Takeshi Motomiya

A Prospective, Randomized, Double-Blind Multicenter Trial of a Single Bolus Injection of the Novel Modified t-PA E6010 in the Treatment of Acute Myocardial Infarction: Comparison With Native t-PA

Abstract Objectives. This prospective, randomized, double-blind multicenter trial evaluated the efficacy and safety of a single bolus injection of the novel modified tissue-type plasminogen activator (t-PA) E6010 in the treatment of acute myocardial infarction compared with that of native t-PA. Background. E6010 is a novel modified t-PA with a prolonged half-life (t1/2alpha ≥23 min) compared with native t-PA (t1/2alpha = 4 min). E6010 can be administered in patients as a single intravenous bolus injection, and early recanalization can be expected. Methods. The efficacy of E6010 was compared with that of native t-PA in 199 patients with acute myocardial infarction who were treated within 6 h of onset in a prospective, randomized, double-blind multicenter trial. Patients were given either 0.22 mg/kg body weight of E6010 intravenously over 2 min or native t-PA (tisokinase) 28.8 mg or 14.4 million IU (10% of the total dose over 1 to 2 min, the remainder infused over 60 min). Results. The primary end point was the recanalization rate of the infarct-related coronary artery at 60 min after the start of treatment. Time to reperfusion was shorter in the E6010 group than in the native t-PA group. Thrombolysis in Myocardial Infarction flow grade 2 or 3 recanalization at 15, 30, 45 and 60 min after administration was observed in 37%, 62%, 74% and 79% (95% confidence interval [CI] 70% to 87%) of the E6010-treated patients and in 14%, 32%, 50% and 65% (95% CI 55% to 74%) of native t-PA-treated patients, respectively (p = 0.032 at 60 min). Conclusions. The present study indicates that, compared with native t-PA, a single bolus injection of E6010 over 2 min produces a higher rate of early recanalization of the infarct-related coronary artery without fatal bleeding complications. (J Am Coll Cardiol 1997;29:1447–53)

Consumption of larger platelets with decrease in adenine nucleotide content in thrombosis, disseminated intravascular coagulation, and postoperative state

Abstract Platelet count, volume, aggregation and ATP and ADP contents were measured in 51 healthy volunteers, 27 patients in the acute stage of thrombosis, 29 patients in the recovery stage of thrombosis, 10 patients with typical DIC syndrome during the course of cancer, and 39 patients one day before, and one day and one week after abdominal operation. A positive correlation was found between platelet mode volume and agaregability in the healthy subjects. In DIC, acute stage of thrombosis, and one week after abdominal operation patients, platelet volume and ADP content decreased significantly. Platelet aggregation increased in thrombosis and in the postoperative state patients, while it decreased in the DIC subjects. In DIC, a decrease in ATP and ADP contents was marked as compared with the other groups. A positive correlation was observed between platelet volume and the adenine nucleotide content. The results suggest that larger platelets with hyperaggregability were consumed easily in thrombosis, DIC and hemostatic plug formation after operation. A mechanism to induce platelet release reaction following secondary aggregation in vivo may be present in thrombosis and postoperative state.

Platelet aggregation during menstrual cycle and pregnancy

Abstract Platelet aggregation induced by ADP, adrenaline and collagen was examined in 20 healthy young men, 42 healthy young women with normal menstrual cycle and 38 pregnant women (7th to 40th week of pregnancy). During menstrual cycle and pregnancy, primary aggregation did not change in intensity or speed. Also secondary aggregation did not change in intensity. However, secondary aggregation induced by ADP and adrenaline frequently observed in follicular phase and less in menstruation and luteal phase with a statistical significance. In pregnant women intensities of primary and secondary aggregation were not different with those of non-pregnant women. However the appearance rate of secondary aggregation markedly increased during pregnancy. Collagen aggregation did not show any difference among any groups. The result suggests that estrogen, which increases in the blood both in pregnancy and follicular phase, might have a role in the appearance of secondary aggregation which is related to platelet release reaction.

Double ventricular responses to a single atrial depolarization in a patient with dual AV nodal pathways

Electrophysiological study was performed in a patient with atrioventricular nodal reentrant tachycardia (AVNRT). Double ventricular responses through dual AV nodal pathways were observed by atrial extrastimulus technique followed by initiation of AVNRT. The drfference in conduction time between the slow and fast AV nodal pathways was longer than 320 msec. A ventricular extrastimulus delivered during sinus rhythm, which was not followed by ventriculoatrial conduction, also induced AVNRT. These findings indicated the presence of an antegrade critical delay and retrograde block in the slow AV nodal pathway, criteria necessary for the occurrence of a double ventricular response.

Increase in heart rate after radiofrequency catheter ablation is mediated by parasympathetic nervous withdrawal and related to site of ablation.

To assess the mechanism for the increased sinus rate after radiofrequency catheter ablation performed for atrioventricular nodal reentrant tachycardia (AVNRT), we studied heart rate variability before and after radiofrequency catheter ablation in 17 patients with AVNRT and in 38 patients with an accessory pathway. The accessory pathway was located at the left ventricular free wall, the right ventricular free wall, or the posterior interventricular septum. An increased sinus rate was observed in patients with AVNRT or with the accessory pathway at the posterior septum or left free wall after radiofrequency ablation. In these groups, high-frequency power, root mean square of successive difference and percent of adjacent cycles that were more than 50 ms apart, all of which are indices reflecting parasympathetic nervous activity, were decreased. The ratio of low-frequency to high-frequency power reflecting sympathovagal balance, was increased in patients with AVNRT or with an accessory pathway at the posterior septum or left free wall. Increases in sinus rate were correlated with decreases in high-frequency power, and percent of adjacent cycles more than 50 ms apart that the increase in heart rate was due to parasympathetic nervous withdrawal.

Activation of platelets in cancer, especially with reference to genesis of disseminated intravascular coagulation.

Seventy-five cancer patients were evaluated on a scale of coagulation abnormalities related to DIC, one point given for each of the following criteria fulfilled and the score (0 to 4) being used. 1. Platelet count less than 150 x 10(3)/mu 1. 2. PT prolonged more than 1 sec over control or APTT prolonged more than 10 sec over control. 3. Fibrinogen less than 250 mg/dl (mean fibrinogen value of the cancer patients minus 1SD). 4. FDP greater than or equal to 20 micrograms/ml. The patients were distributed with 27% for score 0, 38% for 1, 20% for 2, 7% for 3 and 8% for 4. Platelet mode volume in score 4 was smaller than that of the other groups. Platelet aggregation by epinephrine was decreased in score 3 and 4 (P less than 0.01), while it was increased in score 0 (P less than 0.05). ADP-induced aggregation was increased in score 0 and 1 (P less than 0.01 - 0.05). The mean value of beta-thromboglobulin in cancer patients (44 +/- 24 ng/ml) was significantly higher than that of control (22 +/- 13 ng/ml) (P less than 0.01). These results suggest the existence of hyperfunction of platelets in cancer patients and possibility of a triggering mechanism of such activated platelets in the genesis of DIC in cancer.

Cardiomyopathy Characterized by Abnormal Accumulation of Desmin‐type Intermediate Filaments in Cardiac Muscle Fibers: A Case Report and Review of the Literature

A 42 year old Japanese male, who had been suffering from congestive heart failure and electrocardiographic abnormalities (A V block, intraventricular conduction disturbance, ventricular tachycardia), died after a clinical course of 2 years and 1 month. Macroscopic investigation revealed dilation of the left ventricle and thickening of the right ventricular wall. The unique finding in this case was a circumferential fibrous scar in the median circular layer and outer oblique layer of the left ventricular wall. Biopsy and autopsy materials revealed diffuse loss of myofibrils in the central zone of cardiac muscle fibers, and replacement with aniline blue positive homogeneous material (17–35% of the area of one muscle fiber). Electron microscopy revealed abnormal accumulation of fine filamentous material (7.5–25 nm in diameter), which was immunohisto‐chemically proved to be desmin type intermediate filament. Moreover, sarcoplasmic reticulum like material was detected in the degenerated area. At autopsy, degeneration was detected all over the heart. The ventricular muscle fibers were more severely affected than the atrial muscle fibers. The conduction system was also affected, in some parts more severely than the surrounding ordinary muscle fibers. The pathogenesis of this disorder remains to be clarified. Acta Pathol Jpn 39: 266–273, 1989.

Association of humps on monophasic action potentials and ST-T alternans in a patient with Romano-Ward syndrome.

A case of Romano‐Ward syndrome had episodes of torsade de pointes preceded by ST‐T alternans. ST‐T alternans was induced by isoproterenol and abolished by verapamil, lidocaine, mexiletine and MgSO4. A monophasic action potential (MAP) showed humps in MAPs at the right ventricular outflow tract but not at the right ventricular apex in alternate beats. Differences in the MAP duration were noted between the two areas and were associated with ST‐T alternans. Atrial pacing abolished both humps and ST‐T alternans. These results suggest that humps are a possible re/lection of early afterdepolarizations and their appearance is limited to localized regions of the ventricles, which produces regional disparity of repolarization and ST‐T alternans.

Intravascular Aggregation of Platelets and Cerebrovascular Insufficiency

Platelet aggregation undoubtedly plays a major role in the pathogenesis of many types of ischemic cerebrovascular disease. When platelet aggregates occlude a vessel’s lumen, the vasoactive substances released from platelets, such as 5-hydroxytryptamine (serotonin), histamine and prostaglandin endoperoxide, may play a role in the genesis of the ischemic disease. Among these substances, prostaglandin endoperoxide and thromboxane A2 have recently drawn attention, because of their ability to contract the vessels and aggregate platelets. These prostaglandins (PGs) are produced from the arachidonic acid that probably originates from phospholipids in the platelet’s membrane.

Inhibitory Effect of Urografin 76 on Platelet Function and Thrombus Formation in Vascular Catheters

The effect of Urografin 76 on platelet aggregation and thrombus formation in vascular catheter was studied. In vitro experiments revealed that ADP-, epinephrine-, and collagen-induced platelet aggregation was significantly inhibited by Urografin 76 in concentrations greater than 0.3, 1, and 5% respectively. Rabbits that received 10 ml of Urografin 76 demonstrated a transient decrease in platelet aggregation for at least 3 minutes. Urografin 76 was apparently more effective than saline in preventing blood clot formation.