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Circulation Research
APRIL
VOL. XXIV
1969
NO. 4
An Official Journal of the American Heart Association
Factors Affecting Shunting in Experimental
Atrial Septal Defects in Dogs
By John E. Douglas, M.D., Judith C. Rembert, B.S., Will C. Sealy, M.D.,
and Joseph C. Greenfield, Jr., M.D.
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ABSTRACT
Pulmonary and aortic blood flows were measured with electromagnetic
flowmeters in ten unanesthetized dogs with chronic atrial septal defects. The
calculated ratio of pulmonary to systemic flow reflects net bidirectional shunting.
Data were obtained during alterations in rate produced by both atrial and
ventricular pacing and during changes in vascular resistance produced by
drug administration. Results indicate that control ratio of pulmonary to systemic flow depends on the size of the defect. Pacing either atrium at rates
between 210 and 240 beats/min invariably produced both a sustained augmentation of pulmonary flow and a diminished aortic flow. Ventricular pacing
had a similar qualitative response. Angiotensin, methoxamine, and phenylephrine depressed aortic and augmented pulmonary flow. Nitroglycerin, histamine, and isoproterenol reduced the ratio of pulmonary to systemic flow.
These data indicate that the degree of shunting is dynamic in nature. Increasing heart rate and consequent shortening of diastole appears to impair
filling of the left ventricle more than that of the right and results in an increased
left-to-right shunt. Drugs which elevate peripheral vascular resistance increase
the ratio of pulmonary to systemic flow. Conversely, lowering the systemic
resistance decreases the ratio.
ADDITIONAL KEY WORDS
pulmonary blood flow
electromagnetic
flowmeter
tachycardia
systemic blood flow
angiotensin
phenylephrine
methoxamine
nitroglycerin
histamine
isoproterenol
cardiac pacing
• In clinical practice the volume of blood
that is shunted from left to right across an
atrial septal defect is commonly estimated
either by the direct Fick method or by
indicator-dilution techniques. In the application of these methods it is assumed that a
From the Departments of Medicine and Surgery,
Duke University Medical Center, and the Department
of Medicine, Durham Veterans Administration Hospital, Durham, North Carolina 27705.
This study was supported in part by U. S. Public
Health Service Grant HE-09711 from the National
Heart Institute and a grant from the North Carolina
Heart Association. Dr. Douglas was a Postdoctoral
Fellow of the U. S. Public Health Service (no. HE23,257-02.) Dr. Greenfield is the recipient of a Career
Circulation Research, Vol. XXIV, April 1969
relatively steady state or constant flow exists.
In addition, repeated determinations of the
shunt flow by these techniques are subject to a
moderate margin of error. Thus studies of the
effects of various acute procedures on the
shunt flow in atrial septal defects in man have
been limited. Several observations suggest
that the amount of shunting is not in a static
Development Award from the U. S. Public Health
Service (no. 1-K3-HE,28,112.)
The work was presented at the Southern Society
for Clinical Investigation, New Orleans, Louisiana,
January 27, 1968.
Received July 15, 1968. Accepted for publication
February 11, 1969.
493
494
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equilibrium. There is clinical evidence that
changes in both heart rate and rhythm may
alter shunt flow in patients with atrial septal
defects (1-3). Respiratory maneuvers, exercise, and changes in vascular resistance also
have been shown to alter the shunt hemodynamics (4-6). The limitations imposed by the
methods for measuring shunt flow in man
have stimulated the study of experimental
atrial septal defects in animals where pulmonary and systemic flow can be measured
continuously (7). However, previous work
has been largely confined to acute preparations in which the effects of surgery and
anesthesia were unavoidable (7, 8).
This report describes the effects on pulmonary and systemic blood flow produced by
changes in heart rate, changes in vascular
resistance, and administration of isoproterenol
in awake dogs with surgically produced,
chronic atrial septal defects of varying sizes.
Method
Following the induction of anesthesia with
pentobarbital, 30 mg/kg, a right transverse
thoracotomy was performed in a group of mongrel
male dogs weighing 14 to 25 kg. During occlusion
of venous inflow to the heart, an atrial septal
defect was made through a right atriotomy by
excising a circular segment of the membranous
interatrial septum 0.5 to 1.5 cm in diameter. The
atriotomy was repaired, and a pacing electrode
was implanted in the right atrium. The chest was
closed, and the dogs were allowed to convalesce
for 6 to 8 weeks. At this time they were subjected
to a left thoracotomy employing similar anesthetic
techniques. The roots of the aorta and pulmonary
artery were dissected free. Statham electromagnetic flowmeter Q-type transducers were placed
around the aorta and pulmonary artery, particular
caution being taken to avoid constriction or
torsion of either vessel. A strip of silastic sponge
was secured proximal to each transducer to serve
as a cushion and to retard erosion of the vessel.
Pacing electrodes were sewn to both the left atrial
appendage and to the right ventricle near the
interventricular sulcus. The three pacing electrode wires and the leads of the electromagnetic
flowmeter transducers were brought under the
skin and exteriorized. The chest was closed, and
the animal was allowed to recuperate for 4 to 6
days. During this period the transducers adhered
to the vessel wall, thus restricting movement of
the electrodes. This aids in maintaining a
constant flow baseline and in minimizing the
DOUGLAS, REMBERT, SEALY, GREENFIELD
ECG artifact. The dogs were given 10 to 20 mg
of morphine sulfate intravenously. Using lidocaine
hydrochloride as a local anesthetic, a femoral
artery and vein were exposed. Lehman catheters
were inserted via these vessels into the right
atrium, right ventricle, and the thoracic aorta.
During the study the dogs were awake, recumbent, breathing spontaneously, and only minimally restrained.
Intravascular pressures were measured with
Statham no. P23Db transducers. A standard ECG
(usually lead II) was obtained. All recording of
data was carried out on a Sanborn Model 850
eight-channel, direct-writing oscillograph. Both
mean and pulsatile blood flows were recorded
from the aorta and pulmonary artery using a
Statham Model M-4000 multichannel electromagnetic flowmeter. Zero flow was assumed to be
present at the end of diastole. During the course
of study nine different electromagnetic flowmeter
transducers were used. These were calibrated in
vitro in multiple occasions by passing measured
flows of normal saline through them in a known
period of time (9). The calibration factor for the
flow transducers, i.e., flow per unit electromagnetic flowmeter signal, remained within a standard
deviation of ± 7.0% throughout the study. The
flowmeter calibration was found to be linear
(±2.0%) over the range of flows encountered in
this study. Since this study was designed
primarily to assess the changes in shunting
produced by various procedures, the absolute
accuracy of the flowmeter calibration is not as
critical as the linearity. Although comparison of
the control values of flow in the pulmonary artery
with that in the aorta may be subject to a
moderate error, the changes following each
procedure should be accurately recorded.
During the control period, blood samples were
obtained from the aorta for determination of the
oxygen content by a modification of the technique
described by Hickam and Frayser (10). Although
not all measurements were made in every dog, the
general protocol was as follows: At the beginning
of the study, control pressure-flow data were
recorded for approximately 30 minutes. Before
each procedure the blood flows and pressures
were allowed to return to or near the control
state. Data were recorded continually before and
during each experimental state.
Electrical pacing of both atria and the ventricle
was accomplished using the implanted electrodes
and two Grass Instruments Model S-4-B stimulators and isolation units. The pacing rates were
increased in increments of 30 beats/min from an
initial rate of 120 beats/min to 300 beats/min.
Each pacing rate was maintained for 5 minutes,
unless the animal's mean systemic blood pressure
remained below 60 mm Hg. At the higher atrial
Circulation Research, Vol. XXIV, April 1969
SHUNT FLOW IN ATRIAL SEPTAL DEFECTS
495
TABLE 1
Control Data
Diam. of
O:
Dog
(mm)
ASD
sat.
(%)
Heart
rate
(beats/min)
1
2
3
4
5
6
7
8
9
10
0
2
6
6
8
10
12
12
13
15
93
94
96
92
95
90
84
94
92
94
105
100
120
105
120
135
145
140
120
145
Ao BP
syst./diast.
(mm Hg)
RV B P
syst.
(mmsyst. H g )
Aortic blood
flow
range
(ml/min)
150/100
145/70
155/80
140/70
135/85
160/80
130/70
120/85
140/80
120/75
50
50
60
75
70
75
50
60
50
50
1930-2170
2240-2480
1080-1370
2240-2640
2260-2600
1500-2150
2550-2780
1460-1840
800-900
1960-3040
Pulmonary blood
flow
range
(ml/min)
1800-2100
1980-2500
1050-1600
2300-2750
2120-2580
1600-2100
3500-3850
2300-2750
1700-2100
2600-4000
Maximum
change shunt
Range of
flow
P/S ratio (ml/min)
0.9-1.0
0.9-1.0
0.9-1.2
0.9-1.1
0.9-1.1
1.0-1.3
1.4-1.6
1.5-1.8
2.0-2.3
1.1-1.5
50
95
370
340
300
500
440
390
335
500
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ASD = atrial septal effect; Ao BP = aortic blood pressure; RV = right ventricle; P/S ratio = ratio of pulmonary
to systemic flow. The last column tabulates the maximum change inflowacross the defect in each dog during the
initial control period.
pacing rates, variable atrioventricular (A-V)
block frequently occurred. To evaluate the effects
of an irregular ventricular rate on shunt dynamics, data were recorded also during a period of AV block. Several animals were given 1.0 mg of
atropine sulfate when A-V block persisted at
rapid pacing rates, and the atrial pacing was then
repeated. To alter the hemodynamic relationships
of the vascular system, the following drugs were
given sequentially either as an infusion or as a
single bolus: angiotensin amide, 2.0 ^g/min;
methoxamine, 1.0 mg; phenylephrine, 0.5 mg;
histamine phosphate, 27.5 fig; nitroglycerin, 0.2
mg; and isoproterenol hydrochloride, 2.0 fj.g.
Following completion of each study, the dogs
were killed with pentobarbital. Autopsies were
performed, and the hearts were examined to
check the placements of the pacing electrodes
and flow transducers. The atria were opened, and
the septal defect was measured and photographed. The ventricular septum was examined
for possible congenital defects.
The following data were either measured
directly from the recording or computed: systolic,
diastolic, and mean aortic pressure; mean pulmonary and aortic blood flow; right ventricular
systolic pressure; and heart rate. The ratio of
mean pulmonary blood flow to mean aortic flow
was calculated. The net shunt flow was calculated
as pulmonary flow minus aortic flow. Changes in
shunt flow were determined by comparing the
value of shunt flow during the procedure with
that of the control period immediately preceding
it. During the initial 30-minute control period before any procedure, the maximum change in the
shunt was tabulated. Following each procedure
pressure-flow data were analyzed during periods
where a "steady state" was present for at least a
Circulation Research, Vol. XXIV, April 1969
30-second period. If this condition was not
achieved, data were used from the period of maximum change in the shunt. Standard statistical
analysis of the data was carried out on an IBM
Model 1130 digital computer.
Results
Hemodynamic data recorded during the
initial control period are given in Table 1. The
oxygen saturation data indicate that all the
dogs except no. 7 were reasonably well
saturated while breathing room air. This
would tend to exclude the presence of a large
right-to-left shunt, but certainly some degree
of right-to-left shunt could have been present.
These data will yield only the total magnitude
of the shunt. In general, the net left-to-right
shunt was roughly proportional to the size of
the atrial septal defect. There was considerable variation in the pulmonary and systemic
flow among the dogs from moment to moment
during the initial control period. The data in
column 10, Table 1, reflects the variability of
the shunt flow for each dog. For example, in
dog no. 6 there were periods when there was
no shunt detectable, although at other times
pulmonary flow was 25% greater than aortic
flow.
Data recorded during atrial and ventricular
pacing are listed in Table 2. The control rates
are essentially the same as those given in
Table 1. Pacing from either the left or the
496
DOUGLAS, REMBERT, SEALY, GREENFIELD
TABLE 2
Atrial and Ventricular Pacing
Dog
2
3
5
6
8
9
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10
1
2
3
5
6
8
9
10
1
3
5
6
8
9
10
3
5
6
8
Pacing
site
V
A
V
V
A
V
A
V
A
V
A
A
V
A
V
V
A
V
A
V
A
V
A
V
A
V
A
V
V
A
V
A
V
A
V
A
V
A
V
A
V
A
V
Mean
aortic
BP
(mm Hg)
180
89
105
118
108
111
83
97
82
106
101
94
210
120
98
109
109
110
120
81
106
88
112
104
90
84
240
118
110
108
113
102
116
86
84
90
111
120
88
114
270
98
102
91
86
78
80
Mean
pulmonary
flow
(ml/min)
Beats/min
2280
1710
1270
2470
2200
1680
2770
2480
2380
1860
3980
Beats/min
2010
2260
1490
1430
2310
2390
2100
2850
2660
2510
1930
4070
2250
Beats/min
1940
1590
1530
1340
2500
2260
1870
2700
2770
2560
1930
3530
2350
Beats/min
1640
2500
2260
1960
2310
2480
Mean
systemic
flow
(ml/min)
P/S
ratio
2470
1670
1150
2870
1660
1261
1990
1350
1000
760
3040
0.9
1.0
1.1
0.9
1.3
1.3
1.4
1.8
2.4
2.4
1.3
2010
2440
1310
1310
2700
1690
1230
1860
1530
1010
750
1800
1680
1.0
0.9
1.1
1.1
0.9
1.4
1.7
1.5
1.7
2.5
2.6
2.3
1.3
2010
1670
1420
1130
1940
1150
1380
1290
1530
1010
550
1680
1630
1.0
1.0
1.1
1.2
1.3
2.0
1.4
2.1
1.8
2.5
3.5
2.1
1.4
1980
1720
1030
1370
1170
1100
1.7
1.4
2.2
1.4
2.0
2.2
Circulation Research, Vol. XXIV, April
1969
SHUNT FLOW IN ATRIAL SEPTAL DEFECTS
497
TABLE 2 (cont.)
Dog
Mean
aortic
BP
(mm Hg)
Pacing
site
9
A
V
3
5
8
10
A
V
V
A
Mean
pulmonary
flow
(ml/min)
3340
126
1670
94
300 Beats/min
1610
91
1830
56
2220
72
2100
45
Mean
systemic
flow
(ml/min)
P/S
ratio
1200
400
2.8
4.2
690
1140
830
580
2.3
1.6
2.7
3.6
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Data obtained during atrial (A) and ventricular (V) pacing. P/S ratio = ratio of pulmonary
to systemic flow. Control heart rates before each pacing interval were comparable to those in
Table 1. Note that the net left-to-right shunt increased with faster pacing rates, particularly in
the dogs with larger defects. This is most readily appreciated by comparing the respective P/S
ratios.
right atrium produced comparable results. In
most instances atrial pacing at 150 and 180
beats/min augmented total cardiac output
without appreciably changing the ratios of
pulmonary to systemic flow. At 210 to 240
beats/min an increase occurred in the left-toright shunting in dogs 6, 8, 9, and 10 (Table
2). The difference between the ratios of
pulmonary to systemic flow at 180 and 240
beats/min is significant, P<0.01. Figure 1
illustrates the typical response in dogs with
atrial septal defects during pacing at 240
beats/min. Note the abrupt augmentation of
pulmonary flow at the onset of pacing. Atrial
pacing at rates of 270 and 300 beats/min
usually resulted in a decreased left and right
ventricular output. However, aortic flow decreased to a greater extent than pulmonary
with a consequent further increase in the
ratios of pulmonary to systemic flow. During
pacing, both the aortic pressure and the right
ventricular pressure remained relatively unchanged until the highest pacing rates when
they both fell proportionally. When A-V block
occurred during rapid atrial pacing, invariably
the ratios of pulmonary to systemic flow
returned to or near control levels.
During ventricular pacing, the same qualitative changes in shunting occurred as with
atrial pacing (Table 2). Ventricular pacing,
however, generally resulted in a reduced
cardiac output when compared with atrial
Circulation Research, Vol. XXIV, April
1969
pacing at the same rate. Left ventricular
pulsus alternans frequently developed when
pacing the ventricle at 210 beats/min or
faster. Figure 2 illustrates an example of
"total" left ventricular alternans which occurred during ventricular pacing.
Figure 3, the typical response following a
dose of phenylephrine, illustrates the rise in
aortic pressure, the fall in aortic flow and the
slight rise in pulmonic flow. Table 3 summarizes the pressure-flow responses to various
vasopressors. Angiotensin, methoxamine, and
phenylephrine all produced a rise in systemic
blood pressure, a fall in aortic flow, an
increase in pulmonary flow in most dogs, and
an increase in the ratio of pulmonary to
systemic flow. The increase in left-to-right
shunt ranged from 140 ml/min in dog no. 2
with a 2-mm atrial septal defect to nearly
2,000 ml/min in dog no. 10, with a 15-mm
defect. This relationship is highly significant
(P < 0.001). During the drug-induced hypertension, all of the dogs showed an increased
left-to-right flow except no. 9. In this dog with
a control ratio of pulmonary to systemic flow
of 2.6, both the pulmonary and aortic flows
fell approximately 500 ml/min during the
response to phenylephrine. The shunt flow,
however, remained constant. Thus the ratio of
pulmonary to systemic flow during hypertension rose.
In Figure 4 a typical response to transient
DOUGLAS, REMBERT, SEALY, GREENFIELD
498
200
Arterial Pressure
mm Hg
100
°
50r
BEGIN
PACE
STOP
PACE
Atrial Pressure
mm Hg
--•-,>>,-
ECG
Downloaded from http://circres.ahajournals.org/ by guest on May 5, 2017
Aortic Flow
Puls.
ml /sec
\
Aortic Flow
Mean 200
ml/mi
r
Pulmonary Flow
Puls.
ml/sec
150
Pulmonary Flow
Mean
2000
ml/min
..,.;.;.,•.* A/-A,V
T
0L
I sec
FIGURE 1
The response of dog no. 6 to atrial pacing at 240 beats/min. With the onset of pacing, mean
pulmonary flow increases abruptly and mean aortic flow drops.
hypotension is illustrated. Reducing systemic
pressure by the administration of histamine or
nitroglycerin resulted in a significant decrease (P<0.001) in left-to-right shunt. The
aortic flow increased, and a variable change
occurred in pulmonary artery flow. Heart rate
increased in all dogs. Right ventricular pressures remained the same or rose moderately
with histamine and nitroglycerin (Table 4).
Data obtained during isoproterenol infusion
are given in Table 5. There was always both an
inotropic and chronotropic response to isoproterenol given intravenously. Aortic diastolic pressures dropped in 8 animals and
remained the same in one. Aortic systolic
pressure rose in 5 and fell in 4. Peak right
ventricular pressure rose in 7 dogs. Pulmonary
flow (column 6, Table 5) increased as little as
50 ml/min (dog no. 4) or as much as 1300
ml/min (dog no. 2), the average increase
being 800 ml/min. Aortic flow, however,
increased to an even greater extent than
Circulation Research, Vol. XXIV, April
1969
SHUNT FLOW IN ATRIAL SEPTAL DEFECTS
499
200p \ Ventricular Pacing
Arterial Pressure
mmHg
inn
OL
100
Right Ventricular
Pressure
mmHg
5 0 -
"••
0
50
Right AtriaI
Pressure
mmHg
ECG
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Pulmonary Flow
Puls.
ml/sec
Pulmonary Flow
Mean
ml /min
150
0
5000 r
Aortic Flow
Puls
ml/sec
Aortic Flow
Mean
ml /min
160 p.
7500
DOG # 5
I sec
FIGURE 2
The response of dog no. 5 to ventricular pacing at 240 beats/min. Mean pulmonary flow
falls slightly with the onset of ventricular pacing and returns within 30 seconds to approximately prepacing levels. Pulmonary artery pulsus alternans is visible from the beginning of
pacing. Mean aortic flow falls with the onset of pacing and "total" pulsus alternans occurs.
pulmonic, and as a result the ratios of
pulmonary to systemic flow fell (column 7).
The amount of shunted blood fell significantly
(P<0.01) in 8 of the 9 dogs. In dog no. 9,
although the ratio of pulmonary to systemic
flow decreased substantially, there was a slight
increase in left-to-right shunting.
Discussion
It is obvious that over a prolonged period of
Circulation Research, Vol. XXIV, April 1969
time the output of both ventricles in the
mammalian heart must be balanced. As has
been shown by Franklin and co-workers (11),
this balance is extremely sensitive, and the
disparity between the outputs of either
ventricle lasts for a few heart beats at the
most. In the presence of an atrial septal defect
some equilibrium between the two circuits is
mandatory, but their outputs may be persistently unequal. Since with a large atrial septal
DOUGLAS, REMBERT, SEALY, GREENFIELD
500
jPhenyteph''
Arterial Pressure
mm Hg
Right Ventricular
Pressure
mmHg
Right Atnal
Pressure
mmHg
50
50
25
mftimmmm
0
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ECG
— —
Aortic Flow
Puls
ml/sec
Aortic Flow
Mean
ml/min
2000 r0L
Pulmonary Flow
Puls.
m i /sec
Pulmonary Flow
Mean
ml/min
2000 r
DOG # 6
lOsec
FIGURE 3
Response of dog no. 6 to phenylephrine given intravenously. Within 5 seconds after the
elevation of aortic pressure, aortic flow begins to fall and pulmonary artery flow begins to
rise. The greatest reduction in aortic flow and the major change in net shunt flow occurs
within 15 seconds after the hypertensive response.
defect, one can assume that the atria are a
common chamber, filling will occur preferentially into the ventricle with the least
impedance to blood flow. Several factors favor
flow into the right ventricle. Since the area of
the mitral orifice is only 50 to 6035 that of the
Circulation Research, Vol. XXIV, April
1969
501
SHUNT FLOW IN ATRIAL SEPTAL DEFECTS
TABLE 3
Response to Vasopressor Drugs
RV BP
Heart
rate
(beats/min)
155
130
120
115
120
115
95
130
120
130
180
170
200
170
150
130
130
130
130
140
150
150
145
140
200
180
Dog
Status
(mm Hg)
syst.
(mm Hg)
2
CA
DA
CA
DA
CA
DA
CM
DM
140/90
205/165
60
50
155/80
205/140
160/105
205/150
150/80
200/135
145/90
200/140
150/95
195/150
150/100
200/150
140/80
160/110
120/70
150/110
125/75
180/120
55
3
4
5
6
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Ao BP
syst./diast.
7
8
9
10
CA
DA
CA
DA
CP
DP
CM
DM
CA
DA
CP
DP
CA
DA
CP
DP
CA
DA
145/100
205/155
175/100
190/140
135/95
160/130
65
75
80
70
80
80
80
75
90
70
90
55
55
65
70
65
80
50
85
50
75
55
60
Mean
pulmonary
flow
(ml/min)
Mean
systemic
flow
(ml/min)
2870
2100
3010
2100
1110
1120
2870
2970
2030
3380
2470
2750
1085
1960
2500
2080
2310
3290
2920
2990
2930
2630
2330
2450
2600
2490
1930
3250
3600
820
2630
2140
2120
2640
2370
2140
1960
1000
2160
1230
1940
1170
1570
830
1550
580
900
630
960
400
2950
1330
P/S
ratio
1.0
1.0
1.0
1.4
1.1
1.4
1.0
1.3
1.0
1.3
1.0
2.5
1.0
1.9
1.7
2.5
1.9
3.5
1.7
4.0
2.7
4.1
2.6
4.8
1.1
2.7
Change in
shunt flow
(ml/min)
+ 140
+ 265
+ 590
+ 830
+ 510
+ 1500
+ 1160
+ 400
+ 680
+ 670
+ 420
NC
+ 1970
Ao BP = aortic blood pressure; RV = right ventricle; P/S ratio = ratio of pulmonary to systemic flow. In
column 2 the experimental status is listed. The control data for the interval immediately before the administration
of each drug are labeled "C," and the effects of the indicated drug are listed under "D." M = methoxamine; A =
angiotensin; P = phenylephrine. Note that an increase in the P/S ratio occurred in every instance (column 8).
The change in the total shunt concomitant with the pressor response is given in column 9. This value is obtained
by subtracting systemic from pulmonary flow for both the control and experimental intervals. Control value of shunt
is then subtracted from experimental shunt flow and the final result tabulated. A positive sign indicates an increase
in the net amount of shunting from left to right. NC signifies that no change occurred.
tricuspid (12), under conditions of high
cardiac output, relative mitral stenosis may
appear before relative tricuspid stenosis. In
addition, the left ventricular wall is less
compliant than that of the right ventricle.
Thus, during tachycardia when the diastolic
filling period is markedly shortened, left
ventricular filling will be more impeded than
the right. Under such circumstances, if the
atrial septum is intact, left atrial pressure rises
and augments left ventricular filling. In the
presence of a large atrial septal defect, such as
in dogs 7 to 10, however, the left atrial
Circulation Research, Vol. XXIV. April 1969
pressure is not able to rise appreciably above
the right atrial pressure, and the left-to-right
shunt may therefore increase. Even with a
smaller defect where the atrial pressure might
not be equal, the same hemodynamic considerations should apply. It is of interest that
several authors (1, 2) have been impressed by
the morbidity associated with the onset of
arrhythmias, particularly with atrial fibrillation, in patients previously asymptomatic with
atrial septal defects. Our results would lend
support to the concept that the appearance of
exertional dyspnea, fatigue, or other cardiac
DOUGLAS, REMBERT, SEALY, GREENFIELD
502
Nitroglycerine
200
Arterial Pressure
mmHg
100
0
100
Right Ventricular
Pressure
mmHg
Right Atrial
Pressure
mm Hg
50
i. ,
0
50
25
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0
ECG
Aortic Flow
Puls.
ml/sec
l50r
0
Aortic Flow
Mean
ml/mm
2000
0
Pulmonary Flow
Puls.
ml/sec
150
0
Pulmonary Flow
Mean
ml/min
C
2000
n[L
20 sec
FIGURE 4
Response of dog no. 6 to nitroglycerin given intravenously. Simultaneous with the drop in
arterial pressure, the aortic flow increases with little or no change in pulmonary flow.
symptoms in patients with a rapid ventricular
rate might be due to an increase in left-toright shunting. In our dogs there was no
change in the shunt during rapid atrial pacing
when A-V block occurred if the ventricular
rate slowed. Thus, it appears that within the
Circulation Research, Vol. XXIV, April 1969
503
SHUNT FLOW IN ATRIAL SEPTAL DEFECTS
TABLE 4
Response to Vasodilator Drugs
Dog
1
2
3
4
5
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6
7
8
9
10
Status
CH
DH
CH
DH
CN
DN
CH
DH
CH
DH
CH
DH
CN
DN
CH
DH
CH
DH
CN
DN
CH
DH
Ao BP
syst./diast.
(mm Hg)
RV BP
syst.
(mm Hg)
Heart
rate
(beats/min)
Mean
pulmonary
flow
(ml/min)
Mean
systemic
flow
(ml/min)
ratio
145/100
124/60
150/80
110/45
170/90
150/60
170/115
120/60
130/80
90/45
170/115
140/60
170/105
150/70
120/65
85/45
110/70
120/50
150/110
140/90
125/90
95/40
55
100
55
100
65
70
60
60
105
130
110
175
110
140
125
125
1350
1970
2200
2960
970
1190
2920
2890
1420
2040
2240
3240
870
1520
2650
3300
1.0
1.0
1.0
0.9
1.1
0.8
1.1
0.9
70
80
75
100
70
80
55
70
65
85
70
75
55
60
125
140
135
170
130
180
145
180
125
150
120
175
145
185
1840
1940
2070
2580
1870
2460
2280
3590
1530
2410
860
1480
2760
2940
1.4
1.2
1.3
0.9
1.3
0.9
1.6
1.3
1.8
1.3
3.0
2.2
1.3
1.1
2610
2400
2680
2400
2340
2310
3650
4660
2760
3140
2600
3120
3600
3230
P/S
Change in
shunt flow
(ml/min)
NC
— 240
-430
-680
-310
-790
-620
-300
-500
-100
-550
Data tabulated as in Table 3. H = histamine; N = nitroglycerin. Note that the P/S ratios fall with the hypotensive response. The negative sign (column 9) indicates a decrease in the amount of net left-to-right shunting.
limitations of this study an ineffective atrial
contraction does not increase the left-to-right
shunt.
Tanenbaum and Pfaff (8) and more recently Weldon (7) have demonstrated increased
left-to-right shunting and consequent increased ratios of pulmonary to systemic flow
in dogs during the administration of systemic
vasopressor drugs. McCredie (4), however,
did not obtain this response in man with
either methoxamine or norepinephrine. With
norepinephrine, despite a rise in aortic blood
pressure of 25 to 30 mm Hg and a stable heart
rate, McCredie failed to detect a change in the
ratio of pulmonary to systemic flow. Our
results, therefore, confirm those of Tanenbaum and Pfaff (8) and Weldon (7) and not
those of McCredie (4).
Since all dogs had substantial reductions in
their ratios of pulmonary to systemic flow with
Circulation Research, Vol. XXIV, April 1969
systemic vasodilators, despite the variable
changes in peak right ventricular pressure, the
change in shunting under these conditions is
probably due to the drop in peripheral
vascular resistance. In dogs 2, 3, 4, and 6 the
ratio actually fell below 1.0 and suggests that
there was right-to-left shunting.
The increased cardiac output from both the
left and right side in response to cardiac
inotropic drugs is essentially the same as
observed in intact dogs (9). Weldon (7),
noting a drop in the ratio of pulmonary to
systemic flow in his acute atrial septal defect
preparations, attributed the decreased left-toright shunting to a decrease in right ventricular distensibility. However, isoproterenol may
reduce left-to-right shunting by enhancing
left ventricular compliance, thus increasing
the ease of left ventricular filling. It is of
interest that the chronotropic response to
DOUGLAS, REMBERT, SEALY, GREENFIELD
504
TABLE 5
Response to Isoproterenol
Dog
Status
Ao BP
syst./diast.
(mm Hg)
2
CI
DI
CI
DI
CI
DI
CI
DI
CI
DI
CI
DI
CI
DI
CI
DI
CI
DI
150/65
130/65
150/80
190/65
145/100
120/80
135/90
115/55
155/100
195/65
100/60
85/45
120/80
165/60
145/105
180/50
120/70
155/40
3
4
5
6
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7
8
9
10
RV BP
syst.
(mm Hg)
Heart
rate
(beats/min)
Mean
pulmonary
flow
(ml/min)
Mean
systemic
flow
(ml/min)
50
105
60
110
50
50
65
80
75
110
115
180
115
190
120
125
145
155
180
205
125
180
130
160
140
200
145
220
2510
3890
1040
2160
2700
2750
2470
3250
2100
2410
4090
5100
2700
3575
2490
3200
3380
4500
2700
4260
1120
2460
2520
2960
2300
3480
1610
2710
3650
6000
1420
2895
860
1450
2250
4100
70
100
50
105
50
100
P/S
ratio
0.9
0.9
0.9
0.9
1.1
0.9
1.1
0.9
1.3
0.9
1.1
0.9
1.9
1.3
2.9
2.2
1.5
1.1
Change in
shunt flow
(ml/min)
— 180
-220
-390
-400
-790
-1340
-600
+ 120
-730
Data tabulated as in Table 3. I = isoproterenol. All nine dogs had a tachycardia and a reduced P/S ratio following isoproterenol administration. The net left-to-right shunt fell in 8 of the 9 dogs.
isoproterenol produced tachycardias equal to
those which, when pacing, increased left-toright shunting. Despite this chronotropic
response, systemic vascular resistance and
myocardial properties are changed to such an
extent that instead of increasing left-to-right
shunting, isoproterenol produced a decrease.
Regardless of the technique of calibration,
absolute values of blood flow measured with
an electromagnetic flowmeter are subject to a
moderate margin of error as noted in the
method (9). For example, if the two transducers were each off by two standard
deviations in opposite directions, then a 28%
error in the baseline pulmonary and aortic
flow values might be found. This also assumes
that the calibration in vivo is similar to that in
vitro which is certainly another potential
source of error. One point validating the
flowmeter data is the good agreement between pulmonary and aortic flow noted in dog
no. 1 without a defect and in dogs 2, 3, and 4
with small defects. Although the aboslute
values of blood flow may be questioned, as
noted in the method, the linearity of the
electromagnetic flowmeter (±2.0%) is quite
good. Thus the changes in flow from control
levels to that found during the various
procedures are accurately measured.
One of the major difficulties regarding the
interpretation of the data in these studies is
the elevation of 20 to 40 mm Hg above normal
in right ventricular systolic pressure. Although
this finding may be explained to some extent
as artifact introduced by the catheter, the
pressures are higher than normal (11). Since
we did not measure pulmonary artery pressure, a degree of pulmonary stenosis produced
by the flowmeter transducer may have been
present, even though the vessel did not appear
to be constricted at autopsy. The elevated
right ventricular pressure also may have been
due to the left-to-right shunt. Whatever the
cause, this finding would tend to lessen the
degree to which the left-to-right shunt increased with tachycardia. Thus, one might
expect the changes in shunting to be more
dramatic in the patient with an uncomplicated
atrial septal defect.
Circulation Research, Vol. XXIV, April 1969
505
SHUNT FLOW IN ATRIAL SEPTAL DEFECTS
Acknowledgments
The authors wish to express appreciation to Mr.
William Joyner and Mrs. Maxine Mangum for their
technical assistance. The department of Medical Illustration of the Durham Veterans Administration
Hospital rendered valuable support.
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Factors Affecting Shunting in Experimental Atrial Septal Defects in Dogs
JOHN E. DOUGLAS, JUDITH C. REMBERT, WILL C. SEALY and JOSEPH C. GREENFIELD,
Jr.
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Circ Res. 1969;24:493-505
doi: 10.1161/01.RES.24.4.493
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