Clues to the origins of abnormal heart valves

November 10, 2015

October’s featured paper is "Increased systolic load causes adverse remodeling of fetal aortic and mitral valves,” published in the American Journal of Physiology. The paper is published by a team led by Dr. Frederick Tibayan, associate professor of surgery, Division of Cardiothoracic Surgery, in the OHSU School of Medicine.

paper of the month tibayan labThe human heart has four valves. If one or more of the valves don’t perform properly, heart valve disease develops.  Left untreated, advanced heart valve disease can cause heart failure, stroke, blood clots or death due to sudden cardiac arrest.

According to data released by the American Heart Association in 2014, heart valve disease occurs in about 2.5 percent of the generation U.S. population, but that percentage increases with age. In those over 75, occurrence is between 10 to 15 percent. Nearly 100,000 valve surgeries are performed each year to repair or replace valves, and this number is growing rapidly as the population ages.

In one form of the disease – congenital heart valve disease – the exact cause isn’t known, but it develops in utero as the heart is forming. Researchers at OHSU have also been working to establish a link between fetal conditions and adult valvular disease.

Developmental origins

In this month’s highlighted paper, researchers have made progress toward reaching a clearer understanding of the developmental origins of valve disease. In previous studies, scientists at OHSU and elsewhere have shown that an abnormal fetal environment can lead to a predisposition towards cardiovascular disease later in life.

The late David Barker, M.D., Ph.D., director of international collaborations at the OHSU Moore Institute of Nutrition & Wellness and professor of medicine in the OHSU School of Medicine, established a link between low birth weight and the risk of coronary artery disease, launching a field of science called Developmental Origins of Health and Disease.

“We know that intrauterine growth restriction, which affects up to 10 percent of babies born in the U.S., is linked to coronary artery disease and high-blood pressure in the fetus,” said Frederick Tibayan, associate professor of surgery, Division of Cardiothoracic Surgery, in the OHSU School of Medicine. “Drs. Giraud and Thornburg have shown previously that hemodynamic conditions in the womb, like blood pressure, are powerful determinants of heart growth.”

“But we don't know how fetal high blood pressure, which is associated with being born small, affects the growth and remodeling of the heart valves,” he added. “This is the knowledge gap that we are trying to bridge with our work.”

Effects of fetal hypertension

Dr. Tibayan’s research team set out to determine how hypertension during fetal life changes the development of the fetal heart valves. They hypothesized that chronically-elevated blood pressure would detrimentally alter fetal valve growth.

Using a sheep model, they observed changes to valve parts during periods of increased blood pressure, including dilation of the mitral valve annulus and lengthening of the leaflets. The changes in fetal valves may translate to abnormalities in the valves after birth.

“This study showed that fetal hypertension is associated with anatomic remodeling of the valve,” said Dr. Tibayan. 

In a surprise finding, the team also observed the suppression of signaling pathways as well as the suppression of the expression of collagen and elastin, all important for valve development. The team published their findings in the American Journal of Physiology.

“I was intrigued by this paper’s evidence that something as simple as increased fetal blood pressure can alter development of the cardiac valves,” said Mary Heinricher, Ph.D., associate dean for basic research in the OHSU School of Medicine, who selected the paper as the school’s October 2015 Paper of the Month.

The role of epigenetics

The team was intrigued by the downregulation of gene expression. Elastin deposition in the valves takes place only during late gestation and early neonatal life, Dr. Tibayan explained. So the decrease in elastin expression could result in an irrecoverable deficit in this crucial component of valve tissue.

“When we have seen this kind of valve remodeling in previous studies of adult valves, it has been associated with increased mechanical stress on the leaflets and leaking of the valves,” he said.

The team speculates that the downregulation of gene expression is accompanied by epigenetic features – cellular and physiological variations caused by adverse environmental factors such as stress – that make the heart valve more vulnerable in adults and less able to cope with hemodynamic changes later in life, when a normal mature response is needed but no longer possible because of the epigenetic changes.

Next steps

The Tibayan Lab is now working on whether the changes observed in the fetal heart valves might portend a vulnerability of the valve later in life. “We want to determine whether these changes in the valves early in life in fact predispose to valve disease in adult life,” said Dr. Tibayan.

“It will be interesting to see how these changes influence the function of the valves over the lifespan,” said Dr. Heinricher.

The researchers also want to tease out the epigenetic mechanisms underlying these changes. The goal, says Dr. Tibayan, is to develop therapeutics that target the signaling pathways in an effort to prevent or reverse the changes that lead to abnormal valve remodeling.



Am J Physiol Regul Integr Comp Physiol. 2015 Sep 9:ajpregu.00040.2015. doi: 10.1152/ajpregu.00040.2015. [Epub ahead of print]  Increased systolic load causes adverse remodeling of fetal aortic and mitral valves. Tibayan FA1, Louey S2, Jonker SS3, Espinoza HM3, Chattergoon NN3, You F4, Thornburg KL5, Giraud GD6.

More Published Papers

Pictured above: Bottom row,  left to right: Mike Espinoza, George Giraud. Top row, left to right: Samantha Louey, Sonnet Jonker, Frederick Tibayan, Isa Lindgren, Natasha Chattergoon.

About the School of Medicine Paper of the Month

The OHSU School of Medicine spotlights a recently published faculty research paper each month. The goals are to describe to the public the exceptional research happening at OHSU as well as inform our faculty of the innovative work underway across the school’s departments, institutes and disciplines. The monthly paper is selected by Associate Dean for Basic Research Mary Heinricher, Ph.D.