A New Framework for Understanding the Mechanisms of Diastolic Dysfunction

理解舒张功能障碍机制的新框架

• 批准号: 9384617
• 负责人: Daniel B Ennis
• 金额: $ 75.62万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384617
• 关键词: 3D Print; Affect; American; Anatomy; Breathing; Cardiac; Clinical; Clinical Trials; Computer Simulation; Cone; Couples; Data; Decision Making; Diagnosis; Diagnostic; Diagnostic Sensitivity; Diastolic heart failure; Diffuse; Diffusion; Dyspnea; EFRAC; Elements; Equilibrium; Evaluation; Exertion; Exhibits; Failure; Fatigue; Fibrosis; Functional disorder; Heart; Heart failure; Human; Image; Impairment; Laws; Left; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Maps; Measures; Medical Imaging; Methods; Myocardial; Myocardial dysfunction; Patients; Play; Property; Public Health; Relaxation; Reproducibility; Resolution; Role; Shapes; Statistical Distributions; Stress; Symptoms; Syndrome; Techniques; Testing; Therapeutic; Uncertainty; United States; Ventricular; Work; base; blood pump; data modeling; exercise intolerance; extracellular; healthy volunteer; improved; in vivo; insight; longitudinal analysis; magnetic resonance imaging biomarker; new therapeutic target; pressure; prognostic; tool; virtual

PROJECT SUMMARY Heart failure is a clinical syndrome marked by breathlessness, even at low levels of exertion, general fatigue, and fluid retention that is estimated to affect 5.1 million people in the United States. Heart failure with preserved ejection fraction (HFpEF) – wherein the heart adequately pumps blood to the body, but patients still have terrible symptoms – is estimated to account for 50% of all heart failure cases. HFpEF is a vexing clinical problem for which diagnostic and prognostic evaluation remains elusive. Experts agree that impaired filling critically underlies HFpEF, which can be attributed to an increase in diastolic myocardial stiffness. Currently, however, no clinical technique exists for measuring left ventricular diastolic myocardial stiffness. In fact, the very definition of “myocardial stiffness” remains poorly established. Consequently, the ability to study the mechanisms that underlie HFpEF is virtually non-existent and limited therapeutic options will persist without significant advances. The objective of this project is to use an Equilibrium-Material-Stability (EMS) framework that couples patient-specific clinical MRI and LV pressure data in a computational model of the heart to diagnose changes in diastolic myocardial stiffness. The central hypothesis is that the new EMS framework for understanding the mechanisms of diastolic dysfunction in HFpEF will be more sensitive and outperform currently available approaches. The following specific aims outline our approach: AIM #1 – Refine advanced free-breathing MRI methods needed to measure diastolic myocardial stiffness. To accurately estimate regional diastolic myocardial stiffness coefficients our EMS framework incorporates high resolution anatomy, strain data, LV pressure, and our recent work establishing that myofiber orientation maps can be measured in vivo using cardiac diffusion tensor MRI (cDTI). AIM #2 – Validate our in vivo diastolic myocardial stiffness evaluation framework in humans. Our work will establish an acceptable clinical method for measuring global and regional diastolic myocardial stiffness that overcomes limitations associated with using pressure-volume loops. AIM #3 – Measure changes in diastolic myocardial stiffness in a longitudinal study of patients with HFpEF. This will establish the diagnostic sensitivity of the EMS framework with comparison to cardiac MRI biomarkers of increased stiffness, thereby providing mechanistic insight to one critical underlying cause of HFpEF.

项目摘要 心力衰竭是一种临床综合征，即使在低水平的劳累，一般疲劳，也是呼吸困难的标志 估计会影响美国510万人的液体保留率。心力衰竭 保留的射血分数（HFPEF） - 其中，心脏充分地将血液泵入体内，但患者仍在 具有可怕的症状 - 估计占所有心力​​衰竭病例的50％。 HFPEF是一个令人沮丧的临床 诊断和预后评估的问题仍然难以捉摸。专家认为填充受损 关键是HFPEF的基础，这可以归因于舒张压心肌刚度的增加。现在， 但是，没有用于测量左心室舒张心肌刚度的临床技术。实际上， 对“心肌僵硬”的定义仍然很差。因此，研究 HFPEF基础的机制几乎不存在，并且没有有限的治疗选择将持续存在 重大进展。该项目的目的是使用平衡 - 物质稳定性（EMS）框架 在心脏的计算模型中，将患者特异性的临床MRI和LV压力数据融合到 诊断性心肌僵硬的变化。中心假设是新的EMS框架 了解HFPEF中舒张功能障碍的机制将更加敏感和跑赢 当前可用的方法。以下具体目的概述了我们的方法： AIM＃1 - 精炼高级自由呼吸的MRI方法来测量舒张心肌刚度。到 准确估计的区域舒张心肌刚度系数我们的EMS框架包括高 分辨率解剖学，应变数据，LV压力以及我们最近的工作确定肌纤维取向图 可以使用心脏扩散张量MRI（CDTI）在体内测量。 AIM＃2 - 验证人类体内舒张性心肌僵硬评估框架。我们的工作将 建立一种可接受的临床方法，用于测量全球和区域舒张心肌僵硬度 克服与使用压力卷回路有关的限制。 AIM＃3 - 在HFPEF患者的纵向研究中，测量舒张心肌僵硬的变化。这 将建立EMS框架的诊断灵敏度，并与心脏MRI生物标志物进行比较 增加刚度，从而为HFPEF的一个关键根本原因提供了机械洞察力。