Tropoelastin: an in vivo imaging marker of dysfunctional matrix turnover during abdominal aortic dilation
Résumé
Aims: Dysfunctional matrix turnover is present at sites of abdominal aortic aneurysm (AAA) and leads to the accumulation
of monomeric tropoelastin rather than cross-linked elastin. We used a gadolinium-based tropoelastin-specific magnetic
resonance contrast agent (Gd-TESMA) to test whether quantifying regional tropoelastin turnover correlates
with aortic expansion in a murine model. The binding of Gd-TESMA to excised human AAA was also assessed.
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Methods and results:
We utilized the angiotensin II (Ang II)-infused apolipoprotein E gene knockout (ApoE-/-) murine model of aortic dilation
and performed in vivo imaging of tropoelastin by administering Gd-TESMA followed by late gadolinium enhancement
(LGE) magnetic resonance imaging (MRI) and T1 mapping at 3 T, with subsequent ex vivo validation. In a
cross-sectional study (n = 66; control = 11, infused = 55) we found that Gd-TESMA enhanced MRI was elevated and
confined to dilated aortic segments (control: LGE=0.13 ± 0.04mm2, control R1= 1.1 ± 0.05 s-1 vs. dilated LGE
=1.0 ± 0.4mm2, dilated R1 =2.4 ± 0.9 s-1) and was greater in segments with medium (8.0 ± 3.8mm3) and large
(10.4 ± 4.1mm3) compared to small (3.6 ± 2.1mm3) vessel volume. Furthermore, a proof-of-principle longitudinal
study (n = 19) using Gd-TESMA enhanced MRI demonstrated a greater proportion of tropoelastin: elastin expression
in dilating compared to non-dilating aortas, which correlated with the rate of aortic expansion. Treatment with
pravastatin and aspirin (n = 10) did not reduce tropoelastin turnover (0.87 ± 0.3mm2 vs. 1.0 ± 0.44mm2) or aortic
dilation (4.86 ± 2.44mm3 vs. 4.0 ± 3.6mm3). Importantly, Gd-TESMA-enhanced MRI identified accumulation of tropoelastin
in excised human aneurysmal tissue (n = 4), which was confirmed histologically.
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Conclusion: Tropoelastin MRI identifies dysfunctional matrix remodelling that is specifically expressed in regions of aortic aneurysm
or dissection and correlates with the development and rate of aortic expansion. Thus, it may provide an additive
imaging marker to the serial assessment of luminal diameter for surveillance of patients at risk of or with established
aortopathy.