Tropoelastin: A novel marker for plaque progression and instability

Circ Cardiovasc Imaging. 2018 Aug;11(8):e007303. doi: 10.1161/CIRCIMAGING.117.007303. Epub 2018 Aug 20.

Abstract

Background: Elastolysis and ineffective elastogenesis favor the accumulation of tropoelastin, rather than cross-linked elastin, in atherosclerotic plaques. We developed gadolinium-labeled tropoelastin-specific magnetic resonance contrast agents (Gd-TESMAs) for tropoelastin imaging in animal models.

Methods and results: Two peptides, VVGSPSAQDEASPLS and YPDHVQYTHY were selected to target tropoelastin. In vitro binding, relaxivity, and biodistribution experiments enabled characterization of the probes and selecting the best candidate for in vivo MRI. MRI was performed in atherosclerotic apolipoprotein E-deficient (ApoE-/-) mice and New Zealand white rabbits with stable and rupture-prone plaques using Gd-TESMA. Additionally, human carotid endarterectomy specimens were imaged ex vivo. The VVGSPSAQDEASPLS-based probe discriminated between tropoelastin and cross-linked elastin (64±7% vs 1±2%, P=0.001), had high in vitro relaxivity in solution (r1-free=11.7±0.6mM-1s-1, r1-bound to tropoelastin = 44±1mM-1s-1) and favorable pharmacokinetics. In vivo mice vascular enhancement (4wks=0.13±0.007mm2, 8wks=0.22±0.01mm2, 12wks=0.33±0.01mm2, P<0.001) and R1 relaxation rate (4wks=0.90±0.01 s-1, 8wks=1.40±0.03 s-1, 12wks=1.87±0.04s-1, P<0.001) increased with atherosclerosis progression after Gd-TESMA injection. Conversely, statin-treated (0.13±0.01mm2, R1 =1.37±0.03s-1) and control (0.10±0.005mm2, R1 =0.87±0.05s-1) mice showed less enhancement. Rupture-prone rabbit plaques had higher R1 relaxation rate compared with stale plaques (R1=2.26±0.1s-1vs R1=1.43±0.02s-1, P=0.001), after administration of Gd-TESMA that allowed detection of rupture-prone plaques with high sensitivity (84.4%) and specificity (92.3%). Increased vascular R1 relaxation rate was observed in carotid endarterectomy plaques after soaking (R1pre= 1.1±0.26 s-1 vs R1post= 3.0±0.1s-1, P=0.01). Ex vivo analyses confirmed the MRI findings and showed uptake of the contrast agent to be specific for tropoelastin.

Conclusions: MRI of tropoelastin provides a novel biomarker for atherosclerotic plaque progression and instability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Diseases / diagnostic imaging*
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Atherosclerosis / diagnostic imaging*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Biomarkers / metabolism
  • Carotid Artery Diseases / diagnostic imaging*
  • Carotid Artery Diseases / metabolism
  • Carotid Artery Diseases / pathology
  • Contrast Media / administration & dosage*
  • Contrast Media / pharmacokinetics
  • Disease Models, Animal
  • Disease Progression
  • Heterocyclic Compounds / administration & dosage*
  • Heterocyclic Compounds / pharmacokinetics
  • Humans
  • Magnetic Resonance Imaging*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Molecular Imaging / methods*
  • Oligopeptides / administration & dosage*
  • Oligopeptides / pharmacokinetics
  • Organometallic Compounds / administration & dosage*
  • Organometallic Compounds / pharmacokinetics
  • Plaque, Atherosclerotic*
  • Predictive Value of Tests
  • Rabbits
  • Rupture, Spontaneous
  • Tropoelastin / metabolism*

Substances

  • Biomarkers
  • Contrast Media
  • Heterocyclic Compounds
  • Oligopeptides
  • Organometallic Compounds
  • Tropoelastin
  • gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate