Myocardial tissue architecture in heart failure: implications on physiology and fitness

 描述(由申请人提供)：心力衰竭(HF)是美国心血管健康的主要威胁，每年有近55万新病例和超过370亿美元的成本。现有的心力衰竭严重程度的指标(例如，利钠肽、超声心动图、功能分级)并没有揭示出对以纤维化/肥大形式的细胞破坏的理解，这种破坏会导致有害的整体器官结构改变，称为“左室重构”。反过来，不良的左室重构与心功能受损、心肺适合性差、心衰存活率下降有关，使其成为心力衰竭的重要治疗靶点。组织表型(弥漫性间质纤维化、心肌细胞肥大、细胞凋亡)与心力衰竭的预后、进展和逆转左室重构有关。不幸的是，由于不能对心脏进行非侵袭性表型，患者体内对这些心肌组织表型的了解很少。本研究的目的是开发心力衰竭心肌重构的新的心脏磁共振(CMR)标志物，并探讨其与运动血流动力学和新的纤维化/肥厚的RNA生理学标志物的关系。在他的前期工作中，PI开发并验证了cmr技术，以量化患者和动物模型中的心肌细胞大小(通过细胞内水的寿命，τic)和间质纤维化(通过细胞外体积分数，ecv)。他还证明了CMR纤维化可能与新的RNA生物标志物有关，这些RNA生物标志物从机械上参与了左室重构中的纤维化。在此应用程序中， PI将确定多种人类心力衰竭亚型的左室重构的组织特征及其与循环细胞外RNA的关系(目标1)。他将把这些观察扩展到生理学，调查CMR组织标志物、健身和运动血流动力学指数之间的关系(目标2)。最后，他将使用连续的CMR研究慢性心力衰竭患者CMR组织特征与随着时间推移进行的左室重构的关系(目标3)。为了实现这些目标，他组建了一个独特的指导团队，成员包括CMR高级研究员(Michael Jerosch-Herold博士；Warren Manning医学博士)、基础科学家(Anthony Rosenzweig医学博士；Saumya Das医学博士)和一名HF生理学家(医学博士Gregory Lewis)。作为他的培训的一部分，PI将丰富他在人类CMR成像、RNA生物学和运动测试方面的专业知识，作为未来研究的平台，并将在翻译HF研究领域建立重要的持续合作。PI将通过哈佛大学公共卫生学院(公共卫生硕士学位)获得进一步的临床研究统计培训，并将成为他的家乡机构贝丝以色列女执事医疗中心HF研究任务的组成部分。PI的长期目标是在翻译成像-HF研究方面建立独立的研究生涯，专注于疾病的早期阶段进行靶向治疗。这个项目通过提供一种创新的、新颖的方法来评估心力衰竭的严重性，从而解决了NHLBI的任务，这种方法可能会改善对晚期心力衰竭的早期识别，对于这种情况，选择仍然有限。

 DESCRIPTION (provided by applicant): Heart failure (HF) represents a major threat to cardiovascular health in the United States, with nearly 550,000 new cases and over $37 billion in costs annually. Existing metrics of HF severity (e.g., natriuretic peptides, echocardiography, functional class) do not reveal an understanding of cellular disruption in the form of fibrosis/hypertrophy that lead to deleterious whole-organ structural changes termed "LV remodeling." In turn, adverse LV remodeling is associated with impaired cardiac performance, poorer cardiorespiratory fitness, and deceased survival in HF, making it an important therapeutic target in HF. Tissue phenotypes (diffuse interstitial fibrosis, myocyte hypertrophy, apoptosis) have been associated with prognosis, HF progression, and reverse LV remodeling in HF. Unfortunately, these myocardial tissue phenotypes are poorly understood in vivo in patients, owing to an inability to non-invasively phenotype the heart. The aim of this application is to develop novel cardiac magnetic resonance (CMR) markers of myocardial remodeling in HF and to investigate their association with exercise hemodynamics and novel RNA physiologic biomarkers of fibrosis/hypertrophy. In his preliminary work, the PI has developed and validated CMR techniques to quantify cardiomyocyte size (by intracellular lifetime of water, τic) and interstitial fibrosis (by extracellular volume fraction, ECV) in patients and animal models of hear disease. He has also demonstrated that CMR fibrosis may be associated with novel RNA biomarkers that are mechanistically involved in fibrosis in LV remodeling. In this application, the PI will identify a tissue signature of LV remodeling in multiple human HF subtypes and its association with circulating extracellular RNAs (Aim 1). He will extend these observations to physiology, investigating the relationship between CMR tissue markers, fitness and exercise hemodynamic indices (Aim 2). Finally, he will investigate the association of CMR tissue signatures with progressive LV remodeling over time in chronic HF using serial CMR (Aim 3). To accomplish these goals, he has assembled a unique mentoring team consisting of senior CMR investigators (Michael Jerosch-Herold, PhD; Warren Manning, MD), basic scientists (Anthony Rosenzweig, MD; Saumya Das, MD, PhD), and a HF physiologist (Gregory Lewis, MD). As part of his training, the PI will enrich his expertise in human CMR imaging, RNA biology, and exercise testing as a platform for future research, and will establish important ongoing collaborations in the field of translational HF research. The PI will obtain further statistical training in clinical research via the Harvard School of Public Health (MPH degree), and will be integral to the HF research mission of his home institution, the Beth Israel Deaconess Medical Center. The long-term goal of the PI is to establish an independent research career in translational imaging-HF research, focusing on early stages of disease for targeted therapy. This project addresses an NHLBI mission by affording an innovative, novel method for assessing HF severity that might improve early identification of advanced HF, for which there remain limited options.