Portal de Periódicos da CAPES

Scanning Fiber Angioscopy

2017; Lippincott Williams & Wilkins; Volume: 64; Issue: CN_suppl_1 Linguagem: Inglês

10.1093/neuros/nyx322

1524-4040

Luis Savastano, Eric J. Seibel,

Acute Ischemic Stroke Management

AF: autofluorescence AHA: American Heart Association CTA: computed tomography angiography FBA: fiber-bundle angioscopy IVUS: intravascular ultrasound MRA: magnetic resonance angiography MRI: magnetic resonance imaging OCT: optical coherence tomography RGB: red, green, blue SFA: scanning fiber angioscopy Stroke is a leading cause of death and disability.1 Despite efforts in prevention, early diagnosis, and improved treatments, stroke kills more than 160 000 people every year in the United States alone.2 Approximately 795 000 Americans per year—1 every 40 s—experience a new or recurrent clinically evident stroke, although the prevalence of magnetic resonance imaging (MRI)-defined silent cerebral infarction in the general elderly population is estimated to range from 6% to 28%, with higher prevalence in older people.3-6 Although the causes of ischemic stroke may vary with demographic characteristics of the patient population, one of the most common known causes is artery-to-artery embolism from a complicated atherosclerotic plaque at the carotid bifurcation.2,7,8 The management of patients with carotid artery disease, supported by data accumulated in the last 70 yr, is well-defined in evidence-based guidelines that consider the degree of carotid stenosis the main surrogate for carotid-related stroke etiology, risk stratification, and indication for intervention. As a consequence of the keen relevance given to the severity of luminal narrowing, much of the clinical research and imaging developments during the second half of the 20th century were done in an attempt to noninvasively quantify the degree of stenosis. Although the severity of stenosis statistically correlates with the likelihood of suffering future ischemic events, recent biological and clinical data have demonstrated that pathological changes within the vessel wall, rather than degree of stenosis, determine the fate of a plaque.9,10 By extension, structural and biological factors that define plaque stability and vulnerability might be more significant than degree of narrowing in determining the risk profile and root cause of a cardiovascular event. In this regard, clinical experience has repeatedly shown the inadequacy of limiting the assessment of atherosclerosis disease to the degree of stenosis. As an illustrative example, it has been postulated that a large number of cryptogenic strokes (ie, of unknown cause), which account for up to 40% of all ischemic cerebrovascular events, could be due to thromboembolic phenomena from undiagnosed ulcers, fissures, or erosions in complicated substenotic atherosclerotic plaques (ie, 50% stenosis, presumably due to atherosclerosis, required in the ipsilateral carotid artery to classify a stroke as large-artery atherosclerosis.7 Consequently, patients with documented carotid atherosclerotic disease ipsilateral to stroke who did not reach the 50% stenosis limit were classified as cryptogenic—or of unknown etiology—if no other attributable cause was found in the workup. In addition, by defining luminal narrowing as the main determinant in the management of carotid artery disease, the attention in imaging development was focused in optimizing noninvasive quantification of stenosis, which in turn paralleled major efforts to define the ideal technology based on sensitivity, specificity, safety, and cost-effectiveness research.21FIGURE 1: A, António Caetano de Abreu Freire Egas Moniz (1874-1955, public domain image obtained from https://commons.wikimedia.org/wiki/File:Moniz.jpg), author of the landmark 1937 publication titled "Hemiplegia due to thrombosis of the Internal Carotid Artery," which included a cerebral diagnostic angiogram showing complete occlusion of internal carotid artery. B, Charles Miller Fisher (1913-2012, image by J3D3 (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons), author of the landmark 1951 publication titled "Occlusion of the Internal Carotid Artery," which included a diagram of cerebral arteries showing an extensive blood clot filling the right internal carotid artery distal to an area of atherosclerotic narrowing. A second paper published in 1954 included histological images of carotid artery cross sections with thrombi associated with atherosclerosis.PLAQUE VULNERABILITY—MOVING BEYOND THE DEGREE OF STENOSIS Progressive luminal narrowing translates into increasing hemodynamic and tensile stress that destabilizes vulnerable plaques and is a well-known factor that statistically correlates with higher likelihood of suffering future ischemic events.22 However, the classical paradigm focusing on stenosis has changed, based on the growing body of scientific evidence. We now know that the vast majority of cardiovascular events are not due to flow-limiting stenosis from uncontrolled plaque growth, but rather from acute thromboembolic events driven by plaque rupture. Thus, a culprit plaque is not necessarily large, causing clinically significant stenosis (ie, >50%-70%), but vulnerable and thrombogenic, leading to rapid luminal occlusion or distal embolization resulting in stroke, heart attack, or lower limb ischemia, depending on the affected territory.23,24 Histopathologic studies have demonstrated that, independent of the degree of stenosis, vulnerable plaques are characterized by the presence of surface thrombus, ulcer, low fibrous content, heavy macrophage infiltration, and high micro-vessel density.10 This shifting paradigm places superficial thrombosis associated with nonocclusive and inflamed plaque rupture, ulceration, and erosion as the main root-cause and risk-stratification factors for ischemic stroke in patients affected by carotid atherosclerotic disease.25-27 As a result, pre-existing imaging modalities used clinically to quantify carotid artery stenosis were tested to detect these thrombogenic lesions, novel intravascular technologies were developed for high-resolution structural imaging, and new approaches for molecular imaging of plaque vulnerability emerged. NONINVASIVE IMAGING OF ATHEROSCLEROSIS X-ray contrast angiography was the first modality available to image blood vessel lumen and was historically considered the gold standard test for evaluation of carotid artery disease based on high spatial and temporal resolutions. However, the invasive nature, the need for ionizing radiation, and the limited power to identify plaque ulceration—which is considered a key feature associated with plaque vulnerability and a notable indicator of previous plaque rupture and possible future cerebrovascular events—resulted in progressive replacement by noninvasive technology.28 Sonography (and Doppler ultrasonography) was introduced as the first noninvasive platform for carotid artery imaging in the clinical setting. This technology provides relevant information in a low-cost, fast, and safe manner, including degree of stenosis, heterogeneity of the plaque, luminal flow, and the presence of very large ulcerations. However, sonography has low inter-reader reproducibility, may fail to differentiate between subtotal and complete occlusion, has low accuracy for detection of ulcers, and has significant artifact due to calcifications. These limitations caused a gradual trend toward CTA for patients with symptomatic carotid artery disease, which can rapidly provide a luminal cast of large vascular territories and has shown to have higher sensitivity and specificity to detect large ulcerations compared to ultrasound.29,30 However, CTA requires a large contrast bolus, exposes patients to radiation, is inaccurate for calcified plaques, has significant artifact due to metal, and is limited by its spatial resolution to detect targets not causing luminal distortion such as shallow ulcers and erosions. In recent years, MRI has emerged as a noninvasive radiation-free imaging modality able to provide images of the vascular lumen (MRA) and wall (MRI). Luminal casts can be generated with or without contrast agents, although the latter is susceptible to signal saturation and dephasing that leads to signal loss in focal areas of complex flow, such as plaque irregularities or large ulcerations. In addition to depicting the vascular lumen, high-resolution MRI, with a wide variety of pulse sequences such as fast spin echo or black-blood, has emerged for arterial wall imaging and is rapidly becoming the gold standard for detection of large macroscopic intraplaque hemorrhages and lipid-rich necrotic core, allowing for improved patient risk stratification and outcomes.21 This exciting platform is subject to rapid advancements, but continues to be costly and time consuming, and significant technical improvement still needs to occur to overcome the limited resolution and motion artifacts that compromise the ability to detect small but crucial lesions, such as intraluminal thrombi, dissections and ulcerations, and biological markers of plaque vulnerability.31 IMAGING ATHEROSCLEROSIS FROM INSIDE: FOCUS ON OPTICAL ANGIOSCOPY Noninvasive techniques are clinically very valuable and are optimal from an initial screening standpoint. However, the complex nature of atherosclerosis often demands higher resolution approaches to detect thromboembolic lesions and define the potential risk for future rupture.32,33 In addition, noninvasive platforms have limited power to identify early plaques evolving within the arterial intima before luminal irregularity develops, which is the cornerstone of early disease detection and treatment. To provide maximal spatial resolution, several intravascular platforms have emerged in the last 3 decades for intraluminal imaging of atherosclerosis, such intravascular ultrasound (IVUS), optical coherence tomography (OCT), and fiber-bundle angioscopy (FBA).33 OCT and IVUS are the most validated intraluminal technologies and are used extensively to improve the characterization of atherosclerotic lesions and thrombi in coronary arteries, assess stent placement, and reveal angiographically occult lesions.34 Despite their significant clinical and research value, they have inherent risks for atherosclerosis imaging and technological limitations for use in carotid arteries. First, the side-view design of these 2 devices require crossing unstable lesions back and forth (with automated rotational pullbacks for OCT) to reconstruct images of vascular segments after postimaging processing, which could result in plaque rupture and thrombosis. Second, the inability of these commercially available devices to look forward precludes their use in high-degree stenosis or total luminal occlusion, both of which are frequent and clinically relevant scenarios. Third, atherosclerotic disease is overwhelmingly concentrated at the carotid bifurcations, creating a challenge for imaging the flow divider from a lateral-view approach.35 Finally, image quality drops at longer distances between target and probe, decreasing the performance in large nonstenosed vessels, such as carotid artery. Angioscopy, or endovascular endoscopy, is the oldest and least employed intravascular optical platform used to investigate symptomatic atherosclerosis through direct visualization of the internal surface of arteries.36 This technology, introduced in the early 1980s, consists of a white-light source (coupled with filters, as needed), a flexible optical fiber bundle consisting of multiple illumination fibers that transport light forward and collect the reflected light back, and a lens to form an image. FBA was received with great enthusiasm and was initially applied to differentiate arterial wall composition, assess plaque disruption, ulceration, and plaque vulnerability, and to evaluate stent placement.37 Although this technology provided valuable information on the intraluminal environment and was able to demonstrate complicated plaques missed by angiography, the poor image quality (up to 10 000 pixels with current devices), its large size, and excessive stiffness significantly limited its use in clinical settings. Except for a few countries such as Japan where angioscopy is an officially approved and reimbursed diagnostic method for monitoring angioplasty and to diagnose complicated plaques in unstable angina, FBA use is currently limited to evaluation of donor veins for bypass procedures.38 Despite the near extinction of this modality, to date angioscopy is probably the most precise clinical tool available to identify thrombogenic lesions and intravascular thrombus in coronary arteries and to monitor in real time the apposition of stent struts to the arterial wall.39,40 With enhanced performance to navigate vessels, multimodal imaging and improved resolution through technological development of angioscopes may lead to a renaissance of this exciting domain to increase our understanding of the scope and breadth of vascular disease. HIGH-DEFINITION MULTIMODAL SFA Based on the unmet clinical need for improved instruments in response to the contemporary understanding of atherosclerosis biology, we embarked on a quest to develop a novel platform for multimodal high-resolution structural, biochemical, and biological vascular imaging. In addition to NIH grants to support the laboratory of the senior author (ES), the preclinical testing of this technology was supported by the Joint Cerebrovascular Section of the CNS/AANS through the Robert J. Dempsey, MD, Cerebrovascular Research Award, to whom we are very grateful. We invite the interested reader to refer to previously published manuscripts on the engineering specifications of laser-based scanning fiber technology and the preclinical validation conducted in human ex vivo specimens and in 2 translational in Vivo animal models.11,41,42 Briefly, the SFA system consists of a single optical fiber that is scanned by a piezoelectric drive mechanism to illuminate tissue surface with red, green, and blue (RGB) laser beams in an outwardly expanding spiral pattern that projects forward (Figure 2).41 Backscattered (reflectance) light and laser-induced fluorescence are collected by a ring of plastic optical fibers and then digitalized to reconstruct color video images from the entire field of view of the endoscope. The system developed for multimodal endovascular imaging has 4 channels: B-fluorescence (470/28), G-fluorescence (531/46 nm), R-fluorescence (>647 nm), and grayscale reflectance (642 nm). However, different laser combinations throughout the light spectrum are possible, depending on the predefined needs of this imaging technology. The laser power coming out of the distal tip of the endoscope is 20× higher than commercially available FBA, which translates into much sharper images, allowing visualization of smaller targets and improved recognition of the hallmarks of complicated and vulnerable atherosclerotic lesions. To define structural angioscopic patterns of normal and abnormal endoluminal anatomy and differentiate complicated from noncomplicated atherosclerotic plaques with SFA, following institutional approval we prospectively harvested a set of cadaveric carotid and vertebral arteries and matched angioscopic findings to histological analysis. Endovascular surface anatomy was described by contour (flat, elevated, excavated, or punched-out), texture (smooth or ragged), presence of surface defect or thrombus, and grayscale reflectance. Then, it was complemented with label-free biochemical contrast derived from spectral analysis of the major component of atherosclerotic lesions. These data were used to derive a multimodal morphological classifier capable of categorization of the full spectrum of atherosclerotic lesions according to the histopathological classification of the American Heart Association (AHA).27,43,44 The inspection of arterial lumens with SFA revealed the following: Normal endoluminal surface: Delicate smooth endoluminal surface with homogeneous reflectance that histologically corresponds to normal arterial wall with a tunica intima formed by endothelium overlying a thin connective tissue with a prominent internal elastic membrane (Figure 3A).FIGURE 3: SFA with histological correlation (Movat's pentachrome stain) of normal carotid artery A and early B, intermediate C and advanced lesion D. A, Normal artery: delicate smooth endoluminal surfaces with homogeneous reflectance, histologically formed by thin tunica intima, prominent tunica media rich in elastin, and a tunica externa or adventitia. B, Early lesion: slightly raised, pale, small dot-like or streak-like endoluminal lesion with preserved reflectance that histologically corresponds to focal accumulations of fat-laden macrophages at the intima (asterisks). C, Intermediate lesion: longitudinal elevated lesions with preserved reflectance that histologically correspond to dispersed extracellular lipids without apparent necrosis and incipient fibrous cap rich in smooth muscle cells and proteoglycans (asterisk). D, Advanced lesion: prominent lesion with smooth homogeneous surface with preserved reflectance protruding into the lumen causing eccentric stenosis. Histologically, these lesions have a collagen-rich fibrous cap covering a lipidic necrotic core with variable inflammatory infiltration (asterisk).Early lesion: Slightly raised, pale, small dot-like or streak-like endoluminal lesion with preserved reflectance that histologically correspond to focal accumulations of fat-laden macrophages at the intima (intimal xanthomata or AHA grade II; Figure 3B). Intermediate lesion: Longitudinal elevated lesion with preserved reflectance that histologically corresponds to dispersed extracellular lipids without apparent necrosis and incipient fibrous cap rich in smooth muscle cells and proteoglycans (pathologic intimal thickening or AHA grade III; Figure 3C). Advanced lesion: large lesion with smooth homogeneous surface with preserved reflectance protruding into the lumen or causing concentric or eccentric stenosis. Histologically, these lesions have a fibrous cap covering a lipidic necrotic core. The cap is mainly formed by smooth muscle cells in a collagenous proteoglycan matrix, with varying degrees of infiltration by macrophages and lymphocytes (fibrous cap atheroma, AHA grades IV and V, depending on thickness of fibrous cap; Figure 3D). Ulcerated plaque: punched-out lesion with slightly raised, irregular, bead-like borders and a central dark gray crater with diminished reflectance, histologically characterized by an excavation in the endoluminal surface of a plaque caused by partial embolization with exposure of necrotic core to vascular lumen (complicated plaque, AHA grade VI; Figure 4A).FIGURE 4: SFA with histological correlation (Movat's pentachrome stain) of ulcerated plaque A, intraplaque hemorrhage B, and intraluminal thrombus C. A, Ulcerated plaque: punched-out lesion with slightly raised, irregular, bead-like borders and a central dark gray crater with diminished reflectance, histologically characterized by fibrous cap rupture with exposure of necrotic core to vascular lumen (asterisk). B, Intraplaque hemorrhage with luminal obstruction: occlusion of vascular lumen due to obliterating plaque with distinct dark gray area with low reflectance, histologically showing an area with fresh or organized erythrocytes causing disruption of plaque architecture. C, Intraluminal thrombus: occlusive or subocclusive dark gray or black intraluminal lesion with diminished reflectance, histologically formed by erythrocytes, fibrin, and platelets in the vascular lumen.Hemorrhagic plaque: distinct dark gray or black area in the dome of plaque with low reflectance, histologically showing an area with fresh or organized erythrocytes causing disruption of plaque architecture (complicated plaque, AHA grade VI; Figure 4B). Intraluminal thrombus: occlusive or subocclusive intraluminal lesion with variable reflectance (preserved in chronic clots and diminished in acute clots), histologically formed by erythrocytes, fibrin, and platelets in the luminal side of a plaque (Figure 4C). In order to improve the characterization and structural analysis of atherosclerotic lesions, laser-induced fluorescence of endovascular surfaces is used to generate biochemical contrast. Spectral SFA employs the same principes as fluorescence spectrometry, which identifies the constituents of atherosclerotic plaques through analysis of subtle differences in spectral decomposition of the intrinsic fluorochromes within healthy and diseased vessels.45,46 This technique is based on the creation of an excited electronic state by optical absorption and subsequent emission of fluorescence, and is illustrated by the simple electronic-state diagram (Jablonski diagram) shown in Figure 5. Briefly, a photon of energy supplied by the low power lasers of the SFA is absorbed by intrinsic fluorophores of arterial wall, creating an excited electronic singlet state (S2). The excited state exists for a very brief