Researchers from Baylor College of Medicine, Texas Heart Institute, Texas Children’s Hospital and collaborating institutions have improved our understanding of the mechanisms underlying the progression of congenital heart disease (CHD) – a spectrum of heart defects that develop before birth and yet becoming one of the leading causes of infant mortality.
The research published in Nature represents the first reported single-cell analysis of the genes expressed by cardiac cells and immune system cells of patients with congenital heart disease. The team discovered key differences between different types of CHD, providing insight into the mechanisms of the disease, helping to define clinical outcomes and illuminating opportunities for devising personalized treatments.
“When the parents of a child with a newly diagnosed congenital heart disease approach me, they always ask me two questions: ‘Why does my child have this problem?’ and ‘What are you going to do about it?’” said co-author Dr. Diwakar Turaga, assistant professor of pediatrics at Baylor and pediatric cardiac surgery specialist at Texas Children’s. “This study addresses both questions.”
To identify the genetic underpinnings of CHD, the researchers obtained heart tissue samples from multiple patients, which covered different forms of the condition.
They analyzed the gene expression signature of individual cells using a technique called single nuclear RNA sequencing (snRNA-seq). The team studied different types of heart cells and immune cells in each tissue sample. The analysis revealed genetic pathways that are activated in each cell, a way of knowing what the cells are doing.
“This unprecedented analysis showed what abnormal genetic changes each patient has, and answered the first question about the cause of the condition,” Turaga said. “Having this information opens the door to answering the second question. The changes at the genetic and cellular level that lead to the abnormal development of the heart guide researchers and physicians in treatment decisions for CHD.”
Our extensive analysis showed us something new: we expect genetic changes not only in the heart, but also in immune cells.
“Therefore, the treatment of CHD requires a multi-pronged approach. It involves both repairing the genetic pathways altered in cardiac cells and modulating the harmful pro-inflammatory activity of cells of the immune system,” said corresponding author Dr. James Martin, vice chair and professor of integrative physiology, professor and Vivian L. Smith Chair in Regenerative Medicine at Baylor and Director of the Cardiomyocyte Renewal Lab at the Texas Heart Institute.
Our goal is to better understand the biology of CHD, but as we move forward, we also want to develop personalized treatments for these patients.
There’s still a lot of work to be done now that the team, including co-first author Dr. Matthew C. Hill, is on his way to that goal. This is truly the beginning of a personalized medicine approach to treat these conditions.”
“Patients with congenital heart disease are at a much higher risk of heart failure than the general population, despite the amazing surgeries performed after birth to correct their intrinsic heart defects,” said co-first author Zachary Kadow, a graduate student in graduate school. medical scientist. Program (MD/Ph.D.) at Baylor. “We discovered genetic pathways activated in congenital heart disease that are different from those in adult heart failure. This work is a start toward our long-term goal to develop therapies that specifically slow the progression of heart failure in patients with congenital heart disease, enabling them to live longer and healthier.”
“The most exciting part of this work has been the diverse array of congenital heart disease treated, in addition to the new technologies used. Our findings provide important biological insights into the cellular and molecular dynamics of congenital heart disease and will have significant implications for both diagnostic as therapeutic development,” said co-author Hali Long, a graduate student in the Martin lab.
“It’s very exciting that this is the product of a powerful collaboration between one of the most advanced labs in cardiovascular research and the best pediatric heart center,” said co-author Dr. Iki Adachi, associate professor of surgery at the Baylor and Clayton Endowed Chair. in heart transplantation and mechanical support at Texas Children’s.
Other contributors to this work include Yuka Morikawa, Thomas J. Martin, Emma J. Birks, Kenneth S. Campbell, Jeanne Nerbonne, Kory Lavine, Lalita Wadhwa, and Jun Wang. The authors are affiliated with Baylor College of Medicine, Texas Heart Institute, Texas Children’s Hospital, The University of Texas Health Science Center at Houston, University of Kentucky and Washington University School of Medicine, St. Louis.
This work was supported by the Department of Defense (CDMRP) (W81XWH-16- PRMRP-IIRA), National Institutes of Health (1F31HL156681-01, F30HL145908, 5T32HL007208-42, R56 HL142704, R01HL142704, R01HL 127717, R01HL 130804, and R01HL 118761 ) and the Vivian L. Smith Foundation. Further support was provided by Baylor Research Advocates for Student Scientists and Baylor College of Medicine Medical Scientist Training Program, LeDucq Foundation’s Transatlantic Networks of Excellence in Cardiovascular Research (14CVD01: “Defining the Genomic Topology of Atrial Fibrillation”), the MacDonald Research Fund Award ( 16RDM001), a grant from the Saving Tiny Hearts Society, NIH HL149164, HL148785, and University of Kentucky Myocardial Recovery Alliance. The TCBR is supported by Children’s Discovery Institute at Washington University and St. Louis Children’s Hospital (PM-LI-2019-829), NIH through MD Anderson’s Cancer Center Support Grant CA016672, NCI’s Research Specialist 1 R50 CA243707-01A1 and a Shared Instrumentation Award of the Cancer Prevention Research Institution of Texas (CPRIT) (RP121010 and RP180672) and NIH (CA125123 and RR024574, 1S10OD023469).
By Ana María Rodriguez, Ph.D.