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. 2017 Feb 7;38(6):447-455.
doi: 10.1093/eurheartj/ehv677. Epub 2015 Dec 18.

Intravascular fibrin molecular imaging improves the detection of unhealed stents assessed by optical coherence tomography in vivo

Tetsuya Hara  1 , Giovanni J Ughi  2 , Jason R McCarthy  3 , S Sibel Erdem  3 , Adam Mauskapf  1 , Samantha C Lyon  2 , Ali M Fard  2 , Elazer R Edelman  4 , Guillermo J Tearney  5 , Farouc A Jaffer  6
Affiliations

Intravascular fibrin molecular imaging improves the detection of unhealed stents assessed by optical coherence tomography in vivo

Tetsuya Hara et al. Eur Heart J. .

Abstract

Aims: Fibrin deposition and absent endothelium characterize unhealed stents that are at heightened risk of stent thrombosis. Optical coherence tomography (OCT) is increasingly used for assessing stent tissue coverage as a measure of healed stents, but cannot precisely identify whether overlying tissue represents physiological neointima. Here we assessed and compared fibrin deposition and persistence on bare metal stent (BMS) and drug-eluting stent (DES) using near-infrared fluorescence (NIRF) molecular imaging in vivo, in combination with simultaneous OCT stent coverage.

Methods and results: Rabbits underwent implantation of one BMS and one DES without overlap in the infrarenal aorta (N = 20 3.5 × 12 mm). At Days 7 and/or 28, intravascular NIRF-OCT was performed following the injection of fibrin-targeted NIRF molecular imaging agent FTP11-CyAm7. Intravascular NIRF-OCT enabled high-resolution imaging of fibrin overlying stent struts in vivo, as validated by histopathology. Compared with BMS, DES showed greater fibrin deposition and fibrin persistence at Days 7 and 28 (P < 0.01 vs. BMS). Notably, for edge stent struts identified as covered by OCT on Day 7, 92.8 ± 9.5% of DES and 55.8 ± 23.6% of BMS struts were NIRF fibrin positive (P < 0.001). At Day 28, 18.6 ± 10.6% (DES) and 5.1 ± 8.7% (BMS) of OCT-covered struts remained fibrin positive (P < 0.001).

Conclusion: Intravascular NIRF fibrin molecular imaging improves the detection of unhealed stents, using clinically translatable technology that complements OCT. A sizeable percentage of struts deemed covered by OCT are actually covered by fibrin, particularly in DES, and therefore such stents might remain prothrombotic. These findings have implications for the specificity of standalone clinical OCT assessments of stent healing.

Keywords: Fibrin; Molecular imaging; Optical coherence tomography; Stent thrombosis.

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Figures

Figure 1
Figure 1
Intravascular near-infrared fluorescence-optical coherence tomography imaging of fibrin deposition on stents. Rabbits underwent implantation of a 3.5 mm diameter bare metal stent in the aorta. At Day 7, the fibrin molecular imaging agent FTP11-CyAm7 was i.v. injected, followed by near-infrared fluorescence-optical coherence tomography. (A) In vivo 2D near-infrared fluorescence map of stent (upper two rows) and corresponding ex vivo imaging after longitudinally opened (lower two rows). (B) Representative cross-sectional near-infrared fluorescence-optical coherence tomography images at the stent distal edge (i), middle (ii), and proximal edge (iii). (C and D) Histological sections of the proximal stent edge (dotted line in A (i) are shown. Near-infrared fluorescence signal of FTP11-CyAm7 (red) co-localized with fibrin (bright red in Carstairs' staining) and fibrin immunostaining. All scale bars = 1 mm.
Figure 2
Figure 2
Drug-eluting stent exhibit greater fibrin deposition than bare metal stent at Day 7 in vivo. Rabbits were implanted with a nonoverlapping bare metal stent and drug-eluting stent, and then imaged with near-infrared fluorescence-optical coherence tomography after FTP11-CyAm7 fibrin agent injection on Day 7. (A) In vivo 2D near-infrared fluorescence map with bare metal stent (left) and drug-eluting stent (right), corresponding (B) fluorescence microscopy after longitudinally opening stents, (C) fluorescence reflectance imaging and (D) fluorescence microscopy from the outside. Representative in vivo axial near-infrared fluorescence-optical coherence tomography images of (E) Day 7 bare metal stent and (F) Day 7 drug-eluting stent at the distal edge (arrowhead in A). Carstairs' stain (G and H) demonstrates that some areas of bare metal stent tissue coverage are fibrin-negative, but almost all areas of drug-eluting stent tissue coverage are fibrin-positive. (I) In vivo near-infrared fluorescence-fibrin signal from the proximal to distal stent edge of bare metal stent and drug-eluting stent (n = 7 BMS, n = 7 drug-eluting stent). FRI, fluorescence reflectance imaging; FITC, fluorescein isothiocyanate autofluorescence. Scale bars = 1 mm.
Figure 3
Figure 3
Fibrin deposition and persistence is higher in drug-eluting stent than bare metal stent. Rabbits underwent serial near-infrared fluorescence-optical coherence tomography fibrin imaging at Days 7 and 28 (n = 4 rabbits). (A) Representative 2D near-infrared fluorescence images at Day 7 (top row) and Day 28 (middle row). The lower graph shows the corresponding near-infrared fluorescence TBR signal across each stent. (B) Representative cross-sectional near-infrared fluorescence-optical coherence tomography images of a Day 28 healed drug-eluting stent (upper row) and a Day 28 unhealed drug-eluting stent (lower row). In the Day 28 unhealed case, struts are optical coherence tomography-covered but remain near-infrared fluorescence fibrin positive (e.g. 6–12 o'clock, yellow arrows). Co-registration was facilitated using side branches (white arrows). (C) The near-infrared fluorescence fibrin signal decreased from Days 7 to 28 in both bare metal stent and drug-eluting stent (P < 0.001), however, fibrin persistence remained higher in drug-eluting stent (P < 0.001). Scale bars = 1 mm.
Figure 4
Figure 4
Near-infrared fluorescence molecular imaging identifies optical coherence tomography-covered, but unhealed fibrin-rich struts in vivo. (A) The percentage of fibrin-rich neointimal tissue at stent edges was assessed by near-infrared fluorescence-optical coherence tomography. Drug-eluting stent showed significantly higher rate of fibrin-rich covering tissue than bare metal stent. (B) Near-infrared fluorescence-optical coherence tomography images of bare metal stent and drug-eluting stent at Day 7 revealed a diversity of fibrin-rich (yellow arrows) and fibrin-negative (white arrows) struts, even within a single cross-section. (C) Grayscale optical coherence tomography intensity was similar between bare metal stent and drug-eluting stent at both Days 7 and 28 timepoints (n = 4 stents in each group), despite higher fibrin signal in DES > BMS at both Days 7 and 28 at the stent edges. (D) Fibrin immunostaining and endothelial nitric oxide synthase immunostaining (magnified images at bottom) are shown. Most Day 7 drug-eluting stent edge tissue coverage is fibrin-rich and lacks endothelial nitric oxide synthase expression, in contradistinction to Day 7 bare metal stent. #P < 0.05 vs. respective Day 7.
Figure 5
Figure 5
Fibrin molecular near-infrared fluorescence-optical coherence tomography imaging assessment of the healing status of edge stent struts, by stent age (Day 7 or 28), and by stent type (bare metal stent or drug-eluting stent). At both Days 7 and 28, drug-eluting stent shows a higher percentage of unhealed stent struts compared with bare metal stent. At Day 7, 59.8% of bare metal stent struts and 40.7% of drug-eluting stent struts were classified as optical coherence tomography-covered (green + yellow groups) at stent edges, however, drug-eluting stent displayed only a small percentage of stent struts (3.7%) that were truly healed (near-infrared fluorescence-fibrin negative, optical coherence tomography-covered, green group), in contrast to bare metal stent demonstrating 28.1% of struts as healed. At Day 28, both bare metal stent and drug-eluting stent demonstrated substantially improved stent strut healing compared with their respective Day 7 timepoints, however 22.6% of Day 28 drug-eluting stent struts still remained unhealed. (B) Representative near-infrared fluorescence-optical coherence tomography and matched Carstairs' microscopy for the four groups. Arrow indicates thin fibrin layer over the strut.
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