Acute cardiac events after COVID-19 vaccines and during spontaneous SARS-CoV-2 infection

Cardiac adverse events of mRNA coronavirus disease 2019 (COVID-19) vaccines, mainly acute myocarditis, were described shortly after their large-scale implementation.1–4 Since myocarditis is also a known complication of natural infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the balance between the risk of spontaneous and postvaccine disease is essential for estimating the risk/benefit ratio of COVID-19 vaccines.5 Data from Israeli Ministry of Health6 showed an incidence of 4.56 cases of myocarditis for every 100 000 patients aged 16–39 years receiving at least one dose of BNT162b2 vaccine. The incidence raised to 8.33 cases/100 000 in young males. Moreover, in the study of Witberg et al. enrolling 2.5 million vaccinated with at least one dose of BNT162b2 mRNA vaccine (Pfizer-BioNTech), the estimated incidence of myocarditis per 100 000 persons was 2.13 cases, with the higher incidence among males aged between 16 and 29 years. Importantly, the severity of myocarditis was mainly mild or moderate.7 Due to its silent course, these data are likely to underestimate the real burden of postvaccine myocarditis. The prevalence of inflammatory heart disease in the course of COVID-19 disease in young patients can be estimated with a fairly good degree of accuracy thanks to two seminal studies8,9 envisaging a systematic screening for cardiac involvement in two large cohorts of athletes recovering from COVID-19 (789 and 3018 patients, respectively), a large proportion of which was asymptomatic or minimally symptomatic. A first-level return-to-play screening (based on Troponin testing, basal ECG and echocardiography) identified patients with suspected inflammatory heart disease. Cardiac involvement was then confirmed by cardiac magnetic resonance, according to modified Lake Louis Criteria.10–12 The prevalence of cardiac involvement calculated on the basis of this flow-chart ranges between 380 and 500 cases/100 000 (0.38–0.5%) young patients recovering from COVID-19 disease, irrespective of the severity of the acute disease. In one of these articles, a group of athletes was studied by using cardiac magnetic resonance without a previous first-level screening. In this sample, the prevalence of magnetic resonance findings suggesting cardiac involvement was 3%. Authors suggest that this value could represent the upper estimate of cardiac involvement during SARS-CoV2 infection in young patients.9 Albeit with a considerable degree of uncertainty, the data briefly summarized above seem to confirm that inflammatory heart diseases may be both a complication of COVID-19 disease or an adverse event of mRNA COVID-19 vaccines, and suggest that, bearing in mind the limits related to the diagnostic pitfalls of myocarditis, the incidence of cardiac involvement in COVID-19 patients is likely to be much higher than that occurring after vaccination.13 A very recent systematic review and meta-analysis supports this hypothesis, estimating that the risk of myocarditis was more than seven-fold higher in SARS-CoV2 spontaneous infection than after COVID-19 vaccination.14 As a matter of fact, evidence exists that the tendency to develop an acute myocarditis after exposure to an adequate stimulus can be genetically determined.15,16 Preliminary reports suggest that genetic makeup may actually facilitate the onset of post-COVID-19 vaccine myocarditis17 while, on the other hand, it may also trigger an autoinflammatory/autoimmune response to SARS-CoV2 infection,18 potentially able to induce a myocarditis. A massive vaccination campaign like the one organized in many western countries exposes, in a relatively short period, a large part of a population to an immunogenic stimulus potentially able to bring out a predisposition to myocarditis which would have occurred more evasively, over a longer period, during a less intensive vaccination program or during the natural course of epidemics. We should therefore take into account the possibility that some patients with postvaccine myocarditis would have had the same disease triggered by spontaneous infection if not vaccinated. Undoubtedly, we must consider that vaccination exposes people to a guaranteed risk, while spontaneous infection can be avoided. However, one can reasonably assume that, moving towards an endemization scenario, the probability of contracting the infection will gradually approach one. Other pathogenetic pathways could link COVID-19 vaccines and heart diseases. A few cases of fatal acute myocardial infarction after mRNA COVID-19 vaccines (vaccination-to-death interval 8 h–21 days) have been recently reviewed by Baronti et al.19 Postmortem evaluation (macro and microscopic pathology, cardiac magnetic resonance) showed in all cases typical findings of acute myocardial infarction in the presence of a preexisting multivessel atherosclerotic coronary disease. Particularly relevant is the result of genetic testing, showing that all patients of this series were carriers of at least one pro-thrombotic factor. These data seem thus to suggest that vaccines may have a triggering role in patients with genetic predisposition and a preexisting silent coronary obstructive disease. On the other hand, SARS-Cov-2 infection is itself a pro-thrombotic factor, so that COVID-19 turns out to be an independent risk factor for cardiovascular events with a odds ratio of 3.41 for acute myocardial infarction and of 3.63 for ischemic stroke in the 2 weeks following COVID 19 disease.20 In this context, patients with a concomitant preexisting coronary atherosclerotic burden could represent a fragile population prone to thrombotic events during COVID-19.21 An allergic-hyperergic mechanism could also be the basis for an acute myocardial infarction shortly after vaccine administration. Several authors reported on episodes of acute coronary syndrome during acute allergic reactions induced by foods, drugs or exposure to environmental agents: the so-called 'Kounis syndrome'.22 This syndrome was reported in a case report after COVID-19 vaccination. The underlying pathophysiological mechanisms are not strictly related to the COVID-19 vaccination, but to an acute allergic reaction that can occur after any vaccine, drug administration or other acute allergic reaction.23 Histopathology may add a few more interesting data connecting COVID-19 vaccines and acute heart diseases. Both autopsic studies in cases of sudden death and endomyocardial biopsies performed in young patients developing myocarditis early after receiving COVID-19 mRNA vaccine, although yet little more than anecdotal, report heterogeneous findings. In some cases, the typical findings of viral or immune-mediated myocarditis (mononuclear cells infiltrate and necrosis of adjacent cells) were observed.24,25 In other cases, the presence of scattered single-cells necrosis, contraction bands, hypereosinophilic myocites and scanty neutrophilic and hystiocitic infiltrate with no lymphocytic infiltrate were found.26,27 These latter histopathological findings are similar to the myocardial pattern observed in patients deceased from 'stress cardiomyopathy', also known as 'Tako Tsubo cardiomyopathy' or 'broken heart syndrome'. This syndrome is due to a massive catecholamine release, secondary to an intense emotional or physical stress, and its onset is often similar to myocardial infarction, with chest pain, dyspnea and palpitation.28 It may thus be hypothesized that vaccination could prime (most likely in predisposed patients) an intense stress reaction triggering an acute stress cardiomyopathy. Both an acute hyperergic response (Kounis syndrome) and a sympathetic paroxysmal hyperactivity (stress cardiomyopathy) may therefore represent further mechanisms able to induce a vaccine-related cardiac syndrome. Again, the concentration of a large number of vaccinations in a very short interval of time may have highlighted a possible adverse effect that would have been possibly lost during a usual vaccination campaign. In conclusion, COVID-19 mRNA vaccines are associated with a very low incidence of cardiac side effects, mainly in young males, that may rarely be severe. The extent of such cardiac adverse events likely does not significantly affect the risk/benefit ratio of vaccines. Furthermore, the balance between cardiovascular risk and benefit of COVID-19 vaccines should also take into account some indirect effects of pandemics on cardiovascular outcomes, such as the delayed medical treatment in the case of acute heart disease. Actually, a significant reduction in hospitalization for both heart failure (−30% to −66%)29 and acute myocardial infarction (−50%)30 was observed during the first pandemic waves, inducing a significant increase in cardiovascular mortality.29,30 COVID-19 vaccination should therefore be considered the better strategy to reduce the incidence and the severity of the disease, also in patients with cardiac disease, such as those with heart failure, who represent a fragile population in the case of SARS-CoV-2 infection.31 Conflict of interest There are no conflicts of interest.