Cholesterol Crystal Embolization Exacerbates Critical Limb Ischemia.

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.

Different Characteristics and Interleukin-6 Ratios of Scattering-Type Aortic Plaques.

Background Cholesterol crystals (CCs) are related to innate inflammation in spontaneously ruptured aortic plaques (SRAPs), and variability exists in the CCs and interleukin (IL)-6 ratio in SRAPs. Methods The prevalence of scattering-type ruptures that glittered against the light of angioscopic fibers (puff-chandelier ruptures) and those that did not (puff ruptures) was analyzed in 848 patients with suspected coronary artery disease. Overall, 177 puff-chandelier ruptures and 105 puff ruptures were sampled using nonobstructive general angioscopy (NOGA). The sampled plaques were analyzed by direct detection of CCs with polarized light microscopy. The characteristics of the plaque fragments from puff and puff-chandelier ruptures were compared. The Interleukin-6 (IL-6) ratios were calculated for 100 puff-chandelier ruptures and 100 puff ruptures. Results CCs were detected in 54% of puff-chandelier ruptures and 20% of puff ruptures. The longer and shorter dimensions of the puff ruptures were smaller than those of the puff-chandelier ruptures. CCs were more prevalent in puff chandeliers than in puff ruptures (54% vs. 20%, respectively; p<0.0001). The number of CCs was higher in puff chandeliers than in puff ruptures with CCs (median 12,727 (interquartile range (IQR) 3,636-25,909)/10 mL vs. median 3,182 ( IQR 909-9,318)/10 mL) in CC-positive samples (p=0.0120). The IL-6 ratio of puff-chandelier ruptures was higher than that of puff ruptures (p=0.0014). Conclusions Examination of plaque fragments from puff-chandelier and puff ruptures revealed a higher prevalence of CCs in puff-chandelier ruptures compared to puff ruptures. Puff chandeliers exhibited a significantly greater number of CCs, suggesting a potential correlation with inflammatory levels. The IL-6 ratio was also higher in puff-chandelier ruptures. Direct detection of CCs and hematoxylin and eosin staining for SRAPs demonstrated variations in CC degree and dimensions between puff-chandelier and puff ruptures. Puff-chandelier ruptures exhibited more CCs associated with innate inflammation and larger fragments than puff ruptures. NOGA proved effective in detecting diverse characteristics and inflammation levels, as indicated by IL-6, in scattering-type SRAPs.

Atherosclerosis of the aorta before blue toe syndrome: Spontaneously ruptured aortic plaques revealed by non-obstructive general angioscopy.

A 50-year-old man who had undergone endovascular therapy 70 days previously was referred to us for the sudden onset of cyanosis with rest pain in the bilateral lower limbs. The patient was diagnosed with blue toe syndrome. Although computed tomography angiography showed irregular aortic wall thickness, preoperative aortic angioscopy detected a remarkable number of spontaneously ruptured aortic plaques, such as puff-chandelier ruptures, predominantly in the abdominal aorta. Continuous embolization of a large quantity of cholesterol crystals from puff-chandelier ruptures subsequently might be responsible for cholesterol embolization syndrome. Learning objective: A patient presenting with cholesterol embolization syndrome had undergone a non-obstructive general angioscopy. We highlight the numerous spontaneously ruptured aortic plaques demonstrated by non-obstructive general angioscopy.

Angioscopy-Guided Selective Pulmonary Thrombectomy and Angioscopy-Monitored Systemic Thrombosis for a Pulmonary Embolism.

Few modalities have the capacity to demonstrate massive or fragmented thrombi to evaluate the effect of catheter-based or systemic thrombosis for pulmonary embolism (PE). We herein present a patient who underwent a thrombectomy for PE using a non-obstructive general angioscopy (NOGA) system. Small floating mobile thrombi were aspirated using the original method, and massive thrombi were aspirated using the NOGA system. Systemic thrombosis was also monitored via NOGA for 30 minutes. Detachment of thrombi from the wall of the pulmonary artery began two minutes after infusion of a recombinant tissue plasminogen activator (rt-PA). Six minutes after thrombolysis, the thrombi lost their erythematous color, and the white thrombi gradually floated and dissolved. NOGA-guided selective pulmonary thrombectomy and NOGA-monitored systemic thrombosis contributed to improved patient survival. Rapid systemic thrombosis for PE using rt-PA was also demonstrated by NOGA.

Multiple and Multidirectional Fissure Bleedings in a Patient With a Spontaneous Isolated Dissection of the Iliac Artery.

A 63-year-old man with a history of hypertension and dyslipidemia on medication was found to have an enlargement of an asymptomatic iliac artery aneurysm with an ulcer-like projection on computed tomography angiography. The longer and shorter diameter of the right iliac was increased from 24.0 × 18.1 mm to 38.9 × 32.1 mm over four years. Preoperative non-obstructive general angiography revealed multiple, multidirectional fissure bleedings. Fissure bleedings were found where computed tomography angiography appeared normal at the aortic arch. He was diagnosed with spontaneous isolated dissection of the iliac artery and was treated successfully with endovascular treatment.

Demonstrating an Adult Ventricular Septal Defect Using Non-obstructive General Angioscopy.

A ventricular septal defect (VSD) is a common congenital heart disease, and the transcatheter technique for VSD requires practical guidance because it requires a complicated procedure. A non-obstructive angioscopy catheter system via the right ventricle successfully revealed an approximately 3-mm VSD with the shape of a rugby ball at the center of the white membranous septum of Kirklin type II in an older female with suspected coronary artery disease. A white membranous terraced septum was observed to be surrounded by a reddish ventricle. Conservative therapy was performed for her VSD because she did not meet the criteria for surgical treatment.

Cholesterol Crystals as the Main Trigger of Interleukin-6 Production through Innate Inflammatory Response in Human Spontaneously Ruptured Aortic Plaques.

AIM: This study aimed to clarify whether cholesterol crystals (CCs) are the main trigger of innate inflammation in human spontaneously ruptured aortic plaques (SRAPs). METHODS: This study included 260 SRAPs collected during nonobstructive general angioscopy (NOGA) from 126 patients with confirmed or suspected coronary artery disease. Interleukin (IL)-6 levels in SRAPs were measured. IL-6 levels in the Valsalva sinus and femoral or brachial arteries were measured. IL-6 ratios (the IL-6 level in SRAPs and arteries divided by the IL-6 level at the Valsalva sinus at the beginning of the aorta) were calculated. Quantitative analysis of CCs was performed from SRAPs. The correlation between the count of CCs and IL-6 levels in SRAPs and that between the counts of CCs and IL-6 ratios in SRAPs were analyzed. RESULTS: The IL-6 levels in SRAPs were 3.4 [2.1, 7.2] pg/mL, and the IL-6 ratio (median [interquartile range]) in SRAPs was 1.10 [1.00, 1.26]. CCs were detected in 94 of 260 SRAPs (36%). The count of CCs was 11,590 (95% confidence interval, 2,386-30,113) per 10 mL in CC-positive samples. There was a moderate correlation between the counts of CCs and IL-6 ratios in SRAPs (r=0.49, r＜0.0001), whereas there was no correlation between the count of CCs and IL-6 levels in SRAPs. The IL-6 ratios of the brachial and femoral arteries were 1.06 (95% CI, 0.99-1.20) and 1.11 (95% CI, 1.04-1.20), respectively. CONCLUSIONS: CC is the main trigger of IL-6 production through innate inflammatory response in human SRAPs in situ.

Detection of macrophages engulfing cholesterol crystals and docosahexaenoic acid from spontaneous ruptured aortic plaque.

We visualized macrophages engulfing cholesterol crystals from spontaneously ruptured aortic plaques sampled by angioscopy. Docosahexaenoic acid cholesterol ester (DHA-CE) was demonstrated by imaging mass spectrometry. DHA-CE is reported to be produced by macrophages against inflammation. Activities of macrophages against atherosclerosis inside plaques was shown from spontaneously ruptured aortic plaques in situ. Learning objectives: Activities of macrophages such as engulfing cholesterol crystals and producing docosahexaenoic acid cholesterol ester were shown from spontaneously ruptured aortic plaques in situ.

Continuous 1-Month Release of Cholesterol Crystals in a Patient With Acute Coronary Syndrome After Stenting.

Coronary stenting was performed for a 76-year-old patient with acute coronary syndrome with severe stenosis of the right coronary artery. Puff rupture including cholesterol crystals was detected on nonobstructive general angioscopy. One month after intervention, continuous release of cholesterol crystals was found despite successful percutaneous coronary intervention. (Level of Difficulty: Intermediate.).

Debris collected in-situ from spontaneously ruptured atherosclerotic plaque invariably contains large cholesterol crystals and evidence of activation of innate inflammation: Insights from non-obstructive general angioscopy.

BACKGROUND AND AIMS: Development and expansion of cholesterol crystals (CCs) within a lipid rich atherosclerotic core are believed to predispose to plaque rupture. We have used non-obstructive general angioscopy to described a range of appearances of spontaneously ruptured atherosclerotic plaques (SRAPs) in the aorta in-situ, and have confirmed that debris extruding from some SRAPs (puff-chandelier lesions) are rich in cholesterol crystals and leukocytes. The purpose of this study was to characterized the nature of the inflammatory infiltrate of this debris. METHODS: Debris was collected from puff-chandelier lesions at the time of angioscopy in patients with known coronary disease. Prepared specimens were examined by light microscopy, and immunostaining was used to detect markers of activation of the innate inflammatory pathway including CD68, NLRP3, caspase-1, IL-1ß, IL-18, and IL-6. RESULTS: We analysed debris sampled from 20 puff-chandelier lesions. Microscopy confirmed the presence of large CCs, macrophages, fibrin, calcified gruel, lymphocytes, and neutrophils in 100%, 100%, 95%, 25%, 20%, and 15% of the specimens respectively. Immunostaining confirmed the presence of CD68, NLRP3, IL-1ß, and IL-6 within the debris in 100%, 90%, 80%, and 80%, of the specimens respectively. CCs, NLRP3, caspase-1, IL-1ß, IL-18, were also identified in the cytoplasm of macrophages. CONCLUSIONS: Debris from SRAPs with a puff-chandelier appearance invariably contained large CCs associated with a range of activated leukocytes involved in innate inflammation. This observation supports the thesis that the development and enlargement of CCs in the core of lipid rich plaques may precipitate traumatic and inflammatory injury that may lead to plaque rupture.

Novel Methods for Detecting Human Cholesterol Crystals from Sampled Blood.

OBJECTIVE: Nonobstructive general angiography (NOGA) is a novel modality to detect and sample spontaneous ruptured aortic plaques (SRAPs). We aimed to establish novel methods to detect cholesterol crystals (CCs) in sampled SRAPs. METHODS: Blood specimens containing SRAPs were obtained from patients using NOGA. Blood was instantly frozen on a glass slide and subsequently thawed for quantitative analysis and spread onto a filter paper that was rinsed using distilled water. Qualitative analysis was performed for the rinsed water using polarized light microscopy, and the filter paper was embedded in paraffin for histologic analysis. RESULTS: The CCs were clearly observed after hemolysis using the instant freeze-thaw method. The filter paper rinse method indicated free CCs of varying shapes under polarized light microscopy without erythrocytes. On the filter paper, sampled SRAPs showed Lamé-like small particles. Histopathology revealed various atheromatous components. CONCLUSION: A set of novel methods for detecting CCs from sampled blood was established.

Spontaneous ruptured aortic plaque and injuries: insights for aging and acute aortic syndrome from non-obstructive general angioscopy.

Recent advances in non-obstructive general angioscopy (NOGA) have enabled the detection of aortic atherosclerosis. The incidence of spontaneous ruptured aortic plaques (SRAPs) and aortic injuries was found to be high in patients diagnosed with or suspected of having coronary artery disease. These facts may result in a paradigm shift for diseases such as aging and acute aortic syndrome because the incidence of systemic embolic diseases and aortic disease are assumed be high. Aortic thromboembolism has been thought to be mainly iatrogenic and is referred to as "cholesterol embolization syndrome" or "cholesterol crystal embolization", although the cholesterol crystals (CCs) were not demonstrated routinely as real images. Atheromatous materials, fibrins, calcifications, macrophages, and a mixture of such substances are released through a puff or puff-chandelier rupture. Among atheromatous materials, CCs can be easily detected clinically in sampled blood via polarized light microscopy. Atheromatous materials include rich CCs and free monolayers, and multilayer CCs are released when the atheromatous materials from vulnerable plaques break into pieces, such as in puff or puff-chandelier rupture. Released SRAPs seem to be asymptomatic; however, accumulation of SRAPs referred to as accumulated spontaneous asymptomatic plaques may cause aging through systemic "embolic" processes, such as mechanical obstruction and an inflammasome pathway. Unique findings in "atherosclerotic" acute aortic syndrome, such as a clear boundary between the dissected lesion and the normal lesion, fissure/fissure bleeding suggesting an entry or a reentry, and subintimal blood flow detected through NOGA are reported. Fissure/fissure bleeding and subintimal blood flow may be the first or last triggers of "atherosclerotic" acute aortic syndrome. Pre-emptive diagnosis and risk stratification of acute "atherosclerotic" aortic dissection and feedback for endovascular therapy may be enabled through the use of NOGA in the future.

Detecting Free Cholesterol Crystals in a Patient With Spontaneous Cholesterol Embolization Syndrome.

Spontaneous cholesterol embolization is thought to be due to aortic plaque-derived shower emboli; however, flowing cholesterol crystals have not been detected. Free multilayer cholesterol crystals obtained from the femoral artery were observed using polarized light microscopy. Detection of these crystals may indicate the occurrence of spontaneous shower emboli. (Level of Difficulty: Intermediate.).

Detecting intimal tear and subintimal blood flow of thrombosed acute aortic dissection with ulcer-like projections using non-obstructive angioscopy.

A 73-year-old man reporting severe chest and back pain for 20 min was admitted to our hospital. The pain occurred 3 days before admission. Computed tomography angiography showed a hazy-surfaced low-density area in the aortic arch with aneurysmal formation of unknown etiology. It was inconclusive whether the aortic change was acute or chronic because no previous information was available. To investigate the etiology, non-obstructive angioscopy (NOA) was performed. A fissure with blood flow was detected at the surface of the low-density area and active subintimal blood flow was demonstrated on NOA. An entry tear and active blood flow below the intima at the seemingly thrombosed area suggested that the patient had a thrombosing type B aortic dissection. .

Angioscopic Evaluation of Spontaneously Ruptured Aortic Plaques.

BACKGROUND: Spontaneous ruptured aortic plaques (SRAP), which might cause atheromatous embolization, are thought to be mainly iatrogenic and have not been observed directly. OBJECTIVES: The purpose of this study was to clarify the incidence, types, and dimensions of SRAP using angioscopy. METHODS: In a cross-sectional study, 324 consecutive patients diagnosed with or suspected of having coronary artery disease were subjected to intra-aortic scans with nonobstructive angioscopy. Samples of SRAP were taken from the aorta. The dimensions of cholesterol crystals of atheromatous materials were measured with a polarizing microscope and compared with those of the ghost images of cholesterol crystals. RESULTS: SRAP were detected in 262 patients (80.9%); 120 of 262 patients had ruptured aortic plaques below the diaphragmatic level. Samples were successfully obtained from 96 patients. The detected numbers of atheromatous material, fibrin, macrophage, and calcification were 237 (49.1%), 244 (50.6%), 111 (23.0%), and 127 (26.3%) out of 482 samples, respectively. The median lengths and widths of the sampled plaques were 254 µm (interquartile range [IQR]: 100 to 685 µm) and 148 µm (IQR: 535 to 423.5 µm), respectively. The lengths and widths of the cholesterol crystals isolated from atheromatous materials were 40 µm (IQR: 32.7 to 53.7 µm), and 30 µm (IQR: 23 to 38 µm), respectively, compared with the respective dimensions of the ghost images of 86 µm (IQR: 53 to 119) and 13 µm (IQR: 7 to 18 µm). No embolic symptoms were observed within 24 h of general care via cardiac catheterization. CONCLUSIONS: SRAP are commonly scattered, and their dimensions were smaller than previously recognized. (Detecting Ruptured Aortic Plaques by Nonobstructive Angioscopy; UMIN000029772).