Researchers at Stanford Medicine have uncovered biological processes explaining how mRNA COVID-19 vaccines can, in rare instances, cause heart inflammation in younger males. They also propose a potential method to mitigate this risk.
By integrating modern lab techniques with existing data from vaccinated individuals, the research team revealed a two-step immune response. Initially, the vaccine activates a specific type of immune cell, which then stimulates another type. This series of immune reactions can lead to inflammation that harms heart muscle cells and triggers further inflammatory responses.
Vaccines Stay Extremely Safe and Effective
Despite mRNA COVID-19 vaccines being administered billions of times globally with a strong safety record, these findings are still significant, according to Joseph Wu, MD, PhD, director of the Stanford Cardiovascular Institute.
“The mRNA vaccines have been crucial in reducing the impact of the COVID pandemic,” Wu stated, also holding the Simon H. Stertzer, MD, Chair and serving as a professor of medicine and radiology. “Without these vaccines, many more would have suffered severe health consequences or died.”
mRNA vaccines are widely regarded as a major innovation because they can be developed rapidly, adapted for emerging variants, and tailored to combat diverse pathogens. Yet, like any medical treatment, individuals can respond quite differently.
Examining Vaccine-Related Myocarditis
Myocarditis, or heart muscle inflammation, is a rare but recognized side effect of mRNA COVID-19 vaccines. Symptoms may include chest pain, breathlessness, fever, and heart palpitations, manifesting within one to three days post-vaccination and without any viral infection.
Most patients present elevated cardiac troponin levels, a common marker for heart muscle injury (this protein is typically present only in heart muscle, indicating damage when found in blood). The incidence of myocarditis is approximately one case per 140,000 after the first vaccine dose, increasing to about one case per 32,000 following the second dose. The rates are especially elevated among males aged 30 and under, with about one in 16,750 affected.
Generally Mild and Temporary Outcomes
Wu pointed out that most myocarditis occurrences linked to vaccination are short-lived, with normal heart function either fully maintained or restored.
“This isn’t a traditional heart attack,” he noted. “There isn’t the typical blockage of blood vessels. If the symptoms are mild and there’s no lasting structural damage, we typically just monitor these patients.” However, severe inflammation can, in rare cases, lead to significant harm, necessitating hospitalization or, sadly, even resulting in death.
“But the risks from COVID are much higher,” Wu remarked. He highlighted that a COVID-19 infection is about ten times more likely to induce myocarditis than an mRNA vaccine, coupled with various additional risks posed by the virus.
Investigating the Immune Response
Wu co-authored the study, published on December 10 in Science Translational Medicine, alongside Masataka Nishiga, MD, PhD, now at The Ohio State University, and lead author Xu Cao, PhD, a postdoctoral scholar at Stanford.
“Medical scientists are aware that COVID can lead to myocarditis,” Wu said. “To a lesser degree, mRNA vaccines can too, but why?”
Identifying Key Factors
To delve deeper, the team analyzed blood samples from vaccinated individuals, including those who experienced myocarditis. In their comparisons, two proteins emerged as noteworthy.
“CXCL10 and IFN-gamma stood out. We believe these are major contributors to myocarditis,” Wu explained. Both proteins are cytokines, which are signaling molecules immune cells use to communicate.
Interactions Among Immune Cells Post-Vaccination
The researchers cultivated human immune cells known as macrophages in lab settings and introduced them to mRNA vaccines. These macrophages serve as early responders in immune protection.
Post-exposure, the macrophages released numerous cytokines with especially high levels of CXCL10. Their behavior mirrored immune responses documented in vaccinated subjects. When T cells were added, they began generating large amounts of IFN-gamma, a stark contrast to T cells exposed solely to the vaccine, which did not show this spike. This suggested that macrophages mainly produce CXCL10, while T cells predominantly produce IFN-gamma following vaccination.
Evaluating Cytokine Effects on the Heart
To ascertain whether these cytokines directly harm the heart, the researchers vaccinated young male mice, finding elevated cardiac troponin levels indicating heart injury.
They also observed immune cells, including macrophages and neutrophils, infiltrating heart tissue. Neutrophils, known for being short-lived and responding vigorously to threats, are commonly associated with pus formation. This pattern of immune cell infiltration resembles that observed in individuals who develop myocarditis post-vaccination.
Blocking CXCL10 and IFN-gamma reduced the number of immune cells entering the heart and limited damage to healthy tissue.
The team found increased adhesion molecules in heart blood vessels as well, which help immune cells anchor to vessel walls, facilitating their movement into heart tissue.
These findings confirmed that CXCL10 and IFN-gamma contribute directly to cardiac injury and, when blocked, preserve much of the immune response while reducing heart damage indicators.
Testing Human Heart Tissue Models
Wu’s lab focuses on converting human skin or blood cells into stem-like cells capable of becoming heart muscle cells, immune cells, and blood vessel cells. These can be assembled into small, beating clusters mimicking certain heart functions.
When exposed to CXCL10 and IFN-gamma from vaccinated immune cells, these cardiac spheroids showed significant stress-related markers. Using inhibitors to block these cytokines reduced associated damage.
Measures of heart function, like contraction strength and rhythm, deteriorated with cytokine exposure but improved upon blocking the signaling.
Potential Solutions from Soybean-Derived Compounds
Wu considered that a common dietary compound might help protect the heart. Observing that myocarditis is more frequent in males and recognizing estrogen’s anti-inflammatory effects, he revisited genistein, a soy-derived compound previously studied by his team.
In a 2022 study featured in Cell, they found that genistein has anti-inflammatory benefits and can mitigate marijuana-related damage to blood vessels and heart tissue.
“Genistein doesn’t absorb well when taken orally,” Wu noted. “You don’t see anyone overdosing on tofu.”
Evaluating Genistein’s Protective Role
The team conducted further experiments pre-treating cells, cardiac spheroids, and mice (with a substantial oral dosage of genistein). This approach minimized heart damage stemming from mRNA vaccination or the cytokine duo of CXCL10 and IFN-gamma.
The genistein used in these experiments was a more pure and concentrated form than typical supplements.
“It’s plausible that the inflammatory response triggered by mRNA vaccines could also extend to other organs,” Wu added. “There’s some evidence of this in the lungs, liver, and kidneys. Genistein might alleviate those changes as well.”
Wider Implications Beyond COVID Vaccines
Heightened cytokine signaling may represent a broader characteristic of mRNA vaccines. IFN-gamma is particularly vital for the body’s defense against foreign genetic material, including viral RNA and DNA.
“Your body needs these cytokines to fend off viruses; they’re essential for immune response but can become harmful in excessive amounts,” Wu noted. High levels of IFN-gamma can induce myocarditis-like symptoms and disrupt heart muscle proteins.
This risk isn’t confined to COVID vaccines.
“Other vaccines can lead to myocarditis and inflammatory challenges, although symptoms tend to be less specific,” Wu explained. “Moreover, the risks associated with mRNA COVID-19 vaccines have received intense public scrutiny. If someone experiences chest pains after a COVID vaccine, they often rush to the hospital. In contrast, if muscle aches follow a flu vaccine, many simply brush it off.”
Research Support
The study received backing from the National Institutes of Health and the Gootter-Jensen Foundation.
