Serial evaluation of cardioprotective effects of exercise training in heart failure using cardiac diffusion tensor MRI

项目总结/摘要 心力衰竭（HF）占美国死亡人数的1/9，目前影响约600万人， 患病率为250，00 - 400，000，发病率为70，000 - 120，000。目前的治疗不能解决 潜在的功能性心肌丧失和不利的结构重塑。一种新的潜在治疗方法， HF是一种运动（有氧）疗法，已证明具有多种心脏保护特性， 逆转不利的结构重塑。然而，运动疗法的剂量仍然是一个挑战，由于每个 个体的固有差异和相应地，治疗的连续非侵入性监测将是 需要评估结构重塑的变化。此外，目前的非侵入性技术 用替代指标表征结构重塑，因此，对单一临床指标没有共识。 金本位如果没有监测和表征结构重塑程度的工具， 运动疗法在HF患者中的治疗潜力不能完全实现，代表未满足的需求 最终改善治疗。该项目旨在改善运动训练的治疗监测 通过心脏扩散张量揭示其对微结构重塑的影响， MRI（DT-MRI）。DT-MRI是一种独特的非侵入性技术，能够表征心肌纤维 定向和直接反映微观结构重塑。尽管取得了重大进展， 基本挑战限制了当前心脏DT-MRI方法稳健应用于 临床设置。在这个项目中，将开发一种创新的5分钟“按钮”DT-MRI方法， 克服了这样的局限性。我们还利用机构优势，进一步量化体内 DT-MRI在显示心肌微结构中使用新组织清除3D组织学。核心假设 解决这些主要的技术挑战将使心脏DT-MRI的临床翻译能够服务于 作为监测HF对微结构重塑的治疗效果的工具。这是通过扩展 先前开发的用于通过弥散加权MRI进行心肌纤维化检测的技术。的 拟议的项目旨在系统地开发一种创新和强大的临床DT-MRI方法 并在临床前环境中严格验证运动疗法对微结构重塑的影响， 从而为运动疗法的剂量优化奠定基础。

Project Summary / Abstract Heart failure (HF) is accounts for 1 in 9 deaths in the United States and currently affects ~6 million with a prevalence of 250,00-400,000 and incidence of 70,000-120,000. Current therapy does not address the underlying loss of functional heart muscle and adverse structural remodeling. One novel potential treatment of HF is exercise (aerobic) therapy that has demonstrated various cardioprotective properties to halt and potentially reverse adverse structural remodeling. However, dosing of exercise therapy remains a challenge due to each individual's inherent differences and consequentially, serial non-invasive monitoring of the therapy would be necessary to evaluate the change on structural remodeling. Furthermore, current non-invasive technologies characterize structural remodeling with surrogate measures and thus, there is no consensus on a single clinical gold-standard. Without a tool to monitor and characterize the degree of structural remodeling, the evaluation of the therapeutic potential of exercise therapy in HF patients cannot be fully realized representing an unmet need in ultimately improving therapy. The proposed project aims to improve the therapy monitoring of exercise training to cardioprotect against HF by revealing its effect on microstructural remodeling with cardiac diffusion tensor MRI (DT-MRI). DT-MRI is a unique, non-invasive technology capable of characterizing myocardial fiber orientation and directly reflecting microstructural remodeling. However, despite major advances, there are fundamental challenges that limit the capability of current cardiac DT-MRI methods to be applied robustly in a clinical setting. In this project, an innovative 5-min “push button” DT-MRI method will be developed that overcomes such limitations. We also leverage institutional strengths to further quantify the accuracy of in vivo DT-MRI in revealing myocardial microstructure using novel tissue cleared 3D histology. The central hypothesis is that addressing these major technical challenges will allow for clinical translation of cardiac DT-MRI to serve as a tool to monitor the therapeutic effects of HF on microstructural remodeling. This is achieved by extending previously developed technologies used for myocardial fibrosis detection with diffusion-weighted MRI. The proposed project is designed to systematically develop an innovative and robust clinical DT-MRI methodology and rigorously validate in a pre-clinical setting the effects of exercise therapy on the microstructural remodeling of HF thereby laying the groundwork for potential optimization of dosing exercise therapy.