A team of scientists from the University of Maryland School of Medicine has identified a previously unknown gene mutation that leads to heart failure in children, specifically a condition called infantile dilated cardiomyopathy. Remarkably, they have also managed to reverse the effects of this mutation by using a drug on heart muscle cells derived from the patient’s own stem cells. These findings have significant implications for the development of treatments to manage this condition, potentially eliminating the need for heart transplants that are currently the standard treatment for affected children.
To unravel the mystery behind this rare condition that causes heart failure in children, researchers at the University of Maryland School of Medicine focused on identifying new gene mutations responsible for the disorder in an infant patient. Through their efforts, they successfully uncovered the workings of the mutation and employed a drug to effectively reverse its effects in heart muscle cells derived from stem cells taken from the same patient.
The results of this groundbreaking study, recently published in the journal Circulation, indicate the possibility of developing treatments to manage infantile dilated cardiomyopathy without resorting to heart transplants, which are currently the primary treatment option for children with this condition.
Dr. Charles “Chaz” Hong, MD, Ph.D., Melvin Sharoky, MD Professor of Medicine and Physiology, Director of Cardiology Research, and Co-Chief of Cardiovascular Medicine at UMSOM, emphasized the importance of this research, stating, “While significant progress has been made in understanding heart failure in adults, there is still much to learn about the genetic causes of heart failure in infants. The gene mutations we identified had previously been linked to microcephaly in babies but had not yet been associated with human heart disease.”
Infantile dilated cardiomyopathy is a prevalent cause of heart failure in children, accounting for approximately half of all pediatric heart failure cases. However, its primary cause remains largely unknown. Although relatively rare, occurring in approximately one in every 200,000 births, infants with this condition experience reduced heart muscle contraction, leading to inadequate blood pumping.
The gene mutation discovered by Dr. Hong and his colleagues was found to affect the production of a protein found in a cell structure called the centrosome. The centrosome acts as a tether for the cell’s skeleton and is primarily known for its role in cell division. In the absence of this protein, the muscle cells in the heart fail to organize themselves properly and exhibit reduced contractility, ultimately impacting the heart’s ability to pump blood effectively.
Initially, the researchers dismissed their findings, believing that the cell division machinery would not be involved in heart muscle dysfunction. However, it was revealed that this machinery, which was previously assumed to disappear once heart cells matured, relocates within the cell and assumes a new function related to heart muscle performance.
To identify the gene mutation responsible for infant heart failure, the researchers extracted a sample of heart cells from a patient with the disease during a transplant. They then transformed these heart tissue cells into stem cells for further laboratory study. The analysis revealed two distinct mutations of a gene that encodes the Rotatin protein, one from each parent.
The researchers conducted an experiment to remove this same protein from zebrafish hearts, which resulted in the development of heart failure symptoms. Additionally, they observed that fruit fly hearts lacking Rotatin exhibited disorganized muscle cells and diminished contractility, similar to the condition observed in infants with the disorder.
Matthew Miyamoto, the first co-author and a medical student who worked on the project, expressed the significance of the findings, stating, “This is the first human disease known to be caused by disrupting the transition in centrosome structure, which normally occurs shortly after birth.” The researchers then employed the drug C19, known for its ability to organize centrosomes in developing heart muscle cells derived from patients with infantile dilated cardiomyopathy. Remarkably, the drug restored the organization and contractility of the developing heart muscle cells grown in a laboratory dish using the patient’s stem cells.
Dean Mark T. Gladwin, MD, of UMSOM, further emphasized the importance of understanding the tissue-specific programmed process involving centrosomes, particularly in heart muscle development, for future advancements in cardiac regenerative therapy.
Dr. Hong added, “The collaboration between cardiologists, medical student trainees, and laboratory researchers played a crucial role in this biomedical discovery, which we hope will ultimately translate into medical treatments for children with this condition.”
Dr. Patrice Desvigne-Nickens, a medical officer in the Heart Failure and Arrhythmias Branch of the National Heart, Lung, and Blood Institute (NHLBI), a part of the National Institutes of Health, acknowledged the study’s significance, stating, “This study contributes significantly to our understanding of the biological mechanisms underlying infantile dilated cardiomyopathy and its relationship to heart failure. We eagerly await future studies to further clarify and confirm these findings, with the goal of improving heart failure outcomes.”
The study received funding from the NHLBI, the Maryland Stem Cell Research Fund, and an AOA Carolyn L. Kuckein Student Research Fellowship.
The authors have disclosed their interest in a pending patent for using C19 to treat infantile dilated cardiomyopathy, and in accordance with UMB policy, the university is managing this relationship to ensure research objectivity.
Table of Contents
Frequently Asked Questions (FAQs) about heart failure in children
What did the researchers discover regarding heart failure in children?
The researchers identified a new gene mutation responsible for heart failure in children, specifically a condition known as infantile dilated cardiomyopathy.
How did the researchers reverse the effects of the gene mutation?
Using a drug, the researchers successfully reversed the effects of the gene mutation in heart muscle cells derived from the patient’s own stem cells.
What are the implications of these findings?
The findings suggest the potential development of alternative treatments for infantile dilated cardiomyopathy, potentially eliminating the need for heart transplants, which are currently the standard treatment for affected children.
How common is infantile dilated cardiomyopathy?
Infantile dilated cardiomyopathy is relatively rare, occurring in approximately one in every 200,000 births. However, it accounts for about half of all pediatric heart failure cases.
What role does the identified gene mutation play in heart function?
The gene mutation affects the production of a protein called Rotatin, which is crucial for organizing heart muscle cells and maintaining their proper contractility. Mutations in this gene disrupt these processes and contribute to heart failure in infants.
What was the methodology of the study?
The researchers extracted heart cells from a patient with infantile dilated cardiomyopathy and converted them into stem cells for further analysis. They conducted experiments using zebrafish and fruit fly models to validate the effects of the gene mutation. Additionally, they used a drug called C19 to restore organization and function in the heart muscle cells derived from the patient’s stem cells.
Who funded this research?
The study received funding from the National Heart, Lung, and Blood Institute (NHLBI), the Maryland Stem Cell Research Fund, and an AOA Carolyn L. Kuckein Student Research Fellowship.
More about heart failure in children
- University of Maryland School of Medicine: Link
- Circulation Journal: Link
- National Heart, Lung, and Blood Institute (NHLBI): Link
- Maryland Stem Cell Research Fund: Link
- AOA Carolyn L. Kuckein Student Research Fellowship: Link
5 comments
this study is vry important for understanding heart failure in infants, which we dnt knw much abt. gene mutations linkd to microcephaly now found to cause heart disease. groundbreakin work!
as a medical student, I’m inspired by the collaboration between doctors, students, and researchers to make this discovery. hope this leads to better treatments for children with heart failure.
wait, the gene mutation affects centrosome structure? didnt knw it had a role in heart muscle dysfunction! this study brings new insights into tissue-specific processes. fascinatin stuff!
wow researchers discovered new gene mutation causing heart failure in children and it can be reversd wth drug on stem cells! no more heart transplants? amazin!
heart failure in kids is so sad! but this research gives hope for new treatments, avoiding invasive heart transplants. stem cells and gene mutations hold the key. amazin progress!