The key findings, in this case, are as follows: a) the unusual three previous recurrent episodes of perimyocarditis confirmed by CMR and the progressive decrease in the LVGLS since the last event (Table 1); b) the abnormal LVGLS (-12.61%), abnormal reservoir left atrial strain (-22.25%), and abnormal conduit left atrial strain (-14.0%) (6, 7), suggesting an early left ventricular dysfunction stage; c) the myocardial inflammation after ten days of the first dose of the COVID mRNA vaccine; d) the systemic inflammatory cytokine increased in the acute phase; e) the elevated SARS-CoV-2 viral neutralization titer 50 (VNT50) of 1:273 after the first dose, which is very similar to the reported VNT50 after the second dose of the Pfizer vaccine (1:312 after seven days and 1:169 after 21 days) (8); and f) the viral panel and the clinical data which discard a virus as a causal agent.
Vaccination is a well-established part of preventive and public health medicine, but it is not risk-free (3). For example, historically, rare vaccine-induced myocardial inflammation cases were reported following a live smallpox vaccine (incidence of 2.16–7.8 per 100,000 vaccines), with reports occurring up to 30 days post-vaccination (2). The mRNA vaccine-induced myocardial inflammation is mainly among males aged 12 to 39 years, with about 4.8 cases per one million and ≈ 12.6 cases per million of second doses (4, 9). Although myocarditis and pericarditis after vaccination for COVID-19 are two distinct self-limited syndromes (4), myocarditis develops rapidly in younger patients, mainly after the second dose of vaccination (4) pericarditis, affects older patients later, after the first or second dose (4). Our patient had proximate vaccine dose, onset symptoms period, clinical presentation, recovery, and CMR findings (Fig. 1) consistent with an mRNA vaccine-induced perimyocarditis.
The underlying mechanisms of mRNA COVID-19 vaccine-induced myocarditis are not precise. However, some hypotheses suggest that the lymphocytic infiltration results in an immune-mediated myocardial injury (3); molecular mimicry between the spike protein of SARS-CoV-2 and self-antigens could be possible; mRNA vaccine could enhance preexisting dysregulated immune pathways and activates immunologic pathways or inflammatory cytokine expression (9). Here, we observed a possible inflammatory cytokine-mediated cardiotoxicity in the acute phase with a considerable decrease in the recovery phase, but still higher than the control group (10 pre-pandemic PBMC of healthy subjects). Inflammatory cytokines and chemokines are key soluble factors in cardiac diseases as heart failure and myocarditis. We have demonstrated that inflammatory cytokines as TNF-α, IL-6, and IL-1β are soluble mediators linked with ventricular arrhythmias and contractile dysfunction in a rat model of metabolic syndrome (10). Experimental evidence shows that IL-1β induces cardiac fibrosis and hypertrophy and depresses cardiac function. Here, we found an essential increase of the chemokine MCP-1 in the acute phase of vaccine-induced perimyocarditis, MCP-1 increases migration of monocytes and data from animal models and in vitro experiments suggest that MCP-1 can promote cardiac fibrosis (11, 12). The recombinant expression of MCP-1 in cardiac tissue induces myocarditis, cardiac hypertrophy, and dilation. In addition, there is evidence that MCP-1 is critical in the induction of the experimental autoimmune myocarditis model, and its inhibition significantly reduced disease severity (13). We found the elevation of IL-18, a cytokine, is involved in animal models of myocardial infarction with pressure overload effects. The increased risk of cardiovascular disease correlates with high IL-18 levels (14). We proposed that the cardiac injury triggers the inflammatory cascades by inducing cytokines like IL-18 and chemokines as MCP-1 and IL-8 (a critical regulator of neutrophil influx and activation in inflammatory processes (15).
We also observed abnormal distribution of immune subsets in PBMC; after the FACS analysis. The levels of T CD8 + cells were augmented, and the CD4 + cells were diminished in the patient compared with a control group; the ratio of CD4+/CD8 + T cells was reduced 49.08% compared with the control group, possibly explained by the CD8 + increase. On the other hand, NK cells increased five-fold, and non-classic monocytes increased 1.67-fold compared with control subjects. The abnormal immune cell subsets, the increased inflammatory cytokines, and the augmented CRP levels show the patient's inflammatory state after ten days of getting mRNA COVID-19 vaccination, which may trigger cardiac injury and dysfunction.
COVID-19 vaccination's side effects are usually minor (pain, swelling, redness at the injection site), systemic (fatigue, headache, muscle pain, chills, and fever), transient (16), and more common in younger males. They also occur more often after the second dose (16). Our case's principal findings were the abnormalities in the left atrial reservoir, conduit, and LVGLS as the earliest signs of myocardial dysfunction in the setting of preserved ejection fraction myocarditis (LVEF 57%), making the diagnosis of left ventricular dysfunction unlikely based on basic imaging parameters (6, 7). Further, we opened the possibility of the inflammatory cytokine or serum soluble mediators-mediated toxicity associated effects. In this regard, identifying anti-inflammatory compounds that reduce inflammatory cytokines could be helpful to avoid vaccine-induced myocardial inflammation.