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Intravascular optical frequency-domain imaging (OFDI), a second-generation optical coherence tomography (OCT) technology, enables imaging of the three-dimensional (3D) microstructure of the vessel wall following a short and nonocclusive clear liquid flush. Although 3D vascular visualization provides a greater appreciation of the vessel wall and intraluminal structures, a longitudinal imaging pitch that is several times bigger than the optical imaging resolution of the system has limited true high-resolution 3D imaging, mainly due to the slow scanning speed of previous imaging catheters. Here, we demonstrate high frame-rate intravascular OFDI in vivo, acquiring images at a rate of 350 frames per second. A custom-built, high-speed, and high-precision fiber-optic rotary junction provided uniform and high-speed beam scanning through a custom-made imaging catheter with an outer diameter of 0.87 mm. A 47-mm-long rabbit aorta was imaged in 3.7 seconds after a short contrast agent flush. The longitudinal imaging pitch was 34 μm, comparable to the transverse imaging resolution of the system. Three-dimensional volume-rendering showed greatly enhanced visualization of tissue microstructure and stent struts relative to what is provided by conventional intravascular imaging speeds.

Introduction:Fluorescence lifetime imaging (FLIm) is a novel approach allowing biochemical characterization of atherosclerotic plaque without contrast agent. However, advanced multispectral FLIm system produces massive data throughput making image analysis challenging. This study sought to investigate whether machine learning (ML) can be applied to intravascular OCT-FLIm for automated characterization of high-risk coronary plaque.Methods and Results:We built a fully-integrated OCT-FLIm system allowing high-resolution OCT and multispectral FLIm acquisition, and FLIm microscopy enabling lifetime imaging of histologic sections. Accelerated atherosclerosis was produced by balloon denudation in diabetic minipigs fed high-fat diets. Rapid intracoronary imaging (pullback: 20 mm/s, 100 rps) was safely performed. Along with detailed coronary microstructure provided by OCT, multispectral FLIm could accurately visualize lifetime signature of biochemical components of atherosclerotic plaque in vivo. Histologic sections of harvested coronary plaques examined by FLIm microscopy and immunostained to reveal lipid and macrophage. ML classification algorithm, trained with multiple image sets of FLIm microscopy and corresponding immunohistology (Figure, upper), was applied for in vivo OCT-FLIm data. Our dedicated ML algorithm showed performance comparable to that of OCT experts in classifying fibrotic vs. high-risk plaque. Furthermore, our framework demonstrated the capability to differentiate lipid vs. macrophage vs. mixed lesion (Figure, lower), which were indistinguishable with current standalone OCT.Conclusions:Our fully-integrated OCT-FLIm incorporating ML-based systematic signal analysis enabled automated and comprehensive biochemical characterization of coronary atherosclerotic plaques. This highly translatable imaging strategy will open a new avenue for clinical intracoronary detection of high-risk plaques.

Introduction:Stent healing involves a series of cellular reactions such as thrombosis, inflammation, neointimal proliferation, however, there is a lack of in vivoimaging study regarding this process, particularly with relevance to endothelial shear stress (ESS). We evaluated ESS distribution and healing response of a novel thin-strut bioresorbable scaffold (BRS, 100?m) as compared to 157?m-thickness ABSORB.Methods and Results:BRSs and ABSORBs were simultaneously implanted in left coronary arteries of pigs (n = 5). 3D scaffolded-artery model for computational fluid dynamics was reconstructed by fusion of OCT and angiography. Serial OCT-NIRF imaging using macrophage mannose receptor-targeting nanoprobe was performed to assess scaffold-related inflammation. Low ESS areas were significantly lower in thin-strut BRSs than in ABSORBs (p < 0.001). Arterial inflammation was significantly lower in thin-strut BRS than in ABSORB at week 2. At week 3, unlike thick-strut ABSORB with remnant NIRF, inflammation activity dissipated significantly in BRS (Figure). Neointimal thickness at week 4 was lower in BRS than in ABSORB (p < 0.0001). In correlative ESS vs. OCT-NIRF strut-level analyses, inflammation activities were robust at peri-strut low ESS regions and ESS was inversely related with NIRF, suggesting immune-modulating effect of ESS (Figure). There was a positive correlation between NIRF activities and neointimal thickness (p < 0.0001). Ex vivoconfocal fluorescence microscopy and immunohistochemical analysis well corroborated the findings in vivo.Conclusions:Thinner-strut BRS with favorable ESS profile was associated with less inflammation and rapid arterial healing. Our novel multimodal molecular imaging study provides in vivo evidence suggesting that scaffold-related changes in local hemodynamic microenvironment significantly affect early BRS healing by modulating arterial inflammatory response.

Introduction:Macrophages are major contributors of atherosclerotic plaque progression and destabilization. In our previous study, macrophage mannose receptor (MMR)-targeted delivery of PPAR? agonist for 4 weeks could effectively reduce plaque burden and inflammation in murine atheroma.Hypothesis:We hypothesize that MMR-targeted theranostic agent loaded with a PPAR? agonist could 1) rapidly reduce the plaque inflammation in advanced atheroma through inhibition of TLR4/NF-?B signalling pathway and 2) subsequently modulate these inflamed plaques into a stable phenotype.Method and Results:MMR-targeted theranostic agent was constructed by loading lobeglitazone (Lobe), a PPAR? agonist, into the MMR-targeted carrier conjugated with cyanine (Cy) dye (MMR-Lobe-Cy). We investigated its acute anti-inflammatory effects and mechanism both in in vitroand in vivoexperiments, and further evaluated the prolonged effects of acute anti-inflammation on plaque composition. In vivoDay 0 and 7 serial optical coherence tomography (OCT) - near infrared fluorescence (NIRF) imaging was performed in atheromatous rabbit aorta. MMR-Lobe-Cy markedly reduced plaque inflammation without undesirable side effects (Figure A). Western blotting and immunohistochemical analysis demonstrated that anti-inflammatory effect of MMR-Lobe-Cy was mediated by inhibiting the TLR4/NF-?B signalling pathway. Furthermore, acute resolution of inflammation altered the plaque into a stable phenotype with collagen-rich matrix, decreased matrix metalloproteinase 9 (MMP-9) activity and reduced plaque macrophages on Day 14 (Figure B).Conclusion:MMR-Lobe-Cy showed a robust acute anti-inflammatory effect on inflamed plaque in coronary-sized arteries by inhibition of TLR4/NF-?B pathway, and shifted the plaque compositions into a stable phenotype. This novel theranostics could be a promising therapeutic strategy to prevent the acute complications of advanced atherosclerosis.