Weekly Journal Scan: Myocarditis related to COVID-19 mRNA vaccination has less severe course than those associated to SARS-Cov-2 infection or conventional aetiology

This comment refers to ‘Long-Term Prognosis of Patients with Myocarditis Attributed to COVID-19 mRNA Vaccination, SARS-CoV-2 Infection, or Conventional Etiologies’ published in JAMA doi: 10.1001/jama.2024.16380 This cohort study1 has been designed to evaluate the long-term prognosis of patients with myocarditis attributed to COVID-19 mRNA vaccination compared to myocarditis due to SARS-CoV-2 infection or conventional aetiologies. For this purpose, the main French National Health Data System (SNDS), which covers the whole population of France, as well as the national hospital discharge database, COVID-19 vaccination, and SARS-COV-2 infection databases, were explored. The analysis was performed on patients aged between 12 and 49 years hospitalized for myocarditis attributed to COVID-19 mRNA vaccination (within 7 days), SARS-CoV-2 infection (within 30 days), or conventional aetiologies between December 2020 and June 2022. The study patients’ 18-month cardiovascular complications and management were assessed using the French SNDS. All the data were pseudonymized. The clinical outcomes were hospital readmission for myopericarditis, all-cause hospitalization, other cardiovascular events, and all-cause death. The study cohort included 4635 individuals diagnosed with myocarditis based on symptoms, electrocardiography, echocardiography, and cardiac magnetic resonance imaging (MRI). Of these, 558 (12%) had post-vaccine (mean [SD] age, 25.9 [8.6] years; 84% men), 298 (6%) had post-COVID-19 (mean [SD] age, 31.0 [10.9] years; 67% men), and 3779 (82%) had conventional myocarditis (mean [SD] age, 28.3 [9.4] years; 79% men). The first composite clinical outcome included the occurrence of rehospitalization for myopericarditis, another cardiovascular event, or death from any cause. In the second outcome, hospitalization for any reason was added to the first. The first and the second composite outcome were lower in the post-vaccine group: weighted hazard ratio (wHR), 0.55; 95% confidence interval (CI), 0.36–0.86; and wHR, 0.64; 95% CI, 0.48–0.85, respectively. Patients with post-COVID-19 myocarditis had similar outcomes to those with conventional myocarditis. Compared to patients with myocarditis of conventional aetiologies, patients with post-vaccine myocarditis had lower hospitalization for any cause (68 [12.2%] vs. 739 [19.6%]; wHR, 0.69; 95% CI, 0.50–0.94); numerically lower incidence of rehospitalization for myopericarditis (18 [3.2%] vs. 220 [5.8%]; wHR, 0.75; 95% CI, 0.40–1.42), numerically lower cardiovascular events (excluding myopericarditis) (15 [2.7%] vs. 277 [7.3%]; wHR, 0.54; 95% CI, 0.27–1.05). Medical management up to 18 months after hospital discharge followed a similar trend across groups. Patients with myocarditis receiving the mRNA-1273 vaccine (n = 149) reported slightly lower clinical outcomes over 18 months of follow-up as compared to those vaccinated with BioNTech 162b2 (n = 409). During the COVID-19 pandemic, disease prevention by vaccination has been demonstrated to be crucial to reducing the risk of severe infection, hospitalizations, clinically relevant events like pneumonia and multiorgan failure, and mortality.2 Vaccines developed to contrast the SARS-COV-2 pandemic, mainly those based on mRNA technology, have been demonstrated to be effective in saving millions of lives and are also remarkably safe.3 In a recently published Swedish cohort study,4 the vaccine significantly reduced cardiovascular complications of COVID-19, such as acute myocardial infarction, heart failure, stroke, atrial fibrillation, and arrhythmias, which are increased by COVID-19 infection5,6 Nevertheless, safety monitoring post-authorization of mRNA vaccines resulted in the prompt identification of relatively uncommon adverse events, including myocarditis and pericarditis. The association of mRNA vaccines and myocarditis and pericarditis is reported in several studies,7–9 with the highest risk in adolescent and young adult males, estimated to occur at a rate of 2–8 per 100 000 vaccinations. On the other hand, estimates of myocarditis and pericarditis following COVID-19 infection are reported in the range of 50–180 cases per 100 000 infections.9 Outcome data on post-vaccine myocarditis are scarce but generally favourable,10 with a reported lower risk of heart failure at 90 days from admission, as compared to conventional non-COVID myocarditis.11 The added value of the study of Semenzato et al.1 mainly resides in the evaluation and reporting of long-term outcomes and management data of patients hospitalized for myocarditis attributed to COVID-19 mRNA vaccination, as compared to those hospitalized for myocarditis due to either SARS-CoV-2 infection or conventional aetiologies. Besides, the study reports a thorough and large nationwide analysis based on the use of multiple, relevant databases in France. In patients with post-vaccine myocarditis, a more favourable clinical course was recorded in comparison to conventional myocarditis, whereas post-COVID-19 infection myocarditis had comparable consequences to myocarditis by different aetiologies. Some limitations of the study need to be considered. First, as also remarked by the authors, the study included only patients who required hospital admission, which implies that only patients with symptomatic and likely more severe forms of myocarditis were included in this cohort, although the causes of the hospitalizations are not known. In the same direction, the lack of information on echocardiographic and MRI diagnostic assessment prevents any evaluation of the extent and quality of myocardial injury in the three groups. Lastly, the study refers only to patients aged between 12 and 49 years, so the results cannot be extended to older patients, in whom immune senescence could have an impact on the effects of vaccination. Several different hypotheses have been raised regarding the aetiology of post-mRNA vaccine myocarditis.12 In particular, myopericardial damage is thought to be related to a pro-inflammatory response triggered by a spike mRNA sequence recognized by the immune system. Autoimmune responses by molecular mimicry and cross-reactivity between spike proteins represent possible alternative mechanisms. Genetic factors, such as specific HLA genes, may contribute to the pathogenesis of post-vaccine myocarditis. Lastly, the pro-inflammatory Th1 responses to testosterone might explain the higher prevalence of post-vaccine myocarditis in men. The results of this study are reassuring in the sense that one of the most dreadful complications of mRNA vaccines, such as myocarditis, appears to have a lower clinical impact in the long-term, as compared to post-SARS-CoV2 infection, thus supporting vaccination to protect from the most serious consequences of the infection. In this view, the somewhat reassuring signal arising from this study may be important in a period that is characterized by a growing scepticism towards COVID-19 vaccination. The identification of subgroups of patients more susceptible to develop myocarditis on the basis of age, gender, ethnicity, or other variables through a deeper analysis of large multinational databases might provide valuable information in planning adequate preventive strategies within future vaccination campaigns. Supplementary data are not available at European Heart Journal online.