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Ann Thorac Surg 2003;76:1759-1766
© 2003 The Society of Thoracic Surgeons

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Review

Pulmonary arteriovenous malformations after cavopulmonary anastomosis

^a Pediatric and Congenital Heart Surgery, The Children’s Hospital at The Cleveland Clinic, and The Department of Molecular Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

^* Address reprint requests to Dr Duncan, Pediatric and Congenital Heart Surgery/M41, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
e-mail: duncanb{at}ccf.org

	Abstract

Top Abstract Introduction Anatomy and physiology of... Patterns of PAVM development... Molecular mechanisms of PAVM... Future directions Acknowledgments References

 
Pulmonary arteriovenous malformations (PAVMs) are a cause of progressive cyanosis after cavopulmonary anastomosis in children with single ventricle physiology who are on the pathway leading to a Fontan procedure. Investigations into possible mechanisms for the etiology of PAVMs are ongoing and suggest that the liver might play a key regulatory role in the development of these lesions.

	Introduction

Top Abstract Introduction Anatomy and physiology of... Patterns of PAVM development... Molecular mechanisms of PAVM... Future directions Acknowledgments References

 
The clinical introduction of the cavopulmonary shunt (Glenn shunt) in the late 1950s was an important contribution to the treatment of children with cyanotic congenital heart disease. The development of this procedure in an animal model and its ultimate use to successfully treat children with single-ventricle physiology is a classic example of the progression of an innovative surgical concept from the laboratory to clinical application [1, 2]. Subsequently, performance of a bidirectional superior vena cavopulmonary anastomosis has become part of the standard surgical sequence for children with single ventricle physiology who undergo Fontan palliation. In current practice, most children with single-ventricle physiology undergo a neonatal palliative procedure, followed by a bidirectional cavopulmonary anastomosis later in infancy, and ultimately a Fontan procedure in the first years of life. The performance of a bidirectional cavopulmonary anastomosis provides excellent palliation for patients with a single ventricle and has resulted in decreased mortality rates compared with results obtained if the Fontan procedure is performed without this intermediate step in the surgical sequence [3–5].

As is often the case when the treatment of a serious problem with a high mortality rate is refined, new problems are discovered as the number of surviving patients increases. The development of pulmonary arteriovenous malformations (PAVMs) after a Glenn shunt was first noticed during the follow-up of patients who had undergone this procedure years before [6, 7]. These children, whose underlying cardiac disease was otherwise well palliated by the Glenn shunt, became severely cyanotic due to intrapulmonary right-to-left shunting arising from PAVMs. In the current era, with widespread use of the bidirectional cavopulmonary anastomosis as an intermediate step in the palliation of children with single-ventricle physiology, PAVMs continue to be a cause of considerable morbidity [7–12]. Although the bidirectional cavopulmonary anastomosis provides excellent hemodynamic palliation for these children, its durability is often limited by the development of progressive cyanosis due to PAVMs. Despite the recognition of this problem for more than 30 years, the exact cause of PAVMs after cavopulmonary anastomosis remains unknown; however, clues obtained from the clinical study of these lesions and recent laboratory work has increased the understanding of this condition and form the basis for the present review.

	Anatomy and physiology of PAVMs

Top Abstract Introduction Anatomy and physiology of... Patterns of PAVM development... Molecular mechanisms of PAVM... Future directions Acknowledgments References

 
PAVMs that develop after cavopulmonary anastomosis cause intrapulmonary right-to-left shunting whereby systemic venous blood reaches the pulmonary venous system through abnormal vascular connections proximal to the gas exchange units. The course of PAVM development is variable; however, these lesions tend to progress with time. As many as 25% of patients will develop clinically significant PAVMs with increasing cyanosis if followed for several years after cavopulmonary anastomosis [6]. Angiographically, PAVMs appear as dilated and tortuous vessels that extend far into the periphery of the lung with evidence of right-to-left shunting demonstrated by the rapid appearance of contrast in the pulmonary veins after pulmonary artery injection (Fig 1). Contrast echocardiography is considerably more sensitive than angiography for detecting this condition. It shows the early appearance of microbubbles in the pulmonary venous atrium after peripheral venous injection of agitated saline. When used as a screening tool, contrast echocardiography detects intrapulmonary right-to-left shunting in a large percentage of children after cavopulmonary anastomosis, even in the absence of clinically evident PAVMs [10, 13, 14]. Right-to-left shunting due to PAVMs can be detected by contrast echocardiography as early as a few weeks after cavopulmonary anastomosis, whereas classic angiographic changes usually are not seen for months to years.

View larger version (155K): [in this window] [in a new window]   Fig 1. Selective injection of the right lower lobe pulmonary artery in a patient with diffuse pulmonary arteriovenous malformations after a total cavopulmonary shunt (Kawashima procedure). Rapid filling of the pulmonary vein (arrow) is seen in the capillary phase of the injection. (Reprinted from Duncan BW, et al. J Thorac Cardiovasc Surg; 1999;117:931–8 [15]; with permission.)

View larger version (110K): [in this window] [in a new window]   Fig 2. Micrographs of a lung biopsy specimen from a patient with pulmonary arteriovenous malformations. (A) Origin of pulmonary arteriovenous malformation lake (arrows) branching from pulmonary arteriole (BV). Edema (ED) of the pulmonary parenchyma is evident in a perivascular location. (B) Pulmonary arteriovenous malformation chains (BV and *) surrounding an airway (AW) with thin walls demonstrating incomplete elastin staining (arrows) (Movat’s pentachrome, original magnification x 200). (Reprinted from Duncan BW, et al. J Thorac Cardiovasc Surg; 1999;117:931–8 [15]; with permission.)

	Patterns of PAVM development and implications for etiologic mechanisms

Top Abstract Introduction Anatomy and physiology of... Patterns of PAVM development... Molecular mechanisms of PAVM... Future directions Acknowledgments References

Surgical redirection of hepatic venous blood flow to the pulmonary arterial circulation causes PAVMs to regress. The Fontan procedure reliably leads to regression of PAVMs that occur after superior cavopulmonary anastomosis [8, 9]. Redirecting the hepatic venous return to the pulmonary arteries as part of a completion Fontan procedure in children with PAVMs after the Kawashima procedure or in cases of isolated anomalous hepatic venous drainage to the left atrium is also curative for PAVMs [15, 18, 20, 22–26].

Further compelling evidence for the role of the liver in the development of PAVM comes from the observation that PAVMs occur frequently in patients with advanced hepatic failure, as the hepatopulmonary syndrome [27–29]. Histologically, these lesions closely resemble PAVMs that develop in children after cavopulmonary anastomosis. Restoration of hepatic synthetic and metabolic function with orthotopic liver transplantation results in regression of PAVMs that develop in the setting of end-stage liver failure [30, 31].

These clinical observations suggest that the liver may be actively involved in the maintenance of normal pulmonary vascular integrity. PAVMs are highly abnormal vascular channels that appear to develop whenever hepatic venous effluent no longer perfuses the pulmonary arterial circulation directly. The liver performs a variety of synthetic and metabolic functions. To understand the mechanisms of liver-derived control over PAVM development, it is essential to determine the true nature of these abnormal vessels. PAVMs are characterized by greatly increased numbers of pulmonary blood vessels, suggesting that blood vessel proliferation (angiogenesis) plays an important role in PAVM development. However, these blood vessels also have abnormal morphology and often appear as dilated vascular channels with abnormalities in the make-up of the vessel wall. In addition, the physiologic nature of these vessels is abnormal, providing precapillary connections between systemic and pulmonary venous return. These aspects of PAVM development suggest that vascular dilatation, remodeling, and even recruitment of preexisting vascular channels could contribute to the etiology of this condition.

Figure 3 depicts a mechanism for hepatic involvement in PAVM development. According to this scheme, PAVMs develop as a result of pulmonary vascular proliferation and dilatation secondary to the absence of liver-derived factors in the pulmonary circulation after cavopulmonary anastomosis [8, 9, 32]. In this scheme, the liver is responsible for producing an inhibitor of vascular proliferation that is absent from venous blood directly perfusing the lungs after a superior cavopulmonary anastomosis. The liver may also be the source of vasoactive substances that function as inhibitors of pulmonary vascular dilatation or recruitment, with vascular remodeling and dilatation occurring whenever hepatic venous effluent does not directly perfuse the pulmonary vasculature. Alternatively, the liver may be responsible for the degradation of an angiogenic substance that is not removed from the pulmonary circulation after cavopulmonary anastomosis. To understand the role of the liver in this condition, liver-derived elements that contribute to each of these possible aspects of PAVM biology need to be examined.

View larger version (61K): [in this window] [in a new window]   Fig 3. Diagram of the role of the liver in the development of pulmonary arteriovenous malformations (PAVM) after cavopulmonary anastomosis. (VEGF = vascular endothelial growth factor.)

	Molecular mechanisms of PAVM development

Top Abstract Introduction Anatomy and physiology of... Patterns of PAVM development... Molecular mechanisms of PAVM... Future directions Acknowledgments References

Microvessel density in the lung as a measure of angiogenesis after cavopulmonary anastomosis
The development of PAVMs is a time-dependent phenomenon usually requiring at least 1 to 2 years after cavopulmonary anastomosis before clinical and angiographic evidence of PAVMs appears. If a sensitive enough indicator of angiogenesis is used, there should be evidence of increased pulmonary vascular proliferation, even in children who are asymptomatic for PAVMs, at earlier time points after cavopulmonary anastomosis. Starnes and coworkers [34] utilized microvessel density to quantify angiogenic activity in lung biopsy specimens from children who had undergone cavopulmonary anastomosis. Microvessel density is a sensitive indicator of the angiogenic potential of tumors and has been used to predict the likelihood of metastasis. Microvessel density was determined by counting vessels stained with the endothelium-specific marker, von Willebrand factor, in the lungs of children with and without angiographically documented PAVMs after cavopulmonary anastomosis.

After cavopulmonary anastomosis, there were significantly more pulmonary vessels even in the absence of clinical or angiographic evidence of PAVMs. Children at earlier time points after cavopulmonary anastomosis without clinical or angiographic evidence of PAVMs had higher numbers of pulmonary microvessels, which were comparable to those of later postoperative patients with clinically evident PAVMs (Fig 4). Although children who had no clinically evident PAVMs had greatly increased pulmonary microvessel density compared with controls, only patients with clinically and angiographically evident PAVMs demonstrated large dilated vascular channels (vascular lakes). These results suggest that there is a continual angiogenic stimulus in the lungs that is detectable early after cavopulmonary anastomosis; however, the development of symptomatic PAVMs appears to be associated with a histologic transition characterized by the development of pulmonary vascular lakes.

View larger version (11K): [in this window] [in a new window]   Fig 4. Mean microvessel density per high-power field in patients after cavopulmonary anastomosis with clinically evident pulmonary arteriovenous malformations (PAVM), without clinical evidence of PAVM (Asymptomatic Post–CPA [cavopulmonary anastomosis]) and controls. Error bars represent standard deviation. (Reprinted from Starnes SL, et al. J Thorac Cardiovasc Surg; 2000;120:902–7 [34]; with permission.)

The results of immunohistologic staining of PAVMs support the concept that these lesions may be angiogenically active and that VEGF and its receptor are upregulated when factors in hepatic venous effluent are absent from the pulmonary arterial circulation. However, the absence of proliferating cell nuclear antigen staining suggests that these lesions are no longer highly proliferative at the time they become histologically evident. Based on these findings, there is the suggestion that other mechanisms, such as vascular dilatation and remodeling, may also play important roles in the development of PAVMs.

Isolation of a hepatic inhibitor of angiogenesis
A final compelling piece of evidence for the angiogenically active nature of PAVMs after cavopulmonary anastomosis is provided by Marshall and coworkers [36]. The premise of this study was that angiogenic inhibitory activity should be detectable in cultured hepatocytes if the liver exerts a regulatory effect on pulmonary blood vessel proliferation. They found that rat hepatocyte-conditioned media had a strong inhibitory effect on the growth of proliferating bovine capillary endothelium. They attempted to purify this inhibitory activity and found that it was a protein with highly specific inhibitory activity for endothelial proliferation, whereas it demonstrated no inhibitory activity for the proliferation of cultured epithelial or tumor cells. Two-dimensional gel electrophoresis of the end product of the purification revealed four candidate bands which may represent a novel inhibitor of angiogenesis (molecular weight between 45 and 97 kD). The demonstration that hepatocyte-conditioned medium contains inhibitory activity for endothelial proliferation is particularly exciting as an area of ongoing research that may identify the precise agent responsible for control mechanisms exerted by the liver on the pulmonary vasculature.

The role of hepatic synthesis and metabolism of vasoactive substances in PAVM development
Some clinical aspects of PAVM development are not well explained by abnormal angiogenesis alone. Pandurangi and colleagues [21] showed the appearance of PAVMs within 72 hours after a Kawashima procedure. Such rapid appearance of PAVMs cannot be attributed to the complex processes required for true angiogenesis and suggests that recruitment of preexisting vascular channels occurred. Recruitment and dilatation of preexisting vascular channels undoubtedly contribute to PAVM development after cavopulmonary anastomosis. As discussed previously, immunohistologic evaluation of these lesions consistently failed to demonstrate significant staining with proliferating cell nuclear antigen, further suggesting that mechanisms other than vascular proliferation are important in PAVM development [35].

The exuberant appearance of PAVM after the Kawashima procedure in patients with left isomerism and interrupted inferior vena cava with azygous continuation has been attributed to abnormal metabolism of vasoactive substances that reach the pulmonary circulation. The tendency of PAVMs to develop in a high percentage of children who have had this procedure may result from the greater duration of the palliation provided by the total cavopulmonary shunt, which otherwise has been considered to be definitive palliation. PAVMs are most likely to become clinically evident years after the Kawashima procedure [20, 26], although development of PAVMs has been described over a much shorter time course [21, 25]. These patients also develop widespread systemic venovenous collaterals that have been postulated to arise from mesenteric-derived vasoactive substances. These vasoactive factors then bypass hepatic clearance through porto-caval venovenous collaterals, avoid hepatic metabolism, and ultimately reach the lungs [18, 20]. Some of the factors with vasoactive properties that arise in the mesenteric circulation include vasoactive intestinal peptide, substance P, and glucagon [18]; however, to date no studies definitively show elevated serum levels of these agents in affected patients.

Hepatopulmonary syndrome and the role of nitric oxide in PAVM development
Nitric oxide (NO) is another vasoactive substance that has received considerable attention as a possible mediator of pulmonary vascular abnormalities in the hepatopulmonary syndrome. As stated previously, patients with end-stage liver failure often develop PAVMs that are clinically and histologically similar to PAVMs that develop after cavopulmonary anastomosis. Levels of NO are elevated in the exhaled air of patients with the hepatopulmonary syndrome and normalize after orthotopic liver transplantation [37, 38]. The precise mechanism by which chronic liver failure leads to upregulation of the NO biosynthetic pathway in pulmonary vascular smooth muscle is not known; however, it may be due to the lack of hepatic clearance of inflammatory mediators such as endotoxin and various cytokines [39, 40]. In patients with advanced liver failure the pulmonary vasculature presumably has increased exposure to these inflammatory cytokines. Recent evidence suggests that intravascular macrophages in the lung are activated in response to these agents and become a major source of inducible NO synthase. This subsequently leads to increased levels of NO which activate soluble guanylate cyclase in vascular smooth muscle thereby producing increased levels of the second messenger, cyclic guanosine monophosphate, resulting in vasodilatation [41]. Pulmonary vasodilatation secondary to NO upregulation then produces ventilation-perfusion mismatching and intrapulmonary shunting leading to the hypoxemia seen in these patients. Animal models of the hepatopulmonary syndrome have demonstrated elevated NO synthase levels in the lungs [42]. Methylene blue is an oxidizing agent that blocks stimulation of guanylate cyclase by NO. Administration of methylene blue to patients with advanced cirrhosis and severe hepatopulmonary syndrome reduces hypoxemia, reduces the alveolar-arterial difference for the partial pressure of oxygen, and increases pulmonary vascular resistance in these patients [43]. These findings support the role of NO in the development of the hepatopulmonary syndrome and have established a potential therapeutic role for methylene blue in the treatment of this condition.

Investigations into the mechanisms of hepatopulmonary syndrome have clear implications for the study of PAVMs that develop after cavopulmonary anastomosis. Superior cavopulmonary anastomosis may provide a similar physiologic substrate as that seen in the hepatopulmonary syndrome by removing the hepatic clearance function that is normally present for blood reaching the pulmonary arteries. Inflammatory cytokines could then reach the pulmonary circulation and activate NO synthase leading to chronic pulmonary vasodilatation and ultimately PAVMs. The similarities between the abnormal pulmonary physiology in hepatopulmonary syndrome and PAVMs after cavopulmonary anastomosis suggest that investigations into the role NO metabolism plays in PAVM development may be productive.

The role of angiotensin metabolism in PAVM development
Angiotensin is another vasoactive substance that has been studied recently as a possible contributor to the development of PAVMs [44, 45]. A recent study using an ovine model of PAVMs after cavopulmonary anastomosis focused on the metabolic pathway of this potent vasoconstrictor [44]. After unilateral cavopulmonary anastomosis, the shunted lung possessed substantially lower levels of angiotensin-converting enzyme and angiotensin II compared with controls. These changes in enzyme levels and protein activity were only seen early after cavopulmonary anastomosis, with the largest decreases occurring 1 to 5 weeks postoperatively. By 15 weeks after cavopulmonary anastomosis, angiotensin-converting enzyme activity and angiotensin II activities had returned to normal.

These authors subsequently examined the two angiotensin II receptors AT1 and AT2 in the same model [45]. AT1, which is the receptor that primarily mediates the pressor effects of angiotensin II, was found to be persistently elevated at 15 weeks after cavopulmonary anastomosis, whereas AT2 levels demonstrated a transient increase up to 5 weeks postoperatively with return to baseline levels by 15 weeks. Whether these early changes in the angiotensin metabolic pathway are a primary etiologic factor in PAVM development that is maximally manifest months to years after cavopulmonary anastomosis is not known; however, decreased levels of angiotensin II or similar vasoconstrictors could contribute to pulmonary vasodilatation present in this condition.

The role of nonpulsatile pulmonary blood flow in PAVM development
In addition to the role of the liver in this condition, abnormalities in the regional distribution of pulmonary blood flow after cavopulmonary anastomosis have been implicated in PAVM development [16, 46]. Cavopulmonary anastomosis also results in nonpulsatile blood flow to the pulmonary arteries. Freedom from PAVM development has been reported to be a benefit of maintaining an additional source of pulsatile pulmonary blood flow at the time of cavopulmonary anastomosis [47–50]. Although nonpulsatile pulmonary arterial blood flow may contribute to PAVM development after cavopulmonary anastomosis, evidence exists that refutes its central importance. In the hepatopulmonary syndrome, PAVMs develop despite the presence of pulmonary arterial blood flow that is pulsatile and that is normally distributed throughout the pulmonary parenchyma. After the Fontan procedure, PAVM development rarely, if ever, occurs despite nonpulsatile pulmonary blood flow. The benefit from additional sources of pulmonary blood flow in preventing PAVM development may be due not to the provision of a pulsatile pulmonary arterial waveform but rather to the establishment of a more direct connection between hepatic synthetic and metabolic processes and the pulmonary circulation.

The role of hypoxia in PAVM development
Vascular endothelial growth factor is upregulated by hypoxia; the classic example being local tissue hypoxia in tumors that outgrow their vascular supply, resulting in increased VEGF expression and the impetus for vessel ingrowth leading to metastasis. Starnes and coworkers [51] demonstrated that cyanotic children have systemically elevated levels of VEGF in the peripheral circulation. Although this increase in VEGF is not specific to the pulmonary circulation and is therefore unlikely to be the main force behind PAVM development, this finding underlines the complexity of this condition. It is likely that local angiogenic stimuli present in the pulmonary circulation after cavopulmonary anastomosis are acting on a system that is "angiogenically primed" and that demonstrates a more exaggerated vascular proliferative response than would occur in children with normal systemic oxygen saturations. Interestingly, VEGF is also known to be a vascular permeability factor, and high systemic levels of VEGF may further contribute to vessel leakiness and the tendency of these patients to develop effusions postoperatively [51].

	Future directions

Top Abstract Introduction Anatomy and physiology of... Patterns of PAVM development... Molecular mechanisms of PAVM... Future directions Acknowledgments References

 
Development of a small animal model of PAVMs after cavopulmonary anastomosis
A reliable animal model is needed to understand the etiology of this condition and to determine the response to different treatment modalities. Starnes and coworkers [52] developed a rat model to study PAVM development. In this model, a right superior vena cava to right pulmonary artery anastomosis was performed, thereby allowing the left (nonshunted) lung of each animal to serve as a control. Animals were analyzed at 2-month intervals for up to more than a year postoperatively. In all animals studied beyond 4 months after cavopulmonary anastomosis, the microvessel density in the shunted lung was significantly higher than in the control lung (Fig 5). Angiographically evident PAVMs occurred only in animals studied beyond 10 months postoperatively. These findings suggest a time-dependent course for PAVM development similar to that observed clinically: a sensitive assay (microvessel density) detects increased angiogenesis early after cavopulmonary anastomosis while angiographic evidence of PAVMs takes longer to develop. Although there was considerable variability in microvessel density between animals, the ratio of the microvessel density in the shunted lung to that in the control lung demonstrated a nearly linear increase with time after cavopulmonary anastomosis (Fig 6). This small animal model may represent an important new tool by which to study molecular mechanisms involved in the development of PAVMs after cavopulmonary anastomosis. In addition to its role in helping to understand the pathophysiology of this condition, this model may be especially useful in evaluating the effects of angiogenesis inhibitors and other vasoactive substances that could lead to the development of medical therapy for this difficult problem.

View larger version (18K): [in this window] [in a new window]   Fig 5. Mean microvessel density in the lung ipsilateral to the cavopulmonary anastomosis (unshaded bars) versus control lung (shaded bars) for animals at each time point from 2 to 13 months, postoperatively. Error bars represent the standard deviation of the mean. (Reprinted from Starnes SL, et al. Am J Physiol; 2002;283:H2151–5 [52]; with permission.)

View larger version (11K): [in this window] [in a new window]   Fig 6. Linear regression analysis of the ratio of the average number of vessels positive for von Willebrand factor from 10 high-powered fields from shunted lung/average number of vessels positive for von Willebrand factor in 10 high-powered fields from control lung on time after cavopulmonary anastomosis. (Reprinted from Starnes SL, et al. Am J Physiol; 2002;283: H2151–5 [52]; with permission.)

The importance of such study is clear: new therapeutic options for affected children should become available as more is learned. For example, there is currently a growing list of inhibitors of angiogenesis that have been used successfully to treat cancer, childhood hemangiomas, and various inflammatory conditions. Future research may lead to the rational application of angiogenesis inhibitors for the treatment of PAVMs that develop in children after cavopulmonary anastomosis. Beyond the clinical advances that will be made, these studies may reveal new mechanisms of hepatic regulation of pulmonary vascular development. These control mechanisms might have gone undetected were it not for the isolation of the pulmonary blood supply from the liver that occurs after cavopulmonary anastomosis in children with complex congenital heart disease.

	Acknowledgments

Top Abstract Introduction Anatomy and physiology of... Patterns of PAVM development... Molecular mechanisms of PAVM... Future directions Acknowledgments References

 
Doctor Duncan’s laboratory work has been supported by a research grant from the Howard Hughes Medical Institute and by an Established Investigator Grant from the American Heart Association.

	References

Top Abstract Introduction Anatomy and physiology of... Patterns of PAVM development... Molecular mechanisms of PAVM... Future directions Acknowledgments References

 

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