A Novel Magnetic Resonance Imaging Marker of Myocardial Fibrosis

描述(申请人提供)：弥漫性间质心肌纤维化是细胞外基质不适应间质重塑的显著特征，并与心肌功能障碍和心力衰竭有关。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，胶原体积分数是公认的纤维化的组织学标志。我们的方法是基于对比剂前和对比剂后心脏T1的定量成像，以及对基于细胞外Gd的造影剂(；Gd)的心肌分割系数的估计。假设是：a)与健康对照组相比，压力超负荷的心室和心肌肥厚患者的细胞外体积分数显著升高，但低于心肌瘢痕或缺血性心脏病患者的替代纤维化；b)在校正跨细胞膜水交换的影响后，健康对照组和间质纤维化升高患者之间的细胞外体积分数的差异变得更加显著；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；以及d)；Gd可以在造影剂注射后通过动态成像快速而准确地测定，使用基于示踪剂动力学模型的分析来获得独立于心肌血流量水平和毛细血管通透性表面积乘积的Gd估计值。这项研究计划是基于对被诊断为主动脉瓣狭窄、以前没有冠状动脉疾病史的患者进行的MRI研究，这些患者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一种基于MRI的敏感的细胞外基质重塑和弥漫性间质纤维化的标记物，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、预后和治疗产生重要的健康益处。

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.