粒细胞-巨噬细胞集落刺激因子与不稳定型心绞痛的关系

目的　观察不稳定型心绞痛 (UAP)患者血清粒细胞 -巨噬细胞集落刺激因子 (GM- CSF)水平的变化 ,并进一步探讨其与血小板激活及内皮损伤之间的关系。方法　采用液相竞争放射免疫法检测 2 0例不稳定型心绞痛患者(U AP组 )、2 0例稳定型心绞痛患者 (SAP组 )及 2 0例正常对照组 (NC组 )血清 GM- CSF浓度 ,用酶联免疫双抗体夹心法测定其血浆血管性血友病因子 (v WF)及 P-选择素含量。结果　 U AP组血清 GM- CSF、血浆 P-选择素、v WF的水平明显高于 SAP组及正常对照组 (P均 <0 .0 1)。SAP组与对照组比较上述指标虽均升高 ,但无统计学意义 (P>0 .0 5 ) ;U AP患者血清 GM- CSF分别与血浆 P-选择素、v WF呈正相关 (r=0 .5 83及 r=0 .5 74 ;P均 <0 .0 1)。结论　不稳定型心绞痛患者血清 GM- CSF浓度升高 ,其可能与不稳定型心绞痛患者血小板激活和内皮损伤有关     

Hemodynamic, platelet and clinical responses to prostacyclin in unstable angina pectoris

The hemodynamic and platelet effects of prostacyclin (PGI2) were investigated in 27 patients with unstable angina (14 treated patients; 13 control subjects) given a 72-hour infusion (5 ng/kg/min) or placebo. This randomized study was double-blind and conducted as a substudy of a multicenter trial testing the clinical efficacy of PGI2. The clinical and angiographic features were identical in the 2 groups. Blood pressure and heart rate were not modified significantly by PGI2. A recurrence of angina during infusion occurred in 8 treated patients (57.1%) and in 8 control subjects (61.5%). Two patients receiving PGI2 and none in the control group developed a myocardial infarction. Levels of 6-keto-prostaglandin F1 alpha, a stable metabolite of PGI2, increased from baseline values (less than 20 pg/ml) to 605 +/- 41 pg/ml during infusion. Levels of fibrinopeptide A, beta-thromboglobulin, platelet factor 4, thromboxane B2 and the platelet aggregates ratio in blood were similar between the 2 groups before, during and after PGI2 infusion. Prostacyclin reduced ex vivo platelet aggregation to adenosine diphosphate and thromboxane B2 generation by approximately 50% during the infusion period with return of aggregation to baseline and platelet thromboxane B2 production to above baseline after the discontinuation of PGI2. Thus, despite favorable effects of PGI2 upon platelet aggregation and systemic hemodynamics, the prostanoid failed to improve the clinical evolution of unstable angina.     

Optimal platelet inhibition therapy in unstable angina pectoris and after coronary interventions

ASPIRIN AND HEPARIN: In several studies aspirin has been found to be very effective in unstable angina pectoris reducing fatal and non-fatal myocardial infarction by 50-70%. Unfortunately the optimal dose of aspirin is still an open question. Whereas heparin alone shows only a weak effectiveness the combination of aspirin and heparin is superior to aspirin alone and is still the basis of antithrombotic therapy in unstable angina. TICLOPIDINE AND CLOPIDOGREL: Experience with thienopyridine derivatives in unstable angina is limited. Ticlopidine has been found to be superior to aspirin alone. Data with the combination of clopidogrel and aspirin should be available soon. THERAPEUTIC RECOMMENDATION AFTER CORONARY INTERVENTION: Both, ticlopidine and clopidogrel have been found to be very effective in preventing coronary-stent thrombosis when combined with aspirin. Meanwhile ticlopidine has been widely substituted by clopidogrel due to the better safety profile of the latter one. 75 mg clopidogrel daily combined with aspirin is recommended for at least 4 weeks after coronary stenting.     

Fibrinopeptide A, platelet factor 4, and beta-thromboglobulin levels in coronary heart disease

In vivo platelet alpha-granule release and fibrin I formation were measured in 82 patients with ischemic heart disease by radioimmunoassay of platelet factor 4, beta-thromboglobulin, and fibrinopeptide A. The presence and extent of coronary artery disease were determined by coronary arteriography, and the extent of left ventricular regional dysfunction was assessed by contrast left ventriculography. In patients with abnormal coronary arteriograms without previous myocardial infarction, mean levels of platelet factor 4, beta-thromboglobulin, and fibrinopeptide A were not elevated. In patients in whom myocardial infarction had occurred more than 6 mo previously, platelet factor 4 (8.3 ng/ml; p less than 0.01) and beta-thromboglobulin (33.2 ng/ml; p less than 0.001) levels were significantly elevated, but fibrinopeptide A levels were normal. Levels of platelet factor 4 and beta- thromboglobulin were unrelated to the extent of coronary artery disease. In the patients with prior infarction, beta-thromboglobulin correlated directly with extent of left ventricular regional dysfunction (r = 0.53; p less than 0.01) and inversely with ejection fraction (r = -056; p less than 0.05). In a small group of patients with left ventricular aneurysm, mean fibrinopeptide A levels were also elevated. We interpret these findings as indicating that platelet release in patients with ischemic heart disease results from platelet reaction with previously infarcted myocardium rather than with the atherosclerotic coronary arteries.     

Effect of aspirin and ticlopidine on plasma tissue factor levels in stable and unstable angina pectoris

Patients with unstable angina have an increased activation of the coagulation system. Aspirin and ticlopidine given in combination may potentiate each other by the combination of different action mechanisms and may reduce the risk of coronary occlusion and clinical instability. Plasma tissue factor (TF) levels collected into the stenotic coronary artery may be an index of TF expression within the vasculature. In 160 patients undergoing angioplasty for a 81+/-5% coronary lesion, we measured TF in blood samples collected from a vein and from the coronary ostium. Immediately after and 10 minutes after the dilation procedures the samples were withdrawn also beyond the lesion. Heparin 150 U/kg was given as an anticoagulant. All patients were pretreated with 250 mg/day of aspirin. One hundred twenty patients were randomly assigned to receive 24, 48, or 72 hours of ticlopidine treatment (250 mg/twice daily). TF levels did not increase during angioplasty but there was a significantly higher TF expression in unstable than in stable patients, irrespective of the invasiveness of debulking procedures. When ticlopidine was given for 72 hours, TF levels were similar to normal laboratory values both in stable and unstable patients. This combined antiplatelet pretreatment may be of benefit in unstable angina patients, with a favorable cost/benefit ratio.     

氯吡格雷对不稳定型心绞痛患者血小板功能的影响

目的 :观察氯吡格雷对不稳定型心绞痛 （UAP）患者血小板功能的影响 ,探讨其临床应用价值。方法 :UAP患者 85例 ,随机分为氯吡格雷负荷剂量组 （n=30 ） ,氯吡格雷常规剂量组 （n=30 ）及噻氯匹定治疗组 （n=2 5 ）。所有患者在给予阿司匹林 30 0 mg/ d的基础上 ,氯吡格雷负荷剂量组 1次性给予氯吡格雷 （波立维 ） 30 0 mg,氯吡格雷常规剂量组给予波立维 75 mg/ d,噻氯匹定组给予噻氯匹定 （抵克力得 ） 2 5 0 mg/ d,观察 3组患者治疗前 ,氯吡格雷负荷剂量组给药 2 h后 ,氯吡格雷常规剂量组及噻氯匹定组给药 3d后患者血浆 GMP- 14 0含量及血小板最大聚集率（MPAR）的变化。结果 :各组患者治疗后血浆 GMP- 14 0含量及 MPAR较治疗前显著降低 （P<0 .0 1） ,组间血浆GMP- 14 0含量及 MPAR无显著性差异 （P>0 .0 5 ）。结论 :氯吡格雷起效迅速 ,首剂负荷剂量 30 0 mg服药后 2 h即可有效抑制血小板激活 ,可达到服用常规剂量氯吡格雷或噻氯匹定连续 3d抑制血小板激活的效果     

Fibrinopeptide A and beta thromboglobulin in patients with angina pectoris and acute myocardial infarction

The purpose of this study was to investigate the degree of platelet activation and thrombin generation in 40 patients with stable angina pectoris and in 20 patients with acute myocardial infarction (AMI) by determining the plasma beta thromboglobulin (BTG) and fibrinopeptide A (FPA) concentrations. In patients with angina pectoris increased platelet activation correlated with extensive coronary pathology; the activation, however, was not influenced by a previous myocardial infarction, use of oral anticoagulants, beta-blocking agents, or hyperlipidemia. The plasma beta thromboglobulin concentration predicted more accurately the extent of the coronary artery disease than the functional angina pectoris classification. Thrombin generation was within the normal range. In patients with acute myocardial infarction increased platelet activation and enhanced thrombin generation were found, which were not related to the infarct localization, infarct size, or the presence of complications. Consequently, in these patients determination of plasma beta thromboglobulin and fibrinopeptide A concentrations is useless for the diagnosis of venous thromboembolism.     

Management of unstable angina pectoris

The diagnosis of unstable angina may be confirmed if an ECG taken during an episode of pain demonstrates ST-segment changes that resolve when the pain is relieved. An intra-aortic balloon device should be used in the rare patient who has recurrent episodes of ischemia despite maximum drug therapy. Coronary angiography should be performed as soon as possible after the device is inserted.     

Angiographic morphology in unstable angina pectoris

Complex morphology occurs frequently in unstable angina; however, its relation to symptomatic presentation, timing of angiography and hospital outcome has not been investigated. Accordingly, coronary angiography was performed 5 +/- 2 days after qualifying rest pain in 101 consecutive patients presenting with acute coronary insufficiency (n = 67) or crescendo angina (n = 34). Significant coronary artery disease was defined as any greater than or equal to 50% stenosis, and complex morphology as any stenosis with irregularity, overhang or thrombus. Eight of the 67 patients presenting with acute coronary insufficiency later proved to have a myocardial infarction as the qualifying event (creatine kinase twice normal with elevation of MB fraction). There were no myocardial infarctions in the crescendo angina group. Complex morphology occurred in 61% of patients. Thrombus alone occurred in 27% of patients with unstable angina without myocardial infarction, with similar frequencies between the 2 clinical groups. In contrast, intraluminal thrombi were identified in 78% of patients with acute coronary insufficiency who later proved to have a myocardial infarction as the qualifying event. The need for urgent catheterization (less than 48 hours) prompted by recurrent symptoms was associated with the angiographic findings of intraluminal thrombus (46%) and complex morphology (83%). The presence of complex morphology and intracoronary thrombus was associated with a higher incidence of in-hospital cardiac events, i.e., revascularization, myocardial infarction and death, independent of the incidence of multivessel disease.     

Thrombosis-related markers in unstable angina pectoris

While thrombus formation has been implicated in the pathogenesis of unstable angina, the value of thrombus-related markers for distinguishing unstable from stable angina is not well defined. Fibrin D-dimer and plasminogen activator inhibitor were prospectively analyzed in the peripheral blood of 46 patients (26 with unstable angina and 20 with stable angina or normal coronary arteries). Baseline blood samples were drawn within 24 h after rest pain in patients with unstable angina and in 19 of these 26 patients in less than 6 h. In patients with unstable angina, mean +/- SD (median) values for fibrin D-dimer and plasminogen activator inhibitor values measured 0.09 +/- 0.06 (0.07) microgram/ml and 9.1 +/- 9.6 (5.9) IU, respectively, compared to 0.11 +/- 0.10 (0.05) microgram/ml and 5.5 +/- 1.9 (5.0) IU/ml, in patients in the control group (p = NS for all comparisons between the two groups). Recurrent in-hospital pain, coronary anatomy and need for intervention showed no relation to the levels of these markers. In 19 additional patients (9 with unstable angina and 10 control patients) samples from the coronary sinus and the peripheral blood were also analyzed. Again, in patients with unstable angina all samples were drawn less than 24 h after rest pain; in six of nine patients samples were drawn in less than 6 h. A coronary sinus to peripheral blood gradient for either of these markers could not be demonstrated. The differences between peripheral and coronary sinus D-dimer and plasminogen activator inhibitor concentrations were also similar in patients with unstable angina and control patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

不稳定型心绞痛患者血小板表面P-selectin的表达

目的以血小板膜P－selectin为指标，观察心绞痛患者血小板的活化。方法用免疫荧光技术和流式细胞术测定30例心绞痛患者血小板表面P－selectin的表达。结果稳定型心绞痛患者血小板P－selectin阳性率与对照组之间无明显差异，不稳定型心绞痛患者血小板P－selectin阳性率显著高于对照组和稳定型心绞痛患者（P＜0．001）。结论不稳定型心绞痛患者循环中的血小板明显活化。用流式细胞术测定血小板表面活化依赖性膜糖蛋白如P－selectin是一种具有临床应用价值的评价血小板活性的方法。     

Serum levels of interleukin-18 in patients with stable and unstable angina pectoris

Recent evidence suggests that atherosclerosis is an inflammatory disorder in which cytokines appear to play an important role. Special attention centered over the possible contribution of cytokines to the destabilization of the plaque. IL-18 is a proinflammatory cytokine of the IL-1 family, recognized for its ability to promote IFN-gamma secretion. It has recently been detected in human plaques and its administration was associated with increased atherosclerosis in apolipoprotein E (apoE) mice concomitant with an increase in plaque infiltrating inflammatory cells. In our study, we investigated whether patients with established atherosclerosis, with either stable or unstable angina, possessed high levels of IL-18. Patients with stable angina (n=48) were from the outpatient clinic whereas patients with unstable angina (n=73) were recruited upon admission and prior to performance of coronary angiography. Control patients (n=19) were healthy subjects with no evidence of coronary artery disease. Serum levels of IL-18 were assayed by ELISA. Patients with stable and unstable angina exhibited higher serum levels of IL-18 (77.1+/-7.2 and 61.5+/-5.1 pg/ml, respectively) in comparison to control subjects (p=0.002 and p=0.02, respectively). However, levels of IL-18 did not differ significantly between patients with stable and unstable angina. No differences were evident in the serum concentrations of IL-18 in patients with unstable angina (n=17) upon admission and 1-3 months later when the angina was already controlled. Although IL-18 serum levels appear elevated in the presence of coronary atherosclerosis, there is no evidence to associate this progression towards plaque instability.     

Additional molsidomine in refractory unstable angina pectoris

Summary In a prospective single-blind study we examined the effects of additional molsidomine in 20 patients (63±10 years; 15 males, 5 females) with unstable resting angina (3 attacks/24 hours) refractory to triple therapy (nitrates, calcium antagonists, and beta blockers) combined with heparin or aspirin. All but one patient had coronary artery disease documented by coronarography (n=17) or by recent myocardial infarction (n=3). Two patients had angiographically documented severe coronary spasms. Patients entered the study if coronary bypass surgery or PTCA could not be performed within 3 days after angiography (n=9) or was not feasible due to anatomical or technical reasons (n=6), concomitant malignant disease (n=2), or age greater than 75 years (n=3). All patients received molsidomine orally 12 to 24 mg/day. In 15 of the 20 patients molsidomine was given i.v. initially, starting with 20 mg i.v., followed by infusion of 1 to 4 mg/hour. Heart rate and blood pressure did not change significantly, and eight patients had a slight decrease of systolic and diastolic blood pressure. Severe adverse effects did not occur, and moderate headaches were reported by five patients. In 13 patients, unstable angina could be stabilized, and they remained free of resting angina; five had a marked reduction of the frequency of anginal attacks. In two patients, molsidomine was without demonstrable beneficial effects. After a follow-up of 4 weeks, nine patients were free of symptoms after bypass surgery or PTCA, 10 continued to have angina NYHA class II or III, and one patient died due to acute myocardial infarction and cardiogenic shock 4 days after starting additional molsidomine. We conclude that molsidomine is well tolerated and has a marked beneficial effect in patients with refractory unstable angina. Molsidomine should therefore be considered for routine therapy of unstable angina, especially in those patients who are suspected of tolerance to nitrate therapy.     

Usefulness of esmolol in unstable angina pectoris

Esmolol is a new cardioselective β blocker with unique pharmacokinetic properties resulting in a half-life of only 9 minutes. The present multicenter, randomized, placebo-controlled study examined the hemodynamic and antiischemic effects of this compound given as an adjunctive to conventional medical therapy in 113 patients with unstable angina. Fifty-nine patients received esmolol and 54 received matching placebo infusions. Esmolol was titrated in a step-wise manner at dosages of 2 to 24 mg/min until a 25% reduction in the double product was achieved; thereafter, esmolol was continuously infused for up to 72 hours. Esmolol caused a significant and persistent decline in heart rate and blood pressure throughout the entire study period. Clinical events, such as development of acute myocardial infarction or the need for urgent revascularization, occurred in 3 esmolol compared with 9 placebo patients (p = 0.06). There was also a trend toward reduction of silent ischemia as judged by Holter monitoring (mean [± standard deviation] duration/patient/24 hours, 21 ± 81 minutes in the esmolol and 35 ± 128 minutes in the placebo groups). Esmolol-related adverse effects were mostly cardiovascular in origin and could be managed promptly by downward dose titration or cessation of drug infusion. Thus, esmolol appears to be a safe and effective drug for patients with unstable angina because it permits a large degree of flexibility in adapting the desired level of β blockade to the patient's changing clinical presentation.     

Usefulness of carvedilol in unstable angina pectoris

The safety and efficacy of adding oral carvedilol (25 mg twice daily) to standardized treatment of unstable angina was assessed in a multicenter, randomized, double-blind, placebo- controlled trial on 116 patients with acute unstable angina. Patients were monitored in an intensive care unit and underwent 48-hour Holter monitoring to assess transient ischemia. Carvedilol as adjunctive therapy resulted in a significant reduction of median heart rate (65 vs 75 beats/min, p <0.05), mean systolic blood pressure (133 vs 130 mm Hg, p <0.05), and mean rate-pressure product (8,337 vs 10,042, p <0.05). Carvedilol reduced the ischemic burden during 48 hours of treatment by 75% (49 vs 204 minutes), including a 36% reduction of patients with ischemic episodes (p <0.05), a 66% reduction of the mean number of ischemic episodes (8 vs 24, p <0.05), and a 76% reduction in the mean duration of ischemic episodes (50 vs 205 minutes, p <0.05). Side effects occurred in 8 of 59 patients (13.6%) in the carvedilol group and in 5 of 54 patients (8.8%) given placebo. Although not significant, the early onset of maximal blood pressure reduction and the delayed effect on heart rate were closely correlated to drug-induced hypotension and bradycardia in the carvedilol group. Thus, carvedilol as an adjunctive to standardized treatment effectively reduces heart rate and blood pressure, and thus the ischemic burden in patients with unstable angina pectoris, but requires close monitoring of patients at risk for bradycardia or hypotension.     

Treatment of unstable angina pectoris.

Unstable angina pectoris may be manifested as new-onset angina, a change in the anginal pattern, pain at rest with associated electrocardiographic (ECG) changes, or postinfarction angina. Of these, pain at rest with ischemic ECG changes is known to be associated with the poorest prognosis. The pathogenesis of unstable angina pectoris involves a combination of a fixed atherosclerotic obstruction and a dynamic component related to coronary vasoconstriction, thrombus formation, or both. Long-acting nitrates, inhibitors of platelet aggregation, beta blockers, and calcium antagonists are among the agents that have been shown to be effective in the medical management of unstable angina. A study now in progress is evaluating the routine use of thrombolytic therapy for this indication. Although alleviation of symptoms and prevention of death and myocardial infarction are important therapeutic goals, the overall efficacy of a particular medical therapy can best be assessed by objective evaluation of its ability to control ischemia, using such techniques as exercise scintigraphy and ambulatory ECG monitoring. Cardiac catheterization and revascularization are indicated for patients with unstable angina who continue to experience symptoms or who show evidence of silent ischemia despite medical therapy. A study is under way to determine the advisability of routine revascularization of such patients. Revascularization will provide symptomatic relief in most patients with unstable angina and may prolong survival and improve left ventricular function in certain subsets.     

心肌肌钙蛋白I与不稳定型心绞痛患者预后的临床研究

目的观察不稳定型心绞痛(UAP)患者血清肌钙蛋白I(cTnI)含量的变化及其与患者预后的关系,并探讨cTnI与冠状动脉病变程度的关系。方法测定91例UAP患者血清cTnI、磷酸肌酸激酶同工酶(CK-MB)的含量。分析其一般临床特征、冠状动脉病变情况,观察心脏事件发生率,用Logistic回归分析相关因素的影响。结果91例UAP患者中cTnI增高者43例,cTnI增高组与cTnI正常组冠状动脉病变支数、冠状动脉狭窄程度积分比较差异无显著性(P>0.05),通过对心脏事件相关因素的分析,cTnI增高是发生心脏事件的独立危险因素,其相对危险度的估计值为15.82(P<0.01)。结论血清cTnI是UAP患者危险度分层及判断预后的重要生化指标。