An FDA-funded study in eClinical Medicine explores the clinical characteristics, myocardial injury, and longitudinal outcomes of COVID-19 vaccine-associated myocarditis (C-VAM). The authors provide a “detailed phenotypic clinical characterisation” of C-VAM in 33 children, adolescents, and young adults. They also present longitudinal myocardial tissue information in vaccine-associated myocarditis and data on the cardiovascular outcomes of the complication. The results point to a need for “continued clinical surveillance and long-term studies in affected patients”.
Myocarditis and mRNA
Although vaccination is a “public health cornerstone” in managing the SARS-CoV-2 pandemic, mRNA vaccines have been associated with a “rare complication”: myocarditis. Acute myocardial injury and chronic scarring in childhood myocarditis can be characterised by late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) imaging. Despite recent research into the rate of myocardial injury with COVID-19 vaccine-associated myocarditis (C-VAM), the natural history, implications, and overall prognosis for young patients with C-VAM are “insufficiently studied”.
The study
The authors hoped to describe the initial clinical and cardiac imaging characteristics of C-VAM, explore possible risk factors for myocardial injury, and evaluate cardiovascular outcomes in a large cohort of young people diagnosed with C-VAM. They conducted a longitudinal multicentre retrospective observational study across 38 United States member institutions of the Myocarditis After COVID Vaccination (MACiV) study network, comprising paediatric cardiologists and CMR experts.
Participants were up to or 30 years old, with a clinical diagnosis of acute myocarditis after COVID-19 vaccination based on clinical presentation, abnormal biomarkers, and/or cardiovascular imaging findings. The researchers collected biomarkers of myocardial injury (troponin), heart failure (brain-natriuretic peptide BNP or NT-pro-BNP), and systemic inflammation (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]). They also collected results from electrocardiograms (ECGs), telemetry, Holter monitoring, echocardiography, and CMR.
433 patients were enrolled, including 333 with C-VAM and 100 with multisystem inflammatory syndrome in children (MIS-C). 95% of patients had been vaccinated with the monovalent Pfizer-BioNTech COVID-19 mRNA vaccine. 5% had received the monovalent Moderna COVID-19 mRNA vaccine. One patient was also reported to have received the Johnson & Johnson vaccine.
Findings
When they investigated possible risk factors for LGE in C-VAM, the authors found that the odds of having LGE in C-VAM were 2.74 times higher for older adolescents (>15 years) than younger patients, 3.28 times higher for males than females, 7.18 times higher after the first dose, and 4.5 times higher after the second dose than the third dose. The authors note that C-VAM patients in the studied cohort were “predominantly males who presented with chest pain and elevated troponin”. Although clinical course was “nearly always mild” with low prevalence and extent of cardiac dysfunction, myocardial injury was “common”, as demonstrated by higher troponin levels and LGE in 82%.
As LGE is “common” in C-VAM, the authors suggest that the myocardial damage in C-VAM could be attributable to a process that targets cardiomyocytes, leading to injury. Myocardial injury was indicated by imaging markers of cardiomyocyte necrosis and oedema. C-reactive protein was more likely to be elevated than ESR and correlated with LGE severity and lower left ventricular ejection fraction (LVEF) during initial presentation. Thus, CRP “may be of greater diagnostic yield” as an inflammatory marker than ESR.
The finding that younger children were “somewhat less likely” to develop LGE and/or cardiac dysfunction and the observation that older adolescents and young adult males are at “greatest risk” for C-VAM supports the hypothesis of the “influence of sex hormones in the pathogenesis”. Oestrogen appears to have a “protective effect” in myocarditis; testosterone increases the risk of myocardial inflammation. However, it remains unknown whether oestrogen and testosterone are associated with a better or worse prognosis once C-VAM has occurred.
The comparison with MIS-C offered a “better perspective” on the severity of cardiac involvement and myocardial injury in myocarditis associated with COVID-19 vaccination in the paediatric population. MIS-C occurs through a “delayed hyperimmune response” several weeks after exposure to SARS-CoV-2. It is mediated by a non-targeted pro-inflammatory cascade that causes the dysfunction of several systems, including the heart.
The study found a “greater proportion” of white patients in the C-VAM group and black patients in the MIS-C group, which implies “differences in immunisation rates and/or an increased susceptibility to developing these complications”. MIS-C patients were “younger and sicker”; they were more likely to require intensive care management and had a higher prevalence and degree of systemic inflammatory markers and cardiac dysfunction. However, lower troponin levels, “rapid resolution” of cardiac dysfunction after immunomodulatory therapies, and a lower prevalence of LGE in MIS-C than C-VAM suggest that cardiac function was “non-specifically” affected due to the “severe systemic immune response” in MIS-C, rather than “focused injury to the heart” in C-VAM.
There is an emphasis on the need for more information on longer-term outcomes:
“Longer-term monitoring with clinical visits, serial echocardiograms, and heart rate monitoring, to assess for signs of ventricular dysfunction, the development of heart failure, and/or arrhythmias, at least in LGE positive patients, seems warranted.”
Despite C-VAM’s “mild initial course”, myocardial injury is “common”, particularly in older adolescent males who present after a first or second dose of mRNA vaccines.
“While mid-term clinical sequelae are rare and LGE severity decreases over time, the persistence of LGE at follow-up in most patients warrants continued clinical surveillance, additional research, and longer-term studies in this subset of patients.”
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