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Ann Thorac Surg 1998;66:688-691
© 1998 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, California, USA
Address reprint requests to Dr Reddy, 505 Parnassus Ave, M593, San Francisco, CA 94143-0118
Presented at the Workshop on "One and One-Half Ventricle Repairs," Gubbio, Italy, Dec 6–7, 1996.
Abstract
Background. Pulmonary arteriovenous malformations can occur in a variety of clinical situations, including liver disease, systemic disorders, or after palliation of congenital heart disease, with serious clinical consequences.
Methods. We reviewed the potential mechanisms of this condition, diagnostic tools, and clinical management.
Results. Contrast echocardiography is an important diagnostic modality, which has been shown to be more sensitive than pulmonary arteriography, especially when rapid contrast injection is used. The finding that pulmonary capillary vasodilation is observed in hepatopulmonary syndrome, in cirrhotic patients, and after congenital heart repair is strongly suggestive that an unidentified hepatic factor is involved in inhibiting the development of pulmonary arteriovenous malformations.
Conclusions. Prompt detection and treatment of pulmonary arteriovenous malformations is of utmost importance, to prevent serious clinical consequences. It may very well be the case that the etiology of arteriovenous malformations is multifactorial. We are now investigating the role of alterations of gene expression in the vascular remodeling that results in formation of pulmonary arteriovenous malformations.
Pulmonary arteriovenous malformations (AVMs) are an uncommon abnormality of the pulmonary vasculature characterized by a fistulous communication between the pulmonary arteries and veins. These have also been described as pulmonary arteriovenous aneurysms, fistulas, angioma varix, and telangiectasis [1, 2]. The last of these terms indicates the close relationship of pulmonary AVMs to the Osler-Weber-Rendu syndrome, which has been found in 36% of patients with isolated AVMs and 57% of patients with multiple AVMs [3]. Pathogenetically AVMs are preformed or new vessels at an arteriovenous junction, the physiologic patency of which was first demonstrated by Prinzmetal and associates [4] using spherical glass bodies with a diameter several times that of an erythrocyte.
The most frequent site of AVMs is the lower lobe, often in proximity to the pleura [2]. Most patients have no clinical signs or symptoms. However, three types of potentially significant sequelae can develop in patients with AVMs. Depending on the extent of right-to-left shunting (unoxygenated blood traversing the AVMs and returning to the heart without undergoing gas exchange), patients may have severe cyanosis, digital clubbing, decreased exercise capacity, and dyspnea. Interruption of the capillary filter of the lung allows emboli, normally trapped in the pulmonary capillaries, to enter the systemic circulation through the AVMs. Systemic embolization due to this mechanism has been reported to cause cerebrovascular attacks or brain abscesses in a significant number of patients with AVMs [5, 6]. In addition, the abnormal vessels can bleed, causing hemoptysis or hemothorax [7]. Pulmonary AVMs may occur in conjunction with congenital malformation syndromes, after palliation of complex congenital heart disease with a superior cavopulmonary shunt, in the context of systemic disorders such as Osler-Weber-Rendu syndrome, or in patients with liver disease.
Diagnostic criteria
It is possible to make the diagnosis of AVMs when there is pulmonary venous desaturation without evidence of parenchymal lung disease on chest radiographs. Contrast echocardiography is an important diagnostic modality in patients with pulmonary (and systemic) AVMs. Agitated saline solution (approximately 3 mL in patients weighing less than 20 kg and 6 mL in patients weighing more than 20 kg) is injected as rapidly as possible through a peripheral intravenous catheter in the upper extremity or through a side-hole catheter placed in the main or branch pulmonary arteries at the time of pulmonary catheterization [8]. It has been shown that rapid administration of contrast is more important than the volume administered in achieving adequate delivery of contrast, as determined by opacification of the pulmonary artery [9]. Precordial two-dimensional echocardiographic images are obtained from the subcostal, parasternal, or suprasternal views at the time of contrast delivery. The bubbles are approximately 8 to 15 µm in diameter and normally pass through the right side of the heart and are trapped in the alveolar capillaries. If the bubbles bypass the lungs through the AVMs, they appear in the left side of the heart [10]. A study is considered positive if microcavitations are seen in the pulmonary venous atrium within five cardiac cycles of their injection into the pulmonary arterial circulation on at least two injections [9].
Diagnosis by pulmonary arteriography is made on the basis of a rapid arterial-to-venous transit time and a reticular appearance of the lung parenchyma [11]. In our experience, this approach is less sensitive than contrast echocardiography. Another diagnostic modality is scintigraphy, a nuclear medicine technique in which the lungs are scanned after intravenous injection of macroaggregates of human albumin labeled with technetium 99m. The macroaggregates are not captured in segments of the lung vasculature with AVMs [12].
In experimental studies, is possible to assess the presence of pulmonary AVMs by injecting 15-µm fluorescent microspheres into the pulmonary artery and detecting their transit in the systemic circulation. Another direct method for detecting and measuring AVMs in the experimental setting is the casting of the pulmonary vasculature with special resins [13].
Hepatopulmonary syndrome
Hepatopulmonary syndrome consists of the triad of liver dysfunction, intrapulmonary vascular dilatation, and hypoxemia [14]. The hepatic dysfunction may include cirrhosis, portal hypertension, fulminant acute hepatitis, or rejection of an allograft liver transplant. Intrapulmonary vascular dilatation is equivalent to pulmonary AVMs, and is diagnosed as described above. Hypoxemia in this setting is defined as an increased alveolar-arterial oxygen tension gradient (>20 mm Hg) at rest, in the supine or standing position (orthodeoxia). The first description of hepatic dysfunction and hypoxemia was by Fluckiger [15] in 1884, who described a 37-year-old woman with cirrhosis, cyanosis, and clubbing. In 1977, Kennedy and Knudson [16] first coined the term hepatopulmonary syndrome, suggesting an analogy to the hepatorenal syndrome.
Cavopulmonary anastomosis
Cavopulmonary anastomosis, which establishes a communication between the superior vena cava and the pulmonary artery, has been used as a palliative procedure in patients with functional univentricular forms of congenital heart disease for almost 40 years. The development of AVMs after the classic Glenn anastomosis (superior vena cava-to-right pulmonary artery anastomosis) is a well-documented phenomenon with a reported incidence of up to 25% [17]. In recent years, the classic Glenn shunt has been largely replaced by the bidirectional cavopulmonary anastomosis, in which the superior vena cava is anastomosed to the pulmonary artery and superior caval flow perfuses both lungs. The incidence of pulmonary AVMs after bidirectional cavopulmonary anastomosis has not been well characterized, but AVMs definitely occur in this setting as well, although the incidence is most likely lower than with the classic Glenn anastomosis [9, 18]. Both classic and bidirectional Glenn procedures favor distribution of pulmonary flow to the lower lobe [18], which is the site of preferential AVM formation [19]. Other factors of the bidirectional Glenn physiology that may be important are that pulmonary blood flow has low or no pulsatility, and that there is partial systemic desaturation.
The duration of bidirectional cavopulmonary anastomosis that patients can sustain before pulmonary AVMs develop varies. Among our first 123 bidirectional Glenn patients, AVMs had developed in 12 by the time of a recently published review of our experience [18]. Of these, 5 had a bidirectional Glenn for more than 2 years and 4 had the Glenn for more than 3 years. A recent report by Bernstein and associates [20] found the duration of bidirectional cavopulmonary anastomosis to be a significant predictor for the development of AVMs. Thus, although many patients with a bidirectional Glenn for more than 2 or 3 years function well and do not experience a higher incidence of complications at the time of Fontan operation, the risk of AVMs may be an important factor in deciding to complete the Fontan before the bidirectional Glenn has been in place for more than a few years. Our approach is to convert patients from a bidirectional Glenn to an extracardiac conduit Fontan when they reach a weight of 15 kg, which is generally between 2 and 3 years after the bidirectional Glenn in patients who undergo the Glenn procedure in early infancy [18].
Patients with polysplenia syndrome, especially those who undergo bidirectional cavopulmonary anastomosis at a very young age, may have rapid development of fulminant AVMs, with deterioration and even death. This leads us to believe that it may be prudent not to perform a bidirectional Glenn procedure in very young infants with polysplenia and to include an additional source of pulmonary blood flow in patients with heterotaxy [18, 20].
Therapeutic approaches
One of the most vexing aspects of pulmonary AVMs is that there are few reliable treatment options. The most common indication for treatment of AVMs is cyanosis. However, it has been proposed that the risk of systemic embolization justifies the treatment of AVMs even in asymptomatic cases if the diameter of the feeding vessel(s) is more than 3 mm [21]. Shunt-induced hypoxemia is surgically correctable by ligation of the fistulas or partial pneumonectomy [22]. When operation is contraindicated, or as an alternative first-line therapy, balloon or coil embolization of the AVMs may be performed [23]. However, in patients with diffuse AVMs, embolization may not be effective, and this approach does not address the underlying cause. In patients with cavopulmonary anastomosis, surgical takedown of the anastomosis is an option [24], as are cardiac transplantation [25], possibly conversion to a Fontan operation (reported by Quagebeur and associates at the 1997 Annual Meeting of The American Association for Thoracic Surgery), and addition of another source of pulmonary blood flow such as a systemic–pulmonary artery shunt [26]. In patients with polysplenia and a bidirectional Glenn, inclusion of the hepatic veins in the pulmonary circulation has led to resolution of AVMs [27]. Orthotopic liver transplantation has led to resolution of AVMs in patients with hepatopulmonary syndrome [28], although there have also been reported cases in which AVMs did not resolve after transplantation [29].
Pathogenesis of pulmonary arteriovenous malformations
The pathophysiology of AVMs is not well understood, although the structural changes have been well described. Several autopsy studies have used the technique of making a "cast" of the pulmonary circulation by injecting microopaque gelatin dyes under pressure. This technique has been used to document precapillary dilatation and pleural-based vascular dilatation, thin-walled pulmonary vessels, and dilated intraacinar blood vessels [30]. Hypoxemia in the setting of such vascular changes has been attributed to several mechanisms: right-to-left intrapulmonary shunting, alveolar-to-capillary diffusion defect, and alveolar ventilation-perfusion mismatch [14].
The pathogenesis of AVMs remains unclear. Hemodynamic alterations have been suggested, but most intracardiac, pulmonary arterial, and pulmonary capillary wedge pressures are normal [20]. Maldistribution of pulmonary blood flow has also been suggested as a possible cause of AVMs [17]. It has been shown that passive blood return to the lungs after a Glenn shunt results in preferential flow to the lower lobes relative to the upper lobes in comparison with normal subjects. Although this maldistribution of pulmonary blood flow is present in some patients after the Fontan operation, AVMs have rarely been a complication of the Fontan physiology. Absence of pulsatile blood flow has also been implicated in the development of pulmonary AVMs in patients with cavopulmonary anastomosis, but this does not explain the fact that AVMs also occur in patients with biliary atresia who have normal pulsatile pulmonary blood flow.
These considerations suggest that normal hepatic venous blood may play a role in the prevention of AVMs. In patients with hepatic cirrhosis, dilated precapillary and capillary pulmonary vessels develop similar to those seen among patients with a cavopulmonary anastomosis. Pulmonary arteriograms in patients with liver disease and AVMs are similar in appearance to the those of cardiac patients with AVMs. Although abnormal vasoactive agents have been found in hepatic venous blood in patients with cirrhosis [31], the liver is typically normal in patients with cardiac disease and AVMs, thus implicating the absence of a normal factor rather than the presence of an abnormal one. Given the dilation of vessels seen histologically, the putative hepatic product may be involved in vasomotor control rather than angiogenic control. This theory is supported by the reports cited above of resolution of AVMs after liver transplantation in patients with hepatic dysfunction, transplantation in patients with cavopulmonary shunt, or inclusion of the hepatic veins in patients with polysplenia and cavopulmonary anastomosis, all of which result in flow of normal hepatic effluent directly to the lungs.
Pulmonary AVMs are also common in patients with polysplenia variants of visceroatrial heterotaxy syndrome. These patients often have interruption of the inferior vena cava at the intrahepatic level with drainage of inferior vena caval flow into the superior vena cava through the azygos system. In these patients, the Kawashima modification of the Fontan operation is associated with the development of AVMs [1, 11].
References
This article has been cited by other articles:
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  B. S. Kwon, E. J. Bae, G. B. Kim, C. I. Noh, J. Y. Choi, and Y. S. Yun Development of bilateral diffuse pulmonary arteriovenous fistula after Fontan procedure: is there nonhepatic factor? Ann. Thorac. Surg., August 1, 2009; 88(2): 677 - 680. [Abstract] [Full Text] [PDF]
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 S. L. Starnes, B. W. Duncan, C. H. Fraga, S. Y. Desai, T. K. Jones, S. K. Mathur, G. L. Rosenthal, and F. M. Lupinetti Rat model of pulmonary arteriovenous malformations after right superior cavopulmonary anastomosis Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H2151 - H2156. [Abstract] [Full Text] [PDF]
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 E. A. Bacha, R. A. Jonas, J. E. Mayer Jr, S. Perry, and P. J. del Nido MANAGEMENT OF PULMONARY ARTERIOVENOUS MALFORMATIONS AFTER SURGERY FOR COMPLEX CONGENITAL HEART DISEASE J. Thorac. Cardiovasc. Surg., January 1, 2000; 119(1): 175 - 176. [Full Text] [PDF]
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C. Mavroudis, C. L. Backer, L. M. Kohr, B. J. Deal, J. Stinios, A. J. Muster, and D. F. Wax Bidirectional Glenn shunt in association with congenital heart repairs: the 1 1/2 ventricular repair Ann. Thorac. Surg., September 1, 1999; 68(3): 976 - 981. [Abstract] [Full Text] [PDF]
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