Cholesterol Crystal Embolism in a Patient with Spontaneous Ruptured Aortic Plaques Identified by Non-Obstructive General Angioscopy.

Cholesterol crystal (CC) embolism is a disease in which CCs from atherosclerotic lesions embolize peripheral arteries, causing organ dysfunction. In this case, a patient with spontaneously ruptured aortic plaques (SRAPs) identified by non-obstructive general angioscopy (NOGA) may have developed a CC embolism. This is the first report of a CC embolism in a patient with SRAPs identified using NOGA, which further supports the previously speculated pathogenesis of CC embolism due to SRAPs.

Both hyperglycemia and hyperuricemia aggravate acute kidney injury during cholesterol embolism syndrome despite opposite effects on kidney infarct size.

Kidney cholesterol crystal embolism (CCE) occurs in advanced atherosclerosis and induces a thrombotic (micro)angiopathy, a drop in the glomerular filtration rate (GFR), and an ischemic kidney infarction with necroinflammation. We speculated that common metabolic comorbidities such as diabetes or hyperuricemia would independently modulate each of these distinct pathophysiological processes. To test this, experimental CCE was induced by injecting cholesterol crystals into the left kidney artery of mice and thrombotic angiopathy, GFR drop, and infarct size were analyzed after 24 hours in the presence of hyperglycemia (about 500 mg/dL) or hyperuricemia (about 8 mg/dL) or their absence. In healthy mice, unilateral CCE caused diffuse thrombotic angiopathy in interlobar, arcuate and interlobular arteries, followed by a 50% or less drop in GFR compared to baseline and a variable degree of ischemic kidney necrosis. Hyperglycemia but not hyperuricemia aggravated thrombotic angiopathy although both caused a GFR decline, albeit via different mechanisms. Hyperglycemia aggravated GFR loss by increasing necroinflammation and infarct size, while the antioxidative effects of hyperuricemia reasonably attenuated necroinflammation and infarct size but induced a diffuse vasoconstriction in affected and unaffected kidney tissue. Thus, both hyperglycemia or hyperuricemia aggravate CCE-induced acute kidney failure despite having opposite effects on ischemic necroinflammation and infarction.

Crystal Clots as Therapeutic Target in Cholesterol Crystal Embolism.

RATIONALE: Cholesterol crystal embolism can be a life-threatening complication of advanced atherosclerosis. Pathophysiology and molecular targets for treatment are largely unknown. OBJECTIVE: We aimed to develop a new animal model of cholesterol crystal embolism to dissect the molecular mechanisms of cholesterol crystal (CC)-driven arterial occlusion, tissue infarction, and organ failure. METHODS AND RESULTS: C57BL/6J mice were injected with CC into the left kidney artery. Primary end point was glomerular filtration rate (GFR). CC caused crystal clots occluding intrarenal arteries and a dose-dependent drop in GFR, followed by GFR recovery within 4 weeks, that is, acute kidney disease. In contrast, the extent of kidney infarction was more variable. Blocking necroptosis using mixed lineage kinase domain-like deficient mice or necrostatin-1s treatment protected from kidney infarction but not from GFR loss because arterial obstructions persisted, identifying crystal clots as a primary target to prevent organ failure. CC involved platelets, neutrophils, fibrin, and extracellular DNA. Neutrophil depletion or inhibition of the release of neutrophil extracellular traps had little effects, but platelet P2Y12 receptor antagonism with clopidogrel, fibrinolysis with urokinase, or DNA digestion with recombinant DNase I all prevented arterial occlusions, GFR loss, and kidney infarction. The window-of-opportunity was <3 hours after CC injection. However, combining Nec-1s (necrostatin-1s) prophylaxis given 1 hour before and DNase I 3 hours after CC injection completely prevented kidney failure and infarcts. In vitro, CC did not directly induce plasmatic coagulation but induced neutrophil extracellular trap formation and DNA release mainly from kidney endothelial cells, neutrophils, and few from platelets. CC induced ATP release from aggregating platelets, which increased fibrin formation in a DNase-dependent manner. CONCLUSIONS: CC embolism causes arterial obstructions and organ failure via the formation of crystal clots with fibrin, platelets, and extracellular DNA as critical components. Therefore, our model enables to unravel the pathogenesis of the CC embolism syndrome as a basis for both prophylaxis and targeted therapy.

The systemic immune response due to cholesterol crystal embolization syndrome: a case report.

BACKGROUND: Cholesterol crystal embolization syndrome (CES) occurs when an atherosclerotic plaque causes small-vessel embolization, resulting in multi-organ damage. Although CES is pathologically characterized by an infiltration of eosinophils, the implication of the systemic inflammatory response represented by hypereosinophilia is unclear in clinical practice. Herein we present the case of a patient diagnosed with CES who developed multiple allergic organ injuries, including daptomycin-related dermatitis and later vancomycin-induced acute tubulointerstitial nephritis, which was successfully treated by the withdrawal of each medicine with or without corticosteroid therapy, one by one. CASE PRESENTATION: A 76-year-old Japanese man diagnosed with thoracic aneurysm rupture underwent total arch replacement through the open stent graft technique. Postoperatively, he developed methicillin-resistant Staphylococcus epidermidis bacteremia, which was treated with daptomycin. Subsequently, he presented with palpable purpura on both dorsal feet, erythema around his body, and hypereosinophilia. Daptomycin was replaced with vancomycin due to suspicion of drug-induced erythema. The erythema gradually faded. On nine days after vancomycin therapy, the systemic erythema rapidly reappeared followed by acute renal failure. The renal function decline prompted hemodialysis. A skin biopsy revealed cholesterol embolization, whereas a kidney biopsy revealed acute tubulointerstitial nephritis. After vancomycin discontinuation and initiation of systemic corticosteroid treatment, his kidney function was restored to the baseline level. CONCLUSIONS: The present case highlights cholesterol embolization can cause allergic complications in addition to direct organ damage.

Mimics of vasculitis.

While prompt diagnosis of vasculitis is important, recognition of vasculitis mimics is equally essential. As in the case of vasculitis, an approach to mimics based on the anatomic size of vessels can be useful. Infections can mimic vasculitis of any vessel size, including the formation of aneurysms and induction of ANCAs. Genetic disorders and vasculopathies are important considerations in large and medium vessel vasculitis. Cholesterol emboli, thrombotic conditions and calciphylaxis typically affect the medium and small vessels and, like vasculitis, can cause cutaneous, renal and CNS manifestations. Reversible cerebral vasoconstriction syndrome is important to distinguish from primary angiitis of the CNS. As an incorrect diagnosis of vasculitis can result in harmful consequences, it is imperative that the evaluation of suspected vasculitis includes consideration of mimics. We discuss the above mimics and outline a systematic and practical approach for differentiating vasculitis from its mimics.

Cholesterol embolization and arterial occlusion from the Heimlich maneuver.

The Heimlich maneuver is a lifesaving bystander intervention to assist an individual with airway obstruction however, cholesterol embolization syndrome is a rare, but serious potential complication of the Heimlich maneuver. We present the case of the 56-year-old female presenting to the emergency department with acute right foot pain following performance of the Heimlich maneuver who was found to have distal arterial occlusion resulting from cholesterol embolization syndrome. The patient underwent right popliteal artery exploration, right popliteal and tibial thrombectomy, and popliteal patch angioplasty resulting in restoration of blood flow to her right foot.

Proportion and risk factors of cholesterol crystal embolization after cardiovascular procedures: a retrospective national database study.

Cholesterol crystal embolization (CCE) is a rare, mainly iatrogenic condition. The proportion of CCE after cardiovascular procedures has not been fully elucidated. The purpose of this study was to determine the proportion of CCE diagnosed after cardiovascular procedures and to identify risk factors for CCE occurrence. Data on patients aged older than 40 years who underwent cardiovascular procedures between July 2010 and March 2017 were extracted from the Japanese Diagnosis Procedure Combination database. Inpatients diagnosed with CCE within 1 year after procedures in the same hospital were identified. Logistic regression analysis was performed to identify factors associated with the occurrence of CCE. There were 962 patients with CCE in 2,190,300 patients who underwent cardiovascular procedures. The overall proportion of CCE after cardiovascular procedures was 4.4 per 10,000 patients (95% confidence interval 4.1-4.7). The overall in-hospital mortality among patients with CCE was 11% (107/962). Older age, male sex, smoking, heart failure, peripheral vascular disease, cerebrovascular disease, renal insufficiency, diabetes mellitus, hypertension, and aortic aneurism and dissection were significantly associated with the higher occurrence of CCE. Compared with cardioangiography, several procedures were significantly associated with higher occurrence of CCE, including intra-aortic balloon pumping, percutaneous transluminal angioplasty of the renal artery, and transcatheter aortic valve implantation or balloon aortic valvuloplasty. CCE is rare but remains a severe complication of cardiovascular procedures. Atherosclerotic risk factors and certain cardiovascular procedures were associated with CCE.

Association between eosinophilia and renal prognosis in patients with pathologically proven cholesterol crystal embolism.

BACKGROUND: Approximately, 20-70% of patients with cholesterol crystal embolism (CCE) have eosinophilia. However, it remains unknown how eosinophilia influences renal prognosis in patients with CCE. In this study, we investigated the association between eosinophil count (Eo) and renal prognosis in CCE patients on steroid therapy. METHODS: The present study is a single-centered retrospective cohort study in patients with renal dysfunction and CCE from April 2007 to May 2018. This study included the patients who were treated with neither maintenance dialysis nor steroid before CCE diagnosis, and followed-up for kidney function until November 2019. We assessed whether eosinophilia at the time of CCE diagnosis was related to renal death after treating with steroid therapy. RESULTS: Thirty patients with pathologically diagnosed CCE were enrolled and followed-up for 11.0 (5.2-43.4) months. There were significant differences in the white blood cell count (p = 0.01), hemoglobin (p = 0.009), serum creatinine levels (p = 0.008), phosphate (p = 0.049), and Eo (p = 0.008) between the renal survival and renal death groups. Using the receiver operating characteristic curve analysis with Youden index, Eo of 810/µL showed 100% sensitivity and 69.6% specificity for detecting renal death (area under the curve: 0.839). Comparing the outcomes in patients having Eo ≥ and < 810/µL using the log-rank test, there is a significantly higher renal death rate in CCE patients with Eo ≥ 810/µL (p = 0.0016). CONCLUSION: Higher eosinophilia was a prognostic risk factor for renal death in the patients with CCE.

Atheroembolism to the Breast.

We report the case of a woman presenting with livedo reticularis of the breast who was found to have atheroembolism to the breast following upper extremity percutaneous access. Atheroembolism is the embolization of cholesterol crystals off an atherosclerotic plaque that can occur spontaneously or as a result of vascular intervention. This is a unique presentation of an otherwise well-described complication of vascular catheterization, and we propose that livedo reticularis of the breast can be interpreted as a sign of atheroembolism in the appropriate clinical context.

Cholesterol Emboli Co-Existing with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis in a 76-Year-Old Woman.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis injures small vessels and causes severe systemic organ injury. Main target antigens of ANCA are myeloperoxidase and proteinase 3. ANCA strongly associates with the development and progression of the vasculitis. Its manifestations include rapidly progressive glomerulonephritis, interstitial pneumonitis, alveolar hemorrhage, purpura, and neurological disorder. Most patients with ANCA-associated vasculitis in Japan are elderly and have atherosclerotic risk factors. Cholesterol emboli are systemic vascular inflammation triggered by cholesterol crystals. Cholesterol emboli cause kidney dysfunction and ischemia of the intestines, brain, heart, skin, and peripheral nerves. Diabetes mellitus, hypertension, hyperlipidemia, and history of cardiovascular diseases are risk factors of the development of cholesterol emboli. We report a case of ANCA-associated vasculitis coexisting with cholesterol emboli. A 76-year-old woman was diagnosed with ANCA-associated interstitial pneumonitis. She rapidly developed progressive glomerulonephritis, purpura, and peripheral sensory nerve disorder. A kidney biopsy revealed that renal dysfunction was caused by vasculitis of the interlobular arteries and cholesterol emboli. A skin biopsy revealed that purpura was caused by cholesterol emboli. Glucocorticoid and statin therapies were administered. Thereafter, the renal function and other symptoms improved and stabilized. The representative symptoms of ANCA-associated vasculitis and cholesterol emboli are closely similar, and it is difficult to distinguish between these diseases when they coexist. Because the background characteristics of patients with ANCA-associated vasculitis and risk factors of cholesterol emboli overlap, at the time of diagnosing ANCA-associated vasculitis, clinicians should consider the possibility of cholesterol emboli coexistence.

Gastric remnant necrosis secondary to cholesterol crystal embolization after distal gastrectomy in a gastric cancer patient: a case report.

BACKGROUND: Distal gastrectomy with lymph node dissection, a standard operative technique for gastric cancer treatment, is safely performed because the stomach has a rich vascular supply. Gastric remnant necrosis caused by cholesterol crystal embolization following distal gastrectomy has not been described previously. We report a case of gastric remnant necrosis in a patient with cholesterol crystal embolization. CASE PRESENTATION: A 70-year-old man with a history of cholesterol crystal embolization presented to our surgery department with complaints of anorexia and dysphasia. He was diagnosed with gastric cancer invading the pyloric antrum and underwent distal gastrectomy with Billroth 2 reconstruction. On postoperative day 11, he developed abdominal pain without fever. Emergency laparotomy revealed that most parts of the remnant stomach were necrosed. Total gastrectomy with Roux-en-Y reconstruction and abscess drainage were performed. After surgery, anastomotic leakage occurred and was treated conservatively. However, the superior pancreaticoduodenal artery aneurysm suddenly ruptured and he expired. CONCLUSIONS: Gastric remnant necrosis after distal gastrectomy can be a gastrointestinal presentation of cholesterol crystal embolization. Perioperative/intraoperative risk assessments such as preventive total gastrectomy or intraoperative assessment with indocyanine green fluorescence angiography may be desirable to avoid this complication.

Successful treatment of cholesterol crystal embolism with anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody: a case report.

Background: We report a unique case of renal cholesterol crystal embolism (CCE) induced by carotid artery stenting that was successfully treated with evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9).Case presentation: A 77-year-old man with hypertension, hyperlipidemia, and chronic kidney disease was referred to our department for decreased estimated glomerular filtration rate (eGFR)-from 32.0 to 13.9 mL/min/1.73 m2-5 weeks after carotid artery stenting. Further examination revealed livedo reticularis in the bilateral toes and eosinophilia (723/µL). Skin biopsy from livedo reticularis tissue in the bilateral toes showed cholesterol clefts in the small arteries. The patient was therefore diagnosed with CCE. After 25 weeks' administration of evolocumab at a dose of 140 mg subcutaneously administered every 2 weeks, his eGFR had improved from 10.7 to 18.1 mL/min/1.73 m2.Conclusion: Evolocumab may have a beneficial effect on renal involvement in patients with CCE.

Long-term outcome of biopsy-proven cholesterol crystal embolism.

BACKGROUND: Cholesterol crystal embolism (CCE) causes renal damage, and there is an extremely high risk of end-stage renal disease. However, the time course of CCE-related renal deterioration varies and little is known about the subsequent risk of dialysis among patients with biopsy-proven CCE. METHODS: We performed a retrospective cohort study of 38 Japanese patients in whom a histological diagnosis of CCE was made from September 1992 to July 2005. Competing risk regression analysis was used to investigate the association between declining renal function ( ≥ 1.5 elevation of serum creatinine within 26 weeks after CCE) or its subtypes (acute [ < 1 week after CCE], subacute [1 to < 6 weeks], and chronic [6 to < 26 weeks]) and the risk of dialysis, with adjustment for age, baseline serum creatinine, and the precipitating event (iatrogenic or spontaneous). RESULTS: During a median follow-up period of 25.9 weeks, 14 patients (35.9%) started dialysis. Multivariable analysis showed that patients with declining renal function had a higher risk of commencing dialysis than those without declining function (subdistribution hazard ratio [SHR] 9.47; 95% confidence interval [CI] 1.34-66.8). Patients with different renal presentations had a similarly increased risk of commencing dialysis, with the risk being significantly higher for the subacute and chronic patterns of declining renal function (adjusted SHR [95% CI] for acute, subacute, and chronic declining renal function[vs. no decline]: 7.36 [0.85-63.6], 11.9 [1.36-101], and 10.7 [1.49-77.0], respectively). CONCLUSION: Declining renal function after CCE, even later than 6 weeks, was significantly associated with the subsequent risk of dialysis.

Cholesterol embolization syndrome: An under-recognized entity in cardiovascular interventions.

Cholesterol embolization syndrome (CES) is a multi-systemic disease caused by embolization of atherosclerotic plaque contents from proximal large-caliber artery to distal small to medium arteries, occurring spontaneously or more commonly after vascular intervention. This report is a comprehensive review of the reported cases of CES found in our literature search. We discuss the risk factors, clinical manifestations, management, and prognosis of CES. The major predisposing factors for CES include older age, male sex, atherosclerotic cardiovascular risk factors, anticoagulation, and femoral access route. The composite incidence of atheroembolic renal disease was 92% and mortality 63%. Our review highlights the importance to recognize this disease entity for the cardiologist and nephrologist.

[Benign Presentation of a Potentially Fatal Disease]. / Ateroembolismo cutâneo: relato de três casos clínicos.

Atheroembolism is a rare multisystemic disorder that is characterized by release of cholesterol crystals and particles from atheromatous plaques, which can occlude distal vessels and induce an inflammatory response. Most affected individuals are males, older than 60 years of age, with advanced atherosclerotic disease. The abdominal aorta is the most common origin of cholesterol emboli, being the peripheral arteries a rarer source. Cholesterol embolization syndrome is often associated with invasive vascular procedures, although, more rarely, it may occur spontaneously. In this paper, the authors present three cases of spontaneous atheroembolism with cutaneous manifestations and their clinical management. Being an underdiagnosed pathology, knowledge about its clinical manifestations is essential in order to allow an early diagnosis and treatment, to ensure a better prognosis for the patient.

O ateroembolismo é uma doença multissistémica rara caraterizada pela libertação de cristais de colesterol e partículas de placas ateroscleróticas, que podem ocluir vasos sanguíneos periféricos e induzir uma resposta inflamatória. A maioria dos indivíduos afetados é do sexo masculino, com idade superior a 60 anos e doença aterosclerótica avançada. A origem mais frequente de embolização de colesterol é a aorta abdominal, sendo as artérias periféricas uma fonte mais rara. A síndrome de embolização por colesterol surge frequentemente associada a procedimentos vasculares invasivos, embora, mais raramente, possa ocorrer de forma espontânea. Neste artigo os autores apresentam três casos clínicos de ateroembolismo espontâneo com envolvimento cutâneo e respetiva abordagem clínica. Sendo uma patologia subdiagnosticada, torna-se fundamental o conhecimento acerca das suas manifestações clínicas, para permitir um diagnóstico e tratamento precoces de forma a garantir um melhor prognóstico para o doente.

"Pseudo aortoiliac bifurcation" leading to significant plaque shifting in the endovascular treatment of an aortoiliac bifurcation lesion: a case report.

BACKGROUND: Plaque shifting is a serious complication of endovascular treatment (EVT) for aortoiliac bifurcation lesions. It is challenging to predict the occurrence of unfavorable plaque shifting correctly. CASE PRESENTATION: We report the case of an 88-year-old Japanese woman who experienced constant pain at rest in her left leg. The ankle-brachial pressure index of her left leg was 0.57. Computed tomography (CT) angiography revealed severe stenosis of the left common iliac artery (CIA) and total occlusion of the left external iliac artery (EIA). We diagnosed the patient with acute exacerbation of a chronic limb ischemia and administered endovascular treatment (EVT) to treat the left CIA and EIA. The results of initial angiography agreed with those of CT angiography. After placing a self-expandable stent for the left CIA lesion, significant unfavorable plaque shifting occurred. From a comparison between pre- and post-stenting angiography, we realized that the plaque protrusion into the terminal aorta had formed a "pseudo aortoiliac bifurcation" that was situated more proximally compared to the true bifurcation. We had incorrectly assessed the height of the aortoiliac bifurcation and exact plaque position and had underestimated the risk of plaque shifting because of this misunderstanding. The patient ultimately developed fatal cholesterol embolization after EVT. CONCLUSIONS: Plaque protrusion into the terminal aorta can form a "pseudo aortoiliac bifurcation", causing the wrong estimation of the height of the aortoiliac bifurcation; "angiographically", the highest point is not always the true bifurcation. Careful assessment of initial angiography to detect the true aortoiliac bifurcation and exact plaque position is essential to avoid unfavorable plaque shifting.

Efficacy of low-density lipoprotein apheresis combined with corticosteroids for cholesterol crystal embolism.

BACKGROUND: Corticosteroids have been widely used in patients with cholesterol crystal embolism (CCE) and low-density lipoprotein apheresis (LDL-A) was reported to reduce the risk of end-stage renal disease in patients with CCE. This study was designed to evaluate the renoprotective effects of LDL-A in combination with corticosteroids in patients with CCE. METHODS: Thirty-five patients with CCE who, between 2008 and 2013, had shown renal deterioration after vascular interventions were retrospectively evaluated. All patients received corticosteroids; of these, 24 also received LDL-A and 11 did not, designated LDL-A and control groups, respectively. Differences in eGFR (ΔeGFR), 3 months and 1 year after CCE diagnosis, were compared in the two groups. RESULTS: The median estimated glomerular filtration rate (eGFR) in all patients was 38.9 [interquartile range (IQR) 31.9-49.4] ml/min/1.73 m2 at baseline (before vascular intervention). At diagnosis, it was 14.4 (IQR 11.3-21.8) ml/min/1.73 m2. The initial corticosteroid dose was 0.34 ± 0.10 mg/kg/day. The mean number of LDL-A treatment sessions in the LDL-A group was 4.3 ± 1.8. eGFR was increased significantly after LDL-A treatments, from 15.0 (IQR 12.3-20.1) to 19.6 (IQR 14.3-23.6) ml/min/1.73 m2 (P < 0.05). ΔeGFR tended to be higher in the LDL-A than in the control group at 3 months [median 6.5 (IQR 5.1-9.3) vs. 2.6 (IQR -0.6 to 6.3) ml/min/1.73 m2, P = 0.095] and was significantly higher at 1 year [median 7.5 (IQR 5.4-8.7) vs. 2.2 (IQR -3.8 to 5.1) ml/min/1.73 m2, P = 0.019]. CONCLUSIONS: LDL-A plus corticosteroids may restore deteriorated renal function better than corticosteroids alone in patients with CCE.