Download Pulmonary arteriovenous shunting in the normal fetal lung

Journal of the American College of Cardiology
© 2004 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 44, No. 7, 2004
ISSN 0735-1097/04/$30.00
doi:10.1016/j.jacc.2004.06.064
Congenital Heart Disease
Pulmonary Arteriovenous
Shunting in the Normal Fetal Lung
David Michael McMullan, MD,* Frank Louis Hanley, MD,† Gordon Alan Cohen, MD, PHD,*
Michael Alan Portman, MD,* Robert Kirk Riemer, PHD†
Seattle, Washington; and Stanford, California
We hypothesized that pulmonary arteriovenous shunting (PAVS) is normally present in fetal
lungs and that cavopulmonary anastomosis-induced PAVS may represent a return to an
earlier morphologic stage of development.
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. (J Am Coll Cardiol 2004;44:1497–500) © 2004 by the
American College of Cardiology Foundation
OBJECTIVES
The surgical superior cavopulmonary anastomosis is performed
as part of the staged Fontan pathway to treat univentricular
forms of congenital heart disease. Pulmonary arteriovenous
shunting (PAVS) is a known complication following superior
cavopulmonary anastomosis and may have important clinical
consequences (1–3). Several possible causes have been proposed, including direct pulmonary artery (PA)-pulmonary
venous fistulas, increased pulmonary capillary angiogenesis,
and pulmonary capillary dilation (4); however, the etiology and
true morphologic basis of cavopulmonary anastomosis-induced
PAVS remains unknown. A leading theory is that pulmonary
arteriovenous communications develop in response to interruption of normal hepatic venous drainage to the pulmonary
circulation. The resultant absence of an uncharacterized hepatic factor is believed to contribute to the development of
PAVS. Resolution of PAVS occurs after the Fontan procedure
or inclusion of hepatic veins in the pulmonary circulation (5,6).
The presence of occasional pulmonary arteriovenous communications in the human fetus has been previously described
From the *University of Washington School of Medicine, Seattle, Washington;
and †Stanford University School of Medicine, Stanford, California. Supported by
grant HL10108-01 (Dr. McMullan) from the National Heart, Lung, and Blood
Institute.
Manuscript received March 11, 2004; revised manuscript received May 14, 2004,
accepted June 1, 2004.
(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.
METHODS
These studies were performed in compliance with animal
welfare regulations of the University of California-San
Francisco and Food and Drug Administration guidelines.
Furthermore, these studies conformed to the “Position of
the American Heart Association on Research Animal Use,”
adopted by the American Heart Association on November
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McMullan et al.
Fetal Pulmonary Arteriovenous Malformations
JACC Vol. 44, No. 7, 2004
October 6, 2004:1497–500
RESULTS
Abbreviations and Acronyms
LA
⫽ left atrium
PA
⫽ pulmonary artery
PAVS ⫽ pulmonary arteriovenous shunting
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.
Contrast bubbles are normally lost in the pulmonary capillary bed. The presence of bubbles in the left atrium (LA)
within three cardiac cycles of injection into the PA indicates
PAVS (11) (Fig. 1). Contrast material circumventing the
lungs through incompetent pulmonary and tricuspid valves
and foramen ovale would appear in the right atrium before
the LA. Similarly, contrast returning to the left side of the
heart via the ductus arteriosus and an incompetent aortic
valve would appear in the left ventricle before the LA.
Contrast material returning to the LA after ascending aorta
injection indicates the presence of systemic-to-LA shunting
through the bronchopulmonary circulation.
We demonstrated PAVS in all prenatal and some early
postnatal lambs; PAVS was detected by epicardial contrast
echocardiography in all fetal sheep (n ⫽ 13) and neonatal
lambs examined at one (n ⫽ 2) and three (n ⫽ 2) days of
life. Pulmonary arteriovenous shunting was detected in two
of four animals studied between six to nine days of life.
Pulmonary arteriovenous shunting was not observed in
animals examined at four weeks of age (n ⫽ 2) or adult
animals (n ⫽ 5). Direct right-to-left intracardiac or systemic
arteriovenous shunting was not observed in any animal.
Systemic-to-LA shunting through the bronchopulmonary
circulation (bronchopulmonary arterial shunting) was not
observed in fetal animals (n ⫽ 8) after injection of contrast
mixture into the ascending aorta.
DISCUSSION
The mechanism by which PAVS develops following superior cavopulmonary anastomosis is not well-understood. A
leading theory is that pulmonary arteriovenous communications develop in response to the absence of an uncharacterized hepatic factor in blood that is returned to the
pulmonary circulation. Pulmonary arteriovenous shunting
has been shown to develop when hepatic venous drainage
bypasses the pulmonary circulation and resolves once hepatic effluent is redirected to the lungs (5,12,13). Furthermore, unilateral cavopulmonary anastomosis generally results in ipsilateral PAVS (14). Although the mechanism by
which hepatic venous drainage modulates pulmonary vascular modeling is unknown, it is intriguing that hepatopulmonary blood flow patterns observed after cavopulmonary
anastomosis mimic those in the fetal circulation. Normally
the lungs receive approximately 8% of the combined fetal
cardiac output (15). Due to physiologic streaming of vena
cava blood flow though the heart, fetal lungs receive blood
that is relatively deficient in hepatic effluent (16). The
disappearance of fetal PAVS shortly after birth may be
related to normal redirection of hepatopulmonary blood
flow as a consequence of foramen ovale closure. Cavopulmonary anastomosis-induced changes in hepatopulmonary
blood flow, therefore, mimic those of the fetal circulation.
Hence, PAVS observed in this setting may represent regres-
JACC Vol. 44, No. 7, 2004
October 6, 2004:1497–500
McMullan et al.
Fetal Pulmonary Arteriovenous Malformations
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Figure 1. Contrast echocardiogram with injection into the main pulmonary artery demonstrating fetal pulmonary arteriovenous shunting. (A and B) Four
chamber view showing the main pulmonary artery (PA), left atrium (LA), and right atrium (RA) before (A) and during (B) contrast injection. (C and D)
Magnified view in a different orientation of the LA and left ventricle (LV) before (C) and during (D) contrast injection in another fetus.
sion of pulmonary vascular remodeling to an earlier (fetal)
developmental state.
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 ␮m in diameter (normal capillary
diameter ⬍7 ␮m) 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
1500
McMullan et al.
Fetal Pulmonary Arteriovenous Malformations
(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.
Acknowledgment
The authors express their gratitude to Jeffrey R. Fineman,
MD, of the University of California, San Francisco, for
providing intellectual and material assistance that made this
work possible.
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 981050371. E-mail: [email protected].
REFERENCES
1. Chang RK, Alejos JC, Atkinson D, et al. Bubble contrast echocardiography in detecting pulmonary arteriovenous shunting in children
with univentricular heart after cavopulmonary anastomosis. J Am Coll
Cardiol 1999;33:2052– 8.
2. Bernstein HS, Brook MM, Silverman NH, Bristow J. Development of
pulmonary arteriovenous fistulae in children after cavopulmonary
shunt. Circulation 1995;92:II309 –14.
3. Bernstein HS, Ursell PC, Brook MM, Hanley FC, Silverman NH,
Bristow J. Fulminant development of pulmonary arteriovenous fistulas
in an infant after total cavopulmonary shunt. Pediatr Cardiol 1996;17:
46 –50.
JACC Vol. 44, No. 7, 2004
October 6, 2004:1497–500
4. Glenn WW. Superior vena cava-pulmonary artery anastomosis. Ann
Thorac Surg 1984;37:9 –11.
5. Srivastava D, Preminger T, Lock JE, et al. Hepatic venous blood and
the development of pulmonary arteriovenous malformations in congenital heart disease. Circulation 1995;92:1217–22.
6. Shah MJ, Rychik J, Fogel MA, Murphy JD, Jacobs ML. Pulmonary
AV malformations after superior cavopulmonary connection: resolution after inclusion of hepatic veins in the pulmonary circulation. Ann
Thorac Surg 1997;63:960 –3.
7. Tobin CE. Arteriovenous shunts in the peropheral pulmonary circulation in the human lung. Thorax 1966;21:197–204.
8. Topol M. Subpleural vascular anastomoses in lungs of human fetuses.
Folia Morphol (Warsz) 1992;51:329 –37.
9. Anabtawi IN, Ellison RG, Ellison LT. Pulmonary arteriovenous
aneurysms and fistulas: anatomical variations, embryology, and classification. Ann Thorac Surg 1965;122:277– 85.
10. Wilkinson MJ, Fagan DG. Postmortem demonstration of intrapulmonary arteriovenous shunting. Arch Dis Child 1990;65:435–7.
11. Van Hare GF, Silverman NH. Contrast two-dimensional echocardiography in congenital heart disease: techniques, indications and
clinical utility. J Am Coll Cardiol 1989;13:673– 86.
12. Moore JW, Kirby WC, Madden WA, et al. Development of pulmonary arteriovenous malformations after modified Fontan operations.
J Thorac Cardiovasc Surg 1989;98:1045–50.
13. Agnoletti G, Borghi A, Annecchino FP, Crupi G. Regression of
pulmonary fistulas in congenital heart disease after redirection of
hepatic venous flow to the lungs. Ann Thorac Surg 2001;72:909 –11.
14. McFaul RC, Tajik AJ, Mair DD, Danielson GK, Seward JB.
Development of pulmonary arteriovenous shunt after superior vena
cava-right pulmonary artery (Glenn) anastomosis: report of four cases.
Circulation 1977;55:212– 6.
15. Heymann MA. Fetal cardiovascular physiology. In: Creasy RK,
Resnik R, editors. Maternal and Fetal Medicine. Philadelphia, PA:
Saunders, 1984:262.
16. Schmidt KG, Silverman NH, Rudolph AM. Assessment of flow
events at the ductus venosus-inferior vena cava junction and at the
foramen ovale in fetal sheep by use of multimodal ultrasound.
Circulation 1996;93:826 –33.
17. Wagenvoort CA, Wagenvoort N. Arterial anastomoses, bronchopulmonary arteries, and pulmobronchial arteries in perinatal lungs. Lab
Invest 1967;16:13–24.
18. Robertson B. The normal intrapulmonary arterial pattern of the
human late fetal and neonatal lung: a microangiographic and histologic
study. Acta Paediatr Scand 1967;56:249 – 64.
19. Feinstein JA, Moore P, Rosenthal DN, Puchalski M, Brook MM.
Comparison of contrast echocardiography versus cardiac catheterization for detection of pulmonary arteriovenous malformations. Am J
Cardiol 2002;89:281–5.
20. Shaw AM, Bunton DC, Fisher A, et al. V-shaped cushion at the
origin of bovine pulmonary supernumerary arteries: structure and
putative function. J Appl Physiol 1999;87:2348 –56.
21. Elliott FM, Reid L. Some new facts about the pulmonary artery and
its branching pattern. Clin Radiol 1965;16:193– 8.