HYPERTENSION & HYPERTROPHY

心室肥厚是一种重要的适应性机制 伴有全身性动脉高血压。然而，在某个时候， 随着时间的推移，这种代偿过程会导致充血性心力衰竭。这个 我们研究计划的主要目标，是定义基本的 压力的力学、生化和分子生物学特性 超负荷肥大与肥厚消退的独特模型 非人灵长类(狒狒)的渐进性肾性高血压。 建议对一种较小的哺乳动物(豚鼠)进行平行研究以阐明这一点。 物种差异，以促进分析技术的发展，以及 大鼠压力超负荷肥厚的心腔力学研究 不受神经体液影响的孤立心脏 因子与心室血管偶联。使用这种方法，我们建议 要检验以下特定假设：1)压力过载 肥厚与收缩腔弹性、负荷不变有关 独立降低的射血和充盈速度和升高的被动速度 腔室和肌肉僵硬；2)压力超负荷的回归 肥厚的特征是射血速度正常化和 充盈和残余升高的心肌硬度；3)压力 超负荷肥厚与高能磷酸盐减少相关 应对生理应激的储备，这是可逆的 肥大消退；4)肌球蛋白ATPase活性可逆性降低 是缩短和松弛速度减慢的基础 压力超负荷肥大是由转录和/或 β肌球蛋白重链的翻译改变；5)坐标 肌球蛋白轻链的转录和翻译改变 肌球蛋白ATPase活性和力学行为的调节作用 压力超负荷肥大和退行性改变；6)转录 胶原蛋白数量分布和类型的变化在很大程度上决定了 肥厚和肥厚的固有被动室特性 退行性心肌。

Ventricular hypertrophy is an important adaptive mechanism which accompanies systemic arterial hypertension. However, at some point in time, this compensatory process results in congestive heart failure. The major objectives of our research program, is to define the fundamental mechanical, biochemical and molecular biologic properties of pressure overload hypertrophy and hypertrophy regression in a unique model of gradual onset renal hypertension in the non-human primate (baboon). Parallel studies in a smaller mammal (guinea pig) are proposed to elucidate species differences, to facilitate development of analytic techniques, and to examine cardiac chamber mechanics of pressure overload hypertrophy in the isolated heart which is devoid of the influences of neurohumoral factors and ventricular vascular coupling. Using this approach, we propose to test the following specific hypotheses: 1) pressure overload hypertrophy is associated with unchanged systolic chamber elastance, load independent reduced velocities of ejection and filling and elevated passive chamber and muscle stiffness; 2) regression of pressure overload hypertrophy is characterized by normalization of velocities of ejection and filling and residually elevated cardiac muscle stiffness; 3) pressure overload hypertrophy is associated with diminished high-energy phosphate reserves in response to physiologic stress which is reversible upon hypertrophy regression; 4) reversibly reduced myosin ATPase activity underlies diminished velocities of shortening and relaxation during pressure overload hypertrophy and is caused by transcriptional and/or translational alterations in beta myosin heavy chains; 5) coordinate transcriptional and translational alteration of myosin light chains exert a modulatory role on myosin ATPase activity and mechanical behavior in pressure overload hypertrophy and regression; and 6) transcriptional alterations in collagen amount distribution and type largely determine intrinsic passive chamber properties of hypertrophied and hypertrophy regressed myocardium.