Cholesterol Crystals Research Articles

Gasdermin D drives focal crystalline thrombotic microangiopathy by accelerating immunothrombosis and necroinflammation

AbstractThrombotic microangiopathy (TMA) is characterized by immunothrombosis and life-threatening organ failure but the precise underlying mechanism driving its pathogenesis remains elusive. In this study, we hypothesized that gasdermin D (GSDMD), a pore-forming protein that serves as the final downstream effector of the pyroptosis/interleukin-1β (IL-1β) pathway, contributes to TMA and its consequences by amplifying neutrophil maturation and subsequent necrosis. Using a murine model of focal crystalline TMA, we found that Gsdmd deficiency ameliorated immunothrombosis, acute tissue injury, and failure. Gsdmd−/− mice exhibited a decrease in mature IL-1β, as well as in neutrophil maturation, β2-integrin activation, and recruitment to TMA lesions, in which they formed reduced neutrophil extracellular traps in both arteries and interstitial tissue. The GSDMD inhibitor disulfiram dose-dependently suppressed human neutrophil pyroptosis in response to cholesterol crystals. Experiments with GSDMD–deficient, human–induced, pluripotent stem cell–derived neutrophils confirmed the involvement of GSDMD in neutrophil β2-integrin activation, maturation, and pyroptosis. Both prophylactic and therapeutic administration of disulfiram protected the mice from focal TMA, acute tissue injury, and failure. Our data identified GSDMD as a key mediator of focal crystalline TMA and its consequences, including ischemic tissue infarction and organ failure. GSDMD could potentially serve as a therapeutic target for the systemic forms of TMA.

Transcriptomic analysis reveals the critical role of chemokine signaling in the anti-atherosclerosis effect of Xuefu Zhuyu decoction

Ethnopharmacological relevanceThe process of atherosclerosis (AS) is complicated. Transcriptomics technology can assist in discovering the underlying mechanisms and exploring the key targets of Traditional Chinese Medicine (TCM) against atherosclerosis. AimThis study aimed to investigate targets and signaling pathways significantly related to AS and the potential intervention targets of Xuefu Zhuyu decoction by transcriptomics. Materials and methodsAS models were established by subjecting ApoE-/-mice to an 8-week high-fat diet. Structural changes and plaque formation in the aortic root were observed using hematoxylin-eosin staining (HE staining), while Oil Red O staining was employed to visualize lipid deposition within the aortic root plaque. Movat staining and immunohistochemical staining were conducted to examine the components present in the aortic root plaque. Macrophage content within the plaque was observed through immunofluorescence. Additionally, mRNA sequencing was performed on aortic tissues to identify differentially expressed genes. Enrichment analysis was performed using GO and KEGG analysis. Visualization of the protein-protein interaction (PPI) network was achieved using Cytoscape 3.7.1 and STRING. Western blotting (WB) was employed to assess the protein expression of major differentially expressed genes in the aortic tissue. The drug freeze-dried powder of Xuefu Zhuyu decoction was prepared and the RAW264.7 cells were induced by lipopolysaccharide (LPS) to build an in vitro model. Real-time quantitative PCR was employed to measure the mRNA expression of major differential genes. ResultsAfter ApoE-/- mice were fed with an 8-week high-fat diet, observable changes included the thinning of the aortic root wall, the accumulation of foam cells within the plaque, and the formation of cholesterol crystals in the model group. Treatment with Xuefu Zhuyu (XFZY) decoction for 12 weeks significantly reduced the lipid deposition and the number of macrophages (P < 0.05) and significantly increased the collagen content within the plaque (P < 0.01). Enrichment analysis revealed a high enrichment of the Cytokine-cytokine receptor interaction pathway and Chemokine signaling pathway. Noteworthy genes involved in this response included Ccl12, Ccl22, Cx3cr1, Ccr7, Ccr2, Tnfrsf25, and Gdf5. Xuefu Zhuyu decoction significantly downregulated the expression of CX3CL1 and CX3CR1 (P < 0.05) and upregulated the expression of GDF5 (P < 0.01). Compared with control group, in cell models, the mRNA expressions of Ccl12, Ccl22, and Ccr2 were significantly upregulated (P < 0.05 or P < 0.01). Xuefu Zhuyu decoction significantly downregulated the expression of Ccl12, Ccl22, Cx3cr1, Ccr7 and Ccr2 (P < 0.05 or P < 0.01). ConclusionXuefu Zhuyu decoction demonstrates effective regulation of plaque components, retarding plaque progression and preserving plaque stability by modulating lipid metabolism and inflammatory responses. Subsequent transcriptome analysis identified the Cytokine-cytokine receptor interaction and Chemokine signaling pathway as potential key pathways for the therapeutic effects of Xuefu Zhuyu decoction. This insight not only provides crucial avenues for further exploration into the mechanisms underlying Xuefu Zhuyu decoction but also offers valuable perspectives and hypotheses for enhancing disease prevention and treatment strategies.

The relationship between complement C1q and coronary plaque vulnerability based on optical coherence tomography analysis

To determine the association between complement C1q and vulnerable plaque morphology among coronary artery disease (CAD) patients. We conducted a retrospective observational study of 221 CAD patients admitted to The Second Affiliated Hospital of Xi’an Jiaotong University. Intravascular optical coherence tomography was utilized to describe the culprit plaques’ morphology. Using logistic regression analysis to explore the correlation between C1q and vulnerable plaques, and receiver operator characteristic (ROC) analysis assess the predictive accuracy. As reported, the complement C1q level was lower in ACS patients than CCS patients (18.25 ± 3.88 vs. 19.18 ± 4.25, P = 0.045). The low complement-C1q-level group was more prone to develop vulnerable plaques. In lipid-rich plaques, the complement C1q level was positively correlated with the thickness of fibrous cap (r = 0.480, P = 0.041). Univariate and multivariate logistic regression analyses suggested that complement C1q could be an independent contributor to plaques’ vulnerability. For plaque rupture, erosion, thrombus, and cholesterol crystals, the areas under the ROC curve of complement C1q level were 0.873, 0.816, 0.785, and 0.837, respectively (P < 0.05 for all). In CAD patients, the complement C1q could be a valuable indicator of plaque vulnerability.

Layered plaque is associated with high levels of vascular inflammation and vulnerability in patients with stable angina pectoris.

Layered plaque, a signature of previous plaque destabilization and healing, is a known predictor for rapid plaque progression; however, the mechanism of which is unknown. The aim of the current study was to compare the level of vascular inflammation and plaque vulnerability in layered plaques to investigate possible mechanisms of rapid plaque progression. This is a retrospective, observational, single-center cohort study. Patients who underwent both coronary computed tomography angiography (CTA) and optical coherence tomography (OCT) for stable angina pectoris (SAP) were selected. Plaques were defined as any tissue (noncalcified, calcified, or mixed) within or adjacent to the lumen. Perivascular inflammation was measured by pericoronary adipose tissue (PCAT) attenuation at the plaque levels on CTA. Features of plaque vulnerability were assessed by OCT. Layered plaques were defined as plaques presenting one or more layers of different optical densities and a clear demarcation from underlying components on OCT. A total of 475 plaques from 195 patients who presented with SAP were included. Layered plaques (n = 241), compared with non-layered plaques (n = 234), had a higher level of vascular inflammation (-71.47 ± 10.74 HU vs. -73.69 ± 10.91 HU, P = 0.026) as well as a higher prevalence of the OCT features of plaque vulnerability, including lipid-rich plaque (83.8% vs. 66.7%, P < 0.001), thin-cap fibroatheroma (26.1% vs. 17.5%, P = 0.026), microvessels (61.8% vs. 34.6%, P < 0.001), and cholesterol crystals (38.6% vs. 25.6%, P = 0.003). Layered plaque was associated with a higher level of vascular inflammation and a higher prevalence of plaque vulnerability, which might play an important role in rapid plaque progression.Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT04523194 .

Acute Kidney Injury in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention: The Role of Vascular Access Site.

Background: in patients undergoing percutaneous coronary interventions (PCI), radial access should be favoured over femoral access as it reduces the risk of vascular complications and bleeding. Furthermore, a preventive role of radial access in the occurrence of acute kidney injury (AKI), mainly mediated by the reduction of bleeding and cholesterol crystal embolization into renal circulation, has been investigated in several studies, yielding conflicting results. Methods: we designed a retrospective study to appraise the effect of the use of a vascular access site on the occurrence of AKI in a cohort of 633 patients with acute myocardial infarction treated by PCI at our centre from 2018 to 2020. Results: after propensity score adjustment, radial access was associated with a reduced, albeit statistically not significant, incidence of AKI (14.7% vs. 21.0%; p = 0.06) and major bleeding (12.5% vs. 18.7%; p = 0.04) as compared to femoral access. At multivariate analysis, femoral access was an independent predictor of AKI, together with in-hospital occurrence of BARC 3-5 bleeding, Killip class >1 at presentation, female gender, baseline eGFR <60 mL/min, and baseline haemoglobin <12 g/dL. Conclusions: although limited by the observational design, our study supports the hypothesis that radial access may exert a protective role on the occurrence of AKI in patients with acute myocardial infarction undergoing PCI.

EFFECTS OF GARCINIA MANGOSTANA LINN PERICARP EXTRACT AND PHYSICAL EXERCISE ON ATHEROEMBOLIC HISTOPATHOLOGIC FEATURES KIDNEY IN WISTAR RATS WITH METABOLIC SYNDROME

Background: Renal atheroembolism is an under-recognized cause of renal failure . Atheroembolism is caused by cholesterol crystals from ulcerated atherosclerotic plaques and is influenced by inflammation and endothelial dysfunction. The formation of complicated atherosclerotic lesions is a prerequisite for the development of cholesterol crystal emboli. Non-pharmacological therapeutic management (such as diet and physical exercise) is an important factor in preventing and reducing the risk of atherogenesis. Garcinia Mangostana Linn pericarp can inhibit the process of atherosclerosis through the reduction of free radicals and improvement of endothelial function Objective: To investigate the effect of Garcinia Mangostana Linn Pericarp administration along with Physical Exercise on the histopathologic features of renal atheroembolism in Wistar rats with metabolic syndrome. Methods: This study is a true experimental study with research subjects in the form of male Rattus norvegicus Wistar rats which were randomly divided into 3 groups. K (not given therapy), P1 (garcinia pericarp extract 800 mg / kg / day with physical exercise), and P2 (nanoemulsion 50 mg / kg / time of administration with physical exercise). Results: In the group treated with garcinia pericarp extract 800 mg/kg bw/day with physical exercise and the group with nanoemulsion 50 mg/kg bw/day with physical exercise, there were no fatty streaks, inflammation, and impaired myocyte coherence. There was 0-5% fibrous connective tissue, one layer of foam cell layer and myocyte-lipid, no cholesterol crystal embolism was found. Conclusion: The administration of Garcinia Mangostana Linn pericarp extract and/or nanoemulsion with physical exercise can have an effect on the histopathological picture of the kidneys of Wistar rats with metabolic syndrome. There was no difference in effect between the two treatments. However, it could not be compared with the group that was not given any treatment because it had died completely before the end of the study period.

Vascular smooth muscle cells in response to cholesterol crystals modulates inflammatory cytokines release and promotes neutrophil extracellular trap formation

BackgroundThe formation and accumulation of cholesterol crystals (CC) at the lesion site is a hallmark of atherosclerosis. Although studies have shown the importance of vascular smooth muscle cells (VSMCs) in the disease atherosclerosis, little is known about the molecular mechanism behind the uptake of CC in VSMCs and their role in modulating immune response.MethodsHuman aortic smooth muscle cells were cultured and treated with CC. CC uptake and CC mediated signaling pathway and protein induction were studied using flow cytometry, confocal microscopy, western blot and Olink proteomics. Conditioned medium from CC treated VSMCs was used to study neutrophil adhesion, ROS production and phagocytosis. Neutrophil extracellular traps (NETs) formations were visualized using confocal microscopy.ResultsVSMCs and macrophages were found around CC clefts in human carotid plaques. CC uptake in VSMCs are largely through micropinocytosis and phagocytosis via PI3K–AkT dependent pathway. The uptake of CC in VSMCs induce the release inflammatory proteins, including IL-33, an alarming cytokine. Conditioned medium from CC treated VSMCs can induce neutrophil adhesion, neutrophil reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) formation. IL-33 neutralization in conditioned medium from CC treated VSMCs inhibited neutrophil ROS production and NETs formation.ConclusionWe demonstrate that VSMCs due to its vicinity to CC clefts in human atherosclerotic lesion can modulate local immune response and we further reveal that the interaction between CC and VSMCs impart an inflammatory milieu in the atherosclerotic microenvironment by promoting IL-33 dependent neutrophil influx and NETs formation.

Cholesterol trafficking to the ER leads to the activation of CaMKII/JNK/NLRP3 and promotes atherosclerosis

The deposition of cholesterol-rich lipoproteins in the arterial wall triggers macrophage inflammatory responses, which promote atherosclerosis. The NLRP3 inflammasome aggravates atherosclerosis; however, cellular mechanisms connecting macrophage cholesterol accumulation to inflammasome activation are poorly understood. We investigated the mechanisms of NLRP3 inflammasome activation in cholesterol-loaded macrophages and in atherosclerosis-prone Ldlr−/− mice with defects in macrophage cholesterol efflux. We found that accumulation of cholesterol in macrophages treated with modified LDL or cholesterol crystals, or in macrophages defective in the cholesterol efflux promoting transporters ABCA1 and ABCG1, leads to activation of NLRP3 inflammasomes as a result of increased cholesterol trafficking from the plasma membrane to the ER, via Aster-B. In turn, the accumulation of cholesterol in the ER activates the inositol triphosphate-3 receptor, CaMKII/JNK, and induces NLRP3 deubiquitylation by BRCC3. An NLRP3 deubiquitylation inhibitor or deficiency of Abro1, an essential scaffolding protein in the BRCC3-containing cytosolic complex, suppressed inflammasome activation, neutrophil extracellular trap formation (NETosis), and atherosclerosis in vivo. These results identify a link between the trafficking of cholesterol to the ER, NLRP3 deubiquitylation, inflammasome activation, and atherosclerosis.

Biochemical and structural changes in bile in non-alcoholic fatty liver disease

The purpose of the work is to diagnose the early stage of cholelithiasis through a comprehensive study of bile in patients with NAFLD. Materials and methods. We examined 210 patients with NAFLD at the steatosis stage. The diagnosis was confirmed based on general clinical indicators, ultrasound and liver elastography data, and assessment of blood enzyme levels. All patients underwent ultrasound examination of the gallbladder, study of the microscopic and physicochemical properties of bile (specific gravity, acidity, surface tension, viscosity, lithogenicity indices, cholesterol content, bile acids, phospholipids) obtained as a result of multifractional duodenal intubation, and crystallography. Results: Ultrasound examination revealed biliary sludge in 72% of patients. Microscopic examination of bile revealed crystals of cholesterol and calcium bilirubinate in 75.4% of patients. Biochemical analysis of bile revealed significant changes, expressed in increased cholesterol, decreased bile acids, phospholipids, cholate-cholesterol and phospholipid-cholesterol ratios. A study of the physical properties revealed thickening of bile and an increase in its viscosity. Crystallography revealed elements with high optical activity, which became the basis for the formation of gallstones. Conclusions: In patients in the steatosis stage of NAFLD, a decrease in lithogenicity indices, an increase in acidity and thickening of bile are determined, indicating the tendency of bile to stone formation. Signs of biliary sludge (putty-like bile, microlithiasis), characteristic of stage I cholelithiasis, are detected by ultrasound of the gallbladder in 72% of patients in the steatosis stage of NAFLD. Bile crystallography made it possible to identify crystal optical markers indicating changes in the microstructure of gallbladder bile in patients in the steatosis stage of NAFLD. When conducting an examination of patients with NAFLD in the steatosis stage, to diagnose the early stage of cholelithiasis, it is recommended to conduct multifractional duodenal intubation with subsequent study of the physicochemical properties and structural changes of bile.

Thin-cap fibroatheroma in acute coronary syndrome: Implication for intravascular imaging assessment

Acute coronary syndrome (ACS), a significant cardiovascular disease threat, has garnered increased focus concerning its etiological mechanisms. Thin-cap fibroatheroma (TCFA) are central to ACS pathogenesis, characterized by lipid-rich plaques, profuse foam cells, cholesterol crystals, and fragile fibrous caps predisposed to rupture. While TCFAs may be latent and asymptomatic, their pivotal role in ACS risk is undeniable. High-resolution imaging techniques like Optical coherence tomography (OCT) and Intravascular ultrasound (IVUS) are instrumental for effective TCFA detection. Therapeutic strategies encompass pharmacological and interventional measures, including antiplatelet agents, statins, and Percutaneous Coronary Intervention (PCI), aiding in plaque stabilization, inflammation reduction, and rupture risk mitigation. Despite the strong correlation between TCFAs and adverse prognoses in ACS patients, early detection and rigorous treatment significantly enhance patient prognosis and diminish cardiovascular events. This review aims to encapsulate recent advancements in TCFA research within ACS, covering formation mechanisms, clinical manifestations, and prognostic implications.

Estimation of Medium Depolarization Index with Noise Immunity in Catheter-Based PS-OCT toward Vascular Plaques Detection.

Medium depolarization imaging by catheter-based polarization-sensitive optical coherence tomography (PS-OCT) can provide valuable insight into significant features of lipid, macrophages, and cholesterol crystals in atherosclerotic vulnerable plaques. In this paper, we demonstrate a method to achieve an accurate estimation of the medium depolarization index (EMDI) with noise immunity in catheter-based PS-OCT. EMDI is calculated by an iterative approximation based on Lu-Chipman matrix decomposition and Frobenius norm judgment of incoherent averaging of Mueller matrices. Monte Carlo simulation results verify that the medium depolarization measurement by EMDI is 3.3 times more accurate compared with those of the depolarization index (DI) and degree of polarization uniformity (DOPU). In experiments, we design a microsphere suspension with various concentrations and measure EMDI under different additive noise. Consistently, the measurement accuracy by EMDI is increased 2.85 times compared to those by DI and DOPU. For vascular plaques detection, we use protein and cholesterol gel as plaque phantoms. Based on PS-OCT images of plaque phantom in vitro and in ex vivo porcine coronary artery, the recognition rate of plaque by EMDI is 2.99 to 4.65 times higher than those by DI and DOPU evaluated by spatial response of the Laplacian operator (SRLO).

Xanthogranulomatous mastitis: a rare entity presenting with breast lump and mimicking fibroadenoma in a young female

Introduction and importance: Xanthogranulomatous mastitis is a rare chronic granulomatous inflammation of breast tissue, characterized by the presence of multinucleated giant cells, lipid-laden foamy macrophages, and cholesterol crystals. The breast is an extremely rare location for xanthogranulomatous inflammation. Case presentation: The authors describe a case of xanthogranulomatous mastitis in a 26-year-old female patient who presented with a 4×5 cm lump in her right breast. After ultrasonography (revealed a well-circumscribed hypoechoic lesion, with increased vascularity), and surgical consultation, an excisional biopsy was done, and sent for histopathologic examination, which showed features suggestive of xanthogranulomatous mastitis. Clinical discussion: Xanthogranulomatous mastitis, clinically as well as radiologically mimics some other conditions of breast like breast cancer, or fibroadenoma. Ultrasonography usually reveals a well-circumscribed hypoechoic lesion, with increased vascularity, and mammography usually shows BIRADs 3 to 5. Diagnosis is usually based on histopathologic findings of multinucleated giant cells, lipid-laden foamy macrophages, and cholesterol crystals. Treatment is usually surgical excision. Conclusion: Though xanthogranulomatous inflammations are rare in the breast, they must be considered a differential diagnosis in patients presenting with various breast symptoms like lump, pain, or features of breast malignancy.

Alteration of RNA Demethylases by Cholesterol Crystals

Atherosclerosis is a chronic inflammatory disease of the arteries that can lead to cardiovascular diseases. Cholesterol crystals are one of the elements found in atherosclerotic plaques, and they play a significant role in the development and progression of the disease. In this study, we investigated the effects of cholesterol crystals on mRNA modification in macrophages, which are involved in plaque formation and inflammation. We used RAW 264.7 cells, a murine macrophage cell line, and exposed them to cholesterol crystals. We found that cholesterol crystals stimulated the production of pro-inflammatory cytokines, including IL-1β, IL-6, and TNFα. Furthermore, cholesterol crystals were taken up by the macrophages and were detected within the cells. Interestingly, cholesterol crystals upregulated demethylating enzymes FTO and ALKBH5, which are involved in RNA modification. However, the expression of methyltransferases, including METTL3, METTL14, NSUN2, and WTAP remained unchanged. These results suggest that cholesterol crystals can modulate mRNA modification by affecting demethylating enzymes and pro-inflammatory cytokines, potentially contributing to the development of atherosclerosis. Understanding the molecular mechanisms underlying cholesterol crystalinduced atherosclerosis may provide new insights into preventive and therapeutic strategies for cardiovascular diseases.

Anterior chamber cholesterol crystals in stage 5C retinopathy of prematurity

Anterior chamber cholesterol crystals in stage 5C retinopathy of prematurity

The effect of colchicine on cholesterol crystal formation, expansion and morphology: a potential mechanism in atherosclerosis.

Inflammation is pivotal to the progression of atherosclerosis. Cholesterol crystals (CCs) that grow and enlarge within the plaque core can cause plaque rupture and trigger inflammation as they deposit into the atherosclerotic bed. Thus, agents that affect CC formation, expansion, and morphology may reduce cardiovascular (CV) risk independent of lipid-lowering and anti-inflammatory therapy. Because colchicine is highly concentrated in leukocytes that can enter the atherosclerotic plaque core, we tested its effect on the formation and growth of CCs in bench experiments to determine whether it may have direct effects on CCs, independent of its known anti-inflammatory actions. Different dosages of colchicine mixed with cholesterol (0.05-5 mg/ml/g of cholesterol) were used to influence the formation CCs and volume expansion in vitro. These were compared to control samples with cholesterol in ddH2O without colchicine. In an ex vivo study, fresh atherosclerotic human plaques were incubated with and without colchicine in a water bath at 37°C for 48 h to assess the impact of colchicine on CC morphology. Scanning electron microscopy (SEM) was utilized to analyze CC morphology in samples from the various treatment groups. The addition of colchicine to cholesterol caused a substantial dose-dependent reduction in volume (p < 0.05). Pairwise comparisons of volume reduction, showed a significant reduction in volume at 5 mg/ml/g when compared to control (p < 0.02) but the calculated Cohen's d effect size was large for five of the six pairwise comparisons. By SEM, CCs from both in vitro and ex vivo samples treated with colchicine had evidence of dissolution and changes in their morphology as evidenced by the loss of their sharp edges. In contrast, CCs in untreated specimens retained their typical geometric structure. Colchicine can reduce CC formation and expansion and alter CC morphology. These previously unappreciated effects of colchicine may contribute to its clinical benefit in patients with CV disease independent of its anti-inflammatory effects.

Abstract TMP119: Evaluation of Cognitive Function and Plasma Biomarkers in a Microemboli-Based VCID Model in Rats: Applying Clinical Recommendations From MarkVCID and the Lacunar Intervention Trial-2 (LACI-2) to a Preclinical Model

Diabetes doubles the risk of VCID. The underlying reasons are not understood, and preventive therapeutic strategies are lacking. We showed that diabetic but not control rats develop a progressive cognitive decline in a microemboli (ME) model of VCID. Given that cerebrovascular dysfunction is a common pathology between diabetes and VCID, we hypothesized that improvement of endothelial function in diabetes prevents ME-mediated cognitive impairment. Our treatment paradigm was based on the recently reported LACI-2 Trial which assessed the efficacy of isosorbide mononitrate (ISMN) and cilostazol (CZL) in the prevention of small vessel disease (SVD) progression. At 7-8 weeks after diabetes onset, control and diabetic rats were treated with ISMN/CZL for 4 weeks, then injected with cholesterol crystal ME and behavioral outcomes were monitored longitudinally for 16 weeks. Plasma biomarkers recommended by MarkVCID and D eterminants of I ncident S troke C ognitive O utcomes and V ascular E ffects on R ecover Y (DISCOVERY) Consortiums were measured using the angiogenesis (Flt-1, VEGF and FGF), neurology (GFAP, phosphoTau and Neurofilament Light NfL) and amyloid beta 42/40 panels from the Meso Scale Discovery. Behavioral deficits observed in the untreated diabetic rats were not noted in the treated group. Some of the biomarkers were unchanged (Table). This suggests that drug treatment with ISMN/CZL before ME injection prevented the possible deleterious effects of the latter in the diabetic rats by improving the endothelial integrity and it is a viable preventive and possibly therapeutic strategy for VCID.

Pancoronary plaque characteristics in STEMI patients with rapid plaque progression: An optical coherence tomography study

BackgroundNon-culprit plaque progression is associated with recurrent cardiac ischemic events and worse clinical outcomes. Given that atherosclerosis is a systemic disease, the pancoronary characteristics of patients with rapid plaque progression are unknown. This study aims to identify pancoronary plaque features in patients with ST-segment elevation myocardial infarction (STEMI) with and without rapid plaque progression, focused on the patient level. Methods and resultsFrom January 2017 to July 2019, 291 patients underwent 3-vessel optical coherence tomography imaging at the time of the primary procedure and a follow-up angiography interval of 12 months. The final analysis included 237 patients. Overall, 308 non-culprit lesions were found in 78 STEMI patients with rapid plaque progression, and 465 non-culprit plaques were found in 159 STEMI patients without rapid plaque progression. These patients had a higher pancoronary vulnerability (CLIMA-defined high-risk plaque: 47.4% vs. 33.3%; non-culprit plaque rupture: 25.6% vs. 14.5%) and a significantly higher prevalence of other vulnerable plaque characteristics (i.e., lipid-rich plaque, cholesterol crystal, microchannels, calcification, spotty calcification, and thrombus) at baseline versus those without rapid plaque progression. Lesions with rapid progression were highly distributed at the LAD, tending to be near the bifurcation. In multivariate analysis, age ≥ 65 years was an independent predictor of subsequent rapid lesion progression at the patient level, whereas microchannel, spotty calcification, and cholesterol crystal were independent predictors for STEMI patients ≥65 years old. ConclusionsSTEMI patients with subsequent rapid plaque progression had higher pancoronary vulnerability and commonly presented vulnerable plaque morphology. Aging was the only predictor of subsequent rapid plaque progression.

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.

Cholesterol Crystal Dissolution Rate of Serum Predicts Outcomes in Patients With Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement.

Aortic stenosis has pathophysiological similarities with atherosclerosis, including the deposition of cholesterol-containing lipoproteins. The resulting cholesterol crystals activate the NLRP3 (NOD-like receptor protein 3) inflammasome, leading to inflammation and cardiovascular diseases. We aimed to investigate the cholesterol crystal dissolution rate (CCDR) of serum in patients with aortic stenosis and to assess the prognostic value of this biomarker. The study included 348 patients with aortic stenosis undergoing transcatheter aortic valve replacement. The CCDR was measured using flow cytometry to enumerate cholesterol crystals that were added to a serum solution, at baseline and after 2 hours of incubation. Based on the median CCDR, the cohort was stratified into high and low cholesterol crystal dissolvers. The incidence of the primary end point, a composite of 1-year all-cause mortality and major vascular complication, was significantly lower in the high CCDR group (7.3 per 100 person-years) compared with the low CCDR group (17.0 per 100 person-years, P=0.01). This was mainly driven by a lower 1-year mortality rate in patients with a high CCDR (7.3 versus 15.1 per 100 person-years, P=0.04). Unplanned endovascular interventions were significantly less frequent in high cholesterol crystal dissolvers (12.8 versus 22.6 per 100 person-years, P=0.04). Although low-density lipoprotein cholesterol levels were comparable in both groups (101.8±37.3 mg/dL versus 97.9±37.6 mg/dL, P=0.35), only patients with a low CCDR showed a benefit from statin treatment. In multivariate analysis, low CCDR (hazard ratio, 2.21 [95% CI, 0.99-4.92], P=0.04) was significantly associated with 1-year mortality. The CCDR is a novel biomarker associated with outcome in patients with aortic stenosis undergoing transcatheter aortic valve replacement. It may provide new insights into patients' anti-inflammatory capacity and additional prognostic information beyond classic risk assessment.

Involvement of cholesterol crystals in the mechanism of aortogenic cerebral infarction: an angioscopic study.

Involvement of cholesterol crystals in the mechanism of aortogenic cerebral infarction: an angioscopic study.