Investigators have found that shear stress caused by aortic valve stenosis activates white blood cells, leading to potentially harmful inflammation, which in turn accelerates heart disease.

Aortic valve stenosis affects more than 1 in 8 patients over 75 years old and can have a higher mortality rate than most cancers if left untreated. The disease is caused by degeneration and thickening of the aortic valve, which forces blood cells to squeeze through the narrow valve. This squeezing creates intense frictional force, called shear stress.

Although the investigators found that this stress accelerates aortic stenosis, they also identified a potential drug target by pinpointing the receptor that controls the white blood cell overactivity.

“In someone with severe aortic valve stenosis, circulating blood cells come under heavy stress about 1500 times a day,” said Sara Baratchi, PhD, co-chief investigator, in a statement. “We now know this constant frictional force makes the white blood cells hyperactive. If we can stop that inflammatory response, we can hope to slow down the disease.”

The investigators compared immune cells from 24 patients taken before and after aortic valve replacement, which is the most effective treatment for severe stenosis. They also designed a microfluidic organ-on-a-chip system to replicate the conditions inside the aortic valve, both pre- and post-replacement, which enabled the investigators to precisely identify how the cells responded to changes in shear stress.

The team partnered with biomedical engineers, mechano-biologists, and immunologists to create the chip, which can be a cost-effective way to compare health and diseased conditions.

“With this technology, we can meticulously mimic both healthy and diseased organs in the body, at very low cost and in a highly controlled experimental environment,” Baratchi said. “We can build models to simulate different flow situations and identify drug targets, which we hope in future may reduce or even replace the need for animal models.”

In their analysis, the researchers focused on monocytes because they experience the most shear stress when passing through the narrow valve. These cells are also central drivers of the pathology behind aortic stenosis, according to the study.

The investigators found that a membrane protein known as Piezo-1 was the mechanoreceptor primarily responsible for activating these shear stress functions, making it a potential drug target. They also found for the first time that replacing the aortic valve has an anti-inflammatory effect, expanding the known benefits of the procedure.

Notably, monocytes are also known to play a role in atherosclerosis, a condition in which blood flow is obstructed due to a build-up of cholesterol plaque in the artery wall. Based on their findings, the researchers said a drug could potentially target both aortic valve stenosis and atherosclerosis.

REFERENCE
Hyperactive immune cells accelerate heart valve disease: study [news release]. RMIT University; July 9, 2020. https://www.rmit.edu.au/news/all-news/2020/jul/heart-valve-disease. Accessed July 16, 2020.