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Intrauterine production of coarctation of the aorta
Intrauterine production of coarctation of the aorta Studies of hemodynamics and collateral aortic circulation in newborn animals J. Alex Haller, Jr., M.D., I. J. Shaker, M.D. (by invitation), Robert Gingell, M.D. (by invitation), and Charles Ho, M.D. (by invitation), Baltimore, Md.
Coarctation of the aorta in the preductal position (infantile type) has a much higher mortality rate than does coarctation in the postductal position (adult type) .' The frequent association of major intracardiac anomalies with preductal coarctation has been the most accepted explanation for this higher mortality rate." In the presence of a patent ductus arteriosus, however, critical hemodynamic differences might explain the different death rates equally weI!. 3 In addition, the presence or absence of adequate collateral circulation to the distal aorta might be related to the position of the aortic constriction and playa vital role in survival. Although careful clinical and hemodynamic studies of coarctation in infants have contributed greatly to our understanding of this congenital abnormality, no good experimental model has been available for precise hemodynamic studies. The purpose of this paper is to describe a technique for the creation of pre- and postductal coarctation in fetal lambs and to report our hemodynamic From the Divisions of Pediatric Surgery and Pediatric Cardiology, The Johns Hopkins University School of Medicine, Baltimore, Md. 21205. Read at the Fifty-third Annual Meeting of The American Association for Thoracic Surgery, Dallas, Texas, April 16, 17, and 18, 1973.
and angiocardiographic studies to help explain the different mortality rates of pre- and postductal coarctation of the aorta. Operative technique and management of experimental animals
Thirty pregnant ewes of mixed breeds were used with timed gestational ages of 80 to 133 days (term gestation is 138 to 152 days). Each ewe was fasted for 24 hours before operation and then given 50 mg. of Lipo-Lutin and 600,000 units of Bicillin intramuscularly. Induction of anesthesia was begun with 0.4 mg. of atropine and 30 to 40 m!. of 2.5 per cent Surital solution intravenously. Each animal was then intubated with a cuffed endotracheal tube. Anesthesia was maintained with 1 to 2 per cent halothane on an Emerson ventilator. Intraoperatively, each animal received 1 Gm. of ampicillin and 500 ml. of Ringer's lactate via intravenous drip. As the detailed operative technique has been published: only the essential features of the operative technique will be described. A lower midline abdominal incision was made with the electric cautery, care being taken to avoid the tortuous mammary veins. One horn of the pregnant uterus was partially exteriorized and kept moist with 343
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Haller et al.
Fig. 1. Preductal constriction of aorta (coarctation) by nearly complete ligation with IA inch umbilical tape . Operative exposure through left fourth intercostal space of fetal lamb. A, Patent ductus arteriosus. B , Vagu s nerve. C. Intercostal vein. AO, Aorta . PA , Pulmonary a r:ery.
Fig. 2. Postductal coarctation of aorta with umbilical tape constriction. Note relationship to patent ductus arteriosus.
warm saline pads. A 6 to 8 em. incision was made along the antimesenteric border of the uterus , and the left foreleg and chest of the fetal lamb were marsupialized by suture of the fetal skin around the proposed operative site to the edges of the uterotomy. Marsupialization tended to minimize loss of amniotic fluid and prevented inadvertent expulsion of the fetus. The lamb's chest was entered through the fourth intercostal space, and the lung was gently retracted with warm cottonoid packs. The patent ductus arte-
The Journal of Thoracic ond Cord iovascular Surgery
Fig. 3. Aortogram of newborn lamb with postductal coarctation. Collateral circulation is alre ady well formed.
riosus was identified, the pleura over the aorta was incised, and a 1;4 inch umbilical tape was passed carefully around either the preductal or postductal aorta (Figs. 1 and 2). The preductal ligature was tied over a probe to produce a 1 to 2 mm. aortic lumen. (More severe constriction in the postductal aorta resulted in high fetal loss from inadequate aortic blood flow to the placenta .) The chest wall was then closed in layers, the uterotomy closed with a running suture of 2.0 chromic catgut, and the ewe's abdominal wound closed in layers with permanent suture material. Fifty mg. of LipoLutin was given intramuscularly each day for 10 days . The ewes were allowed to feed and drink at will following recovery from anesthesia. Spontaneous delivery was allowed in most animals after an initial trial of cesarean section delivery. Of 14 fetuses in the preductal coarctation group , 5 were born alive, spontaneously, and all animals were stud ied with cardiac catheterization and aortography. Of 20 fetal lambs in the postductal group , 4 were born alive, spontaneously. All 4 had cardiac catheterization and aortography. Seven fetal lambs (4 preductal and 3 postductal) were delivered by cesarean section near term. Six of the 7 lambs died within 24 hours; the seventh lived 8 days and died during cardiac catheterization Aorto-
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Fig. 4. Aortograms of normal lamb (A) and lamb with preductal coarctation (B). Both lambs were 6 months of age but not litter mates. Collateral circulation is somewhat greater in presence of coarctation. Note poststenotic dilatation.
grams were obtained in all 7 lambs within 2 hours of birth . Results Aortography. Aortograms were obtained through the carotid artery . The site of aortic constriction was easily visualized in all studied and was in the correct position according to protocol. Extensive aortic collateral circulation was present in all animals studied. Comparative quantitative differences in the extent of collateral circulation could be determined on subsequent study of the aortograms. Illustrative examples are shown in Fig. 3 and Fig. 4, A and B. Cardiac catheterization. Cardiac catheterization was performed between 3 and 55 days in surviving lambs. Right and retrograde left heart catheterizations were carried out in the research catheterization laboratories of the Department of Pediatrics. The results of these studies are shown in Table I. All lambs with preductal and postductal coarctation had normal pulmonary artery
pressures and no shunting at the ductus arteriosus level. Systolic aortic gradients across the coarcted segment varied from 27 to 54 mm. Hg in the preductal group and from 8 to 35 mm. Hg in the postductal group . Autopsy. Autopsies were performed in all experimental animals except those which were aborted and lost. In all autopsied lambs, the aortic constriction was striking and was more severe in the preductal than in the postductal position. Poststenotic dilatation of the aorta was present in all animals and was more severe in the preductal group . Discussion Intrauterine creation of coarctation of the aorta. In 1967, Jackson and associates- B created postductal coarctation of the aorta in fetal puppies and reported a few postnatal survival studies. Similar studies were carried out by Smith' in 1950 in fetal guinea pigs, but these studies were never reported. Since these early studies, a number of in-
346
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Table I. Comparison of hemodynamic findings in pre- and postductat coarctation of aorta
Lamb No.
Age (days)
Type of coarctation
357 236 258 231 227 904 351 350 314 312
55 8 44 17 31 27 27 3 40 52
Normal Preductal Preductal Preductal Preductal Preductal Postductal Postductal Postductal Postductal
Pulmonary artery pressure" (mm. Hg)
20/ 5 (10) 30/12 (18) 28/13.5 (17) 37/25 (30) 27/10 (15)
Proximal aortic pressure* (mm. Hg)
122/104 (112) 1071 82 ( 88) 107/ 82 ( 88) 127/ 88 (102) 140/100 (120)
Distal aortic pressure * (mm. Hg)
125/102 45/ 35 80/ 73 73/ 66 90/ 80
Systolic pressure gradient (mm. Hg)
(110) ( 40) ( 78) ( 73) ( 85)
No pressures obtained---only cine study available
30/20 (22) 32/13 (19) 18/ 5(11) 23/ 8 (13)
175/116 85/ 50 94/ 80 120/100
(135) ( 64) ( 82) (106)
140/108 70/ 50 86/ 76 100/ 90
(118) ( 58) ( 78) ( 97)
None
48 27 54 50
35 15 8 20
"Figures in parentheses are mean values.
vestigators have produced various congenital type lesions in different animals by means of intrauterine surgical techniques. H. 9 In 1968, Rosenkrantz and associates'? published a comprehensive review of mammalian fetal techniques which included several cardiovascular procedures. The sheep fetus has been extensively studied by Heymann and associates." Their studies on cardiovascular function in the sheep fetus were very helpful in the design of the coarctation experiments reported in this study. Our earlier experience with intrauterine operative procedures on fetal puppies" and fetal pigs" convinced us that mammals with large litters have a higher incidence of postoperative miscarriage. In addition' to the smaller litter, the large size of the sheep fetus made cardiovascular operative procedures somewhat simpler and the hemodynamic studies in the newborn lamb easier. We had the added advantage of several excellent base-line cardiovascular and pulmonary function studies in fetal and newborn lambs. These lamb studies suggest a close similarity in function of the heart and lungs to newborn infants. Lambs which survived the operative procedures and subsequent delivery were generally sturdy animals which tolerated their cardiovascular studies quite well. This experimental preparation appears then to be a useful model for studies of fetal growth and development in the presence of
a severe cardiovascular anomaly and for definitive evaluation of altered hemodynamics in preductal and postductal coarctation of the aorta. Hemodynamic alterations in experimental coarctation of the aorta. Our original hypothesis was that preductal coarctation in a fetal animal would provide minimal or no stimulus to the development of collateral circulation around the constriction because patency of the ductus arteriosus would permit adequate flow to the descending aorta. Therefore, a fetus with preductal coarctation should have very few preformed collateral channels. Thus the descending aorta would have a severely deficient blood flow when the ductus arteriosus closed after birth. In addition, severe hypertension might occur in the proximal aorta because of inadequate collateral outflow, placing increasing strain on the left ventricle and possibly leading to congestive failure. These several factors, we argued, might explain the higher mortality rate associated with preductal as compared with postductal coarctation of the aorta: On the other hand, a coarcted segment in the postductal position of the fetus would necessitate development of adequate collateral aortic circulation if the fetus were to survive, since there is no other route for blood to get to the descending aorta and the placenta. At birth, closure of the patent ductus arteriosus would occur in the pres-
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ence of a very adequate, preformed collateral bed which would ensure satisfactory blood flow to the descending aorta and would decompress the proximal aorta. Comparable survival of newborn lambs with pre- and postductal coarctations probably excludes the collateral circulation hypothesis as an explanation for the higher preductal mortality rate. The aortography studies showed similar collateral aortic circulatory channels in both experimental groups, which strongly suggests that factors other than the position of the coarcted segment were responsible for the development of collateral circulation. It was not possible to produce the same degree of constriction in the postductal position as in the preductal, apparently because severe constriction below the patent ductus arteriosus critically decreased aortic and umbilical artery flow to the placenta. A very severe degree of constriction above the ductus was easily compensated by an increased flow to the descending aorta via the patent ductus arteriosus. Perhaps the stimuli to collateral vessel formation include both obstructed flow to the proximal aorta (preductal coarctation) and inadequate flow or ischemia to the distal aorta (postductal coarctation). No intracardiac abnormalities were associated with the preductal coarctation; therefore, it is possible that the collateral circulation developed differently from that in human subjects. For example, a ventricular septal defect with preductal coarctation might permit a very large left-to-right shunt and pulmonary hypertension rather than aortic hypertension. These altered pressure relationships might change the pattern of collateral aortic circulation. Within our ability to measure visually the collateral aortic circulation which was associated with the two positions of coarctation, there were no differences in survival. The uniform closure of the ductus arteriosus in all experimental lambs strongly suggests that the position of the coarctation does not influence closure of the ductus. Mustard and associates" reported a 90 per
cent mortality rate in patients with preductal coarctation of the aorta associated with a patent ductus as compared with a 60 per cent mortality rate in those with postductal coarctation associated with a patent ductus. These studies suggest that factors other than the coarctation may have been responsible for patency of the ductus arteriosus in that series of patients. The catheterization studies showed normal hemodynamics with the expected pressure gradient across the coarcted site. The mean cardiac outputs of the two groups were comparable as measured by indocyanine green dye studies. These studies resemble closely those reported in infants and young children with coarctation of the aorta. Only in children with severe intracardiac anomalies and/or patent ductus arteriosus were pulmonary artery pressures significantly elevated. The autopsy studies showed a severe stenosis in the preductal position and significant but less striking stenosis in the postductal position. No degenerative or atheromatous changes were seen in the intima or media in these young lambs. In every other way, these experimental lesions appeared comparable to congenital coarctation of the aorta. In her classic series of clinical pathologic studies of coarctation of the aorta, Dr. Maude Abbott' commented upon the high mortality rate associated with the infantile type of coarctation and the lower mortality rate and occasional asymptomatic life course of the adult type of coarctation. She also described and illustrated the extensive collateral circulation associated with the adult form of coarctation of the aorta, emphasizing the main route of collateral circulation through the superior intercostal vessels from the subclavian into the first aortic intercostal vessels. This was also noted by Bla10ck14 in his experimental attempts to bypass the coarcted segment with the subclavian artery. The internal mammary system appeared to be of secondary importance as a collateral channel. Recent clinical observations- 3 have em-
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phasized that the probable explanation for a higher mortality rate in preductal coarctation is the high incidence of associated intracardiac anomalies. In this respect, it is interesting to note that, in 1928, Dr. Maude Abbott' commented in her extensive treatise on coarctation of the aorta, "the graver and more complex anomalies . . . (sic, intracardiac) are very commonly combined with the 'infantile' type but are practically never found associated with the extreme degrees of the classic adult form."
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Conclusions Our studies on pre- and postductal coarctation of the aorta in fetal lambs do not suggest a better explanation for the high mortality rate associated with preductal coarctation than the lethal effects of associated intracardiac anomalies. No significant hemodynamic differences were associated with the position of the two coarcted segments. The patent ductus arteriosus closed in all animals, regardless of the position of the coarcted segment, and the collateral circulation as measured visually from the aortograms did not reveal any noticeable differences. We believe this preparation is a useful model for definitive studies of the altered hemodynamics associated with preand postductal coarctation of the aorta in fetal and newborn animals. The authors are indebted to Dr. Arthur Silverstein, Odd Fellow Professor of Immunology in the Department of Ophthalmology, for his many helpful suggestions and advice in the performance of the intrauterine operative procedures. REFERENCES Abbott, M. E., and Hamilton, W. F.: Coarctation of the Aorta of the Adult Type, Am. Heart J. 3: 381, 1928. 2 Nadas, A. S., and Mody, M. R.: Preductal Coarctation and Hypoplastic Left Heart Complexes, ill Cassels, D. E., editor: The Heart and Circulation in the Newborn and Infant, New York, 1966, Grune & Stratton, Inc. 3 Mustard, W. T., Rowe, R. D., Keith, 1. D., and Sivek, A.: Coarctation of the Aorta With Special Reference to the First Year of Life, Ann. Surg. 141: 429, 1955. 4 Haller, J. A., Jr., Suzuki, H., EI Shafie, M., and Shaker, I. J.: Intrauterine Production of
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14
Coarctation of the Aorta With Normal Birth and Survival, J. Pediatr. Surg. 8: 171, 1973. Jackson, B. T., Piasecki, G. J., and Egdahl, R. H.: Experimental Production of Coarctation of the Aorta in Utero With Prolonged Postnatal Survival, Surg. Forum 14: 290, 1967. Jackson, B. T., and Egdahl, R. H.: The Performance of Complex Fetal Operations in Utero Without Amniotic Fluid Loss or Other Disturbances of Fetal-Maternal Relationships, Surgery 48: 564, 1960. Smith, E. I.: Unpublished data, 1950. Levine, N., Yellin, E., Frater, R. W. M., and State, D.: Hemodynamic Studies of Cardiac Anomalies in the Fetal Lamb: Models of Pulmonary Atresia and Premature Foramen Ovale Closure (Abstr.), Circulation 41, 42: 163, 1970 (Suppl.). Rudolph, A. M., and Heymann, M. A.: Hemodynamic Effects of Interruption of the Aortic Arch in Fetal Lambs (Abstr.), Circulation 41, 42: 163, 1970 (Suppl. III). Rosenkrantz, J. G., Simon, R. c., and Carlisle, J. H.: Fetal Surgery in the Pig With a Review of Other Mammalian Fetal Technics, J. Pediatr. Surg. 3: 392, 1968. Heymann, M. A., and Rudolph, A. M.: Effect of Exteriorization of the Sheep Fetus on its Cardiovascular Function, Circ. Res. 21: 741, 1967. Haller, J. A., Jr., Morgan, W. W., Jr., Rodgers, B. M., Gengos, D. G., and Margulies, S. I.: Chronic Hemodynamic Effects of Occluding the Fetal Ductus Arteriosus, J. THORAC. CARDIOVASC. SURG. 54: 770, 1967. Andrews, H. G., Shermeta, D. W., White, J. J., and Haller, J. A., Jr.: Hepatic Artery Interruption in Fetal and Neonatal Miniature Swine Studies in the Pathogenesis of Biliary Atresia, Surg. Forum 21: 384, 1970. Blalock, A., and Park, E. A.: The Surgical Treatment of Experimental Coarctation of the Aorta, Ann. Surg. 119: 445, 1944.
Discussion DR. GILBERT S. CAMPBELL Little Rock, Ark.
I think it would be remiss not to have at least one person discuss this very fine paper by Dr. Alex Haller. In 1960 Drs. David Snyder, William Jaques, and I reported some studies at the Surgical Forum on creation of postductal coarctation in newborn puppies. In newborn puppies, pulmonary artery pressure is markedly elevated, although it falls toward normal within 5 to 10 days. In those few animals that tolerated postductal coarctation produced at birth and in those few in which the
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ductus arteriosus remained patent, there was a persistent elevation of pulmonary artery pressure. The lung of a normal newborn puppy has marked pulmonary arterial medial hypertrophy. Within I month there is obvious regression of this medial hypertrophy. In pups surviving postductal coarctation of the aorta (induced at birth) with persistent patency of the ductus arteriosus, there is persistence and/or progression of medial hypertrophy following maintenance of pulmonary hypertension. [Slide] Angiograms obtained several months after production of postductal coarctation in newborn calves demonstrated obvious poststenotic dilatation. No dye was observed passing through the duct into the pulmonary artery. Anatomically, the ductus arteriosus was widely patent, and it was very simple to pass a large ballpoint pen through the duct at necropsy. Thus the duct was anatomically widely patent but physiologically closed. We attempted to do what Dr. Haller has done, but in our experiments there were no live births following the induction of in utero coarctation of the aorta at the postductal level. One puppy was
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born alive and appeared to be the runt of the litter. However, the mother, in a moment of anger, engorged the puppy. Thus I have no data on the animal. DR. HALLER (Closing) I would like to thank Dr. Campbell for his comments. The main advantage of using lambs rather than dogs is the smaller litter. The problem with abortion is not nearly so great in small litters as it is in the larger litter animals. I would like to show a slide which is taken from Dr. Maude Abbott's paper in 1928. In her classic paper, in which she showed this extensive development of the collateral circulation, she said in conclusion that the graver and more complex anomalies, the intracardiac ones, are very commonly combined with the infantile type, and they are practically never found associated with even an extreme degree of the classic adult form. The clinical observations which many of us may not have remembered are still valid, and the experimental work does nothing more than document the brilliance of these observations.
Coarctation of the aorta in the preductal position (infantile type) has a much higher mortality rate than does coarctation in the postductal position (adult type) .' The frequent association of major intracardiac anomalies with preductal coarctation has been the most accepted explanation for this higher mortality rate." In the presence of a patent ductus arteriosus, however, critical hemodynamic differences might explain the different death rates equally weI!. 3 In addition, the presence or absence of adequate collateral circulation to the distal aorta might be related to the position of the aortic constriction and playa vital role in survival. Although careful clinical and hemodynamic studies of coarctation in infants have contributed greatly to our understanding of this congenital abnormality, no good experimental model has been available for precise hemodynamic studies. The purpose of this paper is to describe a technique for the creation of pre- and postductal coarctation in fetal lambs and to report our hemodynamic From the Divisions of Pediatric Surgery and Pediatric Cardiology, The Johns Hopkins University School of Medicine, Baltimore, Md. 21205. Read at the Fifty-third Annual Meeting of The American Association for Thoracic Surgery, Dallas, Texas, April 16, 17, and 18, 1973.
and angiocardiographic studies to help explain the different mortality rates of pre- and postductal coarctation of the aorta. Operative technique and management of experimental animals
Thirty pregnant ewes of mixed breeds were used with timed gestational ages of 80 to 133 days (term gestation is 138 to 152 days). Each ewe was fasted for 24 hours before operation and then given 50 mg. of Lipo-Lutin and 600,000 units of Bicillin intramuscularly. Induction of anesthesia was begun with 0.4 mg. of atropine and 30 to 40 m!. of 2.5 per cent Surital solution intravenously. Each animal was then intubated with a cuffed endotracheal tube. Anesthesia was maintained with 1 to 2 per cent halothane on an Emerson ventilator. Intraoperatively, each animal received 1 Gm. of ampicillin and 500 ml. of Ringer's lactate via intravenous drip. As the detailed operative technique has been published: only the essential features of the operative technique will be described. A lower midline abdominal incision was made with the electric cautery, care being taken to avoid the tortuous mammary veins. One horn of the pregnant uterus was partially exteriorized and kept moist with 343
344
Haller et al.
Fig. 1. Preductal constriction of aorta (coarctation) by nearly complete ligation with IA inch umbilical tape . Operative exposure through left fourth intercostal space of fetal lamb. A, Patent ductus arteriosus. B , Vagu s nerve. C. Intercostal vein. AO, Aorta . PA , Pulmonary a r:ery.
Fig. 2. Postductal coarctation of aorta with umbilical tape constriction. Note relationship to patent ductus arteriosus.
warm saline pads. A 6 to 8 em. incision was made along the antimesenteric border of the uterus , and the left foreleg and chest of the fetal lamb were marsupialized by suture of the fetal skin around the proposed operative site to the edges of the uterotomy. Marsupialization tended to minimize loss of amniotic fluid and prevented inadvertent expulsion of the fetus. The lamb's chest was entered through the fourth intercostal space, and the lung was gently retracted with warm cottonoid packs. The patent ductus arte-
The Journal of Thoracic ond Cord iovascular Surgery
Fig. 3. Aortogram of newborn lamb with postductal coarctation. Collateral circulation is alre ady well formed.
riosus was identified, the pleura over the aorta was incised, and a 1;4 inch umbilical tape was passed carefully around either the preductal or postductal aorta (Figs. 1 and 2). The preductal ligature was tied over a probe to produce a 1 to 2 mm. aortic lumen. (More severe constriction in the postductal aorta resulted in high fetal loss from inadequate aortic blood flow to the placenta .) The chest wall was then closed in layers, the uterotomy closed with a running suture of 2.0 chromic catgut, and the ewe's abdominal wound closed in layers with permanent suture material. Fifty mg. of LipoLutin was given intramuscularly each day for 10 days . The ewes were allowed to feed and drink at will following recovery from anesthesia. Spontaneous delivery was allowed in most animals after an initial trial of cesarean section delivery. Of 14 fetuses in the preductal coarctation group , 5 were born alive, spontaneously, and all animals were stud ied with cardiac catheterization and aortography. Of 20 fetal lambs in the postductal group , 4 were born alive, spontaneously. All 4 had cardiac catheterization and aortography. Seven fetal lambs (4 preductal and 3 postductal) were delivered by cesarean section near term. Six of the 7 lambs died within 24 hours; the seventh lived 8 days and died during cardiac catheterization Aorto-
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Fig. 4. Aortograms of normal lamb (A) and lamb with preductal coarctation (B). Both lambs were 6 months of age but not litter mates. Collateral circulation is somewhat greater in presence of coarctation. Note poststenotic dilatation.
grams were obtained in all 7 lambs within 2 hours of birth . Results Aortography. Aortograms were obtained through the carotid artery . The site of aortic constriction was easily visualized in all studied and was in the correct position according to protocol. Extensive aortic collateral circulation was present in all animals studied. Comparative quantitative differences in the extent of collateral circulation could be determined on subsequent study of the aortograms. Illustrative examples are shown in Fig. 3 and Fig. 4, A and B. Cardiac catheterization. Cardiac catheterization was performed between 3 and 55 days in surviving lambs. Right and retrograde left heart catheterizations were carried out in the research catheterization laboratories of the Department of Pediatrics. The results of these studies are shown in Table I. All lambs with preductal and postductal coarctation had normal pulmonary artery
pressures and no shunting at the ductus arteriosus level. Systolic aortic gradients across the coarcted segment varied from 27 to 54 mm. Hg in the preductal group and from 8 to 35 mm. Hg in the postductal group . Autopsy. Autopsies were performed in all experimental animals except those which were aborted and lost. In all autopsied lambs, the aortic constriction was striking and was more severe in the preductal than in the postductal position. Poststenotic dilatation of the aorta was present in all animals and was more severe in the preductal group . Discussion Intrauterine creation of coarctation of the aorta. In 1967, Jackson and associates- B created postductal coarctation of the aorta in fetal puppies and reported a few postnatal survival studies. Similar studies were carried out by Smith' in 1950 in fetal guinea pigs, but these studies were never reported. Since these early studies, a number of in-
346
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Table I. Comparison of hemodynamic findings in pre- and postductat coarctation of aorta
Lamb No.
Age (days)
Type of coarctation
357 236 258 231 227 904 351 350 314 312
55 8 44 17 31 27 27 3 40 52
Normal Preductal Preductal Preductal Preductal Preductal Postductal Postductal Postductal Postductal
Pulmonary artery pressure" (mm. Hg)
20/ 5 (10) 30/12 (18) 28/13.5 (17) 37/25 (30) 27/10 (15)
Proximal aortic pressure* (mm. Hg)
122/104 (112) 1071 82 ( 88) 107/ 82 ( 88) 127/ 88 (102) 140/100 (120)
Distal aortic pressure * (mm. Hg)
125/102 45/ 35 80/ 73 73/ 66 90/ 80
Systolic pressure gradient (mm. Hg)
(110) ( 40) ( 78) ( 73) ( 85)
No pressures obtained---only cine study available
30/20 (22) 32/13 (19) 18/ 5(11) 23/ 8 (13)
175/116 85/ 50 94/ 80 120/100
(135) ( 64) ( 82) (106)
140/108 70/ 50 86/ 76 100/ 90
(118) ( 58) ( 78) ( 97)
None
48 27 54 50
35 15 8 20
"Figures in parentheses are mean values.
vestigators have produced various congenital type lesions in different animals by means of intrauterine surgical techniques. H. 9 In 1968, Rosenkrantz and associates'? published a comprehensive review of mammalian fetal techniques which included several cardiovascular procedures. The sheep fetus has been extensively studied by Heymann and associates." Their studies on cardiovascular function in the sheep fetus were very helpful in the design of the coarctation experiments reported in this study. Our earlier experience with intrauterine operative procedures on fetal puppies" and fetal pigs" convinced us that mammals with large litters have a higher incidence of postoperative miscarriage. In addition' to the smaller litter, the large size of the sheep fetus made cardiovascular operative procedures somewhat simpler and the hemodynamic studies in the newborn lamb easier. We had the added advantage of several excellent base-line cardiovascular and pulmonary function studies in fetal and newborn lambs. These lamb studies suggest a close similarity in function of the heart and lungs to newborn infants. Lambs which survived the operative procedures and subsequent delivery were generally sturdy animals which tolerated their cardiovascular studies quite well. This experimental preparation appears then to be a useful model for studies of fetal growth and development in the presence of
a severe cardiovascular anomaly and for definitive evaluation of altered hemodynamics in preductal and postductal coarctation of the aorta. Hemodynamic alterations in experimental coarctation of the aorta. Our original hypothesis was that preductal coarctation in a fetal animal would provide minimal or no stimulus to the development of collateral circulation around the constriction because patency of the ductus arteriosus would permit adequate flow to the descending aorta. Therefore, a fetus with preductal coarctation should have very few preformed collateral channels. Thus the descending aorta would have a severely deficient blood flow when the ductus arteriosus closed after birth. In addition, severe hypertension might occur in the proximal aorta because of inadequate collateral outflow, placing increasing strain on the left ventricle and possibly leading to congestive failure. These several factors, we argued, might explain the higher mortality rate associated with preductal as compared with postductal coarctation of the aorta: On the other hand, a coarcted segment in the postductal position of the fetus would necessitate development of adequate collateral aortic circulation if the fetus were to survive, since there is no other route for blood to get to the descending aorta and the placenta. At birth, closure of the patent ductus arteriosus would occur in the pres-
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ence of a very adequate, preformed collateral bed which would ensure satisfactory blood flow to the descending aorta and would decompress the proximal aorta. Comparable survival of newborn lambs with pre- and postductal coarctations probably excludes the collateral circulation hypothesis as an explanation for the higher preductal mortality rate. The aortography studies showed similar collateral aortic circulatory channels in both experimental groups, which strongly suggests that factors other than the position of the coarcted segment were responsible for the development of collateral circulation. It was not possible to produce the same degree of constriction in the postductal position as in the preductal, apparently because severe constriction below the patent ductus arteriosus critically decreased aortic and umbilical artery flow to the placenta. A very severe degree of constriction above the ductus was easily compensated by an increased flow to the descending aorta via the patent ductus arteriosus. Perhaps the stimuli to collateral vessel formation include both obstructed flow to the proximal aorta (preductal coarctation) and inadequate flow or ischemia to the distal aorta (postductal coarctation). No intracardiac abnormalities were associated with the preductal coarctation; therefore, it is possible that the collateral circulation developed differently from that in human subjects. For example, a ventricular septal defect with preductal coarctation might permit a very large left-to-right shunt and pulmonary hypertension rather than aortic hypertension. These altered pressure relationships might change the pattern of collateral aortic circulation. Within our ability to measure visually the collateral aortic circulation which was associated with the two positions of coarctation, there were no differences in survival. The uniform closure of the ductus arteriosus in all experimental lambs strongly suggests that the position of the coarctation does not influence closure of the ductus. Mustard and associates" reported a 90 per
cent mortality rate in patients with preductal coarctation of the aorta associated with a patent ductus as compared with a 60 per cent mortality rate in those with postductal coarctation associated with a patent ductus. These studies suggest that factors other than the coarctation may have been responsible for patency of the ductus arteriosus in that series of patients. The catheterization studies showed normal hemodynamics with the expected pressure gradient across the coarcted site. The mean cardiac outputs of the two groups were comparable as measured by indocyanine green dye studies. These studies resemble closely those reported in infants and young children with coarctation of the aorta. Only in children with severe intracardiac anomalies and/or patent ductus arteriosus were pulmonary artery pressures significantly elevated. The autopsy studies showed a severe stenosis in the preductal position and significant but less striking stenosis in the postductal position. No degenerative or atheromatous changes were seen in the intima or media in these young lambs. In every other way, these experimental lesions appeared comparable to congenital coarctation of the aorta. In her classic series of clinical pathologic studies of coarctation of the aorta, Dr. Maude Abbott' commented upon the high mortality rate associated with the infantile type of coarctation and the lower mortality rate and occasional asymptomatic life course of the adult type of coarctation. She also described and illustrated the extensive collateral circulation associated with the adult form of coarctation of the aorta, emphasizing the main route of collateral circulation through the superior intercostal vessels from the subclavian into the first aortic intercostal vessels. This was also noted by Bla10ck14 in his experimental attempts to bypass the coarcted segment with the subclavian artery. The internal mammary system appeared to be of secondary importance as a collateral channel. Recent clinical observations- 3 have em-
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phasized that the probable explanation for a higher mortality rate in preductal coarctation is the high incidence of associated intracardiac anomalies. In this respect, it is interesting to note that, in 1928, Dr. Maude Abbott' commented in her extensive treatise on coarctation of the aorta, "the graver and more complex anomalies . . . (sic, intracardiac) are very commonly combined with the 'infantile' type but are practically never found associated with the extreme degrees of the classic adult form."
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Conclusions Our studies on pre- and postductal coarctation of the aorta in fetal lambs do not suggest a better explanation for the high mortality rate associated with preductal coarctation than the lethal effects of associated intracardiac anomalies. No significant hemodynamic differences were associated with the position of the two coarcted segments. The patent ductus arteriosus closed in all animals, regardless of the position of the coarcted segment, and the collateral circulation as measured visually from the aortograms did not reveal any noticeable differences. We believe this preparation is a useful model for definitive studies of the altered hemodynamics associated with preand postductal coarctation of the aorta in fetal and newborn animals. The authors are indebted to Dr. Arthur Silverstein, Odd Fellow Professor of Immunology in the Department of Ophthalmology, for his many helpful suggestions and advice in the performance of the intrauterine operative procedures. REFERENCES Abbott, M. E., and Hamilton, W. F.: Coarctation of the Aorta of the Adult Type, Am. Heart J. 3: 381, 1928. 2 Nadas, A. S., and Mody, M. R.: Preductal Coarctation and Hypoplastic Left Heart Complexes, ill Cassels, D. E., editor: The Heart and Circulation in the Newborn and Infant, New York, 1966, Grune & Stratton, Inc. 3 Mustard, W. T., Rowe, R. D., Keith, 1. D., and Sivek, A.: Coarctation of the Aorta With Special Reference to the First Year of Life, Ann. Surg. 141: 429, 1955. 4 Haller, J. A., Jr., Suzuki, H., EI Shafie, M., and Shaker, I. J.: Intrauterine Production of
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Coarctation of the Aorta With Normal Birth and Survival, J. Pediatr. Surg. 8: 171, 1973. Jackson, B. T., Piasecki, G. J., and Egdahl, R. H.: Experimental Production of Coarctation of the Aorta in Utero With Prolonged Postnatal Survival, Surg. Forum 14: 290, 1967. Jackson, B. T., and Egdahl, R. H.: The Performance of Complex Fetal Operations in Utero Without Amniotic Fluid Loss or Other Disturbances of Fetal-Maternal Relationships, Surgery 48: 564, 1960. Smith, E. I.: Unpublished data, 1950. Levine, N., Yellin, E., Frater, R. W. M., and State, D.: Hemodynamic Studies of Cardiac Anomalies in the Fetal Lamb: Models of Pulmonary Atresia and Premature Foramen Ovale Closure (Abstr.), Circulation 41, 42: 163, 1970 (Suppl.). Rudolph, A. M., and Heymann, M. A.: Hemodynamic Effects of Interruption of the Aortic Arch in Fetal Lambs (Abstr.), Circulation 41, 42: 163, 1970 (Suppl. III). Rosenkrantz, J. G., Simon, R. c., and Carlisle, J. H.: Fetal Surgery in the Pig With a Review of Other Mammalian Fetal Technics, J. Pediatr. Surg. 3: 392, 1968. Heymann, M. A., and Rudolph, A. M.: Effect of Exteriorization of the Sheep Fetus on its Cardiovascular Function, Circ. Res. 21: 741, 1967. Haller, J. A., Jr., Morgan, W. W., Jr., Rodgers, B. M., Gengos, D. G., and Margulies, S. I.: Chronic Hemodynamic Effects of Occluding the Fetal Ductus Arteriosus, J. THORAC. CARDIOVASC. SURG. 54: 770, 1967. Andrews, H. G., Shermeta, D. W., White, J. J., and Haller, J. A., Jr.: Hepatic Artery Interruption in Fetal and Neonatal Miniature Swine Studies in the Pathogenesis of Biliary Atresia, Surg. Forum 21: 384, 1970. Blalock, A., and Park, E. A.: The Surgical Treatment of Experimental Coarctation of the Aorta, Ann. Surg. 119: 445, 1944.
Discussion DR. GILBERT S. CAMPBELL Little Rock, Ark.
I think it would be remiss not to have at least one person discuss this very fine paper by Dr. Alex Haller. In 1960 Drs. David Snyder, William Jaques, and I reported some studies at the Surgical Forum on creation of postductal coarctation in newborn puppies. In newborn puppies, pulmonary artery pressure is markedly elevated, although it falls toward normal within 5 to 10 days. In those few animals that tolerated postductal coarctation produced at birth and in those few in which the
Volume 66 Number 3 September, 1973
ductus arteriosus remained patent, there was a persistent elevation of pulmonary artery pressure. The lung of a normal newborn puppy has marked pulmonary arterial medial hypertrophy. Within I month there is obvious regression of this medial hypertrophy. In pups surviving postductal coarctation of the aorta (induced at birth) with persistent patency of the ductus arteriosus, there is persistence and/or progression of medial hypertrophy following maintenance of pulmonary hypertension. [Slide] Angiograms obtained several months after production of postductal coarctation in newborn calves demonstrated obvious poststenotic dilatation. No dye was observed passing through the duct into the pulmonary artery. Anatomically, the ductus arteriosus was widely patent, and it was very simple to pass a large ballpoint pen through the duct at necropsy. Thus the duct was anatomically widely patent but physiologically closed. We attempted to do what Dr. Haller has done, but in our experiments there were no live births following the induction of in utero coarctation of the aorta at the postductal level. One puppy was
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born alive and appeared to be the runt of the litter. However, the mother, in a moment of anger, engorged the puppy. Thus I have no data on the animal. DR. HALLER (Closing) I would like to thank Dr. Campbell for his comments. The main advantage of using lambs rather than dogs is the smaller litter. The problem with abortion is not nearly so great in small litters as it is in the larger litter animals. I would like to show a slide which is taken from Dr. Maude Abbott's paper in 1928. In her classic paper, in which she showed this extensive development of the collateral circulation, she said in conclusion that the graver and more complex anomalies, the intracardiac ones, are very commonly combined with the infantile type, and they are practically never found associated with even an extreme degree of the classic adult form. The clinical observations which many of us may not have remembered are still valid, and the experimental work does nothing more than document the brilliance of these observations.