127 - Remarkable Sexual Dimorphism in the Injured Neonatal Heart: Implications for Prematurity Related Cardiac Outcomes

Monday, May 1, 2023

9:30 AM – 11:30 AM ET

Poster Number: 127
Publication Number: 127.427

Manuel E. Cantu Gutierrez, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Abiud Cantu, The Children's Hospital of Philadelphia, Philadelphia, PA, United States; Jonathan Edwards, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Krithika Lingappan, Childrens Hospital of Philadelphia, Philadelphia, PA, United States

Presenting Author(s)

KL

Krithika Lingappan, MD MS PhD (she/her/hers)

Associate Professor
Childrens Hospital of Philadelphia
Philadelphia, Pennsylvania, United States

Background: Morbidities associated with preterm birth have an adverse long-term impact on the cardiopulmonary health of adults born preterm. Young adults born preterm have a greater risk of developing heart failure compared to people who are born at term. The long-term cardiopulmonary health consequences related to preterm birth are a critical area for the need for further translational and clinical research.

Objective: Our objective was to understand the transcriptomic, and functional response in the neonatal heart exposed to early hyperoxic injury. We hypothesized that neonatal hyperoxia exposure will have a profound but differential impact on the atria and ventricles and sex as a biological variable will play a crucial role in mediating these responses.

Design/Methods: Male and female neonatal pups were exposed to hyperoxia (95% FiO2) from PND 1-5 (saccular stage of lung development) postnatally. Hearts (ventricles and atria) from mice of either sex were analyzed for transcriptomic response (bulk RNAseq; PND7 and 12 weeks), proteosome activity (PND 7), and function by echocardiography (10 weeks). 6-8 biological replicates were used per group for the analyses. 2-way ANOVA was used for statistical analysis.

Results:

Striking transcriptomic changes were observed in the neonatal heart predominantly in the atria compared to ventricles when subjected to postnatal injury (Fig 1). Proteosome activity was increased in the hyperoxia-exposed male hearts, but not in the females. Marked sex-specific differences were noted in the atria (Fig 2). At PND 7 (acute response), hyperoxia-exposed male mice showed a greater alteration in their transcriptional landscape with over 820 differentially expressed genes (DEGs) in atria compared to 102 genes in females. Biological pathways including metabolism were upregulated while cell morphogenesis and adhesion were downregulated in male atria. However, at 12 weeks of age (chronic response) the number of DEGs in females (1,031 genes) was greater compared to males (99 genes). Biological pathways related to muscle cell development and cardiac tissue morphogenesis were upregulated while regulation of immune response was downregulated in the female atria. Functional assessment using echocardiography revealed increased end-systolic Left Ventricular Internal Diameter end-systolic along with decreased ejection fraction in hyperoxia-exposed male mice.

Conclusion(s):

Neonatal hyperoxia exposure has a profound but differential impact on the atria and ventricles (atria >ventricles). Sex as a biological variable plays a crucial role in mediating these responses.