Stress response of the hypoplastic mouse heart

What is it about?

Impairment of intrauterine growth in humans and animal models impacts on embryonic and fetal heart development, often resulting in a reduced number of cardiomyocytes at birth. Such incomplete cardiomyocyte endowment (referred to as hypoplasia) is believed to increase the susceptibility towards cardiac disease in adulthood by disturbing an adequate response of the myocardium to pathological conditions. Here we used a genetic mouse model, which results in a ~25% reduction of cardiomyocyte numbers in the neonatal heart. We subjected adult mice to left ventricular pressure overload by constriction of the abdominal aorta. Hypoplastic hearts showed a normal stress response over the first 2 weeks exhibiting the expected increase in left ventricular mass and wall thickness similar to control animals. Surprisingly, after 4 weeks of pressure overload controls show signs of cardiac dysfunction, whereas hypoplastic hearts fully maintain left ventricular dimensions and contractility.

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Why is it important?

It is widely accepted that intrauterine growth restriction (IUGR) in humans increases the risk for cardiovascular disease in adulthood, a phenomenon referred to as fetal or developmental programming. For the heart the increased susceptibility towards cardiac disease is proposed to be the result of a reduced cardiomyocyte complement at birth, which alters myocardial stress response during postnatal life. Indeed, animal models have suggested that the IUGR heart might be more susceptible towards ischemia and reperfusion injury. However, such data has mainly been derived from explanted, retrogradely perfused rat hearts, a somehow artificial system, whereas in vivo studies are lacking. Moreover, apart from ischemia other challenges relevant for the adult heart such as pressure overload, neurohumoral stimulation or cardiotoxicity have rarely been tested in the IUGR heart. Our study shows that cardiac hypoplasia itself does not seem to negatively affect the response of the adult heart towards pressure overload in vivo. In contrast, hypoplastic hearts have a better functional outcome compared to controls, raising the interesting hypothesis that altered intrauterine cardiac growth could condition the heart for certain pathological stimuli during postnatal life. Given that the mouse model used in this study is considerably different from IUGR models, our results urge for longitudinal in vivo studies of different cardiovascular challenges in IUGR hearts.