Research opens door to better treatments for congenital heart disease

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 range of heart defects that develop before birth and remain a leading cause of death in children.

Microscopic view of heart tissue through pediatric heart disease. To see the paper in Nature for more details. Image courtesy of the authors/Nature2022.

Research published in Nature represents the first reported single-cell analysis of genes expressed by cardiac cells and immune system cells from patients with congenital heart disease. The team uncovered key differences between different types of coronary heart disease, which provides insight into disease mechanisms, helps define clinical outcomes, and illuminates possibilities for designing personalized treatments.

Dr. Diwakar Turaga

“When the parents of a child with 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 the co-author Dr. Diwakar Turagaassistant professor of pediatrics at Baylor and Pediatric Cardiac Critical Care Specialist at Texas Children’s. “This study answers both questions.”

To identify the genetic underpinnings of coronary heart disease, the researchers obtained heart tissue samples from several patients, spanning different forms of the disease.

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 every cell, a way of knowing what cells are doing.

“This unprecedented analysis showed the abnormal genetic changes in each patient, answering the first question about the causes of the disease,” Turaga said. “Having this information opens the door to answering the second question. The alterations at the genetic and cellular levels that lead to abnormal heart development guide decisions by researchers and doctors about how to treat coronary artery disease.

Dr James Martin

Our in-depth analysis showed us something new: to expect genetic alterations not only in the heart, but also in immune cells.

“Therefore, treating coronary artery disease requires a multi-pronged approach. This involves both repairing genetic pathways that are impaired in heart cells and modulating the damaging pro-inflammatory activity of immune system cells” , said the corresponding author. Dr James MartinVice President and Professor of integrative physiologyProfessor and Vivian L. Smith Chair in Regenerative Medicine at Baylor and Director of the Cardiomyocyte Renewal Laboratory at Texas Heart Institute.

Our goal is a better understanding of the biology of coronary artery disease, but as we move forward, we would also like to develop personalized treatments for these patients.

There’s still a lot of work to do as a team, including co-first author Dr. Matthew C. Hill, is moving towards this goal. This is truly the start of a personalized medicine approach to treating these conditions.

Zachary Kadow

“Patients with congenital heart disease are at a much higher risk of heart failure than the general population, despite the incredible surgeries performed after birth to correct their intrinsic heart defects,” said the co-first author. Zachary Kadowstudent in Medical Scientist (MD/Ph.D.) Training Program at Baylor. “We have 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 of developing therapies that specifically slow the progression of heart failure in patients with congenital heart disease, allowing them to live longer, healthier lives.

Hali Long

“The most exciting part of this work was the diversity of congenital heart conditions covered, in addition to the new technologies used. Our findings provide important biological insights into cellular and molecular dynamics in congenital heart disease and will have important implications for diagnostic and therapeutic development,” said the co-author. Hali Longgraduate student at the Martin laboratory.

Dr.Iki Adachi

“It’s very exciting that this is the product of a powerful collaboration between one of the most sophisticated laboratories in cardiovascular research and the top pediatric heart center,” the co-author said. Dr.Iki Adachiassociate professor of operation at the Baylor and Clayton Endowed Chair in Cardiac Transplant 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, 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, R01HL0 4 and R01HL 1301804) and the Vivian L. Smith Foundation. Additional 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. TCBR is supported by the University of Washington Children’s Discovery Institute and St. Louis Children’s Hospital (PM-LI-2019-829), NIH through MD Anderson’s Cancer Center Supporting Grant CA016672, the Research Specialist from NCI 1 R50 CA243707-01A1 and a shared Instrumentation Award from the Cancer Prevention Research Institution of Texas (CPRIT) (RP121010 and RP180672) and NIH (CA125123 and RR024574, 1S10OD023469).

By Ana Maria Rodriguez, Ph.D.

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