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An Approach to Study Shape-Dependent Transcriptomics at a Single Cell Level
Published on: November 2, 2020
Connecting transcriptomics with computational modeling to reveal developmental adaptations in pediatric human atrial
Shatha Salameh1,2,3, Devon Guerrelli1,2,4, Jacob A Miller5
1Children's National Heart Institute, Children's National Hospital, Washington, District of Columbia, United States.
Insights
This study reveals age-dependent changes in cardiomyocyte gene expression and electrophysiology in pediatric patients with congenital heart disease, offering insights into cardiac maturation and function.
Area of Science:
- Cardiovascular Biology
- Pediatric Cardiology
- Molecular Cardiology
Background:
- Congenital heart disease affects nearly 1% of newborns, often necessitating early-life surgery.
- Understanding cardiomyocyte maturation is crucial for managing pediatric cardiac diseases and guiding treatment decisions.
- Limited knowledge exists regarding temporal changes in cardiomyocytes during postnatal development.
Purpose of the Study:
- To investigate age-dependent adaptations in cardiac gene expression and electrophysiology in pediatric patients.
- To identify molecular mechanisms underlying human cardiac maturation from infancy to adolescence.
- To correlate gene expression changes with electrophysiological properties like action potential and calcium transients.
Main Methods:
- Analysis of right atrial tissue samples from 117 pediatric patients stratified into five age groups.
- Measurement of age-dependent cardiac gene expression using transcriptomics.
- Computational modeling to simulate action potential and calcium transients based on gene expression data.
Main Results:
- Identified age-dependent changes in biological processes, including cell cycle and structural organization.
- Observed age-related trends in cardiac ion channel and calcium handling gene expression.
- Linked changes in calcium handling (INCX) and repolarization (IK1) to action potential alterations.
- Noted lower IKr expression in younger patients, potentially compensated by increased IKs.
Conclusions:
- This study provides critical insights into the molecular basis of human cardiac maturation.
- Age-dependent shifts in gene expression and electrophysiology are key to understanding pediatric heart development.
- Findings can inform clinical strategies for surgical repair and postoperative care in congenital heart disease patients.
Abstract:
Nearly 1% of babies are born with congenital heart disease-many of whom will require heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate drug therapies, and inform clinical care decisions related to surgical repair and postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is limited. In this study, we collected right atrial tissue samples from pediatric patients (n = 117) undergoing heart surgery. Patients were stratified into five age groups. We measured age-dependent adaptations in cardiac gene expression and used computational modeling to simulate action potential and calcium transients. Enrichment of differentially expressed genes revealed age-dependent changes in several key biological processes (e.g., cell cycle, structural organization), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited age-dependent trends, with changes in calcium handling (INCX) and repolarization (IK1) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We observed a shift in repolarization reserve, with lower IKr expression in younger patients, a finding potentially tied to an increased amplitude of IKs that could be triggered by elevated sympathetic activation in pediatric patients. Collectively, this study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology, shedding light on molecular mechanisms underlying cardiac maturation and function throughout development.NEW & NOTEWORTHY To date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is limited. In this study, we demonstrate age-dependent adaptations in the gene expression profile of >100 atrial tissue samples collected from congenital heart disease patients. We coupled transcriptomics datasets with computational modeling to simulate action potentials and calcium transients for different pediatric age groups.
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