Genetics of the low density lipoprotein receptor:

Fibroblast association (plasma membrane binding plus intracellular accumulation) and degradation of radioiodinated low density lipoprotein (125I-LDL) index plasma membrane LDL receptor activity. Cultured fibroblasts from 23 subjects affected with familial hypercholesterolemia (HC) and from 95 subjects without HC (non-HCs) were tested for 125I-LDL association and degradation. Both LDL receptor activity indices were twice as high in non-HC and HC heterozygous cell strains. This is compatible with a major gene effect on LDL receptor activity. However, a considerable overlap between non-HC and HC heterozygous values was found in the 125I-LDL association assay [median (range) 970 (330-2500), and 450 (250-490), respectively] and in the degradation assay [median (range) 810 (280-2020), and 470 (160-790), respectively]. The values are expressed as ng 125I-LDL X mg cell protein-1 X 4.5 h-1. These great overlaps in the LDL receptor activity indices support the view that the influence of LDL receptor activity on the HC phenotype may be smaller than believed previously. Furthermore, for the diagnosis of HC, these LDL receptor activity assays are far more expensive and have less sensitivity and specificity than simple serum cholesterol determination. The LDL receptor-dependent 125I-LDL association values for the HC heterozygous individuals clustered into four groups. Family data supported the hypothesis that this variation could be due to four different LDL receptor variants, each coded for by different alleles at the LDL receptor locus. If confirmed, this finding may have implications for the understanding of the variable expression of HC and also of the genetic impact on lipoprotein metabolism and susceptibility to atherosclerosis in non-HCs.     

高脂饮食诱导的高胆固醇血症对雄性Wistar大鼠肾脏的毒性作用

目的 研究高胆固醇血症对雄性Wistar大鼠肾脏的毒性作用。方法 用5%胆固醇饲料喂养雄性Wistar大鼠,制备高胆固醇动物模型,分别于实验第30、60和90d测定肾功能、24h尿蛋白、肾皮质胆固醇（Ch）及各磷脂含量,并进行病理形态及组织定量分析。结果 在实验周期内实验组（E组）大鼠血浆肌酐水平无显著变化;第90d,E组24h尿微量白蛋白、肾皮质Ch、磷脂酰胆碱（PC）及磷脂酰乙醇胺（PE）显著高于正常对照组（C组）;病理形态及组织定量分析显示肾小球系细胞增垂、炎性细胞浸润、系膜基质增多、毛细血管塌陷、上皮细胞足突融合,肾小球体积增大。IgG直接免疫荧光阴性,肾小球内无电子致密物沉积。相关分析显示肾小球体积、肾皮质Ch含量及24h尿微量白蛋白排泄率等与血浆总胆固醇（TCh）及低密度脂蛋白（LDL）浓度呈显著正相关关系。结论 饮食诱导的高胆固醇血症可导致Wistar大鼠肾毒性损伤。     

Dietary hypercholesterolemia aggravates contrast media-induced nephropathy

Background Contrast media administration can result in severe nephrotoxicity under pathological conditions such as diabetic nephropathy, congestive heart failure, dehydration, et al. The purpose of this study was to evaluate the effects of dietary hypercholesterolemia on contrast media-induced changes in renal function, blood flow, and histopathology.Methods Rats were fed either on a normal rodent diet ( group N) or a high-cholesterol supplemented diet ( group H; 4% cholesterol and 1% cholic acid) for 8 weeks. Half of the animals ( n = 6) from each diet group were then given a tail vein injection of 60% diatrizoate (6 ml/kg; group NC and group HC)and the other half were administered saline. Total serum cholesterol, triglyceride, serum creatinine,creatinine clearance rate, fractional excretion of sodium and potassium, and cortical nitric oxide production were determined one day following contrast media administration. Renal blood flow was determined by color Doppler flow imaging and pulsed-mode Doppler. Renal histopathology was observed by light microscopy.Results Total serum cholesterol and resistance indices of renal blood vessels increased significantly,while creatinine clearance rate and production of nitric oxide in the renal cortex decreased markedly in group HC and group H when compared to group N and group NC. The creatinine clearance rate decreased significantly in group HC compared to group H. Serum creatinine levels and fractional excretion of sodium and potassium in group HC were significantly higher than those in the other three groups. Severe tubular degeneration and necrosis, protein cast accumulation, and medullary congestion were found in group HC.Conclusion Hypercholesterolemia is a risk factor for contrast media-induced nephropathy.Hypercholesterolemia aggravates contrast media-induced nephrotoxicity through the reduced production of nitric oxide.     

Future Impact of mRNA Therapy on Cardiovascular Diseases

The silver lining of the recent pandemic was that it accelerated the emergence of messenger ribonucleic acid (mRNA) therapeutics. The great promise of mRNA therapeutics was highlighted by the speed at which the vaccines were created, tested, and proven to be relatively safe and highly effective. There are a wide variety of mRNA therapeutics now under development, and dozens of these are in clinical trials. These therapeutics are generating a major paradigm shift in medical therapy, including the treatment of cardiovascular disease. Most of the cardiovascular mRNA therapies are still in preclinical development, although a phase 2a trial of mRNA therapy for myocardial ischemia has been completed with promising results.¹ The application of mRNA therapies to cardiovascular diseases is virtually limitless, and ongoing work includes mRNA therapies for myocardial ischemia, heart failure, arrhythmias, hypercholesterolemia, and arterial occlusive diseases. In addition, mRNA may be used to enhance cell therapies. In the future, mRNA therapies for cardiovascular disease are destined to supplant some of our current biologics and pharmacotherapies and will be used to treat previously untreatable cardiovascular diseases. Furthermore, mRNA therapies can be personalized, and they can be rapidly generated in current Good Manufacturing Practice facilities with a modest footprint, facilitating the rise of hospital-based regional centers of RNA therapeutics.     

Effects of traditional herbal medicine, Hwaotang, on atherosclerosis using the spontaneous familial hypercholesterolemia model, Kurosawa and Kusanagi-hypercholesterolemic rabbits and the venous thrombosis rats

Hwaotang (HOT), a traditional Korean medicinal formulation, is a dried decoctum of a mixture of seven herbal medicines, consisting of Angelica gigantis Radix, Rehmanniae Radix, Paeoniae Radix, Ciniamomi Cortex, Cnidii Rhizoma, Persicae Semen and Carthami Flos. In the present study, the inhibitory effects and anti thrombic properties of HOT on the progression of atherosclerotic lesions were studied using the spontaneous familial hypercholesterolemia (FH) model, Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits and rats. Changes in blood chemistry, pathology and low-density lipoprotein (LDL) oxidation were measured in a control and HOT group. In the control group, the area of atheromatous plaques of the aorta progressed between week 12 (36.65%) and week 14 (46.22%). This progression of atherosclerotic lesions did not occur in the HOT-treated group after 12 (24.24%) and 14 (23.34%) weeks. Antioxidative effects on LDL were seen in the HOT in weeks 12 and 14. HOT improved the hypercholesterolemia in the KHC rabbits. On the other hand, HOT and five of the seven herbs, except Cnidii Rhizoma and Carthami Flos, inhibited the endotoxin-induced hepatic venous thrombosis in high cholesterol diet-treated rats. However, Ciniamomi Cortex showed a very weak inhibitory effect on the endotoxin-induced hepatic venous thrombosis. The extract also inhibited the endotoxin-induced decrease in blood platelets and fibrinogen, and endotoxin-induced increase in fibrin degradation products (FDP) on disseminated intravascular coagulation in normal rats. In conclusion, these results suggest that HOT has inhibitory effects on the development of atheromatous plaque formation in spontaneous FH rabbits. It is also suggested that the antioxidative effects of HOT on LDL led to the beneficial effects observed in this study. The protection by HOT and its herbs on the artificially induced ischemic infarction might be related to their inhibitory effects on disseminated intravascular coagulation, platelet coagulation and thrombotic action.     

人参皂苷抗高脂血症及动脉粥样硬化的实验研究

目的：探讨人参皂苷防治高脂血症、动脉粥样硬化的疗效与可能的机制。方法：给C57／BL—ApoE基因敲除小鼠喂饲胆固醇饲料90天，形成实验性高胆固醇血症和动脉粥样硬化斑块，同时中药治疗组连续给人参皂苷喂养90天，实验结束后测量小鼠血脂，观察动脉壁的光镜改变。结果显示：人参皂苷能抑制血清总胆固醇（TC）、低密度脂蛋白胆固醇（LDL—C）的上升。结论：说明人参皂苷能治疗实验性高脂血症，抑制动脉粥样硬化斑块的形成。     

西立伐他汀降脂治疗及对血小板活化功能、胰岛素抵抗的影响

目的：探讨西立伐他汀对高胆固醇血症患者血脂、血小板活化功能、胰岛素抵抗（IR）的干预作用。方法：对88例高胆固醇血症患者用西立伐他汀治疗4－8wk治疗前后观察血小板颗粒膜蛋白（GMP－140）、空腹血糖（FPG）、空腹胰岛素（FINS）、总胆固醇（TC）、高密度脂蛋白－胆固醇（HDL－C）、低密度脂蛋白－胆固醇（LDL－C）、三酰甘油（TG）,并计算胰岛素敏感指数（ISI）,结果：西立伐他汀能有效降低FBG、FINS、LDL－C、TC、TG、GMP－140,升高ISI（P＜0．05）,但对HDL－C无显著变化（P＞0．05）。结论：西立伐他汀治疗高胆固醇血症或混合性高脂血症患者,在调脂的同时,可抑制血小板活性,改善胰岛素抵抗。     

Eating Habits in Patients with Familial Hypercholesterolemia from North-Eastern Romania

(1) Background: Familial hypercholesterolemia (FH) is a genetic autosomal dominant disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL) that develops deposits of lipids in the arterial wall. Since it is underdiagnosed and undertreated, the disease has a high risk of premature cardiovascular disease and death. Patients are not always aware of the changes they should make in their diet. Thus, our study aimed to evaluate through a food frequency questionnaire their eating habits. (2) Methods: We included 70 patients with FH and 20 subjects in a control group that were evaluated through a physical examination and blood tests. They also completed a food frequency questionnaire. (3) Results: Throughout our study, we observed several aspects: regardless of age, patients with FH had higher carbohydrate intakes compared to the control group; from the same group, a positive correlation was observed between salami intake and the levels of glucose and glycated hemoglobin. Moreover, the sour cream preference was associated with higher liver function tests. In the control group, we observed a higher intake of pasta and fast food and fewer fruit portions. (4) Conclusions: As far as we know, this is the first study from Romania that evaluated the eating habits of patients diagnosed with FH. Our study reveals that, although patients with FH avoid junk food, they still have a high intake of carbohydrates when compared to the control group. Further research is needed in order to get a comprehensive nutritional evaluation of these patients.     

匹伐他汀钙片治疗高胆固醇血症的有效性和安全性研究

目的 评价匹伐他汀钙片治疗高胆固醇血症的有效性和安全性.方法 360例高胆固醇血症患者接1∶1∶1比例随机分为匹伐他汀钙片l mg组、2 rng组和阿托伐他汀钙片10 mg组,经4周筛选期后,符合入选标准的患者接受l mg/2 mg匹伐他汀钙片或10 mg阿托伐他汀钙片治疗(一日1次,口服),治疗8周,观察各组治疗前后血清低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、总胆固醇(TC)和甘油三酯(TG)变化情况.结果 治疗8周后各组LDL-C下降显著,分别为-30.06％、-35.04％和-34.34％,组间差异无统计学意义.匹伐他汀钙片2 mg组降低LDL-C的疗效非劣于阿托伐他汀钙片组,匹伐他汀钙片1 mg组降低LDL-C的疗效劣于阿托伐他汀钙片组.治疗4、8周后匹伐他汀钙降低TC、HDL-C和TG作用与阿托伐他汀钙比较差异无统计学意义.结论 匹伐他汀钙片治疗高胆固醇血症安全有效.