HMN 2025: How Genetic variant may explain why some children with myocarditis develop heart failure

A genetic variant is likely putting some children suffering with myocarditis—inflammation of the heart muscle—at higher risk of developing heart failure, which can be fatal, according to a study published in Circulation Heart Failure.

According to the study, 34.4% of the children who developed dilated cardiomyopathy after developing myocarditis had a genetic variant that made them more susceptible to this condition. In comparison, only 6.3% of control children had these cardiomyopathy gene variants and this difference was highly significant.

Dilated cardiomyopathy is where the heart’s main pumping chamber stretches and becomes thin; it can lead to heart failure, when the heart is unable to adequately perfuse the body with oxygen. Myocarditis is inflammation of the heart and, while rare, it has been identified in a federal database as the leading cause of sudden death among people under the age of 20.

Genetic testing would be beneficial

The findings strongly suggest that genetic testing would be beneficial for all children who present with myocarditis and cardiomyopathy, says Steven E. Lipshultz, MD, corresponding author of the paper and professor of pediatrics at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo.

“Very few doctors do genetic testing for cardiomyopathy-causing pathologic gene variants when a child comes in with new onset heart failure,” Lipshultz says. “That makes this study a game changer.”

The study compared 32 children with dilated cardiomyopathy and myocarditis to those with myocarditis who didn’t have dilated cardiomyopathy, and to heart-healthy controls. Children with cardiomyopathy were part of the Pediatric Cardiomyopathy Registry (PCMR), a network of U.S. and Canadian centers that Lipshultz founded and leads.

“Historically and currently, we have always thought that particular infections lead to myocarditis with heart failure,” says Lipshultz. “But many kids get infections and, in fact, during the first year of life, infants get about seven infections on average. Yet very few infants and children with infections are diagnosed with myocarditis and heart failure or sudden death.”

An additional factor

For that reason, Lipshultz has long suspected there must be an additional factor putting these children at risk, especially when children with common viruses and upper respiratory symptoms develop sudden and severe onset of myocarditis, sometimes tragically resulting in sudden death.

“We previously found, with the help of data from the Centers for Disease Control, that some of these families had genetic mutations that made the immune systems of these children unable to protect them against common viruses,” he explains.

Lipshultz was thinking that if a child had gene mutations for cardiomyopathy, it would reduce their cardiac reserve, the ability of the heart to handle increased physical demand.

A ‘double hit’

He and his colleagues call this the “double hit.” The first “hit” is that the child is born with a pathological cardiomyopathy mutation that places them at higher risk for cardiomyopathy and heart failure, he explains. The second “hit” is when the child gets an infection that ends up infecting the heart muscle cells and leading to myocarditis, inflammation in the heart.

“In the new study, we found that a statistically significantly greater proportion of children coming into children’s hospitals and intensive care units for heart failure and new onset myocarditis had pathological cardiomyopathy gene mutations,” says Lipshultz.

“These mutations result in less cardiac reserve and a higher likelihood of heart failure than those with myocarditis without heart failure. So, it’s very important to identify gene mutations in these patients when they are diagnosed.”

Those mutations, he says, also put these children at much higher risk of getting sick with heart failure with subsequent recurrent myocarditis episodes, which would also put them at increased risk for sudden cardiac death. For that reason, Lipshultz says, they are candidates for implantable cardiac defibrillators.

The bottom line for clinicians, says Lipshultz, is that if you don’t look for pathologic genetic mutations, then you won’t know if the patient is at higher risk for sudden death. “But if you do look and you find concerning risk factors, you should act,” he says.

This work was recognized with a “Top Pediatric Cardiology Research” award when it was presented at the American Heart Association Scientific Sessions by first author Alicia Kamsheh, MD, a pediatric cardiologist at Washington University School of Medicine.

All genetics studies related to this research were led by Stephanie Ware, MD, Ph.D., chair of medical and molecular genetics at Indiana University School of Medicine.

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