LABORATORY INVESTIGATION
ELECTROPHYSIOLOGY
Conduction over an isthmus of atrial myocardium
in vivo: a possible model of Wolff-Parkinson-White
syndrome
HIROSHI INOUE, M.D.,
AND
DOUGLAS P. ZIPES, M.D.
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ABSTRACT Antiarrhythmic drugs appear preferentially to prolong refractoriness of accessory pathways compared with atrial or ventricular muscle in patients with the Wolff-Parkinson-White syndrome.
This response may be due to intrinsic properties of accessory pathways or to depressed conduction
associated with a narrow strip, or isthmus, of tissue. To test the latter possibility, in 16 anesthetized
dogs we surgically isolated a portion of the right atrial myocardium in the form of an ellipse (10 to
25 x 8 to 15 mm). The ellipse was connected to the body of the right atrium by a narrow isthmus
(cross-sectional area [CSA] 1 to 13.5 mm2) and was perfused by the sinus node artery or its branch.
Diastolic threshold (mean + SE 0.16 0.05 vs 0.13 0.02 mA) and effective refractory period
(ERP; 144 4 vs 139 + 5 msec) were the same proximal and distal to the isthmus. In eight dogs,
determination of the ERP of the isthmus was limited by the ERP of the atrial tissue proximal and distal
to the isthmus, and the CSA of the isthmus in these dogs was significantly larger than that in the
remaining seven dogs in which the ERP of the isthmus could be determined (7.4 + 1.4 vs 3.2 0.6
mm2, p < .05). The shortest pacing cycle length (PCL) with 1: 1 conduction from the proximal to the
distal segments did not differ from that in the opposite direction in 16 dogs (154 9 vs 153 + 7 msec).
The CSA of the isthmus correlated inversely with the shortest PCL with 1: 1 conduction in both
directions via the isthmus (r = -.84, p < .01). Vagal stimulation shortened the shortest PCL with
14 vs 143 + 12 msec, p < .02), but
1: 1 conduction from the distal to the proximal segment (153
not in the opposite direction. Procainamide (10 to 20 mg/kg iv, serum concentration 8.6 + 0.8 ,ug/ml)
prolonged the ERP of the proximal site from 145 ± 5 to 170 ± 5 msec (p < .001), the ERP of the
distal site from 143 + 6 to 168 + 6 msec (p < .001) in 12 dogs, and the shortest PCL with 1: l
conduction (proximal to distal from 149 + 8 to 204 + 17 msec, p < .001; distal to proximal from
149 + 7 to 197 + 12 msec, p < .001) in 14 dogs. After procainamide, the increase in the ERP of
the isthmus in both directions was greater than the increase in the ERP of the proximal and distal atrial
7 vs 18 6 msec, p < .001). Infusion of isoproterenol (0.1 gg/kg/min)
segments in five dogs (37
improved conduction over the isthmus, which had been depressed by procainamide in six dogs. We
conclude that an isthmus of atrial tissue depresses conduction. The narrower the isthmus, the greater
the depression of conduction. Procainamide lengthens the ERP of the isthmus more than it lengthens
the ERP of atrial muscle. These findings may help explain the effects of antiarrhythmic drugs on
accessory pathways that act as an isthmus in patients with the Wolff-Parkinson-White syndrome.
Circulation 76, No. 3, 637-647, 1987.
±
±
±
±
ALTHOUGH ACCESSORY PATHWAYS are
thought to be composed of working myocardium,'
refractoriness and conduction in them frequently are
different from those in atrial or ventricular
myocardium.2 5 Block in these muscle bundles often
From the Krannert Institute of Cardiology, Indiana University School
of Medicine, Indianapolis.
Supported in part by the Herman C. Krannert Fund, by grants HL06308 and HL-07 182 from the National Heart, Lung, and Blood Institute
of the National Institutes of Health, Bethesda, and the American Heart
Association, Indiana Affiliate.
Address for correspondence: Douglas P. Zipes, M.D., Krannert Institute of Cardiology, 1001 West 10th St., Indianapolis, IN 46202.
Received March 11, 1987; revision accepted June 11, 1987.
Vol. 76, No. 3, September 1987
occurs during rapid or premature stimulation at a time
when contiguous atrial or ventricular muscle is still
conducting normally. Unidirectional block may be
present.2-5 Antiarrhythmic drugs may preferentially
prolong refractoriness or produce block in the accessory pathway while exerting lesser effects on neighboring normal atrial or ventricular muscle.6 Accessory
pathways with very short refractory periods appear
more resistant to the influence of antiarrhythmic
drugs.
These different responses of accessory pathways
may be due to their intrinsic properties or to the characteristics of conduction over a narrow bridge of tissue.
637
INOUE and ZIPES
For example, Garrey8 demonstrated that fibrillation did
not propagate over an isthmus of ventricular and atrial
muscle while de la Fuente et al.9 showed that conduction block in vitro developed preferentially at the junction of a narrow band of atrial tissue with a larger area.
The effects of antiarrhythmic drugs were not tested in
these studies.8' 9 The concept of impedance mismatch'0 has been offered to explain these observations.
To simulate conduction over an accessory pathway
in vivo, we created an isthmus of atrial tissue. We tested
the hypothesis that an antiarrhythmic drug preferentially depressed conduction over the isthmus.
Methods
Surgical procedures. Thirty-six mongrel dogs of both sex,
weighing 15 to 26 kg, were anesthetized with intravenous achloralose (100 mg/kg) or secobarbital sodium (30 mg/kg).
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Additional amounts of chloralose or secobarbital were injected
needed to maintain anesthesia. No measurements were
obtained for at least 15 min after additional administration of
anesthetics. Dogs were intubated and ventilated with room air
via a volume-cycled respirator (Harvard model 607). The chest
of each was opened through the right fifth intercostal space, and
the heart was suspended in a pericardial cradle. A fluid-filled
cannula placed in the femoral artery was connected to a transducer (Statham p-23Db) to monitor arterial blood pressure, and
a femoral venous cannula was used to infuse normal saline at 100
to 200 ml/hr to replace spontaneous fluid losses. Dogs were
placed on a heating pad, and the thoracotomy was covered by
a plastic sheet. An operating table lamp was used to maintain
epicardial temperature between 37° and 390 C. Arterial blood
gases and pH were monitored and maintained within the physiologic range.
An umbilical tape was placed around the inferior vena cava
for caval obstruction during creation of the arterial isthmus. A
portion of the right atrial wall was surgically isolated in an
elliptical shape (10 to 25 x 8 to 15 mm) except for a narrow
isthmus. The incision was made in a series of connecting cuts,
each less than 1 cm. Each cut was closed with an atraumatic
needle and 5-0 silk and caval obstruction was released for 2 min
before the next cut was created. The sinus node artery or its
branch penetrated the isthmus to prevent, or at least to minimize,
the effect of ischemia (figure 1, top).
Unipolar and bipolar plunge hook electrodes made from
Teflon-coated wires, insulated except for their tips, were placed
proximal and distal to the isolated atrial wall with use of a
25-gauge needle to stimulate the atrial tissue and to record
responses (figure 1, top). The electrodes served as a cathode for
unipolar stimulation. The anode was a 18-gauge needle placed
in the abdominal wall. Surface electrocardiographic lead II, two
atrial electrograms with frequency responses of 30 to 500 Hz,
and arterial blood pressure were recorded on an Electronics for
Medicine recorder at a paper speed of 100 mm/sec. Data were
collected beginning 30 min after the placement of plunge electrodes. The cervical vagosympathetic trunks were isolated, doubly ligated, and cut after determination of baseline values. Two
Teflon-coated wire electrodes were embedded in the distal end
of each vagal nerve for stimulation. Sympathetic nerves were left
intact.
Electrophysiologic study. Effective refractory period was
determined proximal and distal to the isthmus in a random order
by the extrastimulus technique employing a programmable stimulator (Krannert Medical Engineering) and an isolated constant
as
638
current source. Each test site was driven with a 2 msec rect-
angular unipolar stimulus at twice diastolic threshold. Late diastolic thresholds of test sites were measured at a cycle length of
300 msec during each intervention. A train of nine stimuli (S,)
at a constant cycle length of 300 msec was followed by a late
premature stimulus (S2) that produced a propagated atrial
response. The atrial response to S2 was recorded in lead lI and
from the bipolar plunge electrodes proximal and distal to the
isthmus, and displayed on a storage oscilloscope. The SIS2
interval was shortened in steps of 2 msec until S2 failed to
produce a propagated response. Twenty seconds later, the S l S2
interval was increased by 5 msec and the S S2 interval was
shortened by 1 msec decrements until S2 failed to produce a
propagated response. Repeated S,S2 interval determinations
yielded values within 2 msec of each other or the data were
discarded. The effective refractory period of the atrium in the
proximal and distal segments was defined as the longest SIS2
interval at which S2 failed to produce a local atrial response.
Effective refractory period of the isthmus was defined as the
longest S,S2 interval at which conduction over the isthmus in
response to S2 was blocked.
Incremental atrial pacing was carried out to determine the
shortest pacing cycle length at which 1: 1 conduction over the
isthmus occurred. For this particular measurement, current
strength of the pacing stimulus was increased three to four times
diastolic threshold if lack of local response to pacing occurred
before conduction block developed over the isthmus. The pacing
cycle length was shortened in steps of 10 msec every 5 sec. Burst
pacing was also delivered to induce atrial tachyarrhythmias. In
the present study, atrial flutter was defined as a sustained regular
atrial rhythm with a cycle length of 90 to 180 msec, and burst
atrial pacing was required to terminate it.
Vagal stimulation. After measurement of baseline values,
bilateral cervical vagosympathetic trunks were transected in
seven dogs and stimulating electrodes were placed as outlined
above. Ten minutes after vagotomy, electrophysiologic variables were redetermined. Stimulation of the right and left vagal
nerves was performed with separate isolated constant current
sources driven by a digital stimulator (Krannert Medical Engineering). The current strength was set at 0.05 mA greater than
that required to produce asystole with right vagal stimulation and
asystole or complete atrioventricular block with left vagal stimulation of 4 msec rectangular pulses at 20 Hz. Pulse width was
then set at 1 msec and frequency at 5 Hz.
Procainamide injection. Ten to 20 mg/kg of procainamide
was injected intravenously over 4 min. Ten minutes later electrophysiologic variables were redetermined, and arterial blood
was drawn for determination of procainamide level. Effects of
procainamide were observed while both sympathetic and vagal
nerves were intact in nine dogs, and after vagotomy in the
remaining seven dogs. Serum procainamide level was determined by a homogeneous enzyme immunoassay technique.
Isoproterenol infusion. After determination of the effects of
procainamide, isoproterenol was infused intravenously at a dose
of 0.10 ,ttg/kg/min. Measurement of electrophysiologic variables was started after the heart rate became stable about 3 min
after initiation of isoproterenol infusion.
After the experiment, the heart was removed. The suture line
was cut and the dimensions of the isthmus and the remaining
body of isolated atrial myocardium were measured (figure 1,
bottom). If the surgical isolation of the isthmus was found to be
incomplete, i.e., subendocardial muscle bands connecting the
isthmus to the body of the atrium were found intact, the data were
discarded. Cross-sectional area (mm2) of the isthmus was calculated by width (mm) x thickness (mm). The length of the
isthmus was constant at 3 to 4 mm, thereby making results of
the statistical analysis using the volume of the isthmus similar
CIRCULATION
LABORATORY INVESTIGATION-ELECTROPHYSIOLOGY
svc
svc
Proximal segment
S-, EG
EG
1'
Distal segment
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W
FIGURE 1. Top, Schematic diagram of the preparation. Isthmus of atrial tissue was penetrated by the sinus node artery (left)
by a branch of the sinus node artery (right). For the former, the sinus node artery was cut at the opposite end to the isthmus,
but branches to the isthmus were left intact. Bipolar electrodes to record local electrograms (EG) and unipolar electrodes for
stimulation ((3) were placed in the proximal and distal segments. IVC = inferior vena cava; RA = right atrium; RV = right
ventricle; SVC = superior vena cava. Bottom, Diagram of determination of the size of the atrial ellipse and isthmus. The length
and width were determined at the longest and the shortest diameter of an elliptical isolation (unlabeled lines with arrows). Length
(L), width (W), and thickness (T) of the isthmus were determined.
or
to those with the method using the cross-sectional area. Therefore, the cross-sectional area of the isthmus was used in the
following analysis.
Analysis of data. Since changes in electrophysiologic variables of 10 dogs receiving a-chloralose did not differ from those
of six dogs receiving secobarbital, data from these animals were
pooled as a single group and analyzed. In one dog, both effective
refractory period and shortest pacing cycle length with 1: 1
conduction over the isthmus were determined in 10 msec decrements; therefore, data from this dog were included only for
analyses of shortest pacing cycle length with 1: 1 conduction.
The data are expressed as mean + SE. Paired and unpaired t tests
were used to compare the mean values. Spearman rank correlation analysis was used to analyze the correlation between two
variables. Statistical significance level was set at p < .05.
Results
In 15 of 36 dogs, isolation of the atrial wall was
incomplete because small endocardial segments other
than the isthmus remained intact after surgery. In
Vol. 76, No. 3, September 1987
another five dogs, the diastolic pacing threshold of the
atrium proximal to the isthmus exceeded 2.0 mA, probably because of ischemia, while the excitability threshold distal to the isthmus was less than 0.3 mA. Data
from these 20 dogs were discarded and the remaining
16 dogs constituted the study group. Of these 16 dogs,
seven had an isthmus penetrated by the sinus node
artery and nine had an isthmus penetrated by a branch
of the sinus node artery. Diastolic threshold did not
differ at the proximal and the distal sites (0.16 0.05
vs 0.13
0.02 mA) in these 16 dogs.
Reproducibility of measurements was tested in two
dogs. Effective refractory period of atrial segments
(139 2 vs 139 ± 4 msec) and the shortest pacing
cycle length with 1: 1 conduction over the isthmus in
both directions (160 + 23 vs 150 + 18 msec) were
unchanged over a period of 85 to 90 min. Effective
639
INOUE and ZIPES
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refractory period of the isthmus in a proximal-to-distal
direction was constant in one of the two dogs (191 to
183 msec) over a period of 90 min.
Representative examples. In figures 2 to 9, representative examples from one dog are shown. In this dog
the right atrial wall was isolated with the sinus node
artery penetrating the isthmus, as shown in the left
panel of figure 1. The size of the ellipse was 17 x 9
mm and cross-sectional area of the isthmus was 4 mm2.
Baseline effective refractory period of the isthmus in a
proximal-to-distal direction was 193 msec (figure 2, A
and B) and that in the opposite direction was 209 msec
(figure 2, C and D). Effective refractory period of
atrium proximal to the isthmus was 181 msec (figure
3, A and B) and that in atrium distal to the isthmus was
173 msec (figure 3, C and D). The shortest pacing cycle
length with 1: 1 conduction from the proximal site to
the distal site was 210 msec, and that in the opposite
direction was 200 msec (figure 4). Burst atrial pacing
in the distal atrial segment induced atrial flutter in the
body of the atrium with a cycle length of 155 msec.
During atrial flutter, conduction from the distal site to
the proximal site was 2: 1, as expected from the result
of incremental atrial pacing (figure 5).
Procainamide at a dose of 20 mg/kg yielded a serum
procainamide level of 9 gg/ml in this dog. Effective
A
refractory period of the isthmus lengthened to 255 msec
in a proximal-to-distal direction and 265 msec in the
opposite direction. Effective refractory period of the
proximal atrial segment also lengthened to 206 msec
and that of the distal segment lengthened to 201 msec.
The shortest pacing cycle length with 1: 1 conduction
was 270 msec in both directions. At a pacing cycle
length of 260 msec, conduction from the distal to the
proximal segment was blocked completely (figure 6,
B). Spontaneous sinus nodal activity in the atrium distal
to the isthmus interfered with the assessment of whether
conduction was completely blocked during atrial pacing of the proximal segment (figure 6, A).
After administration of procainamide, atrial flutter
could be induced by burst pacing only during vagal
stimulation. During atrial flutter with a cycle length of
175 msec, conduction from the distal to the proximal
segment was also completely blocked (figure 7).
Determination of effective refractory period. Dogs with
an isthmus penetrated by the sinus node artery (n = 7)
had larger cross-sectional areas and longer effective
refractory periods of the proximal atrial segment than
dogs with an isthmus penetrated by a branch of the sinus
node artery (n - 9, table 1). Pacing threshold and other
electrophysiologic variables were not different in the
two groups (table 1). Data regarding cross-sectional
B
ECG
1-:P2h
N
PROXIMAL
300
194f
DISTAL
,,
C
_
_
_
1.
I
_-I
D
ECG
PROXIMAL X-A
S1
DISTAL
-
_
_
S, S2,__
'
300
210
sit!
, L
S1
S2
300 209
200ms
FIGURE 2. Determination of effective refractory period (ERP) of the isthmus by extrastimuli (S2) at a basic pacing cycle length
(S1 S l) of 300 msec. In each panel, surface electrocardiographic lead II (ECG) and electrograms of the proximal and distal segments
are arranged from top to bottom. Conduction over the isthmus from the proximal to the distal segment occurred at an S l S2 interval
of 194 msec (A), but blocked at an S1S2 interval of 193 msec (B). Conduction over the isthmus in a distal-to-proximal direction
occurred at an SIS2 interval of 210 msec (C), but blocked at an SIS2 interval of 209 msec (D).
640
CIRCULATION
LABORATORY INVESTIGATION-ELECTROPHYSIOLOGY
A
B
ECG
SI
SI S2
300 181
t+'~~~~~~~~~~~~~~~~~~~
PROXIMAL -St
300 1
DISTAL
-
D
C
ECG
DDnVIA
E V AI
rri
VdIML
.0
0L
_
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'
_h
%,,I
S2, M.
St , -':
'
Slt
DISTAL
-
30
L
S
si
t
Sli
' 300
174
300 '174
A
_
S2
'173
l
i
-
200ms
FIGURE 3. Determination of effective refractory period (ERP) of the atrial myocardium proximal and distal to the isthmus
in the same dog as in figure 2. ERP of the proximal atrial segment was 181 msec (B), and ERP of the distal segment was 173
msec (D). Abbreviations and format are as in figure 2.
area and electrophysiologic variables from the two
groups were pooled and analyzed.
Effective refractory periods of the atrial myocardium
proximal and distal to the isthmus did not differ in 15
dogs (144 + 4 vs 139 ± 5 msec; figure 8, left top).
Effective refractory periods of the isthmus in a proximal-to-distal direction (160 ± 9 msec in seven dogs)
were not different from those in a distal-to-proximal
direction (173 ± 11 msec in five dogs). In the remaining eight dogs, measurements of effective refractory
period of the isthmus were limited by the refractoriness
of the atrial myocardium proximal or distal to the
A
ECG
PROXIMAL
B
N,
200
_. --
DISTAL
.11
_j
ilk-
a%
kCG~jL~
E
PROXIMAL
DISTAL
The shortest pacing cycle length with 1 1 conduction over
the isthmus. In two dogs, the shortest pacing cycle
ECG
- -----
190-
isthmus. Seven dogs in which the effective refractory
period of the isthmus in both directions or in a proximal
to distal direction could be determined had significantly
smaller cross-sectional area of the isthmus than did the
remaining eight dogs in which determination of effective refractory period of the isthmus was limited by the
effective refractory period of the atrial test site, i.e.,
effective refractory period of the atrium exceeded the
effective refractory period of the isthmus (3.2 ± 1.7
vs 7.4 + 1.4 mm2, p < .05). The effective refractory
periods of the atrial myocardium proximal (141 ± 7
vs 146 + 4 msec) and distal (138 + 8 vs 141 + 6 msec)
to the isthmus were not different in the seven dogs with
effective refractory periods of the isthmus longer than
those of the atrium and the eight dogs with effective
refractory periods of the atrium exceeding those of the
isthmus.
PROXIMAL
I
J;
1
t
,
200ms
FIGURE 4. Determination of the shortest pacing cycle length (PCL)
with 1:1 conduction over the isthmus of the same dog depicted in figure
2. 2: 1 conduction developed at a PCL of 200 msec in a proximal-todistal direction (A) and at a PCL of 190 msec in a distal-to-proximal
direction (B). Abbreviations and format are as in figure 2.
Vol. 76, No. 3, September 1987
DISTAL
v4-4-4
r155`
-I
-
.
l1
i
t1
_~
4
200ms
FIGURE 5. Atrial flutter induced by burst pacing delivered to the distal
segment in the same dog as in figure 2. Conduction over the isthmus
was 2: 1.
641
INOUE and ZIPES
AFTER PROCAINAMIDE
A
ECG
PROXIMAL
DISTAL
*
B
ECG
LA
-
PROXIMAL ,DISTAL
-
24,v
p
--
.,v
-
i- p
*
0t
h
-jr-
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260
,
?
0
4,
rI
.1
- H---
--r
- ,r
-
200 ms
FIGURE 6. Determination of the shortest pacing cycle length (PCL) with 1: 1 conduction over the isthmus after procainamide
in the same dog as in figure 2. A. 2: 1 conduction over the isthmus in a proximal-to-distal direction developed at a PCL of 260
msec. After development of 2: 1 conduction, spontaneous atrial rhythm (P), possibly sinus rhythm, appeared. An asterisk
indicates atrial activity distal to the isthmus elicited by propagation of the spontaneous atrial rhythm. B (not continuous), 2: l
conduction in a distal-to-proximal direction developed at a PCL of 260 msec, and thereafter, conduction was completely blocked.
Sinus rhythm was restored after termination of pacing with resultant 1: 1 conduction over the isthmus. Abbreviations and format
are as in figure 2.
AFTER PROCAINAMIDE
A
ECG
PROXIMAL
DISTAL
175
r
i
,
~v
B
E CG
tt
t
t
t
PROXIMAL
4
DISTAL
1~~~~I
i~~~~~~~A-
1
200ms
FIGURE 7. Atrial flutter induced after procainamide in the same dog as in figure 2. A, During atrial flutter with a cycle length
of 175 msec, conduction over the isthmus in a distal-to-proximal direction was blocked completely. B, Burst atrial pacing was
delivered in the distal atrial segment and terminated the atrial flutter. Sinus rhythm was restored with resultant 1: 1 conduction
over the isthmus. Arrows indicate spikes of burst atrial pacing at a cycle length of 130 msec.
642
CIRCULATION
LABORATORY INVESTIGATION-ELECTROPHYSIOLOGY
TABLE 1
CONTROL
Comparison of cross-sectional areas of the isthmus and electrophysiologic variables in dogs with the isthmus penetrated by the sinus
node artery (group I) and dogs with the isthmus penetrated by a
branch of the sinus node artery (group II)
Group I
(No. of dogs)
Group 11
(No. of dogs)
p
value
Q
z
0
E
a.
W
..E
a
Ir
_3
J
7.3 +1.9 (7)
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Diastolic threshold
(mA)
Proximal segment 0. 1 1 0.02 (7)
Distal segment
0.13 0.03 (7)
Effective refractory
period (msec)
Proximal segment 152+6 (7)
Distal segment
144+± 8 (7)
Effective refractory
period of the
isthmus (msec)
Proximal to distal 172 ± 21 (2)
Distal to proximal
209 (1)
Shortest pacing
cycle length
with 1: 1
conduction
(msec)
Proximal to distal 144± 12 (7)
Distal to proximal 141 ± 11 (7)
(-)
=
±SE
0
Cross-sectional area
(mm2)
M
z
0
3.7±0.7
(9)
0.18 ±+0.08 (9)
0.12± 0.03 (9)
<.05
NS
NS
i-
180-
m
z
0
136±4
135 ±6
(8)
(8)
<.05
NS
to
0
a.
_ E
E
w:
160-
..I
I_
_
140-
-J
J
155 ± 11
165+9
(5)
(4)
a.
NS
(-)
1204,
D
P
P-D
P: PROXIMAL SEGMENT
D: DISTAL SEGMENT
161 + 12 (9)
161 ± 9 (9)
NS
NS
not performed.
length with 1: 1 conduction from the proximal to the
distal segment was greater than that in the opposite
direction by 30 msec or more. In another two dogs, the
shortest pacing cycle length with 1: 1 conduction from
the distal to the proximal segment was longer than that
in the opposite direction by 30 msec. In the remaining
12 dogs, the difference was within ± 10 msec. For the
group as a whole, the shortest pacing cycle length with
1: 1 conduction from the proximal to the distal segment
did not differ from that in the opposite direction (154
+ 9 vs 153 + 7 msec; figure 8, right top). The shortest
pacing cycle length with 1: 1 bidirectional conduction
over the isthmus correlated inversely with the crosssectional area of the isthmus in 16 dogs (r = - .84,
p < .01; figure 9). The correlation between the shortest
pacing cycle length with 1: 1 conduction over the isthmus in both directions and the cross-sectional area of
the isthmus was still significant in seven dogs with the
isthmus penetrated by the sinus node artery (r = - .76,
p < .01) and in the remaining nine dogs with the
isthmus penetrated by a branch of the sinus node artery
(r = -.87, p < .01).
Effects of vagal stimulation. In seven dogs the effects
Vol. 76, No. 3, September 1987
200-
z
0
D-P
D AFROM CONTROL
FIGURE 8. Effective refractory period (ERP) of the atrial myocardium
proximal (P) and distal (D) to the isthmus and the shortest pacing cycle
length (PCL) with 1: 1 conduction over the isthmus in the control state
(top) and after administration of procainamide (bottom). Twelve dogs
in which both ERP and the shortest PCL with 1: 1 conduction were
determined after procainamide are included in the bottom panel. Stippled
parts indicate the increase (A) in ERP and the shortest PCL with 1: 1
conduction induced by procainamide.
on
E
4001
z
0
3201-
0
z
0
280
0
*:CONTROL r= -0.84
0: PROCAINAMIDE rU 0.68
0
-
8
0
240 r8
3
:c
20C
8
0
8
-J
0
C
16C
8
U)
:o
0
*-*
0@
12C
en
I-
0
C,)
C
l
0
o
a
C
0
1'
,
2
h
.
A
4
6
8
,
.
10
12
.
a
14
CROSS SECTIONAL AREA OF ISTHMUS (mm2)
FIGURE 9. The shortest pacing cycle length (PCL) with bidirectional
1: 1 conduction over the isthmus is shown on the ordinate as a function
of the cross-sectional area of the isthmus. Filled circles show the control
value and open circles show the value after procainamide.
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of vagal stimulation were determined. Effective refractory period of atrial myocardium distal to the isthmus
shortened from 148 ± 7 to 139 + 7 msec (p < .05),
but that of atrial myocardium proximal to the isthmus
did not shorten (148 + 8 vs 148 ± 7, p = NS). Vagal
stimulation shortened the shortest pacing cycle length
with 1: 1 conduction over the isthmus in a distal-toproximal direction (153 ± 14 vs 143 ± 12 msec, p <
.02), but not in the opposite direction (153 ± 13 vs 147
± 12 msec, p = NS).
Effects of procainamide. The effects of procainamide
were tested in 15 dogs. In two dogs receiving 10 mg/kg
of procainamide, serum procainamide levels were 4
and 5 pg/ml. In the remaining 13 dogs receiving 20
mg/kg of procainamide, serum procainamide levels
ranged from 7 to 16 ,g/ml (9.3 ± 0.7 ,g/ml). For the
group, serum procainamide level was 8.6 ± 0.8
,ug/ml. After administration of procainamide (serum
procainamide level 6 jug/ml), pacing threshold of the
atrial myocardium proximal to the isthmus increased to
three times the control value in one dog with an isthmus
cross-sectional area of 6 mm2. Atrial tissue proximal
to the isthmus became inexcitable in another dog with
an isthmus cross-sectional area of 1.5 mm2 and with
serum procainamide level of 16 yg/ml. In the remaining 12 dogs, diastolic threshold was not affected by
procainamide at the proximal (0.11 + 0.01 mA before
vs 0. 12 ± 0.02 mA after procainamide) or at the distal
segment (0.11 ± 0.02 before vs 0.12 ± 0.02 mA
after). In these 12 dogs, the effective refractory period
of atrial myocardium proximal to the isthmus lengthened significantly from 145 -+ 5 to 170 ± 5 msec (p
< .001) and that distal to the isthmus lengthened from
143 ± 6 to 168 ± 6 msec (p < .001) after procainamide (figure 8, bottom left). The effective refractory
period did not differ in the proximal and the distal
segments.
After administration of procainamide the effective
refractory period of the isthmus could be determined in
five dogs: bidirectionally in three dogs before and after
procainamide, and bidirectionally and in a distal-toproximal direction in one dog each in which determination of the effective refractory period of the isthmus
was limited by the effective refractory period of the
proximal and distal atrial segments before procainamide administration. The increase in effective refractory period of the isthmus in a proximal-to-distal direction tended to exceed the increase in effective refractory
period of the proximal segment in four dogs (39 ± 14
vs 21 ± 11 msec, p = .07). In a distal-to-proximal
direction the increase in the effective refractory period
of the isthmus was significantly greater than the
644
increase in the effective refractory period of the distal
atrial segment in five dogs (36 ± 9 vs 16 ± 7 msec,
p < .01; figure 10). When the results were pooled, the
increase in effective refractory period of the isthmus in
both directions exceeded the increase in the effective
refractory period of the proximal and distal atrial test
sites in these five dogs (37 ± 7 vs 18 ± 6 msec, p <
.001; figure 10).
After administration of procainamide in 14 dogs, the
shortest pacing cycle length with 1: 1 conduction over
the isthmus lengthened significantly in a proximal-todistal direction from 149 ± 8 to 204 ± 17 msec (p <
.00 1) and in the opposite direction from 149 ± 7 to 197
± 12 msec (p < .001). The shortest pacing cycle length
with 1: 1 conduction after procainamide did not differ
with direction, and still correlated inversely with crosssectional area of the isthmus in 14 dogs (r =- .68, p
< .01; figure 9). After procainamide, Wenckebach
block over the isthmus developed in two dogs during
incremental pacing, one in both directions and other in
a proximal-to-distal direction. Wenckebach block did
not occur during incremental pacing in the control state
in any of the dogs. The increase in the shortest pacing
cycle length with 1: 1 conduction over the isthmus
induced by procainamide did not correlate with its
initial value in the control state.
Effects of isoproterenol. Isoproterenol was infused at
a dose of 0.10 ,ug/kg/min in seven dogs after determination of the effects of procainamide. In six dogs,
isoproterenol shortened the effective refractory period
of atrial myocardium proximal (170 ± 6 vs 140 + 5
PROCAINAMIDE
0
0
*p<O.OOl
cc
**p<0.01
M±SE
0
w
<0
UL-
<0
LLLb.
>
D
P: PROXIMAL SEGMENT
ISTH: ISTHMUS
ISTH
D-P
P+D ISTH
P*D
D: DISTAL SEGMENT
5: AFROM CONTROL
FIGURE 10. Effects of procainamide on the effective refractory period
of the isthmus (ISTH) and that of proximal (P) and distal (D) atrial
segments. Stippled parts indicate the increase in the effective refractory
period induced by procainamide. See text for details.
CIRCULATION
7
LABORATORY INVESTIGATION-ELECTROPHYSIOLOGY
msec, p < .001) and distal to the isthmus (159 ± 9 vs
136 ± 9 msec, p < .001). The shortest atrial pacing
cycle length with 1: 1 conduction also decreased bidirectionally (proximal to distal 190 ± 7 vs 153 + 7,
p < .001; distal to proximal 188 ± 8 vs 160 + 10,
p < .02) in six dogs. Isoproterenol failed to restore
excitability in a remaining dog in which the atrial
myocardium proximal to the isthmus had become inexcitable after administration of procainamide.
Conduction over the isthmus during atrial fibrillation and
atrial flutter. In nine dogs, atrial flutter was induced by
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burst atrial pacing delivered to the atrial myocardium
distal to the isthmus. During atrial flutter, conduction
over the isthmus in a distal-to-proximal direction was
1: 1 in two dogs, 2: 1 in six dogs, and varied from 2: 1
to 6: 1 in a remaining dog before procainamide administration. After procainamide, atrial flutter could be
induced in seven of these nine dogs that had demonstrated 1: 1 conduction (one dog) or 2: 1 conduction
(six dogs) before procainamide. The atrial flutter cycle
length was 10 to 60 msec longer than that before procainamide and conduction over the isthmus in a distalto-proximal direction was 1: 1 in one dog, 2: 1 in five
dogs, and completely blocked in a remaining dog.
Atrial fibrillation was induced in the distal atrial
segment in 11 dogs before administration of procainamide. During atrial fibrillation, electrograms distal to
the isthmus showed irregular, fragmented potentials,
while electrograms proximal to the isthmus showed
discrete potentials that tended to be more regular than
those recorded distal to the isthmus (figure 1 1). After
administration of procainamide, atrial fibrillation was
induced in three of 12 dogs in which burst atrial pacing
was tried. After procainamide, the proximal atrial segment showed slower responses compared with those at
control before administration of procainamide.
Discussion
New findings. The major finding in the present study
is that conduction is depressed over an isthmus of atrial
myocardium, and is more so if the isthmus is narrow.
Procainamide at serum concentrations ranging 4 to 16
gg/ml further depressed conduction over the isthmus
ECG
PROXIMAL
DISTAL
T
t.
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Vol. 76, No. 3, September 1987
IP
v
14
t
in both dirirections. In five dogs with a narrow isthmus,
procainamnide increased the effective refractory period
of the ist]thmus more than it increased the effective
refractoryZ period of the atrium. But in seven dogs with
arelativelly large isthmus the increase in atrial effective
refractory period precluded determination of the effective refracctory period of the isthmus. However, the
amount ocif lengthening of the shortest pacing cycle
length witth 1: 1 bidirectional conduction over the isthmus after procainamide was greater than the increase
in the effeective refractory period of the atrial myocardium proxximal and distal to the isthmus. During atrial
fibrillationrn, the electrogram recorded in the body of the
fibrillatingg atrium distal to the isthmus showed irregular, rapidd, fragmented potentials, while that recorded
proximal tto the isthmus showed discrete potentials that
tended totbe more regular and occurred at a slower rate.
Vagal stinmulation improved conduction over the isthmus in a distal-to-proximal direction, but not in the
opposite cdirection. Isoproterenol offset the effects of
procainarrnide on the conduction over the isthmus.
Electropphysiologic properties of the isthmus. In the
present stiItudy, the effective refractory period of the
isthmus ccould be determined bidirectionally or in a
proximal--to-distal direction in seven of 15 dogs. These
seven doggs had a significantly narrower isthmus than
did the eigght remaining dogs in which determination of
period of the isthmus was limited
effective refractory
X
by the refr.ractoriness of the atrial test sites. The shortest
pacing cy(xcle length with 1: 1 conduction over the isthmus correelated inversely with the cross-sectional area
of the ist.hmus. These observations suggest that conduction o ver the isthmus depends, at least in part, on
its size. IThe width of isthmus in the present study is
compatiblle with the diameter of the human Kent
bundle. ' , 12, 13
SomewThat surprisingly, the effective refractory
period off the isthmus and the shortest pacing cycle
length wilith 1: 1 conduction over the isthmus did not
differ in aa proximal-to-distal direction compared with
distal-to-Fproximal direction. We had expected an
impedancce mismatch, as postulated for some patients
with unidlirectional block over accessory pathways, to
V,
4
m
FIGURE 11. A representative episode of atrial
fibrillation. Electrogram of the distal atrial segment
showed irregular, prolonged, and sometimes fragmented potentials, while that of the proximal segment
showed potentials of shorter duration that were
slower and usually irregular, but that tended to be
regular in the middle part of tracing. Format and
abbreviations are as in figure 2.
200 ms
645
INOUE and ZIPES
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result in preferential distal to proximal conduction. It
is possible that the relatively large size of the atrial
ellipse prevented this from occurring. Fiber orientation
may affect electrophysiologic properties of the isthmus,14 but it was not determined in the present study.
Garrey8 showed in vitro and in vivo that a narrow
muscular bridge connecting two pieces of ventricular
or atrial tissue prevented the extension of fibrillation
from one piece to the other, although the latter showed
irregular contractions. He found that the extension of
the fibrillatory process from one part of the ventricle to
another would be prevented when the bridge of ventricular tissue was less than 1 cm wide.8 Fifteen years
ago we used a similar explanation for the presence of
fibrillation in one atrium or a portion of one atrium and
a slower, more regular response in the other atrium,
similar to atrial flutter (dissimilar atrial rhythm). 15 The
present study provides experimental support for these
observations.
Conduction velocity in a uniform fiber such as a
nerve axon varies approximately as the square root of
the fiber diameter. 1618 Since the uniform fiber in the
present preparation is presumably the atrial muscle
cells, the width of the isthmus, whether numbering 10
or 100 atrial cells, should not affect conduction velocity. While the greater resistivity radially than
longitudinally'9 minimizes the importance of the number of cells laid side to side with respect to conduction
velocity, it may not minimize its importance with
regard to refractoriness or the safety factor for conduction. Impedance mismatch between a source with
reduced current density (isthmus) and a sink with a
large capability to take up the charge without a significant reduction in membrane potential (proximal and
distal atrial muscle) can account for the reduced ability
of the isthmus to conduct compared with proximal and
distal atrial muscle. Similar events may take place at
the Purkinje-muscle junction. The area of the isthmus
would play a role if such geometry were important to
conduction.
Effects of procainamide. Procainamide lengthens the
effective refractory period of atrium, ventricle, and
accessory pathway, thereby lengthening the shortest
pacing cycle length with 1: 1 conduction and the shortest RR interval conducted over the accessory pathway
during atrial fibrillation in most patients with the WolffParkinson-White syndrome.7 20, 21 These antiarrhythmic drugs preferentially prolong the effective refractory period of the accessory pathway so that it exceeds
prolongation of atrial and ventricular refractory
period.6 The present data are compatible with this
clinical observation.
646
It has been proposed that the amount of procainamide-induced lengthening of the effective refractory
period of accessory pathway depends on the control
refractory period of accessory pathway.7 Our data did
not show significant correlation between the initial
value of the shortest pacing cycle length with 1: 1
conduction over the isthmus and the amount of its
lengthening induced by procainamide. However, we
did find that the procainamide-induced increase in the
effective refractory period of the isthmus in five dogs
with a narrow isthmus was greater than the increase in
the effective refractory period of the atrial test sites.
Effects of vagal stimulation and isoproterenol. Vagal
stimulation shortened the refractoriness of atrial myocardium distal to the isthmus and the shortest pacing
cycle length with 1: 1 conduction over the isthmus from
the distal to the proximal segment. This is consistent
with the observation of de la Fuente et al.9 that acetylcholine improved conduction over a narrow band of
atrial muscle in vitro. Vagal stimulation failed to
shorten the refractoriness of the proximal atrial segment
and the shortest pacing cycle length with 1: 1 conduction in a proximal-to-distal direction, probably because
the surgical isolation procedure interrupted efferent
vagal fibers innervating the ellipse and isthmus. While
atropine does not have significant effect on accessory
pathways,22 the effects of vagal stimulation are not
known.
Isoproterenol shortens refractoriness of the accessory pathway and shortest RR interval during atrial
fibrillation in patients with Wolff-Parkinson-White
syndrome.23 In six of seven dogs of the present study
isoproterenol shortened the shortest pacing cycle length
with 1: 1 conduction over the isthmus that had been
lengthened by procainamide. In a remaining dog with
the smallest cross-sectional area of the isthmus in the
present study, however, isoproterenol failed to restore
the excitability of the atrial tissue proximal to the isthmus, which had been suppressed at a higher procainamide level of 16 gg/ml.
Limitations of the present study. Several limitations
exist. First, the reproducibility of electrophysiologic
measurements was tested in only two dogs over a period
of 85 to 90 min, while it took 111 ± 10 min to collect
the data both in the control state and after procainamide
injection in 12 dogs. Therefore, it is possible, but not
likely, that changes in electrophysiologic measurements after procainamide injection were due to the
effects of ischemia rather than of procainamide itself.
While we included only dogs that had refractory periods and excitability thresholds of the ellipse that were
the same as those found in the body of the atrium, it
CIRCULATION
LABORATORY INVESTIGATION-ELECTROPHYSIOLoGY
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is possible that injury from the cut or ischemia of the
isthmus affected some of the results. Depolarized cells
in the isthmus would electrotonically retard conduction
in the isthmus. It is clear that these studies need to be
repeated in vitro with transmembrane recordings; such
studies are underway.
A second limitation is that the effective refractory
period of the isthmus was determined as is done clinically, since electrodes were not placed in the isthmus
itself. Therefore, we could not define the site of conduction block as precisely as de la Fuente et al.9 were
able to do in vitro.9 Also, we could not determine
conduction velocity of the isthmus.
Finally, it is known that anisotropy importantly
influences conduction.'4 The effect of fiber orientation
on electrophysiologic properties of the isthmus was not
determined. However, because we obtained similar
data from isthmus created at two right atrial sites that
were at right angles to each other, it is more likely that
the presence of the isthmus per se rather than the
underlying anisotropy was important.
In conclusion, the present study describes electrophysiologic characteristics of conduction over an
isthmus of tissue and may help explain conduction over
an accessory pathway in patients with the Wolff-Parkinson-White syndrome and the responses of these
patients to antiarrhythmic drugs.
We thank Naomi S. Fineberg, Ph.D., for statistical analysis
of the data, and Robert F. Gilmour Jr., Ph.D., and Milton L.
Pressler, M.D., for their critical comments.
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Conduction over an isthmus of atrial myocardium in vivo: a possible model of
Wolff-Parkinson-White syndrome.
H Inoue and D P Zipes
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Circulation. 1987;76:637-647
doi: 10.1161/01.CIR.76.3.637
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1987 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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