Using Molecular Pathology to Predict Response in Heart Failure

利用分子病理学预测心力衰竭的反应

• 批准号: 7867102
• 负责人: Peter N. Buttrick
• 金额: $ 74.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867102
• 关键词: Activities of Daily Living; Algorithms; Biological Assay; Biological Markers; Biopsy; Caring; Cessation of life; Classification; Clinical; Clinical Trials; Complication; Congestive Heart Failure; Coupled; Data; Devices; Diagnosis; Dilated Cardiomyopathy; Disease; Disease Progression; EFRAC; Early identification; Failure; Genomics; Goals; Health Care Costs; Heart failure; Instruction; Intervention; Mechanics; Messenger RNA; Methodology; MicroRNAs; Molecular; Molecular Profiling; Morbidity - disease rate; Patient Care; Patients; Pharmacotherapy; Phase; Predictive Value; Proteins; Proteomics; Pump; Research Infrastructure; Societies; Tissues; Translating; Transplantation; base; cohort; design; molecular pathology; mortality; predictive modeling; prevent; response; sudden cardiac death; tool

DESCRIPTION (provided by applicant): Congestive heart failure is an enormously prevalent disease in Western society and is associated with substantial morbidity and mortality as well as with staggering health care costs. It is difficult to predict which patients will and will not respond to therapy. The subset of patients who don't respond to pharmacotherapy truly benefit from device therapy and/or consideration of mechanical support and/or transplant but often receive these interventions too late, after their disease has progressed or they have developed a morbid complication. Ejection fraction, functional capacity and multivariate heart failure "scores" have been utilized to guide clinical decisions, but have poor predictive values for disease progression. Our preliminary data, derived from the on-going BORG trial, suggest the general hypothesis that molecular profiling coupled with proteomic and genomic analyses of tissue obtained from an endomyocardial biopsy can offer a robust predictive tool that will allow for the early identification of patients who will and will not respond to pharmacotherapy. Therefore the broad goals of this C-TRIP proposal are first (Phase 1) to validate our methodology using this patient cohort that has already been clinically characterized and from whom serial endomyocardial biopsy material has already been collected and then subsequently (Phase 2) to design and execute a multicenter clinical trial that will use this methodology to prospectively predict heart failure progression. Our goal is to translate a molecular understanding of heart failure into clinical tools which can guide the diagnosis, classification, and management of these patients. Aim1 will develop a predictive algorithm from the analysis of an existing cohort of 72 patients with dilated cardiomyopathy who have undergone serial endomyocardial biopsies before and after initiation of betablocker therapy. This will be based on: A) mRNA profiling B) miRNA array data and C) quantitative proteomic assays targeting protein changes. Aim 2 will establish the infrastructure necessary to conduct a multi-center trial of patients with DCM in order to validate the predictive algorithm, with the goal of minimizing the health costs incurred by these patients and optimizing their care. RELEVANCE (See instructions): Our goal is to develop a personalized targeted approach to patient care incorporating molecular biomarkers from endomyocardial biopsies into a predictive model for heart failure patients. We believe patients identified early as non-responders should receive intervention targeted against preventing sudden cardiac death or death due to pump failure.

描述（由申请人提供）： 充血性心力衰竭是西方社会中极为普遍的疾病，与大量的发病率和死亡率以及惊人的医疗费用有关。很难预测哪些患者会并且不会对治疗做出反应。对药物治疗不反应的患者的子集真正受益于设备治疗和/或考虑机械支持和/或移植的患者，但经常在患病发生后，经常接受这些干预措施过度，或者他们患有病态并发症。射血分数，功能能力和多元心力衰竭“得分”已用于指导临床决策，但疾病进展的预测值较差。我们的初步数据是从正在进行的BORG试验中得出的，这表明总体假设是，分子分析以及从内膜活检获得的组织的蛋白质组学和基因组分析结合，可以提供一个可靠的预测工具，可以为患者的早期识别而无法对药物治疗做出反应。因此，首先，该C-Trip提案的广泛目标是使用已经在临床上表征的该患者队列来验证我们的方法，并且已经收集了连续的心内膜活检材料，然后随后（2阶段）（第2阶段）设计和执行多中心临床试验，该方法将使用此方法来预测心脏失败的进展。我们的目标是将对心力衰竭的分子理解转化为可以指导这些患者诊断，分类和管理的临床工具。 AIM1将通过分析72例膨胀心肌病患者的人群来发展一种预测算法，这些患者在开始Betablocker治疗之前和之后接受了连续的内膜活检。这将基于：a）mRNA分析b）miRNA阵列数据和c）靶向蛋白质变化的定量蛋白质组学测定。 AIM 2将建立对DCM患者进行多中心试验所需的基础设施，以验证预测算法，目的是最大程度地减少这些患者产生的健康成本并优化其护理。 相关性（请参阅说明）：我们的目标是开发一种个性化的靶向方法，以将内膜活检中的分子生物标志物纳入心力衰竭患者的预测模型。我们认为，早期确定为无反应者的患者应接受针对防止泵衰竭引起的心脏死亡或死亡的干预措施。