Effects of L- and D-arginine on the basal tone of human diseased coronary arteries and their responses to substance P

OBJECTIVE: To assess the effects of substance P administration alone and in combination with L- and D-arginine in patients with normal angiograms and in patients with coronary artery disease. DESIGN: Intracoronary infusions of (a) normal saline, (b) the receptor mediated nitric oxide stimulant substance P (5.6 and 27.8 pmol/min) before and after L- or D-arginine (50 and 150 micromol/min), and (c) glyceryl trinitrate (250 microg bolus) were given to 17 patients with coronary artery disease and stable angina, and to six patients with normal angiograms. The diameter of angiographically normal proximal and distal segments and coronary stenoses were measured by computerised quantitative angiography. RESULTS: L-arginine administration was associated with significant dilatation of stenoses (p < 0.01) of proximal segments of both "normal" (p < 0.05) and diseased (p < 0.01) arteries, and of distal segments of diseased arteries (p < 0.01). No significant changes were associated with D-arginine administration. Dose dependent dilatation of all segments including stenoses, was observed with substance P both before and after L-arginine infusion (p < 0.01). The magnitude of dilatation of stenoses and all segments of both "normal" and diseased coronaries was greater after L-arginine (p < 0.05) but not D-arginine and substance P infusion, than it was after saline and substance P infusion. Administration of D- or L-arginine did not change the magnitude of substance P induced dilatation. CONCLUSIONS: Diseased and "normal" coronary arteries dilated in response to substance P and L-arginine but were unaffected by D-arginine infusion. The magnitude of the response to substance P was not increased by L-arginine administration, indicating that it is not critically dependent on the availability of substrate for nitric oxide synthase.     

Vasomotor responses of coronary stenoses to acetylcholine and their relation to serum lipid levels in stable angina pectoris

The effects of acetylcholine administration on coronary stenoses in relation to serum lipids level were evaluated in 18 patients (15 men, 3 women) with coronary artery disease and stable angina. Intracoronary acetylcholine was infused in concentrations 10⁻⁷, 10^−6, 10⁻⁵ M, followed by intracoronary bolus administration of isosorbide dinitrate. Computerized angiography was used to assess the changes in the diameter of stenoses and of proximal and distal segments. During acetylcholine infusion, at concentrations between 10⁻⁷ to 10 ⁻⁵M, there was a significant (p <0.01) dose-dependent constriction of proximal and distal segments and of stenoses reversed by isosorbide dinitrate. There was no correlation between the serum total cholesterol level and the responses of proximal and distal segments to acetylcholine or nitrate. A correlation (p <0.05) was found between the serum total cholesterol level and the response of stenoses to acetylcholine, but there was no correlation with the response to isosorbide dinitrate. In conclusion, in patients with stable angina current serum total cholesterol level correlates with the vasomotor response of coronary stenoses to intracoronary acetylcholine. These findings are consistent with a direct effect of cholesterol, increasing basal coronary vasomotor tone and increasing the stimulated vasoconstrictor response of stenoses.     

L-arginine preferentially dilates stenotic segments of coronary arteries thereby increasing coronary flow

Background and objectives. Oxidized LDL cholesterol and cytokines increase arginase and decrease nitric oxide (NO) synthase expression in human endothelial cells, leading to a decrease in NO production. In arteriosclerotic plaques, characterized by increased oxidized LDL and cytokine levels, a sustained local NO reduction might enhance sensitivity of the downstream guanylyl cyclase system towards an acute NO increase. We tested whether application of the NO synthase substrate l ‐arginine (l ‐arg, 150 μmol min^?1) or the NO donor isosorbide dinitrate (ISDN; 0.3 mg) preferentially dilates stenotic coronary artery segments (CS) subsequently increasing poststenotic coronary blood flow (CBF) in patients with coronary artery disease (CAD). Design, setting and subjects. Changes in coronary diameter and circumferential surface area were assessed by quantitative coronary angiography (QCA) in a nonstenotic upstream segment, the CS, downstream the CS and in a reference vessel (n = 24). CBF was estimated in a subset of 13 patients by QCA and intracoronary Doppler. Results. CS ranged from 62% to 89% (77 ± 5%). l ‐arg increased minimal luminal diameter of the stenotic segment from 0.98 ± 0.06 to 1.14 ± 0.07 mm (P < 0.05) without affecting other coronary segments. Poststenotic CBF increased by 24 ± 3%. ISDN dilated all segments again with a predominance of CS (25 ± 4%) and increased poststenotic CBF by 38 ± 9%. In a multifactorial anova , a medication with an angiotensin‐converting enzyme inhibitor (decreasing inflammation and radical formation) and a ratio of LDL/HDL <3.5 were predictive for an l ‐arg‐induced dilation. Conclusion. The increase in poststenotic CBF without affecting nondiseased arteries highlights the therapeutic potential of l ‐arg in patients with CAD.     

64排CT冠状动脉斑块分析对冠状动脉直接支架术指导作用的研究

目的 探讨64排CT冠状动脉斑块分析对冠状动脉直接支架术的指导意义.方法 连续入选接受64排CT冠状动脉成像（CTA）并冠状动脉直接支架术治疗的患者42例,置入支架44枚.根据支架释放后有无残余狭窄分为2组,组间对比64排CT冠状动脉成像所示斑块的性质、斑块的CT值、钙化长度、横断面最大钙化面积.结果 残余狭窄组患者斑块的最大CT值大于无残余狭窄组（P＜0.01）.Logistic回归分析显示,当斑块的CT值达到648～679时,支架释放时出现残余狭窄的概率为70％～90％.结论 冠状动脉直接支架术支架释放后出现残余狭窄与斑块的最大CT值有关,当斑块有明显大的CT值时,采用直接支架术需谨慎.     

Elimination of variable vasomotor tone in studies with repeated quantitative coronary angiography

Summary In quantitative coronary angiographic studies, unintentional changes of coronary vasomotor tone may have a significant influence on the coronary artery diameters, thereby increasing the variability in the measurements. To obtain objective data on these measurement variabilities, two protocols were designed to assess the influences of ionic and nonionic radiographic contrast media on the mean diameters of angiographically normal coronary arteries. The vessel sizes were determined with the CAAS using automated edge detection techniques. In 21 patients (study no. I), coronary angiograms were taken in identical angiographic projections before (control), and immediately following several (at average 7) subsequent diagnostic dye injections administered over a period of about 7 min. The ionic contrast agent diatrizoate 76% induced a coronary dilation of 19 ± 7% (mean ± s.d., p<0.001; n=10); the nonionic agent iopromide 370 increased the coronary artery diameters by only 6 ± 4% (p<0.01; n=11). In another 11 patients (study no. II) coronary angiograms were obtained using the nonionic contrast medium iopamidol 300 at 5, 8, 10 and 11 min after the control acquisition; this protocol was repeated in the same patients with diatrizoate 76%. With iopamidol, coronary diameter changes were not significant at any time; with diatrizoate, however, coronary dilation was measured at 10 min (2 ± 2%; p<0.01) and at 11 min (10 ± 3%; p<0.001).In a third study it was tested, whether standardization of coronary vasomotor tone (e.g. in coronary angiographic follow-up studies) is possible by the induction of a reproducible maximum coronary dilation with nitrocompounds. In 12 patients, the mean diameters of angiographically normal coronary segments were analyzed before and at various times after i.v. administration (over 4 min) of 0.025 mg SIN-1/kg bodyweight. Coronary dilation was maximal at 10 or 15 min after the onset of the SIN-1-infusion (29 ± 5%; p<0.001). 0.8 mg nitroglycerin given s.l. at 15 min did not further dilate the coronary arteries (28 ± 7%). One hour after SIN-1, coronary dilation still amounted to an average of 24 ± 8% (p<0.001) and became maximal again, when 0.8 mg nitroglycerin was again administered sublingually (28 ± 8%; p<0.001).In conclusion, short-term variability of coronary vasomotor tone induced by ionic radiographic contrast media can be eliminated by the use of nonionic contrast agents and observation of injection intervals of at least 2 min. In quantitative coronary angiographic follow-up studies, as well as during acute interventions (e.g. PTCA), identical baseline vasomotor tone can be achieved by induction of the maximal coronary dilation using nitrocompounds.Dedicated to Prof. Paul R. Lichtlen on the occasion of his 60st birthday.     

老年女性冠心病患者颈动脉粥样硬化和血管内皮依赖性舒张功能的探讨

目的　观察老年女性冠心病患者颈动脉内中膜厚度 (IMT)、粥样斑块发生率及肱动脉内皮依赖性舒张功能的情况。方法　用高分辨超声技术对 89例老年女性行肱动脉血流介导的舒张功能 (FMD)、IMT及颈动脉粥样斑块的检测。结果　老年女性冠心病组FMD较对照组明显减弱 ,分别为 (3.5± 3.1) %及 (7.6± 3.5 ) % ,P <0 .0 0 1,老年女性冠心病组及对照组IMT分别为 (0 .88± 0 .2 0 )mm及 (0 .6 5± 0 .2 3)mm ,颈动脉粥样斑块发生率分别为 6 2 .2 %及11.4 % ,两组比较差异具有显著性意义 ,P <0 .0 0 1。结论　老年女性冠心病患者存在着严重的血管内皮依赖性舒张功能障碍以及颈动脉粥样硬化 ,颈动脉B超及肱动脉血流介导的舒张功能对老年女性冠心病患者有一定的预测价值。     

颈动脉粥样斑块与冠心病的相关性分析

目的 通过颈动脉内中膜厚度（IMT）的测定，探讨颈动脉粥样斑块与冠心病（CHD）的相关性。方法 非脑血管病患者60例分为对照组（13例均无冠心病史），心绞痛组（20例），心肌梗死组（27例）。冠心病诊断依据心电图，运动-静息^99mTc-MIBI心肌显像（SPEC）检查结果；颈动脉粥样斑块用多普勒超声诊断仪检测。结果 对照组颈动脉超声未见狭窄及粥样斑块，其颈动脉内膜厚度／腔内径〈0．1。心绞痛或心肌梗死组80％（38／47）发现存在颈动脉粥样斑块，颈动脉内膜厚度／腔内径〉0．1，收缩期颈内动脉血流速（IC）／颈总动脉血流速（CC）〉0．8，与对照组比较均有显著差异，但心绞痛组与心肌梗死组上述指标未见显著差异。结论 颈动脉粥样斑块与冠心病密切相关，可能是诊断冠心病的一个较好指标。     

单纯冠状动脉旁路移植术及联合应用激光心肌血运重建术治疗重症冠心病的研究

目的　探讨激光心肌血运重建术 (TMLR)对重症冠心病患者心肌缺血、心功能影响的机制。方法　冠心病 3支病变重症冠心病住院患者共 6 0例 ,随机分为两组 ,对照组 30例行单纯冠状动脉旁路移植术 (CABG) ,实验组 30例联合应用CABG +TMLR治疗。观察术后 6个月和 12个月时患者心绞痛分级、左心室射血分数 (LVEF)、6分钟步行距离 (6MWD)和血浆脑利钠肽 (BNP)、血管内皮生长因子 (VEGF)浓度的变化。结果　随访 1年 ,两组死亡率差异无显著性意义 ;两组患者的加拿大心脏病协会心绞痛分级、血浆BNP、VEGF水平和 6MWD在随访 6个月均较术前有明显改善 ,但随访 12个月时两组间无显著性差异。结论　在术后半年 ,CABG +TMLR联合治疗重症冠心病患者在降低心绞痛分级、增加运动耐量等方面均优于单纯CABG ,但术后 1年时 ,两种治疗方案的疗效相近。     

Evidence of partially preserved endothelial dilator function in diseased coronary arteries

OBJECTIVE—To examine the effects of substance P (endothelium dependent vasodilator) and glyceryl trinitrate (endothelium independent vasodilator) on epicardial coronary arteries in patients with normal coronary angiograms and patients with coronary artery disease.
DESIGN—Intracoronary infusions of normal saline, the receptor mediated nitric oxide stimulant substance P (5.6 and 27.8 pmol/min each for five minutes), and glyceryl trinitrate (250 µg bolus) were given in 24 patients with coronary artery disease and stable angina, and in nine patients with normal angiograms. The diameter of proximal and distal coronary segments was measured by computerised quantitative angiography
RESULTS—Proximal segments of patients with coronary artery disease dilated less than those of patients with normal angiograms in response to 27.8 pmol/min substance P (mean (SEM): 7.9 (1.3)% v 15 (2.3)% respectively, p < 0.01). The proximal segments of diseased arteries also dilated less than those of "normal" arteries in response to glyceryl trinitrate (10.2 (1.6)% v 18.4 (2.9)%, respectively, p < 0.01). The responses of distal segments to substance P and glyceryl trinitrate were similar in the two patient groups. There were correlations (all p < 0.001) between the coronary diameter after substance P and after glyceryl trinitrate in normal proximal segments (r = 0.94) and normal distal segments (r = 0.64), in diseased proximal segments (r = 0.95) and diseased distal segments (r = 0.89), and for coronary stenoses (r = 0.93).
CONCLUSIONS—Proximal segments of patients with coronary disease dilated less than the proximal segments of "normal" patients in response to substance P and glyceryl trinitrate. The response to substance P is substantial and closely correlated with the response to glyceryl trinitrate in both "normal" patients and those with coronary disease. This suggests that although the proximal segments of diseased coronary arteries have a reduced capacity to dilate in response to direct stimulation of smooth muscle cell relaxation, they retain much of their endothelium dependent vasodilator function.


Keywords: endothelium; nitric oxide; coronary artery disease; glyceryl trinitrate     

Automatic detection method of stenotic lesions in coronary cineangiograms

A new image processing procedure enabling the automatic detection of coronary artery stenoses by cineangiography was developed. Detection of stenoses was performed using computer image processing by the following procedure. The path of the arteries was extracted by a subtraction method. The thresholding image was obtained from the subtraction image, and converted to a thinning image, which represented the center line of the artery. For measurement of the arterial diameter, the vessel edges were determined by unilateral Gaussian fit to profile curves in sections perpendicular to the center line. Stenoses could then be detected on the basis of the normal diameter of artery estimated by Hough transformation. This method facilitates the detection of stenotic lesions from coronary cineangiograms.     

Effects of insulin dependence on inflammatory process, thrombotic mechanisms and endothelial function, in patients with type 2 diabetes mellitus and coronary atherosclerosis

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by endothelial dysfunction, increased thrombogenicity and abnormal inflammatory response. HYPOTHESIS: We hypothesizsed that insulin dependence/exogenous insulin administration may affect thrombotic/inflammatory status and endothelial function in patients with T2DM and coronary artery disease (CAD). METHODS: Fifty-five patients with T2DM + CAD (26 insulin-treated (INS) and 29 under oral biguanide + sulphonylurea (TABL)) were recruited. Endothelial function was assessed by gauge-strain plethysmography, and serum levels of inflammatory and thrombotic markers were determined by enzyme linked immunosorbent assay. RESULTS: There was no significant difference in endothelium-dependent dilation (EDD) between the study groups, while EDD was correlated with fasting glucose levels in both INS (r = - 0.776, p = 0.0001) and TABL (r = - 0.702, p = 0.0001). Patients in INS group had higher levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein (MCP-1) and vascular cell adhesion molecule (sVCAM-1), compared to TABL. However, TNF-alpha was negatively correlated with protein C (PrtC) only in INS (r = - 0.726, p = 0.01) but not in TABL group (r = - 0.066, p = 0.738). Similarly, sVCAM-1 was correlated with PrtC only among INS patients (r = - 0.451, p = 0.046) but not in TABL (r = 0.069, p = 0.727). In multivariate analysis, insulin dependence was a predictor of IL-6, TNF-alpha, MCP-1 and sVCAM-1 levels independently from the patients' demographic characteristics, the angiographic extend of CAD or the duration of diabetes. CONCLUSIONS: Insulin treatment in patients with type 2 diabetes mellitus affects the expression of inflammatory cytokines and subsequently modifies the thrombotic mechanisms in patients with coronary atherosclerosis, independently from the duration of diabetes and the extend of coronary artery disease.     

Relationship between interleukin-18 levels and characterization of atherosclerotic plaque and percutaneous coronary intervention

Background lnterleuldn-18(IL- 18) plays a key role in the development,progression and outcome of coronary artery disease and its complications.However,its variability relation to the characterization of atherosclerotic plaque and percutaneous coronary intervention are still unknown.Methods Fifty four patients with coronary artery disease [22 patients with stable angina (SA) and 32 patients with acute coronary syndrome (ACS)] were enrolled in this study.All patients underwent percutaneous coronary intervention (PCI).The stability of the plaques at the criminal vessels was assessed with analogical IVUS.Serum IL-18 levels were measured at the time points of 5 rain before PCI,and Oh,6h,24h and lmonth after PCI in all patients.Results ACS group consisted mainly of lipidic unstable plaques while SA group of fibrous stable plaques.Moreover,compared with those in SA group,eccentricity index (EI) and remodeling index (RI) were significantly higher in ACS group.Positive remodeling was seen in ACS group while negative or no remodeling in SA group.Further,serum IL-18 levels were significantly elevated in patients with ACS than those in SA group before PCI,increased at Oh,6h,24h after PCI (P＜0.05)and were not significant different at 1 month after PCI from those before PCI.Conclusions There is significant difference in the composition and structural characteristics of atherosclerotic plaques between ACS and UA groups.PCI triggersd and enhances the inflammatory response in a short time.Serum levels of IL- 18 are the predictors of progression of unstable plaque in atherosclerosis.Post-operative complications of PCI might be reduced by inhibiting IL- 18.(J Geriatr Cardiol 2008;5:21-24)     

How to standardize vasomotor tone in serial studies based on quantitation of coronary dimensions?

In patients with coronary artery disease including those after coronary bypass graft operation and heart transplantation intervention studies based on serial quantitative coronary angiography, in part combined with intravascular ultrasound, are of increasing relevance. Since vasomotor tone of epicardial coronary arteries is influenced by a variety of factors, angiographic follow-up studies require standardization of coronary tone by induction of maximal dilation. We reviewed the effects of the most potent coronary vasodilatory drug groups, calcium antagonists and nitrocompounds, on coronary diameters. Intravenous or intracoronary injections of verapamil, diltiazem, nifedipine, nicardipine, and nisoldipine can cause profound coronary dilation which has been shown to be maximal with verapamil and nisoldipine. Shortcomings of calcium antagonists include short or unknown duration of action after bolus administration, severe drop in blood pressure, and lack of commercial availability of solutions for injection of many substances. Isosorbide dinitrate induces profound coronary dilation; however, after sublingual administration marked blood pressure decrease can occur, and the duration of action and ideal dose of intracoronary isosorbide dinitrate has not been investigated yet. Injections of molsidomine and its active metabolite, SIN-1, cause longlasting, reproducible, maximal coronary dilation, although only after a waiting period of at least 10 minutes; unfortunately, SIN-1 is only commercially available in France. Nitroglycerin induces reproducible maximal coronary dilation and is easy to administer sublingually or as intracoronary bolus injection with rapid onset of action and no major side effects. The short duration of action may require repeated administrations. To date, repeated intracoronary bolus injections of 0.1 mg nitroglycerin every 10 minutes seem to be the optimal known regimen for standardization of coronary vasomotor tone in serial angiographic studies. Further investigations in this field with old and new vasodilatory drugs are recommendable.     

复方丹参、葛根辅助治疗冠心病的疗效研究

目的 评估丹参加葛根作为辅助治疗药物对冠状动脉粥样硬化性心脏病(冠心病)二级预防的疗效及安全性.方法 符合入选标准的冠心病患者100例分为丹参、葛根胶囊治疗组(试验组)和安慰剂组(对照组),每组50例,进行为期6个月的随机、双盲临床研究.6个月后受试者再自愿选择参与6个月的开放试验,期间受试者口服丹参、葛根胶囊的剂量为...     

冠状动脉0钙化积分人群非钙化性斑块的发生率及其危险因素分析简

目的 利用计算机断层扫描（computerized tomography,CT）冠状动脉成像,研究冠状动脉0钙化积分人群非钙化性斑块的发生率及管腔狭窄程度,并分析其相关危险因素.方法 对968例冠状动脉0钙化积分患者的影像学资料和临床资料进行回顾性分析,所有患者均行64层螺旋CT冠状动脉钙化积分扫描及CT冠状动脉成像检查;采用单因素分析和Logistic回归分析冠状动脉非钙化性斑块形成的相关危险因素.结果 968例患者中,203例（21.0％）检出非钙化性斑块,斑块导致轻度狭窄124例（61.1％）、中度狭窄53例（26.1％）、重度狭窄26例（12.8％）.Logistic回归分析显示原发性高血压（高血压）（OR=3.994,P=0.010）、男性（OR=2.663,P=0.000）、吸烟史（OR=1.376,P=0.001）、甘油三酯增高（OR=3.536,P=0.000）、高密度脂蛋白胆固醇降低（OR=0.653,P=0.008）为冠状动脉非钙化性斑块形成的危险因素.糖尿病史、血清甘油三酯和高密度脂蛋白胆固醇浓度与斑块导致的管腔狭窄程度有关.结论 冠状动脉0钙化积分人群中有相当比例的人存在非钙化性斑块,高血压、高脂血症为非钙化性斑块形成的两大独立危险因素.     

冠状动脉斑块消退的调脂治疗策略

4项他汀类药物治疗冠心病患者,以血管内超声评价冠状动脉(冠脉)斑块变化的临床试验(RE-VERSAL、ASTEROID、COSMOS和SATURN)结果一致显示,他汀治疗显著降低LDL-C,同时升高Apo-A1和HDL-C,才能观察到冠脉粥样硬化斑块的消退。适度调脂指通过他汀类药物治疗,达到减少胆固醇流入斑块的目标值:降低LDL-C>45%(达到1.81～2.46mmol/L),同时达到增加胆固醇流出斑块的目标值:升高Apo-A1>9%(达到3.50～3.89mmol/L)和HDL-C>8%(达到1.17～1.42mmol/L),实现冠脉斑块的消退。