Quantitative molecular imaging of cardiac fibrosis and response to treatment using a novel collagen III-specific MR imaging probe

Abstract Background Heart failure (HF) remains a major cause of morbidity and death affecting 64 million people globally[1]. Myocardial fibrosis, characterised by changes in type I (COL1) and III (COL3) collagen levels, may lead to HF [2,3]. Cardiac magnetic resonance (CMR) is a preferred method to detect fibrosis non-invasively, however it provides only indirect measures of fibrosis. Molecular imaging can directly visualise fibrosis, but current imaging probes target COL1. Purpose Here, we developed a COL3-specific probe and used molecular CMR imaging to directly quantify, previously undetectable, COL3 remodelling following myocardial infarction and to monitor treatment response. Methods Myocardial infarction (MI) was induced in mice by permanent ligation of the left anterior descending artery (LAD). Functional and molecular CMR images were acquired at days 10 and 21 post-MI in untreated and mice treated with Enalapril (20mg/kg/day) (n=6/group) using a 3T clinical MRI scanner. A subgroup of untreated mice was also imaged using a negative control probe and Gadovist (n=3). Cardiac function was assessed using 2D short-axis cine images of the left ventricle, and late gadolinium enhancement (LGE) images were obtained using T1-weighted 3D inversion recovery (IR) imaging. T1 mapping was performed using a 2D Look-Locker sequence with thirty inversion recovery images. Results Molecular CMR enabled selective profiling of the natural turnover of COL3 after MI with strong signal enhancement at day 10, and decreased enhancement at day 21 when COL3 is replaced by COL1 (Fig. 1A). Quantitative T1 maps discriminated between infarcted and remote myocardium with lower T1 values in the infarct and higher in the remote myocardium. Importantly, there was no enhancement using the scrambled probe or the clinical agent Gadovist. The imaging data were validated by histology (Fig.1B). Mice treated with Enalapril showed similar enhancement at day 10 compared to untreated mice (Fig. 2A). However, at day 21 mice treated with Enalapril showed higher signal enhancement compared to untreated mice, suggesting that Enalapril may prolong the presence of COL3 in the infarcted myocardium. Quantification of signal enhancement showed the increase in LGE volume and R1 relaxation rates within the infarcted myocardium at day 10, the subsequent decrease at day 21 and the prolongation of the COL3 signal at day 21 in enalapril treated mice (Fig.2B-C) Despite changes in cardiac fibrosis detected with molecular imaging, cardiac function was similar between the groups (Fig. 2D), suggesting that molecular change may precede functional changes. Conclusion(s) Quantitative molecular CMR imaging of COL3 enabled visualisation of changes in COL3 after MI and in response to treatment for the first time. This approach may provide insights into the role of COL3 in cardiac fibrosis and provide an non-invasive method to detect fibrosis early, stage fibrosis and monitor therapeutic response.