Relationship between serum high sensitivity C-reactive protein with angiographic severity of coronary artery disease and traditional cardiovascular risk factors

Serum high-sensitivity C-reactive protein (hs-CRP) is predictive of coronary artery disease (CAD). The aim of this study was to examine the possible association of hs-CRP with presence and severity of CAD and traditional CAD risk factors. This case-control study was carried out on 2,346 individuals from September 2011 to May 2013. Of these 1,187 had evidence of coronary disease, and were subject to coronary angiography, and the remainder were healthy controls (n = 1,159). Characteristics were determined using standard laboratory techniques and serum Hs-CRP levels were estimated using enzyme-linked immunosorbent assay (ELISA) kits, and severity of CAD was assessed according to the score of obstruction in coronary artery. Serum hs-CRP levels were higher in those with severe coronary disease, who had stenosis ≥ 50% stenosis of at least one coronary artery (all p < 0.001 vs. individuals in healthy control), and correlated significantly with the score for coronary artery disease (all p < 0.01). After adjustment for conventional risk factors, regression analysis revealed that smoking habits, fasting blood glucose, total cholesterol, high-density lipoprotein, hs-CRP, blood pressure, anxiety, dietary intake of vitamin E, and cholesterol remained as independent determinants for angiographic severity of CAD. The area under the receiving operating characteristic (ROC) curve for serum hs-CRP was 0.869 (CI 95% 0.721–0.872, p < 0.001). The optimal values for the cut-off point was a serum hs-CRP of 2.78 mg/l (sensitivity 80.20%, specificity 85%) to predict severity of CAD. Increased serum hs-CRP levels are significantly associated with angiographic severity of CAD, suggesting its value as a biomarkers for predicting CAD.     

Association between HindIII (rs320) variant in the lipoprotein lipase gene and the presence of coronary artery disease and stroke among the Saudi population

Lipoprotein Lipase (LPL) is known to be a key enzyme for lipid metabolism specifically in an enzymatic glycoprotein which provide tissues without fatty-acids and eliminates triglycerides (TG) by the circulation. Mutations in LPL were proven to cause alteration in fractions within lipoprotein, causing the development of atherosclerosis which predispose to weakening coronary artery disease (CAD) and stroke. We examined the linkage between genetic variant HindIII in LPL on lipoprotein fractions, stroke occurrences and CAD. In this case-control study, we have recruited 315 CAD cases and 205 age-matched controls. A total of 520 genomic DNA was digested with the purified PCR products for restriction fragment length polymorphism with HindIII restriction enzyme. The distribution of genotypes in a decreasing order were TT, 148 (47%), GT 135 (42.9%) and GG 32 (10.2%) in CAD groups of the study while the pattern in controls were GT 91 (44.4%), TT 86 (42%) and GG 28 (13.7%). None of all the allele or genotype frequencies were found to be significant in our study (p greater than 0.05), while the biochemical levels for both TG and LDL-c were shown to be prone in CAD patients when compare with the controls. Furthermore, the occurence of strokes were more in CAD groups vs. controls: 72 (22.9%) vs. 7 (3.4%) [p 0.000]. This could indicate the influence of HindIII variant on plasma lipid levels, and the possibility of considering it a risk factor for atherosclerosis leading to CAD and stroke occurrence.     

The IL-33-ST2L Pathway Is Associated with Coronary Artery Disease in a Chinese Han Population

The effects of interleukin-33 (IL-33) on the immune system have been clearly demonstrated; however, in cardiovascular diseases, especially in coronary artery disease (CAD), these effects have not yet been clarified. In this study, we investigate the genetic role of the IL-33-ST2L pathway in CAD. We performed three-stage case-control association analyses on a total of 4,521 individuals with CAD and 4,809 controls via tag SNPs in the genes encoding IL-33 and ST2L-IL-1RL1. One tag SNP in each gene was significantly associated with CAD (rs7025417^T in IL33, p_adj = 1.19 × 10⁻²⁸, OR = 1.39, 95% CI: 1.31–1.47; rs11685424^G in IL1RL1, p_adj = 6.93 × 10⁻³⁰, OR = 1.40, 95% CI: 1.32–1.48). Combining significant variants in two genes, the risk for CAD increased nearly 5-fold (p_adj = 8.90 × 10⁻²¹, OR = 4.98, 95% CI: 3.56–6.97). Traditional risk factors for CAD were adjusted for the association studies by SPSS with logistic regression analysis. With the two variants above, both located within the gene promoter regions, reporter gene analysis indicated that the rs7025417 C>T and rs11685424 A>G changes resulted in altered regulation of IL33 and IL1RL1 gene expression, respectively (p < 0.005). Further studies revealed that the rs7025417 genotype was significantly associated with plasma IL-33 levels in the detectable subjects (n = 227, R² = 0.276, p = 1.77 × 10⁻¹⁷): the level of IL-33 protein increased with the number of rs7025417 risk (T) alleles. Based on genetic evidence in humans, the IL-33-ST2L pathway appears to have a causal role in the development of CAD, highlighting this pathway as a valuable target for the prevention and treatment of CAD.     

Effects of a 1,3-diacylglycerol oil-enriched diet on postprandial lipemia in people with insulin resistance

Postprandial hypertriglyceridemia is common in individuals with insulin resistance, and diets enriched in 1,3-diacylglycerol (DAG) may reduce postprandial plasma triglycerides (PPTGs). We enrolled 25 insulin-resistant, nondiabetic individuals in a double-blind, randomized crossover trial to test the acute and chronic effects of a DAG-enriched diet on PPTG. Participants received either DAG or triacylglycerol (TAG) oil, in food products, for 5 weeks. Fasting lipids, and two separate postprandial tests, one with DAG oil and one with TAG oil, were performed at the end of each 5 week diet period. We found no acute or chronic effects of DAG oil on PPTG. Thus, neither the DAG oil PPTG (h/mg/dl) on a chronic TAG diet [area under the curve (AUC) = 503 +/- 439] nor the TAG oil PPTG on a chronic DAG diet (AUC = 517 +/- 638) was different from the TAG oil PPTG on a chronic TAG diet (AUC = 565 +/- 362). Five weeks of a DAG-enriched diet had no acute or chronic effects on PPTG in insulin-resistant individuals. We suggest further studies to evaluate the effects of DAG on individuals with low and high TG levels.     

Plasma PCSK9 Levels Are Elevated with Acute Myocardial Infarction in Two Independent Retrospective Angiographic Studies

Objective

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that promotes degradation of the low density lipoprotein (LDL) receptor. Mutations that block PCSK9 secretion reduce LDL-cholesterol and the incidence of myocardial infarction (MI). However, it remains unclear whether elevated plasma PCSK9 associates with coronary atherosclerosis (CAD) or more directly with rupture of the plaque causing MI.

Methods and Results

Plasma PCSK9 was measured by ELISA in 645 angiographically defined controls (<30% coronary stenosis) and 3,273 cases of CAD (>50% stenosis in a major coronary artery) from the Ottawa Heart Genomics Study. Because lipid lowering medications elevated plasma PCSK9, confounding association with disease, only individuals not taking a lipid lowering medication were considered (279 controls and 492 with CAD). Replication was sought in 357 controls and 465 with CAD from the Emory Cardiology Biobank study. PCSK9 levels were not associated with CAD in Ottawa, but were elevated with CAD in Emory. Plasma PCSK9 levels were elevated in 45 cases with acute MI (363.5±140.0 ng/ml) compared to 398 CAD cases without MI (302.0±91.3 ng/ml, p = 0.004) in Ottawa. This finding was replicated in the Emory study in 74 cases of acute MI (445.0±171.7 ng/ml) compared to 273 CAD cases without MI (369.9±139.1 ng/ml, p = 3.7×10⁻⁴). Since PCSK9 levels were similar in CAD patients with or without a prior (non-acute) MI, our finding suggests that plasma PCSK9 is elevated either immediately prior to or at the time of MI.

Conclusion

Plasma PCSK9 levels are increased with acute MI.     

Butyrylcholinesterase K variant and the APOE-ε4 allele work in synergy to increase the risk of coronary artery disease especially in diabetic patients

We have previously shown that butyrylcholinesterase-K (BCHE-K, G1615A/Ala539Thr) variant increases the risk of coronary artery disease (CAD). In addition, we have found that the presence of APOE-ε4 allele augments the risk of CAD in patients with type II diabetes mellitus (T2DM/CAD). Here we explored the concomitant presences of two alleles of the BCHE-K and APOE-ε4 in increasing the risk of CAD or diabetes in T2DM patients with or without CAD and CAD patients without T2DM. This case–control study comprised 631 subjects undergoing their first coronary angiography. They were matched and randomly assigned into four groups: type II diabetic patients with no sign of CAD (T2DM), type II diabetic patients with CAD/ND (T2DM/CAD), CAD patients with no sign of diabetes (CAD/ND), and healthy individuals (NCAD/ND). BCHE-K variant and APOE genotypes were detected by PCR-RFLP and serum lipid level was measured enzymatically. We found that BCHE-K and APOE-ε4 allele act synergistically to increase the risk of CAD in both T2DM, non-diabetic and total CAD (TCAD = T2DM/CAD + CAD/ND) individuals. The level of synergy 1.5 and 1.2 fold are higher in CAD patients (OR = 4.5; P = 0.011) with T2DM than the non-diabetic CAD patients (OR = 3.07; P = 0.024) and TCAD patients (OR = 3.74; P = 0.018), respectively. The CAD subjects with and without T2DM and TCAD patients carrying both APOE-ε4 allele and BCHE-K had significantly lower plasma HDL-C (P values = 0.008, 0.047, and 0.036, respectively) and higher plasma LDL-C (P values = 0.025, 0.048, and 0.04, respectively), than that of the control carriers both APOE-ε4 and BCHE-K. We have found that BCHE-K and APOE-ε4 allele not only act synergistically to increase the risk of CAD, particularly in T2DM subjects in population from western Iran, who have high levels of LDL-C and low levels of HDL-C, suggesting that a specific therapeutic intervention should be considered for these particular groups of patients.     

2型糖尿病患者血清鸢尾素、摄食抑制因子-1、3-硝基酪氨酸水平与糖脂代谢和阻塞性睡眠呼吸暂停低通气综合征的关系研究

摘要 目的：探讨2型糖尿病（T2DM）患者血清鸢尾素（Irisin）、摄食抑制因子-1（Nesfatin-1）、3-硝基酪氨酸（3-NT）水平与糖脂代谢和阻塞性睡眠呼吸暂停低通气综合征（OSAHS）的关系。方法：选择2020年4月~2021年9月期间中国人民解放军总医院京南医疗区收治的T2DM患者80例作为研究对象,根据多导睡眠图（PSG）检查结果,合并OSAHS的51例患者列为T2DM合并OSAHS组,剩余的29例纳为T2DM未合并OSAHS组。选择同期来中国人民解放军总医院京南医疗区体检的40例健康志愿者作为对照组。对比T2DM患者、对照组的Irisin、Nesfatin-1、3-NT水平,采用Pearson相关性分析显示Irisin、Nesfatin-1、3-NT与糖脂代谢指标的相关性。T2DM患者发生OSAHS的影响因素采用多因素Logistic回归分析。结果：T2DM合并OSAHS组、T2DM未合并OSAHS组Irisin低于对照组,且T2DM合并OSAHS组低于T2DM未合并OSAHS组（P<0.05）。T2DM合并OSAHS组、T2DM未合并OSAHS组Nesfatin-1、3-NT高于对照组,且T2DM合并OSAHS组高于T2DM未合并OSAHS组（P<0.05）。T2DM合并OSAHS组、T2DM未合并OSAHS组糖化血红蛋白（HbAlc）、空腹血糖（FBG）、餐后2 h血糖（2hPG）高于对照组,且T2DM合并OSAHS组高于T2DM未合并OSAHS组（P<0.05）。T2DM合并OSAHS组、T2DM未合并OSAHS组三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、总胆固醇（TC）较对照组高,高密度脂蛋白胆固醇（HDL-C）低于对照组（P<0.05）。Pearson相关性分析结果显示,Irisin与HbAlc、FBG、2hPG呈负相关,Nesfatin-1、3-NT与HbAlc、FBG、2hPG呈正相关（P<0.05）。T2DM合并OSAHS组、T2DM未合并OSAHS组的年龄、合并高血压、体质量指数、AHI、空腹C肽、合并冠心病对比有差异（P<0.05）。Irisin、Nesfatin-1、3-NT、HbAlc、FBG、2hPG、年龄、合并高血压是T2DM患者发生OSAHS的影响因素（P<0.05）。结论：T2DM合并OSAHS患者的Irisin、Nesfatin-1、3-NT水平表达异常,参与着机体的糖脂代谢过程及OSAHS发生,且OSAHS发生同时还受到HbAlc、FBG、2hPG、年龄、合并高血压的影响,可考虑对上述因素进行早期监测,以进行相关干预。     

Potential risk modifications of GSTT1, GSTM1 and GSTP1 (glutathione-S-transferases) variants and their association to CAD in patients with type-2 diabetes

Background

Type-2 diabetes mellitus (T2DM) is a major risk factor for coronary artery disease (CAD) resulting in high morbidity and mortality. Glutathione S-transferases (GSTM1, GSTT1 and GSTP1) are known for their broad range of detoxification and in the metabolism of xenobiotics. Recent studies revealed the relationship of GSTs variants with T2DM and CAD. In this case-control study we ascertained the association of GSTs variants in association with the development of CAD in patients with T2DM.

Methods

From the Southern part of India, we enrolled 222 T2DM patients, 290 T2DM patients with CAD and 270 healthy controls matched for age, sex and origin. Serum lipid profiles were measured and DNA was extracted from the blood samples. Multiplex PCR for GSTM1/T1 (null polymorphism) and PCR-RFLP for GSTP1 (105 A > G), were performed for genotyping of study participants. Gene frequency and lipid profiles were statistically analyzed for disease association.

Results

Regression analysis showed that, GSTM1-null genotype is associated with a 2-fold increase (OR = 2.925; 95% CI = 2.078–4.119; P < 0.0001) and GSTT1-null genotype is associated with a 3-fold increase (OR = 3.114; 95% CI = 2.176–4.456; P < 0.0001) to T2DM development. Ile/Val and Val/Val genotypes of GSTP1 also showed a significant risk for T2DM (OR = 1.423, CI = 1.041–1.946; P = 0.027 and OR = 1.829, CI = 1.064–3.142; P = 0.029). Increased odds ratio showed that GSTT1-null genotype had a moderately higher occurrence in T2DM–CAD patients (OR = 1.918, 95% CI = 1.144–3.214; P = 0.014) than T2DM patients without CAD. The level of HDL has significantly decreased in GSTT1-present than in GSTT1-null genotype (43.50 ± 4.10 vs. 45.20 ± 3.90; P = 0.004) when compared with control and T2DM patients. However, LDL level showed a significant increase in GSTT1-null than GSTT1-present genotype (108.70 ± 16.90 vs. 102.20 ± 12.60; P = 0.005). Although the GSTM1-null polymorphism showed no correlation with lipid profiles among T2DM and T2DM with CAD patients, GSTT1-null polymorphism attained a statistical significance for the level of LDL (127 ± 28.20 vs. 134 ± 29.10; P = 0.039) and triglycerides in T2DM with CAD patients (182.10 ± 21.10 vs. 191.20 ± 24.10; P = 0.018).

Conclusion

Our work concludes that GSTM1, GSTT1 and GSTP1 variants might contribute to the development of T2DM and GSTT1 variant alone is involved in the development of T2DM associated CAD complications in the South Indian population.     

脂蛋白脂酶基因HindⅢ酶切多态性与2型糖尿病的关联研究

为了探讨脂蛋白脂酶(lipoprotein lipase, LPL)基因HindⅢ酶切多态性与2型糖尿病(type 2 diabetes mellitus, T2DM)的关系, 采用病例-同胞对照设计和随机病例-对照设计, 应用PCR-RFLP方法, 对264例T2DM患者和102名正常人LPL基因HindⅢ酶切多态性进行分析。结果表明, T2DM组H+等位基因及H+H+基因型的频率较对照组显著增高(H+: 76.9%比69.1%, P<0.05; H+H+: 59.8%比52%, P<0.05)。根据实验设计分组, 同胞对T2DM组H+等位基因及H+H+基因型的频率较同胞对对照组显著增高(H+: 81.5%比67.8%, P<0.05; H+H+: 68.5%比50.7%, P<0.05), 而随机病例组与对照组间无此频率差异性(P>0.05)。多因素Logistic回归显示T2DM的独立危险因素是空腹血糖和LPL基因型, H+H+ 纯合子患T2DM的危险性是H+H-和H-H-基因型的1.995倍(95% CI: 1.036～3.840, P<0.05)。提示LPL基因HindⅢ多态性与湖北汉族人T2DM的危险性相关, 其中H+等位基因可能是T2DM的遗传危险因素。     

Genetic association of Glutathione peroxidase-1 (GPx-1) and NAD(P)H:Quinone Oxidoreductase 1(NQO1) variants and their association of CAD in patients with type-2 diabetes

Coronary artery disease (CAD) is a major health concern and the leading cause of death in individuals with type-2 diabetes mellitus (T2DM). Glutathione peroxidase-1 (GPx-1) and NAD(P)H: quinone oxidoreductase (NQO1) are known for its broad range of detoxification. The role of functional variants of these genes in the development of various disorders is proven. Hereby, we investigated the possible role of these variants in the development of CAD in T2DM patients of South Indian population. In this case-control study, a total of 539 patients (T2DM = 241; T2DM-CAD = 298) and 285 controls were included. The C198T GPx-1 and C609T NQO1 single-nucleotide polymorphisms were analyzed by PCR-RFLP. Further, these genotypes were correlated with blood lipid profile. Regression analysis showed that GPx1-C/T genotype is associated with a 1.35-fold increase (95% CI = 1.000-1.824; P = 0.048) and GPx1-T/T genotype is associated with a 1.76-fold increase (95% CI = 1.011 to 3.066; P = 0.046) to the T2DM development. Increased odds ratio showed that NQO1-T/T genotype had a higher occurrence of CAD in diabetic patients with CAD (95% CI = 1.003-2.674, P = 0.049) than T2DM patients without CAD. The level of triglycerides alone showed significant increase for GPx-1-C/T and -T/T genotypes in Tukey's Post hoc analysis (177.1 ± 19.2 vs. 184 ± 23.5; P = 0.039 and 177.1 ± 19.2 vs. 190 ± 22.4; P = 0.006) among the patients with T2DM-CAD. Our work concludes that GPx-1 variants might contribute to the development of diabetes and both GPx-1 and NQO1 variants confirm the association of CAD in people with T2DM of South Indian population.     

The negative effect of ANGPTL8 on HDL-mediated cholesterol efflux capacity

Background

It is well known that angiopoietin-like protein 8 (ANGPTL8) exerts its effects on lipid metabolism through the inhibition of lipoprotein lipase and subsequent elevation of plasma triglyceride. However, it is not clear whether ANGPTL8 could affect lipid metabolism via other pathways. The study was aimed to investigate the effects of ANGPTL8 on the function of high-density lipoprotein (HDL), which plays a protective role in atherosclerosis progression.

Methods

Two hundred and ten subjects were recruited. Plasma ANGPTL8 was measured by enzyme-linked immunosorbent assays. Cholesterol efflux capacity was chosen as the biomarker of HDL function and measured via H³-cholesterol loading THP-1 cell models.

Results

ANGPTL8 exhibited no significant difference between CAD group and nonCAD group, but ANGPTL8 in DM group was significantly higher than that in the nonDM group [568.3 (406.2–836.8) vs 458.2 (356.8–755.6), P?=?0.023]. Compared to controls, subjects in CAD group and DM group exhibited significantly lower cholesterol efflux capacity [CAD: 14.58?±?2.06 vs 12.51?±?2.83%, P?<?0.0001; DM: 13.62?±?2.57 vs 12.34?±?3.16%, P?=?0.0099]. ANGPTL8 was inversely correlated with cholesterol efflux capacity (r?=???0.188, P?<?0.01). Regression analysis revealed that plasma ANGPTL8 was an independent contributor to cholesterol efflux capacity (standardized β?=???0.143, P?=?0.023).

Conclusion

ANGPTL8 presents a negative effect on HDL-mediated cholesterol efflux capacity.

     

Association of m.5178C>A variant with serum lipid levels: a systematic review and meta-analysis

Background: Emerging evidence shows that m.5178C>A variant is associated with a lower risk of coronary artery disease (CAD). However, the specific mechanisms remain elusive. Since dyslipidemia is one of the most critical risk factors for CAD and accounts for at least 50% of the population-attributable risk, it is tempting to speculate that the reduced CAD risk caused by the m.5178C>A variant may stem from an improved lipid profile. In order to verify this hypothesis, we conducted the present study to clarify the association of m.5178C>A variant with lipid levels.Methods: By searching ten databases for studies published before 30 June 2021. Thirteen East Asian populations (7587 individuals) were included for the analysis.Results: The present study showed that m.5178C>A variant was associated with higher high-density lipoprotein cholesterol (HDL-C) [standardized mean difference (SMD) = 0.12, 95% confidence interval (CI) = 0.06–0.17, P<0.001] and total cholesterol (TC) (SMD = 0.08, 95% CI = 0.02–0.14, P=0.01) levels. In subgroup analysis, the association of m.5178C>A variant with higher HDL-C levels were observed in Japanese (SMD = 0.09, 95% CI = 0.01–0.17, P=0.03) and Chinese populations (SMD = 0.13, 95% CI = 0.07–0.20, P<0.001). However, the association of m.5178C>A variant with lower low-density lipoprotein cholesterol (LDL-C) levels were only observed in Japanese populations (SMD = −0.11, 95% CI = −0.22 to 0.00, P=0.04).Conclusions: The m.5178C>A variant was associated with higher HDL-C and lower LDL-C levels in Japanese populations, which may contribute to decreased CAD risk and longevity of Japanese.     

罗格列酮联合胰岛素对糖尿病大鼠氧化应激及血脂水平的影响

摘要 目的：探讨罗格列酮（RSG）联合胰岛素（INS）对糖尿病大鼠的氧化应激和血脂水平的影响。方法：30只健康雄性Wistar大鼠,随机分为3组：健康对照组、DM模型组和RSG+INS组,每组10只。采用链脲佐菌素（STZ）造模法进行糖尿病大鼠模型诱导。此后以RSG （3 mg/kg/day）灌胃,INS （2.25 U/kg/day）皮下注射,均连续给药8周,对RSG+INS组大鼠进行干预治疗。每2周定期记录各组大鼠的体重和血糖值1次;药物干预治疗8周后,取各组大鼠血清,对血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL）、高密度脂蛋白（HDL）、糖化血红蛋白（HbA1c）和丙二醛（MDA）的含量以及超氧化物歧化酶（SOD）和谷胱甘肽（GSH）的活性进行检测;应用苏木素碱性复红苦昧酸（HBFP）染色分析心肌形态变化。结果：RSG联合INS组治疗糖尿病大鼠,导致血糖发生时间依赖性下降（均P<0.05）;药物干预处理8周后,RSG+INS组大鼠的血清TC、TG、LDL和HbA1c水平均显著低于DM模型组,而HDL显著高于DM模型组（均P<0.05）;与DM模型组相比,RSG+INS组大鼠的血清MDA含量显著下降,而SOD和GSH活性则显著升高（均P<0.05）;与DM模型组相比,RSG+INS组心肌缺血/氧程度减轻。结论：RSG联合INS可有效对抗糖尿病大鼠体内的氧化应激损伤,改善糖尿病大鼠的脂代谢异常情况,并对心肌组织有一定的保护作用。     

Hepatic lipase: a pro- or anti-atherogenic protein?

Hepatic lipase (HL) plays a role in the metabolism of pro- and anti-atherogenic lipoproteins affecting their plasma level and composition. However, there is controversy regarding whether HL accelerates or retards atherosclerosis. Its effects on different lipoprotein classes show that, potentially, HL may promote as well as decrease atherogenesis. Studies in animals with genetically modulated HL expression show that it depends on the model used whether HL acts pro- or anti-atherogenic. In humans, HL activity seems to correlate inversely with atherosclerosis in (familial) hypercholesterolemia, and positively in hypertriglyceridemia. In normolipidemia, HL activity is weakly associated with coronary artery disease (CAD). Genetically low or absent HL activity is usually associated with increased CAD risk, especially if plasma lipid transport is impaired due to other factors. Since HL promotes the uptake of lipoproteins and lipoprotein-associated lipids, HL may affect intracellular lipid content. We hypothesize that the prime role of HL is to maintain, in concert with other factors (e.g., lipoprotein receptors), intracellular lipid homeostasis. This, and the uncertainties about its impact on human atherosclerosis, makes it difficult to predict whether HL is a suitable target for intervention to lower CAD risk. First, the physiological meaning of changes in HL activity under different conditions should be clarified.     

Strong interaction between T allele of endothelial nitric oxide synthase with B1 allele of cholesteryl ester transfer protein TaqIB highly elevates the risk of coronary artery disease and type 2 diabetes mellitus

Background

The present study was conducted to investigate the possible outcome of interaction between endothelial nitric oxide (NOS3) G894T and cholesteryl ester transfer TaqIB variants on the risk of coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). The sample included a total of 207 CAD patients (102 CAD patients with T2DM and 105 CAD patients without T2DM). There were also 101 patients with T2DM and 92 age- and sex-matched healthy individuals as controls. All study participants were from Western Iran. The sample was genotyped by polymerase chain reaction-restriction fragment length polymorphism.

Results

The presence of NOS3 T allele was not associated with the risk of CAD or T2DM, and the CETP B1 allele was only significantly associated with the increased risk of CAD in total CAD patients (odds ratio (OR)?=?5.1, p?=?0.019). However, the concomitant presence of both CETP B1 and NOS3 T alleles significantly increased the risk of CAD in total CAD patients (OR?=?18.1, p?<?0.001), in CAD patients without T2DM (OR?=?27.1, p?=?0.03), and in CAD patients with T2DM (OR?=?13.5, p?=?0.002). Also, the presence of both alleles increased the risk of T2DM (OR?=?12, p?=?0.004).

Conclusions

Our findings, for the first time, indicate that NOS3 T allele strongly interacts with CETP B1 allele to augment the risk of CAD and T2DM in the population of Western Iran.     

Mice with Chimeric Livers Are an Improved Model for Human Lipoprotein Metabolism

Objective

Rodents are poor model for human hyperlipidemias because total cholesterol and low density lipoprotein levels are very low on a normal diet. Lipoprotein metabolism is primarily regulated by hepatocytes and we therefore assessed whether chimeric mice extensively repopulated with human cells can model human lipid and bile acid metabolism.

Design

FRG [ F ah(−/−) R ag2(−/−)Il2r g (−/−)]) mice were repopulated with primary human hepatocytes. Serum lipoprotein lipid composition and distribution (VLDL, LDL, and HDL) was analyzed by size exclusion chromatography. Bile was analyzed by LC-MS or by GC-MS. RNA expression levels were measured by quantitative RT-PCR.

Results

Chimeric mice displayed increased LDL and VLDL fractions and a lower HDL fraction compared to wild type, thus significantly shifting the ratio of LDL/HDL towards a human profile. Bile acid analysis revealed a human-like pattern with high amounts of cholic acid and deoxycholic acid (DCA). Control mice had only taurine-conjugated bile acids as expcted, but highly repopulated mice had glycine-conjugated cholic acid as found in human bile. RNA levels of human genes involved in bile acid synthesis including CYP7A1, and CYP27A1 were significantly upregulated as compared to human control liver. However, administration of recombinant hFGF19 restored human CYP7A1 levels to normal.

Conclusion

Humanized-liver mice showed a typical human lipoprotein profile with LDL as the predominant lipoprotein fraction even on a normal diet. The bile acid profile confirmed presence of an intact enterohepatic circulation. Although bile acid synthesis was deregulated in this model, this could be fully normalized by FGF19 administration. Taken together these data indicate that chimeric FRG-mice are a useful new model for human lipoprotein and bile-acid metabolism.     

Insulin resistance in Chinese patients with type 2 diabetes is associated with C-reactive protein independent of abdominal obesity

Background

Patients with diabetes mellitus (DM) have high risk of heart failure. Whether some of the risk is directly linked to metabolic derangements in the myocardium or whether the risk is primarily caused by coronary artery disease (CAD) and hypertension is incompletely understood. Echocardiographic tissue Doppler imaging was therefore performed in DM patients without significant CAD to examine whether DM per se influenced cardiac function.

Methods

Patients with a left ventricular (LV) ejection fraction (EF) > 35% and without significant CAD, prior myocardial infarction, cardiac pacemaker, atrial fibrillation, or significant valve disease were identified from a tertiary invasive center register. DM patients were matched with controls on age, gender and presence of hypertension.

Results

In total 31 patients with diabetes and 31 controls were included. Mean age was 58 ± 12 years, mean LVEF was 51 ± 7%, and 48% were women. No significant differences were found in LVEF, left atrial end systolic volume, or left ventricular dimensions. The global longitudinal strain was significantly reduced in patients with DM (15.9 ± 2.9 vs. 17.7 ± 2.9, p = 0.03), as were peak longitudinal systolic (S') and early diastolic (E') velocities (5.7 ± 1.1 vs. 6.4 ± 1.1 cm/s, p = 0.02 and 6.1 ± 1.7 vs. 7.7 ± 2.0 cm/s, p = 0.002). In multivariable regression analyses, DM remained significantly associated with impairments of S' and E', respectively.

Conclusion

In patients without significant CAD, DM is associated with an impaired systolic longitudinal LV function and global diastolic dysfunction. These abnormalities are likely to be markers of adverse prognosis.     

脂质代谢相关基因变异在早发冠心病中作用的研究进展

最新研究表明, 早发冠心病(pCAD)往往具有较强的遗传背景和脂质代谢紊乱等易感基础, 脂代谢相关基因异常导致各类脂质合成、代谢障碍, 最终血管壁发生动脉粥样硬化, 相关研究多集中在(1) 影响低密度脂蛋白代谢的基因, 如：低密度脂蛋白受体、载脂蛋白B、载脂蛋白E等基因; (2) 影响高密度脂蛋白代谢的基因, 如：ATP 结合盒式转运子、载脂蛋白AI及脂蛋白脂酶基因; (3) 脂联素基因、低密度脂蛋白受体相关蛋白基因等。目前已发现这些脂质代谢基因与pCAD密切相关, 有些基因的突变可造成以pCAD为特征的遗传性疾病。文章对上述基因与pCAD的发生发展进行综述, 以期为冠心病的预防和个体化治疗提供理论依据。