Researchers Link Bicuspid Aortic Valve Disease to Defective Cilia

September 30th, 2019 - Posted to Cardiothoracic Vascular Surgery

Bicuspid Aortic Valve DiseaseBicuspid aortic valve (BAV) disease affects about 70 million people throughout the world and is the most common birth defect that involves the heart valves.

Researchers have discovered that genetic variations that occur in human primary cilia during the development of the heart valve are the reason for BAV disease.

In BAV disease, two of the aortic valve leaflets get fused together and thus impair the functions of the valve. A healthy aortic valve has three leaflets and therefore in patients with BAV, the defective valves will eventually have to be repaired or replaced through surgery.

Role of Cilia in Heart Health and Disease

An article published online in the journal Circulation on August 7, 2019, explains the way researchers used animal models and human data to establish that aortic valve narrowing and BAV disease is caused by the disruption of the exocyst. The exocyst is crucial for the development of cilia because it acts as a shuttling complex that helps move the cilia cargo to the cell membrane. Thus, disruption of the exocyst impairs ciliogenesis and leads to BAV in mice and heart defects in zebrafish.

Researchers at the Medical University of South Carolina (MUSC) discovered that a mutation in the gene that controls the production of cilia (tiny antennae on the cell surface) is linked to BAV disease. Cilia are present in most cells and these look similar to tiny antennae that sense the surroundings and transmit information to each other. In the same way, cilia function as signaling hubs during the development of the heart valves and coordinate the way extracellular matrix and cells need to arrange in order to form a mature tissue.

More about the Research Findings

The genomes of healthy adults and patients with BAV disease were compared first in a genome-wide association study. The most associated differences were detected in or near the genes that are crucial for the regulation of cilia production through the exocyst. Then, animal models were used to find out whether the mutations occur in a central exocyst protein Exoc5. When the gene for Exoc5 was knocked out or disabled in zebrafish, severe obstruction resulted in blood flow from the heart that in turn lead to poor functions of the heart and premature death. Additionally, there were signs of other ciliopathies. Surprisingly, the injection of the proper gene sequence for Exoc5 into the zebrafish prevented the development of heart defects, which proves that the genetic mutation was the cause of the disease.

The researchers disabled the Exoc5 gene in mice, particularly in the cells of the heart valves. Mice having both disabled copies of gene died during early development whereas mice with a single copy of the disabled gene attained birth but with a high rate of BAV disease and problems associated with cilia production.

Clinical Implications of the Study

Often, the patients with BAV disease develop aortic valve calcification leading to stenosis or narrowing of the opening of the valve. This leads to severe functional defects within the heart for which surgery is indicated. Now that the cause of the heart valve birth defect has been found to be disruption in cilia and exocyst, the development of new therapies and ways to treat the BAV disease without surgery can be triggered.