Lipoprotein(a) and aortic valve stenosis: A casual or causal association?

AimsThis review aims to provide an update of available methods for imaging calcification activity and potential therapeutic options.Data SynthesisAortic valve calcification represents the most common heart valve condition requiring treatment among adults in Western societies. No medical therapies are proven to be effective in treating symptoms or reducing disease progression. Therefore, surgical or transcatheter aortic valve replacement remains the only available treatment option. Elevated circulating concentrations of lipoprotein(a) is strongly associated with degenerative aortic stenosis. This relationship was first observed in prospective observational studies, and the causal relationship was confirmed in genetic studies.ConclusionsNew therapeutic targets have been identified and new imaging techniques could be used to test the effectiveness of new agents and further clarify the pathophysiology of AVS. No therapy that specifically lowers Lp (a) levels has been approved for clinical use.     

氧化型低密度脂蛋白介导单核细胞与血管内皮细胞粘附的单细胞定量研究

利用细胞微管吸吮技术对单核细胞与血管内皮细胞间的粘附力行单细胞定量测量，以两种细胞间的临界分离应力Ｓｃ来表示细胞的粘附性。观察氧化型低密度脂蛋白对单核细胞与培养人脐静脉内皮细胞粘附的影响。结果显示：氧化型低密度脂蛋白可使内皮细胞对正常单核细胞的粘附性明显增大，其发生较缓慢，４ｈ达峰值并维持至２４ｈ以后。经氧化型低密度脂蛋白处理的内皮细胞对中性粒细胞的粘附性无明显提高。单核细胞和中性粒细胞经氧化型低密度脂蛋白处理后，对内皮细胞的粘附性均有迅速提高，１ｈ达峰值，２４ｈ内逐渐减弱。实验结果提示氧化型低密度脂蛋白可选择性地提高单核细胞与内皮细胞相互粘附性，这种选择性的促粘附作用进一步证明它在动脉粥样硬化发生、发展中起重要作用。     

低浓度乙醇对血管内皮细胞损伤的保护作用

目的研究乙醇对氧化低密度脂蛋白(ox-LDL)诱导的人脐带静脉内皮细胞损伤的保护作用与内源性一氧化氮合酶抑制物的关系。方法在培养的人脐带静脉内皮细胞中加入ox-LD(L100μg/ml)诱导内皮细胞损伤。检测细胞培养液中非对称性二甲基精氨酸(ADMA)、丙二醛(MDA)、乳酸脱氢酶(LDH)、一氧化氮(NO)和肿瘤坏死因子-(αTNF-α)的含量。结果体外给予ox-LD(L100μg/ml)显著诱导内皮细胞损伤,增加培养液中ADMA、MDA、LDH和TNF-α水平,而降低NO水平。两个剂量乙醇(5或15μg/ml)均能显著抑制ox-LDL所致ADMA、MDA、LDH和TNF-α浓度升高和NO的降低。结论低剂量乙醇对ox-LDL诱导的人脐带静脉血管内皮细胞损伤有保护作用,其保护作用与降低ADMA和TNF-α浓度有关。     

单纯性肥胖患者脂蛋白脂酶基因多态性

目的 探讨脂蛋白脂酶(LPL)基因HindⅢ多态性与单纯性肥胖患者体脂分布、脂质代谢的关系。方法 采用PCR-RFLP对98例单纯性肥胖患者和51名正常对照组LPL基因第8内含子HindⅢ酶切位点进行多态性分析,并测定体脂分布指标与血脂水平。结果LPL HindⅢ位点在两组中均以H+等位基因为主。两组等位基因频率及基因型差异均无显著性,但肥胖组H+H+基因型者血浆甘油三酯水平明显增高、高密度脂蛋白胆固醇明显降低(P均<0.05),腰围、腹腔内脏脂肪面积也显著高于非H+H+基因型者(P<0.05)。结论LPL HindⅢ基因多态性对肥胖患者的血脂水平及脂肪分布有影响。具有HindⅢ酶切位点的H+等位基因可能是单纯性肥胖患者出现腹型肥胖和脂代谢紊乱的遗传易感因素之一。     

Lipoprotein(a): Pathophysiology,measurement, indication and treatment in cardiovascular disease. A consensus statement from the Nouvelle Société Francophone d’Athérosclérose (NSFA)

Central Illustration. Pathophysiological pathways providing a causal link between high plasma concentrations of lipoprotein(a) (Lp(a)) and atherosclerotic vascular disease and aortic valve stenosis (AVS). Clinical outcomes are related to accelerated atherosclerosis complicated by atherothrombosis (myocardial infarction, stroke), peripheral artery disease (PAD) or aortic valve replacement (AVR) caused by valve calcification and aortic stenosis. Apo(a): apolipoprotein(a); LDL: low-density lipoprotein; OxPL: oxidized phospholipids; NSFA: Nouvelle Société Francophone d’Athérosclérose; SP: serine-protease domain; V: plasminogen kringle V (reproduced with permission).

     

Blood rheology and cardiovascular risk factors in type 1 diabetes: relationship with microalbuminuria.

Whole blood and plasma viscosity, erythrocyte aggregation and deformability, plasma fibrinogen, lipids, lipoproteins, apolipoproteins, and measures of blood glucose control were compared between 21 Type 1 diabetic patients with microalbuminuria (overnight albumin excretion rate 30-200 micrograms min-1) and 21 patients with albumin excretion below this range matched for age, sex, and duration of diabetes. Patients with microalbuminuria had significantly higher glycosylated haemoglobin (9.4 +/- 1.6 (+/- SD) vs 7.9 +/- 1.8% (normal range 5.0 to 7.6%)), total-cholesterol (5.6 +/- 1.1 vs 4.6 +/- 1.3 mmol l-1), apolipoprotein B (0.82 +/- 0.21 vs 0.66 +/- 0.14 g l-1), and apolipoprotein B:A1 ratio (0.58 +/- 0.18 vs 0.50 +/- 0.15) than those without microalbuminuria (all p less than 0.05). HDL-cholesterol was also raised (1.71 +/- 0.46 vs 1.43 +/- 0.37 mmol l-1, p less than 0.05). Lipoprotein(a) concentration was possibly higher in the microalbuminuric group (median (95% Cl) 105 (82-140) vs 72 (52-114) mg l-1, p = 0.06). No differences were seen in any of the rheological measurements. These results confirm the presence of potentially atherogenic lipoprotein changes in Type 1 diabetic patients with microalbuminuria, but suggest that altered blood rheology does not predate the development of nephropathy.     

激素敏感脂酶基因高度表达对泡沫细胞形成的作用

中国仓鼠卵细胞在给予β－ＶＬＤＬ后，细胞内蓄积胆固醇酯，形成泡沫样细胞。以腺病毒基因转移方法书激素敏感脂酶基因转染到中国仓鼠卵细胞中，得到了来自激素敏感脂酶的胆固醇酯水解活性高度表达，此时，β－ＶＬＤＬ导致的胆固醇酯蓄积作用被阻断，提示增加胆固醇酯水解可以防止泡沫细胞形成。     

Effect of testosterone on lipolysis in human pre-adipocytes from different fat depots

Aim/hypothesis Regional differences in lipolysis, with higher lipolytic activity in visceral than subcutaneous fat, are important for the development of insulin resistance and might be influenced by testosterone.Methods We studied testosterone-regulated lipolysis and protein expression (by western blot) in fully differentiated pre-adipocytes from visceral (omental) and abdominal subcutaneous adipose tissue from 52 human subjects. These cells were isolated and cultured in a serum-free medium.Results Testosterone caused a specific, time- and concentration-dependent 50% reduction of catecholamine-stimulated lipolysis in the subcutaneous depot. Half of the maximum effect occurred at 10 nmol/l. The inhibitory effect was due to the inability of -adrenoceptors and cyclic AMP to stimulate the protein kinase A, hormone-sensitive lipase complex. Testosterone caused a depot-specific 50% reduction of the protein expression of hormone-sensitive lipase and ₂-adrenoceptors in differentiated subcutaneous pre-adipocytes, but no change in ₁-adrenoceptors, protein kinase A subunits or perilipin expression. In contrast, testosterone had no effect on lipolysis or protein expression in the visceral depot. However, testosterone receptors were present in both depots, and the hormone inhibited adipocyte leptin secretion. Similar effects on lipolysis were observed with dihydrotestosterone.Conclusions/interpretation Testosterone in physiological concentrations causes a depot-specific reduction of catecholamine-stimulated lipolysis in subcutaneous fat cells, probably due to reduced protein expression of ₂-adrenoceptors and hormone-sensitive lipase. This could be an important pathogenic factor underlying regional differences in lipolysis and development of insulin resistance and hyperandrogenic polycystic ovary syndrome.Abbreviations PCOS polycystic ovary syndrome - GPDH glycerol-3-phosphate dehydrogenase - AR adrenergic receptor - HSL hormone-sensitive lipase - PKA protein kinase A - OD optical density - dcAMP dibutyryl cyclic AMP     

Lipoprotein lipase gene variants and progression of nephropathy in hypercholesterolaemic patients with type 2 diabetes

Objective. Recent prospective studies have identified hyperlipidaemia as an independent determinant of diabetic nephropathy. Lipoprotein lipase (LPL) is a key enzyme in the postprandial processing of triglycerides and VLDL. Among a number of common sequence variants of the LPL, HindIII has been associated with coronary heart disease and, more recently, with microalbuminuria in type 2 diabetes. We evaluated the progression of renal disease in hypercholesterolaemic type 2 diabetic patients in relation to this polymorphism. Design and subjects. We followed up for 4 years 65 consecutively enrolled microalbuminuric patients with type 2 diabetes; of whom 28 had hypercholesterolaemia (6.62 ± 0.9 mmol L^?1, group A) and 37 were normocholesterolaemic (4.68 ± 0.5 mmol L^?1, group B). Main outcome measures. After performing the genetic analyses, albumin excretion rate (AER) and estimated glomerular filtration rate (GFR), calculated by the simplified equation of the MDRD Study Group, were repeated every year. Results. In group A, AER increased more (?AER: 11 [38] vs. 4 [18] μg min^?1 per year in group B, P < 0.0001) while GFR declined faster (?3.5 ± 2.1 vs. ?2.0 ± 1.4 mL min^?1 per year, P < 0.02). Patients homozygous for the allele + of HindIII showed a significantly faster decline of GFR and a higher increase of AER (both P = 0.0001) even after adjustment for cholesterol levels and anthropometric variables. Conclusions. In hypercholesterolaemic type 2 diabetic patients with microalbuminuria, the renal disease has an accelerated course, particularly in those carrying the H₊/H₊ genotype of the HindIII polymorphism at the LPL locus.     

冠心病患者脂蛋白脂酶活性和载脂蛋白C的变化及意义

观察３０例冠心病、２０例高脂血症患者的血脂含量、载脂蛋白Ｃ及血浆脂蛋白脂酶活性的变化，结果显示：高脂血症患者血浆脂蛋白ＣⅡ水平比正常人高４５．７２％，（Ｐ〈０．００１），且与血甘油三酯值呈明显正相关（ｒ＝０．５９９，Ｐ〈０．００１）；冠心病患者血浆脂蛋白酶性显著低于正常人（Ｐ〈０．０１）。提示：高脂血症患者血浆载脂蛋白ＣⅡ水升高可能是甘油三酯升高的重要原因，冠心病患者的血浆脂蛋白脂酶活性降低，可能