Tetrahydrobiopterin improves endothelial function in patients with coronary artery disease

Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthase (NOS) and a scavenger of oxygen-derived free radicals. Decreased availability of BH4 leads, under in vitro conditions, to reduced nitric oxide (NO) production and increased superoxide formation. We studied the effect of exogenous BH4 on endothelial function of angiographically normal vessel segments in patients with coronary artery disease. Nineteen patients with coronary artery disease underwent quantitative coronary angiography with simultaneous coronary flow velocity measurements (Cardiometrics FloWire). Data were obtained in angiographically normal segments of the left coronary artery at baseline, after intracoronary (i.c.) administration of acetylcholine (Ach; 10(-4) M), after infusion of BH4 (10(-2) M), and after co-infusion of ACh and BH4. At the end of the study, 300 microg nitroglycerin (NTG) i.c. was administered to obtain maximal vasodilation. At each step, flow velocity was determined before and after 18 microg adenosine i.c. to assess coronary flow velocity reserve. In 15 patients, ACh induced coronary vasoconstriction of -18 +/- 3% (endothelial dysfunction; p < 0.0001 vs. baseline), and in four patients, vasodilation of +39 +/- 20%. In the 15 patients with endothelial dysfunction, BH4 alone did not influence vessel area but prevented vasoconstriction to ACh (+2 +/- 3%, NS, vs. baseline). Correspondingly, calculated volume flow showed the highest value after co-infusion of ACh and BH4. Coronary flow velocity reserve was comparable during the various infusion steps. BH4 prevents ACh-induced vasoconstriction of angiographically normal vessels in patients with coronary artery disease. Thus substitution of this cofactor of NOS may represent a new approach for the treatment of endothelial dysfunction.     

性别对非阻塞性冠状动脉疾病患者冠状动脉微血管功能障碍的影响

目的 分析非阻塞性冠状动脉疾病患者冠状动脉微血管功能障碍(CMD)的影响因素。方法 根据左心室整体冠状动脉血流储备(LV-CFR)界值,经冠状动脉造影证实不存在任何冠状动脉直径狭窄≥50%病变的408例患者分为CMD组(LV-CFR<2,139例)和对照组(LV-CFR≥2,269例)。分析CMD发生以及LV-CFR的影响因素。结果 男性和女性患者CMD发病率相仿(32.5%vs.35.0%)(P>0.05)。CMD组BMI和LDL-C较对照组升高(P<0.05)。Logistic回归分析显示,相对于男性患者,女性CMD发生风险并未增加(P>0.05),而高LDL-C和高BMI是CMD发生的独立危险因素(P<0.05)。多重线性回归分析显示,LV-CFR与LDL-C呈负相关(P<0.05),而与性别没有明显相关性(P>0.05)。结论 性别对CMD的发生和LV-CFR无明显影响。     

Ranolazine in patients with coronary artery disease

Traditional anti-anginal agents such as beta-blockers and nitrates improve symptoms of cardiac ischemia by affecting either blood pressure or heart rates. Despite aggressive therapy, many patients suffer persistent angina, and optimal therapy is limited by intolerance to traditional agents. Ranolazine, a novel anti-anginal agent that is approved for use in the US, is felt to improve ischemic symptoms by reducing myocardial cellular sodium and calcium overload via inhibition of the late sodium current (I(Na)) of the cardiac action potential. Several Phase-III trials in patients with chronic angina have demonstrated that ranolazine improves exercise tolerance and reduces ischemic symptoms as compared with placebo. In the largest evaluation of ranolazine, the MERLIN-TIMI 36 trial (Metabolic Efficiency with Ranolazine for Less Ischemia in non ST elevation acute coronary syndrome), ranolazine did not reduce the risk of death or recurrent myocardial infarction in patients with non-ST-elevation acute coronary syndromes, but it did improve ischemic symptoms over the subsequent year of therapy. Thus, ranolazine offers clinicians a new therapy in the long-term treatment of patients with chronic angina.     

Ranolazine in patients with coronary artery disease

Traditional anti-anginal agents such as β-blockers and nitrates improve symptoms of cardiac ischemia by affecting either blood pressure or heart rates. Despite aggressive therapy, many patients suffer persistent angina, and optimal therapy is limited by intolerance to traditional agents. Ranolazine, a novel anti-anginal agent that is approved for use in the US, is felt to improve ischemic symptoms by reducing myocardial cellular sodium and calcium overload via inhibition of the late sodium current (I_Na) of the cardiac action potential. Several Phase-III trials in patients with chronic angina have demonstrated that ranolazine improves exercise tolerance and reduces ischemic symptoms as compared with placebo. In the largest evaluation of ranolazine, the MERLIN-TIMI 36 trial (Metabolic Efficiency with Ranolazine for Less Ischemia in non ST elevation acute coronary syndrome), ranolazine did not reduce the risk of death or recurrent myocardial infarction in patients with non-ST-elevation acute coronary syndromes, but it did improve ischemic symptoms over the subsequent year of therapy. Thus, ranolazine offers clinicians a new therapy in the long-term treatment of patients with chronic angina.     

Cigarette smoking is independently associated with markers of endothelial dysfunction and hyperinsulinaemia in nondiabetic individuals with coronary artery disease.

BACKGROUND: Oxidative stress and endothelial dysfunction have been introduced as a unifying pathological mechanism for early atherosclerotic disease. They are caused by a variety of stimuli including cigarette smoking (environmental) and type 2 diabetes (disease factor). However, the role of hyperinsulinemia, a marker of insulin resistance, as a risk factor for atherosclerosis remains to be clarified. STUDY OBJECTIVES: To study the relationship of smoking, hyperinsulinaemia and biochemical markers of oxidative stress and endothelial dysfunction, in patients with coronary artery disease. DESIGN: Case-control study of 5-year survivor status in smokers, former smokers and nonsmokers with angiographically documented stable coronary artery disease classified by self-reporting of smoking status together with plasma cotinine measurements. SETTING: Cardiology and cardiac surgery unit of a tertiary care referral centre. PATIENTS AND METHODS: Plasma levels of vitamins C, E and selenium, and the adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were assessed in 214 patients at baseline together with the glucose and insulin response to an oral glucose challenge. Sixty known or newly diagnosed type 2 diabetic patients (28%) were identified and excluded from further analysis. RESULTS: E-selectin and ICAM-1, serving as markers of endothelial dysfunction, significantly correlated with hyperinsulinaemia (p < 0.05). Circulating immunoreactive insulin was elevated in active smokers and former smokers as compared to non-smokers after an oral glucose load (p < 0.05 for the area under the insulin time curve), despite a similar glucose response. Smoking was associated with a decrease in antioxidant vitamins C (p = 0.02) and E (p = 0.03), and an increase of E-selectin (p < 0.05) and ICAM-1 (p < 0.001). Low baseline ICAM-1 and high vitamin C levels emerged as the most significant multivariate predictors of 5-year survival (p < 0.001). CONCLUSIONS: Hyperinsulinaemia in smokers is linked with markers of endothelial dysfunction. Impaired vascular reactivity can thus be a new possible mechanism linking insulin resistance and smoking.     

Decreased plasma and cardiac matrix metalloproteinase activities in patients with coronary artery disease and treated with pravastatin

Matrix metalloproteinase (MMP), which is activated by oxidative stress, plays an important role in the development of ventricular remodeling in coronary artery disease. Pravastatin is shown to reduce oxidative stress. We tested the hypothesis that cardiac oxidative stress and MMP activity are reduced in patients with coronary artery disease and treated with pravastatin. Forty-eight patients who underwent coronary artery bypass graft surgery (CABG) were studied. Twenty-four patients had the serum low-density lipoprotein (LDL) cholesterol level >2.59 mM, and were treated with pravastatin (10 mg/day) for 2 months before CABG (pravastatin group). The other 24 had LDL cholesterol相似文献   

Quality of life in patients with severe left ventricle dysfunction due to coronary artery disease

Background  

The majority of randomized trials comparing surgical treatment with percutaneous coronary intervention exclude patients with severe left ventricle dysfunction, resulting in the lack of a clear strategy for treatment.     

Prevention and endothelial therapy of coronary artery disease

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Improvement in endothelial dysfunction in patients with systemic lupus erythematosus with N-acetylcysteine and atorvastatin

Objective:

To study the effects of N-acetylcysteine (NAC) and atorvastatin on endothelial dysfunction in patients with systemic lupus erythematosus (SLE).

Materials and Methods:

Thirty-two SLE patients and age, sex-matched 10 healthy control subjects were studied. The patients were between 17 and 65 years of age and positive for diagnostic tests, such as antinuclear antibodies (ANA). Photoplethysmogram (PPG) detects the changes in the amount of light absorbed by hemoglobin, which reflects changes in the blood volume. Pulse wave analysis was performed at rest, 30 s, 90 s after shear stress, and 10 min after 300 μm of salbutamol inhalation.

Results:

Stiffness index (SI) of patients before the treatment was 8.46±2.78 cm/s and of controls was 6.07±1.4 cm/s (P = 0.002) and that of reflection index (RI) was 73±13 for patients and 65±7 for controls (P = 0.001). The percentage change in RI after salbutamol inhalation for controls and patients were -16±6 and -7±4 (P = 0.001), respectively, indicating the presence of endothelial dysfunction. The percentage decrease in RI after salbutamol inhalation was from -2.36±0.76 to ?7.92±1.46 in patients treated with N-acetylcysteine (NAC, P = 0.007). The percentage decrease in RI after salbutamol inhalation was from ?6.36΁1.21 to -9.92±1.21 in patients treated with atorvastatin (P = 0.05). This indicated the improvement in endothelial function. There was decrease in C-reactive protein (CRP) from 1.03±0.72 mg/dL to 0.52±0.22 mg/dL and that of malondialdehyde (MDA) from 11.20±4.07 nmol/mL to 8.81±2.79 nmol/mL with N-acetylcysteine treatment (P < 0.05). The CRP was decreased from 1.11±0.92 mg/dL to 0.440.16 mg/dL (P = 0.05) and that of MDA was decreased from 9.37±3.29 nmol/mL to 8.51±3.27 nmol/mL after treatment with atorvastatin. It showed improvement in oxidative stress with these treatments.

Conclusion:

The presence of arterial stiffness indicated endothelial dysfunction. There was reduction in RI and SI with treatment of N-acetylcysteine and atorvastatin suggesting improvement in endothelial dysfunction. There was decrease in CRP (a marker of inflammation) and MDA after treatment with N-acetylcysteine suggesting improvement in endothelial dysfunction. There was reduction in CRP after treatment with atorvastatin, suggesting improvement in endothelial function. Improvement in endothelial dysfunction is associated with decreased incidence of cardiovascular and cerebrovascular accidents.     

Improvement of bradykinin endothelium-mediated vasodilation of forearm resistance circulation by quinaprilat in patients with coronary artery disease with or without left ventricular dysfunction.

Angiotensin-converting enzyme (ACE) inhibition potentiates bradykinin and acetylcholine endothelium-mediated vasodilation. Three groups were studied. Group I (n = 10) was the reference group; group II was composed of nine patients with coronary artery disease; and group III of seven patients with coronary artery disease and left ventricular dysfunction. Forearm blood flow was measured with plethysmography. Acetylcholine and bradykinin were administered in a random order in the brachial artery at infusion rates of 40 and 80 microg/min and 10, 30, 100 pmol/min, respectively. Then quinaprilat was infused alone at the rate of 50 microg/min and then coinfused with acetylcholine and bradykinin. Five of the reference subjects were pretreated with acetylsalicylate. Acetylcholine and bradykinin increased forearm blood flow in a dose-dependent manner in the three groups. However, the vasodilator responses to both agents were significantly lower in the two groups of patients than in the reference group. Quinaprilat significantly enhanced the vasodilator response to acetylcholine only in subjects of the reference group, whereas it enhanced the vasodilator response to each dose of bradykinin, both in subjects of the reference group and in patients. Pretreatment with aspirin did not change the vasodilator responses in any group. In healthy persons, quinaprilat had no effect on its own on forearm blood flow but enhanced the response to bradykinin and even acetylcholine. In patients with coronary disease, short-term administration of quinaprilat was able to improve the impaired response to bradykinin. The response to acetylcholine, however, could not be significantly enhanced in contrast to that in healthy subjects.     

冠心病患者血清FGF23水平与血管内皮功能和冠状动脉病变程度相关性分析

目的 探讨成纤维细胞生长因子23(FGF23)与冠心病患者血管内皮功能和冠状动脉病变程度的相关性.方法 纳入经冠状动脉造影证实的214例冠心病患者,根据肱动脉血流介导性舒张(FMD)分为FMD损伤组(138例,FMD＜6％)和FMD正常组(76例,6％≤FMD＜20％).采用ELISA法测定患者血清FGF23、一氧化氮...     

Safety of bivalirudin in patients with coronary artery disease

INTRODUCTION: Various limitations of unfractionated heparin (UFH) have triggered a search for new antithrombotic therapies for patients with coronary artery disease (CAD). Bivalirudin is a direct thrombin inhibitor with several pharmacological advantages over UFH and is currently endorsed by practice guidelines, particularly in patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI). To maximize effectiveness of an antithrombotic regimen and reduce complications, both ischemic and bleeding risks should be known when an antithrombotic strategy is chosen. AREAS COVERED: This review focuses on the safety and tolerability of bivalirudin in patients with CAD in the setting of currently approved indications. Synthesis of evidence has been made from clinical trials, systematic reviews, meta-analyses and registries (1992 - 2011). The reader is provided with an overview of pharmacological properties of bivalirudin and its efficacy, with special emphasis on its safety in patients with CAD. EXPERT OPINION: Bivalirudin has an impressive safety profile in CAD patients treated with PCI. Bivalirudin is the antithrombotic of choice in suspected or verified heparin-induced thrombocytopenia. For ST elevation myocardial infarction patients undergoing primary PCI, bivalirudin should become the preferred antithrombotic agent together with early institution of antiplatelet therapy.     

Safety of bivalirudin in patients with coronary artery disease

Introduction: Various limitations of unfractionated heparin (UFH) have triggered a search for new antithrombotic therapies for patients with coronary artery disease (CAD). Bivalirudin is a direct thrombin inhibitor with several pharmacological advantages over UFH and is currently endorsed by practice guidelines, particularly in patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI). To maximize effectiveness of an antithrombotic regimen and reduce complications, both ischemic and bleeding risks should be known when an antithrombotic strategy is chosen.

Areas covered: This review focuses on the safety and tolerability of bivalirudin in patients with CAD in the setting of currently approved indications. Synthesis of evidence has been made from clinical trials, systematic reviews, meta-analyses and registries (1992 – 2011). The reader is provided with an overview of pharmacological properties of bivalirudin and its efficacy, with special emphasis on its safety in patients with CAD.

Expert opinion: Bivalirudin has an impressive safety profile in CAD patients treated with PCI. Bivalirudin is the antithrombotic of choice in suspected or verified heparin-induced thrombocytopenia. For ST elevation myocardial infarction patients undergoing primary PCI, bivalirudin should become the preferred antithrombotic agent together with early institution of antiplatelet therapy.     

Correlation between osteocalcin‐positive endothelial progenitor cells and spotty calcification in patients with coronary artery disease

Immature endothelial progenitor cells (EPC) carrying osteocalcin (OCN) might mediate vascUlar calcification in coronary artery disease (CAD). Spotty calcification within atherosclerotic plaque is associated with cardiovascular events. The aim of the present study was to assess the correlation between immature EPC levels and spotty calcification in CAD patients. In the 224 CAD patients studied, 76 had acute myocardial infarction (AMI), 102 had unstable angina pectoris (UAP), and 46 had stable angina pectoris (SAP). The levels of OCN‐positive (OCN+) EPC were analysed by flow cytometry. The status of spotty calcification was determined by cardiac computed tomography angiography. OCN+ EPC and calcium deposits were significantly increased in acute coronary artery syndrome (ACS) when compared with those in SAP patients. Positive correlation was also revealed between the number of OCN+ EPC and the frequency of spotty calcification and levels of serum high‐sensitivity C‐reactive protein (hs‐CRP) and serum alkaline phosphatase in AMI and UAP patients. In summary, the number of OCN+ EPC is positively related to the frequency of spotty calcification in ACS patients. Serum hs‐CRP and serum alkaline levels are thought to contribute to the elevation of OCN+ EPC.     

冠心病合并血糖异常患者冠状动脉病变特点分析

目的探讨冠状动脉粥样硬化性心脏病（冠心病）合并血糖异常患者冠状动脉病变的特点。方法对我院行冠状动脉造影术确诊为冠心病的236例患者临床资料进行回顾性分析,其中血糖异常组114例,血糖正常组122例,对其临床特点和冠状动脉造影结果进行对比分析。结果两组患者年龄、性别比、吸烟史、体质指数、高密度脂蛋白胆固醇、心肌梗死发生率和冠状动脉病变部位等方面比较差异均无统计学意义（均P〉0．05）。血糖异常组高血压、胆固醇、甘油三酯、低密度脂蛋白胆固醇以及载脂蛋白B水平均高于血糖正常组（P〈0．05或P〈0．01）;血糖异常组冠状动脉病变的狭窄程度重,中、重度狭窄及多支病变发生率显著增高（均P〈0．叭）。结论冠心病伴血糖异常患者多同时伴有冠心病的其他危险因素,其冠状动脉病变复杂,病变程度严重,多支病变增多。     

Sustained contraction and endothelial dysfunction induced by reactive oxygen species in porcine coronary artery

A combination of purine and xanthine oxidase (XOD) dose-dependently elicited sustained contraction of porcine coronary arterial rings and resulted in increased concentrations of superoxide anions and hydrogen peroxide. These contractile responses appeared, with a delay, after the application of purine and XOD, used as a reactive oxygen species (ROS)-generating system. Coronary arteries precontracted with prostaglandin F(2alpha) failed to relax in response to substance P after exposing the arterial preparation to this ROS-generating system. The contractile response of the coronary artery to the ROS-generating system was almost completely inhibited by catalase (130 U/ml), and was partially inhibited by superoxide dismutase (60 U/ml), or mannitol (30 mM). A voltage-dependent L-type Ca(2+) channel antagonist, nicardipine, had no effect on contraction. Dysfunction of endothelial cells was completely prevented by catalase, but not by superoxide dismutase or mannitol. These results suggest that superoxide anions, hydrogen peroxide and hydroxyl radicals might be involved in eliciting sustained, delayed-onset coronary artery contraction, which is not related to L-type Ca(2+) channels. They also suggest that hydrogen peroxide might play a major role in endothelial dysfunction of the porcine coronary artery.     

Nitrate therapy and nitrate tolerance in patients with coronary artery disease

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Highlights► We discuss the mechanisms of the anti-ischemic actions of organic nitrates. ► We discuss side effects of chronic nitrate therapy like nitrate tolerance and endothelial dysfunction. ► We provide evidence for a role of nitrates in the phenomenon of ischemic preconditioning.