Molecular and functional MRI enables detection of cardiac fibrosis and evaluation of treatment response after chordin-like 1 gene therapy in myocardial infarction.

Abstract

Cardiac fibrosis (CF), characterised by accumulation of collagen and elastin, drives adverse cardiac remodelling and heart failure after myocardial infarction (MI). Currently, there are no non-invasive imaging methods to sensitively and directly assess CF and evaluate treatment response and no regenerative therapies for patients with MI. We hypothesised that functional and molecular magnetic resonance imaging (MRI) of collagen and elastin can detect and measure cardiac fibrosis and changes in response to Chordin-like 1 (Chrdl1) gene therapy after MI. Methods: MI was induced in mice by permanent occlusion of the coronary artery. Mice received adeno-associated vectors serotype 9 (AAV9) expressing Chrdl1 (AAV9-Chrdl1) or an empty polylinker (AAV9-Control) by either intramyocardial injection, at the time of MI, or intravenous injection at 1 week post-MI. Mice receiving AAV9-Chrdl1 intramyocardially were imaged in vivo at 4 weeks after treatment. Animals treated intravenously were imaged before treatment, at 1 week post-MI, and again at 3 weeks after treatment. In vivo cine MRI at 3 Tesla was used to assess cardiac function. Molecular MRI was used to measure CF and treatment response using late gadolinium enhancement and T1 mapping after administration of collagen and elastin specific gadolinium probes. The imaging data were complemented by tissue analyses. Results MRI showed that intramyocardial treatment with AAV9-Chrdl1, immediately after MI, improved the ejection fraction (EF) (+48%) and decreased collagen (-62.1%) and elastin (-80%) fibrosis after 4 weeks of treatment compared with mice receiving AAV9-Control. Systemic administration of AAV9-Chrdl1 at 1 week post-MI, when CF was established and fibrogenesis was ongoing, effectively improved the EF (+6.9%) and reduced collagen (-42.1%) and elastin (-14.8%) fibrosis after 3 weeks of treatment. Conversely, in mice receiving the AAV9-Control the EF worsened (-30.7%) and CF increased (collagen +22.2% and elastin +40.8%). Changes in CF measured by MRI were validated by histology. Conclusions: This study shows the power of functional and molecular MRI to detect the therapeutic efficacy of Chrdl1 on cardiac fibrosis. Chrdl1 treatment inhibited the development and reduced existing collagen and elastin fibrosis resulting in improved cardiac function. This non-invasive image-guided theranostic strategy has the potential to accelerate the development of effective anti-fibrotic therapies.