Fetal Cardiac Hypertrophy: Vascular/Metabolic Adaptation

先天性心脏病显著地改变了胎儿的正常生长发育。此外，患有先天性心脏病的胎儿在子宫和围产期的发病率过高，这可能与胎儿全身和心肌血流动力学受损有关。胎儿心脏对压力负荷或慢性贫血的适应，如发生在许多先天性心脏病变或胎儿病理状态，导致心室质量增加。对于超载的胎儿心脏如何调整其微血管和代谢途径以适应心肌能量需求的增加，人们知之甚少。这些代偿性心肌反应可能对近期和长期生存都有重大影响。在成人心脏中，伴随肥厚反应的分子和形态变化已被广泛研究，包括一些“胎儿”通路的再激活。然而，在胎儿心脏中，增加心室质量的分子触发因素以及伴随的血管和代谢反应尚不清楚。我们在胎羊中获得的初步数据表明，在妊娠晚期，一些基因的表达发生了发育变化，这些基因可能对调节超负荷心脏的血管和代谢反应很重要。本提案中概述的研究的直接目标是：(1)确定胎儿心脏在施加临床重要刺激后质量增加时微血管和代谢适应的分子和形态学基础；(2)研究这些反应在胎儿发育的不同阶段是如何被调节的。从这些研究中获得的信息将提高我们对超载胎儿心肌代偿变化的理解，并有助于指导与使心脏恢复到更“正常”生理有关的新研究。最终的结果是希望婴儿有一个更“正常”的心脏和循环生理将提高生存率，发病率更低。

Congenital heart disease significantly alters the normal growth and development of the fetus. Furthermore, fetuses with congenital heart disease have excessively high in utero and perinatal morbidity that may be related to impaired fetal systemic and myocardial hemodynamics. Adaptation of the fetal heart to a pressure load or chronic anemia, as occurs with a number of congenital heart lesions or fetal pathologic states, results in an increase in ventricular mass. Little is known on how the overloaded fetal heart adapts its microvasculature and metabolic pathways to accommodate the increase energetic demands of the myocardium. These compensatory myocardial responses likely have a major influence on both immediate and long term survival. In the adult heart, the molecular and morphologic changes that accompany the hypertrophic response have been extensively studied and include reactivation of a number of "fetal" pathways. However, in the fetal heart, the molecular triggers for increasing ventricular mass and the accompanying vascular and metabolic responses are poorly understood. Our preliminary data obtained in fetal sheep demonstrate that during the third trimester of gestation there are developmental changes in the expression of a number of genes that are likely important in regulating the vascular and metabolic response of the overloaded heart. The immediate goals of the studies outlined in this proposal are: (1) to determine the molecular and morphologic basis of microvascular and metabolic adaptations of the fetal heart as it increases in mass following the imposition of clinically important stimuli; (2) to investigate how these responses are regulated at different stages of fetal development. Information gained from these studies will improve our understanding of the compensatory changes of the overloaded fetal myocardium and help direct new investigations related to returning the heart to more "normal" physiology. The end result is hoped to be that the infant with a more 'normal' heart and circulatory physiology will have improved survival with less morbidity.