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）：弥漫性间质性心肌纤维化是细胞外基质适应不良的间质重塑的一个突出特征，并且与心肌功能障碍和心力衰竭相关。我们建议使用对比增强磁共振成像（MRI）来测量细胞外体积分数，作为细胞外基质扩张的标志。细胞外基质的扩张总是与总胶原体积分数的增加有关，总胶原体积分数是公认的纤维化组织学标志。我们的方法基于定量对比前和对比后心脏 T1 成像，以及细胞外钆对比剂 (Gd) 的心肌分配系数的估计。假设是：a）与健康对照相比，心室压力超载和心肌肥厚的患者的细胞外体积分数显着升高，但低于缺血性心脏病患者的心肌疤痕或替代性纤维化； b) 通过校正跨细胞膜水交换的影响，健康对照和间质纤维化程度升高的患者之间的细胞外体积分数差异变得更加显着； c) 细胞外体积分数与总胶原体积分数相关，这将通过 INOS 抑制在小鼠间质纤维化模型中进行测试； d) 可以在造影剂推注后通过动态成像快速准确地确定 Gd，使用基于示踪动力学模型的分析来获得独立于心肌血流水平和毛细血管通透性表面积乘积的 Gd 估计值。该研究计划基于对被诊断为主动脉瓣狭窄且既往没有冠状动脉疾病史且将接受主动脉瓣置换术的患者进行的 MRI 研究。健康、年龄和性别匹配的志愿者将使我们能够确定纤维化相关 MRI 指数的正常范围。我们的长期目标是开发一种基于 MRI 的细胞外基质重塑和弥漫性间质纤维化的敏感标记，这可以减少对心脏组织活检的需要。我们预计，这种基于 MRI 的标记物的成功开发将为心肌纤维化进展可能导致心肌功能障碍并最终导致心力衰竭的患者的风险分层、预后和治疗带来重要的健康益处。 公众健康相关性：由于衰老或心脏病导致心肌内过度纤维化，导致心室壁僵硬、心脏泵功能下降、心室扩张，最终导致心力衰竭。我们建议开发一种利用磁共振成像评估心肌弥漫性纤维化的新方法。