Stanford Medicine study shows why mRNA-based COVID-19 vaccines can cause myocarditis

New research points to two substances secreted by immune system cells induced by the myocardium in recipients of an mRNA-based COVID-19 vaccine—and suggests strategies to moderate this effect.

Stanford Medicine researchers have uncovered a biological process by which mRNA-based vaccines against Covid-19 can cause heart damage in some young men and teenagers, and they have shown a possible way to reduce the likelihood.

Using advanced but now routine laboratory techniques and published data from vaccinated individuals, researchers have demonstrated a two-step sequence in which these vaccines activate one type of immune cell, which in turn activates another type of immune cell.The resulting inflammatory activity directly damages heart muscle cells, leading to further inflammatory damage.

The mRNA vaccine for COVID-19 has now been administered several billion times and has been safety tested and proven to be very safe, said Joseph Wu, PhD, director of the Stanford Cardiovascular Institute.

Wu and Simon X "mRNA vaccines have done a tremendous job in reducing the Covid epidemic. Without these vaccines, more people would have gotten sick, more people would have been seriously ill, and more people would have died," said Sterzer, MD, professor of medicine and radiology.

mRNA vaccines are considered a breakthrough because they can be produced rapidly in response to sudden microbial changes and can be adapted to fight different pathogens.But, as with all vaccines, not everyone who gets the flu will have a mild reaction.

One rare but real risk of covid-19 mRNA vaccines is myocarditis, or inflammation of the heart tissue.Symptoms - chest pain, shortness of breath, fever and palpitations - appear in the absence of viral infection.Ac happens quickly: within one to three days after the shot.Clinical signs of myocardial injury have been established.(Cardiac troponin is normally found in the heart. When found in the blood, it damages heart muscle cells.)

Vaccine-related myocarditis occurs in about one in 140,000 vaccinated people after the first dose and affects one in 32,000 people after a second dose.For reasons that are unclear, the incidence among vaccinated men aged 30 or younger is one in 16,750 vaccinated.

Fortunately, most of these cases end well, said Wu, with full liver function preserved or restored.Recovery is usually fast.

"It's not a heart attack in the normal sense," he said."There is no blockage of the arteries as seen in a normal heart. When the symptoms are mild and the pain is not affecting the heart, we look at these patients to make sure they are recovering."

However, Wu said that if the damage to the heart is severe, it can be very debilitating, leading to hospitalization;ICU admission for critical patients;and death, though it is rare.

“But COVID is worse,” he added. A case of COVID-19-induced myocarditis is about 10 times more likely than with an mRNA-based COVID-19 vaccine, Wu said. And that doesn't include all the other problems it causes.

Wu shares lead authorship of the study describing his team's findings, published Dec. 10 in the journal Science Translational Medicine, with Masataka Nishiga, MD, PhD, a former postdoctoral researcher at Stanford and now an assistant professor at Ohio State University.The leader of the study is current postdoctoral researcher Xu Cao, Ph.D.

"Medical scientists are well aware that COVID itself can cause myocarditis," Wu said."In small amounts, mRNA can also be a drug." The question is why?

To find out, he and his colleagues first analyzed data from blood draws of people vaccinated for Covid-19, some of them developed myocarditis.Compared to those who do not, they saw higher levels of a couple of proteins in the blood of vaccines injured with myocardis.

Medical scientists are quite aware that COVID itself can cause myocarditis.To a lesser extent, the same as mRNA injection.The question is: why?

"Two proteins called CXCL10 and IFN-gamma appear. These two are the main cause of myocarditis," Wu said.They work as a tag team.

CXCL10 and IFN-gamma both belong to a class of proteins called cytokines, signaling substances that immune cells release to conduct chemical conversations with each other.

Hoping to listen to these communications, the scientists cultured human immune cells called macrophages—the immune system's fierce first responder cells—in a dish and injected them with mRNA vaccines.

Macrophages responded by secreting various cytokines, but, in particular, significant amounts of CXCL10.They generally mimic macrophage vaccine responses reported in humans, as shown by comparison with published data from vaccinated individuals.

When scientists gave a front plate to another type of immune cell - T cell, wandering guard can recognize and rise immune attack on specific pathogens, but can also stimulate a general activation of the immune system - or even T cells only put it in a solution of anti-aging macrophages to wash, they saw the uptic signal and IFN-gamma.But the T cells treated with the vaccine type, and no macrophages or bats of their own produced only IFN-gamma.These results indicate that macrophages are the main source of CXCL10 and T cells are the main source of IFN-gamma in response to mRNA vaccination.

But did the two cytokines together directly contribute to heart damage? When the researchers vaccinated young male mice, they found elevated levels of cardiac troponin, a widely used diagnostic marker for heart muscle damage.

The investigators observed that macrophages and another lead inmate immune cell type, neutrophils—short-term first responders—died in the familiar battle (usually with bacterial or fungal pathogens) and infiltrated the mice's heart tissue, a key component of abscesses.This also occurs in patients with post-injection myocarditis.

This infiltration of macrophages and neutrophils into the heart—a “shoot first, ask questions later” warrior immune cells—often releases friendly fire, causing additional damage to healthy tissues, including the myocardium, and can be reduced by blocking CXCL10 and IFN-gamma activity.

Also observed in the hearts of the mice was an increase in the number of cell-surface molecules that bind macrophages, neutrophils and other types of white-blood-cells, causing them to adhere to endothelial cells, which line all blood vessels including the one in the heart.

So yes, CXCL10 and IFN-gamma directly contributed to heart failure in these miceAnd blocking them preserved the immune response to the vaccine while reducing vaccine-induced cardiac troponin levels.

Wu's lab excels in technology that involves transforming human skin cells or blood cells into hollow cells, which can be directed to differentiate into cardiomyocytes, macrophages and endothelial cells and assemble into spherical structures that mimic the rhythmic contractions of the heart.

The researchers treated these "heart spheroids" with a CXCL10- and IFN-gamma-enriched bath of macrophages and vaccine-stimulated T cells.They saw a significant increase in cardiac stress markers, rescued by an inhibitor of the two cytokines.

Beating capacity of heart spheroids, beating rate, and other measures of healthy cardiac function were all impaired but, again, partially restored by cytokine inhibitors.

Saved by soy

Wu believed that a simple dietary supplement could prevent the damage.Given the higher rates of myocarditis among men and the well-known anti-inflammatory properties of estrogen, he returned to a compound he had studied a few years earlier.

In a 2022 paper published in Cell, Wu's team identified genistein, a mild estrogen-like substance extracted from soybeans, that has anti-inflammatory activity and the ability to counteract marijuana-induced damage to blood vessels and heart tissue.

"Genistein is poorly absorbed when taken orally," Wu said."No one has ever overdosed on tofu."

Wu and his colleagues conducted several experiments similar to those described above, pre-existing cells, heart sites, and mice (the latter by large oral administration) with genistein.This would prevent most of the adverse effects of the mRNA vaccine or the CXCL10/IFN-gamma combo on heart cells and organs.

The genistein pills Wu and his colleagues used were purer and more intense than nutritional supplements found in health food stores.

“It is reasonable to believe that the inflammatory response to an mRNA vaccine could spread to other organs,” Wu said."We and others have seen some evidence of this in the lungs, liver and kidneys. It is possible that genistein may also reverse these changes."

Increased inflammatory cytokine signaling may be a class effect of mRNA vaccines.IFN-gamma signaling is a fundamental defense mechanism against foreign DNA and RNA molecules, including viral nucleic acids, Wu said.

"Your body needs these cytokines to fight viruses. It's necessary for the immune response, but they can become toxic in large quantities," he said.IFN-gamma secreted in large quantities, no matter how noble it may be, can cause myocarditis-like symptoms and breakdown of structural proteins of the heart muscle.

This risk may be greater than that of an mRNA-based COVID-19 vaccine.

"Other vaccines can cause myocarditis and inflammatory problems, but the symptoms tend to be more diffuse," Wu said."Furthermore, the risk of mRNA-based COVID-19 vaccines has received significant public attention and media coverage.If you have chest pain from the COVID vaccine, you go to the hospital to have it checked, and if your serum troponin is positive, you are diagnosed with myocarditis.If you have muscle aches or a few days after your flu shot, you just skip it.

Research by the National Institutes of Health (Grant R01 HL113006, R01 HL141371, R01 HL141851, R01 HL163680, and R01 HL176822) and the Gutter-Jensen Foundation.