Candidate Identification for the Elusive "Hepatic Factor"

Ramani Ramchandran, PhD and Andrew D. Spearman, MD
Amount Funded: $32,000

The bidirectional Glenn (BDG) is a common surgery for patients with complex congenital heart disease (CHD). The BDG connects the largest vein from the upper body, the superior vena cava (SVC), directly to the arteries connected to the lungs, the pulmonary arteries. The veins from the lower body are still connected to the heart but go directly to the body without first traveling to the lungs to add oxygen to the blood. Thus, the BDG allows infants and children with complex CHD to survive with the trade-off of lower oxygen levels in the blood. An unintended side-effect of the BDG is that pulmonary arteriovenous malformations (PAVMs) develop. PAVMs are abnormal blood vessel malformations in the lungs that further decrease oxygen levels in the blood. PAVMs increase over time in patients with BDG. A subsequent surgery after the BDG, the Fontan palliation, connects the largest vein from the abdomen and lower body, the inferior vena cava (IVC), directly to the pulmonary arteries. With the Fontan palliation, all veins from the liver and lower body travel to the lungs to pick up oxygen. The Fontan palliation gradually resolves PAVMs if there is equal blood flow to both lungs. The observations that PAVMs develop in patients after the BDG (which prevents blood from the liver from traveling to the lungs) andresolve in patients after Fontan (which re- establishes blood flow from the liver to the lungs), led to the hypothesis that a factor produced by the liver is protective against development of PAVMs and can resolve existing PAVMs. The liver factor, though, remains unidentified. Because the liver is made up mostly of cells called hepatocytes, this liver factor is referred to as the "hepatic factor."

Previous experiments show that PAVMs develop due to abnormal activity of blood vessels cells in the lung, called endothelial cells (ECs). Recent experiments give insight that an important protein in the lung ECs, Matrix Gla Protein (MGP), can specifically regulate PAVM development. Despite previous work, the identity of the "hepatic factor" remains unknown. The objective of this study is to identify "hepatic factor" candidates that will resolve PAVMs. We hypothesize that hepatocytes secrete the "hepatic factor" into the circulation to stabilize lung (pulmonary) EC activity and increase MGP expression in lung ECs, in order to prevent PAVMs.

We will investigate this hypothesis in two aims:

Aim 1: To define the molecular characteristics of the "hepatic factor" by directly testing products of hepatocyte secretion on pulmonary ECs.

Aim 2: To define the effect of hepatocyte secretion and hepatic vein blood on MGP expression in pulmonary ECs.

Accomplishing these aims will allow development of therapies targeting the "hepatic factor" to treat and prevent PAVMs in patients with complex CHD and BDG. By eliminating PAVMs from children with complex CHD, we will increase the oxygen levels in their blood, improve their quality of life, and potentially improve their survival. Thus, this research is directly aligned with the Mend a Heart Foundation’s mission of extending and enriching the lives of children born with CHD.