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Introduction: Evidence suggests that a significant proportion of cryptogenic strokes may be due to artery-to-artery emboli from substenotic complicated carotid plaques. Thus, carotid artery disease not meeting etiological criteria for stroke (i.e. <50% stenosis) could still harbor thrombo-emboligenic lesions undetectable by standard imaging modalities. We developed an ultrathin, high-resolution, laser-based angioscope (4.7F, 200.000 pixels), capable of detecting such lesions.Hypothesis: We hypothesized that, unlike conventional imaging modalities, high-definition angioscopy would accurately detect small thrombi and ulcers in non-stenosing complicated atherosclerotic plaques.Methods: After institutional approval, the carotid arteries from 2 patients with cryptogenic strokes were harvested post-mortem and endoluminal surface videos were obtained with multimodal SFA. Angioscopic findings were compared to 25 carotid arteries autopsied from subjects with and without atherosclerosis, and 5 carotid endarterectomy (CEA) specimens from symptomatic patients. After angioscopy, all specimens were processed for histology and blindly reviewed by a pathologist; lesions were then matched to endoscopic findings. Subsequently, we tested the SFA in an in vivo rabbit model of atherosclerosis.Results: Punched-out lesions with slightly raised, irregular bead-like borders were encountered in the ipsilateral substenotic carotid arteries (<25%) of patients with cryptogenic stroke. This pathognomonic angioscopic architecture corresponded to ulcerated plaques, and was found exclusively in CEA specimens removed after stroke. As a prelude for clinical use, we demonstrated that SFA generates high quality images in vivo.Conclusions: Laser angioscopy reveals ulcerated plaques in carotid arteries with low-degree stenosis, obtained post-mortem from patients with cryptogenic strokes. Clinically, this novel platform could be used to identify ulcerated carotid plaques or intraluminal thrombi; such diagnostic resolution could help establish the etiology of a subset of cryptogenic strokes that present with low-degree carotid stenosis.