Cholesterol-embolization syndrome: current perspectives.

Cholesterol-embolization syndrome (CES) is a multisystemic disease with various clinical manifestations. CES is caused by embolization of cholesterol crystals (CCs) from atherosclerotic plaques located in the major arteries, and is induced mostly iatrogenically by interventional and surgical procedures; however, it may also occur spontaneously. Embolized CCs lead to both ischemic and inflammatory damage to the target organ. Therefore, anti-inflammatory agents, such as corticosteroids and cyclophosphamide, have been investigated as treatment for CES in several studies, with conflicting results. Recent research has revealed that CES is actually a kind of autoinflammatory disease in which inflammasome pathways, such as NLRP3 and IL1, are induced by CCs. These recent findings may have clinical implications such that colchicine and IL1 inhibitors, namely canakinumab, may be beneficial in the early stages of CES.

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.

Ileus caused by cholesterol crystal embolization: A case report.

Cholesterol crystal embolization (CCE) is a rare systemic embolism caused by formation of cholesterol crystals from atherosclerotic plaques. CCE usually occurs during vascular manipulation, such as vascular surgery or endovascular catheter manipulation, or due to anticoagulation or thrombolytic therapy. We report a rare case of intestinal obstruction caused by spontaneous CCE. An 81-year-old man with a history of hypertension was admitted for complaints of abdominal pain, bloating, and anorexia persisting for 4 mo. An abdominal computed tomography revealed intestinal ileus. His symptoms were immediately relieved by an ileus tube insertion, and he was discharged 6 d later. However, these symptoms immediately reappeared and persisted, and partial resection of the small intestine was performed. A histopathological examination indicated that small intestine obstruction was caused by CCE. At the 12-mo follow-up, the patient showed no evidence of CCE recurrence. Thus, in cases of intestinal obstruction, CCE should also be considered.

Association between absolute blood eosinophil count and CKD stages among cardiac patients.

Elevated eosinophil count was shown to be associated with the development of cholesterol embolization syndrome, a potentially life-threatening condition, after catheter-based procedures. We investigated the association between stages of chronic kidney disease (CKD) and the absolute eosinophil count (AEC) among cardiac patients. CKD stages were determined solely on the estimated glomerular filtration rate or requirement for hemodialysis. Eosinophilia is defined as an eosinophil count exceeding 500/µL. A total of 1022 patients were enrolled in the current study, and eosinophil counts (/µL) in the first through fourth eosinophil count quartiles were <88, 88 to 154, 155 to <238, and 238 ≤, respectively, and 29 patients (2.8 %) had eosinophilia. Correlation coefficient between the AEC and age was -0.188 (P = 0.001) in women and -0.042 (n.s.) in men (by Spearman's correlation test). Patients with higher CKD stages had a higher prevalence of the highest AEC quartile or eosinophilia. Logistic regression analysis using severe renal dysfunction (i.e., CKD stage 4 or 5) as the dependent variable, the highest AEC quartile had a significant positive association with an odds ratio of 1.99 (95 % confidence interval, 1.20-3.31, P < 0.01) after adjustment for sex, age, systolic blood pressure, and total white blood cell count. Similarly, after adjustment for the same variables, eosinophilia was associated with severe renal dysfunction with an odds ratio of 2.60 (95 % confidence interval, 1.08-6.26, P < 0.05). Eosinophil count was positively associated with higher CKD stages among cardiology patients, some fraction of which might be related to subclinical cholesterol embolization.

Ateroembolia de colesterol / Cholesterol atheroembolism

La ateroembolia de colesterol (AEC) es una enfermedad sistémica poco conocida y con un pronóstico sombrío. En estas últimas décadas, su incidencia ha aumentado considerablemente. El diagnóstico es difícil y parte de una alta sospecha clínica, dada la inespecificidad de sus síntomas y el frecuente inicio tardío, semanas después de haber estado expuesto a factores predisponentes (procedimientos endovasculares, tratamiento anticoagulante). Se confirma por la biopsia del órgano afectado. A continuación presentamos un caso clínico de una paciente con AEC de origen espontáneo que presentaba manifestaciones cutáneas, donde la sospecha clínica de esta enfermedad fue la clave para su diagnóstico y un temprano manejo terapéutico (AU)

Cholesterol atheroembolism (CAE) is a rarely known systemic disease with bad prognosis. In the last decades, the incidence of this disorder has increased considerably. The diagnosis is difficult and starts with a clinical suspicion, given the lack of specific symptoms and the frequent late onset during the weeks after exposure of the patient to predisposing factors (angiographic procedures or anticoagulant treatments). It is confirmed by biopsy of the affected organ. Below we report the case of a patient with spontaneous CAE who presented skin manifestations, where clinical suspicion of this disease was the key to diagnosis and early therapeutic management (AU)

An unusual case of a patient who lost his native kidneys and renal allograft from cholesterol crystal emboli.

Cholesterol crystal emboli (CCE) syndrome involving native kidneys is an underdiagnosed condition. CCE is rare in renal allografts. It may present with acute kidney injury, but usually not acute graft loss. CCE should be considered in patients with a history of atherosclerosis and an invasive arterial procedure who present with acute or chronic renal allograft dysfunction. Therapy for CCE is mainly supportive and carries a high rate of mortality. To the best of our knowledge, this is the first reported case of a patient who lost his native kidneys and renal allograft due to CCE arising from his own vasculature.

Low-Density Lipoprotein Apheresis Ameliorates Renal Prognosis of Cholesterol Crystal Embolism.

Drugs such as corticosteroids and statins have been used to treat cholesterol crystal embolism (CCE), but the prognosis remains poor. This study evaluated the efficacy of low-density lipoprotein apheresis (LDL-A) in patients with CCE. Patients with CCE who showed renal deterioration after vascular interventions were studied retrospectively. Information on demographic variables, clinical measurements, and medication use was collected. The outcomes were incidence of maintenance dialysis and mortality at 24 weeks. A total of 49 patients with CCE were included, among whom 37 (76%) were diagnosed pathologically and the remainder were diagnosed clinically. The median estimated GFR at baseline and at diagnosis were 40.5 and 13.4 mL/min per 1.73 m(2) , respectively. Corticosteroids were used in 42 patients (86%), statins in 30 patients (61%), and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in 29 patients (59%). LDL-A was performed in 25 patients (LDL-A group), and not in 24 patients (control group). Smoking (100% vs. 72%, P = 0.02), white blood cell count (8900/mm(3) vs. 7000/mm(3) ) and corticosteroid use (96% vs. 75%) were higher in the LDL-A group compared with the control group, but there were no differences in other demographic and clinical parameters between the groups. Patients in the LDL-A group had a lower incidence of maintenance dialysis (2/25 (8%) vs. 8/24 (33%), P < 0.05), and a trend towards lower mortality (2/25 (8%) vs. 7/24 (29%), P = 0.074). These results suggest that LDL-A decreases the risk of maintenance dialysis in severe renal CCE patients after vascular interventions.

Atheroembolism during percutaneous renal artery revascularization.

INTRODUCTION: Atheroembolization during renal artery angioplasty and stenting (RA-PTAS) has been postulated as a cause for the inferior renal function results observed when compared with those with surgical revascularization. To further characterize procedure-associated atheroembolism, we analyzed recovered atheroembolic debris and clinical data from patients undergoing RA-PTAS with distal embolic protection (DEP). METHODS: RA-PTAS procedures were performed with DEP using a commercially available temporary balloon occlusion and aspiration catheter system between July 2005 and December 2006. Following RA-PTAS but prior to deflation of the distal occlusion balloon, the static column of blood proximal to the balloon was aspirated and submitted for embolic particle analysis. Angiograms, demographics, and laboratory data were reviewed. Glomerular filtration rate (eGFR) was estimated before RA-PTAS and at 4 to 8 weeks postintervention using the abbreviated Modification of Diet in Renal Disease formula. Associations between clinical factors, captured particle counts, and changes in renal function were examined using univariate techniques and multiple linear regression. RESULTS: Twenty-eight RA-PTAS procedures were performed with DEP. Mean total number of embolic particles counted per procedure was 2033 +/- 1553 for particles 20-60 microm and 265 +/- 132 for particles >60 microm. Significant positive associations with quantity of captured particles 20 to 60 microm were observed for African American race (P = .002), predilation (P = .005), and stent diameter (P < .001); a significant negative association was observed for preoperative aspirin use (P =.016). Quantity of captured particles >60 microm was positively associated with ratio of stent to renal artery diameter (P =.009). Change in eGFR was positively associated with preoperative aspirin use (P = .006) and preoperative eGFR (P < .001), while a negative association was observed for captured particle counts >60 microm (P = .015). CONCLUSION: These results demonstrate the liberation of thousands of atheroembolic particles during RA-PTAS. Clinical, anatomic, and device-related factors may be predictive of procedural embolization, and increasing captured particle counts >60 microm were associated with inferior renal function results. Further investigation is warranted to establish relationships between atheroembolism, end organ functional impairment, and clinical responses.

LDL apheresis for cholesterol embolism following coronary artery bypass graft surgery--a case report.

A 76-year-old man without any prior history of abnormal urinalysis findings or renal insufficiency demonstrated mild renal dysfunction after coronary bypass graft surgery (CABG). Two months after CABG, pain and blueness in the toes (blue toe syndrome) appeared and, the serum creatinine level (S-Cr) increased from 1.2 to 2.0 mg/dL. On admission (3 months later), the urinary protein level was 0.5 g/day, white blood cell count 8,300/microL with eosinophils (Eo) 10.5%, S-Cr 2.1 mg/dL, and low-density lipoprotein (LDL) 106 mg/dL. Acute renal failure and blue toe syndrome due to a cholesterol embolism (CE) were diagnosed. Alprostadil 40 microg/day orally for 2 weeks and alprostadil 40 microg/day intravenously were used for 5 weeks, and Eo were 250/microL, S-Cr 2.5 mg/dL; however, blue toe syndrome gradually developed. At 8 weeks after admission, limaprost alfadex 30 microg/day orally was used for 3 weeks. However, the Eo gradually rose to 1,520/microL, S-Cr to 3.0 mg/dL, and LDL to 135 mg/dL, and LDL apheresis was therefore performed 20 times for CE. The data just after LDL apheresis was performed 10 times were as follows: Eo 1,120/microL, S-Cr 4.0 mg/dL, and LDL 89 mg/dL, and blue toe syndrome had disappeared. At 10 months after the first LDL apheresis, the Eo were 630/microL, S-Cr 2.9 mg/dL, and LDL 109 mg/dL. As a result, LDL apheresis was found to be beneficial for the treatment of CE with acute renal failure and blue toe syndrome after CABG.

Serum levels of soluble P-selectin are increased and associated with disease activity in patients with Behçet's syndrome.

Behçet's syndrome (BS) is a relapsing, chronic, inflammatory disease characterized by endothelial dysfunction, atherothromboembogenesis, and leukocytoclastic vasculitis with complex immunologic molecular interactions. Generalized derangements of the lymphocyte and neutrophil populations, activated monocytes, and increased PMNLs motility with upregulated cell surface molecules such as ICAM-1, VCAM-1, and E-selectin, which are found on the endothelial cells, leukocytes, and platelets, have all been demonstrated during the course of BS. Our aim is to investigate the association of serum concentrations of soluble P-selectin in patients with BS, and to evaluate whether disease activity has an effect on their blood levels. This multicenter study included 31 patients with BS (15 men and 16 women) and 20 age- and sex-matched healthy control volunteers (11 men and nine women). Neutrophil count, erythrocyte sedimentation rate, and acute-phase reactants as well as soluble P-selectin levels were determined. The mean age and sex distributions were similar (P > .05) between BS patients (35 years) and control volunteers (36 years). Serum levels of soluble P-selectin in patients with BS (399 +/- 72 ng/mL) were significantly (P < .001) higher when compared with control subjects (164 +/- 40 ng/mL). In addition, active BS patients (453 +/- 37 ng/mL) had significantly (P < .001) elevated levels of soluble P-selectin than those in inactive period (341 +/- 52 ng/mL). This study clearly demonstrated that serum soluble P-selectin levels are increased in BS patients when compared with control subjects, suggesting a modulator role for soluble P-selectin during the course of platelet activation and therefore, atherothrombogenesis formation in BS, especially in active disease.

[Current pharmacological principles to inhibit platelet function and their clinical implications. Focus on clopidogrel]. / Aktuelle pharmakologische Prinzipien der Plättchenfunktionshemmung und ihre Implikationen für die Klinik. Fokus auf Clopidogrel.

Clopidogrel is a further-developed analog of ticlopidine and currently the only therapeutic alternative for long-term prophylaxis and therapy of atherothrombosis. According to the CAPRIE trial, clopidogrel causes significantly less gastrointestinal bleeding than plain aspirin (ASA). There is an increased antiplatelet efficacy by combining clopidogrel with ASA as shown in several clinical trials, such as CURE and CREDO. An active metabolite of clopidogrel causes irreversible inhibition of the P2Y12-ADP receptor at the platelet surface, but does not alter the metabolism of arachidonic acid. Clopidogrel has additional effects on the ADP-induced expression of adhesion molecules (P-selectin, GPIIb/IIIa) and inflammatory mediators (CD40L). These actions, shown ex vivo, might be clinically relevant. Similar to ASA there can be variable antiplatelet activities of Clopidogrel. Their frequency can not be precisely estimated yet. There is neither a generally accepted definition of insufficient responsiveness (against inhibitors of platelet function) nor any generally accepted procedure to measure it, including definition of normal range.

The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.

BACKGROUND: Cholesterol embolization syndrome is a systemic disease caused by distal showering of cholesterol crystals after angiography, major vessel surgery, or thrombolysis. METHODS: We prospectively evaluated a total of 1,786 consecutive patients 40 years of age and older, who underwent left-heart catheterization at 11 participating hospitals. The diagnosis of CES was made when patients had peripheral cutaneous involvement (livedo reticularis, blue toe syndrome, and digital gangrene) or renal dysfunction. RESULTS: Twenty-five patients (1.4%) were diagnosed as having CES. Twelve patients (48%) had cutaneous signs, and 16 patients (64%) had renal insufficiency. Eosinophil counts were significantly higher in CES patients than in non-CES patients before and after cardiac catheterization. The in-hospital mortality rate was 16.0% (4 patients), which was significantly higher than that without CES (0.5%, p < 0.01). All four patients with CES who died after cardiac catheterization had progressive renal dysfunction. The incidence of CES increased in patients with atherosclerotic disease, hypertension, a history of smoking, and the elevation of baseline plasma C-reactive protein (CRP) by univariate analysis. The femoral approach did not increase the incidence, suggesting a possibility that the ascending aorta may be a potential embolic source. As an independent predictor of CES, multivariate regression analysis identified only the elevation of pre-procedural CRP levels (odds ratio 4.6, P = 0.01). CONCLUSIONS: Cholesterol embolization syndrome is a relatively rare but serious complication after cardiac catheterization. Elevated plasma levels of pre-procedural CRP are associated with subsequent CES in patients who undergo vascular procedures.

Atheroembolic renal failure requiring dialysis: potential for renal recovery? A review of 43 cases.

AIMS: Our objectives were to review the characteristics of patients who developed atheroembolic renal disease requiring dialysis as well as their renal function recovery and survival rates. METHODS: All cases of atheroembolic disease with renal failure severe enough to require dialysis were reviewed from January 1984 to December 2000 in two centers. The diagnosis of atheroemboli was based on clinical presentation and/or biopsy. Acute renal failure was defined as a serum creatinine >200 micromol/l if normal at baseline or doubling from baseline if chronic renal failure, whereas renal function recovery was the ability to discontinue renal replacement therapy for >or=3 months. RESULTS: Forty-three cases were identified (37 males and 6 females; mean age 67 +/- 5 years); the average time to acute renal failure and to diagnosis was similar at 36 days. The majority of patients had at least one precipitating factor identified (58% coronary angiography, 26% angiography, 16% vascular surgery, 2% anticoagulation); 1 had a spontaneous presentation whereas 7 had more than one factor. More than 90% had underlying hypertension and chronic renal dysfunction with a baseline creatinine of 195 +/- 81 micromol/l, approximately 80% had coronary artery disease, 80% were smokers, 60% had a history of abdominal aorta aneurysm, >50% presented with intermittent claudication, and 56% were anticoagulated at the time of the event. Most patients were nonoliguric (80%), had increased hypertension (71%), blue toes (67%), livedo reticularis (52%), whereas abdominal pain and central nervous system symptoms were present in 33 and 7% of the cases, respectively. Eosinophilia was found in 88%, while hypocomplementemia was present in less than 15%. When compared to the 12 patients with recovery of renal function (after a mean delay of 409 +/- 336 days), the 31 patients who did not recover function presented with more severe intermittent claudication and underlying chronic renal dysfunction (p < 0.05). Indeed, the only variable found to unfavorably influence renal function recovery was the presence of intermittent claudication. Patients were mainly treated by intermittent hemodialysis except for 5 (2 on CRRT and 3 on peritoneal dialysis). Renal function recovery was associated with a higher chance of survival; 33% of patients died in the first year after diagnosis. CONCLUSION: Atheroembolic renal disease carries a high mortality rate reflective of the extensive cardiovascular disease of affected patients; nevertheless, the potential for renal function recovery appears greater than for other vascular causes of renal failure.

Potential therapeutic effect of simvastatin on progressive renal failure and nephrotic-range proteinuria caused by renal cholesterol embolism.

We report our experience with a 62-year-old Japanese man with cholesterol crystal embolism after angiographic procedures performed because of intermittent claudication. In addition to progressive renal failure and nephrotic-range proteinuria, cutaneous ischemia, consisting of livedo reticularis in the lower limbs and digital necrosis at the tip of the right toe, and fundoscopic findings showing several white spots in the branches of retinal artery were also observed. Progressive renal failure and nephrotic-range proteinuria were halted just after treatment with simvastatin. Thus, simvastatin can exert a beneficial therapeutic effect on renal cholesterol embolism.

C-reactive protein and atherothrombosis.

Circulating concentrations of C-reactive protein (CRP), the classical acute phase protein and sensitive systemic marker of inflammation, significantly predict atherothrombotic events and outcome after acute myocardial infarction, demonstrating the key role of inflammation in atherosclerosis and its complications. The binding specificity of CRP for low density lipoproteins, for modified low density lipoproteins, and for damaged and dead cells, coupled with the capacity of bound CRP to activate complement, and with the presence of CRP in atheroma and acute myocardial infarction lesions, all suggest a possible pathogenetic role of CRP. Development of drugs to block binding of CRP to its various ligands in vivo will enable this hypothesis to be tested.