Using genetics-guided biomechanics and patient-derived stem cells, it may be possible to predict what type of inherited heart defect a child will develop, according to authors of a newly published study in the journal Cell.
The technology, developed by a multi-institutional team led by the Cincinnati Children’s Heart Institute, would allow doctors to intervene earlier to help patients manage their conditions and help inform future pharmacologic treatment options.
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Lead study author Jeffery Molkentin, a researcher in the Division of Molecular Cardiovascular Biology at Cincinnati Children’s and at the Howard Hughes Medical Institute in Chevy Chase, Maryland, explained:
“The technology is a mathematical model where people who are suspected to contain mutations that lead to hypertrophic (HCM) or dilated cardiomyopathy (DCM) based on a family history, and potentially based on an early phenotypic manifestation, could be analyzed to determine eventually what type of cardiomyopathy they may show.”
The researchers studied mice with known mutations in sarcomere encoding genes. These mutations underlie hypertrophic or dilated cardiomyopathies, which affect as many as one in 500 people, they said.
“Some patients with HCM mutations develop this disease later in life, and sometimes earlier in life, too. We used the mouse as a model to try to understand how these mutations lead to the change in the heart mass, or change in cardiac remodeling and that could be used to predict what might happen to patients,” said Molkentin.
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The researchers generated the mathematical model to measure the tension dynamics of a patient’s cardiac myocytes, enabling them to predict whether the patient might get either HCM or DCM.
“The way you do that now — and this fits into personalized medicine — is if you can get a skin biopsy sample, or even blood from a patient, you can make iPSC cells,” said Molkentin.
iPSC cells are induced pluripotent stem cells, and they can be convinced to become cardiac myocytes. “You can basically take a skin biopsy from a patient, isolate their fibroblasts, convert them into cardiac myocytes, measure their tension dynamics and, using our mathematical model, predict potentially what type of disease these patients might get and how severe the disease will be,” said Molkentin.
Comparing the technology to personalized medicine, Molkentin said, “We can first genotype patients who are suspected to potentially be at risk, generate fibroblast cultures from biopsies or from their blood , turn them into cardio myocytes, measure them and use the model to predict what phenotype they might get.”
There are no effective drug regimens to manage the conditions today; the only effective treatment is a heart transplant, Molkentin explained.
So, would this new technology reduce the need for drug companies developing new drugs or reduce the number of heart transplants? “It might inform how we could treat patients earlier before they manifest the disease by putting them on cardiac-sparing drugs, like beta blockers or ACE inhibitors, drugs that generally have a protective profile for patients already in heart failure,” said Molkentin.
If drugs are developed to treat HCM and DCM, the researchers’ technology would partner well with the drugs. “The technology would suggest which patients would be appropriate for each of the two types of drugs,” said Molkentin.
“If we knew the patients who were at risk, we might monitor them more carefully and prophylactically put them on potentially cardiac-acting drugs that are known to spare the heart in heart failure. That’s one possibility but it’s never been tested so we don’t actually know that will work.”
A second possibility is if patients have hypertrophic cardiomyopathy mutations and it appears to be a severe phenotype based on generating iPSC cells and making myocytes, those patients potentially would be monitored for arrhythmic events, Molkentin said.
“There is a potential that this be a cardiovascular indication for personalized medicine, where patients are genotyped and then risk assessments are made,” Molkentin said.
Photo: Cincinnati Children’s Heart Institute