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

摘要 心力衰竭(HF)是导致发病率、死亡率和医疗费用上升的主要原因 弗吉尼亚州不成比例增加的心衰类型是射血分数保持不变的心衰。 (HFpEF)，通常由左心室(LV)压力超负荷(LVPO)引起。是…的基石 HFpEF是指左室舒张功能障碍和细胞外基质(ECM)重构，其中这些结构 变化并不是轻易就能逆转的。细胞外基质重塑的关键途径是转录后 由microRNAs(MiRs)调节。这个合作项目的指导性假设是 特定MIR配置文件中的特定和可量化的变化，这些变化调节关键的ECM过程，并可以 在HFpEF患者和HFpEF的大型动物模型中都发现，对运动有预测作用 HFpEF级数的响应和衰减及其对表型的机械引导 HFpEF心肌成纤维细胞的重编程综合项目成果包括 建立新的精确度更高的分子工具来检测发病和减弱 HFpEF的进展以及为患有这种疾病的退伍军人寻找新的治疗靶点 毁灭性的心力衰竭综合症。在本项目中，将使用LVPO诱导的HFpEF的大型动物模型 为了进行功能性(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MIR盒中的设定点变化 ECM/成纤维细胞激活过程导致难治性HFpEF，由持续性HFpEF定义 尽管去除了LVPO刺激，但仍有表型。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的miR信号的出现，进而 难治性HFpEF。这些研究将为开发新的诊断学提供基础 提供早期发现，并为新的治疗方向提供基础 高频脉冲射血恢复心肌可塑性。在这个项目中，指导假设是一个关键 在HFpEF的发生发展中，分子事件是由特定的转录后调控的丢失 调节ECM动态平衡和成纤维细胞激活的miRs盒，导致难治性 HFpEF的形式。在HFpEF的发展过程中整合标准化的锻炼方案将 防止miR转录后控制的这种丧失，减少ECM堆积和成纤维细胞 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.