BS44 Understanding the role of cardiac fibrosis in the development and treatment of heart failure using molecular imaging probes and novel therapeutics

Introduction

Cardiac fibrosis after myocardial infarction (MI) is a hallmark of the failing heart. Activation of myofibroblasts after MI can lead to excessive deposition of extracellular matrix (ECM) proteins and the development of a fibrotic scar rich in collagen and elastin, that can impair cardiac function. Currently, there is a clinical need for diagnosis and treatment of cardiac fibrosis. Chordin-like 1 (Chrdl1) is a TGF-β1 antagonist that was recently discovered to inhibit fibrosis. In this study, we used molecular MRI to non-invasively quantify cardiac fibrosis and monitor the antifibrotic effects of Chrdl1 in a mouse model of MI.

Methods

MI was induced in CD1 mice by permanent occlusion of the left anterior descending artery. The adeno-associated viral vectors serotype 9 (AAV9) expressing Chrdl1 (AAV9-Chrdl1) or an empty vector (AAV9-Control) were injected intramyocardially at the border region of the infarct at the time of ligation. In vivo MRI was performed at a clinical 3 Tesla scanner at 4 weeks post-MI. 2D cine scans were used to assess cardiac function. Fibrosis was quantified using collagen (Gd-EP3533) and elastin (Gd-ESMA) specific contrast agents. Late gadolinium enhancement (LGE) was assessed using a 3D gradient echo inversion recovery sequence. LGE size was quantified as a percentage of LGE volume over myocardial volume. For T1 mapping, a 2D Look-Locker sequence was used with an inversion pulse followed by the acquisition of 30 inversion recovery images. The relaxation rate (R1, s-1) was calculated as 1/T1.

Results

Cine MRI showed that mice treated with AAV9-Chrdl1 had significantly lower end-diastolic volume and higher ejection fraction compared with the AAV9-Control group (figure 1A-C). Molecular MRI using the collagen and elastin agents showed selective enhancement of the infarcted myocardium (figure 1A). Animals treated with AAV9-Chrdl1 had significantly lower LGE size (%) compared to the AAV9-Control group for both agents (figure 2A-B). Quantitative T1 mapping showed significantly higher R1 values in the infarcted compared to the remote myocardium in the AAV9-Control group but not the AAV9-Chrdl1 group. Importantly, the R1 of the infarct was significantly lower in mice treated with Chrdl1 compared to the AAV9-Control group for both contrast agents (AAV9-Chrdl1 R1collagen= 1.54 s-1 vs AAV9-Control R1collagen= 2.34 s-1 ; AAV9-Chrdl1 R1elastin= 1.57 s-1 vs AAV9-Control R1elastin= 2.02 s-1). Overall, these data suggest that Chrdl1 treatment preserved cardiac function and reduced fibrosis after MI.

Discussion

Molecular MRI of collagen and elastin enables the selective detection and quantification of cardiac fibrosis in vivo. Using this imaging modality, we show that Chrdl1 preserved cardiac function and reduced cardiac fibrosis in vivo. Together these findings show that molecular MRI is a promising tool to diagnose the extent of cardiac fibrosis and non-invasively assess the antifibrotic effects of novel therapies.

Acknowledgments

This work was supported by the King’s BHF Centre of Research Excellence RE/18/2/34213 and PG/2019/34897.

Disclosure

Prof. Mauro Giacca is founder, equity holder and consultant of Forcefield Therapeutics, which is developing Chrdl1 as a treatment for myocardial infarction. I and the other authors have no financial interest or relationship to disclose regarding the subject matter of this presentation.

References

Ruozi G, et al. Cardioprotective factors against myocardial infarction selected in vivo from an AAV secretome library. Science Translational Medicine 2022;14(660). Helm P, et al. Postinfarction myocardial scarring in mice: molecular MR imaging with use of a collagen-targeting contrast agent. Radiology 2008;247(3). Ramos I, et al. Simultaneous assessment of cardiac inflammation and extracellular matrix remodeling after myocardial infarction. Circulation. Cardiovascular Imaging, 2018;11(11).

Conflict of Interest

N/A