Abstract 334: Proliferation of Cardiomyocytes from a Rat Model of Heart Hypoplasia

Abstract

Decreased cardiomyocyte proliferation has been implicated in underdevelopment of the left ventricle in Hypoplastic Left Heart Syndrome (HLHS). However, it is not clear if cardiomyocytes in HLHS have an inherent defect that inhibits proliferation or if it is the result of abnormal external cues (eg, alterations to mechanical loading or extracellular matrix). We hypothesized that cardiomyocytes from hypoplastic hearts would be capable of proliferation if removed from the unhealthy cardiac environment. We used the rat model of congenital diaphragmatic hernia (CDH) via nitrofen treatment in the pregnant dam at E10 to induce heart hypoplasia in the developing fetuses; control dams were gavaged with olive oil only. Fetuses were harvested at E21 and the presence of CDH was determined. CDH+ hearts were smaller and abnormally shaped compared to healthy controls (Fig. 1A). Ki67 staining revealed that CDH+ hearts had significantly lower cell proliferation vs. healthy hearts (Fig. 1B). However, when cells were placed in culture, CDH+ cardiomyocytes expanded more rapidly compared to control cardiomyocytes (Fig. 1C). CDH+ cells also had smaller, more disorganized sarcomeres (not shown) and decreased expression of cardiac genes compared to controls (Fig. 1D), suggesting that CDH+ cells were less mature. Our findings suggest that cardiomyocytes from hypoplastic hearts may be arrested in an immature state but are not necessarily defective, and have potential for proliferation and growth. Strategies that aim to increase cardiomyocyte proliferation during development in HLHS may be a novel strategy to encourage left ventricular growth and lead to better outcomes in these patients.