Myocardial Plasticity in Heart Failure with Preserved Ejection Fraction (HFpEF)

摘要 心力衰竭（HF）是美国心脏病患者发病率、死亡率和医疗保健费用不断上升的主要原因。 弗吉尼亚不成比例增加的HF类型是射血分数保留的HF （HFpEF），通常由左心室（LV）压力超负荷（LVPO）引起。的基石 HFpEF是LV舒张功能障碍和细胞外基质（ECM）重塑，其中这些结构性 变化不容易逆转。ECM重塑的关键途径是转录后 microRNAs（miRs）的作用。这项合作计划的指导假设是， 在特定miR谱中特异性和可量化的变化，其调节关键ECM过程， 在HFpEF患者和HFpEF的大型动物模型中鉴定， HFpEF进展的反应和衰减，并在机制上指导表型 HFpEF心肌成纤维细胞的重编程。综合项目成果包括 建立精确度更高的新的分子工具，以检测发病和减弱 HFpEF的进展以及为患有这种疾病的退伍军人确定新的治疗靶点 严重的心力衰竭综合征本项目将利用LVPO诱导的HFpEF大型动物模型 为了进行功能（LV局部心肌硬度）和运动研究以及miR 侧写指导性假设是，调节细胞增殖的miR盒中的设定点偏移， ECM/成纤维细胞活化过程导致难治性HFpEF，定义为持续性HFpEF 表型，尽管去除LVPO刺激。在一组平行的研究中，将证明， 标准化的运动方案将防止这种促纤维化miR信号的出现， 难治性HFpEF。这些研究将为开发新的诊断方法提供基础 以提供早期检测，并且还为针对糖尿病的新的治疗方向提供基础。 用HFpEF恢复心肌可塑性。在这个项目中，指导假设是， HFpEF发展中的分子事件是由一种特异性的转录后控制的丧失， 调节ECM稳态和成纤维细胞活化的miR盒，其导致难治性 HFpEF的形式。在HFpEF进展期间整合标准化运动方案将 防止这种miR转录后控制的丧失，减弱ECM积累和成纤维细胞 激活，从而防止难治性HFpEF表型的发展。

Abstract Heart failure (HF) is a leading cause of morbidity, mortality, and escalating health care costs within the VA. The type of HF that is increasing disproportionately is HF with a preserved ejection fraction (HFpEF), commonly caused by left ventricular (LV) pressure overload (LVPO). A cornerstone of HFpEF is LV diastolic dysfunction and extracellular matrix (ECM) remodeling, in which these structural changes are not readily reversible. A critical pathway for ECM remodeling is post-transcriptional regulation by the microRNAs (miRs). The guiding hypothesis of this collaborative program is that a specific and quantifiable shift in a specific miR profile, which regulate key ECM processes and can be identified in both HFpEF patients and a large animal model of HFpEF, is predictive for exercise response and attenuation of HFpEF progression and mechanistically directs phenotype reprogramming of HFpEF myocardial fibroblasts. The integrative project outcomes include establishing new molecular tools with improved precision to detect onset and attenuate the progression of HFpEF as well as identify novel therapeutic targets for Veterans suffering from this devastating HF syndrome. In this project, a large animal model of LVPO induced HFpEF will be utilized in order to perform functional (LV regional myocardial stiffness) and exercise studies as well as miR profiling. The guiding hypothesis is that a setpoint shift in a cassette of miRs that regulate the ECM/fibroblast activation process causes a refractory form of HFpEF, defined by a persistent HFpEF phenotype despite removal of the LVPO stimulus. In a parallel set of studies, it will be demonstrated that a standardized exercise regimen will prevent the emergence of this profibrotic miR signature and in turn refractory HFpEF. These studies will provide the foundation for the development of novel diagnostics to provide early detection and moreover provide the foundation for a novel therapeutic direction for the restoration of myocardial plasticity with HFpEF. In this project, the guiding hypothesis is that a key molecular event in the development of HFpEF is the loss of post-transcriptional control by a specific cassette of miRs that regulate ECM homeostasis and fibroblast activation, which results in a refractory form of HFpEF. Integrating a standardized exercise protocol during the progression of HFpEF will prevent this loss of miR post-transcriptional control, attenuate ECM accumulation and fibroblast activation, and thereby prevent the development of a refractory HFpEF phenotype.