Stanford Medicine investigators have unearthed the biological process by which mRNA-based vaccines for COVID-19 can cause heart damage in some young men and adolescents-and they’ve shown a possible route to reducing its likelihood. Using advanced but now common lab technologies, along with published data from vaccinated individuals, the researchers identified a two-step sequence in which these vaccines activate a certain type of immune cell, in turn riling up another type of immune cell. The resulting inflammatory activity directly injures heart muscle cells, while triggering further inflammatory damage. The mRNA vaccines for COVID-19, which have now been administered several billion times, have been heavily scrutinized for safety and have been shown to be extremely safe, said Joseph Wu, MD, PhD, the 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 viewed as a breakthrough because they can be produced quickly enough to keep up with sudden microbial strain changes and they can be rapidly adapted to fight widely divergent types of pathogens. But, as with all vaccines, not everyone who gets the shot experiences a purely benign reaction. One rare but real risk of the mRNA-based COVID-19 vaccines is myocarditis, or inflammation of heart tissue. Symptoms — chest pain, shortness of breath, fever and palpitations — appear in the absence of any viral infection. And they happen quickly: within one to three days after a shot. Most of those affected have high 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 found circulating in blood, it indicates damage to heart muscle cells.) Vaccine-associated myocarditis occurs in about one in every 140,000 vaccinees after a first dose and rises to one in 32,000 after a second dose. For reasons that aren’t clear, incidence peaks among male vaccinees age 30 or below, at one in 16,750 vaccinees. Fortunately, most of these cases end well, Wu said, with full heart function retained or restored. Recovery is typically swift. “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.” However, Wu noted, if the inflammation is severe the resulting heart injury can be quite debilitating, leading to hospitalizations; ICU admissions for critically ill patients; and deaths, albeit rarely. “But COVID’s worse,” he added. A case of COVID-19 is about 10 times as likely to induce myocarditis as an mRNA-based COVID-19 vaccination, Wu said. That’s in addition to all the other trouble it causes. Wu shares senior authorship of a study describing his team’s findings, to be published Dec. 10 in Science Translational Medicine, with former Stanford Medicine postdoctoral scholar Masataka Nishiga, MD, PhD, now an assistant professor at The Ohio State University. The study’s lead author is current postdoctoral scholar Xu Cao, PhD. “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 find out, he and his colleagues first analyzed data from blood draws of individuals vaccinated for COVID-19, some of whom developed myocarditis. Comparing those who did with those who didn’t, they noticed high levels of a couple of proteins in the blood of vaccinees who wound up with myocarditis. “Two proteins, named CXCL10 and IFN-gamma, popped up. We think these two are the major drivers of myocarditis,” Wu said. They operate like a tag team. CXCL10 and IFN-gamma both belong to a class of proteins called cytokines: signaling substances that immune cells secrete to carry on chemical conversations with one another. Hoping to listen in on these communications, the scientists generated human immune cells called macrophages — fierce first-responder cells of the immune system — in a dish and incubated them with mRNA vaccines. The macrophages responded by pumping out various cytokines but, most notably, pronounced amounts of CXCL10. They also otherwise generally mimicked the vaccine responses of macrophages reported in humans, as shown by comparison with published data from vaccinated individuals. When the scientists further supplied the dish with an additional kind of immune cell — T cells, roving sentinels that can recognize and mount immune attacks on specific pathogens but can also incite general arousal of …

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