© 2015, Wiley Periodicals, Inc. DOI: 10.1111/echo.12888
Echocardiography
INTRAPULMONARY SHUNTS AND THEIR CLINICAL IMPLICATIONS FOR THE ECHOCARDIOGRAPHER
Embryology and Anatomy of Intrapulmonary Shunts David Michael McMullan, M.D., FACS,* and R. Kirk Riemer, Ph.D.† *Congenital Cardiac Surgery, Seattle Children’s Hospital, Seattle, Washington; and †Department of Cardiothoracic Surgery, Pediatric Cardiac Surgery Division, Stanford University School of Medicine, Stanford, California
Pulmonary vascular shunting poses a major clinical risk. In this brief overview, we discuss the morphological aspects of shunting vessels in the lung, their development, and the regulation of their patency. (Echocardiography 2015;32:S190–S194) Key words: pulmonary arteriovenous malformation, pulmonary artery, shunt Unique anatomic and physiologic features of the pulmonary circulation determine the efficiency and adequacy of gas exchange. A small degree of intrapulmonary shunting, primarily due to bronchial artery-to-pulmonary venous connections that do not affect gas exchange, is present in healthy adults. However, the presence of clinically important intrapulmonary connections between pulmonary arteries and veins that bypass alveolar capillary gas exchange units is a hallmark feature of several cardiac and noncardiac disease states. The anatomic basis for nonphysiologic intrapulmonary shunting is variable and, in many cases, appears to be related to abnormal blood flow patterns through preexisting vasculature structures with abnormal morphologic features. Normal development of the lungs and pulmonary circulation occurs through complex patterns of early fetal foregut differentiation and subsequent interactions between primordial respiratory and cardiac tissue. Lung development and differentiation begins at ~28 days gestation when a median ventral diverticulum, the sulcus laryngotracheitis, develops from the primitive foregut. This outgrowth of tissue elongates to become the primitive lung bud (true lung primordium), which is surrounded by a venous plexus that is an extension of the foregut plexus of veins. The lung bud then bifurcates into units that further develop into the left and right main bronchi. The investing venous plexus then fuses with primitive pulmonary arterAddress for correspondence and reprint requests: R. Kirk Riemer, Ph.D., Department of Cardiothoracic Surgery, Pediatric Cardiac Surgery Division, Stanford University School of Medicine, Stanford,California 94305. Fax: 650-723-9521; E-mail: [email protected]
S190
ies that arise from the sixth aortic arch. The resulting small arteriovenous fistulae then undergo further differentiation and septation to form capillaries and larger vessels. A confluence of some of these venous channels forms a single venous trunk adjacent to the heart, which ultimately fuses with the left atrium to become a portion of the posterior wall of the left atrium.1 After completion of lung differentiation, the overwhelming majority of pulmonary arterial blood flow passes through perialveolar capillary networks before returning to the heart via the pulmonary veins. However, a small portion of blood in the pulmonary circulation bypasses the perialveolar capillary networks, resulting in a physiologic “shunt.” The morphologic and physiologic features of these extracapillary pathways have been the subject of clinical and basic scientific investigation for decades.2,3 An important and unique characteristic of some intrapulmonary shunts is that the underlying anatomic structures responsible for bypassing the perialveolar capillary network appear to respond to physiologic and biochemical stimuli. Inducible pulmonary arteriovenous shunting has been observed in healthy adults during exercise, and it has been proposed that dynamic anatomic intrapulmonary shunting may play a role in impaired pulmonary gas exchange observed during exercise at room air.4 Hypoxia increases shunting, whereas breathing 100% oxygen reduces blood flow through pulmonary arteriovenous shunts.5,6 The negative impact of increased oxygen tension on intrapulmonary shunting does not appear to be modified by pharmacologic modulators of pulmonary vascular tone, such as sildenafil, nifedipine, and acetazolamide.7
Pulmonary AVMs
The capacity to recruit accessory intrapulmonary shunt pathways appears to decrease with age. Exercise and hypoxia-induced anatomic shunting are significantly reduced in older subjects (≥50 years) than their younger counterparts, and older subjects are less likely to have echocardiographic evidence of intrapulmonary shunting at rest than younger individuals.8 Although the signaling pathways that regulate flow through inducible pulmonary shunts that are unknown, catecholamines have been shown to increase intrapulmonary shunts either by direct effects on pulmonary vasculature smooth muscle or by increasing overall pulmonary blood flow.6 Characterization of the unique anatomic structures responsible for intrapulmonary arteriovenous shunting in humans has been the focus of investigations for several decades. Early studies identified what may be described as dilated precapillary arteriovenous communications within the lung parenchyma.2 These so-called supernumerary vessels appear to branch at right angles from precapillary pulmonary arteries and communicate directly with pulmonary veins.9 The luminal diameter of these arteriovenous connections in infants may be as large as 60 lm when measured using calibrated microsphere injection techniques.10 Naturally occurring anatomic pulmonary arteriovenous shunts have also been identified in other mammalian species under normal physiologic conditions, including nonhuman primates.11,12 Microscopic examination of bovine lungs has revealed the presence of V-shaped structures within the walls of supernumerary arteries near their origin from parent conventional arteries.11 The walls in this region of the supernumerary artery contain dynamic musculoelastic cushions, which appear to act as sphincters that regulate the flow of blood into supernumerary vessels. While a direct relationship between sphincter-like cushions embedded in supernumerary vessels and inducible pulmonary arteriovenous shunting has not been established, the potential for these structures to modulate supernumerary vessel blood flow and thereby divert blood away from perialveolar capillary networks suggests that they may play a role in inducible pulmonary arteriovenous shunting.13,14 The presence of pulmonary arteriovenous communications in the human fetus has been described.15 Echocardiography with a simple saline solution agitated to produce microbubbles as the contrast agent6,16,17 was used to demonstrate pulmonary arteriovenous shunting in fetal lambs, suggesting that these structures play a functional role during fetal life.18 The purpose of these channels during fetal development has not been clearly established, but they may play a role in regulating pulmonary vascular resistance and
pulmonary blood flow by acting as functional pressure relief valve to protect the thin-walled perialveolar vasculature. Fetal pulmonary arteriovenous shunting disappears during early neonatal life and is not present in healthy adolescent or adult sheep.14 The 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, suggesting that these processes may be mediated by similar mechanical and biochemical factors. The presence of intrapulmonary shunting beyond the neonatal period may represent the persistence of recruitable fetal arteriovenous communications. There is histologic evidence of clinically significant persistent intrapulmonary arteriovenous communications in the lungs of some premature infants who develop severe perinatal hypoxemia.19 Taken together, these observations suggest that pathologic pulmonary arteriovenous shunting observed in some disease states may be related to incomplete maturation of the functional units responsible for regulating pericapillary blood flow. Echocardiographic evidence of pulmonary arteriovenous shunting beyond the neonatal period is uncommon and, when present, frequently represents a pathologic response to extrapulmonary disease of the liver. Pulmonary arteriovenous shunting also develops in up to 60% of patients who undergo Glenn superior cavopulmonary anastomosis as part of the staged Fontan pathway to treat univentricular forms of congenital heart disease.20 It is commonly believed that PAVMs develop in response of the absence of a putative hepatic-derived venous factor in the pulmonary circulation of these patients because inclusion of hepatic venous drainage prevents or reverses the development of pulmonary shunting in these patients.21,22 Although the elusive hepatic factor responsible for shunting has yet to be identified, there is additional evidence that the liver may exert a tonic inhibitory influence on shunting via AVMs. For example, some hepatic disease states are associated with pulmonary shunting (cirrhosis, hepatopulmonary syndrome). Animal models of the Glenn superior cavopulmonary anastomosis have provided important insights into the vascular morphological changes responsible for induced pulmonary arteriovenous shunting.14 Using calibrated microspheres and corrosion casting techniques, numerous central pulmonary arteriovenous malformations are identifiable within several weeks of the Glenn procedure. These abnormal vascular channels are ≥15 lm in diameter and completely bypass alveolar capillary beds. Increased numbers of parenchymal thin-walled vessels have been reported in clinical studies of patients following Glenn cavoS191
McMullan and Riemer
pulmonary anastomosis.23 These patients also have histologic evidence of increased angiogenesis and pulmonary microvessel density. However, it is unclear whether these vascular structures are of pulmonary or systemic origin or whether they mediate arteriovenous shunting. Prominent tortuous subpleural vessels also develop after cavopulmonary anastomosis before the appearance of echocardiographic evidence of arteriovenous shunting in an animal model of the Glenn procedure.14 The observed vascular changes in the lung periphery appear to be derived from bronchial arteries, indicating that they do not directly contribute arteriovenous shunting. Interestingly, there is evidence that networks of subpleural vessels that join pulmonary arteries and veins are present during midgestation but disappear during later gestational development in humans.15 It is unclear whether the vascular changes that contribute to pulmonary arteriovenous shunting following Glenn anastomosis are the result of structural vascular remodeling (e.g., angiogenesis) or represent altered flow patterns through preexisting vascular beds. There is at least one clinical report of a patient developing rapid onset of clinically significant pulmonary arteriovenous shunting within 72 hours of superior cavopulmonary anastomosis.24 This case strongly suggests that the underlying process that leads to arteriovenous shunting in children following Glenn anastomosis is one of the rerecruitments of preexisting vascular channels. Developing lungs normally receive ~8% of the combined fetal cardiac output blood that they receive is relatively deficient in hepatic effluent because of physiologic streaming of vena cava blood flow through the heart.25,26 Disappearance of fetal arteriovenous shunting shortly after birth may be related to normal redirection of hepatopulmonary blood flow due to closure of the foramen ovale. Cavopulmonary anastomosis-induced changes in hepatopulmonary blood flow therefore mimic those of the fetal circulation. The development of pulmonary arteriovenous shunting in this setting may represent regression of pulmonary vascular remodeling to an earlier (fetal) developmental state. The gross morphology of intrapulmonary shunts, as well as their location within different lung regions is quite variable, although some characteristic presentations may be noted. In angiograms, pathologic shunting vessels present a range of sizes from multiple fine shunts of a reticular or snowflake-like pattern in peripheral lung (well illustrated in McElhinney et al.27), to large, often glomular-like complexes structurally associated with a secondary arterial lobule 2 located in peripheral lung as well as closer to the hilum.28 As children with HHT (hereditary hemorrhagic S192
telangiectasia) tend to be of more advanced age (ca 10 years old) when shunting requires clinical evaluation, their shunting vessels tend to be larger than seen in children undergoing surgical cavopulmonary anastomoses (ca 1 year old). Considering the natural history of intrapulmonary shunting induced either by surgical cavopulmonary anastomosis or by HHT1 genetics (see below), it appears likely that angiographically detectable, clinically significant shunts start out small, at near capillary-like dimensions. Over time, these small shunts enlarge29 possibly through a process typical of physiologic flowinduced vascular enlargement. Shunting may also be reversed under specific conditions. In conditions where the interruption of normal hepatic blood delivery to the affected lung (e.g., surgical cavopulmonary anastomosis) is the inducing stimulus, shunting may be completely eliminated by restoration of hepatic flow delivery through surgery.27 The time course of this reversal is in the order of months, not hours. By contrast, the acute shunting demonstrated during vigorous exercise appears to emanate from an increased patency of normally closed shunts, serving as a type of “pop-off” valve in situations of high pulmonary blood flow or “kinetic energy.”4 Such acutely opening and rapidly closing shunts are possibly the same shunt structures identified in normal fetal lungs. Whether these dynamic shunts may transition to permanently open shunts when an elevated flow condition persists is still unproven. However, such a transition appears quite likely from the large body of data accumulated over the last half century. Importantly though, the shunting vessels demonstrated in normal lung are reportedly not immediately recognizable as arteriovenous connections in histologic sections, a situation that has continued to impair our understanding of shunt structure. As explained by Tobin,2 shunts that allow glass beads as large as 200 microns to bypass capillaries may not be identified in histologic sections of normal lungs, apparently due to their collapse from the elastic contraction of lung tissue and shrinkage by the fixation process. Nonetheless, the weight of available evidences supports the concept that the structures responsible for acute shunting are present in all lungs but not continuously patent, and may at least initially, be distinct from shunting structures arising through genetic or surgical inducement processes. Further, it is worth considering the possibility that chronic flow through the acute type of shunt may result in their remodeling to shunting vessels functionally and histologically indistinguishable from the genetically induced shunts. Regardless of potentially multiple regulatory mechanisms, all vessels ultimately share a funda-
Pulmonary AVMs
mental vascular structural remodeling process (i.e. changes in cellular adhesion, migration, proliferation, and differentiation.). HHT is a disease characterized by dysregulated angiogenesis and results in AVMs in pulmonary and other vascular beds. Mutations in two different transforming growth factor (TGFbeta) signaling receptors, activin receptor-like kinase1 (Alk1), and endoglin (Eng) are associated with HHT, and the disease is now classified as HHT types 1 and 2. The HHT type 1 genotype, with a loss of function mutation in Eng, is more associated with intrapulmonary shunting 28 than is the HHT2 Alk1 mutation genotype.30 TGFbeta signaling is required for normal development of vascular structures but derangement of this signaling pathway results in abnormal vascular wall structure. Eng binds TGFbeta and facilitates receptor activation by presenting it to TGFbeta receptor type one (TGFBRI), which then forms a complex with TGFbeta receptor type two (TGFBRII), initiating downstream signaling via Smads2/3. Recent molecular genetic analysis of HHT1 has implicated a second layer of regulation critical to TGFBRI signaling mediated by the extracellular protease Adam17, a gene mutated in some HHT1 patient cohorts.31 When active Adam17 is expressed, it cleaves TGFBRI and paradoxically, this apparently results in normally regulated angiogenesis by limiting downstream TGFbeta signaling via smad2/3, whereas mutated Adam17 permits the excessive angiogenesis associated with HHT.31 These results demonstrate that regulation of vascular remodeling by TGFbeta family ligands and signaling receptors occurs through a complex, multilayered series of mechanisms that are achieving greater clarity but still incompletely understood. An important overarching implication of these molecular signaling events for the induction of intrapulmonary shunting is that vascular wall integrity is necessarily reduced to enable the angiogenic process, rendering a vessel more susceptible to flow and pressure dynamics and thereby creating a condition for potential vessel enlargement under an increased flow or pressure environment. Summary and Perspective: The clinical risks of significant pulmonary vascular shunting are manifold. The majority of cases of intrapulmonary shunting may emanate from genetic or congenital mechanisms involving vascular remodeling, or an apparent failure of fetal circulatory paths to regress. However, shunting can also develop acutely, suggesting probable mechanical control of shunt patency through still undefined mechanisms. The anatomic basis of many types of pulmonary shunting has been dis-
cussed from the perspectives of the sheep fetus or surgical models causing the induction of shunting. Many more investigation is needed to develop more optimal approaches for identifying and quantitating shunting as well as the potential contribution of the bronchial circulation to shunting. A question deserving more attention is how capillary dimension is determined and regulated, and whether more direct evidence for capillary plasticity eventuating in the formation of a physical shunt may be found. Further, a promising direction to pursue may be further identification of common structural and regulatory signaling connections between genetic lesions in which vascular remodeling is implicated (e.g., in TGFbeta receptor signaling), and acute shunting in which reversible occlusion appears to be modulated by a variety of physiologic conditions. References 1. Anabtawi IN, Ellison RG, Ellison LT: Pulmonary arteriovenous aneurysms and fistulas. anatomical variations, embryology, and classification. Ann Thorac Surg 1965;122:277–285. 2. Tobin CE: Arteriovenous shunts in the peropheral pulmonary circulation in the human lung. Thorax 1966;21: 197–204. 3. Hoffman JI: Normal and abnormal pulmonary arteriovenous shunting: Occurrence and mechanisms. Cardiol Young 2013;23:629–641. 4. Stickland MK, Welsh RC, Haykowsky MJ, et al: Intra-pulmonary shunt and pulmonary gas exchange during exercise in humans. J Physiol 2004;561:321–329. 5. Laurie SS, Yang X, Elliott JE, et al: Hypoxia-induced intrapulmonary arteriovenous shunting at rest in healthy humans. J Appl Physiol 2010;109:1072–1079. 6. Laurie SS, Elliott JE, Goodman RD, et al: Catecholamineinduced opening of intrapulmonary arteriovenous anastomoses in healthy humans at rest. J Appl Physiol 2012;113:1213–1222. 7. Elliott JE, Friedman JM, Futral JE, et al: Sildenafil, nifedipine and acetazolamide do not allow for blood flow through intrapulmonary arteriovenous anastomoses during exercise while breathing 100% oxygen. Exp Physiol 2014;99:1636–1647. 8. Cameron Norris H, Mangum TS, Duke JW, et al: Exerciseand hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses is reduced in older adults. J Appl Physiol 2014:116:1324–1333. 9. Elliott FM, Reid L: Some new facts about the pulmonary artery and its branching pattern. Clin Radiol 1965;16:193–198. 10. Wilkinson MJ, Fagan DG: Postmortem demonstration of intrapulmonary arteriovenous shunting. Arch Dis Child 1990;65:435–437. 11. 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;87:2348–2356. 12. Lovering AT, Stickland MK, Kelso AJ, et al: Direct demonstration of 25- and 50-microm arteriovenous pathways in 1healthy human and baboon lungs. Am J Physiol Heart Circ Physiol 2007;292:H1777–H1781. 13. Starnes SL, Duncan BW, Fraga CH, et al: Rat model of pulmonary arteriovenous malformations after right supe-
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14.
15. 16.
17.
18. 19.
20. 21.
22.
23.
rior cavopulmonary anastomosis. Am J Physiol Heart Circ Physiol 2002;283:H2151–H2156. McMullan DM, Reddy VM, Gottliebson WM, et al: Morphological studies of pulmonary arteriovenous shunting in a lamb model of superior cavopulmonary anastomosis. Pediatr Cardiol 2008;29:706–712. Topol M: Subpleural vascular anastomoses in lungs of human fetuses. Folia Morphol (Warsz) 1992;51:329–337. Van Hare GF, Silverman NH: Contrast two-dimensional echocardiography in congenital heart disease: Techniques, indications and clinical utility. J Am Coll Cardiol 1989;13:673–686. Hong SN, Nayar A, Srichai MB, et al: A case of an anomalous superior vena cava with anomalous pulmonary veins-when two wrongs do not make a right. Echocardiography 2011;28:E39–E41. McMullan DM, Hanley FL, Cohen GA, et al: Pulmonary arteriovenous shunting in the normal fetal lung. J Am Coll Cardiol 2004;44:1497–1500. Galambos C, Sims-Lucas S, Abman SH: Histologic evidence of intrapulmonary anastomoses by three-dimensional reconstruction in severe bronchopulmonary dysplasia. Ann Am Thorac Soc 2013;10:474–481. Bernstein HS, Brook MM, Silverman NH, et al: Development of pulmonary arteriovenous fistulae in children after cavopulmonary shunt. Circulation 1995:92:II309–II314. Shah MJ, Rychik J, Fogel MA, et al: Pulmonary AV malformations after superior cavopulmonary connection: Resolution after inclusion of hepatic veins in the pulmonary circulation. Ann Thorac Surg 1997;63:960–963. Srivastava D, Preminger T, Lock JE, et al: Hepatic venous blood and the development of pulmonary arteriovenous malformations in congenital heart disease. Circulation 1995;92:1217–1222. Starnes SL, Duncan BW, Kneebone JM, et al: Pulmonary microvessel density is a marker of angiogenesis in chil-
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25. 26.
27.
28. 29. 30.
31.
dren after cavopulmonary anastomosis. J Thorac Cardiovasc Surg 2000;120:902–907. Pandurangi UM, Shah MJ, Murali R, et al: Rapid onset of pulmonary arteriovenous malformations after cavopulmonary anastomosis. Ann Thorac Surg 1999;68: 237–239. Heymann MA: Fetal cardiovascular physiology. In Creasy RK, Resnik R (eds): Maternal and Fetal Medicine. Philadelphia, PA: Saunders, 1984, p. 262. 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– 833. McElhinney DB, Marx GR, Marshall AC, et al: Cavopulmonary pathway modification in patients with heterotaxy and newly diagnosed or persistent pulmonary arteriovenous malformations after a modified Fontan operation. J Thorac Cardiovasc Surg 2011;141:1362– 1370.e1. Giordano P, Lenato GM, Suppressa P, et al: Hereditary hemorrhagic telangiectasia: Arteriovenous malformations in children. J Pediatr 2013;163:179–186.e1-3. Cartin-Ceba R, Swanson KL, Krowka MJ: Pulmonary arteriovenous malformations. Chest 2013;144:1033– 1044. Mahmoud M, Upton PD, Arthur HM: Angiogenesis regulation by TGFbeta signalling: Clues from an inherited vascular disease. Biochem Soc Trans 2011;39:1659– 1666. Kawasaki K, Freimuth J, Meyer DS, et al: Genetic variants of Adam17 differentially regulate TGFbeta signaling to modify vascular pathology in mice and humans. Proc Natl Acad Sci USA 2014;111:7723–7728.
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Echocardiography
INTRAPULMONARY SHUNTS AND THEIR CLINICAL IMPLICATIONS FOR THE ECHOCARDIOGRAPHER
Embryology and Anatomy of Intrapulmonary Shunts David Michael McMullan, M.D., FACS,* and R. Kirk Riemer, Ph.D.† *Congenital Cardiac Surgery, Seattle Children’s Hospital, Seattle, Washington; and †Department of Cardiothoracic Surgery, Pediatric Cardiac Surgery Division, Stanford University School of Medicine, Stanford, California
Pulmonary vascular shunting poses a major clinical risk. In this brief overview, we discuss the morphological aspects of shunting vessels in the lung, their development, and the regulation of their patency. (Echocardiography 2015;32:S190–S194) Key words: pulmonary arteriovenous malformation, pulmonary artery, shunt Unique anatomic and physiologic features of the pulmonary circulation determine the efficiency and adequacy of gas exchange. A small degree of intrapulmonary shunting, primarily due to bronchial artery-to-pulmonary venous connections that do not affect gas exchange, is present in healthy adults. However, the presence of clinically important intrapulmonary connections between pulmonary arteries and veins that bypass alveolar capillary gas exchange units is a hallmark feature of several cardiac and noncardiac disease states. The anatomic basis for nonphysiologic intrapulmonary shunting is variable and, in many cases, appears to be related to abnormal blood flow patterns through preexisting vasculature structures with abnormal morphologic features. Normal development of the lungs and pulmonary circulation occurs through complex patterns of early fetal foregut differentiation and subsequent interactions between primordial respiratory and cardiac tissue. Lung development and differentiation begins at ~28 days gestation when a median ventral diverticulum, the sulcus laryngotracheitis, develops from the primitive foregut. This outgrowth of tissue elongates to become the primitive lung bud (true lung primordium), which is surrounded by a venous plexus that is an extension of the foregut plexus of veins. The lung bud then bifurcates into units that further develop into the left and right main bronchi. The investing venous plexus then fuses with primitive pulmonary arterAddress for correspondence and reprint requests: R. Kirk Riemer, Ph.D., Department of Cardiothoracic Surgery, Pediatric Cardiac Surgery Division, Stanford University School of Medicine, Stanford,California 94305. Fax: 650-723-9521; E-mail: [email protected]
S190
ies that arise from the sixth aortic arch. The resulting small arteriovenous fistulae then undergo further differentiation and septation to form capillaries and larger vessels. A confluence of some of these venous channels forms a single venous trunk adjacent to the heart, which ultimately fuses with the left atrium to become a portion of the posterior wall of the left atrium.1 After completion of lung differentiation, the overwhelming majority of pulmonary arterial blood flow passes through perialveolar capillary networks before returning to the heart via the pulmonary veins. However, a small portion of blood in the pulmonary circulation bypasses the perialveolar capillary networks, resulting in a physiologic “shunt.” The morphologic and physiologic features of these extracapillary pathways have been the subject of clinical and basic scientific investigation for decades.2,3 An important and unique characteristic of some intrapulmonary shunts is that the underlying anatomic structures responsible for bypassing the perialveolar capillary network appear to respond to physiologic and biochemical stimuli. Inducible pulmonary arteriovenous shunting has been observed in healthy adults during exercise, and it has been proposed that dynamic anatomic intrapulmonary shunting may play a role in impaired pulmonary gas exchange observed during exercise at room air.4 Hypoxia increases shunting, whereas breathing 100% oxygen reduces blood flow through pulmonary arteriovenous shunts.5,6 The negative impact of increased oxygen tension on intrapulmonary shunting does not appear to be modified by pharmacologic modulators of pulmonary vascular tone, such as sildenafil, nifedipine, and acetazolamide.7
Pulmonary AVMs
The capacity to recruit accessory intrapulmonary shunt pathways appears to decrease with age. Exercise and hypoxia-induced anatomic shunting are significantly reduced in older subjects (≥50 years) than their younger counterparts, and older subjects are less likely to have echocardiographic evidence of intrapulmonary shunting at rest than younger individuals.8 Although the signaling pathways that regulate flow through inducible pulmonary shunts that are unknown, catecholamines have been shown to increase intrapulmonary shunts either by direct effects on pulmonary vasculature smooth muscle or by increasing overall pulmonary blood flow.6 Characterization of the unique anatomic structures responsible for intrapulmonary arteriovenous shunting in humans has been the focus of investigations for several decades. Early studies identified what may be described as dilated precapillary arteriovenous communications within the lung parenchyma.2 These so-called supernumerary vessels appear to branch at right angles from precapillary pulmonary arteries and communicate directly with pulmonary veins.9 The luminal diameter of these arteriovenous connections in infants may be as large as 60 lm when measured using calibrated microsphere injection techniques.10 Naturally occurring anatomic pulmonary arteriovenous shunts have also been identified in other mammalian species under normal physiologic conditions, including nonhuman primates.11,12 Microscopic examination of bovine lungs has revealed the presence of V-shaped structures within the walls of supernumerary arteries near their origin from parent conventional arteries.11 The walls in this region of the supernumerary artery contain dynamic musculoelastic cushions, which appear to act as sphincters that regulate the flow of blood into supernumerary vessels. While a direct relationship between sphincter-like cushions embedded in supernumerary vessels and inducible pulmonary arteriovenous shunting has not been established, the potential for these structures to modulate supernumerary vessel blood flow and thereby divert blood away from perialveolar capillary networks suggests that they may play a role in inducible pulmonary arteriovenous shunting.13,14 The presence of pulmonary arteriovenous communications in the human fetus has been described.15 Echocardiography with a simple saline solution agitated to produce microbubbles as the contrast agent6,16,17 was used to demonstrate pulmonary arteriovenous shunting in fetal lambs, suggesting that these structures play a functional role during fetal life.18 The purpose of these channels during fetal development has not been clearly established, but they may play a role in regulating pulmonary vascular resistance and
pulmonary blood flow by acting as functional pressure relief valve to protect the thin-walled perialveolar vasculature. Fetal pulmonary arteriovenous shunting disappears during early neonatal life and is not present in healthy adolescent or adult sheep.14 The 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, suggesting that these processes may be mediated by similar mechanical and biochemical factors. The presence of intrapulmonary shunting beyond the neonatal period may represent the persistence of recruitable fetal arteriovenous communications. There is histologic evidence of clinically significant persistent intrapulmonary arteriovenous communications in the lungs of some premature infants who develop severe perinatal hypoxemia.19 Taken together, these observations suggest that pathologic pulmonary arteriovenous shunting observed in some disease states may be related to incomplete maturation of the functional units responsible for regulating pericapillary blood flow. Echocardiographic evidence of pulmonary arteriovenous shunting beyond the neonatal period is uncommon and, when present, frequently represents a pathologic response to extrapulmonary disease of the liver. Pulmonary arteriovenous shunting also develops in up to 60% of patients who undergo Glenn superior cavopulmonary anastomosis as part of the staged Fontan pathway to treat univentricular forms of congenital heart disease.20 It is commonly believed that PAVMs develop in response of the absence of a putative hepatic-derived venous factor in the pulmonary circulation of these patients because inclusion of hepatic venous drainage prevents or reverses the development of pulmonary shunting in these patients.21,22 Although the elusive hepatic factor responsible for shunting has yet to be identified, there is additional evidence that the liver may exert a tonic inhibitory influence on shunting via AVMs. For example, some hepatic disease states are associated with pulmonary shunting (cirrhosis, hepatopulmonary syndrome). Animal models of the Glenn superior cavopulmonary anastomosis have provided important insights into the vascular morphological changes responsible for induced pulmonary arteriovenous shunting.14 Using calibrated microspheres and corrosion casting techniques, numerous central pulmonary arteriovenous malformations are identifiable within several weeks of the Glenn procedure. These abnormal vascular channels are ≥15 lm in diameter and completely bypass alveolar capillary beds. Increased numbers of parenchymal thin-walled vessels have been reported in clinical studies of patients following Glenn cavoS191
McMullan and Riemer
pulmonary anastomosis.23 These patients also have histologic evidence of increased angiogenesis and pulmonary microvessel density. However, it is unclear whether these vascular structures are of pulmonary or systemic origin or whether they mediate arteriovenous shunting. Prominent tortuous subpleural vessels also develop after cavopulmonary anastomosis before the appearance of echocardiographic evidence of arteriovenous shunting in an animal model of the Glenn procedure.14 The observed vascular changes in the lung periphery appear to be derived from bronchial arteries, indicating that they do not directly contribute arteriovenous shunting. Interestingly, there is evidence that networks of subpleural vessels that join pulmonary arteries and veins are present during midgestation but disappear during later gestational development in humans.15 It is unclear whether the vascular changes that contribute to pulmonary arteriovenous shunting following Glenn anastomosis are the result of structural vascular remodeling (e.g., angiogenesis) or represent altered flow patterns through preexisting vascular beds. There is at least one clinical report of a patient developing rapid onset of clinically significant pulmonary arteriovenous shunting within 72 hours of superior cavopulmonary anastomosis.24 This case strongly suggests that the underlying process that leads to arteriovenous shunting in children following Glenn anastomosis is one of the rerecruitments of preexisting vascular channels. Developing lungs normally receive ~8% of the combined fetal cardiac output blood that they receive is relatively deficient in hepatic effluent because of physiologic streaming of vena cava blood flow through the heart.25,26 Disappearance of fetal arteriovenous shunting shortly after birth may be related to normal redirection of hepatopulmonary blood flow due to closure of the foramen ovale. Cavopulmonary anastomosis-induced changes in hepatopulmonary blood flow therefore mimic those of the fetal circulation. The development of pulmonary arteriovenous shunting in this setting may represent regression of pulmonary vascular remodeling to an earlier (fetal) developmental state. The gross morphology of intrapulmonary shunts, as well as their location within different lung regions is quite variable, although some characteristic presentations may be noted. In angiograms, pathologic shunting vessels present a range of sizes from multiple fine shunts of a reticular or snowflake-like pattern in peripheral lung (well illustrated in McElhinney et al.27), to large, often glomular-like complexes structurally associated with a secondary arterial lobule 2 located in peripheral lung as well as closer to the hilum.28 As children with HHT (hereditary hemorrhagic S192
telangiectasia) tend to be of more advanced age (ca 10 years old) when shunting requires clinical evaluation, their shunting vessels tend to be larger than seen in children undergoing surgical cavopulmonary anastomoses (ca 1 year old). Considering the natural history of intrapulmonary shunting induced either by surgical cavopulmonary anastomosis or by HHT1 genetics (see below), it appears likely that angiographically detectable, clinically significant shunts start out small, at near capillary-like dimensions. Over time, these small shunts enlarge29 possibly through a process typical of physiologic flowinduced vascular enlargement. Shunting may also be reversed under specific conditions. In conditions where the interruption of normal hepatic blood delivery to the affected lung (e.g., surgical cavopulmonary anastomosis) is the inducing stimulus, shunting may be completely eliminated by restoration of hepatic flow delivery through surgery.27 The time course of this reversal is in the order of months, not hours. By contrast, the acute shunting demonstrated during vigorous exercise appears to emanate from an increased patency of normally closed shunts, serving as a type of “pop-off” valve in situations of high pulmonary blood flow or “kinetic energy.”4 Such acutely opening and rapidly closing shunts are possibly the same shunt structures identified in normal fetal lungs. Whether these dynamic shunts may transition to permanently open shunts when an elevated flow condition persists is still unproven. However, such a transition appears quite likely from the large body of data accumulated over the last half century. Importantly though, the shunting vessels demonstrated in normal lung are reportedly not immediately recognizable as arteriovenous connections in histologic sections, a situation that has continued to impair our understanding of shunt structure. As explained by Tobin,2 shunts that allow glass beads as large as 200 microns to bypass capillaries may not be identified in histologic sections of normal lungs, apparently due to their collapse from the elastic contraction of lung tissue and shrinkage by the fixation process. Nonetheless, the weight of available evidences supports the concept that the structures responsible for acute shunting are present in all lungs but not continuously patent, and may at least initially, be distinct from shunting structures arising through genetic or surgical inducement processes. Further, it is worth considering the possibility that chronic flow through the acute type of shunt may result in their remodeling to shunting vessels functionally and histologically indistinguishable from the genetically induced shunts. Regardless of potentially multiple regulatory mechanisms, all vessels ultimately share a funda-
Pulmonary AVMs
mental vascular structural remodeling process (i.e. changes in cellular adhesion, migration, proliferation, and differentiation.). HHT is a disease characterized by dysregulated angiogenesis and results in AVMs in pulmonary and other vascular beds. Mutations in two different transforming growth factor (TGFbeta) signaling receptors, activin receptor-like kinase1 (Alk1), and endoglin (Eng) are associated with HHT, and the disease is now classified as HHT types 1 and 2. The HHT type 1 genotype, with a loss of function mutation in Eng, is more associated with intrapulmonary shunting 28 than is the HHT2 Alk1 mutation genotype.30 TGFbeta signaling is required for normal development of vascular structures but derangement of this signaling pathway results in abnormal vascular wall structure. Eng binds TGFbeta and facilitates receptor activation by presenting it to TGFbeta receptor type one (TGFBRI), which then forms a complex with TGFbeta receptor type two (TGFBRII), initiating downstream signaling via Smads2/3. Recent molecular genetic analysis of HHT1 has implicated a second layer of regulation critical to TGFBRI signaling mediated by the extracellular protease Adam17, a gene mutated in some HHT1 patient cohorts.31 When active Adam17 is expressed, it cleaves TGFBRI and paradoxically, this apparently results in normally regulated angiogenesis by limiting downstream TGFbeta signaling via smad2/3, whereas mutated Adam17 permits the excessive angiogenesis associated with HHT.31 These results demonstrate that regulation of vascular remodeling by TGFbeta family ligands and signaling receptors occurs through a complex, multilayered series of mechanisms that are achieving greater clarity but still incompletely understood. An important overarching implication of these molecular signaling events for the induction of intrapulmonary shunting is that vascular wall integrity is necessarily reduced to enable the angiogenic process, rendering a vessel more susceptible to flow and pressure dynamics and thereby creating a condition for potential vessel enlargement under an increased flow or pressure environment. Summary and Perspective: The clinical risks of significant pulmonary vascular shunting are manifold. The majority of cases of intrapulmonary shunting may emanate from genetic or congenital mechanisms involving vascular remodeling, or an apparent failure of fetal circulatory paths to regress. However, shunting can also develop acutely, suggesting probable mechanical control of shunt patency through still undefined mechanisms. The anatomic basis of many types of pulmonary shunting has been dis-
cussed from the perspectives of the sheep fetus or surgical models causing the induction of shunting. Many more investigation is needed to develop more optimal approaches for identifying and quantitating shunting as well as the potential contribution of the bronchial circulation to shunting. A question deserving more attention is how capillary dimension is determined and regulated, and whether more direct evidence for capillary plasticity eventuating in the formation of a physical shunt may be found. Further, a promising direction to pursue may be further identification of common structural and regulatory signaling connections between genetic lesions in which vascular remodeling is implicated (e.g., in TGFbeta receptor signaling), and acute shunting in which reversible occlusion appears to be modulated by a variety of physiologic conditions. References 1. Anabtawi IN, Ellison RG, Ellison LT: Pulmonary arteriovenous aneurysms and fistulas. anatomical variations, embryology, and classification. Ann Thorac Surg 1965;122:277–285. 2. Tobin CE: Arteriovenous shunts in the peropheral pulmonary circulation in the human lung. Thorax 1966;21: 197–204. 3. Hoffman JI: Normal and abnormal pulmonary arteriovenous shunting: Occurrence and mechanisms. Cardiol Young 2013;23:629–641. 4. Stickland MK, Welsh RC, Haykowsky MJ, et al: Intra-pulmonary shunt and pulmonary gas exchange during exercise in humans. J Physiol 2004;561:321–329. 5. Laurie SS, Yang X, Elliott JE, et al: Hypoxia-induced intrapulmonary arteriovenous shunting at rest in healthy humans. J Appl Physiol 2010;109:1072–1079. 6. Laurie SS, Elliott JE, Goodman RD, et al: Catecholamineinduced opening of intrapulmonary arteriovenous anastomoses in healthy humans at rest. J Appl Physiol 2012;113:1213–1222. 7. Elliott JE, Friedman JM, Futral JE, et al: Sildenafil, nifedipine and acetazolamide do not allow for blood flow through intrapulmonary arteriovenous anastomoses during exercise while breathing 100% oxygen. Exp Physiol 2014;99:1636–1647. 8. Cameron Norris H, Mangum TS, Duke JW, et al: Exerciseand hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses is reduced in older adults. J Appl Physiol 2014:116:1324–1333. 9. Elliott FM, Reid L: Some new facts about the pulmonary artery and its branching pattern. Clin Radiol 1965;16:193–198. 10. Wilkinson MJ, Fagan DG: Postmortem demonstration of intrapulmonary arteriovenous shunting. Arch Dis Child 1990;65:435–437. 11. 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;87:2348–2356. 12. Lovering AT, Stickland MK, Kelso AJ, et al: Direct demonstration of 25- and 50-microm arteriovenous pathways in 1healthy human and baboon lungs. Am J Physiol Heart Circ Physiol 2007;292:H1777–H1781. 13. Starnes SL, Duncan BW, Fraga CH, et al: Rat model of pulmonary arteriovenous malformations after right supe-
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