Myocardial injury after COVID-19 mRNA-1273 booster vaccination

The objective of this prospective study by Swiss researchers was to investigate the incidence and possible mechanisms of oligosymptomatic myocardial injury after COVID-19 mRNA-1273 (Moderna) booster vaccination. The findings showed that myocardial injury after mRNA-1273 booster vaccination occurred in one out of 35 people (2.8%), which was higher than the incidence estimated in meta-analyses of hospitalized cases with myocarditis (incidence of 0.0035%) after the second vaccination. Myocardial injury was mild and transient, and it was more frequent in women than in men.

Myocarditis and/or pericarditis are rare adverse cardiac events observed most frequently in adolescent and young adult males during the first week after the second dose of mRNA vaccine (BNT162b2 or mRNA-1273), although it can also occur in other demographic groups after a single or third (booster) dose of mRNA vaccines. The etiology of vaccine-associated myopericarditis remains unknown. Early hypotheses suggested that the SARS-CoV-2 spike (S) protein, which can be found in the blood, may induce cardiac-targeted autoantibodies through molecular mimicry. Another hypothesis is that hypersensitivity myocarditis may be responsible for the pathology. Another possible mechanism is autoimmune myocarditis, which is driven by T helper type 17 responses, but there is no evidence to support this pathology yet. 

In this study, the authors hypothesized that myocardial injury associated with mRNA-1273 booster vaccination may be more common than currently thought, because the symptoms can be unspecific, mild, or even absent, escaping passive surveillance that detects only hospitalized cases.

About the study

The objectives of this prospective active surveillance study were to investigate the incidence of oligosymptomatic myocardial injury after COVID-19 mRNA-1273 booster vaccination, to make early diagnosis and to avoid the possible aggravation of myocardial injury, and, finally, to explore a possible underlying mechanisms.

The incidence of myocardial injury associated with mRNA-1273 booster vaccination was evaluated in 777 employees of the University Hospital, Basel. The median age was 37 years, and 69.5% of participants were women. The study also included 3716 eligible controls who were matched in age, gender, and history of coronary artery disease/acute myocardial infarction, and had comparable baseline characteristics. Criteria for exclusion were cardiac events or cardiac surgery within 30 days prior to vaccination, or patients missing the high-sensitivity cardiac troponin T (hs-cTnT) measurement on day 3 after vaccination.

On day 3 (48–96 hours) after the vaccination, participants were assessed for possible myocarditis-related symptoms and a venous blood sample was taken for the measurement of hs-cTnT. Myocardial injury associated with the mRNA vaccine was defined as an acute dynamic hs-cTnT elevation above the gender-specific 99th percentile upper-limit (8.9 ng/L in women and 15.5 ng/L in men) without evidence of any alternative cause. Furthermore, major adverse cardiac events (MACE) including acute heart failure, cardiac death, life-threatening arrhythmias and acute myocardial infarction were assessed at a 30-day follow-up.

Researchers also explored the potential mechanisms of myocardial injury after COVID-19 mRNA vaccination. They examined the levels of anti-IL-1RA autoantibodies, the antibodies against nucleoprotein (NP) or spike (S1) protein of SARS-CoV2, and 14 biomarkers of systemic inflammation, including IL-1β, IL-6, IL-8, IL-10, IL-12p70, IFN-α, IFN-β, IFN-λ1(IL-29), IFN-λ2/3(IL-28), IFN-γ, TNF-α, IP-10, and GM-CSF.


On day 4, the concentrations of hs-cTnT were significantly higher in the overall cohort receiving the mRNA-1273 booster (median 5 ng/L) in comparison to the matched controls (median 3 ng/L). Out of 777 participants, 40 (5.1%) had elevated hs-cTnT concentrations above the gender-specific ULN cutoffs for myocardial injury adjudication. There was no history of heart disease among the participants with elevated markers of myocardial injury related to mRNA vaccination. Eleven participants (50%) reported unspecific symptoms including fever and chills, and two had chest pain. Furthermore, the two participants, both female, who had vaccine-associated myocardial injury and chest pain met the criteria of Brighton Collaboration case definition level 2, which indicates probable myocarditis.

In 18 of 40 participants, it was concluded that there is probably an alternative cause for elevated hs-cTnT concentrations after vaccination. 22 participants (2.8%) were found to have myocardial injury associated with mRNA-1273 vaccine. The median age for this group was 46 years, and the median concentration of hs-cTnT was 13.5 ng/l.

Out of 22 people with myocardial injury after vaccination, 20 were women and two were men. This gender difference was statistically significant. However, the incidence of vaccine-associated myocardial injury declined in women (9 cases) and increased in men (5 cases) if a uniform ULN cutoff for adjudication of 14 ng/L was used. The authors have noted that their findings are different from the majority of reported clinical cases of myocarditis associated with vaccination, because this myocarditis mostly affects young men.

All cases were mild, with only a transient and brief period of myocardial injury. No changes in the electrocardiogram (ST-segment depression or T-wave inversion) were found. 775 participants (99.7%) completed thirty-days of MACE follow-up, and no participant developed MACE. According to threshold that imaging experts established (usually a hs-cTnT concentration of 50-100 ng/L), cardiomyocyte injury associated with vaccination was below the limit for cardiac MRI late gadolinium enhancement in myocarditis, so, cardiac MRI was not performed. 

The concentrations of IL-1RA, anti-IL-1RA, anti-S1 and anti-NP (a serological evidence for prior infection with SARS-CoV2), as well as the majority of tested markers of systemic inflammation, were not significantly different between participants with myocardial injury after mRNA-1273 vaccination and those without myocardial injury. The only differences were found in the levels of IFN-λ1 and GM-CSF, which were lower in cases with mRNA-1273 vaccine-associated myocardial injury.

The researchers emphasized that their findings supported the research hypothesis. After mRNA-1273 booster vaccination, markers of myocardial injury were elevated in one of 35 people (2.8%). The elevation of hs-cTnT was independent of previous COVID-19 infections or the interval from the last dose of vaccine. It is important to investigate whether decreased blood levels of IFN-λ1 and GM-CSF may reduce myocardial protection and thereby promote vaccine-associated myocardial injury.

This article was published in European Journal of Heart Failure.

Buergin N, Lopez-Ayala P et al. gender-specific differences in myocardial injury incidence after COVID-19 mRNA-1273 Booster Vaccination. Eur J Heart Failure 10.1002/ejhf.2978 (Open Access)