Investigating age-dependent adaptations in right atrial tissue using human and animal models

Clinical trial data on the pediatric population is extremely limited, which impedes our ability to comprehensively study cardiac physiology during postnatal development. This is because pediatric research studies are hindered by several limitations – including the scarcity of human tissue, small sample size, and underutilization of preclinical models. Notably, guinea pigs have been accepted as a translational model as both species undergo comparable developmental changes in the myocardium. Cardiac function relies on age-dependent differences in various factors such as ion channel expression, inward and outward currents, and excitation-contraction coupling. By characterizing the normal developmental process of the human heart, we can better understand cardiac pathophysiology and establish translatable preclinical models. This study aimed to investigate molecular driving factors throughout postnatal development in human right atrial cardiac tissue samples and translate these findings to age-specific changes in electrophysiology and calcium handling using a pediatric preclinical model. We hypothesize that age-specific changes in right atrial gene expression occur early in life and are similar between humans and guinea pigs, supporting the model's translational applicability. Right atrial appendages of acyanotic patients who underwent surgical correction of congenital heart defects were collected and stored for analysis. Total RNA was isolated and global gene expression was analyzed using human Clariom S arrays. Guinea pig right atrial tissue was collected after ex-vivo electrocardiogram recordings, and global gene expression was analyzed using guinea pig gene 1.0 ST arrays. Age-dependent changes in signal intensities and fold change (FC) for genes involved in cardiac electrophysiology and intracellular calcium handling were observed in human right atrial tissue. Expression of KCNH2 (gene associated with I } Kr , FC= 1.67, p<0.05), KCNJ3 (gene encoding I KAch , FC= 2.75, p<0.0001), and RYR2 (gene encoding RyR, FC= 1.76, p<0.001), increased with age while KCNJ2/4/12 (genes associated with I K1 , FC= -1.19) trended towards a decrease with age. Additional ontology enrichment analysis revealed genes related to cell cycle regulation, cell structure, and metabolism were among the most differentially expressed in our neonate group compared to adults using a fold change cutoff of ≥|1.25|, P value threshold of 0.05, and a 0.1 false discovery rate. Our preclinical guinea pig model exhibited similar adaptations in ionic currents including an increase in Kcnj3 (FC= 1.29, p<0.0001) and Ryr2 expression (FC= 1.14, p<0.001). This study characterized age-specific adaptations in human pediatric right atrial tissue, providing insight into the timing of developmental changes in cardiac gene expression. These age-dependent differences were validated using a translational animal model, supporting the urgent need for preclinical models to study pediatric cardiac physiology. American Heart Association and Children’s Heart Foundation 24PRE1198328 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.