Congenital heart malformations used to be a death sentence for many newborns. But as medical care and surgeries have improved, most infants born with heart defects — nearly 1 in 100 babies in the United States — live to adulthood. As they do, another matter has come to light: As many as half of people with congenital heart disease (CHD) have neurodevelopmental issues such as autism.
Having CHD may raise the chances of being diagnosed with autism by anywhere from about one-third to sixfold, according to estimates from the past five years; A 2023 meta-analysis of all previous studies pegged the increased likelihood at twofold.
Many children with CHD also have some traits that resemble autism but don’t merit a diagnosis, such as problems with theory of mind and executive function, which includes working memory, cognitive flexibility, planning and self-regulation. “There’s also the question of what do we do with everything that lies in between,” says Johanna Calderon, chair in neurodevelopment at the University of Montpellier in France and lead scientist of the Cardiac Neurodevelopmental Team at the French National Institute of Health and Medical Research.
Scientists used to think that these neurodevelopmental issues stemmed from the life-saving surgeries that infants with CHD typically undergo. Techniques such as deep hypothermia to achieve circulatory arrest and circulating the blood externally were thought to damage the brain by reducing blood flow to it or causing blood clots.
But as it turns out, factors related to heart surgery account for only 5 to 8 percent of differences in neurodevelopmental issues among people with CHD, according to a 2019 review. And milder heart defects are more strongly linked to autism than severe ones, another 2019 study showed. What’s more, many children with CHD show signs of atypical brain development before they even enter the operating room.
“We’ve come a long way in this field of cardiac neurodevelopment,” says Ashok Panigrahy, professor of radiology and radiologist-in-chief at the University of Pittsburgh in Pennsylvania. “I started working in this field when I was a medical student in the ’90s, and at that time we felt that the poor brain outcomes were related to cardiac surgeries themselves, and we don’t feel that way anymore.”
Instead, neurodevelopmental outcomes are more likely determined by genetic mutations that affect both the heart and the brain, and by CHD-related brain changes in utero, recent research suggests, meaning heart defects in children should not be treated in isolation. And differences in the home environment, hospital care and socio-economic factors may contribute to outcomes as well.
“The more we know, it starts to get more complicated,” Panigrahy says.
Certain genetic mutations can raise the chances of both CHD and neurodevelopmental issues, mounting evidence suggests.
Children with CHD plus another congenital defect or a neurodevelopmental condition are three times more likely than would be expected by chance to have a harmful mutation, unlike children with CHD alone, according to a 2015 paper published in Science. “We discovered that if you look at de novo changes that are damaging, they tend to be in genes that are expressed in both heart and brain,” says Bruce Gelb, dean of child health research at the Icahn School of Medicine at Mt. Sinai in New York City, who led the work. “That, I think, is just because Mother Nature reuses genes, and uses the same gene programs to do more than one function.”
This study, along with a follow-up study in 2017 in Nature Genetics, identified 19 genes with harmful de novo mutations among 2,871 people with CHD; de novo mutations in these genes had previously been linked to autism. Many of these genes modify chromatin, which determines how DNA is packaged in cells and expressed into proteins.
A 2021 study found a total of 101 genes that influence a person’s susceptibility to both autism and CHD. Five of these genes — including SCN2A — encode ion channels; none of the five had been previously linked to CHD. Disrupting SCN2A in frogs affected the development of both the heart and the brain.
More clues continue to crop up. Mice with autism-linked mutations in genes involved in the Wnt/beta-catenin pathway, which governs cell growth and cell death, have malformations in their hearts, a 2022 study showed. And according to a study published in February, mutations in the autism-linked MYT1L gene lead to the faulty expression in the brain of SCN5A, a gene that is normally only expressed in the heart and also encodes an ion channel.
In general, for CHD genetics, it is still early days, Gelb says. “If we are at 50 percent, that’s generous, so there’s still a lot of discovery to do on genetics alone,” he says. As for CHD cases that have not yet been linked to genetic mutations, “the predominant thought is that it is genetic; we just don’t understand the genetics yet.”
The Science and Nature Genetics papers used data from the Pediatric Cardiac Genomics Consortium, which has recruited more than 13,600 people with CHD, plus their parents. Now in its third year of investigation, the focus has shifted from the underlying causes of CHD to how genetic variation relates to outcomes, including neurological ones, Gelb says. “The question is, if you look at genetic variation in kids with CHD, does it help differentiate between the kids with CHD who tend to do better versus worse?” he says.
Part of the challenge in moving CHD research forward has been the difficulty of modeling genetic forms of the condition in mice, because mutations that affect the heart tend to be lethal. But one team has managed to develop a mouse model of a rare but severe heart defect called hypoplastic left heart syndrome (HLHS), which requires complex surgery for a baby to survive. Some fetuses with HLHS have microcephaly, and people with the syndrome are at high risk for neurodevelopmental conditions.
Only a few genes have been linked to HLHS thus far, so the team developed their model by creating mutant mice at random until they found a phenotype that matched HLHS. Two genes were at work, the team found when they sequenced the mouse: SAP130, which is a chromatin-modifying gene, and PCDHA9, a gene that in people has been linked to autism and affects the formation of synapses.
“It was really exciting, because it would be the first mouse model of HLHS,” says study investigator George Gabriel, an M.D./Ph.D. student at the University of Pittsburgh, who collaborates with Panigrahy.
Only about 25 percent of mice with mutations in the two genes have HLHS, and some without HLHS develop microcephaly anyway. “That really led us to think it’s the genes that are causing the brain phenotype as well as the heart phenotype,” rather than the heart defect driving the brain changes, Gabriel says.
Mice missing only SAP130 in just the brain develop microcephaly without CHD and show problems with social interactions, Gabriel and his colleagues found. And animals lacking only PCDHA9 develop with either a structurally normal heart or nonlethal CHD; they survive to adulthood and have social difficulties but no microcephaly. So both genes are needed for HLHS and are responsible for different changes in the brain, the researchers concluded.
Gabriel and his colleagues also found changes in DNA methylation in their mouse model. These epigenetic changes “could represent a gene-environment interaction that could help explain some of the brain findings in HLHS,” Gabriel says.
The team now aims to develop a pig model of HLHS, which would give medical students a chance to practice heart surgery and enable scientists to study how HLHS affects brain development after surgery in an animal more similar to humans.
Whether driven by genetics or an abnormally developing heart, brain differences in children with CHD begin in the womb. Some fetuses with CHD have reduced brain volume, reduced cortical folding or white-matter injury, according to a review published in February. At birth, brain development in these children tends to be four to six weeks behind schedule.
The hippocampus may be particularly vulnerable. Babies with CHD have connectivity differences in this area, Panigrahy and his colleagues have found. Other research has revealed reduced hippocampal volume in utero and, in children with CHD, this reduced volume tracks with problems in working memory and long-term memory.
Children and adolescents with CHD also show reduced cerebral blood flow, which relates to poorer performance on a cognitive battery, according to a 2021 study. The blood flow alterations may reflect differences in the function and structure of the executive network and the default network, which is active when a person is at rest and has been implicated in autism. “There’s definitely overlap” between the networks affected in CHD and those linked to autism, says Panigrahy, who led the work, which involved 27 children and adolescents with CHD and 53 controls.
The genetic ties between CHD and autism, though preliminary, already have clinical implications. “It helps us better understand what we’re supposed to be monitoring and looking out for,” says Sonia Monteiro, associate professor of pediatrics at Baylor College of Medicine in Houston, Texas.
Monteiro, who also directs the Cardiac Developmental Outcomes Program at Texas Children’s Hospital, says she has seen seemingly inexplicable differences in neurodevelopmental outcomes among the children with CHD whom she treats in her clinical work: “We see kids with similar hospital courses, who might have had the same heart diagnosis, who don’t have autism.”
Understanding the interplay between the two conditions could also prevent autism traits from getting swept under the rug by both parents and physicians. “I also sometimes run into families where some of the social deficits or language delays they want to just attribute to the child having had surgery and being in the hospital,” she says, “and so that also requires education; although those are risk factors for having delays, this autism diagnosis is something separate.”
Because of her clinic’s awareness of the link between the two conditions, Monteiro says, it diagnoses autism in children with CHD at an average of 34 months of age, according to a July study, lower than the U.S. average of 4 years. That’s no surprise, she says: “With all the things you’re keeping track of [in children with CHD], I think the development can kind of be put on the back burner.”
Overall, cardiac programs throughout the U.S. and Europe have increased their vigilance around neurodevelopmental difficulties. That has been demonstrated by the establishment of the Cardiac Neurodevelopmental Outcome Collaborative in 2016, a network of centers across the U.S. and in Europe whose mission is to “determine and implement best practices of neurodevelopmental services.”
Children with CHD need close observation for neurodevelopmental issues even into adolescence, Calderon says. “It’s not just caring about the heart; I think it’s about really caring about the whole child, I would say even the whole family, to improve outcomes,” she says.
With children who have difficulties that do not add up to a diagnosis of autism, the danger is that they may slip through the cracks. “These are kids who don’t necessarily receive remedial services for social issues; they kind of, like, go a little bit undetected for a while,” Calderon says. “It’s not severe enough to be really taken care of.”
Those early difficulties could snowball later on; one-quarter of children and teenagers with CHD struggle with behavioral problems, and Calderon says that is no coincidence. “I wonder if the accumulation of non-treated social difficulties may play a substantial role in the emergence of mental health challenges,” she says.
Social-demographic factors may have an important impact on neurodevelopment in children with CHD. Panigrahy’s group is analyzing data from an MRI study of newborns to probe this question. He is also exploring how the length of a baby’s hospital stay influences outcomes, because of factors such as isolation from parents. The next frontier is understanding how the home environment affects outcomes, Panigrahy says. Calderon has launched a study that plans to follow a cohort of women from the second trimester of pregnancy until their children are 1 to 2 years old, to determine whether prenatal maternal and paternal stress influences outcomes for children with CHD.
Treatments, however, are still elusive. A training program to improve working memory in children with CHD did not help with social-communication issues, Calderon and her colleagues found.
Interventions could come in unexpected forms. In Australia, a clinical trial is measuring the effects of a four-month exercise program on people who have received a Fontan bypass, a type of open-heart surgery to remedy severe CHD. The primary focus is aerobic capacity, although the study is also looking at psychological and cognitive effects.
Panigrahy has launched a study of how exercise affects brain networks in children with CHD. Calderon has also begun an exercise study of 8- to 25-year-olds with CHD, to see whether the intervention improves neurodevelopmental outcomes.
“We’re at the point where the intervention field in CHD is really expanding, and I think it’s really a great thing,” Calderon says. “It’s time.”
This content was originally published here.