Pulmonary arteriovenous malformations after the superior cavopulmonary shunt: mechanisms and clinical implications

Abstract

Children with functional single ventricle heart disease are commonly palliated down a staged clinical pathway toward a Fontan completion procedure (total cavopulmonary connection). The Fontan physiology is fraught with long-term complications associated with lower body systemic venous hypertension, eventually resulting in significant morbidity and mortality. The bidirectional Glenn shunt or superior cavopulmonary connection (SCPC) is commonly the transitional stage in single ventricle surgical management and provides excellent palliation. Some studies have demonstrated lower morbidity and mortality with the SCPC when compared with the Fontan. Unfortunately the durability of the SCPC is significantly limited by the development of pulmonary arteriovenous malformations (PAVMs) which have been commonly attributed to the absence of hepatic venous blood flow and the lack of pulsatile flow to the affected lungs. Abnormal angiogenesis has been suggested as a final common pathway to PAVM development. Understanding these fundamental mechanisms through the investigation of angiogenic pathways associated with the pathogenesis of PAVMs would help to develop medical therapies that could prevent or reverse this complication following SCPC. Such therapies could improve the longevity of the SCPC, potentially eliminate or significantly postpone the Fontan completion with its associated complications, and improve long-term survival in children with single ventricle disease.

Keywords: Fontan operation; angiogenesis; cavopulmonary connection; congenital heart disease; pulmonary arteriovenous malformations; single ventricle; superior.

Figure 1

Role of the liver in the development of pulmonary arteriovenous malformations (PAVMs) after superior cavopulmonary connection (SCPC): Isolation of the lungs from hepatic venous return results in a reduced exposure to angiogenesis inhibitors, increased expression of pro-angiogenic substances and PAVM development. VEGF: Vascular endothelial growth factor, which is an angiogenic factor. “Reprintedfrom: Pulmonary arteriovenous malformations after cavopulmonary anastomosis, Vol 76, Author(s): Brian W. Duncan, MD, Shailesh Desai, PhD, Pages No.1759-1766, Copyright (2003), with permission from Elsevier: License number 2845581266282, date: Feb 10, 2012.

Figure 2

Schematic comparing hepatic venous flow before and after the superior cavopulmonary connection (Glenn shunt). A. In the normal circulation, deoxygenated venous return (blue lines) from the superior vena cava (SVC) and the inferior vena cava (IVC, which contains hepatic effluent – indicated as green “stars”) mix in the right heart before being pumped through to both lungs. The oxygenated blood (red lines) is then returned to the left heart for systemic distribution. B. As depicted schematically for a unidirectional Glenn shunt, venous return from the SVC is redirected to the right lung, bypassing the right heart. This diversion of flow causes the right lung to receive steady (non-pulsatile) flow that is devoid of the hepatic effluent. Initially, normal oxygenation of blood occurs. C. However, with the development of PAVMs as late sequelae to the Glenn, where venous blood is shunted through low resistance conduits and does not get oxygenated, cyanosis can become manifest (purple line).

Figure 3

An angiogram showing diffuse PAVMs of the right lung 8 months after a SCPC (arrow). “Reprinted from: Pulmonary arteriovenous malformations after cavopulmonary anastomosis, Vol 76, Author(s): Brian W. Duncan, MD, Shailesh Desai, PhD, Pages No.1759-1766, Copyright (2003), with permission from Elsevier: License number 2845581266282, date: Feb 10, 2012. Fig 1. Selective injection of right lower lobe pulmonary artery in a patient with diffuse PAVMs.

Figure 4

A. Angiogenic and anti-angiogenic factors that potentially contribute to angiogenesis culminating in PAVM formation in the setting of SCPC. The angiogenic factors, angiopoietin-1, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β, matrix metalloproteinases (MMPs), and receptors for angiopoietin-1 (TIE-2), hypoxia inducible factor (HIF)-1α, and heme oxygenase (HO)-1 have been reported to be increased in the setting of SCPC. Conversely, the abundance of anti-angiogenic factors (angiostatin and endostatin) are reduced culminating in a strong angiogenic signal. B. Paracrine signaling between the endothelial and smooth muscle cells as well as signaling from circulating factors likely culminate in PAVM formation. For example, angiopoietin-1 can be synthesized and released from the smooth muscle cells, which would then bind to TIE-2 receptors that are found predominantly on the endothelial cells. This paracrine signaling loop may be evoked through changes in the biomechanical forces and biochemical milieu that occur following the SCPC.