Science sub-journal: The reasons behind the sex differences in myocarditis

Myocarditis has been in the public spotlight over the past few years because of cases
associated with the SARS-CoV2 vaccine or related situations.
Another form of myocarditis is associated
with immune checkpoint inhibitors (ICIs) used in cancer treatment.
ICI-induced myocarditis is a potentially fatal side effect of ICI use, and adverse effects on the heart appear to affect women
disproportionately.
This finding contrasts with other forms of myocarditis, with more cases reported in male patients
.

A study co-led by researchers at the University of California, San Francisco and the University of Texas Anderson Cancer Center, published Nov.
2 in Science Translational Medicine, sheds new light on
the underlying biology behind these sex differences.

The UCSF Cardiac Oncology Research Group has been studying myocarditis caused by myocardial infarction and has built several mouse models of the new syndrome that it hopes will use to develop better strategies to help patients
.
One such model is the genetic mouse model
.

"This model replicates many of the characteristics of the syndrome in humans and leads to sudden death," said Javid Moserich, MD, the William Grussmann Contributing Professor and chair
of the Department of Cardiac Oncology and Immunology at the UCSF Heart and Vascular Center.
"Strangely, however, in this model, the female mice were affected
.
"

Meanwhile, MD Anderson's team, led by Associate Professors of Molecular and Cellular Oncology, Dr.
Liuqing Yang and Dr.
Chunru Lin, generated other models
of myocardial infarction-myocarditis.
The researchers bred tumor-bearing mice treated with ICI (combination therapy with anti-PD-1 and anti-ctla-4 antibodies) that exhibited several cardiovascular toxicities, including myocarditis and
arrhythmias.
In this model, female mice were also more
affected than male mice.

"The sex differences observed in two mouse models of myocardial infarction-myocarditis are particularly interesting because male sex is considered a risk factor in non-myocardial infarction myocarditis (viral or autoimmune) in the general population and defines a more severe process
," Moslehi said.
If this opposite sex difference in myocardial infarction-myocarditis is correct, this suggests that immune checkpoints and sex hormones may interact
.
”

As it turned out, Moslich was right
.
Preliminary research by MD Anderson's team identified two heart factors, called MANF and HSPA5, that normally help protect the heart from immune invasion
.
These factors are weakened
in myocarditis models and in the tissues of the human heart of infected patients with myocarditis.
These factors are further reduced in female mice and are regulated
by estrogen.
Adding these factors back to the disease-mitigating mice suggests a causal relationship
.

"These models and our data suggest that the role of the endocrine-cardiac-immune pathway, which has not been previously valued, may provide a way to
reduce inflammation in the heart," Yang and Lin said.

While the sex differences in mouse models are compelling, Moslehi stressed that more research is needed to extend this work to humans
.
"We need more human studies to convincingly demonstrate that myocardial infarction myocarditis preferentially affects women
," Moslehi said.
"It's especially difficult to figure this out in humans because many of the patients traditionally treated are men, both because more men typically participate in clinical trials and because the type of cancer initially treated with ICI occurs more often in
men.
"