Pulmonary Arteriovenous Malformations Formation Research Articles

Abstract 13627: Hepatic Venous Return to Lungs in Fontan is Dependent on Age-Dependent Caval Flow Ratio

Introduction: The Fontan procedure is performed between 2-4 years of age and is a palliative technique for patients born with single ventricle defects. The Fontan physiology is the result of a total cavopulmonary connection between superior and inferior vena cava (SVC and IVC) and the hepatic veins to the pulmonary arteries (PA). Maldistribution of hepatic blood flow to the lungs can result in the formation of pulmonary arteriovenous malformations (PAVM) and resulting cyanosis. Hepatic blood flow distribution (HFD) to right and left lungs is highly dependent on the local flow dynamics. We sought to investigate the impact of SVC-to-IVC flow ratio and age on HFD. Methods: SVC and IVC flow data measured by cardiac MRI (CMR) from 81 Fontan patients were collected to establish the relationship between SVC: IVC flow ratio vs. age. 3D Patient-specific computational fluid dynamics (CFD) modeling was performed for 5 patients who underwent Fontan procedure with an extracardiac conduit to quantify the HFD to the right and left PAs. We evaluated the dependency of HFD on SVC: IVC flow ratio by quantifying HFD to different SVC: IVC flow ratios (2, 1.0, and 0.5) for a given Fontan anatomy. Results: SVC: IVC flow ratio inverted at ~10 years of age (n=81, Figure A) indicating a clear shift to lower body predominance in overall caval flow. CFD analysis (n=5) showed that the shift in SVC-IVC flow had a significant effect on the HFD (Fig. B-F). Change in HFD was more substantial as SVC: IVC flow ratio shifted from 2 to 1 [~5-10 years] with an average % change of 21±6 compared to the HFD change that occurred for a shift of 1 to 0.5 [9±11 for ~10-20 years] (Fig. B-F). Conclusion: Well-balanced distribution of HFD is essential to prevent PAVMs and to ensure long-term efficacy of a Fontan. This study highlights how SVC: IVC flow ratios change over time and can impact HFD to PAs. Interventions to address HFD maldistribution should not be considered in isolation and should incorporate predictions of SVC: IVC changes over time.

Hepatic factor may not originate from hepatocytes.

Pulmonary arteriovenous malformations (PAVMs) develop universally in patients with univentricular congenital heart disease. They are believed to form due to lack of an unidentified factor from hepatocytes that perfuses the lungs to maintain vascular homeostasis and prevent PAVM formation. This unidentified factor is termed hepatic factor; however, the identity, mechanism, and origin of hepatic factor are unknown. Several hepatic factor candidates have been previously proposed, but few data are available to support previous hypotheses. Recent data showed that soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is enriched in hepatic vein blood and may be a potential hepatic factor candidate. We used imaging and molecular approaches with wild-type mice to determine whether sVEGFR1 originates from hepatocytes in the liver. To our surprise, we identified that sVEGFR1 is negligibly expressed by hepatocytes but is robustly expressed by the non-parenchymal cell population of the liver. This suggests that hepatic factor may not originate from hepatocytes and alternative hypotheses should be considered. We believe it is necessary to consider hepatic factor candidates more broadly to finally identify hepatic factor and develop targeted therapies for CHD-associated PAVMs.

Roles of cyclooxygenase 2 and hepatic venous flow in patients with HHT or hepatopulmonary syndrome

BackgroundHereditary hemorrhagic telangiectasia (HHT) and hepatopulmonary syndrome are disorders characterized by the development of multiple pulmonary arteriovenous malformations (PAVM). Presentation of the hypothesisCOX2 may be at the origin of a cascade of pro inflammatory events to favour angiogenesis and PAVM development. Testing the hypothesisHHT and hepatopulmonary syndrome mouse models may be used to show its effects on PAVM formation. Anti COX-2 therapy could also be tested in human individuals, particularly in patients presenting a hepatopulmonary syndrome or HHT with small PAVM. Implication of the hypothesisPAVMs are one of the main causes of morbidity in patients presenting with HHT disease, owing to the risks of rupture as well as paradoxical embolism exposing to stroke and/or cerebral abscess. Percutaneous embolization has become the treatment of choice of PAVM. Anti COX2 may prevent from PAVM development and subsequent related complications and avoid either surgery and/or percutaneous embolization and thus subsequent related complication.

Transcatheter brachial fistula creation for treatment of pulmonary arteriovenous malformations

Pulmonary arteriovenous malformations (PAVMs) are thought to form as a result of exclusion of hepatic venous blood from part of the pulmonary circulation. Surgical arteriovenous (AV) fistula creation has demonstrated therapeutic potential to reverse PAVM formation. We sought to demonstrate the feasibility and safety of transcatheter AV fistula creation for this indication. Fluoroscopically guided puncture from the basilic vein into the brachial artery using a Brockenbrough needle and sharpened 0.014" wire created a tract between these vessels. After balloon dilation of the tract, a covered stent was deployed, resulting in a functioning brachial AV fistula. The procedure was technically successful, with no clinical complications at 4 months follow-up. Repeat diagnostic catheterization revealed marked improvement in systemic saturation and near-resolution of PAVMs in the pilot patient. This report suggests that transcatheter brachial arteriovenous fistula formation is technically feasible, and may be effective in managing PAVMs in select single-ventricle patients.

Pulmonary Artery Endothelial Cell Phenotypic Alterations in a Large Animal Model of Pulmonary Arteriovenous Malformations After the Glenn Shunt

Longevity of the superior cavopulmonary connection (SCPC) is limited by the development of pulmonary arteriovenous malformations (PAVM). The goal of this study was to determine whether phenotypic changes in pulmonary artery endothelial cells (PAEC) that favor angiogenesis occur with PAVM formation. A superior vena cava to right pulmonary artery connection was constructed in 5 pigs. Pulmonary arteries were harvested at 6 to 8 weeks after surgery to establish cultures of PAEC and smooth muscle cells, to determine cell proliferation, gene expression, and tubule formation. Abundance of proteins related to angiogenesis was measured in lung tissue. Contrast echocardiography revealed right-to-left shunting, consistent with PAVM formation. While the proliferation of smooth muscle cells from the right pulmonary artery (shunted side) and left pulmonary artery (nonshunted side) were similar, right PAEC proliferation was significantly higher. Expression profiles of genes encoding cellular signaling proteins were higher in PAECs from the right pulmonary artery versusleft pulmonary artery. Protein abundance of angiopoietin-1, and Tie-2 (angiopoietin receptor) were increased in the right lung (both p < 0.05). Tubule formation was increased in endothelial cells from the right pulmonary artery compared with the left pulmonary artery (404 ± 16 versus 199 ± 71 tubules/mm(2), respectively; p < 0.05). These findings demonstrate that PAVMs developed in a clinically relevant animal model of SCPC concomitantly with differential changes in PAEC proliferative ability and phenotype. Moreover, there was a significant increase in the angiopoietin/Tie-2 complex in the right lung, which may provide novel therapeutic targets to attenuate PAVM formation after a SCPC.

Prevalence of Pulmonary Arteriovenous Malformations in Children versus Adults with Hereditary Hemorrhagic Telangiectasia

It is unclear whether pulmonary arteriovenous malformations (PAVMs) in hereditary hemorrhagic telangiectasia develop later in life or are preformed in childhood. We show that the prevalence of PAVMs in children is similar to that in their parents, providing evidence against de novo PAVM formation in hereditary hemorrhagic telangiectasia.

Alveolar Exhaled Nitric Oxide is Elevated in Hereditary Hemorrhagic Telangiectasia

Patients with intrapulmonary shunt due to hepatopulmonary syndrome have diffuse pulmonary microvascular dilatation. Studies have shown that these patients have increased exhaled nitric oxide (NO) levels, suggesting that alveolar capillary NO production is increased. We speculated that alveolar capillary NO overproduction might have a similar mechanistic role in the development of shunting vessels, arteriovenous malformations, in hereditary hemorrhagic telangiectasia (HHT), in which 30-45% of patients have pulmonary arteriovenous malformations (PAVMs). Our objective was to determine if alveolar exhaled NO is elevated in patients with HHT compared to controls. We measured the alveolar fraction of exhaled NO (200 ml/s expiratory flow rate) in HHT subjects with and without a history of PAVMs and in healthy, nonsmoking controls with no known lung disease. We compared 58 HHT subjects to 49 healthy controls. Exhaled NO was significantly greater in HHT subjects (mean = 12.0 ppb, SD = 3.5) than in controls (mean = 10.5 ppb, SD = 3.2) (p = 0.02). We detected a significantly higher level of alveolar exhaled NO in subjects with HHT compared to healthy controls, suggesting that alveolar capillary NO production may be increased in HHT and may have a mechanistic role in PAVM formation.

Morphological Studies of Pulmonary Arteriovenous Shunting in a Lamb Model of Superior Cavopulmonary Anastomosis

The formation of pulmonary arteriovenous malformations (PAVMs) is now well described following surgical connection of the superior vena cava to the pulmonary arteries. The behavior of PAVMs is as fascinating as their cause is elusive. These abnormal vascular connections produce intrapulmonary shunting. The resulting systemic hypoxemia can be both progressive and clinically significant. The incidence and clinical impact of PAVMs are increased in patients operated on at a young age and in those with heterotaxy syndrome (left isomerism/polysplenia). Although the exact causes of PAVMs are not known, they are clearly associated with anatomic configurations in which there is no direct passage of hepatic venous blood to the pulmonary arterial system. They develop whenever hepatic venous blood must first pass through the systemic circulation before reaching the pulmonary vascular bed. One of the most intriguing clinical characteristics of PAVMs is their regression following surgical redirection of hepatic venous blood to the pulmonary arterial system. Regression can occur after either a completion Fontan procedure or heart transplantation. The clinical importance of PAVMs has been limited by the widespread practice of limiting the length of time between a superior cavopulmonary anastomosis and a completion Fontan procedure. Progression to a Fontan procedure improves systemic oxygenation both by eliminating intracardiac right-to-left shunting and by causing regression of the PAVMs. Various imaging techniques have been used to demonstrate PAVMs after a superior cavopulmonary anastomosis. These techniques may be either direct, showing the PAVMs, or indirect, showing the shunt resulting from the PAVMs. The most sensitive techniques are indirect: radionuclide pulmonary perfusion scanning and contrast echocardiography. Using these indirect techniques for detection, intrapulmonary shunting is essentially universal after superior cavopulmonary anastomosis [14]. Direct imaging techniques include pulmonary angiography and histological examination. Histological study of an autopsy specimen from a patient who died due to severe PAVMs showed numerous abnormal, thin-walled vessels [1]. Histological examination of lung biopsies from patients with PAVMs have shown large, dilated blood vessels (‘‘lakes’’) as well as smaller, clustered vessels (‘‘chains’’) in the pulmonary parenchyma [2, 11]. Lung biopsies from patients with a superior cavopulmonary anastomosis, but without PAVMs, have shown increased microvessel density, which may precede the formation of the dilated vessels (lakes) seen in patients with PAVMs [11]. Given the vascular nature of PAVMs, research on the molecular mechanisms of PAVM formation has focused on factors involved in angiogenesis. To date, mechanistic research on humans has been limited. Lung biopsies of children after superior cavopulmonary anastomosis have shown alterations in the vascular endothelial growth factor (VEGF) pathway, with increased levels of both VEGF and its receptor [12]. More extensive work has been carried out in two animal models of superior cavopulmonary anastomosis. Duncan et al. [10] developed a rat model to study potential mediators. They demonstrated increased levels of VEGF messenger RNA as well as protein levels of other angiogenic factors in the lungs of rats after superior cavopulmonary anastomosis [9, 13]. Although technically challenging, this small animal model may prove particularly useful in elucidating molecular mechanisms and testing the effects of angiogenesis inhibitors. S. M. Bradley (&) Pediatric Cardiac Surgery, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA e-mail: bradlesm@musc.edu

Pulmonary nodular opacities in children with hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is a rare inherited disorder of vascular endothelium that can result in the formation of pulmonary arteriovenous malformations (pAVMs). We observed that small pulmonary nodules, possibly representing early vascular malformations, are more common in these children than in the general population. To describe and characterize the small pulmonary nodules seen on chest CT examination in the lungs of children with HHT. We followed 19 children who had undergone chest CT as part of their initial diagnostic evaluation in the HHT clinic of a pediatric hospital. Chest CT scans were reviewed independently by two radiologists blinded to clinical data. Pulmonary nodules were analyzed according to lobar distribution, anatomic position in the lung (outer, mid, inner third), shape (round, linear, V- or Y-shaped, ill-defined), presence of overt AVMs, and nodule size (<or= or >5 mm). We also reviewed a control group of chest CT scans performed on 25 age-matched children. A total of 35 pulmonary nodules were identified on the CT scans in 15 of the 19 children. Multiple nodules were seen in eight children (42%), solitary nodules were seen in seven children (37%) and no nodules were seen in the remaining four children (21%). The nodules were found to be nonspecific with regard to multiple factors other than their anatomic position within the lung. The chest CT scans of 2 of the 25 age-matched controls revealed a total of only four nodules, a significantly lower total (P = 0.0001 vs. children with HHT). Nonspecific nodules are commonly seen in children with HHT.

Creation of a Brachial Arteriovenous Fistula for Treatment of Pulmonary Arteriovenous Malformations After Cavopulmonary Anastomosis

Pulmonary arteriovenous malformations (PAVMs) occur in approximately 20% of patients after unidirectional superior cavopulmonary anastomosis (CPA), and frequently after bidirectional CPA in patients with polysplenia syndrome. It is hypothesized that exclusion of a growth-modulating factor produced in the liver may predispose to PAVM formation. Resolution of PAVMs after inclusion of hepatic venous effluent into the cavopulmonary circulation has been reported. An upper extremity systemic arteriovenous (AV) fistula may be created to augment pulmonary blood flow and improve oxygenation in hypoxemic patients with CPA, but there has been no systematic investigation of the effects of such fistulas on PAVMs after CPA. We studied 11 patients with PAVMs who underwent creation of a brachial AV fistula a median of 11 years after CPA. Eight patients had discontinuous pulmonary arteries or unilateral flow of a bidirectional CPA and were not considered good candidates for Fontan completion; the other 3 patients had polysplenia and unilateral hepatic venous streaming after Fontan completion. Three patients died of progressive complications of their heart disease 4 to 18 months after AV fistula creation. Pulmonary arteriovenous malformations resolved after creation of a brachial AV fistula in 4 of 5 surviving patients with unilateral flow of a superior CPA, but in none of 3 patients with polysplenia who had unilateral hepatic venous streaming after Fontan completion and PAVMs in the contralateral lung. These findings are consistent with the "hepatic factor" hypothesis, according to which the development of PAVMs is facilitated when an unidentified factor produced or metabolized in the liver does not reach the pulmonary circulation before traversing another capillary bed. Patients with unilateral superior CPA flow and PAVMs who are not considered candidates for Fontan completion may benefit from a brachial AV fistula.

Invited commentary

Suda and colleagues have produced an intriguing investigation of the relationship of vascular endothelial growth factor (VEGF) in patients with cyanosis and the palliative or reparative operations that these patients receive. The topic is an important one, in that VEGF has been hypothesized to play at least a contributory role in the pathophysiology of pulmonary arteriovenous malformations (PAVM). Because PAVM are known to regress in many, if not all, patients who undergo Fontan procedures, the failure of VEGF levels to normalize after the Fontan may at first be taken to undermine the theory that VEGF is a causative factor in PAVM formation and persistence. Although that may indeed be the case, it would be premature to exclude VEGF as an actor in this process. It is known that PAVM occur in a significant proportion of patients with unidirectional or bidirectional cavopulmonary connections over a sufficient period of time; however PAVM do not occur in all such patients. It is much more likely that it is a combination of hemodynamic and humoral factors that determine the presence of PAVM and their likelihood of dilatation (which may in fact be a greater variable than their presence). Accordingly, it is possible that elevation of serum VEGF is a necessary but not sufficient condition for PAVM that attain a clinical degree of significance. Likewise, it is a fascinating observation that VEGF levels normalize after biventricular repairs. Here, as well, caution should be exercised in interpreting these data. The underlying anatomy is so profoundly different in hearts for which biventricular repair is possible as opposed to those for which Fontan palliation remains the best acceptable option that comparisons of vascular derived growth factors may be of little relevance. Furthermore, the observations are at relatively few points in time, thus opening a very narrow window on a process that evolves over many years. Despite these reservations, Suda and colleagues have explored an important avenue that improves our understanding of a poorly understood clinical problem.

The role of oxidative stress in the development of pulmonary arteriovenous malformations after cavopulmonary anastomosis

Background: Cavopulmonary anastomosis is used for palliation of cyanotic heart disease. Clinically significant pulmonary arteriovenous malformations occur in up to 25% of patients after surgical intervention. Cavopulmonary anastomosis creates several modifications to pulmonary physiology that may contribute to the development of pulmonary arteriovenous malformations, including reduced pulmonary blood flow and the exclusion of inferior vena caval effluent. Objective: By comparing the expression of angiogenic and stress-related proteins after cavopulmonary anastomosis and pulmonary artery banding, we sought to determine which genes were upregulated independent of reduced pulmonary blood flow. Methods: Lambs aged 35 to 45 days were placed into 1 of 3 groups: cavopulmonary anastomosis (n = 6), pulmonary artery banding (n = 6), and sham control (n = 6) animals. In our model pulmonary arteriovenous malformations are detectable by means of bubble-contrast echocardiography 8 weeks after cavopulmonary anastomosis. Lung tissue was harvested for Western blotting at 2 and 5 weeks after surgery. Results: Cavopulmonary anastomosis and pulmonary artery banding both increased angiogenic gene expression, but only cavopulmonary anastomosis induced the expression of endothelial stress-related genes. Vascular endothelial growth factor was upregulated 2.5-fold after both cavopulmonary anastomosis (P =.002) and pulmonary artery banding (P =.007). Only cavopulmonary anastomosis upregulated 2 stress-related genes, HO1 and GLUT1, 2.7-fold (P =.002) and 3.8-fold (P =.03), respectively. Hypoxia-inducible factor was upregulated 4-fold (P =.003) after cavopulmonary anastomosis. Pulmonary artery banding failed to induce the increased expression of any of these proteins. Conclusions: Reduced pulmonary blood flow induces a pulmonary angiogenic response but not an endothelial stress response. These results suggest that oxidative stress is more relevant to the formation of pulmonary arteriovenous malformations than angiogenic signaling alone because pulmonary artery banding does not result in pulmonary arteriovenous malformations. Oxidative stress of the pulmonary endothelium resulting from cavopulmonary anastomosis may predispose the affected vasculature to arteriovenous shunting.J Thorac Cardiovasc Surg 2002;124:479-85

Pulmonary arteriovenous malformations in and out of the setting of congenital heart disease

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.