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It started as a respiratory illness – or so everyone thought. But it quickly became apparent that SARS-CoV-2, the virus that causes COVID-19, was so much more.

"Since the beginning, the virus showed a very dramatic ability to affect different organs and systems beyond the respiratory system," said Dr. Chiara Giannarelli, an associate professor in the departments of medicine and pathology at NYU Grossman School of Medicine. "Early on, there was some evidence the virus was damaging the heart, causing an increased risk of heart attacks and strokes in these patients. But no one was looking at the vasculature," the blood vessels that carry the virus throughout the body and in and out of the heart.

From her lab in New York City, Giannarelli had front-row seats in the spring of 2020 to the epicenter of COVID-19 infections in the U.S. Because her research already focused on the complex relationship between inflammatory and immune cells in the arteries and their role in atherosclerosis – the root of cardiovascular disease – she felt well positioned to investigate.

Meanwhile, other research teams were looking into what the virus was doing to the heart muscle. Cases of myocarditis, an inflammation of the heart muscle, were being identified as the cause of death in some people with COVID-19.

As researchers dug into both questions, one thing became clear: The body's overzealous immune response to the virus – known as severe acute respiratory syndrome-coronavirus-2, or SARS-CoV-2 – was responsible for most of the damage it wrought, said Dr. DeLisa Fairweather, vice chair of translational research for the department of cardiovascular diseases at the Mayo Clinic's Florida campus in Jacksonville.

The same mechanisms involved in COVID-related cardiovascular events are responsible for COVID-related myocarditis, said Fairweather, lead author of a review article on COVID-19 and myocarditis.

"In one case, it's happening in the blood vessel walls, and in the other, it's in the heart muscle," she said. "It's just in a different location. What's important is the immune response to the virus."

SARS-CoV-2 is a large, enveloped RNA virus, meaning it is surrounded by an extra layer of cell membrane that allows it to fuse with healthy cells in our body. It typically enters the body through the eyes, nose or mouth, then targets the lungs. Cells in the lungs and blood vessels contain an abundance of ACE2 receptors, which the virus infiltrates using a spike protein on its outer membrane. These receptors are the virus's main entryway to host cells. They also play a vital role in cardiovascular function, including regulating inflammation. Once SARS-CoV-2 infiltrates the host cell, it empties its genetic material and begins to replicate.

Fairweather said the real problem is that once inside the host cells, the virus targets mitochondria, small structures inside a cell that produce its energy, and hijacks them to replicate itself.

"We die without mitochondria," she said. "So this sends out a big alarm to the rest of the body." In some people, the perceived danger triggers extremely high levels of inflammation and an excessive immune system response known as a cytokine storm.

Fairweather likened the response to the sounding of a DEFCON 4 alarm, calling out an entire army when only a few troops may be needed. "It's overkill," she said. "Why this happens is a question that's not well understood yet."

What researchers do understand is that the inflammatory cytokines that charge to the rescue play a role in atherosclerosis, the buildup and rupture of plaque in the arteries that can lead to a heart attack or stroke. Because SARS-CoV-2 was linked to a greater risk for these cardiovascular problems, Giannarelli and her team wanted to know if the virus was getting into arteries and what it was doing once it got there.

They analyzed tissue specimens from autopsies of people who were hospitalized and died from COVID-19. In immune cells known as macrophages that reside in the heart, they discovered the presence of a viral RNA sequence corresponding to the SARS-CoV-2 spike protein. A macrophage is a type of white blood cell that stimulates other immune system cells.

Next, the researchers recreated a SARS-CoV-2 infection in human tissue in the lab to see whether the virus could continue to replicate within these macrophages. While the virus was unable to efficiently generate new infectious viral particles within these cells, it did trigger an outsized immune system response, Giannarelli said.

In addition, they found white blood cells containing high levels of lipids were less efficient at clearing the virus than other cells. Lipid-filled cells may be offering the virus the perfect host environment "that allows it to persist and to continue to trigger an inflammatory response for a longer period of time," Giannarelli said.

Fueling greater inflammation inside preexisting blood vessel plaque can lead to pieces breaking off, she said. "This is what creates heart attacks and strokes."

Indeed, a recent study published in the journal found a prolonged increased risk for heart attacks and strokes in people infected with the virus in 2020, up to three years following their initial infections.

But myocarditis can show up in people infected with the virus who had no evidence of previous heart disease, Fairweather said.

That may be due to another type of immune cell called a mast cell, she said. Like macrophages in the heart, mast cells also carry ACE2 receptors. When SARS-CoV-2 infiltrates these cells, they amplify the immune response and trigger the excessive inflammation that leads to myocarditis.

The good news, Fairweather said, is that as people build immunity to the virus through vaccinations and reinfection, their bodies will learn how to fight the virus better and with more appropriate immune response levels.

Older adults, people with weaker immune systems and those with heart disease will remain more vulnerable than others, she said, but for most people, "the immune system should calm down and therefore the threat should go down over time."