A rare risk of mRNA-based COVID-19 vaccines is myocarditis, or inflammation of the heart tissue. The symptoms (chest pain, difficulty breathing, fever and palpitations) appear in the absence of viral infection, revealed a new study by researchers in the United States.

MADRID, December 11 (EUROPA PRESS).- Researchers of Stanford Medicine (United States) have discovered the biological process by which vaccines based on mRNA against the COVID-19 can cause heart damage in some young men and adolescents, and have shown a possible route to reduce its likelihood. The work is collected in Science Translational Medicine.

Using advanced but already common laboratory technologies, along with published data from vaccinated people, the researchers identified a two-step sequence in which these vaccines They activate a specific type of immune cell, which in turn stimulates another type of immune cell. The resulting inflammatory activity directly damages heart muscle cells, while triggering further inflammatory damage.

The mRNA COVID-19 vaccines, which have already been administered billions of times, have been thoroughly vetted for safety and have been shown to be extremely safe, said Joseph Wu, director of the Stanford Cardiovascular Institute.

“mRNA vaccines have been instrumental in mitigating the COVID pandemic,” Wu noted. “Without these vaccines, more people would have gotten sick, more people would have suffered serious effects, and more people would have died.” mRNA vaccines are considered a breakthrough because they can be produced quickly enough to adapt to sudden changes in microbial strains and can be quickly adapted to combat very diverse types of pathogens. However, as with all vaccines, not everyone who receives the injection experiences a completely benign reaction.

A rare but real risk of mRNA-based COVID-19 vaccines is myocarditis, or inflammation of the heart tissue. Symptoms (chest pain, difficulty breathing, fever and palpitations) appear in the absence of viral infection. And they happen quickly: one to three days after the injection. Most sufferers have elevated blood levels of a substance called cardiac troponin, a well-established clinical indicator of heart muscle injury. (Cardiac troponin is normally found exclusively in the heart muscle. When it circulates in the blood, it indicates damage to heart muscle cells.)

Vaccine-associated myocarditis occurs in approximately one in every 140,000 vaccinated after the first dose and increases to one in every 32,000 after the second. For unknown reasons, incidence peaks among vaccinated males age 30 or younger, with one in every 16,750 vaccinated. Fortunately, most of these cases have a good outcome, Wu recalled, with cardiac function completely preserved or restored. Recovery is usually quick.

“It is not a heart attack in the traditional sense,” he stressed. “There is no blockage of the blood vessels as there is in most common heart attacks. When the symptoms are mild and the inflammation has not caused structural damage to the heart, we simply observe these patients to make sure they recover.”

However, Wu noted, if the inflammation is severe, the resulting heart injury can be quite debilitating, leading to hospitalizations, ICU admissions for seriously ill patients, and deaths, although in rare cases. “But COVID is worse,” he warned. A case of COVID-19 is approximately 10 times more likely to induce myocarditis than an mRNA-based COVID-19 vaccine. This adds to all the other problems it causes.

In this work, the researchers first analyzed data from blood draws from people vaccinated against COVID-19, some of whom developed myocarditis. When comparing those who developed it with those who did not, they observed elevated levels of a couple of proteins in the blood of vaccinated people who developed myocarditis.

“Two proteins appeared, called CXCL10 and IFN-gamma. We believe that these two are the main drivers of myocarditis,” Wu said.

Both CXCL10 and IFN-gamma belong to a class of proteins called cytokines: signaling substances that immune cells secrete to carry out chemical conversations with each other. Hoping to listen to these communications, the scientists generated human immune cells called macrophages (first responder cells of the immune system) in a dish and incubated them with mRNA vaccines.

Macrophages responded by releasing various cytokines, but especially pronounced amounts of CXCL10. Furthermore, they generally mimicked macrophage responses to the vaccine seen in humans, as demonstrated by comparison with published data from vaccinated individuals.

When the scientists added an additional type of immune cell to the plate (T cells, mobile sentinels capable of recognizing and mounting immune attacks against specific pathogens, but which can also incite general activation of the immune system), or even when they simply immersed the T cells in the solution in which the vaccinated macrophages had been bathed, they observed a marked increase in the production of IFN-gamma by the T cells. However, T cells incubated with the mRNA vaccine in the absence of macrophages or incubation water only produced standard amounts of IFN-gamma. These results demonstrated that macrophages are the main source of CXCL10 and that T cells are the main source of IFN-gamma in response to mRNA vaccination.

The question is whether the two cytokines, together, contributed directly to the cardiac injury. To answer this question, the researchers vaccinated young male mice and detected elevated levels of cardiac troponin, the widely used clinical marker for heart muscle damage.

The researchers also observed infiltration of macrophages and another type of front-line immune cell, neutrophils (short-lived first responder cells that survive to die in a glorious battle, usually against bacterial or fungal pathogens, and which are the main component of pus) into the heart tissue of the mice. This also occurs in patients with post-vaccine myocarditis.

This infiltration of macrophages and neutrophils into the heart—which comes at a cost, as these fire-first-question-later warrior immune cells often unleash friendly fire, causing collateral damage to healthy tissue, including heart muscle—could be minimized by blocking the activity of CXCL10 and IFN-gamma.

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

So, yes, CXCL10 and IFN-gamma directly contributed to cardiac injury in these mice. And its blockade largely preserved the immune response to vaccination, while reducing cardiac troponin levels induced by it.

Wu’s lab excels in a technology that involves transforming human skin cells or blood cells into white blood cells that can then be guided to differentiate into cardiomyocytes, macrophages and endothelial cells, and fuse into spherical structures that mimic the rhythmic contractions of the heart.

The researchers treated these “cardiac spheroids” with bath water enriched with CXCL10 and IFN-gamma, derived from vaccine-stimulated macrophages and T cells, respectively. They observed a significant increase in cardiac stress markers, recovered by inhibitors of both cytokines.

The compressibility of cardiac spheroids, heartbeat rate, and other measures of healthy cardiac function were impaired, but were again partially restored by cytokine inhibitors.

On the other hand, the work showed that elevated inflammatory cytokine signaling could be a class effect of mRNA vaccines. Importantly, IFN-gamma signaling is a critical defense mechanism against foreign DNA and RNA molecules, including viral nucleic acids, Wu said.

The body needs these cytokines to protect itself from viruses. They are essential for the immune response, but can be toxic in large quantities, he explained. IFN-gamma secreted in large quantities, no matter how noble its purpose, can trigger myocarditis-like symptoms and degradation of structural proteins of the heart muscle.

That risk likely extends beyond mRNA-based COVID-19 vaccines. “Other vaccines can cause myocarditis and inflammatory problems, but the symptoms tend to be more diffuse,” Wu said. “Furthermore, the risks of mRNA-based COVID-9 vaccines have received intense public scrutiny and media coverage. If you get chest pain from a COVID-19 vaccine, you go to the hospital to get checked, and if your serum troponin is positive, you’re diagnosed with myocarditis. If you get muscle or joint pain from a flu shot, you just ignore it.”