Kistrin, a polypeptide platelet GPIIb/IIIa receptor antagonist, enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activator in a canine preparation

BACKGROUND. Kistrin is a 68-amino acid polypeptide from the venom of the Malayan pit viper Agkistrodon rhodostoma, which inhibits the platelet GPIIb/IIIa receptor. Its effect on thrombolysis, reocclusion, and bleeding associated with administration of recombinant tissue-type plasminogen activator (rt-PA) was studied in a canine model of coronary artery thrombosis. METHODS AND RESULTS. Coronary patency was monitored for 2 hours by ultrasonic flow probe and repeated coronary angiography. The rt-PA was given as 0.45-mg/kg bolus injections at 15-minute intervals until recanalization or to a maximum of four boluses. Four groups of four or five dogs were studied: a control group that received intravenous heparin (4,000-unit bolus and 1,000 units each hour) and three groups that received heparin and 0.48, 0.24, or 0.12 mg/kg kistrin, administered as a 10% bolus injection and an infusion during a 60-minute period. In the control group, reflow occurred in four of five dogs within 37 +/- 47 minutes but was followed by cyclic reflow and reocclusion. Kistrin at a dose of 0.48 and 0.24 mg/kg reduced the time to reflow to 6 +/- 5 and 10 +/- 3 minutes, respectively, and abolished reocclusion. With 0.12 mg/kg kistrin, reflow occurred in all four animals, within 27 +/- 23 minutes, and reocclusion occurred in two animals. Kistrin induced a dose-related prolongation of the template bleeding time: with 0.48 mg/kg kistrin, the bleeding time was prolonged from 3.8 +/- 1.3 minutes before infusion to 29 +/- 2 minutes during infusion, but it was shortened to 8.3 +/- 2.6 minutes at 90 minutes after the end of infusion. Kistrin also caused a dose-related inhibition of platelet aggregation with ADP and collagen: with 0.48 mg/kg kistrin, platelet aggregation was abolished during the infusion but had partially recovered toward the end of the observation period. Pathological examination of recanalized coronary arterial segments of dogs given 0.48 or 0.24 mg/kg kistrin revealed widely patent arteries with some platelets layered on the damaged intimal surface. CONCLUSIONS. Kistrin increases the rate and extent of thrombolysis with a reduced dose of rt-PA, and it prevents reocclusion. At an effective dose, it is associated with a transient prolongation of the bleeding time and inhibition of platelet aggregation. Kistrin may offer promise as adjunctive treatment to thrombolytic agents in patients with acute myocardial infarction.     

Efficacy of intracoronary thrombolysis versus percutaneous transluminal coronary angioplasty for treating acute myocardial infarction]

The usefulness of percutaneous transluminal coronary angioplasty (PTCA) in patients with evolving myocardial infarction remains controversial. We retrospectively assessed the efficacy of PTCA on myocardial salvage in acute myocardial infarction in comparison with the efficacy of intracoronary thrombolysis (ICT). Sixty-two patients with initial anteroseptal myocardial infarction who had been treated within 6 hrs after the onset of chest pain were categorized into 4 groups: 1) spontaneous recanalization: n = 14, 2) successful PTCA: n = 25 (this group was further subdivided into 2 groups: direct PTCA group, primary PTCA without prior ICT: n = 19; and rescue PTCA group, PTCA after unsuccessful ICT: n = 6), 3) successful ICT group (n = 12), and 4) unsuccessful recanalization group (n = 11). Left ventricular function in the chronic phase was assessed by contrast ventriculography using the global ejection fraction (EF) and regional wall motion (RWM) was assessed by the centerline method. Patients with recanalization had a significantly higher EF than did those without (62 +/- 12 vs 50 +/- 13%, p < 0.01). The mean EFs for groups with successful reperfusion were as follows: 65 +/- 8% for the spontaneous recanalization group, 61 +/- 14% for PTCA group (64 +/- 13% for direct PTCA group, 51 +/- 13% for rescue PTCA group) and 60 +/- 12% for the ICT group. The EFs for the spontaneous recanalization group and the direct PTCA group were significantly greater than that for the rescue PTCA group. The time to reperfusion and the thrombolysis in myocardial infarction (TIMI) flow grade before reperfusion did not affect the preservation of global left ventricular function. RWM of the infarcted area in patients with recanalization were less hypokinetic than that in patients without (p < 0.01). The mean RWM (SD/chord) in the successfully reperfused groups were -2.3 +/- 1.2 for the spontaneous recanalization group, -2.6 +/- 1.2 for the PTCA group (-2.3 +/- 1.1 for the direct PTCA group, -3.3 +/- 1.0 for rescue PTCA group) and -3.0 +/- 0.5 for the ICT group. Hypokinesis of the infarcted area was more severe in the rescue PTCA group than in the spontaneous recanalization group and the direct PTCA group (multiple comparison test p < 0.01, respectively), and hypokinesis was more severe in the ICT group than in the direct PTCA group (Student's t-test, p < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

Combined medical and mechanical recanalization in acute myocardial infarction

A technique of combined medical and mechanical recanalization was employed in 96 patients with acute transmural myocardial infarction. The mean time between onset of symptoms and admission to hospital was 170 +/- 65 min (X +/- SD). After 10 +/- 16 min, 250,000 U streptokinase was administered intravenously for 20 min. Intracoronary thrombolysis was commenced within 38 +/- 14 min. First coronary angiograms demonstrated reperfusion, an open vessel in 25/96 patients (26%). In 15/71 patients (21%) reperfusion occurred during thrombolysis therapy, before mechanical recanalization could be performed. Recanalization was achieved mechanically in 37/71 patients (52%) with occluded coronary vessels. In 8/71 patients (11%) mechanical recanalization failed but the vessel opened during thrombolysis. In 12/96 patients (12%), the coronary vessel remained occluded. Thus, reperfusion could be achieved in 88% of the patients. Reperfusion rate was 76% in the first 38 patients and 95% subsequently. After reperfusion, coronary thrombi were found in 25/96 patients (26%) but dissolved during thrombolysis in 16/25 patients (64%). Peripheral coronary embolism was observed in 3/25 patients (12%). For the whole group, reocclusion occurred in 8/84 patients (10%). By combined medical and mechanical recanalization, the recanalization rate could be increased with low reocclusion rate. Trends showed an improvement in regional and global left ventricular function in patients with anterior myocardial infarction.     

Abnormal cardiocoronary thromboxane A2 production in patients with unstable angina

Thromboxane B2 (TXB2), the stable metabolite of thromboxane A2 (TXA2), was measured in the coronary sinus and in aortic blood before and after cold pressor test (CPT) in 21 patients suffering from ischemic heart disease (7 affected by stable effort angina and 14 by unstable angina) and in 12 patients not suffering from myocardial ischemia (control group) during coronary angiography. Aspirin (10 mg/kg intravenously) was administered before catheterization in order to prevent platelet and leukocyte TXA2 formation. Control subjects and patients with effort angina had TXB2 resting levels lower than unstable angina patients without a transcardiac gradient which, on the contrary, was found in unstable angina patients. Only in these patients CPT resulted in a significant TXB2 increase more marked in the coronary sinus (from 50.0 +/- 18.9 pg/ml to 73.0 +/- 35.1 pg/ml, p less than 0.001) than in the aorta (from 33.4 +/- 17.1 pg/ml to 42.6 +/- 24.0 pg/ml, p less than 0.05), so that the transcardiac TXB2 gradient significantly increased. In all but two unstable angina patients, TXB2 elevation was not associated with a fall of cardiac lactate extraction. The resting and CPT-induced TXB2 gradients were unrelated to the presence and severity of coronary angiographic lesions. These results indicate that unstable angina patients show an abnormal cardiocoronary capacity to synthesize TXA2, which seems not to be elicited by the occurrence of myocardial ischemia.     

急性脑梗死静脉溶栓/桥接治疗24 h内血小板活化的研究进展

急性脑梗死目前最理想的治疗是尽快使闭塞的血管再通,静脉溶栓治疗是急性脑梗死确证有效的开通闭塞动脉的急救措施,桥接治疗提高了闭塞血管的再通机率,但仍有一部分患者存在残余血管狭窄。已知血小板在急性脑梗死的发生和发展中起着重要作用。溶栓/桥接治疗后导致血管再通后再闭塞的关键因素之一是溶栓后24 h内禁止抗血小板聚集药物的使用,血小板的聚集与活化使一部分残余动脉狭窄患者发生了动脉再闭塞。本文针对血小板活化机制及近年来关于急性脑梗死静脉溶栓/桥接治疗后血小板活化状态及抗血小板治疗联合静脉溶栓/桥接治疗的研究进行综述,以探讨在静脉溶栓/桥接治疗后24 h内使用抗血小板聚集药物的可行性及安全性,从而改善患者的预后。     

Defective platelet aggregation and increased platelet turnover in patients with myelofibrosis and other myeloproliferative diseases

In 9 patients with myeloproliferative diseases (MPD) (6 with myelofibrosis, MF, 1 with Ph1 positive chronic granulocytic leukaemia, CGL, 1 with primary eosinophilia, PE, 1 with pre-leukaemia syndrome, preL) collagen, epinephrine, and ADP-induced aggregation, N-ethylmaleimide-induced malondialdehyde (MDA) production, beta-thromboglobulin (beta-TG) plasma levels, and platelet turnover were studied. Collagen-induced aggregation was found to be normal in 7 patients, absent in 1, and reduced in 1. In all but 3 patients, aggregation with ADP was markedly reduced. Epinephrine-induced aggregation was decreased in 7 patients. No difference was found between mean MDA production in MPD (3.21 +/- 0.50 nmol/10(9) PLTs) and in control group of 21 normal subjects (3.04 +/- 0.26 nmol/10(9) PLTs). Mean beta-TG levels were significantly higher (P less than 0.01) in MPD patients (165.00 +/- 28.29 ng/ml) than in healthy controls (81.76 +/- 14.63 ng/ml). Mean platelet production half-time was significantly shorter in MPD (2.48 +/- 0.24 d) than in the control group (3.43 +/- 0.17 d), after adjustment for age by covariance analysis (P less than 0.005). Our data do not indicate an abnormal prostaglandin synthesis and are consistent with the hypothesis that a disseminated intravascular platelet aggregation might take place in MPD patients.     

Plasma beta-thromboglobulin values in thrombocytopenic patients with acute leukemia

Plasma beta-thromboglobulin (beta-TG) levels were measured in 14 healthy subjects and in 20 acute leukemia (AL) patients, newly diagnosed, with highly variable values for venous platelet counts. For healthy subjects the plasma beta-TG levels ranged 12-38 (mean 17) ng/ml. In this group of patients with AL, a highly significant positive correlation (P < 0.001) between the values for plasma beta-TG and venous platelet count was present. During a thrombocytopenic period, the plasma beta-TG concentraton was measured in nine of the AL patients immediately before and 10 to 12 hours after platelet transfusion therapy. Fourteen platelet transfusions were administered when the patient's highest temperature of the day was < 38.5 degrees C, and 18 when the highest temperature of the day was greater than or equal to 38.5 degrees C. The mean pre-transfusion and post-transfusion beta-TG values for the 14 platelet transfusions were 7 +/- 2 and 20 +/- 5 ng/ml, respectively. The corresponding means for the 18 transfusions given to febrile patients were 5 +/- 2 ng/ml and 11 +/- 2 ng/ml, respectively. Of the pretransfusion values, 11/14 and 14/18 were below the control range. We conclude that the plasma beta-TG values are considerably lower in thrombocytopenic patients than in subjects with normal platelet counts. Further work should provide reference values for plasma beta-TG over a wide range of venous platelet counts.     

Plasma beta-thromboglobulin and platelet factor 4 concentrations in patients with atrial fibrillation

The clinical significance of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF-4) levels were evaluated in 26 patients with atrial fibrillation (af) complicated by valvular heart disease (VHD), 73 patients with af but without valvular heart disease and 57 normal subjects. The beta-TG level was significantly higher in af patients without VHD than in normal subjects (49.4 +/- 35.8 ng/ml vs 31.2 +/- 14.0 ng/ml, p less than 0.01) and in af patients with VHD than in normals (64.1 +/- 52.8 ng/ml vs 31.2 +/- 14.0 ng/ml, p less than 0.01). Af patients with or without VHD tended to show high levels of PF4 compared with normals (af patients without VHD: 34.1 +/- 45.5 ng/ml, af patients with VHD: 18.6 +/- 27.2 ng/ml, normals: 11.6 +/- 8.2 ng/ml). There was no correlation between beta-TG levels and age in af patients without VHD or in normals. There was also no correlation between beta-TG levels and heart rate in af patients without VHD. The activation of platelets was suggested in patients with atrial fibrillation on the basis of increased levels of platelet releasing substances, especially in those with VHD. The high levels of beta-TG and PF4 in patients with atrial fibrillation may be one explanation for the high incidence of thromboembolism in these patients, indicating the necessity of antiplatelet therapy.     

Augmented platelet reactivity and thromboxane A2 production possible aggravating factors in unstable angina

We examined platelet aggregation and plasma levels of thromboxane B2, a stable metabolite of thromboxane A2, in patients with unstable angina and correlated these platelet indices with the response to antianginal conventional therapy such as isosorbide dinitrate and calcium channel blocker. Eight of 36 patients exhibited anginal attacks more than 5 times/week in spite of the therapy, designated refractory unstable angina, associated with augmented platelet aggregation induced by arachidonate (0.3 mM, 71 +/- 3%, mean +/- SEM) and collagen (2 micrograms/ml, 72 +/- 5%), and elevated plasma levels of thromboxane B2 (350 +/- 19 pg/ml). In the remainder of the patients whose anginal attacks were effectively subsided by the therapy, platelet aggregation was much lower (arachidonate: 34 +/- 9%, collagen: 31 +/- 8%, p less than 0.01) and plasma levels of thromboxane B2 were also lower (295 +/- 12 pg/ml, p less than 0.05). To evaluate the effect of selective thromboxane A2 blockade on clinical findings and platelet reactivity in refractory unstable angina, OKY-046 (600 mg/day, p.o.) was administered to another 14 patients with refractory unstable angina in addition to the conventional therapy. We found that platelet aggregation induced by arachidonate (71 +/- 4%) and collagen 65 +/- 8%) was markedly reduced (44 +/- 7% and 24 +/- 3%, respectively, p less than 0.01) and plasma levels of thromboxane B2 (358 +/- 31 pg/ml) and thromboxane B2 production in serum (29 +/- 5 ng/ml) were also significantly reduced after OKY-046 treatment (262 +/- 21 pg/ml, p less than 0.05, and 1.4 +/- 0.2 ng/ml, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiaggregative aspirin dosage at the affected vessel wall

The present study, using patients with Takayasu's disease (pulseless disease), characterized by segmentally affected arterial lesions and stenotic conditions with a nonspecific inflammatory morbid condition, was designed to assess whether or not a low dose of aspirin can practically exert its preventive effect against the aggregation of platelets that have just passed along a rough-surfaced arterial wall. Twenty Japanese women with Takayasu's disease were selected under the following criteria: A unilateral upper extremity was angiographically confirmed to be affected with the disease, while the contralateral limb was almost normal. Systolic blood pressure on the affected side was almost half that on the nonaffected side. The patients showed neither a positive CRP nor an accentuated ESR. In these patients, mean plasma levels of TXB2 and 3 microM ADP-induced platelet aggregation in blood obtained from the affected side were 156.5 +/- 17.7 pg/ml, and 59.5 +/- 6.0%, respectively, which were significantly high as compared with 104.5 +/- 17.6 and 41.7 +/- 8.8%, respectively, in samples from the nonaffected side. Forty and eighty mg of aspirin per day administered to two randomly composed groups, respectively, showed an improvement in platelet aggregability and TXB2 levels on the nonaffected side. In the affected limbs, though 80 mg/day led to significant decreases in TXB2 levels (108.0 +/- 7.8 pg/ml, p less than 0.05) and platelet aggregability (21.3 +/- 7.6%), the 40-mg regimen showed no significant reductions (134.6 +/- 9.4 pg/ml, 35.6 +/- 17.1%). Plasma levels of 6-keto PGF1 alpha revealed no differences between 40- and 80-mg regimens, or between before and after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of tissue-type plasminogen activator during acute myocardial infarction in men. Effect of a prostacyclin analogue.

BACKGROUND. Coronary reocclusion complicates the thrombolytic therapy of acute myocardial infarction despite the routine use of aspirin. This is consistent with experimental studies demonstrating that multiple agonists, in addition to thromboxane A2, mediate the platelet activation underlying reocclusion. Consequently, a more potent antiplatelet therapy with a broader spectrum of activity than aspirin may be required in this setting. Prostacyclin and its more stable analogue, iloprost, inhibit platelet aggregation to all known agonists and exert an additional effect over aspirin alone. Experiments in animal models have demonstrated, however, that iloprost increases the clearance of tissue-type plasminogen activator (t-PA) and impairs thrombolysis in vivo. This study examines whether a similar interaction occurs in humans. METHODS AND RESULTS. Twelve patients with acute myocardial infarction received t-PA intravenously, 60 mg in the first hour and a maintenance infusion of 13.3 mg/hr for 3 hours. Patients were assigned in a double-blind fashion to iloprost (2 ng/kg/min) or placebo following the initial 90 minutes of the maintenance infusion of t-PA. Iloprost decreased mean arterial blood pressure (-10 +/- 2.9 mm Hg, p less than 0.05) but did not alter heart rate. Steady-state plasma iloprost concentration was 591 +/- 64 pmol/l. At this concentration, iloprost markedly inhibited platelet aggregation in vitro, particularly in the presence of aspirin. Steady-state clearance of t-PA was unchanged by iloprost (454 +/- 65 versus 443 +/- 136 ml/min in controls, p = NS). Furthermore, neither elimination kinetics nor plasma protein binding of t-PA was altered by iloprost. CONCLUSIONS. At plasma levels that exert a potent antiplatelet effect, iloprost did not alter the pharmacokinetics of t-PA in men. Prostacyclin analogues may prove useful as an adjunct to plasminogen activators, particularly in patients at high risk for thrombotic reocclusion.     

Immediate or delayed angioplasty during the acute phase of myocardial infarction. Apropos of 118 cases

The results of immediate percutaneous transluminal coronary angioplasty (PTCA) (260 +/- 167 minutes after onset of pain and an average of 56 minutes after thrombolysis) and deferred PTCA (average 9.6 days, range 1 to 30 days after infarction) were compared in 118 consecutive patients with acute myocardial infarction. The overall primary success rate of PTCA was 82.2 per cent; it was higher in those patients undergoing deferred angioplasty (96% vs 78%; p less than 0.05). The primary success rate of immediate PTCA was related to the severity of the stenosis before dilatation: 75 per cent success in occluded compared to 84 per cent in suboccluded vessels (over 90% stenosis) and 100 per cent success in vessels with under 90 per cent stenosis. Eighty one per cent of failed angioplasties occurred in patients with occluded arteries, the majority being left anterior descending (LAD) arteries (71.4%). The incidence of restenosis was 13.4 per cent. This complication was diagnosed at coronary arteriography performed 40 days after PTCA in 1 case, 47 days after PTCA in another case and at the 6 month control in 11 cases. Reocclusion was observed in 21 patients (21.7% of immediate successes). The occlusion was diagnosed at the first control after an average of 8 days in 15 cases. The interval between the onset of pain and thrombolysis and dilatation was significantly longer in the group with reocclusion compared with patients without reocclusion (314 minutes vs 193 minutes for thrombolysis, p less than 0.01; and 356 minutes vs 204 minutes fort PTCA, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Follow-up of prostaglandin plasma levels after acute myocardial infarction

Prostaglandin plasma levels are elevated in patients with transient myocardial ischemia. We measured 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane (B2(TXB2) in venous blood of 32 patients with myocardial infarction on the first, third, and seventh days. TXB2 and 6-keto-PGF1 alpha levels in these patients (up to 117 +/- 237 pg/ml and 96 +/- 105 pg/ml mean +/- SD, respectively) differed significantly from levels in normal control subjects (10 +/- 12 pg/ml and 4 +/- 7 pg/ml mean +/- SD, respectively) (p less than 0.01). Prostaglandin values remained elevated from day 1 through day 7. In most patients, 6-keto-PGF1 alpha levels prevailed over those of TXB2. In a subgroup suffering from cardiac arrhythmias, the ratio of 6-keto-PGF1 alpha/TXB2 was inverse. It is concluded that prostaglandin generation is increased for at least 7 days after myocardial infarction. A disturbed ratio of 6-keto-PGF1 alpha/TXB2 in favor of the latter might be associated with cardiac arrhythmias in myocardial infarction.     

Monitoring of fibrin generation during thrombolytic therapy of acute myocardial infarction with recombinant tissue-type plasminogen activator

Fibrinopeptide A (FPA) is a very sensitive marker of fibrin generation in vivo. Because an imbalance between thrombogenic and thrombolytic forces may be responsible for the failure to recanalize and for reocclusion of coronary arteries, such a marker could be of eminent value during thrombolytic treatment of acute myocardial infarction. Thirty-four consecutive patients with acute myocardial infarction (peak creatine kinase level, 1,869 +/- 1,543 IU/l) were treated with 100 mg recombinant tissue-type plasminogen activator (rt-PA) 3.1 +/- 1.1 hours after onset of chest pain. Angiography 12.5 +/- 6.1 days later revealed an 81% patency rate of the infarct-related vessel. FPA plasma levels (normal, 1.9 +/- 0.5 ng/ml) were 34 +/- 46 ng/ml on admission and 93 +/- 86 ng/ml (538 +/- 674% with respect to each patient's admission level) after 90 minutes of rt-PA infusion (p less than 0.01). In patients without evidence of reocclusion (including three primary failures), FPA levels fell under continuous heparin infusion to 6.7 +/- 9.7 ng/ml (24 +/- 33%, p less than 0.01) within 30 minutes and were 3.1 +/- 2.2 ng/ml (15 +/- 15%, p less than 0.01), 1.6 +/- 1.1 ng/ml (8 +/- 10%, p less than 0.01), and 2.5 +/- 3.0 ng/ml (12 +/- 16%, p less than 0.01) 30 minutes, 9 hours, and 21 hours, respectively, after completion of rt-PA therapy. Five patients sustained intermittent or permanent coronary reocclusion after primary thrombolytic success. Their early postlytic FPA levels (13-51 ng/ml) remained high or increased again despite adequate anticoagulation. FPA allows the monitoring of fibrin generation during acute myocardial infarction and thrombolytic therapy. Despite successful recanalization, fibrin generation is increased under rt-PA administration before anticoagulation. Patients under anticoagulation with postlytic FPA levels less than 5 ng/ml or below their admission value seem to be at low risk of reocclusion for several days. FPA levels that are persistently high or that increase again despite adequate anticoagulation indicate ongoing fibrin generation. However, whether FPA can indeed be considered a useful marker of reocclusion remains to be confirmed in a larger population of patients with acute myocardial infarction.     

Platelet aggregation and thromboxane A2 production after adrenergic stimulation in young healthy humans

The effects of adrenergic stimulation on platelet aggregation (platelet aggregation ratio; PAR), beta-thromboglobulin (beta-TG) release and plasma thromboxane B2 (TxB2) levels were investigated in 25 healthy young volunteers. Adrenergic stimulation induced by cold application was checked by evaluating the changes in the calculated vascular resistance in the forearm. A prompt increase in platelet aggregates and plasma beta-TG and TxB2 concentrations was observed after adrenergic stimulation. PAR changed from resting values of 0.97 +/- 0.05 to 0.75 +/- 0.08 (p less than 0.001) at the end of cold application. At the same time, beta-TG plasma concentration increased from 32.09 +/- 19.64 to 135.48 +/- 37.97 ng/ml (p less than 0.001) and TxB2 plasma levels changed from 0.49 +/- 0.24 to 0.99 +/- 0.39 pmol/ml (p less than 0.001). TxB2 levels, but not PAR and beta-TG concentration came back to the resting values at the end of the observation period (10 min). Aspirin, as the lysine acetylsalicylate equivalent to 5 mg/kg i.v. of acetylsalicylic acid, although able to completely inhibit platelet cyclooxygenase failed to inhibit the plasma TxB2 increase induced by adrenergic stimulation. This strongly suggests that the increase in plasma TxB2 following adrenergic stimulation is of extraplatelet origin. Also beta-TG and PAR changes were not affected by aspirin administration.     

A randomized trial of elective stenting after balloon recanalization of chronic total occlusions.

OBJECTIVES: The aim of this study was to assess the role of Wiktor stent implantation after recanalization of chronic total coronary occlusions with regard to the clinical and angiographic outcome after six months. BACKGROUND: Beside the common use of stents in clinical practice, the number of stent indications proven by randomized trials is still limited. METHODS: Eighty-five patients with a thrombolysis in myocardial infarction grade 0 chronic coronary occlusion were examined. After standard balloon angioplasty, the patients were randomly assigned to stent implantation, or percutaneous transluminal coronary angioplasty (PTCA) alone (no further intervention). Quantitative coronary angiography was performed at baseline and after six months. RESULTS: The minimal lumen diameter did not differ immediately after recanalization (stent group 1.61 +/- 0.30 mm vs. PTCA group 1.65 +/- 0.36 mm), and increased after stent implantation to 2.51 +/- 0.41 mm. After six months, the stent group still had a significantly greater lumen (1.57 +/- 0.59 vs. 1.06 +/- 0.90 mm; p < 0.01) and a significantly lower restenosis and reocclusion rate (32% and 3%) compared with the PTCA group (64% and 24%); restenosis analysis according to treatment was 72% (PTCA) versus 29% (stent, p < 0.01). Late loss was equal in both groups. At follow-up, the stent patients had a better angina class (p < 0.01), and fewer cardiac events (p < 0.03). A meta-analysis including this trial and three other controlled trials with the Palmaz-Schatz stent showed concordant results. CONCLUSIONS: Stent implantation after reopening of a chronic total occlusion provides a better angiographic result, corresponding to a better clinical outcome with fewer recurrence of symptoms and reinterventions after six months.     

Percutaneous transluminal coronary angioplasty for treatment of acute myocardial infarction: comparison with percutaneous transluminal coronary recanalization

Percutaneous transluminal coronary angioplasty (PTCA) was evaluated as a means of reperfusion of the infarct-related coronary artery, and the results were compared with those of percutaneous transluminal coronary recanalization (PTCR). There were no difference in sex, age, infarct location and time from the onset to start of treatment between 135 patients with evolving acute myocardial infarction treated with PTCA (PTCA group) and 113 patients treated with PTCR alone (PTCR group). Fifty-nine patients in the PTCA group underwent PTCA following PTCR; the remaining 76 patients were without prior PTCR. Successful PTCA, defined as a 20% or more reduction in percent luminal stenosis diameter, was achieved in 123 (90%) of the 135 patients in the PTCA group. The reperfusion rate was 93% in the PTCA group and 77% in the PTCR group (p less than 0.01). Residual stenosis immediately after the treatment was 30 +/- 13% in the PTCA group and 70 +/- 16% in the PTCR group (p less than 0.01). In the PTCA group, three cases developed serious complications which were associated with angioplasty: coronary perforation, side branch occlusion resulting in cardiogenic shock and exacerbation of cardiogenic shock. The latter two patients died, however, there was no difference in hospital mortality rate: 6% in the PTCA group versus 11% in the PTCR group. At follow-up angiography performed four weeks after admission, reocclusion of the successfully recanalized arteries was observed in 3% of the PTCA group and in 14% of the PTCR group (p less than 0.01). Regional wall motion was evaluated by left ventriculography using a wall motion score system which consisted of six grades; from normal counted as 0, to dyskinesis counted as 5. There was no difference in the wall motion score between the successful PTCA group and the successful PTCR group (2.6 +/- 1.4 versus 2.8 +/- 1.4), but the scores of both groups were better than those of the non-recanalized group (3.4 +/- 1.0: p less than 0.01). In conclusion, PTCA and PTCR have the same effect on hospital mortality rate and regional wall motion, but PTCA has a higher reperfusion rate and a lower reocclusion rate than does PTCR. Although PTCA has a potential disadvantage inducing serious complications, it appears to be a useful treatment for acute myocardial infarction.     

Angioplasty triggers intracoronary leukotrienes and lipoxin A4. Impact of aspirin therapy.

BACKGROUND. Percutaneous transluminal coronary angioplasty (PTCA) is a widely used and important method of reperfusing coronary arteries. However, it is also associated with serious complications such as acute reocclusion and accelerated restenosis. The factors as well as the mechanisms involved in PTCA-associated complications remain to be fully elucidated. Because peptidoleukotrienes and lipoxins are potent vasoactive compounds, the formation of which is not inhibited by aspirin (ASA) treatment in vitro, it is possible that these eicosanoids are involved in PTCA-associated untoward events. To test this, we determined the intracoronary levels of peptidoleukotrienes and lipoxin A4 (LXA4) as well as thromboxane (TX) and 5S,12S-dihydroxyeicosatetraenoic acid (5S,12S-DiHETE; a product of double dioxygenation) after plaque rupture and evaluated the impact of ASA therapy. METHODS AND RESULTS. PTCA was performed on 12 patients with coronary artery disease, six undergoing ASA therapy and six without ASA therapy, for at least 2 weeks before PTCA. By means of a technique that permitted sampling of intracoronary blood at the plaque site in situ, samples were taken immediately before and 10 seconds after initiation of plaque rupture. Lipoxygenase (LO)-derived products, including LXA4 and 5S,12S-DiHETE, and a marker of cyclooxygenase activity, i.e., TXB2, were quantitated after extraction and chromatography using deuterium-labeled internal standards and electron capture negative ion chemical ionization mass spectrometry. Peptidoleukotrienes (LTC4 and LTD4) were quantitated after reverse-phase high-performance liquid chromatography coupled with radioimmunoassay. Intracoronary blood taken before PTCA showed no detectable levels of these eicosanoids (the minimum limits of detection were within the picomole range). In contrast, each of these LO products was detected after PTCA. Patients undergoing ASA treatment showed elevated levels of each LO product examined compared with those not receiving ASA. Eicosanoid levels were (mean +/- SEM): LTC4, 7.10 +/- 1.22 ng/ml (ASA) versus 0.48 +/- 0.10 ng/ml; LTD4, 4.92 +/- 0.56 ng/ml (ASA) versus 1.17 +/- 0.48 ng/ml; LXA4, 24.98 +/- 4.11 ng/ml (ASA) versus 15.83 +/- 2.43 ng/ml; 5S,12S-DiHETE, 19.47 +/- 3.98 ng/ml (ASA) versus 11.98 +/- 1.83 ng/ml; TXB2, complete blockage (ASA) versus 31.04 +/- 7.38 ng/ml (p less than 0.05 for LTC4 and LTD4). To distinguish between dilatation of whole blood versus dilatation of whole blood and atheroma for contribution of eicosanoids, we also monitored their formation in Gore-tex grafts. Upon balloon inflation, TXB2 was generated, but LO products were not detected. In contrast, injection of platelet- and leukocyte-directed agonists within the graft led to both peptidoleukotriene and lipoxin formation. CONCLUSIONS. The results indicate that PTCA triggers the intraluminal release of peptidoleukotrienes and LXA4 and that ASA therapy enhances their appearance in intracoronary blood. In addition, they provide direct evidence for LO products (LTC4, LTD4, and LXA4) in a local milieu in vivo. Moreover, the presence of the double dioxygenation product 5S,12S-DiHETE (a potential marker of 5- and 12-LO interactions) suggests that transcellular metabolic events can contribute to eicosanoid formation in vivo.     

Percutaneous transluminal coronary angioplasty after intracoronary streptokinase in evolving acute myocardial infarction

To achieve optimal myocardial revascularization and prevent rethrombosis of the infarct-related coronary artery, percutaneous transluminal coronary angioplasty (PTCA) was attempted in 18 patients with evolving acute myocardial infarction (9 anterior and 9 inferior) after administration of intracoronary streptokinase. PTCA was attempted 338 +/- 151 minutes after the onset of symptoms. After thrombolytic therapy, 11 patients had a severe residual stenosis and 7 a persistent total occlusion of the infarct-related coronary artery. PTCA was successful in 13 of 18 patients: in 9 of 11 with coronary stenoses and in 4 of 7 with total coronary occlusions. PTCA reduced the severity of the coronary lesion from 91 +/- 2% to 27 +/- 7% (p less than 0.001), and the transstenotic pressure gradient from 38 +/- 5 to 6 +/- 2 mm Hg (p less than 0.01). One patient in cardiogenic shock died during urgent coronary surgery after unsuccessful PTCA. After PTCA, all patients received heparin and antiplatelet agents. One patient had reinfarction with reocclusion of the infarct-related artery 5 days after PTCA. The other 12 patients had an uneventful hospital course, and cardiac catheterization before hospital discharge (8 to 17 days) revealed reocclusion of the infarct-related coronary artery in 3 and persistent patency in 9. Persistent patency of the infarct-related artery was associated with preservation of left ventricular end-diastolic volume (initial 86 +/- 6 ml/m2, follow-up 91 +/- 6 ml/m2), and improvement in left ventricular ejection fraction in some patients.     

Systemic and transcardiac platelet activity in acute myocardial infarction in man: resistance to prostacyclin

There is increasing evidence that platelets play an important role in the pathogenesis of acute ischemic heart disease. Therefore an understanding of factors that influence platelet performance is important. This study was undertaken (1) to characterize during evolving myocardial infarction platelet activity in the peripheral circulation and across the ischemic/infarcting myocardial compartment, the locus of presumed platelet hyperactivity, and (2) to evaluate the effects of prostacyclin (PGI2), a most potent antiplatelet agent and vasodilator. A total of 59 patients with evolving myocardial infarction were studied. Twenty-two patients were instrumented with arterial and coronary sinus catheters and received intravenous infusion of PGI2, 13 +/- 4.5 ng/kg/min (mean +/- SD), for 90 min. In 15 patients with anterior myocardial infarction, transcardiac platelet function and response to PGI2 were studied. Plasma levels of beta-thromboglobulin (beta-TG) and of thromboxane B2 (TxB2), in vivo measures of platelet activity, were elevated three- and 10-fold. 6-Keto-prostaglandin F 1 alpha, the stable end product of PGI2, was less than 10 pg/ml, reflecting a leftward shift of the TxB2/PGI2 ratio. Platelets circulating during evolving myocardial infarction ("ischemic platelets") were hyperaggregable in response to ADP and relatively resistant to PGI2, both in vivo and in vitro. Concentrations of platelet cyclic AMP and the cyclic AMP response to PGI2 were diminished. The platelet hyperreactivity, expressed by plasma beta-TG, platelet aggregation, and PGI2-induced inhibition of aggregation, was most intense early during infarct evolution and decreased with time. The increased platelet performance resulted in "platelet fatigue," indicated by decreased contents of beta-TG of the ischemic platelet and decreased TxA2 production in response to collagen. However, the ischemic platelet produced twice normal TxA2 in response to arachidonic acid (stimulus and substrate), demonstrating a heightened metabolic capacity. TxA2 was produced across the ischemic/infarcting compartment in 10 of 15 patients with anterior myocardial infarction. The antiplatelet effect of PGI2 was greatly diminished. In summary, the data define an abnormal pattern of platelet behavior during evolving myocardial infarction, characterized by a proaggregatory environment, heightened platelet reactivity in both the peripheral and coronary circulation, and relative resistance to PGI2. The clinical consequences of the data are that the patient in the acute phase of myocardial infarction may benefit from suppression of platelet function and requires significantly greater doses of PGI2 than normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)