The uncommon condition that causes pediatric heart failure has been linked to unique gene alterations, according to researchers at the University of Maryland School of Medicine (UMSOM). After learning how the mutation operates, they were able to use medicine to block its effects on cardiac muscle cells made from the patient’s stem cells.
Despite extensive research on heart failure in adults, Charles “Chaz” Hong, MD, PhD, Melvin Sharoky, MD Professor of Medicine and Physiology, Director of Cardiology Research, and Co-Chief of Cardiovascular Medicine at UMSOM, stated that there is still much to learn about the genetic causes of heart failure in infants. Although human heart disease has not yet been linked to mutations in the gene we found, they have been linked to microcephaly in infants.
About half of juvenile heart failure cases are caused by infantile dilated cardiomyopathy, a prevalent cause of heart failure whose root cause is often unknown. Even though it’s very uncommon, affecting one in 200,000 newborns, babies with the disorder have hearts that don’t contract as well, which prevents them from pumping as much blood as they should.
The centrosome, a cell component that serves as a tether for the cell’s skeleton and is best recognized for its function during cell division, is where this genetic mutation made by Dr. Hong and his colleagues was found to typically create a protein.
The researchers hypothesized that without this protein, the muscle cells in the heart were unable to neatly arrange themselves and could not contract as efficiently, which in turn impaired the heart’s pumping.
The cell division machinery would be implicated in this form of cardiac muscle malfunction, but we first discounted our results as artifacts, according to Dr. Hong. “We believed that the cell division machinery completely disappeared once the heart cells matured, but it transpired that it relocates to a new location within the cell and assumes a new function in heart muscle function,” said Dr. Lee.
The researchers took a sample of heart cells from the patient’s ill heart after it was removed during a transplant in order to detect the gene mutation that causes newborn heart failure. They then transformed this cardiac tissue into stem cells so they could create additional cells and do in vitro research on them. They discovered that the patient had two distinct mutations in the gene that typically codes for the Rotatin protein, one from each parent.
The zebrafish hearts exhibited symptoms of heart failure after the researchers removed this protein from them in an experiment. The muscle cells in these hearts were disordered and did not contract as they should, similar to what occurs in newborn hearts with the condition, the researchers discovered when they examined fruit fly hearts lacking Rotatin.
“This is the first human disease known to be caused by disrupting the transition in centrosome structure which normally occurs shortly after birth,” said Matthew Miyamoto, the first co-author who worked on this study as a rising second-year medical student in Dr. Hong’s lab.
When growing heart muscle cells from the patient with infantile dilated cardiomyopathy were employed, the medication C19 was known to arrange centrosomes. The medication restored the capacity of the patient’s stem cells used to generate the growing cardiac muscle cells in a dish to contract and organize themselves.
“Because centrosomes play such a fundamental role in heart muscle development, specifically cell replication, structure, and function, a better understanding of this tissue-specific programmed process will be highly relevant to future cardiac regenerative therapy efforts,” said Mark T. Gladwin, MD, UMSOM Dean and John Z. and Akiko K. Bowers Distinguished Professor as well as Vice President for Medical Affairs at the University of Maryland, Baltimore (UMB).Dr. Hong continued, “This scientific finding, which we hope may one day result in medical therapies for children with this problem, was only made possible by cooperation between cardiologists, medical student trainees, and laboratory researchers.
The National Heart, Lung, and Blood Institute (NHLBI), a division of the National Institutes of Health, concurred. Patrice Desvigne-Nickens, MD, a medical officer in the Heart Failure and Arrhythmias Branch of the Division of Cardiovascular Sciences, agreed. The basic foundations of juvenile dilated cardiomyopathy and its connection to heart failure are better understood thanks to this work, she said. Future research is anticipated in an attempt to better the outcomes for those with heart failure.
