Males of a certain age
Evidence that such myocarditis predominates in young adult men and adolescent boys, especially following a second vaccine dose, is remarkably consistent.
The risk was elevated only among mRNA-based vaccine recipients who were younger than 40 in the recent Nature Medicine analysis. Among that group, estimates after a second dose numbered fewer than 1 case per 100,000 for Pfizer-BioNTech and 1.5 per 100,000 for Moderna.
In a third analysis from Israel – also in NEJM, from Guy Witberg, MD, Rabin Medical Center, Petah Tikva, and colleagues, based on 2.5 million people aged 16 and older with at least one Pfizer-BioNTech injection – 2.1 cases per 100,000 were estimated overall, but the number rose to 10.7 per 100,000 among those aged 16-29 years.
In Dr. Mevorach’s NEJM report, estimates after a second Pfizer-BioNTech vaccine dose were 1 per 26,000 males versus 1 in 218,000 females, compared with 1 myocarditis case in 10,857 persons among “the general unvaccinated population.”
Most recipients of a first vaccine dose were younger than 50, and 16- to 29-year-olds accounted for most who completed two doses, noted Dr. Mevorach. Younger males bore the brunt of any myocarditis: the estimated prevalence after a second dose among males aged 16-19 was 1 per 6,637, compared with 1 per 99,853 females in the same age range, the group reported.
In the BMJ report, based on about 5 million people 12 years of age or older in Denmark, the estimated rates of myocarditis or pericarditis associated with Moderna immunization were 2 per 100,000 among women but 6.3 per 100,000 for men. The incidence and sex difference was much lower among those getting the Pfizer-BioNTech vaccine: 1.3 per 100,000 and 1.5 per 100,000 in women and men, respectively.
Sex hormones may be key
The predominance of vaccine-associated myocarditis among adolescent and young adult males is probably more about the myocarditis itself than the vaccines, observed Biykem Bozkurt, MD, PhD, who has been studying COVID-related myocarditis at Baylor College of Medicine, Houston.
Male sex historically is associated in both epidemiologic studies and experimental models with a greater propensity for most any form of myocarditis, Dr. Bozkurt said in an interview. Given that males aged 16-19 or so appear to be at highest risk of myocarditis as a complication of SARS-CoV-2 vaccination, the mechanism may well be related to sex hormones.
“Therefore, testosterone is implicated as a player in their higher risk of inflammation and injury and lack of adaptive response in terms of healing, and in terms of prevention of injury,” Dr. Bozkurt said. For its part, estrogen inhibits proinflammatory processes and, in particular, “blunts cell-mediated immune responses.”
“We don’t know the mechanism, but a theory that attributes a protective role to estrogen, or a risk associated with testosterone, is reasonable. It makes sense, at least based on epidemiological data,” Dr. Ammirati agreed. Still, “we do not have any direct evidence in human beings.”
Sex-associated differences in experimental myocarditis have been reported in the journals for at least 70 years, but “the testosterone literature and the estrogen literature have not been evaluated in detail in vaccine-associated myocarditis,” Dr. Cooper said.
Most myocarditis in the laboratory is viral, Dr. Cooper observed, and “the links between testosterone, viruses, and inflammation have been pretty well worked out, I would say, if you’re a mouse. If you’re a human, I think it’s still a bit uncertain.”
Were it to apply in humans, greater testosterone levels might independently promote myocarditis, “and if estrogen is cardioprotective, it would be another mechanism,” Dr. Cooper said. “That would translate to slight male predominance in most kinds of myocarditis.”
In males, compared with females, “the heart can be more vulnerable to events such as arrhythmias or to immune-mediated phenomena. So, probably there is also higher vulnerability to myocarditis in men,” Dr. Ammirati noted.
Male predominance in vaccine-related myocarditis is provocative, so it’s worth considering whether testosterone is part of the mechanism as well as the possibility of estrogen cardioprotection, Dr. Ammirati said. But given limitations of the animal models, “we don’t really have robust data to support any part of that.”
Although myocarditis is in some way immune mediated, “and hormones can modulate the response,” the mechanism has to be more than just sex hormones, he said. “They probably cannot explain the specificity for the heart. It’s not a systemic response, it’s an organ-specific response.”