of the lateral boundaries of
the reentrant circuit with subsequent penetration by a secondary
activation wave front or a reflected impulse generated within the
circle path (return reexcitation).12 27 41 This
most likely occurs as a result of slowing conduction in the reentrant
circuit to a greater extent than surrounding tissues, allowing the
eccentric wave front to penetrate the reentrant circuit or returning
wave front to reactivate the circle path
prematurely.27 Failure of wave front propagation
after premature activation of the reentrant circuit may then result
from local elimination of the excitable gap, due to marked transient
shortening of the tachycardia cycle length below the local
effective refractory period.27
Spinelli and Hoffman12 and Derakhchan et
al42 have demonstrated that the excitable gap of
the experimental canine atrial flutter was not significantly changed by
propafenone. This finding is due to marked slowing of conduction
velocity that neutralizes an increase of the refractory period and
exposes a similar or more excitable gap of the reentrant circuit.
Therefore, Spinelli and Hoffman12 and Inoue et
al11 suggested that propafenone or other class I
antiarrhythmia drugs terminated atrial flutter primarily by
depressing conduction to a critical point beyond which wave front
propagation becomes impossible. In the present study, termination
of typical atrial flutter by propafenone was preceded by prolongation
and oscillation of flutter cycle length with long-short
cycle length at sites proximal to the site of eventual block in the
right atrial isthmus.
Study Limitations
Conclusions
Received August 13, 1997;
revision received December 1, 1997;
accepted January 14, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Electropharmacologic Effects of Class I and Class III Antiarrhythmia Drugs on Typical Atrial Flutter
Insights Into the Mechanism of Termination
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Acute effects of class I
and class III antiarrhythmia drugs on the reentrant circuit of
typical atrial flutter are not fully studied. Furthermore, the critical
electrophysiologic determinants of flutter termination by
antiarrhythmia drugs are not clear.
Key Words: atrial flutter • antiarrhythmia agents • drugs
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Previous mapping
studies in patients with typical atrial flutter have demonstrated a
macroreentrant circuit localized to the right atrium with a partially
or fully excitable gap.1 2 3 4 5 6 7 8 It was controversial
as to whether elimination of the excitable gap through prolongation of
the refractory period,9 10 11 or depression of the
conduction to a critical point beyond which propagation of conduction
would become impossible,12 13 was responsible for
experimental canine atrial flutter termination. In the Sicilian Gambit,
conduction and excitability are considered vulnerable
parameters, and sodium channel–blocking agents are chosen
for treatment of typical atrial flutter.14
However, there are clinical evidences that new class III
antiarrhythmia drugs such as ibutilide or dofetilide may be
more effective than the class I and old class III
antiarrhythmia drugs for conversion of typical atrial flutter
to sinus rhythm.15 16 17 In addition, the critical
electrophysiologic determinants of antiarrhythmia drug efficacy
in typical atrial flutter are not fully delineated. Therefore, in this
study we will investigate the electropharmacologic effects and acute
termination mechanisms of ibutilide (new class III) compared with
propafenone (class IC) and amiodarone (old class III) in
patients with typical atrial flutter.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient Characteristics
Thirty-six patients with clinically documented paroxysmal
typical atrial flutter were included. There were 22 men and 14 women,
with a mean age 53±17 years (range, 22 to 78). All patients were
refractory to or intolerant of a mean of 3±1 (range, 2 to 5)
antiarrhythmia drugs before referral. Eight patients had
associated cardiovascular diseases including
hypertension (4 patients), coronary heart disease (3 patients),
and mitral valve prolapse (1 patient).
Each patient gave informed consent. As described previously, all
antiarrhythmia drugs were discontinued for at least five
half-lives before the study.18 19 The orifices of
inferior vena cava and coronary sinus were
identified by venograms. In all patients, a 7F, 20-pole, deflectable
"halo" catheter with 10-mm paired spacing (Cordis-Webster) was
positioned around the tricuspid annulus to record the right atrial
activation in the lateral wall and the low right atrial isthmus
simultaneously.18 We put the distal
tip of the halo catheter into the coronary sinus, with the
electrode poles 1,2 (H1) located at the ostium in each patient (Fig 1A
and 1B). A 7F deflectable decapolar
catheter with 2-mm interelectrode distance and 5-mm space between each
electrode pair was also inserted into the coronary sinus
through the internal jugular vein. The position of the proximal
electrode pair at the ostium of the coronary sinus was
confirmed with contrast injection. Four multipolar, closely spaced
(interelectrode space, 2 mm) electrode catheters with a
deflectable tip (Mansfield Division of Boston Scientific Inc) were
introduced from the right and left femoral veins and placed in the low
right atrium (free wall), right atrial isthmus, high right atrial
septum, and His bundle area for recording and stimulation.
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Figure 1. Radiographs in the right anterior oblique
projection (A) and left anterior oblique (LAO) projection (B)
show the positions of the halo catheter and multielectrode catheters in
the low right atrium (LRA), coronary sinus (CS) and His bundle
region (HBE). The orifice of the inferior vena cava is
delineated by the dashed line. In the LAO view, H1 is located at the
ostium of the coronary sinus (OCS), H2 to H5 are located within
the low right atrial isthmus, and H6 to H10 are located within the free
wall. The sparing distances of H1 to H2, H2 to H4, and H4 to H5
represent the lengths of septal, middle, and lateral isthmus,
respectively. H1 represents the distal electrode poles (1,2)
and H10 represents the proximal electrode poles (19,20).
As described previously, each patient underwent a baseline
electrophysiologic study in the fasting, unsedated
state.18 19 None of the included patients had an
episode of sustained atrial flutter shortly before entering the study.
A programmed digital stimulator (DTU-210 or 215, Bloom Associates Ltd)
was used to deliver electrical impulses of 2.0 ms in duration at twice
diastolic threshold. The study protocol included (1)
incremental pacing from the low right atrium and ostium of the
coronary sinus at pacing cycle lengths of 500, 400, 300, and
250 ms to measure the activation time in the low right atrial isthmus
and lateral wall; (2) burst atrial pacing from the above sites at
progressively shorter cycle lengths until 2:1 atrial capture to induce
atrial flutter; (3) single extrastimulus testing with 400-ms drive
cycle length that was performed at the above pacing sites, septal wall,
and right atrial isthmus to determine the atrial effective refractory
periods. 
, the H1 electrode pair is located at the ostium of the
coronary sinus, H2 to H5 electrode pairs are located within the
low right atrial isthmus, and H6 to H10 electrode pairs are located
within the lateral free wall. Conduction velocity in the low right
atrial isthmus was measured from the septal portion to the lateral
portion (H1 to H5) and from the lateral portion to the septal portion
(H5 to H1) during pacing from the coronary sinus ostium and low
lateral right atrium (near the H6 electrode pair), respectively.
Conduction velocity in the lateral wall (H6 to H10) was only measured
during pacing from the low right atrium (near the H6 electrode pair)
because activation of the lateral free wall during pacing from the
coronary sinus ostium represents bidirectional
conduction through the interatrial septum and low right atrial isthmus
with collision of wave fronts in the mid-lateral free wall.
The study population was divided into three groups. There were
12 patients in each group. After baseline study, sustained typical
atrial flutter was induced. Group 1 patients received
intravenous infusion of ibutilide, 0.02 mg/kg over 10
minutes; group 2 patients received intravenous infusion of
propafenone, 2 mg/kg over 10 minutes followed by 0.4 mg/min; and group
3 patients received intravenous infusion of
amiodarone, 10 mg/kg over 10 minutes followed by 30 mg/h.
Efficacy of antiarrhythmia drugs for conversion of atrial
flutter was determined after the beginning of administration, and
patterns of termination were evaluated. If atrial flutter was not
converted at 15 minutes after completion of the drug-loading infusion,
incremental atrial pacing was performed carefully to terminate it
without inducing atrial fibrillation. The electrophysiologic study
protocol and measurement were repeated immediately after spontaneous or
pacing-induced termination of atrial flutter to observe the
pharmacologic effects on the atrial conduction velocity and effective
refractory period.
The low right atrial isthmus was defined as a path formed by the
orifice of the inferior vena cava, eustachian valve/ridge,
coronary sinus ostium, and tricuspid
annulus.18 Counterclockwise (typical) atrial
flutter was defined as an atrial flutter with craniocaudal activation
of the anterior and lateral walls of the right atrium and caudocranial
activation of the atrial septum, inverted P waves in the
inferior leads, and a positive P wave in lead
V1. Clockwise atrial flutter was defined as an
atrial flutter with a similar flutter cycle length and reverse
activation sequence of the counterclockwise flutter. Atypical atrial
flutter was defined as an atrial flutter other than the
counterclockwise and clockwise atrial flutters.
Quantitative values are expressed as mean±SD. The
Wilcoxon signed rank test was used for statistical comparison
of the conduction velocity and effective refractory periods before and
after infusion of antiarrhythmia drugs. Statistical comparison
of effective refractory period in the low right atrium, right atrial
isthmus, right atrial septal wall, and coronary sinus ostium,
and comparison of continuous data among three groups were performed
with the use of Kruskal-Wallis one-way ANOVA test. A value of
P<.05 was considered to be statistically significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Group 1 Patients
Conduction Velocity
Conduction velocity from the septal isthmus to the lateral isthmus
during pacing from the coronary sinus ostium and from the
lateral isthmus to the septal isthmus during pacing from the low
lateral right atrium at 500-, 400-, 300-, and 250-ms drive cycle
lengths was significantly lower than that in the lateral wall during
pacing from the low lateral right atrium before and after infusion of
ibutilide (Table). Ibutilide only decreased conduction
velocity in the isthmus at 250-ms pacing cycle length but did not
significantly change conduction velocity in the lateral wall at any
pacing cycle length (Fig 2A and 2B).
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Table 1. Conduction Velocity at Different Pacing Cycle Lengths in the
Three Groups
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Figure 2. Conduction velocity in the right atrial free wall
(FW) and low right atrial isthmus (IS) during different pacing cycle
lengths in the baseline state and after infusion of ibutilide. A,
Results from coronary sinus ostial pacing. B, Results from low
right atrial pacing. *P<.05, baseline vs ibutilide;
P<.05, 500 ms vs other pacing cycle
lengths.
At baseline study the effective refractory period at the low right
atrial isthmus and coronary sinus ostium (215±18 and 213±23
ms) was significantly longer than that at the septal and low right
atrium (193±23 and 198±21 ms) (P<.05). Ibutilide
significantly prolonged the effective refractory periods to a similar
extent in the septal right atrium (251±37 ms, +31±19%), low right
atrium (256±24 ms, +30±16%), right atrial isthmus (273±28 ms,
+28±20%), and coronary sinus ostium (260±13 ms, +24±12%)
(Figs 3 and 4).
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Figure 3. Effects of ibutilide on the effective refractory
period at the low right atrial isthmus (drive cycle length, 400 ms).
Before drug infusion, the isthmus effective refractory period was 210
ms (A). After drug infusion, the isthmus effective refractory period
was prolonged to 270 ms (B). IST indicates isthmus; HIS PX, proximal
His bundle area; and CS OS, coronary sinus ostium.
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Figure 4. Effective refractory periods (ERP) of the low
right atrial isthmus (IST), right atrial septum (SEP), right
posterolateral atrium (RPL), and coronary sinus ostium (CSO) in
the baseline state (open columns) in group 1 patients. Infusion of
ibutilide significantly increased the atrial ERP (dashed columns).
*P<.05.
Typical (counterclockwise) atrial flutter was induced in all
patients, and clockwise atrial flutter was induced in 4 of 12 patients.
The baseline cycle length of counterclockwise atrial flutter was
226±22 ms. After ibutilide infusion during counterclockwise atrial
flutter, the flutter cycle length was prolonged to 264±22 ms, with
termination of atrial flutter in 8 (67%) of 12 patients. Most of the
increase in cycle length was due to an increase (86±19%) of
activation time in the low right atrial isthmus (Fig 5). Oscillation of flutter
cycle length without change of activation sequence resulting in
interruption of reentry circuit was found in 4 patients (Fig 6). Two patients had abrupt termination
of atrial flutter without cycle length oscillation, and 2
patients had termination after premature activation of the reentrant
circuit (Fig 7).
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Figure 5. Effects of ibutilide on the low right atrial
isthmus (between H1 and H5 electrode pairs) during typical atrial
flutter. Before drug infusion, the flutter cycle length was 210 ms and
isthmus activation time was 80 ms (A). After drug infusion, the flutter
cycle length was prolonged to 250 ms and isthmus activation time was
110 ms (B). Thus the increase (30 ms) of isthmus activation time
contributed to 75% of the increase (40 ms) in flutter cycle length.
HIS PX indicates proximal His bundle area; CS OS, coronary
sinus ostium; and HAL, halo.
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Figure 6. A case of typical atrial flutter terminated by
intravenous infusion of ibutilide. Oscillation
of the flutter cycle length results in conduction block of the
circulating wave front between H2 and H3 electrode pairs in the
isthmus. HIS PX indicates proximal His bundle area; CS OS,
coronary sinus ostium; and HAL, halo.
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Figure 7. Another case of typical atrial flutter terminated
by intravenous infusion of ibutilide. Premature eccentric
activation of the reentrant circuit at H6 electrode pair (*) during the
last two beats of atrial flutter results in failure of wave front
propagation between H5 and H4 electrode pairs in the isthmus. HIS PX
indicates proximal His bundle area; CS OS, coronary sinus
ostium; and HAL, halo.
Conduction Velocity
Conduction velocity from the septal isthmus to the lateral isthmus
during pacing from the coronary sinus ostium and from the
lateral isthmus to the septal isthmus during pacing from the low
lateral right atrium at 500-, 400-, 300-, and 250-ms drive cycle
lengths was significantly lower than that in the lateral wall during
pacing from the low lateral right atrium before and after infusion of
propafenone (Table). Propafenone significantly decreased conduction
velocity in the isthmus and lateral wall with use-dependent effects
(Fig 8A and 8B).
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Figure 8. Conduction velocity in the right atrial free wall
(FW) and low right atrial isthmus (IS) during different pacing cycle
lengths in the baseline state and after infusion of propafenone. A,
Results from coronary sinus ostial pacing. B, Results from low
right atrial pacing. *P<.05, baseline vs propafenone;
P<.05, 500 ms vs other pacing cycle lengths.
At baseline study, the effective refractory period at the
low right atrial isthmus and coronary sinus ostium (204±17 and
205±22 ms) was significantly longer than that at the septal and low
right atrium (184±17 and 193±17 ms) (P<.05). Propafenone
significantly prolonged the effective refractory periods to a similar
extent in the septal right atrium (229±26 ms, +25±13%), low right
atrium (230±27 ms, +19±11%), right atrial isthmus (262±40 ms,
+29±18%), and coronary sinus ostium (235±26 ms, +15±12%)
(Fig 9).
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Figure 9. Effective refractory periods (ERP) of the low
right atrial isthmus (IST), right atrial septum (SEP), right
posterolateral atrium (RPL), and coronary sinus ostium (CSO) in
the baseline state (open columns) in group 2 patients. Infusion of
propafenone significantly increased the atrial ERP (dashed columns).
*P<.05.
Typical (counterclockwise) atrial flutter was induced in all
patients, and clockwise atrial flutter was induced in 5 of 12 patients.
The baseline cycle length of counterclockwise atrial flutter was
204±18 ms. After propafenone infusion during counterclockwise atrial
flutter, the flutter cycle length was prolonged to 342±46 ms, with
termination of atrial flutter in 4 (33%) of 12 patients. Most of the
increase in cycle length was due to an increase (64±13%) of
activation time in the low right atrial isthmus (Fig 10). These 4 patients had cycle length
oscillation with conduction block in the isthmus resulting
in termination of atrial flutter.
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Figure 10. Effects of propafenone on the low right atrial
isthmus (between H1 and H5 electrode pairs) during typical atrial
flutter. Before drug infusion, the flutter cycle length was 200 ms and
isthmus activation time was 70 ms (A). After drug infusion, the flutter
cycle length was prolonged to 300 ms and isthmus activation time was
130 ms (B). Thus the increase (60 ms) of isthmus activation time
contributed to 60% of the increase (100 ms) in flutter cycle length.
HIS PX indicates proximal His bundle area; CS OS, coronary
sinus ostium; and HAL, halo.
Conduction Velocity
Conduction velocity from the septal isthmus to the lateral isthmus
during pacing from the coronary sinus ostium and from the
lateral isthmus to the septal isthmus during pacing from the low
lateral right atrium at 500-, 400-, 300-, and 250-ms drive cycle
lengths was significantly lower than that in the lateral wall during
pacing from the low lateral right atrium before and after infusion of
amiodarone (Table). Amiodarone significantly decreased
conduction velocity in the isthmus at 250-ms pacing cycle length but
did not significantly change conduction velocity in the lateral wall at
any pacing cycle length (Fig 11, A and
B).
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Figure 11. Conduction velocity in the right atrial free wall
(FW) and low right atrial isthmus (IS) during different pacing cycle
lengths in the baseline state and after infusion of amiodarone.
A, Results from coronary sinus ostial pacing. B, Results from
low right atrial pacing. *P<.05, baseline vs
amiodarone; P<.05, 500 ms vs other pacing
cycle lengths.
At baseline study, the effective refractory period at the low
right atrial isthmus and coronary sinus ostium (210±17 and
213±16 ms) was significantly longer than that at the septal and low
right atrium (185±17 and 194±22 ms) (P<.05).
Amiodarone significantly prolonged the effective refractory
periods to a similar extent in the septal right atrium (218±21 ms,
+18±11%), low right atrium (223±19 ms, +16±10%), right atrial
isthmus (237±19 ms, +13±9%), and coronary sinus ostium
(234±18 ms, +10±7%) (Fig 12).
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Figure 12. Effective refractory periods (ERP) of the low
right atrial isthmus (IST), right atrial septum (SEP), right
posterolateral atrium (RPL), and coronary sinus ostium (CSO) in
the baseline state (open columns) in group 3 patients. Infusion of
amiodarone significantly increased the atrial ERP (dashed
columns). *P<.05.
Typical (counterclockwise) atrial flutter was induced in all
patients, and clockwise atrial flutter was induced in 4 of 12 patients.
The baseline cycle length of counterclockwise atrial flutter was
217±14 ms. After amiodarone infusion during counterclockwise
atrial flutter, the flutter cycle length was slightly prolonged to
233±17 ms, with termination of atrial flutter in 4 (33%) of 12
patients. All of the increase in cycle length was due to an increase of
activation time in the low right atrial isthmus. One patient had abrupt
termination of atrial flutter caused by conduction block in the isthmus
without cycle length oscillation (Fig 13) and 3 patients had termination
after premature activation of the reentrant circuit.
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Figure 13. A case of typical atrial flutter terminated by
intravenous infusion of amiodarone. Abrupt failure
of wave front propagation between H2 and H3 electrode pairs in the
isthmus without flutter cycle length oscillation during the
last six beats of atrial flutter is demonstrated. HIS PX indicates
proximal His bundle area; CS OS, coronary sinus ostium; and
HAL, halo.
Propafenone decreased conduction velocity in the isthmus and
lateral wall to a greater extent than did ibutilide and
amiodarone at all pacing cycle lengths (Fig 14). Ibutilide and propafenone
increased atrial effective refractory period to a greater extent than
did amiodarone (Fig 15).
Ibutilide was more effective in termination of typical atrial flutter
than propafenone and amiodarone (67% versus 33% versus 33%,
P<.05).
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Figure 14. Comparison of the extent of decreased conduction
velocity (CV) in the isthmus (A) and free wall (B) at different pacing
cycle lengths (PCL) among three groups. *P<.05, group 1
vs group 2 vs group 3.
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Figure 15. Comparison of the extent of increased effective
refractory period (ERP) at different atrial locations and all-site ERP
among the three groups. *P<.05, group 1 vs group 2 vs
group 3. Also see Fig 12 definitions.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Major Findings
In addition to a lower conduction velocity, the low atrial isthmus
had a longer effective refractory period than did the septal and free
walls in the right atrium. Ibutilide significantly increased atrial
effective refractory period and prolonged the flutter cycle length.
Propafenone markedly prolonged the flutter cycle length due to a
predominant increase of activation time in the low right atrial
isthmus. Amiodarone had the least effects on the atrial flutter
circuit although it mildly increased atrial effective refractory
period. Ibutilide was more effective than was propafenone and
amiodarone in converting typical atrial flutter, which occurred
with cycle length oscillation, abruptly without variability
of flutter cycle length, or after premature activation of the reentrant
circuit.
Ibutilide fumarate is a novel class III antiarrhythmia
drug that prolongs the action potential duration and effective
refractory periods in both the atria and
ventricles.20 21 22 Its cellular electrophysiologic
mechanisms involve increasing a slow inward plateau sodium current and
inhibiting the outward repolarizing potassium
current.23 24 In contrast to class I
antiarrhythmia drugs, it does not appear to significantly
decrease conduction velocity.20 In conscious dogs
with Y-shaped right atrial incisions, Buchanan et
al25 reported that oral ibutilide could increase
atrial effective refractory period and prevent reinduction of
experimental atrial flutter. In a subsequent study, they demonstrated
that intravenous ibutilide increased the flutter cycle
length before termination of atrial flutter in 8 of 8 dogs, and it was
more effective in converting and in preventing reinitiation of atrial
flutter than sematilide, lidocaine, and
encainide.21 Recently, they compared ibutilide
and d,l-sotalol in an intravenous
crossover study by using the canine atrial sterile pericarditis model;
the results showed that ibutilide converted atrial flutter in dogs in
which sotalol was not successful, and it had a lower incidence of
reinduced arrhythmia compared with sotalol after termination of
atrial flutter.26 In the present study,
intravenous ibutilide significantly increased atrial
effective refractory period in patients with clinical atrial flutter by
24% to 31%. In contrast, ibutilide only decreased conduction velocity
in the isthmus (with a longer effective refractory period) at 250-ms
pacing cycle length without slowing conduction in the free wall at any
pacing cycle length. Although we did not record atrial monophasic
action potentials, the significant slowing of conduction velocity in
the isthmus may be due to impingement of paced beats on the relative
refractory period of the preceding beat, thus reducing upstroke
velocity of the action potential and indirectly reducing conduction
velocity.27 Thus prolongation of atrial flutter
cycle length after ibutilide infusion was due to a predominant increase
of activation time in the right atrial isthmus.
Recent entrainment mapping studies of human typical atrial flutter
have demonstrated that this arrhythmia is an anatomically based
reentrant circuit in the right atrium.1 2 3 4 5 6
Furthermore, our previous and current studies have demonstrated slow
conduction properties in the low right atrial isthmus during atrial
pacing and typical atrial flutter.18 In contrast,
Kinder et al34 reported that decremental
conduction is not characteristic of activation through the isthmus when
activation is assessed parallel and adjacent to the tricuspid annulus.
The different findings may be explained by the fact that Kinder et al
did not map multiple points between the coronary sinus ostium
and inferolateral tricuspid annulus sites, but it was demonstrated in
our previous study18 that more medial sites of
the isthmus near the coronary sinus ostium have more conduction
delay. An important feature of an anatomically defined, ordered
reentrant circuit is that there exists a gap of either partially or
completely excitable tissue between the crest of the circulating
reentrant impulse and the relative refractory
"tail."7 8 14 Therefore
antiarrhythmia drugs theoretically can interrupt typical atrial
flutter by abolishing the excitable gap through prolongation of the
atrial refractory period or slowing of isthmus conduction to a critical
point beyond which propagation of the circulating impulse becomes
impossible.9 10 11 12 13 This study showed that
termination of typical atrial flutter by ibutilide, propafenone, and
amiodarone was due to failure of wave front propagation through
the low right atrial isthmus, which occurred with cycle length
oscillation, abruptly without variability of cycle length,
or after premature activation of the reentrant circuit.
Several aspects of the methodology used in this study may limit
our conclusions about the termination mechanism of atrial flutter by
antiarrhythmia drugs. First, it is a major problem to measure
conduction time in human study. However, we used the halo catheter to
map multiple sites around the tricuspid annulus so that the measured
activation time should be close to the real conduction time from which
conduction velocity is derived. Second, determination of the excitable
gap and refractory period during atrial flutter was not performed
because programmed stimulation might itself terminate atrial flutter,
and the stimulation site relative to the reentrant circuit might affect
the measurement of the excitable gap and refractory period. Third,
there might be insufficient mapping resolution, and measurement of the
local electrophysiologic properties was not performed at the time of
tachycardia termination, at which time the effects of the
antiarrhythmia drugs were likely different. Thus the exact
mechanism of termination remains to be investigated. Fourth, the
postdrug electrophysiologic study was not performed at the same time in
all patients, so that differences in serum drug level might have
contributed to variation in measurement of refractory period and
conduction velocity. Finally, we were not certain that the halo and
coronary sinus catheters were directly in the path of the
atrial flutter circuit; thus assumptions regarding conduction time and
velocity are less certain.
Ibutilide, with its unique cellular electrophysiologic effects,
increases atrial refractory period so much that it can decrease
conduction velocity in the isthmus at short pacing cycle length by
encroachment of the relative refractory period. Propafenone, a sodium
channel–blocking agent, predominantly depressed conduction velocity in
the isthmus and free wall with use dependency and significantly
increased atrial refractoriness. Amiodarone had fewer effects
on atrial refractory period and conduction velocity than did ibutilide
and propafenone. Ibutilide was more effective in conversion of typical
atrial flutter than was propafenone and amiodarone. Termination
of typical atrial flutter was due to failure of wave front propagation
through the low right atrial isthmus, which occurred with cycle length
oscillation, abruptly without variability of cycle length,
or after premature activation of the reentrant circuit by an eccentric
wave front.
Acknowledgments
This study was supported in part by grants from the National
Science Council (NSC 85–2331-B-075–071, 85–2331-B-010–047,
85–2331-B-010–048, 86–2314-B-010–048, 86–2314-B-075–034,
86–2314-B-075–098) and Tzou's Foundation (VGHYM-S4–30,
VGHYM-S4–31), Taipei, Taiwan, ROC.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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