MALADAPTIVE MECHANISMS AND THERAPEUTIC APPROACHES IN HEART FAILURE

已知许多心脏调节反应和基因程序与心脏的功能有关。 适应条件的压力，运动的心脏超负荷，但成为 当心脏衰竭时，不充分或不适应。 的总目标 项目4是研究这些转变的发病机制， 专注于心脏进展状态的3个重要前兆 失败：心肌细胞肥大，力-频率改变 与肾上腺素能刺激的关系及其对肾上腺素能刺激的反应， 灌注-收缩关系。 该项目的重点将是 评估完整循环条件下整个心脏的反应。 为此，定量微血管造影和超声心动图方法 现在可用于研究小鼠，大鼠和更大的心脏功能 心力衰竭的动物模型。 这些技术也将允许在 携带候选基因的转基因小鼠的体内表型表征 项目1开发的已知会影响肥大或 心肌功能障碍，如Ras和β-MHC突变体。 适应性或 还将研究心脏肥大的适应不良作用， 使用外源性给药的小鼠和大鼠实验性心力衰竭 生长因子（最初是胰岛素样生长因子-1 [IGF-1]）。 的 力-频率关系受损的功能意义 在离体肌肉从失败的人类心脏将进行研究， 完整的衰竭心脏，并与项目3合作， 电生理学和荧光研究在分离的细胞从这些 心脏对Ca 2+转运系统功能成分的影响， 特别是肌浆网和Na+/Ca 2+交换剂，将被 与mRNA和蛋白质以及超微结构的测量相关 通过Ca 2+转运蛋白的免疫染色进行分析（项目5）。 的 力-频率效应的反应性受损， 在正常条件下通过肾上腺素能刺激或运动增强， 将被调查，和潜在的治疗方法（包括β- 阻滞剂和卡托普利）用于改善受损的基础力-频率 在一个完整的心脏中， 失效模式 这种模式也将与荧光相结合 微球技术，也调查假设， 冠状动脉血流调节，特别是由于心率增加， 休息或肾上腺素能刺激期间，可能导致不利的灌注- 扩张型心功能不全的匹配收缩 心肌病 最后，一个临床组成部分将启动以下研究： 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。 这些在完整心脏中的研究应该提供关于 肥大的机制和功能效应，力-频率 哈特衰竭与心肌血流量的关系， 未来的研究，其临床意义和潜力， 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.