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Published on: May 12, 2017
Patient-Specific Heart Rate Modulates Developmental Electrophysiology in Transcriptomic-Guided In Silico Models of
Gabriella M Ellks1, Mario J Mendez1, Devon Guerrelli2,3,4
1Department of Biomedical Engineering, The Ohio State University, Columbus, OH.
Insights
Pediatric atrial electrophysiology matures with age, influenced by intrinsic heart rate and developmental changes. Computational models reveal how heart rate and maturation interact to shape cardiac electrical activity in developing hearts.
Area of Science:
- Computational biology
- Pediatric cardiology
- Cardiac electrophysiology
Background:
- Pediatric cardiac electrophysiology undergoes significant developmental changes.
- Previous models did not fully account for age- and patient-specific heart rates.
- Understanding these dynamics is crucial for pediatric cardiac health.
Purpose of the Study:
- To investigate the interplay between developmental maturation and heart rate in pediatric atrial electrophysiology.
- To develop gene expression-guided computational models incorporating intrinsic heart rate.
- To predict age- and rate-dependent electrophysiological biomarker changes.
Main Methods:
- Generated virtual patient-specific atrial cardiomyocyte populations (n=117) using gene expression data.
- Simulated populations at intrinsic and fixed pacing rates.
- Quantified action potential and calcium transient biomarkers; used partial least squares regression.
Main Results:
- Intrinsic-rate pacing showed increased action potential duration and upstroke velocity with age.
- Early repolarization shortened, resting membrane potential became more negative, and alternans decreased with age.
- Developmental differences persisted at fixed rates; intrinsic-rate simulations showed stronger age associations.
Conclusions:
- Pediatric atrial electrophysiology is shaped by both intrinsic developmental remodeling and heart rate modulation.
- Interactions among ionic conductances, calcium handling, age, and heart rate determine electrophysiological phenotypes.
- Age- and rate-dependent factors are critical for understanding pediatric cardiac electrical activity.
Abstract:
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 patient's 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.
