Preserved Heart Function after Left Ventricular Pressure Overload in Adult Mice Subjected to Neonatal Cardiac Hypoplasia

Objectives: Intrauterine growth restriction in animal models reduces heart size and cardiomyocyte number at birth. Such impaired cardiomyocyte endowment is believed to increase susceptibility toward cardiovascular disease in adulthood, a phenomenon referred to as developmental programming. The consequences of a reduced cell number for postnatal cardiac function in vivo, however, are largely unexplored.

Methods: Using a previously described mouse model of impaired myocardial development leading to neonatal cardiac hypoplasia, this study aimed at investigating the response of affected mice to pressure overload in adulthood, applied by abdominal aortic constriction (AAC) for 4 weeks.

Results: Echocardiography revealed a similar hypertrophic response in hypoplastic hearts compared with controls over the first 2 weeks (LV mass 132.38 ± 7.02 vs. 125.29 ± 5.62 mg). Strikingly, control mice appear to adapt to pressure overload thereafter resulting in partial normalization of LV mass (112.25 ± 6.67 mg) and wall thickness (0.8 ± 0.04 mm) 4 weeks after AAC, yet affected mice exhibit sustained hypertrophy (LV mass 141.79 ± 4.17 mg, wall thickness 1.02 ± 0.04 mm, p < 0.01 vs. controls). Furthermore, control mice develop mild contractile dysfunction 4 weeks after AAC whereas hypoplastic hearts fully maintain LV dimensions and function (ejection fraction 43.39 ± 5.09 vs. 61.66 ± 3.47%, p < 0.05). At the cellular level controls show the expected increase in cardiomyocyte cross sectional area compared with sham operated animals (+29.4%), but this hypertrophic response is markedly attenuated in hypoplastic hearts (+15.4%). In contrast, AAC mediated induction of fibrosis or cell cycle activity was not different between groups. Expression of fetal genes, indicative of pathological conditions, was similar in hypoplastic and control hearts after AAC. Among various signaling pathways involved in cardiac hypertrophy, p38 MAP-kinase activity is increased in hypoplastic hearts but not controls compared with the respective sham operated animals, suggesting its involvement in the differential growth performance.

Conclusion: Based on the mouse model used in this study, our data indicate that adult hearts after neonatal cardiac hypoplasia show an altered growth response to pressure overload, eventually resulting in better functional outcome compared with controls. This raises the hypothesis that intrauterine development might prime the heart for certain pathological insults during postnatal life.