Regulation of Fetal Cardiac Growth After Correction of Increased Hemodynamic Load

描述（由申请人提供）：拟议项目的目的是确定胎儿心脏生长的机制如何通过从长时间增加的心血管容量或压力负荷中恢复而改变。胎儿心脏通过改变其正常生长模式，非常敏感地适应血流动力学负荷条件的变化。在正常生长期间，胎儿经历广泛的心肌细胞增殖（在终末分化之前）以及心肌细胞增大。胎儿治疗的可能性提出了一个问题，即胎儿心脏在纠正血流动力学负荷改变后如何恢复。增加的容量负荷和增加的压力负荷都增加了心脏与体重的比率，但从这些条件中恢复可能不同。目标1：当胎儿心脏/体重在短暂的加速心肌细胞增殖期后恢复正常时，心肌内的心肌细胞数量是正常的。我们发现贫血胎儿肥大的心脏中的心肌细胞并不较大，这一发现支持了这一假说。因此，在复苏后，胎儿心脏将含有正常数量的心肌细胞。目标二：当胎儿心脏/体重在短暂的加速心肌细胞增大后恢复正常时，心肌内的心肌细胞数量减少。这一假说得到了高血压诱导心肌细胞增大的研究结果的支持。因此，在复苏后，胎儿心脏将含有较少数量的心肌细胞。目标3：在压力负荷后的恢复期，胎儿心脏中的细胞凋亡和与细胞凋亡相关的信号通路被激活，而不是容量负荷。容量负荷（由于贫血）不会增加动脉压，因此容量负荷的校正不会改变收缩期壁应力，细胞凋亡不会被强烈刺激。相反，在高血压期间，胎儿心脏将通过减小心室曲率半径和增加壁厚度来使壁应力正常化。在卸载时，心室壁应力将下降并诱导细胞凋亡。胎儿具有非凡的生长和适应能力。许多婴儿在出生前对先天性心血管疾病的耐受性较好。我们正试图了解胎儿的心脏是如何从这种情况中恢复的。这将帮助我们知道什么时候胎儿治疗效果最好。

DESCRIPTION (provided by applicant): The objective of the proposed project is to determine how the mechanisms of fetal cardiac growth are altered by recovery from an extended period of increased cardiovascular volume or pressure load. The fetal heart very sensitively adjusts to alterations in hemodynamic loading conditions by modifying its normal growth patterns. During normal growth, the fetus undergoes extensive cardiomyocyte proliferation (prior to terminal differentiation) as well as cardiomyocyte enlargement. The possibility of fetal therapies raises the question of how the fetal heart recovers after correction of altered hemodynamic loading conditions. Increased volume load and increased pressure load both increase the ratio of the heart to body weight, but recovery from these conditions may be different. Aim 1: When the fetal heart/body weight normalizes following a transient period of accelerated cardiomyocyte proliferation, the number of myocytes within the myocardium is normal. This hypothesis is supported by our finding that myocytes are not larger in hypertrophied hearts of anemic fetuses. Following recovery, the fetal heart will therefore contain a normal number of myocytes. Aim 2: When the fetal heart/body weight normalizes following a transient period of accelerated cardiomyocyte enlargement, the number of myocytes within the myocardium is reduced. This hypothesis is supported by our finding that hypertension induces cardiomyocyte enlargement. Following recovery, the fetal heart will therefore contain a fewer number of myocytes. Aim 3: Apoptosis and signaling pathways associated with apoptosis are activated in the fetal heart in the recovery period following a pressure load, but not a volume load. Volume load (due to anemia) does not increase arterial pressures, therefore correction of volume load will not change systolic wall stress and apoptosis will not be strongly stimulated. In contrast, during hypertension the fetal heart will normalize wall stress by reducing the ventricular radius of curvature and increasing wall thickness. Upon unloading, ventricular wall stress will fall and induce apoptosis. Fetuses have a remarkable capacity for growth and adaptation. Many babies tolerate congenital cardiovascular diseases better before they are born. We are trying to learn how the hearts of fetuses recover from such conditions. This will help us know when fetal therapies will do the most good.