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