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

摘要 心力衰竭 (HF) 是导致发病率、死亡率和医疗费用不断上升的主要原因 弗吉尼亚州。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 是左心室舒张功能障碍和细胞外基质 (ECM) 重塑，其中这些结构 变化不容易逆转。 ECM 重塑的关键途径是转录后 受 microRNA (miR) 的调控。该合作计划的指导性假设是 特定 miR 图谱中的特定且可量化的变化，调节关键的 ECM 过程，并且可以 在 HFpEF 患者和大型 HFpEF 动物模型中均发现了这一点，可预测运动 HFpEF 进展的反应和减弱以及机械地指导表型 HFpEF 心肌成纤维细胞的重编程。综合项目成果包括 建立精度更高的新分子工具来检测发病并减弱 HFpEF 的进展以及为患有此病的退伍军人确定新的治疗靶点 毁灭性的心力衰竭综合症。在该项目中，将利用 LVPO 诱导的 HFpEF 的大型动物模型 以便进行功能性（左室局部心肌僵硬度）和运动研究以及 miR 分析。指导性假设是，调节 miR 盒的设定值发生变化。 ECM/成纤维细胞激活过程导致难治性 HFpEF，定义为持续性 HFpEF 尽管去除了 LVPO 刺激，但表型仍然存在。在一组平行研究中，将证明 标准化的运动方案将防止这种促纤维化 miR 特征的出现，进而 难治性 HFpEF。这些研究将为新型诊断方法的开发奠定基础 提供早期检测，并为新的治疗方向奠定基础 用 HFpEF 恢复心肌可塑性。在这个项目中，指导性假设是一个关键 HFpEF 发展中的分子事件是特定转录后控制的丧失 调节 ECM 稳态和成纤维细胞活化的 miR 盒，从而导致难治性 HFpEF 的形式。在 HFpEF 进展期间整合标准化运动方案将 防止 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.