Abstract
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Objectives: Thin-cap fibro atheroma (TCFA) are the unstable lesions in coronary artery disease (CAD) that are prone to rupture resulting in substantial morbidity and mortality worldwide. Early clinical diagnosis and effective risk stratification of these lesions has the potential to dramatically impact management of CAD and prevent progression to catastrophic events. However, their small size, and complex morphological/biological features make early detection and risk assessment difficult. To enable detection and characterization of vulnerable plaque structure and biology, we developed a Circumferential-Intravascular-Radioluminescence-Photoacoustic-Imaging (CIRPI) system (Fig. 1).
Methods: The CIRPI system includes a novel optical probe combined circumferential radioluminescence imaging (CRI) and photoacoustic tomography (PAT). The probe’s CaF2:Eu based scintillating imaging window captures a 360° view of human (n=7) and murine carotid (n=10) arterial plaques by detecting optical radiation from the energy deposited by β-particles during 18F-FDG decay. A tunable laser-based photoacoustic imaging system characterized tissue constituents of TCFA at 7 different wavelengths—540-560 nm (calcification), 920 nm (cholesteryl ester), 1040 nm (phospholipids), 1180 nm (elastin/collagen), 1210 nm (cholesterol), and 1235 nm (triglyceride). Each A-line computed from an average of 400 A-lines; 330 A-lines created a single B-scan. Human carotid endarterectomy samples (25-28 mm length) were imaged with the CRI system pre (control) and post 18F-FDG (50 µCi) injection within ~1h of tissue collection followed by PAT imaging. For FVB mice, carotid lesions were created by 4 weeks of high-fat diet and diabetes induction, followed by left carotid ligation. An hour after 18F-FDG (200 Ci)IV injection left, right (control) carotid arteries, and heart (+ control) were harvested for imaging intact with the CRi Maestro before imaging with the CIRPI system. Results were verified with IVIS-200, autoradiography, histology, and ultrasound imaging.
Results: This dual-modality hybrid imaging tool was able to detect and characterize human and murine atherosclerotic plaques. The catheter-based-CRIPI-probe detected data on human plaque inflammation, through a 60x higher (4.96×104±2.25×104 vs. 8.37×102±6.63×101 photon counts, p=0.001) 18F-FDG radioluminescent signal (Fig. 2c-d), which was enriched by analyses of the plaque tissue constituents and morphologic characterization provided by photoacoustic imaging (Fig. 3a). Confirmatory IVIS-200 images exhibited similar results (62x). PAT imaging system detected TCFA constituents such as calcification, severe lipid/fatty acid in the form of mostly cholesteryl ester, phospholipid, cholesterol, and triglyceride in human samples. Also, we have observed the presence of elastin/collagen. Murine carotid plaques from ligated left carotid artery (LCA) showed 63x (3.10×104±9.41×102 vs. 4.90×102±2.40×102 photon counts, p=0.02) higher radioluminescent signal to the control, non-ligated right carotid artery (RCA), due to plaque macrophages (Fig. 4). PAT images of murine LCA over a range of wavelengths showed no prominent photoacoustic signals except at 1180 nm, which elucidated the presence of elastin/collagen throughout the length of the vessel (Fig. 5a). All human plaque burdens ranged from 20-55%, unlike 10% or less for mice. The CIRPI images of human and murine samples were highly correlated with histological analyses (Fig. 3d-g, 5d-g).
Conclusion: The CIRPI system will drive a paradigm shift in the diagnosis and risk stratification of CAD by uniting cellular, molecular, and morphologic data for a more complete pathologic and prognostic characterization of vulnerable plaques enabling clinical detection and early diagnosis of TCFA, and improving risk assessment. Research Supports: Authors gratefully acknowledge the financial support from an NIH K99/R00 award (1 K99 HL127180-01).
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