Targeted Imaging of Fibrosis in the Left Atrium

摘要 意义：心房纤维化在房颤（AF）和心力衰竭的发展中起着核心作用， 这是老年人的常见病症，并与显著的发病率和死亡率相关。这 提案通过以下方式解决了对非侵入性方法表征心房纤维化的未满足的诊断需求 1型胶原蛋白的非侵入性分子成像，这是心房纤维化的标志性病理学。假设：我们 假设胶原结合钆螯合物将定位在纤维化心房组织中，从而使得 心房纤维化的靶向分子成像将以高度的准确性进行。初步数据： Collagen Medical的专有探针CM-101对1型胶原蛋白的亲和力和特异性良好， 确立了习我们的初步疗效数据已经确定，CM-101可以量化大鼠中的纤维化负荷。 慢性肝病胆管结扎模型（BDL）。此外，CM-101增强了T1和T2的差异。 犬心肌梗死模型中的信号强度与左心室纤维化负荷相关 脑室在这里，我们首次提出使用代理成像左心房纤维化使用猪模型 房颤的症状具体目标：在本快速通道提案的第1阶段，具体目标1中，我们旨在建立 与非靶向对照相比，CM-101特异性地在心房纤维化区域中积累， 它可以在体内用T1加权序列成像。建立猪局灶性左心房纤维化模型 将使用射频消融导管。过渡到第2阶段的选通决策标准为 基于组织特异性与非靶向对照的定量评估和体内成像。同相 2，具体目标2的赠款，我们将证明CM-101增强MRI量化斑片状和 弥漫性左心房纤维化，并将胶原靶向剂与 目前的金标准，晚期钆增强（LGE）使用非靶向剂（Gd-DOTA）。 总体影响：我们预计CM-101的针对性和特异性将产生更多的 准确的数据比LGE使用非靶向螯合物，目前的黄金标准。总的来说， 这些研究将支持IND申请并加速转化为临床领域。

Abstract Significance: Atrial fibrosis plays a central role in the development of atrial fibrillation (AF) and heart failure, which are both common conditions in the elderly and associated with significant morbidity and mortality. This proposal addresses an unmet diagnostic need for non-invasive methods to characterize atrial fibrosis through non-invasive molecular imaging of type 1 collagen, the hallmark pathology of atrial fibrosis. Hypothesis: We hypothesize that a collagen-binding gadolinium chelate will localize in fibrotic atrial tissue, thus enabling targeted molecular imaging of atrial fibrosis to be performed with a high degree of accuracy. Preliminary data: The affinity and specificity of Collagen Medical’s proprietary probe CM-101 for type 1 collagen are well established. Our preliminary efficacy data have established that CM-101 can quantify fibrosis burden in a rat bile duct ligation model (BDL) of chronic liver disease. Additionally, CM-101 enhanced differences in T1 and signal intensity in a canine myocardial infarct model were shown to be related to the fibrosis burden in the left ventricle. Here, for the first time, we propose to use the agent to image left atrial fibrosis using a porcine model of atrial fibrillation. Specific Aims: In Phase 1, Specific Aim 1, of this Fast Track proposal we aim to establish that CM-101 specifically accumulates in regions of atrial fibrosis as compared with a non-targeted control and that it can be imaged in vivo with T1 weighted sequences. A porcine model of focal left atrial fibrosis created using radiofrequency ablation catheters will be used. The gating decision criteria for a transition to Phase 2 are based on quantitative assessment of tissue specificity vs. non-targeted control and in vivo imaging. In Phase 2, Specific Aim 2 of the grant, we will demonstrate the ability of CM-101 enhanced MRI to quantify patchy and diffuse left atrial fibrosis in a porcine model of atrial fibrillation and will compare the collagen targeted agent to the current gold standard, late gadolinium enhancement (LGE) using the non-targeted agent (Gd-DOTA). Overall Impact: We anticipate that the targeted and specific nature of CM-101 will produce significantly more accurate data than LGE using non-targeted chelates, the current gold standard. Together, data obtained in these studies will support an IND application and accelerate translation into the clinical realm.