Effect of alpha-tocopherol and beta-carotene supplementation on coronary heart disease during the 6-year post-trial follow-up in the ATBC study.

AIMS: To evaluate the 6-year post-trial effects of alpha-tocopherol and beta-carotene supplementation on coronary heart disease (CHD) in the alpha-tocopherol, beta-carotene cancer prevention (ATBC) study. METHODS AND RESULTS: 29,133 male smokers, aged 50-69 years were randomised to receive alpha-tocopherol 50 mg, or beta-carotene 20 mg, or both, or placebo daily for 5-8 years. At the beginning of the post-trial follow-up, 23,144 men were still at risk for a first-ever major coronary event (MCE), and 1255 men with pre-trial history of myocardial infarction (MI) were at risk for MCE. Post-trial risk for MCE (n=2059) was 0.95 (95% confidence interval 0.87-1.04) among alpha-tocopherol recipients compared with non-recipients, and 1.14 (1.04-1.24) among beta-carotene recipients compared with non-recipients. The risk for non-fatal MI (n=993) was 0.96 (0.85-1.09) and 1.16 (1.03-1.32), and for fatal CHD (n=1066) 0.94 (0.83-1.06) and 1.11 (0.99-1.25), respectively. Among men with pre-trial MI no effects were observed in post-trial risk of MCE (n=257). CONCLUSION: beta-Carotene seemed to increase the post-trial risk of first-ever non-fatal MI but there is no plausible mechanism to support it. Our findings do not advocate the use of alpha-tocopherol or beta-carotene supplements in prevention of CHD among male smokers.     

The efficacy of a 'master switch gene' HIF-1alpha in a porcine model of chronic myocardial ischaemia.

AIMS: Therapeutic angiogenesis is a potential new treatment for patients unsuitable for conventional revascularization strategies. We investigated angiogenesis via a 'master switch gene' hypoxia inducible factor (HIF-1alpha). METHODS AND RESULTS: Ameroid occluders were placed around the left circumflex coronary artery of 74 pigs. Three weeks later, pigs were randomized to receive (i) adenovirus encoding HIF-1alpha (Ad2/HIF-1alpha VP-16 10(10) particles); (ii) plasmid DNA encoding HIF-1alpha (pHIF-1alpha NFkappaB 500 microg); (iii) pHIF-1alpha NFkappaB 2500 microg; and (iv) adenoviral control (Ad2/CMV-empty vector 10(10) particles). Twenty injections (50 microL each) were administered epicardially via re-thoracotomy. Three weeks after gene delivery significant (ANOVA P=0.02) changes in myocardial perfusion during stress were seen in the area adjacent to injections. Post hoc testing (Bonferroni) demonstrated that the AdHIF-1alpha group was significantly (P=0.02) different from the Ad2/control. There were also significant (ANOVA P=0.02) differences in resting left ventricular (LV) function. Post hoc (Bonferroni) showed that the AdHIF-1alpha group was significantly different from the Ad2/control (P=0.03). No significant changes in any parameter were seen with plasmid HIF-1alpha. There were no differences in collateralization or capillary growth. CONCLUSION: Ad2/HIF-1alpha increased myocardial perfusion and improved LV function. Plasmid HIF-1alpha was not associated with improvements in any bioactivity endpoints.     

The prognostic value of exercise testing early after myocardial infarction in patients treated with thrombolytics

Exercise testing early post A MI was evaluated as a predictorof re infarction in patients treated with thrombolytics. AMIpatients exercise-tested prior to discharge were included inthe study (n = 178). The patients were followed for 2.9±0.9years (mean±1 SD) for the development of new cardiacevents defined as cardiac death or reinfarction. Cox regressionanalysis of clinical and exercise test variables showed thatthere was significant predictive value of treating heart failurewith drugs from two or more therapeutic groups (P<0.001;hazard ratio 9.4 (3.1–28.2) (estimate and 95% confidenceinterval)), such as those with a previous history of myocardialinfarction (P = 0.001; hazard ratio 4.0 (1.7–9.6)) andof significant ST depression (P = 0.029; hazard ratio 2.5 (1.1–5.7)).Significant ST depression could be substituted by the ST/HRindex (P = 0.042; hazard ratio 2.8 (1.2–6.8)). The exercise test had independent but limited prognostic valuein AMI patients treated with thrombolytics. The ST/HR indexdid not improve the predictive value of the exercise test.     

TNF-alpha induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-gamma agonist pioglitazone.

AIMS: Inflammation contributes to the pathogenesis of cardiovascular disease. Tumour necrosis factor (TNF)-alpha, in particular, is a key mediator of inflammation and vascular dysfunction and progression of atherosclerotic disease. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, not only improves insulin sensitivity, but may also have anti-inflammatory effects. The aims of this study were to investigate the acute effects of local intra-arterial infusion with low-dose TNF-alpha on resistance vessel endothelial function in type 2 diabetes and to determine whether short-term pioglitazone treatment protects against vascular dysfunction induced by this inflammatory stimulus. METHODS AND RESULTS: A randomized, parallel, placebo-controlled, double blind trial with 30 mg pioglitazone once daily for 4 weeks was performed in 16 male patients with recently diagnosed type 2 diabetes. Forearm plethysmography (FBF) was used to evaluate the effect on resistance vessel responses of intra-arterial administration of serotonin (NO-dependent vasodilation) and nitroprusside (endothelium-independent vasodilation) followed by another FBF-measurement during the second hour of intra-arterial infusion with TNF-alpha (10 ng/100 mL forearm volume/min for 2 h). Endothelial-dependent FBF of type 2 diabetic patients was significantly impaired (25.4%) by intra-arterial TNF-alpha infusion (P = 0.01), whereas nitroprusside-induced vasodilation did not change. Treatment with pioglitazone for 4 weeks completely blocked TNF-alpha-induced impairment of endothelial-dependent FBF compared with placebo. No significant changes in plasma concentrations of TNF-alpha, interleukin-6, soluble TNF-alpha-receptors, or CD40L were observed. CONCLUSION: Pioglitazone treatment can convey direct protection against cytokine (TNF-alpha)-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes.     

Prognostic value of serum gamma-glutamyl transferase activity after myocardial infarction.

AIMS: Serum gamma-glutamyl transferase activity (gamma-GT) is able to catalyse low-density lipoprotein oxidation and has been detected in coronary atherosclerotic plaques. gamma-GT has been documented as an independent risk factor for cardiac mortality in middle-aged men. The purpose of this study is to determine the prognostic value of gamma-GT in patients with coronary artery disease. METHODS AND RESULTS: In a prospective study, gamma-GT and other cardiac risk factors were evaluated in 469 consecutive subjects with angiographically documented coronary artery disease, using mortality and mortality plus non-fatal myocardial infarction as end-points. gamma-GT showed an independent prognostic value beyond known established risk factors in the subgroup of 262 patients with previous myocardial infarction. At a 6-year follow-up, cardiac mortality was 25.2% in patients with gamma-GT >40 U x l(-1)vs 13.9% in those with gamma-GT <40 U x l(-1)(P=0.038). When both cardiac mortality and non-fatal myocardial infarction were considered as end-points, these events were recorded in 32.7% of patients with gamma-GT >40 U x l(-1)and in 20.4% of those with levels <40 U x l(-1)(P=0.031). Excess mortality and non-fatal infarction in patients with high gamma-GT levels were concentrated in the first 2 years of follow-up (P=0.014). The association of gamma-GT values >40 U x l(-1), previous myocardial infarction, and multiple vessel disease identified a subgroup of 168 patients with the highest risk of cardiac events at 6 years (P=0.024). The relationship between gamma-GT levels and cardiac events remained significant after adjustment for cardiac risk factors, and possible confounders, including alcohol consumption. gamma-GT did not show significant prognostic value in the 207 patients without previous myocardial infarction. CONCLUSION: gamma-GT is an independent cardiac risk factor in ischaemic patients with established coronary atherosclerosis and previous myocardial infarction.     

Rosuvastatin increases vascular endothelial PPARgamma expression and corrects blood pressure variability in obese dyslipidaemic mice.

AIMS: Statins improve atherosclerotic diseases through cholesterol-reducing effects. Whether the latter exclusively mediate similar benefits, e.g. on hypertension, in the metabolic syndrome is unclear. We examined the effects of rosuvastatin on the components of this syndrome, as reproduced in mice doubly deficient in LDL receptors and leptin (DKO). METHODS AND RESULTS: DKO received rosuvastatin (10 mg/kg/day or 20 mg/kg/day) or saline for 12 weeks. Saline-treated DKO mice had elevated blood pressure (BP) and nitric oxide-sensitive BP variability recorded by telemetry. Compared with saline, rosuvastatin (20 mg/kg/day) had no effect on weight gain and a minor effect on plasma cholesterol. Despite incomplete correction of insulin sensitivity, rosuvastatin fully corrected BP and its variability (P = 0.01), in conjunction with upregulation of PPARgamma (but not PPARalpha) in the aortic arch. Rosuvastatin similarly increased PPARgamma (P = 0.002) and SOD1 (P = 0.01) expression in isolated endothelial cells. Both GW9662, a PPARgamma-specific antagonist, and siRNA raised against PPARgamma abrogated rosuvastatin's effect, which was reproduced in PPARgamma- (but not PPARalpha-) dependent transactivation assays. CONCLUSION: Beyond partial improvement in insulin sensitivity, rosuvastatin normalized BP homeostasis in obese dyslipidaemic mice independently of changes in body weight or plasma cholesterol. Upregulation of PPARgamma and SOD1 in the endothelium may be involved as a unique vasculoprotective effect of statin treatment.     

Plasma tumour necrosis factor-alpha and early carotid atherosclerosis in healthy middle-aged men.

AIMS: Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine, which is implicated in some metabolic disorders and may play a role in the development of cardiovascular disease. We examined whether plasma TNF-alpha is related to established cardiovascular risk indicators, plasma levels of soluble cellular adhesion molecules and carotid artery intima-media thickness determined by ultrasound examination in a population-based cohort of 96 healthy 50-year-old men. METHODS AND RESULTS: TNF-alpha and cellular adhesion molecules were measured with enzyme-linked immunosorbent assays. Plasma TNF-alpha concentration was associated with systolic and diastolic blood pressure, degrees of alimentary lipaemia, plasma very low density lipoprotein triglyceride, low density lipoprotein (LDL) cholesterol concentrations and peak LDL particle size. Two indices of insulin resistance as well as all soluble cellular adhesion molecules correlated positively with TNF-alpha. The plasma TNF-alpha concentration was associated with common carotid intima-media thickness in univariate analysis. In contrast, soluble E-selectin and postprandial triglycerides, but not TNF-alpha, were independent determinants of common carotid intima--media thickness. CONCLUSION: The plasma TNF-alpha concentration is associated with degrees of early atherosclerosis and correlates with metabolic and cellular perturbations that are considered important for the vascular process.     

Isolated ventricular non-compaction: clinical study and genetic review.

Isolated non-compaction of the ventricular myocardium (INVM), sometimes referred to as 'spongy myocardium', is a congenital and exceedingly rare cardiomyopathy. Isolated ventricular non-compaction occurs in the absence of other structural heart diseases and, hypothetically, it is due to the arrest of myocardial morphogenesis. Isolated non-compaction of the ventricular myocardium may manifest itself from infancy to young adulthood with a high mortality rate. Both sexes are affected. In our study, we present a case of INVM (left and right ventricles) in a 3-year-old girl, diagnosed by two-dimensional echocardiography. The anomaly presented as a restrictive cardiomyopathy. The girl was admitted to our hospital with heart failure, when she was 10 months old. She was treated with dopamine, digoxin, furosemide, spironolactone, and acenocoumarol and her condition improved. Presently, the girl remains asymptomatic and for 3 years of follow-up, her development has been almost normal. We here describe the genetic background of this disorder (based on a literature review).     

空腹血糖与冠状动脉病变程度的相关性

目的探讨空腹血糖（FPG）水平与冠状动脉（下称冠脉）病变程度的相关性。方法回顾分析913例高度怀疑冠心病（CHD）而行冠脉造影的患者的临床资料,冠脉造影病变程度由是否诊断CHD、冠脉病变支数和冠脉病变Gensini总积分三方面表示。对FPG水平与冠脉病变程度进行单因素和多因素分析。结果FPG与冠脉病变程度密切相关：（1）Logistic回归结果显示FPG与冠脉有无病变显著相关（OR值1.462,95%CI为1.178~1.813,P〈0.01）;（2）多元逐步回归结果显示在校正了年龄、性别等因素之后,FPG与冠脉病变支数（r=0.164,P〈0.01）、冠脉病变总积分（r=0.088,P〈0.05）仍然独立相关。随着FPG的升高,冠脉病变支数增加。结论冠心病高危人群的FPG水平与冠脉病变程度密切相关,即使在糖尿病前期,随着FPG升高,冠脉病变程度也更加严重。     

雄激素受体基因多态性与男性冠心病关系的研究

目的:雄激素受体(AR)基因外显子1区基因片断CAG多态性与男性冠心病(CAD)及其危险因素的关系。方法:125例冠脉造影证实的男性冠心病人均接受检查,CAD严重程度采用冠脉狭窄≥50%的支数(0～3),分别计算心肌梗塞栓塞(TIMI)危险积分,外周血AR转录激活区CAG重复序列的长度采用PCR法测定。结果:CAG重复长度为13～30次,CAG重复≥24次者为长AR基因组,<24次者为短AR基因组。与长AR基因组比较:短AR基因组患者具有较低的平均体重指数(BMI)(t=-3.024,P=0.005)和较低水平的高密度脂蛋白(HDL)(t=-2.610,P=0.010);短AR基因组出现明显冠脉狭窄的可能性较大(x2=4.82,P=0.028),TIMI危险积分较高(M-W检验,z=-2.644,P=0.008)。Spearman相关分析表明,AR基因CAG长度和TIMI危险积分显著负相关(r=-0.230,P=0.010),这种相关性独立于年龄、BMI、LDL、UA和HDL之外(偏相关系数r=-0.250,P=0.006)。结论:具有短AR基因者与更加严重的冠心病相关,提示CAG多态性与男性CAD病情发展相关,AR表达增多,雄激素敏感性增高可能是男性CAD发病率较高的原因之一。     

Influence of TNF gene polymorphism in patients with acute and fulminant hepatitis

Background Tumor necrosis factor (TNF) is involved in liver damage, especially in fulminant hepatitis (FH). Our previous data showed that the serum level of TNF- was markedly increased in FH. To investigate the mechanism of the overproduction of TNF in FH patients, polymorphism of the TNF gene was studied.Methods We analyzed 120 healthy subjects (controls), 63 patients with acute hepatitis (AH), and 32 patients with FH. Of the 32 FH patients, 21 died or received liver transplantation (FH-D), and 11 survived with intensive therapy (FH-S). The TNF- promoter region at –1031, –863, –857, –308, and –238, and TNF- Nco1 polymorphism sites were studied.Results (1) The four groups showed no differences in polymorphisms of positions –857, –308, and –238. The allelic frequencies of positions –1031C and –863A in the FH-D patients were significantly higher compared to findings in control subjects. (2) The allelic frequency of B2 in the TNF- gene was significantly higher in FH patients, and particularly in the FH-D patients, compared to control subjects. (3) When the patients were divided into four groups by etiology, hepatitis A virus (HAV), HBV, HCV, and non-A non-B non-C, the allelic frequencies of positions –863A and TNF- B2 in FH patients were increased in the non-A non-B non-C group compared to controls.Conclusions FH patients with a poor prognosis had higher frequencies of positions –1031C and –863A in the TNF- promoter region, and higher frequencies of the B2 allele of the TNF- gene. These data suggest that the genomic background may be associated with the prognosis of acute liver failure.     

血管紧张素转换酶基因缺失多态性与冠状动脉病变

目的 :探讨血管紧张素转换酶 ( ACE)基因的插入 /缺失 ( insertion/deletion,I/D)多态性与冠状动脉病变的相关性。方法 :应用聚合酶链反应 ( PCR)扩增技术检测 86例行冠状动脉造影患者的 ACE基因 I/D多态性。结果 :冠状动脉异常组的 DD基因型频率 0 .41,D等位基因频率 0 .5 2 ,显著高于冠状动脉正常组的 0 .15和 0 .2 9( P <0 .0 5 ) ;DD基因型与冠状动脉病变有关 ( OR=3.97,P<0 .0 5 )。多支病变与 DD基因型的关系更为密切 ( OR=4.72 ,P<0 .0 5 )。冠状动脉正常组、单支病变组和多支病变组的 DD型频率依次为 0 .15、0 .33和 0 .46( P <0 .0 5 ) ,D等位基因频率为 0 .2 9、0 .44和 0 .5 6( P <0 .0 1)。结论 :ACE基因的 I/D多态性与冠状动脉病变及其严重程度相关 ,DD型及 D等位基因频率随冠状动脉病变及其程度的加重而逐渐升高。在冠状动脉病变患者中 DD及 ID型患者的吸烟率、甘油三酯及血压显著低于 型者 ( P <0 .0 5 ) ,说明 D等位基因及 DD基因型可能是冠心病低危人群冠状动脉病变的重要危险因素之一。     

NPC1L1基因多态性与冠心病的关系

目的:在上海地区汉族人群中探讨NPC1L1(Niemann-Pick C1-like1)基因启动子区-762T>C多态和编码区1679C>G多态与冠心病(CAD)的关系。方法:运用实时定量PCR基因分型技术,对经冠状动脉造影证实的361例CAD患者和421例对照者进行基因分型。结果:单位点分析发现,-762T>C多态的基因型分布在2组间有显著性差异(P=0.041),应用Logistic回归分析,在显性模式下,-762T>C多态增加CAD发病风险[比值比(OR)=0.74,95%可信区间(CI):0.56～0.99,P=0.042)]。1679C>G多态的基因型分布在2组间无显著差异,应用Logistic回归分析,在显性模式下,1679C>G多态与CAD发病风险之间亦关系密切(OR=0.81,95%CI:0.61～0.99,P=0.046)。单倍型分析发现,3种单倍型分布在2组间无统计学意义。结论:NPC1L1基因启动子区-762T>C多态可能与上海地区汉族人群的CAD发病相关,携带C等位基因者能显著降低CAD的发生风险。     

Association of angiotensin II type 1 receptor gene A1166C polymorphism with the presence of diabetes mellitus and metabolic syndrome in patients with documented coronary artery disease

Background

There are relatively limited data available on the genetic susceptibility to diabetes mellitus and metabolic syndrome in the Iranian population. We have therefore investigated the association between the angiotensin II type I receptor gene polymorphism (AT₁R/A1166C) and the presence of diabetes mellitus and metabolic syndrome in a well defined group of patients.

Methods

Patients with angiographically defined coronary artery disease (CAD) (n = 309) were evaluated for the presence of AT₁R/A1166C polymorphism. These patients were classified into subgroups with (n = 164, M/F: 109/55) and without (n = 145, M/F: 84/61) diabetes mellitus. The AT₁R polymorphism was assessed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) based method.

Results

There was a higher frequency of polymorphic genotypes (AC + CC) in the diabetic compared with the non-diabetic group (p = 0.01). When determined for each gender separately, this difference remained significant in the males (p = 0.04) but not in females (p = 0.09). With regard to the allele frequencies, the C allele was significantly higher and the A allele frequency was lower in the diabetic group (p = 0.01). This remained significant after gender segregation for males (p = 0.01) but not females. In the binary logistic regression analysis, only serum fasting glucose was found as the independent predictor for the presence of diabetes in the CAD patients (β = 1.16, p < 0.001 for total population and β = 1.29, p < 0.001 for male subjects). There was no significant difference in genotype or allele frequencies between subgroups with and without metabolic syndrome, this being unaffected by gender or the definition of metabolic syndrome used apart from a significantly lower frequency of C allele in male subjects with metabolic syndrome defined by the NCEP ATP III criteria (p = 0.04).

Conclusion

The AT₁R/A1166C polymorphism may be associated with the presence of diabetes mellitus in male subjects with documented CAD.     

肺炎衣原体感染增加糖尿病患冠心病的危险性

目的　本研究旨在探讨肺炎衣原体感染与冠心病的关系。方法　 142 2例冠状动脉造影证实有冠心病或急性心肌梗死的患者和 2 97例冠状动脉造影证实的非冠心病患者作为对照 ,应用ELISA方法检测血液中的肺炎衣原体 (chlamydiapneumoniae,Cp)特异性IgG抗体 (CpIgG)。所有个体分为有、无冠心病 ,有、无冠心病危险因素 (年老、男性、吸烟、糖尿病、血脂紊乱、高血压、CpIgG抗体阳性、较少体力劳动和体重指数 ) ,应用logistic回归分析 ,得出调整OR(比值比 )值 ,用于评估危险因素对冠心病的危险性。结果　冠心病患者组CpIgG阳性率 ( 31 1%)高于对照组 ( 2 4 9%) (P =0 0 35 ) ,但logistic回归分析显示 ,调整OR值为 1 2 95 ( 95 %CI:0 96 2～ 1 743 ,P =0 10 8) ,表明Cp感染与冠心病的发病关系不明显 ,而年龄≥ 5 5岁、男性、吸烟、高血压、糖尿病是冠心病的独立危险因素 ;进一步分组研究表明 ,CpIgG阳性组中 (n =5 16 ) ,糖尿病的调整OR值为 4 90 1( 95 %CI:1 44 9～ 16 5 81,P =0 0 1) ,而CpIgG阴性组 (n =12 0 3)调整OR值为 1 6 75 ( 95 %CI:0 988～ 2 841,P >0 0 5 ) ,表明Cp感染增加了糖尿病对冠心病的危险性 ;老年、男性和吸烟的调整OR值 ,CpIgG阳性组也高于CpIgG阴性组。结论　Cp感染与冠心病发病     

老年人脂蛋白相关磷脂酶A2与冠心病冠状动脉病变程度及危险因素的关系

目的 观察老年人脂蛋白相关磷脂酶A2(Lp-PLA2)水平与冠心病冠状动脉造影病变程度及冠心病危险因素的关系. 方法 测定90例临床怀疑冠心病行冠状动脉造影老年患者Lp-PLA2、超敏C反应蛋白(hs-CRP),血脂等指标,根据冠状动脉造影结果以病变支数及Gensini积分评价冠状动脉病变程度,分析Lp-PLA2与冠心病的关系. 结果冠心病组Lp-PLA2水平较对照组明显升高[(352.7±129.0)μg/L与(204.0±59.7)μg/L,P<0.01].Lp-PLA2水平随着冠状动脉病变支数和Gensini积分的增加而升高.Lp-PLA2与年龄(r=0.25,P<0.05)、三酰甘油(r=0.33,P<0.01)、低密度脂蛋白胆固醇(r=0.27,P<0.05)、载脂蛋白B(r=0.36,P<0.01)呈正相关.在冠心病组,Lp-PLA2与年龄呈正相关(r=0.29,P<0.05).Stepwise回归分析结果显示Lp-PLA2与冠心病相关. 结论 冠心病患者Lp-PLA2水平升高,其水平的高低可能反映冠状动脉病变的严重程度.为冠心病的危险因素之一.     

Association between T174M polymorphism in the angiotensinogen gene and risk of coronary artery disease: a meta-analysis

Background Angiotensinogen (AGT) T174M gene polymorphism has been suggested to be linked to risk of coronary artery disease, however, results from studies of this association have been inconsistent. In this study, we assess the relationship between AGT T174M gene polymorphism and coronary artery disease. Methods We conducted a meta-analysis of 18 case-control studies with 8,147 coronary artery disease cases and 5,344 controls in Google scholar, PubMed, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases to identify eligible studies published by July, 2012. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated from these studies. Results Overall, a significant association was found between angiotensinogen T174M polymorphism and coronary artery disease risk when all studies were pooled into the meta-analysis (TT vs. MM: OR = 0.53, 95% CI = 0.40–0.71; dominant model: OR = 1.16, 95% CI = 1.01–1.35; recessive model: OR = 0.54, 95% CI = 0.40–0.72). In a stratified analysis, the results indicate a significant associa?tion in Caucasians suffering from coronary stenosis (TT vs. MM: OR = 0.38, 95% CI = 0.23–0.63; recessive model: OR = 0.39, 95% CI = 0.23–0.64). No significant increased risk for coronary artery disease was found in Asians. Conclusions The meta-analysis indicate a significant associa?tion of T174M polymorphism with coronary stenosis risk in Caucasians.