Cholesterol Crystal Embolization Exacerbates Critical Limb Ischemia

Abstract

Chronic life-threatening ischemia (CLTI), characterized by chronic severe ischemic ulcers or gangrene in the legs with arterial occlusive disease, has a high rate of amputation and mortality. However, how lower extremity artery disease (LEAD) leads to CLTI is not fully understood yet. Here, we report a 79-year-old man with resting pain and gangrene in the left first and fifth toes for a year who had undergone repetitive endovascular treatment (EVT) that temporarily improved the ischemia. Non-obstructive general angioscopy (NOGA) revealed yellow and red floating emboli at the occluded left superficial femoral artery (SFA). Although a second EVT for the reoccluded SFA was successful, amputation of the left lower knee remained necessary because of osteomyelitis of the left heel. Cholesterol crystals (CCs) associated with innate inflammation were detected in spontaneously ruptured aortic plaques (SRAPs) via aortic screening using the NOGA, in occluded SFAs, and on the surface of the muscle cross-section of the amputated legs via a polarizing microscope. Histopathological analysis demonstrated CCs in small vessels in various stages of patchy necrosis and muscle regeneration. In this case, the process of CC embolization, such as the embolic source of CCs, occlusion in arteries, small arteries, and deposition in muscles, was confirmed in CLTI. CCs are the principal trigger of IL-6 production through the innate inflammatory response in spontaneously ruptured aortic plaques. Mechanical ischemia and chronic inflammation due to embolized CCs may cause chronic limb damage. In this case, the CC embolization might exacerbate CLTI.

Keywords: angioscopy; cholesterol crystals; cholesterol embolization syndrome; chronic life-threatening ischemia; endovascular treatment (evt).

Figure 1. Clinical course of the patient.

X: the day of an admission; eGFR: estimated glomerular filtration rate.

Figure 2. Aortography and angioscopy before and after the first endovascular treatment.

(A) Aortography before the endovascular treatment (EVT) on admission. An occlusion is shown in the left superficial femoral artery (SFA). (B) Non-obstructive general angioscopy (NOGA) shows the smooth arterial surface (#) proximal to the occluded site (*) in the left SFA. (C) Yellow (Y) and red floating puff-like emboli (E) in the occluded site shown. (D) Aortography after EVT.

Figure 3. Aortography and angioscopy before and after the second endovascular treatment.

(A) Aortography before the second EVT; (B) puff-like emboli in an occlusion site shown via NOGA; (C) red thrombi in the stent shown via NOGA; (D) aortography after the second EVT.

Figure 4. Histopathology obtained during the second endovascular treatment and computed tomography of the aorta.

(A) An organized in-stent thrombus stained with hematoxylin-eosin (HE) staining. Bar: 200 μm. (B) A fresh in-stent thrombus stained with HE staining. Bar: 500 μm. (C) Cholesterol crystals are detected in blood samples from the occluded site. Bar: 50 μm. (D) Maximum intensity projection of the computed tomography angiography of the aorta. Severe calcification is distributed in the entire aorta.

Figure 5. The distribution of spontaneously ruptured aortic plaques in the thoracic (A), the abdominal (B), and the iliac and femoral arteries (C).

PC: puff chandelier; E: erosion; F: fissure, FB: fissure bleeding; SB: subintimal bleeding. Image credits: Sei Komatsu.

Figure 6. Histopathology of an amputated limb.

(A) Cholesterol crystals are directly detected via the stamp method and visualized using polarized light microscopy (×100); (B) macroscopic images of the flexor hallucis longus muscle. N: normal; R: regenerative tissue; F: fibrosis; scale Bar: 1 mm. (C) Hematoxylin-eosin stain of the atheroemboli with CCs in the posterior tibial artery (×100); (D) empty clefts suggest cholesterol crystals in the small arteries (arrows) (×200); (E) histopathological image of the flexor hallucis longus muscle stained using hematoxylin and eosin. N: patchy necrosis, R: regeneration, and D: degeneration (×100). (F) Histopathological image of the flexor hallucis longus muscle stained with Masson’s trichrome. D: patchy degeneration, F: fibrosis (×200).