A Novel Magnetic Resonance Imaging Marker of Myocardial Fibrosis

一种新型的心肌纤维化磁共振成像标志物

• 批准号: 8035495
• 负责人: Michael Jerosch-Herold
• 金额: $ 42.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035495
• 关键词: Age; Aging; Agreement; Anabolism; Animals; Aortic Valve Stenosis; Area; Benefits and Risks; Binding; Biopsy; Blood; Blood flow; Bolus Infusion; Capillary Permeability; Cardiac; Chronic; Cicatrix; Collagen; Contrast Media; Coronary; Coronary heart disease; Detection; Development; Diagnosis; Diffuse; Dilated Cardiomyopathy; Disease; Extracellular Matrix; Extracellular Space; Fibrosis; Functional disorder; Gadolinium; Gadolinium DTPA; Gadopentetate Dimeglumine; Gender; Goals; Health Benefit; Heart; Heart Diseases; Heart failure; Hematocrit procedure; Hypertrophic Cardiomyopathy; Hypertrophy; Image; Injection of therapeutic agent; Kinetics; Lead; Link; Magnetic Resonance Imaging; Measurement; Measures; Methods; Modeling; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardial tissue; Myocardium; Myopathy; Necrosis; Nitric Oxide; Nitric Oxide Synthase; Normal Range; Operative Surgical Procedures; Partition Coefficient; Patients; Placebos; Pump; Recording of previous events; Relative (related person); Relaxation; Research; Resolution; Review Literature; Risk Factors; Rodent Model; Schedule; Signal Transduction; Signs and Symptoms; Solid; Stratification; Surface; Surrogate Markers; Testing; Time; Tissue Sample; Tissues; Tracer; Ventricular; Water; Weight; Wild Type Mouse; aortic valve replacement; base; diabetic cardiomyopathy; extracellular; gadolinium oxide; healthy volunteer; heart function; hypertensive heart disease; indexing; inhibitor/antagonist; interstitial; mouse model; novel; novel strategies; outcome forecast; pressure; public health relevance; simulation; sudden cardiac death; volunteer

DESCRIPTION (provided by applicant): Diffuse interstitial myocardial fibrosis is a prominent feature of maladaptive interstitial remodeling of the extracellular matrix, and is associated with myocardial dysfunction and heart failure. We propose to use contrast-enhanced magnetic resonance imaging (MRI) to measure the extracellular volume fraction as a marker of expansion of the extracellular matrix. An expansion of the extracellular matrix is invariably linked to an increase of total collagen volume fraction, an accepted histological marker of fibrosis. Our approach is based on quantitative pre- and post-contrast cardiac T1 imaging, and the estimation of the myocardial partition coefficient for an extracellular gadolinium-based contrast agent (;Gd). The hypothesis' are: a) the extracellular volume fraction is significantly elevated in patients with pressure-overloaded ventricles and myocardial hypertrophy, compared to healthy controls, but lower than in myocardial scar or replacement fibrosis in patients with ischemic heart disease; b) differences of the extracellular volume fraction between healthy controls and patients with elevated interstitial fibrosis become more significant by correcting for the effects of the transcytolemmal water exchange; c) the extracellular volume fraction correlates with the total collagen volume fraction, which will be tested in a mouse model of interstitial fibrosis by INOS inhibition; and d) ;Gd can be determined rapidly and accurately by dynamic imaging after a contrast bolus injection, using a tracer kinetic model-based analysis to obtain a ;Gd estimate which is independent of the levels of myocardial blood flow and the capillary permeability surface area product. The research plan is based on MRI studies in patients diagnosed with aortic stenosis with no previous history of coronary disease, who will undergo aortic valve replacement. Healthy, age- and gender-matched volunteers will allow us to define the normal range of the fibrosis-related MRI index. Our long term goal is the development of a sensitive MRI-based marker of extracellular matrix remodeling and diffuse interstitial fibrosis which could reduce the need for cardiac tissue biopsies. We anticipate that the successful development of such an MRI-based marker will have important health benefits for risk stratification, prognosis and treatment in patients where the progression of myocardial fibrosis could lead to myocardial dysfunction, and ultimately heart failure. PUBLIC HEALTH RELEVANCE: Excessive fibrosis within the heart muscle as a result of aging, or of heart disease contributes to a stiffening of the ventricular walls, a decline of the pump-function of the heart, dilation of the ventricles, and ultimately also to heart failure. We propose the development of a novel method for assessment of diffuse fibrosis in the heart muscle with magnetic resonance imaging.

描述（由申请人提供）：弥漫性间质心肌纤维化是细胞外基质的不良适应性间质重塑的重要特征，并且与心肌功能障碍和心脏失败有关。我们建议使用对比增强的磁共振成像（MRI）来测量细胞外体积分数作为细胞外基质膨胀的标志。细胞外基质的膨胀与总胶原蛋白体积分数的增加始终是纤维化的组织学标记。我们的方法基于定量前和对比后心脏T1成像，以及基于细胞外illium的造影剂（; gd）的心肌分区系数的估计。假设是：a）与健康对照组相比，患有压力重量的心室和心肌肥大的患者的细胞外体积分数显着升高，但低于心肌疤痕或替代性纤维化的患有缺血性心脏病的患者； b）健康对照组与升高间隙纤维化患者之间细胞外体积分数的差异通过纠正跨胞菌水交换的影响而变得更加显着； c）细胞外体积分数与总胶原蛋白体积分数相关，将通过iNOS抑制在间质纤维化的小鼠模型中测试；和d）; gd可以在对比度注射后通过动态成像来快速，准确地确定，使用基于示踪动力学模型的分析获得A; GD估计值，GD估计值与心肌血流和毛细管渗透性表面积无关。该研究计划基于对诊断患有主动脉狭窄的患者的MRI研究，没有以前的冠状动脉疾病史，他们将接受主动脉瓣置换。健康，年龄和性别匹配的志愿者将使我们能够定义与纤维化相关的MRI指数的正常范围。我们的长期目标是开发基于敏感的MRI基于细胞外基质重塑和弥漫性间质纤维化的标记，这可能会减少对心脏组织活检的需求。我们预计，这种基于MRI的标记的成功发展将在风险分层，预后和治疗中具有重要的健康益处，而心肌纤维化进展可能导致心肌功能障碍并最终导致心脏衰竭。 公共卫生相关性：由于衰老或心脏病导致心肌内部纤维化过多，有助于心室壁的僵硬，心脏泵功能下降，心室扩张，最终导致心力衰竭。我们提出了一种新的方法，用于通过磁共振成像评估心肌中弥漫性纤维化的新方法。