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Researchers at Stanford Medicine have identified the biological steps that explain how mRNA-based COVID-19 vaccines can, in rare cases, lead to heart inflammation in some adolescent and young adult males. Their work also points to a potential strategy for lowering that risk.
By combining modern laboratory techniques with previously published data from vaccinated individuals, the team uncovered a two-stage immune response. In this process, the vaccine activates one type of immune cell, which then stimulates another. Together, these immune reactions drive inflammation that can damage heart muscle cells and set off additional inflammatory effects.
Vaccines Remain Highly Safe and Effective
The findings come despite the fact that mRNA COVID-19 vaccines have been given billions of times worldwide and continue to show an excellent safety record, said Joseph Wu, MD, PhD, director of the Stanford Cardiovascular Institute.
“The mRNA vaccines have done a tremendous job mitigating the COVID pandemic,” said Wu, the Simon H. Stertzer, MD, Professor and a professor of medicine and of radiology. “Without these vaccines, more people would have gotten sick, more people would have had severe effects and more people would have died.”
mRNA vaccines are considered a major advance because they can be developed quickly, adjusted as viruses change, and tailored to target very different pathogens. Still, as with any medical intervention, reactions are not identical for everyone.
Understanding Vaccine-Associated Myocarditis
One uncommon but documented side effect of mRNA COVID-19 vaccines is myocarditis, which refers to inflammation of the heart muscle. Symptoms can include chest pain, shortness of breath, fever and heart palpitations. These symptoms occur without a viral infection and typically appear within one to three days after vaccination.
Most affected individuals show elevated levels of cardiac troponin in their blood, a widely used marker of heart muscle injury. (Cardiac troponin is normally found exclusively in the heart muscle. When found circulating in blood, it indicates damage to heart muscle cells.)
The condition occurs in roughly one out of every 140,000 people after a first vaccine dose and increases to about one in 32,000 after a second dose. Rates are highest among males age 30 and younger, where it affects about one in 16,750 vaccine recipients.
Outcomes Are Usually Mild and Temporary
Wu emphasized that the majority of myocarditis cases linked to vaccination resolve quickly, with heart function either fully preserved or restored.
“It’s not a heart attack in the traditional sense,” he said. “There’s no blockage of blood vessels as found in most common heart attacks. When symptoms are mild and the inflammation hasn’t caused structural damage to the heart, we just observe these patients to make sure they recover.”
In rare instances, however, severe inflammation can cause serious injury, leading to hospitalization, intensive care treatment or death.
“But COVID’s worse,” Wu said. He noted that a COVID-19 infection is about 10 times more likely to cause myocarditis than an mRNA-based COVID-19 vaccine, in addition to the many other risks posed by the disease.
A Closer Look at the Immune Response
Wu is a senior author of the study, publisded Dec. 10 in Science Translational Medicine, along with Masataka Nishiga, MD, PhD, a former Stanford postdoctoral scholar now at The Ohio State University. The study’s lead author is Xu Cao, PhD, also a postdoctoral scholar at Stanford.
“Medical scientists are quite aware that COVID itself can cause myocarditis,” Wu said. “To a lesser extent, so can the mRNA vaccines. The question is, why?”
Suspects Identified
To answer that question, the team analyzed blood samples from vaccinated individuals, including some who developed myocarditis. When they compared these samples with those from people who did not develop heart inflammation, two proteins stood out.
“Two proteins, named CXCL10 and IFN-gamma, popped up. We think these two are the major drivers of myocarditis,” Wu said.
Both CXCL10 and IFN-gamma are cytokines, signaling molecules that immune cells use to communicate and coordinate their activity.
How Immune Cells Interact After Vaccination
The researchers grew human immune cells called macrophages in laboratory dishes and exposed them to mRNA vaccines. Macrophages act as early responders in immune defense.
After exposure, the macrophages released multiple cytokines, with especially high levels of CXCL10. Their behavior closely matched immune responses previously documented in vaccinated people.
When T cells were added to the system, either directly or by exposing them to fluid from the macrophage cultures, the T cells began producing large amounts of IFN-gamma. In contrast, T cells exposed to the vaccine alone did not show this spike. These findings showed that macrophages primarily produce CXCL10, while T cells are the main source of IFN-gamma following vaccination.
How the Cytokines Affect the Heart
To determine whether these cytokines directly harm the heart, the team vaccinated young male mice and observed increased cardiac troponin levels, indicating heart muscle injury.
They also found that immune cells, including macrophages and neutrophils, had entered heart tissue. Neutrophils are short-lived immune cells that respond aggressively to threats and are a major component of pus. Similar immune cell infiltration is seen in people who develop myocarditis after vaccination.
Blocking CXCL10 and IFN-gamma reduced the number of these immune cells entering the heart and limited damage to healthy tissue.
The researchers also detected increased levels of adhesion molecules in heart blood vessels. These molecules help immune cells latch onto vessel walls, making it easier for them to move into heart tissue.
Together, these findings confirmed that CXCL10 and IFN-gamma directly contribute to heart injury. Blocking them preserved much of the immune response to vaccination while lowering signs of heart damage.
Testing Human Heart Tissue Models
Wu’s lab specializes in converting human skin or blood cells into stem-like cells that can become heart muscle cells, immune cells and blood vessel cells. These cells can be assembled into small, beating clusters that mimic aspects of heart function.
When these cardiac spheroids were exposed to CXCL10 and IFN-gamma collected from vaccinated immune cells, markers of heart stress rose sharply. Using inhibitors to block the cytokines reduced this damage.
Measures of heart function, including contraction strength and beating rhythm, were impaired by the cytokines but improved once the signaling was blocked.
Saved by a Soybean
Wu suspected that a widely available dietary compound might help protect the heart. Since myocarditis is more common in males and estrogen has anti-inflammatory effects, he revisited genistein, a soy-derived compound his team had studied previously.
In a 2022 study published in Cell, the researchers showed that genistein has anti-inflammatory properties and can counter marijuana-related damage to blood vessels and heart tissue.
“Genistein is only weakly absorbed when taken orally,” Wu said. “Nobody ever overdosed on tofu.”
Testing Genistein’s Protective Effects
The team repeated their experiments while pre-treating cells, cardiac spheroids and mice (the latter by oral administration of large quantities) with genistein. This treatment reduced much of the heart damage caused by either mRNA vaccination or the CXCL10 and IFN-gamma combination.
The form of genistein used in the study was more purified and concentrated than supplements commonly sold in stores.
“It’s reasonable to believe that the mRNA-vaccine-induced inflammatory response may extend to other organs,” Wu said. “We and others have seen some evidence of this in lung, liver and kidney. It’s possible that genistein may also reverse these changes.”
Broader Implications Beyond COVID Vaccines
Heightened cytokine signaling may be a broader feature of mRNA vaccines. IFN-gamma, in particular, plays a critical role in defending the body against foreign DNA and RNA, including viral genetic material.
“Your body needs these cytokines to ward off viruses. It’s essential to immune response but can become toxic in large amounts,” Wu said. Excessive IFN-gamma can lead to myocarditis-like symptoms and breakdown of heart muscle proteins.
This risk is not limited to COVID vaccines alone.
“Other vaccines can cause myocarditis and inflammatory problems, but the symptoms tend to be more diffuse,” Wu said. “Plus, mRNA-based COVID-19 vaccines’ risks have received intense public scrutiny and media coverage. If you get chest pains from a COVID vaccine you go to the hospital to get checked out, and if the serum troponin is positive, then you get diagnosed with myocarditis. If you get achy muscles or joints from a flu vaccine, you just blow it off.”
Funding and Support
The study was supported by the National Institutes of Health (grants R01 HL113006, R01 HL141371, R01 HL141851, R01 HL163680 and R01 HL176822) and the Gootter-Jensen Foundation.
