BS17 Molecular MRI of collagen III detects cardiac fibrosis and treatment response

Introduction Heart failure (HF) has reached epidemic proportions, affecting about 64 million people globally and is the main cause of death and disability[1]. Cardiac fibrosis, characterised by changes in type I (COL1) and III (COL3) collagen, drive HF[2,3]. After a myocardial infarction (MI), both COL1 and COL3 increase in the infarcted myocardium[4]. COL3 increases in the early stages of remodelling, and it is later replaced by COL1[5]. Non-invasive methods to selectively image and quantify collagen lacking or limited to COL1. Here, we developed and used an imaging probe that specifically binds to COL3 to image remodelling after MI and used it as a tool to detect enalapril, an ACE inhibitor commonly used to treat HF patients, treatment response. Method Previously we developed a COL3-binding probe and demonstrated the probes' high affinity and specificity[6]. Here, we labelled the probe with Gadolinium [Gd(III)] for in vivo CMR studies. In vivo functional and molecular CMR was performed using a 3 Tesla clinical scanner at days 10 and 21 post-MI (n=6/ group). The same mice were imaged the next day with a negative control probe, and again the next day with Gadovist (n=3) for comparison. The COL3-probe was used as a tool to monitor the effect of enalapril on myocardial fibrosis after MI. Mice were administered enalapril (20 mg/kg/day) immediately after MI and imaged at days 10 and 21 (n=6/ group). 2D short axis cine images covering the left ventricle (LV) were used to assess cardiac function parameters including ejection fraction (EF,%). T1-weighted 3D inversion recovery (IR) images were used to acquire Late Gadolinium Enhancement (LGE) images of the LV 60 min after intravenous injection of the probe (0.2 mmol/kg). T1 mapping was performed using a 2D Look-Locker sequence with an inversion pulse applied followed by the acquisition of 30 inversion recovery. Results Molecular CMR enabled selective profiling of the natural turnover of COL3 after MI with the signal increasing at day 10, when COL3 is elevated, and decreasing at day 21 as COL3 is replaced by COL1 (figure 1A). The imaging data were validated by histology showing co-localisation of the MRI signal with COL3 (green) at day 10 and reduction at day 21. Quantitative T1 maps discriminated between infarcted and remote myocardium with lower T1 values in the infarct and higher in the remote myocardium. No enhancement was observed using the control probe or the clinical agent Gadovist. Mice receiving enalapril showed similar enhancement at day 10 compared to untreated mice (figure 1B). However, at day 21 mice treated with enalapril showed a significantly higher LGE volume compared with untreated mice (figure 1B), indicating that enalapril may prolong the accumulation of COL3 (figure 1C). However, despite changes in the COL3 observed with molecular imaging, cardiac function was similar between the groups (figure 1D) suggesting that molecular changes may precede functional changes. Discussion We have developed the first probe suitable for molecular imaging of COL3. Combining this probe with quantitative CMR, enabled imaging of previously undetectable changes in COL3 remodelling after myocardial infarction and in response to treatment. This could address a considerable knowledge gap in the roles of COL3 in cardiac fibrosis. Our approach may provide a new tool to investigate the imaging, therapeutic and functional roles of COL3 in myocardial fibrosis non-invasively that remain elusive. Conflict of Interest None