VENTRICULAR REMODELING IN HEART FAILURE

申请人在以病人为导向的研究和临床研究者的培训方面有成功的记录。然而，他只有10%的时间被保护用于以患者为导向的临床研究，因为临床职责广泛且要求很高。如果获得资助，申请人将有50%的时间用于临床CHF研究和发起的新项目。更重要的是，该奖项将使申请人能够更专注于其资助的以患者为导向的充血性心力衰竭（CHF）左心室重构领域的研究项目，并获得将分子生物学的新发展转化为临床研究所需的新技能。目前，申请人是由NHLBI/VA合作研究项目资助的BEST （β受体阻滞剂评估生存试验）研究的超声心动图核心实验室的联合首席研究员和主任。这项BEST超声心动图亚研究的具体目的是：1)确定哪些超声心动图变量是CHF患者生存和血流动力学改善的独立预测因素；2)评估β受体阻滞剂治疗是否能改善左室重构；3)评估收缩储备是否能预测β受体阻滞剂治疗对左室重构的有利反应。这个奖项，如果授予，将允许在两年内完成这个项目。此外，研究者正在开发一种新的方法，通过对比超声心动图定量评估心肌血流储备比使用新的全氟碳填充微球。这种方法已经在狗身上得到了验证，最近在人类身上得到了资助。研究者的长期目标是利用该方法1)评估微血管功能在临床CHF和左室重构发展中的作用，2)评估特定CHF治疗对微血管功能的影响。这项工作计划在初步验证研究完成后，在本拨款提案的后期进行。最后，如果获得这笔资助，研究者将能够进行涉及慢性二尖瓣反流中左室重构分子信号的转化研究。该项目的长期目标是确定即将发生左室衰竭的患者进行早期手术干预，并为慢性二尖瓣反流和扩张型心肌病患者的左室偏心重塑制定治疗靶点。

The applicant has established a record of success in patient- oriented research and training of clinical investigators. However, only 10 percent of his time is protected for patient-oriented clinical research because of extensive and demanding clinical duties. If awarded, this grant will allow the applicant to devote 50 percent of his time performing funded clinical CHF studies and initiated novel projects. More importantly, this award will enable the applicant to more narrowly focus his funded patient-oriented research program in the area of left ventricular (LV) remodeling in congestive heart failure (CHF) and to acquire new skills need to translate new developments in molecular biology into clinical research. Currently, the applicant is co-principal investigator and Director of the Echocardiography Core Lab for the BEST (Beta-Blocker Evaluation of Survival Trial) Study sponsored by the NHLBI/VA Cooperative Studies Program. The specific aims of this BEST Echocardiography Substudy are to 1) determine which echocardiographic variables are independent predictors of survival and hemodynamic improvement in CHF, 2) assess whether beta-blocker therapy improves LV remodeling, and 3) evaluate whether contractile reserve predicts a favorable response of LV remodeling to beta-blocker therapy. This award, if grant, will allow completion of this project within two years. In addition, the investigator is developing a new method of quantitative assessment of myocardial blood flow reserve ratio by contrast echocardiography using new perfluorocarbon-filled microspheres. This method has been validated in dogs and its validation in humans has recently been funded. The long term goals of the investigator are to use this method to 1) assess the role of microvascular function in the development of clinical CHF and LV remodeling, and 2) evaluate the effect of specific CHF therapies on microvascular function. This work is planned for the later years of this grant proposal after initial validation studies have been completed. Finally, if awarded this grant will allow the investigator to conduct translational research involving the molecular signals for LV remodeling in chronic mitral regurgitation. The long range goals of this project are to identify patients in whom LV failure is imminent for early surgical intervention and to develop therapeutic targets for eccentric LV remodeling in chronic mitral regurgitation and dilated cardiomyopathies.