Biology subjects

d'Udekem, Y.

Publications and source records attributed to d'Udekem, Y..

4 recordsLinked to original sources

bioRxiv2026

Functional Assessment and Extended Culture of Human Pediatric Cardiac Tissue Slices for Preclinical Testing

Background: Living human myocardial slices preserve native tissue architecture, but their application to pediatric cardiac physiology or prolonged functional testing remains limited. We adapted a passive culture method for small surgical myocardial specimens obtained from patients with congenital heart disease (CHD). Methods: Atrial and ventricular specimens were obtained from 41 cardiac surgery patients (7.7{+/-}11.1 years; 1 day-49 years). Myocardial tissue was sectioned into slices and studied acutely, or maintained under free floating, rocking cell culture conditions without electrical or mechanical stimulation. Calcium transients were recorded in response to external pacing (0.2-2 Hz) at baseline, and after isoproterenol or norepinephrine exposure. Selected preparations underwent viability, histological, and gene expression analyses. Results: Pacing evoked calcium transients were recorded from all four cardiac chambers, exhibiting expected frequency-dependent shortening. Mean interslice and intraslice coefficients of variation were 11.1% and 7.6%. Viability was 85.8 {+/-} 5.6% post-slicing and 78.8 {+/-} 5.0% after 3-5 hours. Calcium transients remained detectable through 178 days in atrial and 119 days in ventricular slices. Calcium transient durations were relatively stable during extended culture. Beta-adrenergic agonists shortened calcium transient durations (isoproterenol: 32% atrial, 25% ventricular at 0.3 Hz); responses to isoproterenol persisted to approximately 120 days in selected atrial slices and 60 days in ventricular slices. Selected histological features were preserved, although some extracellular matrix and apoptosis related transcripts changed. Conclusions: Small surgical specimens support repeated physiological measurements and pharmacological testing during extended passive culture, providing a platform for human developmental and disease-specific cardiac research.

physiology↗

bioRxiv2026

Patient-Specific Heart Rate Modulates Developmental Electrophysiology in Transcriptomic-Guided In Silico Models of Pediatric Human Atrial Cardiomyocytes

Cardiac electrophysiology adapts throughout pediatric development, driven by factors including age-associated ion channel expression changes and decreasing heart rate. Our prior transcriptomic-guided simulations of human atrial cardiomyocytes predicted developmental-associated changes in electrophysiology biomarkers at a fixed pacing rate, leaving the contribution of age- and patient-specific heart rate unresolved. In this study, we incorporated intrinsic heart rate into gene expression-guided computational models to predict the interaction between developmental maturation and pacing rate to shape atrial electrophysiology. Virtual patient-specific populations of atrial cardiomyocytes were generated from the right atrial cardiomyocyte gene expression data from 117 patients, spanning neonates to young adults. We simulated each population at pacing rates corresponding to each patients intrinsic ECG-based heart rate and at fixed rates corresponding to the patient cohort minimum, median, and maximum. Action potential and calcium transient biomarkers were quantified, and partial least squares regression assessed key biomarker dependencies. For intrinsic-rate pacing conditions, action potential duration at 50% and 90% repolarization increased with age, whereas early repolarization shortened; maximum upstroke velocity increased, resting membrane potential became more negative, and alternans prevalence decreased. Developmental differences persisted during fixed-rate pacing conditions, indicating that differences were not explained solely by the faster heart rates of younger patients. Notably, intrinsic-rate simulations exhibited stronger age associations for upstroke velocity and alternans than fixed-rate simulations. Sensitivity analyses indicated that electrophysiological phenotypes arose from interactions among ionic conductances, calcium handling, age, and heart rate. Collectively, we find that pediatric atrial electrophysiology reflects both intrinsic developmental remodeling and rate-dependent modulation.

biophysics↗

bioRxiv2025

Chamber-Specific Transcriptomic Insight into Cardiac Development using Guinea Pig and Human Heart Tissue

The heart undergoes significant molecular and functional adaptations throughout postnatal development. However, to date, our understanding of these dynamic changes in the human heart is limited. Moreover, advances in pediatric cardiac research can be hindered by a lack of preclinical models that accurately reflect human heart maturation. Guinea pigs may serve as a useful model for human cardiac research, as the guinea pig and human myocardium have similar ion channel expression and cardiovascular drug responsiveness. Despite these similarities, gene expression patterns during postnatal heart development have not been comprehensively investigated. In this study, we first characterized transcriptional changes in neonatal, juvenile, and adult guinea pig hearts - identifying gene ontologies and pathways associated with cardiac maturation. Second, we compared the transcriptional profile of right atria and left ventricular tissue to highlight unique and shared chamber-specific patterns in guinea pigs over time. Finally, we conducted a cross-species comparison of the right atrial transcriptome between humans and guinea pigs to identify conserved maturation markers and gene expression patterns. Our findings provide a molecular framework for understanding age- and chamber-specific cardiac development, supporting the guinea pig as a promising preclinical model for studying human heart maturation. By identifying conserved gene programs and developmental markers across species, this study lays the groundwork for age-specific pharmacological strategies and computational models that can help to refine treatment decisions and outcomes for pediatric cardiology patients. New and NoteworthyExisting knowledge on postnatal heart development and cardiomyocyte maturation is limited. We investigated age-dependent transcriptional changes in neonatal, juvenile, and adult guinea pig hearts - and then conducted a cross-species comparison to identify age-specific patterns that are conserved in the guinea pig and human atria. Expanding our knowledge of chamber- and age-specific gene expression patterns can inform and guide the selection of cardiovascular therapies in the pediatric population, where developmental differences are understudied.

genomics↗

bioRxiv2024

Connecting Transcriptomics with Computational Modeling to Reveal Developmental Adaptations in the Human Pediatric Myocardium

BackgroundNearly 1% or 1.3 million babies are born with congenital heart disease (CHD) globally each year - many of whom will require palliative or corrective 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 cardiovascular drug therapies, and inform clinical care decisions related to surgical repair, myocardial preservation, or postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is largely limited to animal models. MethodsRight atrial tissue samples were collected from n=117 neonatal, infant, and pediatric patients undergoing correct surgery due to (acyanotic) CHD. Patients were stratified into five age groups: neonate (0-30 days), infant (31-364 days), toddler to preschool (1-5 years), school age (6-11 years), and adolescent to young adults (12-32 years). We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. ResultsEnrichment of differentially expressed genes (DEG) was explored, revealing age-dependent changes in several key biological processes (cell cycle, cell division, mitosis), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited both linear trends and sudden shifts across developmental stages, 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 also note a shift in repolarization reserve, with lower IKr expression in younger patients, a finding likely tied to the increased amplitude of IKs triggered by elevated sympathetic activation in pediatric patients. ConclusionThis study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology among patients with CHD, shedding light on molecular mechanisms underlying cardiac development and function across different developmental stages.

cell biology↗