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J Am Coll Cardiol, 2004; 44:1497-1500, doi:10.1016/j.jacc.2004.06.064 © 2004 by the American College of Cardiology Foundation |
* University of Washington School of Medicine, Seattle, Washington
Stanford University School of Medicine, Stanford, California
Manuscript received March 11, 2004; revised manuscript received May 14, 2004, accepted June 1, 2004.
* Reprint requests and correspondence: Dr. David Michael McMullan, University of Washington School of Medicine, 4800 Sand Point Way NE,PO Box 3571/4G-1, Seattle, Washington 98105-0371 (Email: mcmullan{at}u.washington.edu).
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Abstract |
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BACKGROUND: The surgical superior cavopulmonary anastomosis is performed as part of the staged Fontan pathway to treat univentricular forms of congenital heart disease; PAVS is a known sequela after superior cavopulmonary anastomosis and may have important clinical consequences. Although the etiology and true morphology of the structures responsible for PAVS are unknown, a leading theory is that PAVS is caused by absence of normal hepatic venous drainage to the pulmonary circulation.
METHODS: To determine whether normal fetal lungs demonstrate PAVS, we performed contrast echocardiograms on 13 fetal lambs, 8 neonatal lambs, 4 juvenile lambs, and 4 adult sheep using a blended mixture of saline and blood injected directly into the proximal pulmonary artery.
RESULTS: Pulmonary arteriovenous shunting was detected by direct epicardial echocardiography in all fetal lambs (n = 13) and neonatal animals studied at one and three days of life (n = 4) and in two of four animals studied at six to nine days of life. Pulmonary arteriovenous shunting was not present in animals studied at four weeks of life (n = 2) and in adult sheep (n = 5).
CONCLUSIONS: These studies demonstrate that PAVS is normally present in late gestation fetal and early neonatal lambs but then disappears during the later neonatal period. Furthermore, these findings suggest that PAVS associated with cavopulmonary anastomosis or other processes affecting the developing pulmonary circulation may represent a return to an earlier morphologic stage of development.
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The presence of occasional pulmonary arteriovenous communications in the human fetus has been previously described (7,8). Anabtawi et al. (9) proposed that pulmonary arteriovenous fistulas may represent the persistence of minute arteriovenous communications present in the normal fetal and neonatal lung that enlarge to become fistulous and cause precapillary shunting and arterial desaturation later in life. Although there is indirect anatomic evidence linking neonatal PAVS to the presence of abnormal pulmonary vascular structures (10), a relationship between these structures and direct pulmonary arteriovenous communications in the fetus has not been established. The development of pulmonary arteriovenous malformations after surgical cavopulmonary anastomosis may be the result of altered normal postnatal development of the infant lung, leading to phenotypic regression to more primitive (fetal) pulmonary circulation. The purpose of this study was to establish whether pulmonary arteriovenous malformations are present in the normal fetus and to elucidate the natural history of these structures.
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Furthermore, these studies conformed to the "Position of the American Heart Association on Research Animal Use," adopted by the American Heart Association on November 11, 1984, and were approved by the University of California-San Francisco Animal Research Institutional Review Committee.
Fetal studies. Thirteen mixed-breed Western ewes (125 to 145 days gestation; term 145 days) were operated on under sterile conditions. They were preanesthetized with ketamine hydrochloride (10 mg/kg intramuscularly), intubated, then anesthetized with continuous 1% to 2% isoflurane anesthesia. An 18-gauge catheter was inserted into a maternal pedal vein. A midline incision was made in the ventral abdomen, and the pregnant horn of the uterus was exposed. Through a small uterine incision, the left fetal forelimb and chest were exposed, and a left lateral thoracotomy was performed in the third intercostal space. Fetal anesthesia consisted of local anesthesia with 1% lidocaine hydrochloride and ketamine hydrochloride (20 mg intramuscularly). Succinylcholine hydrochloride (3 to 5 mg intramuscularly) was administrated to prevent fetal breathing movements. The pericardium was incised along the main pulmonary trunk, and suspended with tacking sutures. A flexible 18-gauge catheter was introduced into the proximal main PA and secured with a 5.0 proline (Ethicon Inc., Somerville, New Jersey) purse-string suture. An additional flexible catheter was introduced into the ascending aorta in eight of the animals. Two-dimensional cross-sectional epicardial contrast echocardiography was performed using a diagnostic ultrasound system (Aloka Co. Ltd., Tokyo, Japan) and recorded on videotape. A vigorously agitated mixture of saline and blood was used as echogenic contrast solution (11). With all four cardiac chambers visualized, 3 mm of contrast solution was rapidly injected into the main PA of each animal. Eight animals received an additional injection of contrast (3 ml) into the ascending aorta to rule out possible bronchopulmonary shunting. At the conclusion of the study, the fetuses were euthanized with a lethal dose of pentobarbital and delivered from the uterus.
Lamb and adult sheep studies. Eight neonatal (one to nine days of life), two juvenile (four weeks of life), and five adult sheep were preanesthetized with ketamine hydrochloride (10 mg/kg intramuscularly), intubated, then anesthetized with continuous 1% to 2% isoflurane anesthesia. After midline sternotomy, the pericardium was incised, and main PA was cannulated with an 18-gauge catheter. Contrast solution (3 ml, neonatal animals; 5 ml, juvenile and adult animals) was rapidly injected into the main PA. Direct epicardial bubble-contrast echocardiography was performed as previously described. At the conclusion of the study, the animals were euthanized with a lethal dose of pentobarbital.
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Discussion |
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In this study, we observed that PAVS was present in all fetal animals. Occasional direct bronchopulmonary arterial (17), bronchial arteriovenous (17), and pulmonary arteriovenous (8) communications in fetal lung have been previously characterized using sectional microscopy and corrosion casting techniques. The functional importance of these structures is unknown, and most are believed to disappear after birth (18). Using gelatin and microsphere injection techniques, Wilkinson and Fagan (10) demonstrated the presence of direct pulmonary arteriovenous communications measuring up to 55 µm in diameter (normal capillary diameter <7 µm) in postmortem infants. Because these observations were made in the postmortem setting, it is unclear whether these structures represent pathologically altered lung development or abnormal postnatal persistence of normal fetal vascular structures. Furthermore, the highly complex nature of the developing pulmonary circulation precludes systematic and comprehensive evaluation using microscopic techniques.
Contrast echocardiography is a highly sensitive method of detecting left-to-right and PAVS (1,19). Using this technique, we were able to accurately detect PAVS and differentiate it from bronchopulmonary shunting. Our finding that PAVS is present in all fetal animals suggests that direct arteriovenous communications are normally present in the fetal pulmonary circulation and may play a role in normal lung development.
We established that fetal PAVS disappears during early neonatal life and is not present in adolescent or adult sheep. The observed time course of PAVS resolution parallels that of other dynamic changes occurring in the pulmonary circulation such as closure of the ductus arteriosus and falling pulmonary vascular resistance. It is possible that these processes are mediated by similar mechanical and pharmacologic factors. Small, poorly perfused "supernumerary" arteries are present in the normal pulmonary circulation (20,21). Utilizing a unique muscular sphincter, these structures are believed to function as recruitable sources of pulmonary blood flow when oxygenation demands are high (20). Additional studies are needed to further characterize these structures and determine if they play a role in fetal PAVS.
Findings from this study support the concept that cavopulmonary anastomosis-induced PAVS results from alterations in normal lung development due to altered hepatopulmonary blood flow. Because PAVS progresses over time and may be more fulminate in younger patients (3), prolonging normal postnatal hepatopulmonary circulation may confer some protection from subsequent cavopulmonary anastomosis-induced PAVS. Future studies involving the creation of cavopulmonary anastomoses in adult animals are designed to further evaluate the effect of age on of the development of cavopulmonary anastomosis-induced PAVS.
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  A. T. Lovering, L. M. Romer, H. C. Haverkamp, D. F. Pegelow, J. S. Hokanson, and M. W. Eldridge Intrapulmonary shunting and pulmonary gas exchange during normoxic and hypoxic exercise in healthy humans J Appl Physiol, May 1, 2008; 104(5): 1418 - 1425. [Abstract] [Full Text] [PDF]
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