Several of the adverse events that occur in acute coronary syndromes and after percutaneous coronary revascularization procedures are believed to be mediated by platelets. Recently, using molecular biology techniques, the platelet glycoprotein IIb/IIIa receptor was identified as the final common pathway for platelet aggregation. Thus, blocking the action of this receptor would seem to be an attractive proposition for reducing ischemic complications. A monoclonal antibody was the first agent in this new pharmacological family to be designed, but several peptide and peptide-like substances have subsequently been developed. This paper reviews the development of this class of agents and the various preclinical and clinical trials that have been undertaken. Early studies evaluated such agents during percutaneous coronary revascularization procedures. Because of the overwhelming benefits observed in such patients, together with the current limitations of treatments for acute coronary syndromes, the scope of investigations has been extended. Preliminary reports have been encouraging. (Jpn Circ J 1998; 62: 233 - 243)

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The use of small aortic valve prostheses raises concerns about harmful effects of residual obstruction to left ventricular outflow. The present study was undertaken to examine long-term clinical and echocardiographic results in 193 patients who underwent isolated aortic valve replacement (AVR) with a St Jude Medical (SJM) valve of 25 mm or smaller. The study subjects comprised 128 male and 65 female patients with a mean age of 54.1 years. The patients were divided into 2 groups according to the size of the valve prosthesis used for AVR. Small valves (19 or 21 mm) were implanted in 49 patients (group S) and large valves (23 or 25 mm) were used in 144 patients (group L). The group S patients were mainly female, older, and had smaller body surface areas. There were no significant differences in early and late mortality in group S as compared with group L. Furthermore, there was no difference in the incidence of valve-related or cardiac, non-valve-related death, including the incidence of sudden death, between the 2 groups, and they enjoy a similar level of daily routine activity regardless of the valve size used. Left ventricular (LV) function (ejection fraction, fractional shortening, LV mass index, LV end-systolic volume index, and LV end-diastolic volume index) measured by echocardiography improved significantly and returned to normal values after AVR in both groups. Moreover, no significant differences were observed in the postoperative variables of the LV function. These results suggest that 19-mm and 21-mm SJM valves can be safely used for AVR in the majority of Japanese patients. (Jpn Circ J 1998; 62: 244 - 248)

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To detect a significant narrowing of the left anterior descending artery in patients with inferior/posterior myocardial infarction, 200 patients underwent standard exercise testing. Age, gender, and grade of stenosis of the left anterior descending artery were similar in 138 patients with inferior myocardial infarction and 62 with posterior myocardial infarction. In patients with left anterior descending artery stenosis, there were more lateral leads with ST-segment depression (1.8±1.0 vs 1.1±1.1; p<0.01) and fewer anterior leads with ST-segment depression (2.1±1.4 vs 2.9±.4; p=0.02) in those with inferior myocardial infarction than in those with posterior myocardial infarction. Applying the criterion of exercise-induced ST-segment depression ≥0.1 mV, sensitivities and specificities in detecting left anterior descending artery stenosis were 98% and 21% respectively in inferior myocardial infarction and 94% and 26% respectively in posterior myocardial infarction. In contrast, discriminant analysis revealed sensitivities and specificities of 77% and 91% respectively in inferior myocardial infarction and 71% and 81% respectively in posterior myocardial infarction using the variables related to severity of inducible ischemia and lateral and anterior lead ST-segment depression. These results indicate that a multivariate approach underscoring the site of myocardial infarction can help in identifying stenosis of the left anterior descending artery in patients with inferior/posterior myocardial infarction. (Jpn Circ J 1998; 62: 249 - 254)

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The incidence of thromboembolic complications among 288 patients with atrial fibrillation (AF) who were followed up during an average period of 7.2 years was examined retrospectively. The annual incidence of thromboembolic complications was 1.6% in total, 1.7% in valvular heart disease (n=128), and 2.1% in non-valvular heart disease (n=117). No thromboembolism occurred in lone AF (n=43), defined as the complete absence of any underlying disease. The type of AF before embolic attack was chronic in 26 cases and paroxysmal in 6 cases. The cardiac rhythm at the time of the embolic attack was AF, except in 2 cases in which ECG was not recorded. In all patients with thromboembolic complications who were receiving antithrombotic therapy during the follow-up, the anticoagulant effect just before the embolic attack was found to be insufficient. Major bleeding was not observed in the patients receiving antithrombotic therapy. Thromboembolism in AF in long-term follow-up tends to occur more frequently in patients with underlying heart disease and in those with chronic AF compared rather than paroxysmal AF; it rarely occurs in lone AF. We should not hesitate to administer sufficient anticoagulant therapy in AF patients who are at high risk of developing thromboembolic complications. (Jpn Circ J 1998; 62: 255 - 260)

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We conducted a large population-based study to assess levels of glycated hemoglobin A1c (HbA1c) and to evaluate the correlation between HbA1c and other cardiovascular risk factors in Japan. A total of 910 men and 1,890 women aged 30-69 years participated in the Jichi Medical School Cohort Study (1993-95). Mean HbA1c was 5.61% in men and 5.49% in women. HbA1c levels were significantly correlated with levels of triglycerides, fibrinogen, and factor VII, and inversely correlated with high-density lipoprotein (HDL)-cholesterol level in both sexes. Lipoprotein(a) was inversely correlated in men. Blood pressure, body mass index (BMI), and total cholesterol were significantly associated with HbA1c in women. After adjusting for significant variables in univariate analyses, fibrinogen and factor VII remained as significant correlates in men, and BMI and total cholesterol in women. The authors conclude that HbA1c level is correlated not only with classical cardiovascular risk factors, but also with fibrinogen and factor VII. Our results suggest that HbA1c could be an alternative to blood glucose in evaluating atherosclerotic risk in a large-sized population study. (Jpn Circ J 1998; 62: 261-266)

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The most common mechanism of sustained ventricular tachycardia (VT) is re-entry with an excitable gap, but the electrophysiologic properties and response to antiarrhythmic drugs in the area of slow conduction are not yet fully known. The purpose of this study was to assess the effects of a class I antiarrhythmic drug (procainamide) and class III agents (amiodarone, E-4031, and MS-551) on re-entrant VT using the width of the zone of entrainment. The cycle length (CL) of VT (VTCL) , the block CL that was the longest paced CL that interrupted the VT, and the width of the zone of entrainment, defined as the difference between VTCL and block CL, were compared before and after treatment with antiarrhythmic drugs. The VTCL was prolonged significantly from 308±63 to 410±77 msec after procainamide (p<0.005) but was not changed after the administration of the class III agents: from 294±50 to 292±13 msec after amiodarone, and from 305±47 to 313±31 msec after E-4031 or MS-551 (p=NS). The block CL was prolonged from 255±61 to 331±70 msec after procainamide (p<0.01), from 256±20 to 260±25 msec after amiodarone, and unchanged after E-4031 or MS-551 (253 ±31 msec before and 270±43 msec after) (p=NS). The width of the zone of entrainment as a representative of the width of the excitable gap was changed from 52±26 to 79±35 msec (p<0.05) after procainamide, whereas it was unchanged after amiodarone (48±7 msec before and 43±7 msec after) and after E-4031 or MS-551 (50±10 msec before and 40±9 msec after). Therefore, amiodarone, E-4031, and MS-551 did not affect VTCL and block CL whereas procainamide increased these parameters. The excitable gap substituting as the zone of entrainment was increased by procainamide but slightly reduced by amiodarone, E-4031, and MS-551. The effects of these antiarrhythmic drugs on the excitable gap of re-entrant VT were variable and should be examined further. (Jpn Circ J 1998; 62: 267-273)

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The aim of the study was to determine whether or not dipyridamole thallium-201 single-photon emission computed tomography (²⁰¹Tl-SPECT) has significant additive value for predicting perioperative cardiac events in patients with arteriosclerosis obliterans (ASO) undergoing vascular surgery. Routine preoperative ²⁰¹Tl-SPECT was performed in 106 consecutive patients with ASO (age 68±8.9 years; 91 men and 15 women). The frequency of reversible defects in a clinical high-risk group (n=44) was significantly higher than in a low-risk group (n=62; 55% vs 24%, p<0.01). Perioperative cardiac events occurred in 9 patients, including 4 cardiac deaths, 1 non-fatal myocardial infarction, and 4 cases of unstable angina. Although clinical risk stratification was useful in predicting cardiac events (19% in the high-risk group vs 2% in the low-risk group, p<0.01), the positive predictive value was low. When considering a combination of 2 or more than 2 risk factors and a large reversible defect as a predictor, the positive predictive value and specificity increased from 19% to 47% and from 64% to 91%, respectively, whereas the sensitivity remained unchanged (89%). These results suggest that the addition of ²⁰¹Tl-SPECT data to clinical risk-stratified patients with ASO allows better prediction of perioperative cardiac events. (Jpn Circ J 1998; 62: 274-278)

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The aim of this study was to determine whether initial potentials of the P-wave on a signal-averaged electrocardiogram (SAE) during sinus rhythm reflect indices of electrophysiologic measurements in the high lateral right atrium. A total of 67 patients underwent P-wave signal averaging during electrophysiologic testing. The correlation between root mean square voltages for the initial 10 and 20 msec of the P-wave on the SAE and indices of electrophysiologic measurements, sinus node recovery time (SRT) and sinoatrial conduction time (SACT), obtained from programmed stimuli, was evaluated. It was found that the initial potentials of the P-wave on the SAE correlated negatively with SRT and SACT (-0.37 ≤ r ≤ -0.30). It was concluded that the initial potentials correlated with indices of electrophysiologic measurements, although the statistical significance was weak. (Jpn Circ J 1998; 62: 279 - 283)

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An association between genetic factors and susceptibility to coronary spasm has not been proven. Because we encountered 7 patients with familial occurrence of vasospastic angina (VSA) in 3 families, the association of a genetic factor with coronary spasm was assumed. HLA typing as one of the genetic markers was performed in the 3 families, and the affected members in each family were found to share a HLA haplotype, carrying both HLA-DR52 and DQ6. This raised the possibility that one of the susceptibility genes for coronary spasm is located in the HLA region. To assess this possibility, HLA typing was performed and compared in 110 patients with VSA but without a family history of VSA (VSA group) and 55 patients with chest pain syndrome (CPS group) as control subjects. All patients underwent a provocation test for coronary spasm, and spasm was angiographically documented in the VSA group but not in the CPS group. Of all HLA antigens, the frequency of only HLA-DR2 was significantly higher in the VSA group than in the CPS group (39.1% vs 18.2%, p<0.01). The result implied that HLA-DR2 is in linkage disequilibrium with a susceptibility gene of VSA and thus is possibly involved in susceptibility to coronary spasm in some patients with VSA. (Jpn Circ J 1998; 62: 284 - 288)

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In order to quantify underlying atrial conduction properties in patients with atrial fibrillation (AF) using clinical electrophysiology techniques, atrial conduction curves relating intra-atrial conduction times to extrastimulus prematurities during programmed atrial stimulation were drawn. Based on the presence or absence of AF episodes, 95 subjects were divided into 2 groups: control (n=42); and AF (n=53). During programmed stimulation introduced from the right atrial appendage, an atrial conduction curve was drawn for each patient. For most of the control subjects, when the extrastimulus prematurity was increased by 10-ms steps, the intra-atrial conduction times also increased gradually; the maximum stepwise prolongation in intraatrial conduction time was 11.O±3.4msec. For patients with AF, a 10-msec increase in extrastimulus prematurity often produced a sudden marked prolongation in the intra-atrial conduction time; the maximum stepwise prolongation of intra-atrial conduction time was 21.4±5.9msec. In contrast to the gradual atrial conduction curves recorded in control subjects, the sudden prolongation of intra-atrial conduction time was remarkable on the curves obtained in patients with AF. Statistical significance was clearly established (p<0.0001). This difference could be related to differences in the underlying conduction properties in patients with and without AF. (Jpn Circ J 1998; 62: 289-293)

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It is not clear why late reperfusion therapy in patients with acute myocardial infarction is effective. An investigation was carried out as to whether or not reperfusion conducted 12 h after coronary occlusion causes myocardial salvage in dogs. Coronary arteries were occluded in 11 mongrel dogs and a portion of the occlusion (late reperfusion area; LR area) reperfused 12 h later; the other part was left occluded (permanent occlusion area; PO area). The dogs were maintained for 4 weeks after reperfusion. Regional myocardial blood flow (Q_m) was measured by the non-radioactive colored microsphere method. In both areas, the transmurality of necrosis was measured by triphenyl tetrazolium chloride staining, and the amount of viable myocardium and the extent of fibrosis was determined by Azan-Mallory staining. Q_m decreased markedly after coronary occlusion to similar levels in both areas until 12 h. Q_m transiently increased in the LR area only following reperfusion after 12 h. The transmurality of necrosis in the PO area was 83.8±10.5%, but that in the LR area was 58.7±21.3%, a significant decrease (p<0.01). In the outer layer, the amount of viable myocardium was significantly greater, and the extent of myocardial fibrosis was significantly less in the LR area. Evaluation in the same heart of dogs confirmed the myocardial salvage effects of late reperfusion (12 h after coronary occlusion). (Jpn Circ J 1998; 62: 294 - 298)

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Local drug delivery following percutaneous transluminal coronary angioplasty (PTCA) may prevent restenosis by achieving higher local tissue concentrations of drugs than systemic administration. However, it remains unknown whether vascular damage and the ensuing intimal thickening is associated with the degree of infusion pressure achieved by local delivery. Therefore, local delivery of normal saline was performed using a channeled balloon catheter (Transport™) to the rabbit iliac artery with different infusion pressures of 0, 3, 5, 7, and 12 atm (n=4 for each). The extent of vascular damage and the development of intimal thickening were determined histopathologically 14 days after the procedure, In 10 additional rabbits, to assess the degree of vessel penetration, local delivery of indocyanine green dye solution was performed in a similar fashion. After 1 h, the green dye penetrated deeply at the higher infusion pressures of 7 and 12 atm. The incidence of internal elastic lamina laceration and occurrence of total occlusion as a result of thrombus formation demonstrated an increase proportional to the degree of local infusion pressure. When the vascular injury score in each arterial section was plotted against the infusion pressure, a significant relation was observed (r=0.717, p<0.0001). At 0, 3, 5, 7, and 12 atm, neointimal areas of 0.160±0.005, 0.163±0.008, 0.189 ±0.017, 0.260±0.027, and 0.329 ±0.033 mm², respectively, were observed. Smooth muscle cell (SMC) prolifer-ative activity also increased in proportion to the local infusion pressure. We have demonstrated for the first time that local delivery infusion pressure itself is related to the severity of vascular damage, resulting in the development of intimal thickening and an associated increase in SMC proliferative activity. Therefore, we suggest that infusion pressure is a key determinant of vascular injury during local drug delivery, with lower pressure causing the least neointimal response. (Jpn Circ J 1998; 62: 299 - 304)

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We report a rare case of a 41-year-Old male patient, a professional musician, with dilated cardiomyopathy and sustained ventricular tachycardia (VT) that was refractory to class I antiarrhythmic drugs. Severe myolysis developed after 10 months' administration of amiodarone (400 mg/day) in combination with mexiletine (300 mg/day) and disopyramide (400 mg/day). He had been suffering from severe moving muscle pain and an extremely high (16,830 IU/ml) serum level of creatine kinase (CK). The dosage of amiodarone was reduced from 400 mg/day to 200 mg/day without reduction of mexiletine or disopyramide and the patient's symptoms diminished. However, sustained VT developed, and so the dosage of the drug was increased to 250 mg/day. The high serum level of CK also decreased and returned to the normal range after the reduction in amiodarone dosage. Electrophysiologic examination of moving muscle revealed normal motor and sensory conduction velocities and, furthermore, the electromyogram revealed normal potentials and normal motor units. We conclude that severe myolysis developed as a result of the high dose and chronic administration of amiodarone. This is the first report of a Japanese patient showing rare and serious adverse effects in response to amiodarone treatment. (Jpn Circ J 1998; 62: 305 - 308)

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In this report, cardiac abnormalities in 2 diabetic patients with a mutation in the mitochondrial tRNA^Leu(UUR)gene are described. The 2 patients exhibited left ventricular dilation and diffuse decreased wall motion. Cardiac catheterization studies revealed normal coronary angiography. In both patients, light microscopic examination of hematoxylin and eosin-stained sections revealed myocyte hypertrophy and perinuclear vacuolization and electron microscopy revealed an increase in the number and size of mitochondria and abnormal configuration of cristae. These findings suggest that mutations in mitochondrial DNA, such as an A→G mutation at position 3243, should be considered as a cause not only of diabetes mellitus but also of cardiac involvement in patients with diabetes mellitus. (Jpn Circ J 1998; 62: 309 - 310)

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This study was designed to measure circulating hepatocyte growth factor (HGF) in a rat model of arterial thrombosis. The carotid endothelial surface of rats was denuded with a balloon catheter and partially occluded. The amount of thrombus formation was expressed as the difference between the wet weights of paired treated and nontreated carotid arteries. Thrombus weight increased gradually up to 60 min after denudation. Plasma HGF did not increase before 30 min, but had significantly increased by 60 min compared with all previous measurements (p<0.05). Measurements of circulating HGF may be useful in the early diagnosis of arterial thrombosis. (Jpn Circ J 1998; 62: 311 - 313)

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