MALADAPTIVE MECHANISMS AND THERAPEUTIC APPROACHES IN HEART FAILURE

许多心脏调节反应和基因程序是已知的 适应应激条件，运动心脏超负荷却变得 当心脏衰竭时不充分或不适应。的总体目标 项目4是研究这些转变的发病机制， 关注心脏进行性状态的三个重要前兆 衰竭：心肌细胞肥大，作用力频率改变 肾上腺素能刺激的关系及其在心肌中的反应 灌流-收缩关系。这个项目的重点将放在 在完整的循环条件下评估整个心脏的反应。 为此，定量微血管造影术和超声心动图方法 现在可用于研究小鼠、大鼠和更大鼠的心脏功能 心力衰竭的动物模型。这些技术还将允许 携带候选基因转基因小鼠的活体表型特征 由项目1开发的已知影响肥大或 心肌功能障碍，如RAS和β-MHC突变。自适应或 心肌肥大的适应不良作用也将在 外源性给药对小鼠和大鼠实验性心力衰竭的影响 生长因子(最初是胰岛素样生长因子-1)。这个 已报道的力频关系受损的功能意义 将在人体心脏衰竭的分离肌肉中进行研究 完好无损的失败之心，并与项目3合作 这些细胞的电生理和荧光研究 心脏上的钙离子转运系统的功能组件， 特别是肌浆网和钠/钙交换器， 与信使核糖核酸、蛋白质和超微结构测定相关 钙离子转运蛋白免疫染色分析(项目5)。这个 作用力-频率效应的反应性受损，这是明显的 在正常情况下通过肾上腺素能刺激或锻炼来增强， 将进行研究，以及潜在的治疗方法(包括Beta- 阻滞剂和卡托普利)用于改善受损的基础力量频率 关系和肾上腺素能反应将在一颗完整的心脏中被探索 故障模型。这样的模型也将与荧光相结合 微球技术也调查了损伤的假说 冠脉血流调节，特别是由于心率增加 休息或在肾上腺素能刺激时，可能会导致不良的血流灌注- 扩张型心脏收缩配对伴心功能损害 心肌病。最后，一个临床部分将启动关于 大鼠力-频关系及其对肾上腺素能刺激的反应 扩张型心肌病患者。 这些对完整心脏的研究应该会提供关于 力频肥大的机制及功能效应 HART衰竭与心肌血流量的关系，为临床治疗HART衰竭奠定基础 未来对其临床意义和治疗潜力的研究 治疗性修改。

A number of cardiac regulatory responses and gene programs are known to be adaptive in conditions of stress, exercise of cardiac overload but become inadequate or maladaptive when the heart fails. The overall goals of Project 4 are to investigate the pathogenesis of these transitions, focusing on 3 important precursors of the progressive state of heart failure: myocardial cell hypertrophy, alterations in force-frequency relations and their response to adrenergic stimulation, and in myocardial perfusion-contraction relations. The emphasis in this project will be on assessing responses in the whole heart under intact circulatory conditions. To this end, quantitative microangiographic and echocardiographic methods are now available for studying cardiac function in murine, rat and larger animal models of heart failure. These techniques also will allow the in vivo phenotypic characterization of transgenic mice harboring candidate genes developed by project 1 which are known to influence hypertrophy or myocardial dysfunction, such as Ras and beta-MHC mutants. The adaptive or maladaptive role of cardiac hypertrophy will also be studied in experimental heart failure in mice and rats using exogenous administration of growth factors (initially insulin-like growth factor-1 [IGF-1]). The functional significance of impaired force-frequency (FF) relations reported in isolated muscle from failing human hearts will be investigated in the intact failing heart, and in collaboration with Project 3 electrophysiologic and fluorescence studies in isolated cells from these hearts on the functional components of the Ca2+ transport system, particularly the sarcoplasmic reticulum and the Na+/Ca2+ exchanger, will be correlated with measurements of mRNA and proteins and ultrastructural analysis by immunostaining of Ca2+ transport proteins (Project 5). The impaired responsiveness of force-frequency effects, which is markedly enhanced by adrenergic stimulation or exercise under normal conditions, will be investigated, and potential therapeutic approaches (including beta- blockade, and captopril) for improving impaired basal force-frequency relations and adrenergic responsiveness will be explored in an intact heart failure model. Such models also will be combined with fluorescent microsphere technology to also investigate the hypothesis that impaired coronary blood flow regulation, particularly due to increased heart rate at rest or during adrenergic stimulation, can lead to unfavorable perfusion- contraction matching with impaired cardiac function in dilated cardiomyopathy. Finally, a clinical component will initiate studies on force-frequency relations and their response to adrenergic stimulation in patients with dilated cardiomyopathy. These investigation in the intact heart should provide new information on the mechanisms and functional effects of hypertrophy, force-frequency relations and myocardial blood flow in hart failure, laying the basis for future investigations on their clinical significance and potential for therapeutic modification.