Getting to the heart of HCM

Stem-cell model of heart condition reveals how the fibrosis is perpetuated

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NEW YORK—Hypertrophic cardiomyopathy (HCM) is an excessive thickening of the heart linked to several rare and common conditions. Some theories as to the nature and mechanisms of HCM exist, but new answers are now available thanks to work out of the Icahn School of Medicine at Mount Sinai.
The disorder the team focused on in their work, cardiofaciocutaneous syndrome (CFC), is caused by a mutation in the BRAF gene. Fewer than 300 people worldwide have this condition, according to the National Institutes of Health, but HCM features in a number of other illnesses as well. There are multiple kinds of HCM, says Dr. Bruce D. Gelb, director of The Mindich Child Health and Development Institute and Professor in the Departments of Pediatrics, Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. He notes that the most common forms present in adolescence or early adulthood and occur in one in 500 people. The type focused on in this work presents much earlier, in infancy or early childhood, and can even present in utero.
“At present, there is no curative option for HCM in patients with these related genetic conditions,” Gelb commented. “If our findings are correct, they suggest we might be able to treat HCM by blocking specific cell signals—which is something we know how to do.”
According to Gelb, roughly 40 percent of CFC patients have HCM, and while this implies a pathogenic link, it’s never been fully explained. One of the main goals with this study was to determine the role that the RAS/MAP kinase (RAS/MAPK) pathway plays in causing HCM in patients with CFC and other conditions such as Noonan syndrome and Costello syndrome.
Gelb and his team used skin cells from CFC patients and rendered them into iPS cells, which were then turned into cardiomyocytes. Some of the changes in the cardiomyocytes were caused by interactions with fibroblast-like cells; fibroblasts produce collagen as well as other proteins, and make up a large portion of total heart tissue. They found that the fibroblast-like cells produced an excess of transforming growth factor beta (TGF-beta), which triggered hypertrophy in the cardiomyocytes.
This ran counter to the team’s expectations going in, which were that the hypertrophy was cell-autonomous, or a characteristic of the cardiomyocytes themselves.
TGF-beta is also of interest in other conditions, says Gelb, including potentially Marfan syndrome, which is characterized by heart issues, among other symptoms. “During heart development, TGF-beta—or TGF-beta like substances—play some role in some of the normal cardiac development processes,” he adds.
This work also dispelled some theories about the RAS pathway and its role in these conditions.
“Our working assumption was that the RAS pathway would be excessively turned on in the heart cells, but that’s not what we found; that was one of the surprises,” Gelb tells DDNews. “We assumed that the reason you were getting HCM in this disorder was because the heart cells themselves were turned on with excess activated MAP kinase leading to hypertrophy. But that’s not what we found; we found this cycle whereby the other cells, the fibroblast-like cells, do have activated MAP kinase and moreover, they’re activated—they’re proliferative, turning over quickly and making collagen. Another typical property of activated fibroblasts is that they pump out TGF-beta, and that’s what our fibroblasts are doing. Then, that TGF-beta is getting to the cardiomyocytes and resulting in hypertrophy.”
Gelb said that the biggest surprise was that all of this might be “a signaling circle” that perpetuates itself: fibroblasts trigger the release of TGF-beta, which induces hypertrophy in cardiomyocytes, which causes fibroblasts to release even more of the growth factor.
Though unexpected, the results do offer some hope, according to Gelb, who comments that “It does imply that we might have the possibility of a therapy here, at least for kids with HCM in the context of RAFopathy.”
Next, Gelb says, the team wants to see if their results are “a generalizable phenomenon.” The cardiomyocytes they used were developed from iPS cells with BRAF mutations, he explains, but HCM and the other RAFopathies are the result of mutations in a number of genes.
“For all kids with all RAFopathies and HCM, is it always the case that we observe this phenomenon of the cell non-autonomous effect of signaling from the fibroblasts to the cardiomyocytes? If it’s true, then that would imply that we could treat any of them by blocking TGF-beta,” says Gelb.

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