Findings provide some of the first evidence
of potential therapeutic targets for condition affecting thousands
of patients with single ventricle congenital heart
disease
PHILADELPHIA, April 24,
2024 /PRNewswire/ -- As patients with congenital
heart diseases live longer, researchers are attempting to
understand some of the other complications they may face as they
age. In a new study, a team from Children's Hospital of
Philadelphia (CHOP) used
state-of-the-art technologies to understand the underlying biology
of Fontan-associated liver disease (FALD).
The findings, published today in Science Translational
Medicine, reveal unprecedented insights into how the disease
develops and potential therapeutic targets for future treatment
options.
The Fontan operation is the current standard of care for
single-ventricle congenital heart disease. In this surgery, blood
carried by the inferior vena cava, a vein that carries deoxygenated
blood from the lower body into the heart, is channeled directly
into the pulmonary arteries. After this operation, all the
deoxygenated blood from the body is delivered to the lungs but
without the benefit of a pump, resulting in the potential for
venous congestion. Approximately 80,000 people worldwide have had a
Fontan procedure.
The Fontan circulation (FC) – when the heart receives oxygenated
blood from the lungs and pumps it to the body – is life-sustaining
for individuals with single ventricle type of congenital heart
disease but comes with many potential challenges. Patients with FC
can face potentially life-threatening complications from
early-onset hepatic fibrosis, now known as FALD. As more patients
undergo the Fontan surgery for single-ventricle congenital heart
disease, FALD has become a more recognized problem. Little
information exists on FALD, yet it is distinct from other forms of
liver disease, which is why researchers at CHOP wanted to
understand the basic biology that could lead to better treatment
options and improve these patients' quality of life.
"As our expertise with Fontan surgery improves and the number of
survivors increase, we want to be able to offer these patients an
improved quality and duration of life," said study co-author
Jack Rychik, MD, Director of the
Fontan Rehabilitation, Wellness, Activity and Resilience
Development (FORWARD) Program at CHOP, one of the first
multidisciplinary clinics established in the world focused on
Fontan circulation specific care. "This study allowed us to achieve
a deeper understanding of Fontan-associated liver disease, and this
translational research is something we hope leads us to studies
that cure and improve the outcomes for patients born with half a
heart."
In the study, researchers generated the first complete atlas of
RNA and epigenetic statuses of human FALD at a single-cell level by
studying tissues samples from patients with early-stage disease.
The atlas revealed profound cell-type specific changes in livers
with Fontan circulation. The most significant changes were observed
in central hepatocytes, cells that play a key role in proper liver
function. The researchers found that these hepatocytes had
significant metabolic reprograming that preceded the activation of
other cells closely associated with FALD, suggesting that central
hepatocytes are a key part in understanding the origins of the
disease.
The researchers also identified how Activins A and B, signaling
molecules involved in several key developmental processes, may play
a role in the development of fibrosis, or the thickening or
scarring of tissue that in this case can contribute to FALD,
suggesting that they may serve as potential therapeutic
targets.
"Our findings make the case that there may be some way for us to
blunt the process that leads to scarring at the cellular level,"
said senior study author Liming Pei, PhD, an associate professor of
Pathology and Laboratory Medicine at CHOP and member of the CHOP
Cardiovascular Institute. "The pathways we identified are worth
studying in additional models and confirming whether that
information could lead to the discovery of new therapeutic
options."
This study was supported by the Office of the Assistant
Secretary of Defense for Health Affairs through the Peer Reviewed
Medical Research Program under Awards W81XWH20-1-0042,
W81XWH20-1-0089, W81XWH22-1-0058 and W81XWH22-1-0561, NIH
R01DK111495, U54HL165442, U01HL166058, P30DK019525, the American
Heart Association Established Investigator Award 227477, a CHOP
Foerderer Award, an SVRF grant from Additional Ventures, and by the
Robert & Dolores Harrington Endowed Chair in Cardiology at the
Children's Hospital of Philadelphia.
Hu et al, "Single-cell multiomics guided mechanistic
understanding of Fontan-associated liver disease." Sci Transl
Med. Online April 24, 2024. DOI:
10.1126/scitranslmed.adk6213.
About Children's Hospital of Philadelphia:
A non-profit, charitable
organization, Children's Hospital of Philadelphia was founded in 1855 as the
nation's first pediatric hospital. Through its long-standing
commitment to providing exceptional patient care, training new
generations of pediatric healthcare professionals, and pioneering
major research initiatives, the hospital has fostered many
discoveries that have benefited children worldwide. Its pediatric
research program is among the largest in the country. The
institution has a well-established history of providing advanced
pediatric care close to home through its CHOP Care Network, which
includes more than 50 primary care practices, specialty care and
surgical centers, urgent care centers, and community hospital
alliances throughout Pennsylvania
and New Jersey, as well as the
Middleman Family Pavilion and its dedicated pediatric
emergency department in King of
Prussia. In addition, its unique family-centered care and
public service programs have brought Children's Hospital of
Philadelphia recognition as a
leading advocate for children and adolescents. For more
information, visit https://www.chop.edu.
Contact: Natalie Solimeo
Children's Hospital of Philadelphia
solimeon@chop.edu
267.426.6246
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SOURCE Children's Hospital of Philadelphia