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Experimental infundibular pulmonic stenosis
Experimental infundibular pulmonic stenosis Effects of positive inotropic agents A model of infundibular pulmonic stenosis was created in 14 puppies. The animals later received intravenous infusions of isoproterenol and calcium chloride and increments of acetyl strophanthidin. Cardiac output, peak systolic gradient (PSG) infundibular blood flow, and area of the right ventricular outflow orifice were determined with each provocative measure. Isoproterenol infusion narrowed the infundibular orifice area in 11 of 14 dogs, an average decrease of 29 per cent from base line (p 0.05). In 10 of 11 animals receiving calcium chloride, there was an average decrease of 14 per cent in orifice size (p < 0.001); in all 12 dogs receiving acetyl strophanthidin, the narrowing of the orifice averaged 18 per cent (p 0.001). Right ventricular angiocardiography and necropsy studies demonstrated marked infundibular narrowing, right ventricular hypertrophy, and a dilated chamber distal to the obstruction. Stimulation of the contractile state of the myocardium, in the presence of muscular infundibular pulmonic stenosis, may be detrimental because of the dynamic characteristics of this obstruction.
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Kent W. Jones, M.D., Michael Jones, M.D., Stephen B. Colvin, M.D., Scott 1. Allen, M.D., and Lawrence L. Michaelis, M.D., Bethesda, Md.
Infundibular pulmonic stenosis is a commonly encountered congenital cardiac malformation which occurs singly, in conjunction with valvular pulmonic stenosis, and in association with other congenital intracardiac defects. This lesion was first created experimentally in adult dogs by Sabiston and Williams! and by Alden and his associates." These authors were able to create right ventricular hypertension but did not investigate the hemodynamics of the obstruction. Mason's group" demonstrated the dynamic nature of this muscular obstruction in patients by the use of isoproterenol infusion. From the Clinic of Surgery, National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. 20014. Received for publication Dec. 28, 1973. Address for reprints: Lawrence L. Michaelis, M.D., Clinic of Surgery, National Heart and Lung Institute, Bethesda, Md. 20014.
They postulated that other interventions which stimulate the contractile state of the myocardium, such as digitalis glycosides, may also cause obstruction to pulmonary blood flow. In the present study, infundibular pulmonic stenosis was created surgically in puppies. After the animals had grown for 5 to 6 months, cardiac catheterization was performed with infusion of inotropic medications. The effects of these provocative interventions were studied, and a dynamic subpulmonic obstruction was demonstrated. Material and methods Foxhound puppies, weighing between 4.2 and 6.5 kilograms, were anesthetized by intravenous injection of 2.5 per cent sodium thiamylol (0.1 c.c. per kilogram of body weight). They were intubated and placed on a volume respirator delivering 100 per cent
699
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Jones et al.
Thorocic ond Cord iovos culor Surgery
AFTER ISU PREL
BEFORE ISUPREL
mm Hg
200
15 0
10 0
50
1111
o
"2198 Mean Gradi ent (mm Hg i
44
Cardia c Output ( L/ ml n ) 2.0 0 .22 Ori f ice Area (cm 2 )
Fig. 1. Anteroposterior view of the canine heart demonstrating the anatomic location of the infundibular obstruction. RCA , Right coronary artery. LAD, Left anterior descending coronary artery.
oxygen and 0.25 to 0.50 per cent halothane. A right thoracotomy was made through the fourth intercostal space, and the pericardium was incised anterior to the phrenic nerve. A No. 1 silk suture was placed through the anterior wall of the right ventricle, to the right of the anterior descending branch of the left coronary artery, and posteriorly through the septal band of the crista supraventricularis; it was brought out through the anterior wall of the right ventricle just to the ventricular side of the right coronary artery (Fig. 1). Then , it was tied tight enough to elevate the systolic right ventricular pressure to approximately one half of the systemic level, while producing an easily palpable thrill over the outflow tract. Sixteen of 26 animals survived the operative procedure and the early postoperative period. The 10 deaths occurred within 48 hours after operation and were thought to be due to acute right heart failure, probably from too tight an initial outflow tract constriction . At autopsy , the right ventricle appeared dilated and the outflow tract mark-
J.
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Fig. 2. Simultaneous right ventricular-pulmonary artery (RV and PA) pressure recordings . Isoproterenol infusion augmented the gradient while narrowing the infundibular orifice area .
edly constricted, but no other abnormalities were found . After a 5 to 6 month period of growth, the 16 survivors were anesthetized as described earlier. A left thoracotomy was performed through the fourth intercostal space, and an indwelling catheter was inserted into the pulmonary artery distal to the pulmonic valve. The opposite end of this catheter was embedded in the subcutaneous tissue of the left thorax. One to 2 weeks later, the animals were again anesthetized with sodium thiamylol, intubated, and placed on a volume respirator that delivered air. An 8 inch catheter was inserted into the femoral artery and was attached to a densitometer. A No. 7 Cournand end-hole catheter was placed in the right ventricle via the femoral vein, and a No. 8 Judkins pig-tailed catheter was inserted into the left ventricle from the opposite femoral artery. A small cutdown was made in the subcutaneous tissue of the left thorax to expose the distal end of the pulmonary artery catheter, and the right ven.tricular and pulmonary artery catheters were attached to an electromanometer for simul-
Volume 67 Number 5
701
Experimental infundibular pulmonic stenosis
May, 1974
Table I. Effects of isoproterenol infusion in 14 dogs Peak systolic gradient (mm. Hg)
Mean gradient (mm. Hg)
II
BV
II
BV
156 204 178 180 180 208 176 231 215 175 256 216 120 173 190.6 33.9 9.1
30 95 61 29 35 58 42 28 86 44 103 91 81 49 59.4 26.8 7.2
90 158 87 98 81 147 83 76 162 96 155 173 123 87 115.4 35.8 9.6
17.5 68.1 36.0 19.2 22.1 44.4 25.0 20.6 58.8 31.9 77.0 61.4 58.3 30.9 40.80 20.27 5.42
Heart rate (beats/ min.)
BV
Mean S.D.± S.E.! Per cent change
I
126 144 126 116 133 148 160 168 150 152 178 184 116 151 146.6 21.5 5.7
Significance
+ 30% p
< 0.001
I
+ 94%
P
<
0.001
II
BV
55.3 93.2 50.0 62.9 48.2 106.1 45.3 58.8 103.3 72.5 97.8 107.0 83.0 59.0 74.46 23.18 6.20
2.9 2.3 3.0 1.4 2.2 2.0 1.3 2.8 2.6 1.4 5.3 2.3 1.3 2.0 2.34 1.04 0.28
I
+ 82% p
<
Cardiac output (L./min.)
0.001
I
Infundibular orifice area (sq. em.)
BV
2.7 3.8 2.9 1.9 2.5 2.2 1.4 3.6 3.6 2.9 3.6 3.6 1.4 2.3 2.67 0.79 0.21
0.77 0.18 0.28 0.22 0.36 0.22 0.17 0.51 0.24 0.26 0.38 0.15 0.11 0.19 0.289 0.174 0.047
+ 14%
N.S.
I
II
II
0.24 0.22 0.25 0.18 0.26 0.15 0.13 0.38 0.21 0.22 0.15 0.16 0.10 0.21 0.204 0.069 0.019
- 29% P
<
0.05
Legend: BV, Base-line values. II, Values after isoproterenol infusion. S.D., Standard deviation. S.E., Standard error. N.S.
Not significant.
taneous recording of base-line pressures. Cardiac output was determined by injection of Cardio-Green dye into the left ventricle with sampling from the femoral artery. The base-line area of the infundibular orifice was calculated by the method of Godin and Gorlin--cthat is, the mean right ventricularpulmonary artery gradient and the calculated cardiac output were used to determine infundibular blood flow. Two animals died early in the catherterization study, prior to pharmacologic intervention. One experienced ventricular fibrillation shortly after the induction of anesthesia, and the second died from anoxia due to respirator malfunction. After stable base-line values had been obtained, 14 dogs were subjected to intravenous isoproterenol infusion (2 to 3 meg. per minute). One animal developed ventricular fibrillation following this infusion, and a technical error in a second animal prevented further study. Therefore, 12 dogs re-
ceived intravenous infusion of calcium chloride (16 to 24 mg. per minute) and increments of acetyl strophanthidin (0.5 to 1.5 mg. over 10 to 15 minutes). A recorder malfunctioned during one calcium infusion, and, as a result, valid measurements were obtained in only 11 animals. Cardiac output, infundibular blood flow, and orifice area were determined with each provocative measure, and new base-line values were obtained following each intervention. Two to 3 weeks after catheterization, 3 dogs were lightly anesthetized, a small incision was made over the external jugular vein, and a polyethylene catheter, Y8 inch in diameter, was threaded into the right ventricle under fluoroscopic visualization. After hand injection of 15 C.c. of 60 per cent sodium iothalamate contrast material, single-plane selective right ventricular angiocardiograms were taken with an 11 by 14 inch Sanchez-Perez film changer (exposing 2 films per second).
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Table II. Effects of calcium chloride infusion in 11 dogs Heart rate (beats/min.)
BV
Mean S.D.± S.E.±
Per cent change Significance
148 132 112 124 160 145 155 159 148 111 127 138.3 17.9 5,4
I
Peak systolic gradient (mm. Hg)
CCI
BV
140 130 104 124 145 140 154 158 140 113 120 133.5 16.9 5.1
68 44 39 24 55 47 26 61 65 67 43 49.0 15.6 4.7
-3%
I CCI 113 76 74 64 114 87 49 99 86 84 84 84.5 19,4 5.9
Mean gradient (mm. Hg)
+ 72%
N.S.
<
p
I
BV 52.5 27.0 24.6 17.5 44,4 31.5 17.6 42.2 41.6 31.5 29,4 32.71 11.27 3.39
CCI 87.9 44.0 42.8 42,4 76.8 53.9 34.9 64.3 68,4 60.0 56.7 57,46 16.18 4.88
Cardiac output (LJmin.)
BV 2.3 3,4 1.8 1.5 1.6 1.4 2.3 1.6 2.1 1.9 1,4
2.6 4.3 2.2 1.9 1.8 1.6 2.8 2.0 2.0 2.2
1.94 0.59 0.18
2.23 0.83 0.25
<
p
1.1
BV
0.001
<
p
I CCI 0.19 0,40 0.22 0.24 0.15 0.15 0,42 0.17 0.17 0.19 0.10 0.218 0.102 0.Q31
0.25 0,46 0.25 0.32 0.17 0.17 0,45 0.17 0.20 0.20 0.16 0.255 0.110 0.033
+ 15%
+ 75%
0.001
I CCI
Infundibular orifice area (sq. em.)
- 14%
0.02
<
p
0.001
Legend: CCI, Values after calcium chloride infusion. For other abbreviations, see Table I.
Table III. Effects of parenteral acetyl strophanthidin in 12 dogs Peak systolic gradient (mm. Hg)
Mean gradient (mm, Hg)
AS
BV
AS
BV
97 156 108 126 116 129 139 126 147 146 88 115 124.4 20.7 5.9
60 33 28 18 83 43 17 68 33 72 43 70 47.3 22.5 6.5
88 54 44 27 98 59 28 92 82 99 70 77 68.2 25.7 7.4
35.8 25.0 18.0 16.0 50.8 27.0 15,4 42.8 21.0 55.0 36.9 49.6 32.78 14.34 4.14
Heart rate (beats/min.)
BV
Mean
S.D.± S.E.±
Per cent change
109 128 96 129 136 136 130 132 148 176 103 128 129.3 21.0 6.1
I
+ 44%
- 3%
Signifi-
cance
N.S.
I
p
<
0.001
AS
BV
59.5 36.0 33,4 22.0 70.9 37.0 20.2 51.6 53.0 62.5 47.0 53.6 45.56 15.93 4.60
2.3 2.6 1.6 2.2 1,4 1.3 2.0 1.7 1.8 1.9 1.9 1.3 1.83 0,41 0.17
I
+ 39% p
<
Cardiac output (L./min.)
0.001
I
Infundibular orifice area (sq. em.)
BV
1.9 3.0 1.6 1.9 1.2 1.2 1.8 1,4 2.5 1.5 1,4 0.8 1.68 0.59 0.17
0.23 0.34 0.30 0.57 0.15 0.18 0.51 0.17 0.26 0.17 0.23 0.11 0.268 0.143 0.041
AS 0.17 0.33 0.21 0,46 0.13 0.16 0,40 0.14 0.23 0.15 0.18 0.Q7 0.219 0.118 0.034
- 18%
- 8%
N.S.
I
AS
P
<
0.001
Legend: AS, Values after parenteral administration of acetyl strophanthidin, For other abbreviations, see Table I.
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Experimental infundibular pulmonic stenosis
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1 (0.77)\
ISOPROTERENOL
BEFORE CALCIUM CHLORIDE
AFTER CALCIUM CHLORIDE
0.5 mm Hg
0.4
N
E
~
a:
lJJ
. MM
-
200
-
-
150
-
RV
-
50
PA
t.>
!
i:i:
~0.2
#2198
Mean Gradient (mm Hg)
0.1
oL--------------'-----Fig. 3. Comparison of base-line infundibular orifice areas (square centimeters) to those obtained following isoproterenol infusion.
Six dogs were put to death after. completion of the study, and their hearts were examined at necropsy. The remaining 8 survivors were kept for further observations. Results The results of the various provocative interventions are summarized in Tables I through III. The average resting peak systolic gradient (PSG) across the infundibular obstruction was 59 mm. Hg, with a mean gradient of 40.8 mm. Hg, a cardiac output of 2.3 L. per minute, and an infundibular orifice area of 0.29 sq. em. These initial values were used as base lines for the isoproterenol study. Data were subjected to paired statistical analysis to assess significance. Isoproterenol. In the 14 dogs receiving isoproterenol infusion, there was an average rise in the PSG to 115 'mm, Hg, and the mean right ventricular-pulmonary artery gradient rose to 74.5 mm. Hg (Fig. 2). The average cardiac output rose slightly to 2.7 L. per minute, while the orifice area de-
44
Cardiac Output (Llmin) 1.6 Orifice Area Icm2) 0,17
o 77
1.8
0.15
Fig. 4. Simultaneous right ventricular-pulmonary artery pressure recordings. Calcium chloride infusion augmented the gradient while narrowing the infundibular orifice area.
creased to 0.20 sq. em. (Fig. 3). In 11 of the 14 animals, the orifice size decreased, the average change being 29 per cent (p < 0.05). Calcium chloride. Data were obtained in 11 dogs that received an intravenous infusion of calcium chloride. The average PSG increased from a base line of 49 mm. Hg to 85 mm. Hg, while the mean gradient rose from 32.7 to 57.5 mm. Hg (Fig. 4). There was a slight increase in cardiac output, from 1.9 to 2.2 L. per minute, and the orifice area narrowed from 0.25 to 0.22 sq. em. (Fig. 5). In 10 of the 11 dogs, there was a reduction in orifice area, with an average decrease of 14 per cent (p < 0.001). Acetyl strophanthidin. Increments of intravenous acetyl strophanthidin were administered to 12 dogs, and all recorded data were obtained while the animals were in normal sinus rhythm. There was an average increase in the PSG from a base line of 47 mm. Hg to 68 mm. Hg, while the mean right ventricular-pulmonary artery gradient rose from 32.8 to 45.6 mm. Hg (Fig. 6). The cardiac output decreased from 1.8 to
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CONTROL
Thoracic and Cardiovascular Surgery
CALCIUM CHLORIDE
BEFORE ACETYL STROPHANTHIDIN
AFTER ACETYL STROPHANTHIDIN
~~ mm Hg
-200-
0.4
-150N
E
SO.3 <[
w a: <[ w o
iL 0.2
n: o
0.1
OL------L------
Fig. 5. Comparison of base-line infundibular orifice areas (square centimeters) to those obtained following calcium chloride infusion.
Mean Gradient (mm Hg)
51
71
Cardiac Output (L/mm) Orifice Area (cm 2)
1.4
1.3
0.15
0.13
Fig. 6. Simultaneous right ventricular-pulmonary artery pressure recordings. Acetyl strophanthidin augmented the gradient while narrowing the infundibular orifice area.
Discussion 1.7 L. per minute, and the orifice area narrowed from 0.27 to 0.22 sq. em. (Fig. 7). All 12 animals exhibited a reduction in orifice area, with an average decrease of 19 per cent (p < 0.001). Angiocardiography. Selective right ventricular angiocardiograms showed marked infundibular narrowing with a dilated chamber distal to the obstruction (Fig. 8). The right ventricular wall was markedly thickened, and the pulmonic valve appeared normal. Pathologic findings. Necropsy observations on the hearts of 6 dogs revealed right ventricular and septal hypertrophy. The average thickness of the right ventricular free wall was 8.1 mm. (3 to 12 mm. range), compared to a 9.8 mm. (5 to 15 mm. range) average thickness of the left ventricular free wall. A dilated chamber was present distal to the infundibular obstruction, and 3 of the animals had thickened and deformed pulmonary valve leaflets. Direct measurement of the stenotic infundibular orifice compared closely with the resting orifice areas calculated at the time of catheterization.
A similar model has previously been described for surgical creation of infundibular pulmonic stenosis in adult dogs.v > We elected to create this lesion in puppies, with the theory that they would develop right ventricular hypertrophy and progressive compromise of the outflow tract during growth. Documentation of the anatomic similarity of the animal model to clinically encountered infundibular pulmonic stenosis is borne out by the angiocardiographic and necropsy findings discussed above. Brock- described the pulmonary infundibulum as being developmentally and anatomically separate from the remainder of the right ventricular muscle mass, and he felt that it functioned independently. Brock also postulated that in congenital cardiac lesions with infundibular pulmonic stenosis, such as tetralogy of Fallot, the obstruction was dynamic, with the increasing tonus in the infundibular musculature causing decreased pulmonary blood flow and an accompanying increase in right-to-left shunting. Numerous authors have hypothesized the dynamic nature of the obstruction in this disorder and have attributed the cyanotic
Volume 67
Experimental infundibular pulmonic stenosis
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May, 1974
0.6
CONTROL
ACETYL STROPHANTHIDIN
0.5
0.4 N
E S
LJ.I
!1iO.3 LJ.I
o ii: ~
o
0.2
0.1
0'--------'------
Fig. 7. Comparison of base-line infundibular orifice areas (square centimeters) to those obtained following intravenous administration of acetyl strophanthidin.
and syncopal episodes seen in children with Fallot's tetralogy to a spasm of the infundibular musculature. J ohnson" felt that augmented myocardial tone caused by release of norepinephrine was responsible for this condition; he recommended diminishing sympathetic activity as a means of controlling the disorder. Cumming' described 5 patients with tetralogy of Fallot and a history of cyanotic attacks whose right-to-left shunt was increased with isoproterenol infusion. Tikoff and assoc iates" told of a patient with a large ventricular septal defect, pulmonary hypertension, and syncopal episodes in whom right ventricular infundibular obstruction was produced by isoproterenol infusion. Taussig" documented that children with tetralogy of Fallot can obtain relief of extreme cyanosis by squatting, oxygen inhalation, and intravenous morphine. Wood' ? described 2 cases in which "functional pulmonic atresia, " was documented by loss of the outflow tract murmur on auscultation
Fig. 8. Selective right ventricular angiocardiogram demonstrating marked infundibular stenosis, right ventricular hypertrophy, a dilated infundibular chamber distal to the obstruction, and a normalappearing pulmonic valve. IS, Infundibular stenosis. PV, Pulmonic valve.
and phonocardiography; the condition was relieved with cyclopropane anesthesia. Numerous cases have now been described of management of this disorder with beta adrenergic blocking agents; in most reports the results were favorable. Honey's group!' and Shah and Kidd> documented a significant rise in the arterial oxygen saturation in patients with FaUot's tetralogy after treatment with beta blocking agents. Singh and Gotsman].' studied 2 children by phonocardiography and found that the length and amplitude of the outflow murmur was increased after administration of pronethalol. Erickson and associates 14 described 10 patients with tetralogy of Fallot and a history of hypercyanotic spells who experienced marked improvement with long-term propranolol therapy. Mason and colleagues- compared a group of patients with subvalvular pulmonic stenosis against a second group who had discrete obstruction of the right ventricular outflow tract. When these patients were given isoproterenol infusion, the former group
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Thoracic and Cardiovascular Surgery
showed an increase in the PSG, with a rise in cardiac output but an accompanying decrease in the calculated orifice area. On the other hand, the latter group demonstrated a rise in the PSG but no change in orifice area. The authors raised the question of whether other interventions that stimulate myocardial contractility, such as administration of digitalis glycosides, may produce a similar augmentation of the obstruction. In this study, we have shown the usefulness of the above-described model as a means of evaluating the hemodynamic relationships of infundibular pulmonic stenosis. We also revealed the dynamic nature of this muscular obstruction. Isoproterenol infusion produced a significant narrowing of the outflow orifice area. In addition, we have shown that other positive inotropic agents, calcium chloride and acetyl strophanthidin, also aggravate the obstruction. This lesion appears to respond in a manner very similar to the well-documentedw-" dynamic obstruction found in the left ventricular outflow tract of patients with idiopathic hypertrophic subaortic stenosis. The changes in the pulmonic valve observed in 3 of 6 dogs at necropsy are of interest, since the valve was not involved in the operative procedure. These lesions probably resulted from the jet of blood through the proximal stenotic lesion striking the valve leaflets.
fusion narrowed the orifice area in 11 of 14 dogs by an average of 29 per cent (p < 0.05). Ten of 1I animals that received calcium chloride infusion had an average decrease in orifice size of 14 per cent (p < 0.001), and the 12 dogs receiving acetyl strophanthidin showed a narrowing of the outflow tract orifice that averaged 18 per cent (p < 0.001). Selective right ventricular angiocardiography in 3 dogs and necropsy studies on the hearts of 6 animals demonstrated marked infundibular narrowing, right ventricular hypertrophy, and a dilated chamber distal to the obstruction. Three of the 6 animals had thickened, deformed pulmonary valve leaflets. This experimental model demonstrates that stimulation of the contractile state of the myocardium may be detrimental in the presence of muscular infundibular pulmonic stenosis because of the dynamic characteristics of this obstruction. We wish to express our appreciation to Lee Amsler and Allen Nimmons for their excellent technical assistance throughout this investigation. REFERENCES
2
Summary A model of infundibular pulmonic stenosis was created in 14 puppies by suture approximation of the anterior wall of the right ventricle to the septal band of the crista supraventricularis. Five to 6 months later the animals underwent cardiac catheterization. They received intravenous infusions of isoproterenol and calcium chloride and increments of acetyl strophanthidin. The cardiac output, PSG, infundibular blood flow, and orifice area were determined with each provocative measure. The average resting PSG was 59 mm. Hg, the mean gradient 40 mm. Hg, and the orifice area 0.29 sq. em. Isoproterenol in-
3
4
5 6 7
Sabiston, D. C., Jr., and Williams, G. R.: The Experimental Production of Infundibular Pulmonic Stenosis, Ann. Surg. 139: 325, 1954. Alden, J., Hadley, F. J., Adams, W. L., and Baronofsky, I. D.: Cardiodynamics of Experimental Infundibular (Pulmonary) Stenosis: Surgical Forum: Clinical Congress of the American College of Surgeons, 1952, Philadelphia, 1953, W. B. Saunders Company, p. 299. Mason, D. T., Braunwald, E., and Ross, J., Jr.: Hemodynamic Alterations Induced by Isoprenaline in Patients With Obstruction to Right Ventricular Outflow, Br. Heart J. 27: 884, 1965. Godin, R., and Godin, S. G.: Hydraulic Formula for Calculation of the Area of the Stenotic Mitral Valve, Other Cardiac Valves, and Control Circulatory Shunts, Am. Heart J. 41: 1, 1951. Brock, R. C.: Control Mechanisms in the Outflow Tract of the Right Ventricle in Health and Disease, Guys Hosp. Rep. 104: 356, 1955. Johnson, A. M.: Norepinephrine and Cyanotic Attacks in Fallots' Tetralogy, Be. Heart J. 23: 197, 1961. Cumming, G. R.: Effect of Isoproterenol on
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8
9
10 11
12 13
Right to Left Shunts in Patients With Pulmonary Stenosis, Am. J. Cardio!. 15: 622, 1965. Tikoff, G., Schmidt, A. M., and Tsagaris, T. J.: Isoproterenol-Induced Right Ventricular Infundibular Obstruction, Am. J. Cardiol, 20: 873, 1967. Taussig, H. B.: Tetralogy of FaIIot: Especially the Care of the Cyanotic Infant and Child, Pediatrics 1: 307, 1948. Wood, P.: Attacks of Deeper Cyanosis and Loss of Consciousness (Syncope) in Fallot's Tetralogy, Br. Heart 1. 20: 282, 1958. Honey, M., Chamberlain, D. A., and Howard, J.: The Effect of Beta-Sympathetic Blockade on Arterial Oxygen Saturation in FaIIot's Tetralogy, Circulation 30: 501, 1964. Shah, P. M., and Kidd, L.: Circulatory Effects of Propranolol in Children With Fallot's Tetralogy, Am. J. Cardio!. 19: 653, 1967. Singh, S. P., and Gotsman, M. S.: Pronethalol for Cyanotic Attacks, Br, Heart J. 28: 98, 1966.
14 Erickson, R. 0., Thoren, C., and Zetterquist, P.: Long-Term Treatment With Propranolol in Selected Cases of FaIIot's Tetralogy, Br. Heart J. 31: 37, 1969. 15 Braunwald, E., and Ebert, P. A.: Hemodynamic Alterations in Idiopathic Hypertrophic Subaortic Stenosis Induced by Sympathomimetic Drugs, Am. J. Cardio!. 10: 489, 1962. 16 Braunwald, E., Lambrew, C. T., Rockoff, S. D., Ross, J., Jr., and Morrow, A. G.: Idiopathic Hypertrophic Subaortic Stenosis: A Description of the Disease Based Upon an Analysis of 64 Patients, Circulation 30: 3, 1964 (Suppl. IV). 17 Pierce, G. E., Morrow, A. G., and Braunwald, E.: Idiopathic Hypertrophic Subaortic Stenosis: Intraoperative Studies of the Mechanism of Obstruction and Its Hemodynamic Consequences, Circulation 30: 152, 1964 (Suppl. IV).
<
<
Kent W. Jones, M.D., Michael Jones, M.D., Stephen B. Colvin, M.D., Scott 1. Allen, M.D., and Lawrence L. Michaelis, M.D., Bethesda, Md.
Infundibular pulmonic stenosis is a commonly encountered congenital cardiac malformation which occurs singly, in conjunction with valvular pulmonic stenosis, and in association with other congenital intracardiac defects. This lesion was first created experimentally in adult dogs by Sabiston and Williams! and by Alden and his associates." These authors were able to create right ventricular hypertension but did not investigate the hemodynamics of the obstruction. Mason's group" demonstrated the dynamic nature of this muscular obstruction in patients by the use of isoproterenol infusion. From the Clinic of Surgery, National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. 20014. Received for publication Dec. 28, 1973. Address for reprints: Lawrence L. Michaelis, M.D., Clinic of Surgery, National Heart and Lung Institute, Bethesda, Md. 20014.
They postulated that other interventions which stimulate the contractile state of the myocardium, such as digitalis glycosides, may also cause obstruction to pulmonary blood flow. In the present study, infundibular pulmonic stenosis was created surgically in puppies. After the animals had grown for 5 to 6 months, cardiac catheterization was performed with infusion of inotropic medications. The effects of these provocative interventions were studied, and a dynamic subpulmonic obstruction was demonstrated. Material and methods Foxhound puppies, weighing between 4.2 and 6.5 kilograms, were anesthetized by intravenous injection of 2.5 per cent sodium thiamylol (0.1 c.c. per kilogram of body weight). They were intubated and placed on a volume respirator delivering 100 per cent
699
700
The Journol of
Jones et al.
Thorocic ond Cord iovos culor Surgery
AFTER ISU PREL
BEFORE ISUPREL
mm Hg
200
15 0
10 0
50
1111
o
"2198 Mean Gradi ent (mm Hg i
44
Cardia c Output ( L/ ml n ) 2.0 0 .22 Ori f ice Area (cm 2 )
Fig. 1. Anteroposterior view of the canine heart demonstrating the anatomic location of the infundibular obstruction. RCA , Right coronary artery. LAD, Left anterior descending coronary artery.
oxygen and 0.25 to 0.50 per cent halothane. A right thoracotomy was made through the fourth intercostal space, and the pericardium was incised anterior to the phrenic nerve. A No. 1 silk suture was placed through the anterior wall of the right ventricle, to the right of the anterior descending branch of the left coronary artery, and posteriorly through the septal band of the crista supraventricularis; it was brought out through the anterior wall of the right ventricle just to the ventricular side of the right coronary artery (Fig. 1). Then , it was tied tight enough to elevate the systolic right ventricular pressure to approximately one half of the systemic level, while producing an easily palpable thrill over the outflow tract. Sixteen of 26 animals survived the operative procedure and the early postoperative period. The 10 deaths occurred within 48 hours after operation and were thought to be due to acute right heart failure, probably from too tight an initial outflow tract constriction . At autopsy , the right ventricle appeared dilated and the outflow tract mark-
J.
r-,
~L
r'1
\I \,J~
lA,
I'"
0 .5 sec 10 6 2 .3 0 . 15
Fig. 2. Simultaneous right ventricular-pulmonary artery (RV and PA) pressure recordings . Isoproterenol infusion augmented the gradient while narrowing the infundibular orifice area .
edly constricted, but no other abnormalities were found . After a 5 to 6 month period of growth, the 16 survivors were anesthetized as described earlier. A left thoracotomy was performed through the fourth intercostal space, and an indwelling catheter was inserted into the pulmonary artery distal to the pulmonic valve. The opposite end of this catheter was embedded in the subcutaneous tissue of the left thorax. One to 2 weeks later, the animals were again anesthetized with sodium thiamylol, intubated, and placed on a volume respirator that delivered air. An 8 inch catheter was inserted into the femoral artery and was attached to a densitometer. A No. 7 Cournand end-hole catheter was placed in the right ventricle via the femoral vein, and a No. 8 Judkins pig-tailed catheter was inserted into the left ventricle from the opposite femoral artery. A small cutdown was made in the subcutaneous tissue of the left thorax to expose the distal end of the pulmonary artery catheter, and the right ven.tricular and pulmonary artery catheters were attached to an electromanometer for simul-
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Table I. Effects of isoproterenol infusion in 14 dogs Peak systolic gradient (mm. Hg)
Mean gradient (mm. Hg)
II
BV
II
BV
156 204 178 180 180 208 176 231 215 175 256 216 120 173 190.6 33.9 9.1
30 95 61 29 35 58 42 28 86 44 103 91 81 49 59.4 26.8 7.2
90 158 87 98 81 147 83 76 162 96 155 173 123 87 115.4 35.8 9.6
17.5 68.1 36.0 19.2 22.1 44.4 25.0 20.6 58.8 31.9 77.0 61.4 58.3 30.9 40.80 20.27 5.42
Heart rate (beats/ min.)
BV
Mean S.D.± S.E.! Per cent change
I
126 144 126 116 133 148 160 168 150 152 178 184 116 151 146.6 21.5 5.7
Significance
+ 30% p
< 0.001
I
+ 94%
P
<
0.001
II
BV
55.3 93.2 50.0 62.9 48.2 106.1 45.3 58.8 103.3 72.5 97.8 107.0 83.0 59.0 74.46 23.18 6.20
2.9 2.3 3.0 1.4 2.2 2.0 1.3 2.8 2.6 1.4 5.3 2.3 1.3 2.0 2.34 1.04 0.28
I
+ 82% p
<
Cardiac output (L./min.)
0.001
I
Infundibular orifice area (sq. em.)
BV
2.7 3.8 2.9 1.9 2.5 2.2 1.4 3.6 3.6 2.9 3.6 3.6 1.4 2.3 2.67 0.79 0.21
0.77 0.18 0.28 0.22 0.36 0.22 0.17 0.51 0.24 0.26 0.38 0.15 0.11 0.19 0.289 0.174 0.047
+ 14%
N.S.
I
II
II
0.24 0.22 0.25 0.18 0.26 0.15 0.13 0.38 0.21 0.22 0.15 0.16 0.10 0.21 0.204 0.069 0.019
- 29% P
<
0.05
Legend: BV, Base-line values. II, Values after isoproterenol infusion. S.D., Standard deviation. S.E., Standard error. N.S.
Not significant.
taneous recording of base-line pressures. Cardiac output was determined by injection of Cardio-Green dye into the left ventricle with sampling from the femoral artery. The base-line area of the infundibular orifice was calculated by the method of Godin and Gorlin--cthat is, the mean right ventricularpulmonary artery gradient and the calculated cardiac output were used to determine infundibular blood flow. Two animals died early in the catherterization study, prior to pharmacologic intervention. One experienced ventricular fibrillation shortly after the induction of anesthesia, and the second died from anoxia due to respirator malfunction. After stable base-line values had been obtained, 14 dogs were subjected to intravenous isoproterenol infusion (2 to 3 meg. per minute). One animal developed ventricular fibrillation following this infusion, and a technical error in a second animal prevented further study. Therefore, 12 dogs re-
ceived intravenous infusion of calcium chloride (16 to 24 mg. per minute) and increments of acetyl strophanthidin (0.5 to 1.5 mg. over 10 to 15 minutes). A recorder malfunctioned during one calcium infusion, and, as a result, valid measurements were obtained in only 11 animals. Cardiac output, infundibular blood flow, and orifice area were determined with each provocative measure, and new base-line values were obtained following each intervention. Two to 3 weeks after catheterization, 3 dogs were lightly anesthetized, a small incision was made over the external jugular vein, and a polyethylene catheter, Y8 inch in diameter, was threaded into the right ventricle under fluoroscopic visualization. After hand injection of 15 C.c. of 60 per cent sodium iothalamate contrast material, single-plane selective right ventricular angiocardiograms were taken with an 11 by 14 inch Sanchez-Perez film changer (exposing 2 films per second).
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Table II. Effects of calcium chloride infusion in 11 dogs Heart rate (beats/min.)
BV
Mean S.D.± S.E.±
Per cent change Significance
148 132 112 124 160 145 155 159 148 111 127 138.3 17.9 5,4
I
Peak systolic gradient (mm. Hg)
CCI
BV
140 130 104 124 145 140 154 158 140 113 120 133.5 16.9 5.1
68 44 39 24 55 47 26 61 65 67 43 49.0 15.6 4.7
-3%
I CCI 113 76 74 64 114 87 49 99 86 84 84 84.5 19,4 5.9
Mean gradient (mm. Hg)
+ 72%
N.S.
<
p
I
BV 52.5 27.0 24.6 17.5 44,4 31.5 17.6 42.2 41.6 31.5 29,4 32.71 11.27 3.39
CCI 87.9 44.0 42.8 42,4 76.8 53.9 34.9 64.3 68,4 60.0 56.7 57,46 16.18 4.88
Cardiac output (LJmin.)
BV 2.3 3,4 1.8 1.5 1.6 1.4 2.3 1.6 2.1 1.9 1,4
2.6 4.3 2.2 1.9 1.8 1.6 2.8 2.0 2.0 2.2
1.94 0.59 0.18
2.23 0.83 0.25
<
p
1.1
BV
0.001
<
p
I CCI 0.19 0,40 0.22 0.24 0.15 0.15 0,42 0.17 0.17 0.19 0.10 0.218 0.102 0.Q31
0.25 0,46 0.25 0.32 0.17 0.17 0,45 0.17 0.20 0.20 0.16 0.255 0.110 0.033
+ 15%
+ 75%
0.001
I CCI
Infundibular orifice area (sq. em.)
- 14%
0.02
<
p
0.001
Legend: CCI, Values after calcium chloride infusion. For other abbreviations, see Table I.
Table III. Effects of parenteral acetyl strophanthidin in 12 dogs Peak systolic gradient (mm. Hg)
Mean gradient (mm, Hg)
AS
BV
AS
BV
97 156 108 126 116 129 139 126 147 146 88 115 124.4 20.7 5.9
60 33 28 18 83 43 17 68 33 72 43 70 47.3 22.5 6.5
88 54 44 27 98 59 28 92 82 99 70 77 68.2 25.7 7.4
35.8 25.0 18.0 16.0 50.8 27.0 15,4 42.8 21.0 55.0 36.9 49.6 32.78 14.34 4.14
Heart rate (beats/min.)
BV
Mean
S.D.± S.E.±
Per cent change
109 128 96 129 136 136 130 132 148 176 103 128 129.3 21.0 6.1
I
+ 44%
- 3%
Signifi-
cance
N.S.
I
p
<
0.001
AS
BV
59.5 36.0 33,4 22.0 70.9 37.0 20.2 51.6 53.0 62.5 47.0 53.6 45.56 15.93 4.60
2.3 2.6 1.6 2.2 1,4 1.3 2.0 1.7 1.8 1.9 1.9 1.3 1.83 0,41 0.17
I
+ 39% p
<
Cardiac output (L./min.)
0.001
I
Infundibular orifice area (sq. em.)
BV
1.9 3.0 1.6 1.9 1.2 1.2 1.8 1,4 2.5 1.5 1,4 0.8 1.68 0.59 0.17
0.23 0.34 0.30 0.57 0.15 0.18 0.51 0.17 0.26 0.17 0.23 0.11 0.268 0.143 0.041
AS 0.17 0.33 0.21 0,46 0.13 0.16 0,40 0.14 0.23 0.15 0.18 0.Q7 0.219 0.118 0.034
- 18%
- 8%
N.S.
I
AS
P
<
0.001
Legend: AS, Values after parenteral administration of acetyl strophanthidin, For other abbreviations, see Table I.
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Experimental infundibular pulmonic stenosis
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CONTROL
1 (0.77)\
ISOPROTERENOL
BEFORE CALCIUM CHLORIDE
AFTER CALCIUM CHLORIDE
0.5 mm Hg
0.4
N
E
~
a:
lJJ
. MM
-
200
-
-
150
-
RV
-
50
PA
t.>
!
i:i:
~0.2
#2198
Mean Gradient (mm Hg)
0.1
oL--------------'-----Fig. 3. Comparison of base-line infundibular orifice areas (square centimeters) to those obtained following isoproterenol infusion.
Six dogs were put to death after. completion of the study, and their hearts were examined at necropsy. The remaining 8 survivors were kept for further observations. Results The results of the various provocative interventions are summarized in Tables I through III. The average resting peak systolic gradient (PSG) across the infundibular obstruction was 59 mm. Hg, with a mean gradient of 40.8 mm. Hg, a cardiac output of 2.3 L. per minute, and an infundibular orifice area of 0.29 sq. em. These initial values were used as base lines for the isoproterenol study. Data were subjected to paired statistical analysis to assess significance. Isoproterenol. In the 14 dogs receiving isoproterenol infusion, there was an average rise in the PSG to 115 'mm, Hg, and the mean right ventricular-pulmonary artery gradient rose to 74.5 mm. Hg (Fig. 2). The average cardiac output rose slightly to 2.7 L. per minute, while the orifice area de-
44
Cardiac Output (Llmin) 1.6 Orifice Area Icm2) 0,17
o 77
1.8
0.15
Fig. 4. Simultaneous right ventricular-pulmonary artery pressure recordings. Calcium chloride infusion augmented the gradient while narrowing the infundibular orifice area.
creased to 0.20 sq. em. (Fig. 3). In 11 of the 14 animals, the orifice size decreased, the average change being 29 per cent (p < 0.05). Calcium chloride. Data were obtained in 11 dogs that received an intravenous infusion of calcium chloride. The average PSG increased from a base line of 49 mm. Hg to 85 mm. Hg, while the mean gradient rose from 32.7 to 57.5 mm. Hg (Fig. 4). There was a slight increase in cardiac output, from 1.9 to 2.2 L. per minute, and the orifice area narrowed from 0.25 to 0.22 sq. em. (Fig. 5). In 10 of the 11 dogs, there was a reduction in orifice area, with an average decrease of 14 per cent (p < 0.001). Acetyl strophanthidin. Increments of intravenous acetyl strophanthidin were administered to 12 dogs, and all recorded data were obtained while the animals were in normal sinus rhythm. There was an average increase in the PSG from a base line of 47 mm. Hg to 68 mm. Hg, while the mean right ventricular-pulmonary artery gradient rose from 32.8 to 45.6 mm. Hg (Fig. 6). The cardiac output decreased from 1.8 to
704
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0.5
CONTROL
Thoracic and Cardiovascular Surgery
CALCIUM CHLORIDE
BEFORE ACETYL STROPHANTHIDIN
AFTER ACETYL STROPHANTHIDIN
~~ mm Hg
-200-
0.4
-150N
E
SO.3 <[
w a: <[ w o
iL 0.2
n: o
0.1
OL------L------
Fig. 5. Comparison of base-line infundibular orifice areas (square centimeters) to those obtained following calcium chloride infusion.
Mean Gradient (mm Hg)
51
71
Cardiac Output (L/mm) Orifice Area (cm 2)
1.4
1.3
0.15
0.13
Fig. 6. Simultaneous right ventricular-pulmonary artery pressure recordings. Acetyl strophanthidin augmented the gradient while narrowing the infundibular orifice area.
Discussion 1.7 L. per minute, and the orifice area narrowed from 0.27 to 0.22 sq. em. (Fig. 7). All 12 animals exhibited a reduction in orifice area, with an average decrease of 19 per cent (p < 0.001). Angiocardiography. Selective right ventricular angiocardiograms showed marked infundibular narrowing with a dilated chamber distal to the obstruction (Fig. 8). The right ventricular wall was markedly thickened, and the pulmonic valve appeared normal. Pathologic findings. Necropsy observations on the hearts of 6 dogs revealed right ventricular and septal hypertrophy. The average thickness of the right ventricular free wall was 8.1 mm. (3 to 12 mm. range), compared to a 9.8 mm. (5 to 15 mm. range) average thickness of the left ventricular free wall. A dilated chamber was present distal to the infundibular obstruction, and 3 of the animals had thickened and deformed pulmonary valve leaflets. Direct measurement of the stenotic infundibular orifice compared closely with the resting orifice areas calculated at the time of catheterization.
A similar model has previously been described for surgical creation of infundibular pulmonic stenosis in adult dogs.v > We elected to create this lesion in puppies, with the theory that they would develop right ventricular hypertrophy and progressive compromise of the outflow tract during growth. Documentation of the anatomic similarity of the animal model to clinically encountered infundibular pulmonic stenosis is borne out by the angiocardiographic and necropsy findings discussed above. Brock- described the pulmonary infundibulum as being developmentally and anatomically separate from the remainder of the right ventricular muscle mass, and he felt that it functioned independently. Brock also postulated that in congenital cardiac lesions with infundibular pulmonic stenosis, such as tetralogy of Fallot, the obstruction was dynamic, with the increasing tonus in the infundibular musculature causing decreased pulmonary blood flow and an accompanying increase in right-to-left shunting. Numerous authors have hypothesized the dynamic nature of the obstruction in this disorder and have attributed the cyanotic
Volume 67
Experimental infundibular pulmonic stenosis
Number 5
705
May, 1974
0.6
CONTROL
ACETYL STROPHANTHIDIN
0.5
0.4 N
E S
LJ.I
!1iO.3 LJ.I
o ii: ~
o
0.2
0.1
0'--------'------
Fig. 7. Comparison of base-line infundibular orifice areas (square centimeters) to those obtained following intravenous administration of acetyl strophanthidin.
and syncopal episodes seen in children with Fallot's tetralogy to a spasm of the infundibular musculature. J ohnson" felt that augmented myocardial tone caused by release of norepinephrine was responsible for this condition; he recommended diminishing sympathetic activity as a means of controlling the disorder. Cumming' described 5 patients with tetralogy of Fallot and a history of cyanotic attacks whose right-to-left shunt was increased with isoproterenol infusion. Tikoff and assoc iates" told of a patient with a large ventricular septal defect, pulmonary hypertension, and syncopal episodes in whom right ventricular infundibular obstruction was produced by isoproterenol infusion. Taussig" documented that children with tetralogy of Fallot can obtain relief of extreme cyanosis by squatting, oxygen inhalation, and intravenous morphine. Wood' ? described 2 cases in which "functional pulmonic atresia, " was documented by loss of the outflow tract murmur on auscultation
Fig. 8. Selective right ventricular angiocardiogram demonstrating marked infundibular stenosis, right ventricular hypertrophy, a dilated infundibular chamber distal to the obstruction, and a normalappearing pulmonic valve. IS, Infundibular stenosis. PV, Pulmonic valve.
and phonocardiography; the condition was relieved with cyclopropane anesthesia. Numerous cases have now been described of management of this disorder with beta adrenergic blocking agents; in most reports the results were favorable. Honey's group!' and Shah and Kidd> documented a significant rise in the arterial oxygen saturation in patients with FaUot's tetralogy after treatment with beta blocking agents. Singh and Gotsman].' studied 2 children by phonocardiography and found that the length and amplitude of the outflow murmur was increased after administration of pronethalol. Erickson and associates 14 described 10 patients with tetralogy of Fallot and a history of hypercyanotic spells who experienced marked improvement with long-term propranolol therapy. Mason and colleagues- compared a group of patients with subvalvular pulmonic stenosis against a second group who had discrete obstruction of the right ventricular outflow tract. When these patients were given isoproterenol infusion, the former group
The Journal af
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Jones et al.
Thoracic and Cardiovascular Surgery
showed an increase in the PSG, with a rise in cardiac output but an accompanying decrease in the calculated orifice area. On the other hand, the latter group demonstrated a rise in the PSG but no change in orifice area. The authors raised the question of whether other interventions that stimulate myocardial contractility, such as administration of digitalis glycosides, may produce a similar augmentation of the obstruction. In this study, we have shown the usefulness of the above-described model as a means of evaluating the hemodynamic relationships of infundibular pulmonic stenosis. We also revealed the dynamic nature of this muscular obstruction. Isoproterenol infusion produced a significant narrowing of the outflow orifice area. In addition, we have shown that other positive inotropic agents, calcium chloride and acetyl strophanthidin, also aggravate the obstruction. This lesion appears to respond in a manner very similar to the well-documentedw-" dynamic obstruction found in the left ventricular outflow tract of patients with idiopathic hypertrophic subaortic stenosis. The changes in the pulmonic valve observed in 3 of 6 dogs at necropsy are of interest, since the valve was not involved in the operative procedure. These lesions probably resulted from the jet of blood through the proximal stenotic lesion striking the valve leaflets.
fusion narrowed the orifice area in 11 of 14 dogs by an average of 29 per cent (p < 0.05). Ten of 1I animals that received calcium chloride infusion had an average decrease in orifice size of 14 per cent (p < 0.001), and the 12 dogs receiving acetyl strophanthidin showed a narrowing of the outflow tract orifice that averaged 18 per cent (p < 0.001). Selective right ventricular angiocardiography in 3 dogs and necropsy studies on the hearts of 6 animals demonstrated marked infundibular narrowing, right ventricular hypertrophy, and a dilated chamber distal to the obstruction. Three of the 6 animals had thickened, deformed pulmonary valve leaflets. This experimental model demonstrates that stimulation of the contractile state of the myocardium may be detrimental in the presence of muscular infundibular pulmonic stenosis because of the dynamic characteristics of this obstruction. We wish to express our appreciation to Lee Amsler and Allen Nimmons for their excellent technical assistance throughout this investigation. REFERENCES
2
Summary A model of infundibular pulmonic stenosis was created in 14 puppies by suture approximation of the anterior wall of the right ventricle to the septal band of the crista supraventricularis. Five to 6 months later the animals underwent cardiac catheterization. They received intravenous infusions of isoproterenol and calcium chloride and increments of acetyl strophanthidin. The cardiac output, PSG, infundibular blood flow, and orifice area were determined with each provocative measure. The average resting PSG was 59 mm. Hg, the mean gradient 40 mm. Hg, and the orifice area 0.29 sq. em. Isoproterenol in-
3
4
5 6 7
Sabiston, D. C., Jr., and Williams, G. R.: The Experimental Production of Infundibular Pulmonic Stenosis, Ann. Surg. 139: 325, 1954. Alden, J., Hadley, F. J., Adams, W. L., and Baronofsky, I. D.: Cardiodynamics of Experimental Infundibular (Pulmonary) Stenosis: Surgical Forum: Clinical Congress of the American College of Surgeons, 1952, Philadelphia, 1953, W. B. Saunders Company, p. 299. Mason, D. T., Braunwald, E., and Ross, J., Jr.: Hemodynamic Alterations Induced by Isoprenaline in Patients With Obstruction to Right Ventricular Outflow, Br. Heart J. 27: 884, 1965. Godin, R., and Godin, S. G.: Hydraulic Formula for Calculation of the Area of the Stenotic Mitral Valve, Other Cardiac Valves, and Control Circulatory Shunts, Am. Heart J. 41: 1, 1951. Brock, R. C.: Control Mechanisms in the Outflow Tract of the Right Ventricle in Health and Disease, Guys Hosp. Rep. 104: 356, 1955. Johnson, A. M.: Norepinephrine and Cyanotic Attacks in Fallots' Tetralogy, Be. Heart J. 23: 197, 1961. Cumming, G. R.: Effect of Isoproterenol on
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8
9
10 11
12 13
Right to Left Shunts in Patients With Pulmonary Stenosis, Am. J. Cardio!. 15: 622, 1965. Tikoff, G., Schmidt, A. M., and Tsagaris, T. J.: Isoproterenol-Induced Right Ventricular Infundibular Obstruction, Am. J. Cardiol, 20: 873, 1967. Taussig, H. B.: Tetralogy of FaIIot: Especially the Care of the Cyanotic Infant and Child, Pediatrics 1: 307, 1948. Wood, P.: Attacks of Deeper Cyanosis and Loss of Consciousness (Syncope) in Fallot's Tetralogy, Br. Heart 1. 20: 282, 1958. Honey, M., Chamberlain, D. A., and Howard, J.: The Effect of Beta-Sympathetic Blockade on Arterial Oxygen Saturation in FaIIot's Tetralogy, Circulation 30: 501, 1964. Shah, P. M., and Kidd, L.: Circulatory Effects of Propranolol in Children With Fallot's Tetralogy, Am. J. Cardio!. 19: 653, 1967. Singh, S. P., and Gotsman, M. S.: Pronethalol for Cyanotic Attacks, Br, Heart J. 28: 98, 1966.
14 Erickson, R. 0., Thoren, C., and Zetterquist, P.: Long-Term Treatment With Propranolol in Selected Cases of FaIIot's Tetralogy, Br. Heart J. 31: 37, 1969. 15 Braunwald, E., and Ebert, P. A.: Hemodynamic Alterations in Idiopathic Hypertrophic Subaortic Stenosis Induced by Sympathomimetic Drugs, Am. J. Cardio!. 10: 489, 1962. 16 Braunwald, E., Lambrew, C. T., Rockoff, S. D., Ross, J., Jr., and Morrow, A. G.: Idiopathic Hypertrophic Subaortic Stenosis: A Description of the Disease Based Upon an Analysis of 64 Patients, Circulation 30: 3, 1964 (Suppl. IV). 17 Pierce, G. E., Morrow, A. G., and Braunwald, E.: Idiopathic Hypertrophic Subaortic Stenosis: Intraoperative Studies of the Mechanism of Obstruction and Its Hemodynamic Consequences, Circulation 30: 152, 1964 (Suppl. IV).