高血脂兔主动脉粘附分子VCAM-1基因表达的研究

目的：研究高血脂对主动脉血管细胞粘附分子１（ＶＣＡＭ－１）基因表达的影响。方法：采用胆固醇喂饲法建立兔高血脂模型,在喂饲后１,６周处死动物,应用组织原位杂交、免疫组织化学等方法检测产动脉ＶＣＡＭ－１的表达,并与正常组对比。结果：喂饲胆固醇１周后高血脂很快诱导主动脉内皮细胞表达ＶＣＡＭ－１,并在６周后动脉粥样硬化（ＡＳ）病灶内也有丰富表达。结论：高血脂促进动脉ＶＣＡＭ－１表达,是其促进ＡＳ发病的机制     

大豆异黄酮对高胆固醇血症大鼠血及肝脏MDA含量和SOD活力的影响(英文)

目的 :研究大豆异黄酮对高胆固醇血症大鼠血液及肝脏丙二醛 (MDA )、超氧化物歧化酶(SOD)的影响。方法 :根据血胆固醇水平 ,5 0只雄性Wistar大鼠随机分为 5组 ,正常对照组 (NC)、高胆固醇血症对照组 (HC)和 3个大豆异黄酮治疗组。除正常对照组以外 ,各组均喂以高胆固醇饲料。同时 ,3个治疗组分别灌胃给予 30 ,6 0 ,12 0mg·kg- 1大豆异黄酮 ,对照组给予相应的溶媒 ,持续 9wk。实验结束时 ,分离血清、红细胞 ,取出肝脏 ,制备肝匀浆。采用黄嘌呤氧化酶法测定红细胞和肝匀浆SOD活力 ,以硫代巴比妥酸法测定血清和肝匀浆MDA含量。结果 :与正常对照组比较 ,高胆固醇血症对照组大鼠红细胞及肝匀浆SOD活力明显降低。大豆异黄酮 6 0和 12 0mg·kg- 1组大鼠红细胞及肝脏SOD活力比高胆固醇血症对照组明显升高 (P <0 .0 1和P <0 .0 5 )。高胆固醇血症对照组大鼠血清及肝匀浆MDA含量与正常对照组比较明显升高。与高胆固醇血症对照组比较 ,大豆异黄酮 30和 6 0mg·kg- 1组大鼠血清MDA含量及 30和 12 0mg·kg- 1组大鼠肝脏MDA含量明显降低 (P <0 .0 5 )。结论 :对于高胆固醇血症大鼠红细胞及肝脏SOD活力的降低及血清和肝脏MDA水平的升高 ,能被大豆异黄酮部分逆转     

Volumetric Assessment of Plaque Progression With 3-Dimensional Ultrasonography Under Statin Therapy

BACKGROUND AND PURPOSE: Lowering of serum cholesterol levels with HMG-CoA reductase inhibitors (statins) slowed the progression of atherosclerosis in the carotid arteries in several clinical trials using carotid artery intima media thickness as primary outcome measure. Whereas conventional ultrasonography is limited to thin 2-dimensional image planes, 3-dimensional (3D) ultrasonography provides quantitative measurement of the entire carotid artery plaque volume. This study aims to assess the feasibility of 3D ultrasonography to monitor plaque progression in hypercholesterolemic patients. METHODS: The authors prospectively assessed the progression of 31 carotid artery plaques over 15.1 +/- 4.5 months in a study of 23 patients (6 women, 17 men; mean age = 61.7 +/- 7.5 years) with hypercholesterolemia under therapy with HMG-CoA reductase inhibitors. All patients were maintained on a lipid-lowering diet. Sixteen patients were additionally treated with statins. Quantitative measurements of carotid artery plaque volumes were performed after 3D reconstruction of exactly parallel transverse duplex ultrasound scans (slice distance = 0.1 mm) into volumetric 3D data sets and segmentation of voxels representing the carotid artery plaque. RESULTS: Within the treatment group, plaques were significantly less frequently progressive if they had a hypoechoic echogenicity (11%, n = 9 vs 64%, n = 14; P = .016) or if baseline serum cholesterol levels were above 8.0 mmol/L (9%, n = 11 vs 75%, n = 12; P = .002). CONCLUSION: Three-dimensional ultrasonography extends the measurement of the arterial wall thickness to the 3D volume of an entire atherosclerotic plaque including analysis of its morphology and configuration. However, further clinical trials with an adequate sample size to achieve sufficient statistical power are necessary to assess the effect of statin therapy on plaque progression.     

高血压与高胆固醇血症对颅内动脉硬化形成的影响

目的:探讨高血压和高胆固醇血症单独或协同对颅内动脉退变的影响。方法:以雄性家兔为实验对象,分成4组:正常对照组(N组)、单纯高血压组(HT组)、单纯高胆固醇血症组(CH组)和高血压加高胆固醇血症组(HT CH组)。每日饲喂胆固醇造成高胆固醇血症,用双肾动脉狭窄法制成肾性高血压。实验结束后,兔脑标本全部HE染色,部分标本Masson、PTH和苏丹IV染色。另有部分标本进行电镜检查。结果:N组和CH组颅内脑实质内、外动脉未见明显异常。HT组光镜下可见脑实质内、外小动脉肌层增厚、血管收缩及透明变性。电镜下平滑肌细胞被激活,内皮细胞分泌物较多。在HT CH组,3只兔脑实质外较大动脉出现动脉粥样硬化病变。脑实质内、外小动脉病变与单纯高血压组所见相同。结论:单纯高血压可导致颅内小动脉发生动脉硬化;高血压和高胆固醇血症共同作用可导致脑实质外较大动脉发生动脉粥样硬化;而单纯高胆固醇血症不易造成颅内动脉退变。     

Integrin mediated adhesion of mononuclear cells from patients with familial hypercholesterolemia

BACKGROUND: Low-density lipoproteins (LDL) can induce the adhesion of monocytes to endothelial cells. Monocytes of patients with familial hypercholesterolemia (FH) are exposed to high concentrations of LDL, and it has been reported that adhesiveness of these cells in hypercholesterolemic patients is enhanced. We investigated whether LFA-1 or VLA-4 mediated adhesion is altered in FH patients and whether HMG-CoA reductase inhibitors influence this adhesion. PATIENTS AND METHODS: LFA-1 and VLA-4 mediated adhesion to ICAM-1 and VCAM-1 coated beads was investigated using freshly isolated monocytes and T-lymphocytes from patients with homozygous FH, heterozygous FH (before and after cholesterol lowering treatment), and from controls. In addition, the expression of beta1- and beta2-integrins on these cells was determined. RESULTS: Both LFA-1 and VLA-4 mediated adhesion and integrin expression of monocytes and CD3+ cells from patients with homozygous FH and heterozygous FH was similar to that of monocytes from a control population. Treatment with HMG-CoA reductase inhibitors did not affect the adherence to ICAM-1 or VCAM-1, and did not influence the expression of integrins. CONCLUSIONS: In contrast to studies by others, we demonstrated in the present study that the actual LFA-1 and VLA-4 mediated adhesion of T-lymphocytes and monocytes is not altered in patients with FH.     

大蒜素对实验性高胆固醇血症家兔血和主动脉cAMP的影响

用普通料加胆固醇(0.5g/kg·d)喂饲新西兰兔15周,塑造高胆固醉血症模型,结果表明:胆固醇组血胆固醇明显升高,主动脉 cAMP 水平显著降低。加喂大蒜素(20mg/kg·d)可防止高胆固醇血症的发生,并能使主动脉 cAMP 水平维持正常,为大蒜素防治动脉粥样硬化提供实验依据。     

Risk Factors for Silent Brain Infarcts and White Matter Disease in a Real-World Cohort Identified by Natural Language Processing

ObjectiveTo assess the frequency of silent brain infarcts (SBIs) and white matter disease (WMD) and associations with stroke risk factors (RFs) in a real-world population.Patients and MethodsThis was an observational study of patients 50 years or older in the Kaiser Permanente Southern California health system from January 1, 2009, through June 30, 2019, with head computed tomography or magnetic resonance imaging for nonstroke indications and no history of stroke, transient ischemic attack, or dementia. A natural language processing (NLP) algorithm was applied to the electronic health record to identify individuals with reported SBIs or WMD. Multivariable Poisson regression estimated risk ratios of demographic characteristics, RFs, and scan modality on the presence of SBIs or WMD.ResultsAmong 262,875 individuals, the NLP identified 13,154 (5.0%) with SBIs and 78,330 (29.8%) with WMD. Stroke RFs were highly prevalent. Advanced age was strongly associated with increased risk of SBIs (adjusted relative risks [aRRs], 1.90, 3.23, and 4.72 for those aged in their 60s, 70s, and ≥80s compared with those in their 50s) and increased risk of WMD (aRRs, 1.79, 3.02, and 4.53 for those aged in their 60s, 70s, and ≥80s compared with those in their 50s). Magnetic resonance imaging was associated with a reduced risk of SBIs (aRR, 0.87; 95% CI, 0.83 to 0.91) and an increased risk of WMD (aRR, 2.86; 95% CI, 2.83 to 2.90). Stroke RFs had modest associations with increased risk of SBIs or WMD.ConclusionAn NLP algorithm can identify a large cohort of patients with incidentally discovered SBIs and WMD. Advanced age is strongly associated with incidentally discovered SBIs and WMD.     

The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification

PurposeIn 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified.MethodsThe multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached.ResultsThe consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others.ConclusionEstablishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.     

A scoping review of interventions increasing screening and diagnosis of familial hypercholesterolemia

PurposeFamilial hypercholesterolemia (FH) is one of the most common genetic conditions, with a prevalence of approximately 1 in 250 individuals. If left untreated, FH greatly increases risk for cardiovascular disease and premature death. Currently, FH is largely underdiagnosed and interventions are needed to increase identification. The purpose of this study was to identify effective interventions aimed at increasing FH diagnosis.MethodsA scoping review of the literature addressing interventions to increase FH detection was conducted. Included studies detailed interventions that increased screening and detection of FH globally. Studies were characterized by intervention type and analyzed for themes using the Consolidated Framework for Implementation Research.ResultsA total of 46 studies across 32 countries were included in the review. All studies were effective in increasing FH detection. In total, 12 different intervention types were extracted with the most used being cascade and electronic medical record screening-based interventions.ConclusionGiven the diversity of effective interventions identified in this review, future efforts could explore approaches that maximize identification through a combination of interventions. Our results support one such strategy that uses electronic medical records to screen for index cases and a 2-step indirect and direct contact method of index cases’ relatives.