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。 这两种情况在老年人中都很常见，并与严重的发病率和死亡率有关。这 该提案解决了对非侵入性方法表征心房纤维化的未得到满足的诊断需求 心房纤维化的标志性病理--1型胶原的非侵入性分子成像。假设：我们 假设胶原结合的Gd螯合物将定位于纤维化的心房组织，从而使 心房纤维化的靶向分子成像要有很高的准确度。初步数据： 胶原蛋白医学公司的专有探针CM-101对1型胶原的亲和力和特异性良好 已经成立了。我们的初步疗效数据已经证实，CM-101可以量化大鼠的纤维化负担 慢性肝病胆管结扎模型。此外，CM-101增强了T1和 犬心肌梗死模型中的信号强度与左侧心肌纤维化的负担有关 脑室。在这里，我们第一次使用该试剂对猪的左房纤维化模型进行成像。 房颤的症状。具体目标：在此快速通道提案的第一阶段，具体目标1，我们的目标是建立 与非靶向对照相比，CM-101在心房纤维化区特异性聚集 它可以在体内用T1加权序列进行成像。猪局灶性左房纤维化模型的建立 将使用射频消融导管。过渡到阶段2的门控决策标准是 基于组织特异性与非靶向对照和活体成像的定量评估。同相 2，赠款的具体目标2，我们将演示CM-101增强MRI量化斑块和 在猪心房颤动模型中出现弥漫性左房纤维化，并将胶原靶向制剂与 目前的金标准是使用非靶向试剂(Gd-DOTA)的晚期Gd增强(LGE)。 总体影响：我们预计CM-101的针对性和特殊性将产生更多 比使用非靶向螯合物的LGE更准确的数据，这是目前的黄金标准。总而言之，在 这些研究将支持IND的应用，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.