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: 8010881
• 负责人: Peter N. Buttrick
• 金额: $ 75.1万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010881
• 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）： 充血性心力衰竭在西方社会是一种非常普遍的疾病，并且与大量的发病率和死亡率以及惊人的医疗保健费用相关。很难预测哪些患者会对治疗产生反应，哪些患者不会。对药物治疗无反应的患者亚组确实受益于器械治疗和/或考虑机械支持和/或移植，但通常在疾病进展或出现病态并发症后接受这些干预太晚。射血分数、功能容量和多变量心力衰竭“评分”已被用于指导临床决策，但对疾病进展的预测价值较差。我们的初步数据，来自正在进行的博格试验，建议的一般假设，分子谱结合蛋白质组学和基因组学分析的组织从子宫内膜异位症活检可以提供一个强大的预测工具，将允许早期识别患者谁会和不会响应药物治疗。因此，该C-TRIP提案的广泛目标是首先（第1阶段）使用已经临床表征并且已经收集了连续肌内膜活检材料的患者队列来验证我们的方法，然后（第2阶段）设计并执行多中心临床试验，该试验将使用该方法来前瞻性预测心力衰竭进展。我们的目标是将对心力衰竭的分子理解转化为临床工具，以指导这些患者的诊断，分类和管理。Aim 1将通过分析现有的72例扩张型心肌病患者的队列，开发一种预测算法，这些患者在开始β受体阻滞剂治疗前后进行了连续的肌内膜活检。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。目标2将建立必要的基础设施，对DCM患者进行多中心试验，以验证预测算法，目标是最大限度地减少这些患者的健康成本并优化他们的护理。 相关性（参见说明）：我们的目标是开发一种个性化的有针对性的患者护理方法，将来自肌内膜活检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，早期确定为无应答者的患者应接受针对预防心源性猝死或泵衰竭导致的死亡的干预。

项目成果

Targeted myocardial gene expression in failing hearts by RNA sequencing.

• DOI: 10.1186/s12967-016-1083-6
• 发表时间: 2016-11-25
• 期刊: Journal of translational medicine
• 影响因子: 7.4
• 作者: Dhar K;Moulton AM;Rome E;Qiu F;Kittrell J;Raichlin E;Zolty R;Um JY;Moulton MJ;Basma H;Anderson DR;Eudy JD;Lowes BD
• 通讯作者: Lowes BD