Myocardial Injury Related to SARS-CoV-2 mRNA Vaccination: The Plot Thickens

This article refers to ‘Sex-specific differences in myocardial injury incidence after COVID-19 mRNA-1273 booster vaccination’ by N. Buergin et al., published in this issue on pages 1871–1881. On 11 March 2020, the World Health Organization declared COVID-19 a global pandemic. The epidemic's effects were immediate and devastating, resulting in immense worldwide morbidity and mortality as well as extensive social and economic consequences; hence, extensive global efforts were made to develop effective vaccines. These efforts resulted in a record-time development of the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) messenger ribonucleic acid (mRNA) vaccines that soon there-after were proven to be highly effective and safe, and dramatically changed the face of the disease.1-3 Simultaneously with the increased use of mRNA vaccines, emerging reports have raised a possible association between vaccine administration and the occurrence of myocarditis4, 5; these were confirmed in large-scale population studies that estimated the risk for vaccine-associated myocarditis to be 1.4 per 100 000 vaccinated individuals, specifically among young males.6, 7 Although considered benign and self-limited, reports on this rare adverse event raised concerns regarding the cardiac safety of mRNA vaccines. In this issue of the journal, Buergin et al.8 report the incidence of vaccine-associated myocardial injury in hospital employees who received the mRNA-1273 booster and underwent active surveillance using high-sensitivity cardiac troponin T (hs-cTnT) measurements with sex-specific upper limit of normal (ULN) cutoffs. In addition, and in order to investigate a potential mechanism for myocardial injury in vaccine recipients, levels of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and inflammatory mediators were measured. Vaccine-associated myocardial injury was defined as acute dynamic hs-cTnT-elevation over the sex-specific ULN (8.9 ng/L for women and 15.5 ng/L for males) on day 3, without indication of an alternative cause, and regardless of symptoms or abnormalities in the electrocardiogram or cardiac imaging and occurred in 22 out of 777 (2.8%) vaccine recipients; it was mild and asymptomatic in all of the cases, and significantly more prevalent in women than in men, with 20 cases occurring in women and only two in men. No difference was found in serological evidence of prior infection with SARS-CoV-2 between recipients with vaccine-associated myocardial injury and those without. Levels of interferon (IFN)-λ1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) were significantly lower in participants with vaccine-associated myocardial injury. The authors are to be congratulated on performing the largest prospective trial thus far to investigate and scale the important observation on vaccine-associated myocardial injury. Their results are supported by two previous prospective studies in asymptomatic recipients of mRNA vaccines against SARS-CoV-2. Levi et al.9 demonstrated in their study that two (one male and one female) of 324 (0.62%) healthcare workers with normal baseline troponin levels who received the BNT162b2 vaccine had vaccine-associated myocardial injury; in their study, 59.2% of the participants were female. In a different study by Mansanguan et al.10 among 301 adolescents (32.9% of whom were female), five (1.7%) males had vaccine-associated myocardial injury after the administration of the BNT162b vaccine. It is important to highlight that differences between the mRNA-1273 and BNT162b vaccines were demonstrated. While the former was shown to produce better protection against COVID-19, the latter had a lower risk of myocarditis. The higher rate of vaccine-associated myocardial injury in the current study may, in part, be explained by increased immune response provoked by the mRNA-1273 vaccine.11, 12 Cumulatively, these three studies performed on different populations, age groups and vaccines, demonstrate that the overall incidence of vaccine-associated myocardial injury is higher than previously reported in studies using passive surveillance (up to 3%). A novel finding by Buergin et al. compared with the previous passive and active surveillance studies is a higher incidence of myocardial injury among female recipients. This finding contradicts previous observational studies that reported vaccine-associated myocarditis primarily in young males and was not identified in the two smaller prospective trials. The authors were able to identify this novel distinction by the use of the currently accepted sex-specific ULN cutoffs for hs-cTnT.13 Indeed, a sensitivity analysis with sex-equal troponin cutoff identified troponin elevation in 1.8% with no significant difference between males and females. It is possible that similar to the diagnosis of acute coronary disease, clinical myocarditis is underdiagnosed or underreported among females and that by not using sex-specific ULN cutoffs for hs-cTnT previous studies have missed myocardial injury among females. Alltogether, although current information on sex-specific myocardial injury after SARS-CoV-2 mRNA vaccination is conflicting, the findings of the current work should prompt clinicians to increase awareness towards possible myocardial injury among females after vaccination. Vaccines might cause myocardial injury via multiple mechanisms. These include direct cardiomyocyte injury or an immune alteration simulating an autoimmune response. In the study by Buergin et al., recipients with myocardial injury had reduced levels of IFN-λ1 and GM-CSF suggesting the latter condition. The researchers suggest that low concentrations of these mediators could potentially contribute to dysregulated inflammatory response resulting in myocardial injury. However, since biomarkers were measured on day 3 after vaccination and baseline measurements were not reported, one cannot determine with certainty that the observed low levels of IFN-λ1 and GM-CSF contribute to or are a consequence of vaccine-associated myocardial injury. A prior study by Thurner et al.14 evaluated the prevalence of antibodies neutralizing interleukin-1 receptor antagonist (IL-1RA) and progranulin in 69 patients with suspected SARS-CoV-2 mRNA vaccine-associated myocarditis. Increased incidence of anti-IL-1RA antibodies was demonstrated in patients under the age of 21 and histologically confirmed myocarditis. This finding, however, was not seen in older patients with histologically confirmed myocarditis. Due to major disparities in baseline characteristics of study cohorts including age, it is impossible to determine which mechanism prevails but it seems that an immune dysregulation mechanism is common to both studies and additional research is needed. Other crucial questions regarding the pathogenesis of vaccine-associated myocardial injury are yet to be answered as well. Such is the fundamental question of whether myocardial injury is attributable particularly to mRNA vaccines against SARS-CoV-2 or is a more general side effect that pertains to mRNA vaccines in general. In summary, Buergin et al. demonstrate in this study an increased risk of mild vaccine-related myocardial injury. Currently, this potential side effect of mRNA vaccines is not linked with substantial illness. Considering previous studies that showed a higher risk of myocarditis secondary to SARS-CoV-2 infection than after mRNA vaccination against COVID-19,15 one should not defer vaccination against COVID-19 based on these results. Nevertheless, some major gaps in current knowledge should be addressed. These include the mechanism of myocardial injury, the characterization of vaccine recipients in whom myocardial injury may occur, the appropriate post-vaccination follow-up, and the possible long-term consequences of myocardial injury associated with vaccination. Conflict of interest: none declared.