The American Heart Association (AHA) has now joined the effort against Long COVID, funding 10 research proposals that aim to get to the bottom of the mysterious disease that impacts about 30% of COVID-19 survivors.

One of these studies is led by Lina Shehadeh, Ph.D., a professor of medicine at the University of Miami’s Miller School of Medicine, who received a $1 million grant from the AHA to identify Long COVID’s underlying cause(s) and molecular processes.*

Connecting the Dots

Shehadeh explains that, since Long COVID is a systemic disease that can impact any organ, the circulatory system becomes a viable research target because of its connection to all other body systems. In fact, in its animal-based studies, Shehadeh’s team has seen early signs of dysfunction in endothelial cells that line blood vessel walls. “Now,” she says, “we are working to connect the dots and explain this cascade.”

By studying mice and human blood samples, Shehadeh’s team hopes to learn more about a chain of events they believe may underlie Long COVID symptoms. This chain, they say, starts with the coronavirus causing lung inflammation and impaired cholesterol regulation, and ends with endothelial cell dysfunction.

Immune System Overdrive

Shehadeh is looking into evidence of an overactive immune response when coronavirus spike proteins meet with LDL cholesterol receptors on infected lung cells. This meeting forms net-like structures as the immune system overproduces neutrophils (a type of white blood cell) in the lungs.

Shehadeh says that when the virus overwhelms or defeats these neutrophils, they burst in the lungs and release the net-like structures, a process called netosis. It’s believed these structures then make their way into the circulatory system, and become embedded in blood vessel walls. 

“This would explain the loss of normal homeostasis in the vascular walls,” she says, “and the tendency toward thrombus [blood clotting] we see so often in COVID long-haulers.” For the study, the team is:

• Inducing COVID-19 infections in mice, which they’ve observed leads to excess LDL cholesterol in lung cells, and endothelial cell dysfunction in blood vessels.
• Taking blood samples from about 150 Long COVID patients, to measure neutrophils and check for netosis, along with taking MRI images of the heart and lungs to look for any changes.

Shehadeh noted that, thus far, genes governing cholesterol production in infected mice have been altered, which doesn’t yet make sense since blood cholesterol and fat levels have been normal.

Treatment Application

Shehadeh says the medical community will have a better knowledge base for treating Long COVID if her study can meet its objectives:

• Observing repeatedly in mice that the virus binding to LDL cholesterol receptors in lung cells leads to inflammation, impaired cholesterol regulation, netosis, and eventual endothelial dysfunction.
• Human blood sample findings support the mouse model evidence. 

“We know netosis is a disaster that causes systemic damage, and currently, steroids are used in many COVID-19 patients to help prevent this inflammatory cascade,” she explains. “If we understand the full chain of events from inflammatory triggers to the morbidity we see in Long COVID, we can work on finding an existing drug or other new therapy that removes these [net-like structures] from the vessel walls or prevent endothelial damage to begin with.”

*University of Miami Health System. (2022, May 12). Researchers on the Trail to Unraveling Long COVID-19. Newswise. https://www.newswise.com/coronavirus/researchers-on-the-trail-to-unraveling-long-covid-19