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  • Researchers have investigated the incidence of heart inflammation after Pfizer and Moderna vaccination in Denmark.
  • They found that both vaccines, and especially Moderna, are linked to an increased rate of inflammation in two areas of the heart.
  • The scientists stress that — as the absolute numbers were small — the vaccines are still beneficial for personal and societal health.

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Previous research has suggested a link between SARS-CoV-2 vaccination and myocarditis and myopericarditis. Myocarditis is inflammation of the heart muscle, while myopericarditis is inflammation of the membrane around the heart. In the most severe cases, both conditions can lead to heart failure and death.

The inflammation is usually triggered by viral, bacterial, or fungal infection. Evidence suggests that it occurs especially after the second booster dose of the Pfizer and Moderna mRNA vaccines.

The underlying cause of the link between COVID-19 vaccines and myocarditis is unclear. However, scientists have observed a similar link with the smallpox vaccine in adults.

The Centers for Disease Control and Prevention (CDC) and the European Medicines Agency are engaged in ongoing investigations to confirm and clarify any link. Currently, little publicly available research has assessed the incidence of the conditions in a complete population.

In a recent study, researchers from Denmark analyzed national healthcare data to identify links between mRNA vaccination and a diagnosis of myocarditis or myopericarditis.

They found that mRNA vaccination against COVID-19 was linked to a significantly increased risk of both heart conditions. However, the absolute rates of these conditions after the vaccinations were low.

The study was published in BMJ.

“The percentage of myocarditis cases associated with vaccination is not surprising, as it is very similar to studies in the United States and Israel,“ Dr. April Stempien-Otero, a cardiologist at the University of Washington Medical Center’s Heart Institute, in Seattle, told Medical News Today. Dr. Stempien-Otero was not involved in the recent research.

“This study also confirms that these cases are mild, similar to data from the U.S. Myocarditis has been reported with other vaccines in the past, so it is also not surprising to find [the same thing] with this vaccine. However, why this vaccine causes myocarditis is still unknown,” she confirmed.

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The researchers combined data about vaccinations from the Danish Vaccination Register with data about hospital-based diagnoses from the country’s National Patient Register to visualize post-vaccine health outcomes for Denmark’s entire population over 12 years old.

The team incorporated data from blood samples kept by the Register of Laboratory Results for Research to characterize cases of myocarditis or myopericarditis via measurement of troponin levels. These are a marker for myocarditis, and doctors detect this marker in over a third of people with the condition.

In addition, the researchers included data about SARS-CoV-2 polymerase chain reaction (PCR) tests from the Danish Microbiology Database.

Altogether, the researchers included 4,931,775 individuals in their study. They followed the participants for 28 days after both their first and second vaccine doses, between October 1, 2020, and October 5, 2021.

When analyzing the data, the researchers excluded people who had received different kinds of vaccines and people with positive SARS-CoV-2 test results to avoid confounding outcomes of contracting the infection.

By the end of the period, 83.8% of individuals had received Pfizer vaccines and 12% had received Moderna vaccines. The remaining 4.2% had received Johnson & Johnson vaccines.

At follow-up, 269 people had myocarditis or myopericarditis. Of these, 40% were 12–39 years old, and 73% were male.

Altogether, the rate of developing myocarditis or myopericarditis within 28 days of any SARS-CoV-2 mRNA vaccine was 1.7 per 100,000 vaccinated individuals.

Among those who had received the Pfizer vaccine, the researchers noted, the rate of myocarditis or myopericarditis was 1.4 cases per 100,000 individuals — with 1.5 cases per 100,000 males, which was not significant, and 1.3 per 100,000 females, which was significant.

Meanwhile, those who had received Moderna vaccines were significantly more likely to develop myocarditis or myopericarditis in the 28 days after vaccination, compared with unvaccinated individuals. Altogether, there was an average of 4.2 cases per 100,000 people.

When looking at incidence rates for men and women, the researchers found that Pfizer and Moderna vaccines were linked to 1.3 and 2 cases per 100,000 among women, and 1.5 and 6.3 cases per 100,000 among men, respectively.

The team noted, however, that people who had received either mRNA vaccine had around half the risk of cardiac arrest or death, compared with unvaccinated individuals at follow-up.

To explain the results, the study authors say that Moderna may elicit a stronger immune response than the Pfizer vaccine, due to its inclusion of more mRNA.

“The most obvious explanation would be that the Moderna vaccine contains more mRNA than the Pfizer vaccine, and as a result, elicits a stronger immune response, and […] this might be what causes inflammation in the heart muscle in rare cases,” senior study author Anders Hviid, a professor of pharmacoepidemiology at the University of Copenhagen, told MNT.

Dr. Amanda Verma, an assistant professor of medicine at the Washington University COVID Cardiology Clinics, who was not involved in the study, concurred: “A possible explanation may be related to the dose: Moderna vaccination is a much higher dose, compared to Pfizer, perhaps triggering a more robust immune response, leading to myopericarditis. Future studies looking at the relationship of dose and rates of myocarditis would be interesting.”

Dr. Anuradha Lala-Trindade, an associate professor of medicine and cardiology at Mount Sinai Hospital, who was also not involved in the research, expanded on this point: “Though the vaccines are similar and confer high rates of immunity, there are differences that are still being explored. Patients who received Moderna’s vaccine had significantly higher concentrations of anti-spike antibodies in some studies.”

“Other studies have suggested a higher immune response as a result of Moderna, which may potentially explain the authors’ observed findings of higher rates, although [these were] still very low overall, of ‘myocarditis’ among those who received the Moderna vaccine.”

Dr. Stempien-Otero, however, pointed out that the discrepancy likely stems from differences in sample sizes. “The numbers of patients studied who received the Moderna vaccine was quite a bit lower, [so] with more patients studied, it is likely that the incidence would have been similar to [that of] Pfizer.”

The researchers stress that although mRNA vaccines are linked to an increased risk of myocarditis and myopericarditis, vaccines against COVID-19 are still extremely beneficial when COVID-19 case rates are still high. This is because the absolute rate of these side effects is still very low.

The study authors highlight some limitations of their analysis. They note, for example, that because vaccination was optional, their results may reflect “health consciousness” rather than the effects of the vaccine and so may not translate to the whole population.

They also say that increased public awareness of vaccine side effects such as myocarditis may have introduced a detection bias, meaning that more cases of the condition were diagnosed than would have been otherwise.

“A possible link between the mRNA vaccines and myocarditis [has] been publicized widely,“ said Prof Hviid. “Thus, we cannot discount that some of the association that we observe could be due to earlier detection or detection of very mild cases that would otherwise have gone unnoticed. However, this does not explain the difference between the two vaccines.”

“The weaknesses, aside from what is already outlined by the authors, including surveillance bias, however, revolve around the definition of myocarditis,“ Dr. Lala-Trindade said.

“The authors define myocarditis as an elevated troponin level (one above [the] upper limit of normal), [at least a] 24-hour stay in hospital, and [a diagnosis based on the International Classification of Diseases] of myocarditis or myopericarditis. Herein lies the challenge.”

“The diagnosis of myocarditis can be elusive and almost always involves [electrocardiography], echocardiographic, and often cardiac MRI corroboration of clinical findings. In many circumstances, endomyocardial biopsy is performed for what is often considered the ‘gold standard’ for diagnosing myocarditis,“ she added.

“Further, not all cases of myocarditis are the same, and they range in severity of illness [and] presentation — from mild asymptomatic troponin elevation signifying myocardial injury to cardiogenic shock. Thus, classifying these 269 individuals with myocarditis may not indeed represent a cohort who truly had clinically meaningful myocarditis,” she concluded.

“The authors note a 14-fold increased risk of cardiac arrest or death within 28 days after SARS-CoV-2 testing, compared to uninfected individuals, while vaccinated individuals actually had a reduced risk of cardiac arrest or death,” Dr. Verma pointed out.

And, she added, “None of the patients with myocarditis in the study suffered death or heart failure within 28 days.“

“The overall rate of myocarditis is extremely low. The rate of myocarditis with COVID-19 infection is much higher, as is morbidity [and] mortality.”

– Dr. Amanda Verma

“The vaccinations are not perfect, but they are working to save lives, a stark contrast to the risks of infection,“ she noted.

Dr. Stempien-Otero said, “To me, the most critical part of the study is in the raw data. Although vaccination increased the risk of mild myocarditis twofold, the absolute number of cases was quite small — 69.”

“If the statistics stay true for the whole country, that would equal [about] 385 cases. On the other hand, [about] 26,000 people died of COVID-19 who were unvaccinated.”

“Those numbers show that the risk of dying from COVID-19 if unvaccinated is [about] 1,000 times the risk of getting mild myocarditis from the vaccine.”

– Dr. April Stempien-Otero

“People should not be too concerned about this adverse event. It is rare, and it is most likely mild. The individual and societal benefits of vaccination still clearly outweigh the risks. Especially when the alternative is infection, which in itself may cause myocarditis, severe COVID-19 disease, and long COVID,” Prof. Hviid explained.

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