The influenza virus is notorious for bringing fever, aches, chills, and sweats to its hosts. But, some people who have a severe version of the flu can develop heart problems, even when their hearts have been previously healthy. This complication, which has remained poorly understood, can be very serious—even life-threatening.

A new study from the Ohio State University shows a link between a genetic mutation, influenza virus and heart irregularities. The study, led by Jacob Yount, PhD, associate professor of microbial infection and immunity appears in the Proceedings of the National Academy of Sciences in a paper titled, “IFITM3 protects the heart during influenza virus infection”.

In humans, mutations in the gene encoding the antiviral restriction factor IFN-induced transmembrane protein 3 (IFITM3) are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to cardiac dysfunction during infection is unclear. The gene is responsible for making a protein critical in the earliest stages of the human immune response, mounting a defense that creates difficulty for viruses trying to invade cells.

“By knocking out this gene in mice, and infecting them with various strains of flu, we were able to show that this gene’s absence increases the chances of heart abnormalities—decreased heart rate and irregular heartbeat—and death,” Yount said. “There’s been no known link between this gene and flu-related heart complications until now.”

The question that Yount asked was, how, specifically, does IFITM3 make people sicker and if it was related to heart problems, particularly in those with no previous cardiovascular disease?

“Flu can exacerbate underlying heart disease, but it can also affect the hearts of people who are otherwise healthy, typically in cases where people are so sick with the flu that they’ve been hospitalized,” said Yount.

The researchers discovered that IFITM3 prevents efficient dissemination and replication of influenza virus in heart tissue, thereby limiting cardiac fibrosis and electrical dysfunction during infection.

Since IFITM3 polymorphisms are among the only human genetic factors that have been reproducibly associated with hospitalization and mortality during influenza virus infection, their findings are relevant to the serious threat of influenza virus infection to human health. Furthermore, IFITM3 KO mice provide one of the first models for studying cardiac complications of influenza.

Though scientists have been documenting the connection between flu deaths and heart complications since the 1918 influenza pandemic that killed at least 50 million people worldwide, the mechanics of why flu leads to heart trouble haven’t been clear.

“A lot of people have assumed that systemic inflammation from the infection stresses or harms the heart, but this new finding suggests that some people may be genetically predisposed to these complications,” Yount said. Previous research has shown the mutations aren’t uncommon. About 20% of Chinese people and about 4% of people of European ancestry have IFITM3 mutations, he said.

Understanding the underlying causes of flu deaths could lead to therapies that might save at-risk people, Yount said. His lab is now working on testing experimental therapies in mice.

When Yount and his collaborators examined the heart tissue from the genetically-altered mice, they confirmed that the heart tissue was infected with flu virus. They also found a possible explanation for connections between the gene, the flu, and the heart abnormalities: fibrosis. Fibrosis is the buildup of collagen in tissue. Collagen plays an important role in connecting muscle fibers, but too much can be a problem.

“Too much of this collagen can cause ‘bumps in the road’ that could disrupt the electrical flow of the heart—that could explain the erratic heart rhythms we saw in this experiment,” Yount said.

The study also found varying degrees of flu-related heart abnormalities depending on the virulence of the flu strain. The most harmful flu they tested led to highly erratic heart rhythms, lasting heart damage, and greater chance of death. A moderate strain resulted in reversible, temporary heart abnormalities. When gene-deficient mice were given the weakest of three flu strains in the study, heart irregularities weren’t seen.

“It’s exciting to now have a model to help us answer more questions about why flu is causing these heart problems and to test drugs that might help people,” Yount said. “For now, there’s no treatment that specifically focuses on the cardiac complications from the flu.”

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