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，其特征是呼吸困难，即使在低水平的劳累，全身疲劳， 和体液潴留，估计影响美国510万人。心力衰竭 射血分数保留（HFpEF）-其中心脏充分泵血到身体，但患者仍然 有可怕的症状-估计占所有心力衰竭病例的50%。HFpEF是一种令人烦恼的临床 诊断和预后评估仍然难以捉摸的问题。专家们认为， HFpEF的关键基础，这可归因于舒张期心肌硬度的增加。目前， 然而，没有临床技术用于测量左心室舒张心肌硬度。实际上 “心肌僵硬”的定义仍然很不明确。因此，研究 HFpEF的基础机制几乎不存在，如果没有 重大进展。本项目的目标是使用平衡材料稳定性（EMS）框架 将患者特定的临床MRI和LV压力数据耦合到心脏的计算模型中， 诊断舒张期心肌硬度的变化。核心假设是， 了解HFpEF中舒张功能障碍的机制将更敏感， 目前可用的方法。以下具体目标概述了我们的方法： 目的#1 -完善测量舒张期心肌硬度所需的高级自由呼吸MRI方法。到 准确估计局部舒张心肌僵硬系数，我们的EMS框架结合了高 分辨率解剖学，应变数据，LV压力，以及我们最近建立肌纤维方向图的工作， 可以使用心脏扩散张量MRI（cDTI）在体内测量。 目的#2 -在人体内建立舒张期心肌硬度评估框架。我们的工作将 建立一种可接受的临床方法，用于测量整体和局部舒张心肌硬度， 克服了与使用压力-容积环相关的限制。 目的#3 -在HFpEF患者的纵向研究中测量舒张期心肌硬度的变化。这 将建立EMS框架的诊断灵敏度，并与以下心脏MRI生物标志物进行比较： 增加的硬度，从而为HFpEF的一个关键的潜在原因提供了机制上的见解。