[Update on cholesterol crystal embolism]. / État des lieux de la maladie des emboles de cholestérol.

Cholesterol crystal embolism is a systemic pathology associated with diffuse atherosclerosis. Pathophysiology corresponds to tissue necro-inflammation secondary to arteriolar occlusion associated with microembolism from atherosclerotic plaques of large diameter arteries. The clinical presentation is heterogeneous and polymorphic. Multiple organs may be the targets, but preferential damage is skin, kidneys and digestive system. It is a serious pathology, underdiagnosed, with a poor prognosis. The risk factors for developing the disease remain the same risk factors as atheroma. The factors favouring migration of microembolism remain mainly vascular interventional procedures; easy to diagnose, they oppose spontaneous embolic migrations or secondary to the introduction of antithrombotic treatment, whose diagnosis is more difficult and the prognosis more severe. The diagnosis of the disease remains mostly a diagnosis of elimination and often refers to a bundle of clinical, biological, morphological and histologic arguments. The treatment is poorly codified and the subject of few publications. It will favour both symptomatic treatment (and mainly that of pain) and complications (high blood pressure, renal insufficiency). The aetiological support remains less consensual. The treatment of atherosclerotic plaques consists, of course, in the correction of classical cardiovascular risk factors, the introduction of a statin. It will be discussed in the implementation of surgery or angioplasty to exclude potentially responsible atherosclerotic lesions. Eviction of antithrombotic therapy should be considered in terms of the benefit-risk balance, but often in favour of maintaining it. Finally, other treatments may be proposed in a case-by-case basis, such as oral or intravenous corticosteroid therapy, colchicine or LDL aphaeresis.

Cholesterol Crystal Embolism and Chronic Kidney Disease.

Renal disease caused by cholesterol crystal embolism (CCE) occurs when cholesterol crystals become lodged in small renal arteries after small pieces of atheromatous plaques break off from the aorta or renal arteries and shower the downstream vascular bed. CCE is a multisystemic disease but kidneys are particularly vulnerable to atheroembolic disease, which can cause an acute, subacute, or chronic decline in renal function. This life-threatening disease may be underdiagnosed and overlooked as a cause of chronic kidney disease (CKD) among patients with advanced atherosclerosis. CCE can result from vascular surgery, angiography, or administration of anticoagulants. Atheroembolic renal disease has various clinical features that resemble those found in other kidney disorders and systemic diseases. It is commonly misdiagnosed in clinic, but confirmed by characteristic renal biopsy findings. Therapeutic options are limited, and prognosis is considered to be poor. Expanding knowledge of atheroembolic renal disease due to CCE opens perspectives for recognition, diagnosis, and treatment of this cause of progressive renal insufficiency.

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)

Molecular mechanisms of crystal-related kidney inflammation and injury. Implications for cholesterol embolism, crystalline nephropathies and kidney stone disease.

Crystals are particles of endogenous inorganic or organic composition that can trigger kidney injury when deposited or formed inside the kidney. While decades of research have focused on the molecular mechanisms of solute supersaturation and crystal formation, the pathomechanisms of crystal-induced renal inflammation remain largely unknown. The recent discovery of the intracellular NLRP3 inflammasome as a pattern recognition platform that translates crystal uptake into innate immune activation via secretion of IL-1ß and IL-18 revised the pathogenesis of gout, silicosis, asbestosis, atherosclerosis and other crystal-related disorders. As a proof of concept, the NLRP3 inflammasome was now shown to trigger inflammation and acute kidney injury (AKI) in oxalate nephropathy. It seems likely that this and potentially other innate immunity mechanisms drive crystalline nephropathies (CNs) that are associated with crystals of calcium phosphate, uric acid, cysteine, adenine, certain drugs or contrast media, and potentially of myoglobin during rhabdomyolysis and of light chains in myeloma. Here, we discuss the proven and potential mechanisms of renal inflammation and kidney injury in crystal-related kidney disorders. In addition, we list topics for further research in that field. This perspective may also provide novel therapeutic options that can help to avoid progressive tissue remodeling and chronic kidney disease in patients with kidney stone disease or other CNs.

Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c.

Racial differences in the pathophysiology of atherothrombosis are poorly understood. We explored the function and transcriptome of platelets in healthy black (n = 70) and white (n = 84) subjects. Platelet aggregation and calcium mobilization induced by the PAR4 thrombin receptor were significantly greater in black subjects. Numerous differentially expressed RNAs were associated with both race and PAR4 reactivity, including PCTP (encoding phosphatidylcholine transfer protein), and platelets from black subjects expressed higher levels of PC-TP protein. PC-TP inhibition or depletion blocked PAR4- but not PAR1-mediated activation of platelets and megakaryocytic cell lines. miR-376c levels were differentially expressed by race and PAR4 reactivity and were inversely correlated with PCTP mRNA levels, PC-TP protein levels and PAR4 reactivity. miR-376c regulated the expression of PC-TP in human megakaryocytes. A disproportionately high number of microRNAs that were differentially expressed by race and PAR4 reactivity, including miR-376c, are encoded in the DLK1-DIO3 locus and were expressed at lower levels in platelets from black subjects. These results suggest that PC-TP contributes to the racial difference in PAR4-mediated platelet activation, indicate a genomic contribution to platelet function that differs by race and emphasize a need to consider the effects of race when developing anti-thrombotic drugs.

[Granulocyte colony stimulating factor attenuated myocardial apoptosis via Janus kinase 2/signal transducer and activator of transcription signal transduction pathway in rats with coronary microembolization].

OBJECTIVE: To investigate the effects of granulocyte colony stimulating factor (G-CSF) on myocardial apoptosis following coronary microembolization (CME) and possible role of Janus kinase/singnal transducer and activator of transcription (JAK/STAT) pathway in this process. METHODS: A total of 92 male Sprague Dawley rats were randomized into CME (n = 24), G-CSF (100 microg x kg(-1) x d(-1) i.p. 2 hours post CME for 5 days, n = 24), JAK2 inhibitor AG490 (G-CSF plus AG490, 5 mg x kg(-1) x d(-1) i.p. 2 hours post CME for 5 days, n = 24), all rats received left ventricular injection of homologous microthrombotic particle suspension post clamping the ascending aorta. Sham-operated group (n = 20) served as control. The rats were sacrificed at day 3, 7, 14 and 28 after operation. The myocardial mRNA expressions of Bcl-2, Bax, Fas, FasL and GAPDH which was used as the intercomparison, were evaluated by real time PCR. The ratio of Bcl-2/Bax was compared. The protein expression of Caspase-3, cleaved PARP, t-JAK2, p-JAK2, t-STAT3 and p-STAT3 were detected by western blot. Myocardial apoptosis were examined by TUNEL staining. RESULTS: Compared with Sham rats, the mRNA of Bcl-2, Bax, Fas and FasL significantly increased whereas the ratio of Bcl-2/Bax (0.28 +/- 0.04 vs. 2.98 +/- 0.49) significantly decreased and the protein expression of Caspase-3 (0.762 +/- 0.129 vs. 0.133 +/- 0.027), PARP (0.992 +/- 0.146 vs. 0.386 +/- 0.074) and the myocardial apoptosis index (17.2 +/- 1.9 vs. 1.2 +/- 0.6) significantly increased in CME hearts (all P < 0.05). rhG-CSF significantly attenuated CME induced changes and cotreatment with JAK2 inhibitor AG490 abolished the effects of rhG-CSF. The protein expressions of t-JAK2 and t-STAT3 among the groups were similar. P-JAK2 and p-STAT3 protein expressions were significantly increased in G-CSF group compared to other groups (P < 0.05). CONCLUSION: G-CSF attenuated myocardial apoptosis induced by CME via JAK2/STAT3 pathway.

Enhanced scavenging of lipid substances is a possible effect of corticosteroids in the treatment of cholesterol crystal embolism.

Cholesterol crystal embolism (CCE) is a systemic refractory disease especially prevalent amongst elderly patients suffering from atherosclerosis. Treatment of this condition remains controversial due to difficulties in diagnosis. Corticosteroid therapy may be an important treatment option despite its elusive mechanisms. To clarify the role of corticosteroid in CCE therapy, we collected the samples from six autopsied subjects with CCE, three of whom were clinically given various doses of corticosteroid to investigate stable atherosclerosis-related substances, advanced glycation end-products (AGE), and several AGE receptors such as scavenger receptor class B type 1 (SR-B1), receptor for AGE (RAGE), and galectin-3 in the liver tissues and atherosclerotic areas by immunostaining using a tissue macro-array technique. An intense expression of AGE and its receptors was identified in the enlarged Kupffer cells of CCE cases, which were given relatively high doses of corticosteroid. In addition, numerous mononuclear cells in the intimal atheromatous plaque presented strong expressions of AGE and SR-B1. In conclusion, we speculated that corticosteroid treatment for CCE may upregulate the activations, including phagocytic capacity of Kupffer cells mediated by overexpression of RAGE and scavenger receptors, resulting in efficient clearance of the lipid substances from the blood circulation released from atherosclerotic areas.

Technology insight: targeting of biological molecules for evaluation of high-risk atherosclerotic plaques with magnetic resonance imaging.

Identification of high-risk atherosclerotic lesions prone to rupture and thrombosis may greatly decrease the morbidity and mortality associated with atherosclerosis. The development of magnetic resonance imaging contrast agents that specifically target components of the atherosclerotic plaque might enable non-invasive detection of high-risk lesions. This review discusses a variety of molecules present in atherosclerotic plaque that could serve as targets for specific contrast agents. Ultimately, such agents may allow the identification of high-risk atherosclerotic lesions in patients and enable treatment of these patients before lesion progression and complications.

Cholesterol emboli to the kidney: an immunoperoxidase study.

Cholesterol emboli (CE) are an increasingly recognised cause of renal impairment in the elderly population, especially following diagnostic vascular procedures and aortic surgery. They can present as part of a multisystem disease which can mimic many conditions, depending on the site of the emboli. As a pathological entity, it was described by Florey in 1945. Relatively few cases have been reported in the literature. At this stage there is no accepted treatment protocol for CE induced renal failure. Little is known about the precise nature of the cells involved in the proliferating tissue surrounding CE in the kidney. To date, all studies on CE have involved routine Haematoxylin and Eosin (H&E) stains. By studying the cellular interactions, hopefully this will contribute further to our understanding of CE in the kidney. Nine (n = 9) out of 1150 consecutive renal biopsies over a six year period were analysed. Standard three- and four-layered peroxidase-antiperoxidase techniques were employed. A panel of antibodies to specific cells were used. The particular cells analysed were the myofibroblast, smooth muscle, endothelium, macrophage, neutrophil, T cell and B cell. All vessels in the biopsy specimen containing CE were analysed. T cell, B cell, macrophage and neutrophil infiltrates were counted and expressed as cells/mm2 using a 0.022 mm2 graticule under 400 (10x40) magnification. The vessel and perivascular space were analysed. The myofibroblast, smooth muscle and endothelial cell proliferation were graded semiquantitatively. Vessels without evidence of CE were used as controls. The data were subjected to statistical analysis using the unpaired non-parametric Mann-Whitney Two Sample test. P values <0.05 were accepted as significant. Histological sections demonstrated the host response in the vessel to CE involve a significant response including the myofibroblast, endothelium, T cell and macrophage. The B cell response was absent and the smooth muscle cell response was not significantly different. The perivascular responses were not different for the cells studied. This study has characterised the host response to CE in the human kidney by demonstrating the presence of the myofibroblast, macrophage T cell and endothelial cell response. The myofibroblast is a cell which is increasingly being recognised in the host response of both granulation tissue and pathological tissue. The population at risk for CE is growing and the disease is increasingly iatrogenic in origin. Currently our only treatment is prevention.