A Novel Magnetic Resonance Imaging Marker of Myocardial Fibrosis

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间质性重塑的显著特征，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相关，总胶原体积分数是纤维化的公认组织学标志物。我们的方法是基于定量的前和后对比心脏T1成像，和心肌分配系数的估计细胞外钆基造影剂（;Gd）。假设是：a）与健康对照相比，在具有压力超负荷心室和心肌肥大的患者中，细胞外容积分数显著升高，但低于缺血性心脏病患者的心肌瘢痕或替代纤维化; B）健康对照组和间质纤维化升高患者之间的细胞外容积分数的差异通过校正细胞膜水的影响变得更加显著交换; c）细胞外体积分数与总胶原体积分数相关，这将在间质纤维化的小鼠模型中通过INOS抑制进行测试;和d）;Gd可以通过造影剂团注后的动态成像快速和准确地确定，使用基于示踪剂动力学模型的分析以获得a ; Gd估计值与心肌血流量水平和毛细血管通透性表面积乘积无关。这项研究计划是基于MRI研究的患者诊断为主动脉瓣狭窄，没有冠心病史，谁将接受主动脉瓣置换术。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敏感的基于MRI的细胞外基质重塑和弥漫性间质纤维化的标志物，这可以减少对心脏组织活检的需求。我们预计，这种基于MRI的标记物的成功开发将对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、预后和治疗具有重要的健康益处。 公共卫生相关性：由于衰老或心脏病导致的心肌内的过度纤维化导致心室壁变硬、心脏泵功能下降、心室扩张，并最终导致心力衰竭。我们提出了一种新的方法来评估弥漫性心肌纤维化的磁共振成像的发展。

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.