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550，000例新发病例和超过370亿美元的费用。HF严重程度的现有度量（例如，利钠肽，超声心动图，功能分类）没有揭示对纤维化/肥大形式的细胞破坏的理解，纤维化/肥大导致称为“LV重构”的有害的整个器官结构变化。反过来，不利的LV重构与心脏功能受损、心肺适应性较差和HF生存率下降相关，使其成为HF的重要治疗靶点。组织表型（弥漫性间质纤维化、肌细胞肥大、细胞凋亡）与HF的预后、HF进展和逆转LV重塑相关。不幸的是，这些心肌组织表型在患者体内了解甚少，这是由于无法非侵入性表型的心脏。本申请的目的是开发HF心肌重塑的新型心脏磁共振（CMR）标志物，并研究其与运动血流动力学和纤维化/肥大的新型RNA生理生物标志物的相关性。在他的初步工作中，PI开发并验证了CMR技术，以量化心脏疾病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（通过细胞外容积分数，ECV）。他还证明CMR纤维化可能与新的RNA生物标志物相关，这些生物标志物在机制上参与了LV重塑中的纤维化。在本申请中， PI将鉴定多种人HF亚型中LV重塑的组织特征及其与循环细胞外RNA的相关性（目的1）。他将这些观察扩展到生理学，研究CMR组织标志物，健身和运动血液动力学指标之间的关系（目标2）。最后，他将使用系列CMR研究CMR组织特征与慢性HF中随时间推移进行性LV重构的相关性（目标3）。为了实现这些目标，他组建了一个独特的指导团队，由资深CMR研究人员（Michael Jerosch-Herold，PhD; Warren Manning，MD）、基础科学家（Anthony Rosenzweig，MD; Saumya Das，MD，PhD）和HF生理学家（Gregory刘易斯，MD）组成。作为培训的一部分，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，并将在转化HF研究领域建立重要的持续合作。PI将通过哈佛公共卫生学院（MPH学位）获得临床研究的进一步统计培训，并将成为其所在机构Beth Israel Deaconess Medical Center的HF研究使命的组成部分。PI的长期目标是在转化成像-HF研究中建立独立的研究生涯，专注于靶向治疗的疾病早期阶段。该项目通过提供一种评估HF严重程度的创新、新颖方法来解决NHLBI使命，该方法可能改善晚期HF的早期识别，而晚期HF的选择仍然有限。

 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.