Targeted Imaging of Fibrosis in the Left Atrium

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.