The past fifty years of antiarrhythmic drug development have seen limited success in prolonging life and reducing morbidity. It is likely that arrhythmias are in most instances final common pathways through which changes in the cardiac substrate and in trigger mechanisms are expressed. We propose that the development and administration of therapies for the arrhythmias themselves, while offering a panacea for a disease entity that has evolved and is being overtly manifested, is also an admission of failure to identify and prevent evolution of the substrate and triggers such that arrhythmias can occur. We suggest that while strategies for treatment and prevention of recurrence of arrhythmias still warrant exploration, greater hope for the future lies in identifying means for earlier diagnosis of the arrhythmogenic substrate and triggers, and in developing therapies that are "upstream" to the arrhythmia and prevent their initial expression. Means to achieve this end are suggested, using specific arrhythmias as examples. Similarly, to increase the likelihood that clinical studies of new therapies can be successfully concluded and interpreted, we suggest new approaches to patient selection, risk stratification, trial endpoints, outcome events and trial methodologies. (Jpn Circ J 1998; 62: 633 - 648)

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The present study was performed to determine the relation between oxygenated hemoglobin (oxy-Hb) changes in working muscles and ventilatory parameters. Six active normal subjects, 21 sedentary normal subjects and 16 patients with heart failure performed an incremental exercise with expired gas analysis. Deoxygenation of the vastus lateralis muscle was monitored for oxy-Hb changes using near-infrared spectroscopy. Near the anaerobic threshold (AT), oxy-Hb started to decrease, forming the first inflection point (P1). Near the respiratory compensation point (RCP), the second inflection point (P2) was observed. Oxygen uptake at the AT, RCP, P1 and P2 decreased in magnitude first in the active normal subjects, then in sedentary normal subjects and finally in the heart failure patients. High correlation was demonstrated between AT and P1 (r=0.8, p<0.0005) and between RCP and P2 (r=0.9, p<0.0005). In 12 sedentary normal subjects who underwent repeat exercise, reproducibility was confirmed for both P1 and P2. Constant work rate exercises were performed in 5 sedentary normal subjects, and in all of them the oxy-Hb remained unchanged below the AT work rate, whereas oxy-Hb decreased above the AT work rate. Exercise capacity, with respect to both working muscle deoxygenation and ventilation, could be evaluated in detail by the concomitant use of near-infrared spectroscopy and expired gas analysis. (Jpn Circ J 1998; 62: 649 - 657)

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Brain natriuretic peptide (BNP) secretion increases after myocardial infarction (MI); its plasma level may reflect the degree of left ventricular dysfunction. This study examines how aerobic exercise therapy for MI influences BNP secretion. Subjects included 70 patients (mean age, 62.0±11.3 years) who were divided into four groups: (1) 20 patients with an anterior MI and exercise training; (2) 20 patients with an anterior MI and no exercise training; (3) 15 patients with an inferior MI and exercise training; and (4) 15 patients with an inferior MI and no exercise training. The training groups performed aerobic exercise 3 times a week for 2 months. Exercise intensity was defined as a heart rate of anaerobic threshold (AT), derived from the treadmill cardiopulmonary exercise testing at 1 month after the onset of MI. The subjects underwent cardiopulmonary exercise testing again at 3 months after the onset of MI. To measure BNP, blood samples were obtained in the resting state and immediately after the peak exercise. AT and peak oxygen uptake increased in the training group with anterior MI and in both the training and nontraining groups with inferior MI. Significant serial change in plasma BNP level was not observed in the inferior MI groups. Plasma BNP level decreased longitudinally only in the nontraining anterior MI group. It was concluded that exercise training in patients with an anterior MI could delay the recovery of left ventricular function, but will increase exercise tolerance. (Jpn Circ J 1998; 62: 658 - 664)

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As percutaneous transluminal coronary angioplasty has become an increasingly common procedure replacing coronary artery bypass grafting (CABG), the clinical profile of the patients referred for CABG has changed markedly. A retrospective study of the changes in the clinical profile and surgical outcome of patients who underwent CABG during the past 10 years was conducted. Between March 1982 and February 1996, 1010 patients underwent isolated CABG at Nara Medical University. The first 100 consecutive patients who underwent CABG in 1984-85 (group 1) were compared with the first 100 consecutive patients who underwent CABG in 1994-95 (group 2). Preoperative risk increased significantly during the decade with respect to patient age (p<0.001), the presence of diabetes mellitus (p=0.048), the number of diseased vessels (p<0.001), left main trunk disease (p=0.008), the presence of aortic or peripheral vascular disease (p=0.032),and the need for emergency surgery (p=0.013). Operative procedures have become more complicated with respect to the number of total and arterial grafts, duration of the aortic cross-clamp and cardiopulmonary bypass. Hospital mortality for elective CABG has not changed (2%) and the overall mortality has not increased significantly (from 2% to 3%) during the decade. In conclusion, although the preoperative risks have increased and more complicated procedures are required, CABG continues to be performed safely with low mortality rates. (Jpn Circ J 1998; 62: 665 - 669)

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The association of the autonomic nervous system with coronary vasospasm has been controversial. The aim of the present study was to examine the involvement of the autonomic nervous system in coronary vasospasm by applying the head-up tilt (HUT) test to patients with coronary vasospastic angina. Fifteen consecutive patients with coronary vasospastic angina and without significant organic coronary stenoses underwent the HUT test. Prior to the test, coronary spasm was documented angiographically by using an intracoronary injection of acetylcholine or ergonovine. The HUT test was performed in the early morning and repeated in the afternoon if the test was positive in provoking angina pectoris and syncope or presyncope. If the test was negative, it was repeated under intravenous infusion of isoproterenol at a rate of 1-2μg/min. The HUT test under isoproterenol infusion in the morning provoked vasospastic angina with syncope or presyncope in 9 of the 15 patients. In the test-positive group, heart rate was significantly reduced (104±17 beats/min to 84±25 beats/min, p<0.05), which preceded a reduction in systolic blood pressure (158±25 mmHg to 125±17 mmHg, p<0.01), angina attack and syncope. The HUT test without isoproterenol infusion in the morning and the HUT test in the afternoon with or without isoproterenol infusion failed to provoke angina. The heart rate reduction preceding reduced systemic blood pressure and anginal attack suggested that parasympathetic nerve excitation plays an important role in coronary vasospasm. The results also implied that the HUT test combined with isoproterenol infusion is useful for the provocation of coronary spasm. (Jpn Circ J 1998; 62: 670 - 674)

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A total of 502 patients presenting in Utsunomiya city and its suburbs during a 10-year period were studied to determine the clinical features of ischemic heart disease and to identify coronary risk factors. The male/female ratio was 1.21, but the ratio decreased with increasing age. The duration of chest pain showed a continuous spectrum between angina and infarction, with a short duration of chest pain not being useful for excluding the diagnosis of myocardial infarction. Hypertension was more common than hypercholesterolemia in this study, although the prevalence of the latter increased slightly with time, along with the shift towards a modernized occupational pattern. Smoking was a more important risk factor for ischemic heart disease in younger individuals than in the elderly, and diabetes mellitus was highly associated with the development of myocardial infarction. The incidence of radiologically diagnosed cardiac hypertrophy and aortic calcification decreased over time. These changes may have resulted in part from improved blood pressure control and the development of new antihypertensive and cholesterol-lowering agents. (Jpn Circ J 1998; 62: 675 - 679)

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Candoxatril is an inhibitor of neutral endopeptidase, a membrane-bound enzyme that degrades atrial natriuretic peptide. The effects of candoxatril on hemodynamic parameters and cardiovascular hypertrophy were evaluated in the rat model of myocardial infarction. Myocardial infarction was induced by left coronary artery ligation in rats and they were treated either with candoxatril (10 mg/kg per day) or a vehicle for up to 4 weeks. Systolic blood pressure and body weight did not change for up to 4 weeks between the 2 groups. At the end of treatment, hemodynamic parameters were measured, and then plasma, heart, lungs and kidneys were collected. Kidney neutral endopeptidase, as measured by the quantitative autoradiographic method, was significantly inhibited in candoxatril-treated rats compared with that in controls (66.6±3.2% of control, p<0.001). On the contrary, there were no significant differences in right atrial pressure, left ventricular end-diastolic pressure, systemic pressure, and plasma level of atrial natriuretic peptide between the 2 groups. There were also no significant differences in cardiac weight and lung weight. These data indicate that inhibition of neutral endopeptidase by candoxatril at a dose of 10 mg/kg per day did not oppose cardiac hypertrophy in the rat model of myocardial infarction in spite of significant neutral endopeptidase inhibition. (Jpn Circ J 1998; 62: 680 - 686)

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The purpose of this study was to evaluate a therapeutic strategy of percutaneous transluminal coronary angioplasty (PTCA) in patients with recurrent angina following coronary artery bypass grafting. The study looked at 112 branches associated with graft failure, excluding new lesions in the native coronary artery (NCA). Chronic total occlusion (CTO) was observed in 50% of NCA (56/112) and in 68% of the grafts (76/112). Thirty-three branches (29%) showed CTO in both NCA and the graft. The overall success rate was 86% (96/112). The success rate on NCA was 98% (44/45) in non-CTO, while in CTO it was significantly lower at 62% (18/29). As to grafts, the success rate was 94% (32/34) in non-CTO, while it was 50% (2/4) in CTO. These characteristics, with respect to lesion morphology and the prevalence of CTO, exerted an influence on the selection of the access vessels for revascularization. Early outcome depended on the result of treatment of CTO. (Jpn Circ J 1998; 62: 687 - 690)

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In humans, the coronary arteries course not only subepicardially but also intramyocardially. The intramyocardial course of the coronary artery is reported to lead to acute ischemic heart disease and, as well, it may be symptomless. The aim of this study was to investigate the long-term ischemic effects of bridged arteries on the myocardium, and was carried out on 8 autopsy hearts with myocardial bridges and 2 hearts without myocardial bridges. The samples from the myocardium were examined with light microscopy. In the myocardium supplied by the bridged arteries, it was observed that there was an increase in the intercellular connective tissue, which was rich in collagen bundles, lymphocytes, fibroblasts and macrophages. Compression of the coronary artery by myocardial bridges may cause chronic degenerative changes, which may remain silent for a long time. (Jpn Circ J 1998; 62: 691 - 694)

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Patients who have mitochondrial myopathy can present with specific pathological conditions (eg, diabetes mellitus and deafness). A 36-year-old woman presented with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). An investigation was conducted into whether the abnormalitiy of mitochondrial DNA (a T to C transition at position 3271 in the mitochondrial tRNA [Leu(UUR)] gene) influences nuclear DNA synthesis by cells in the heart, skeletal muscles, and brain. Myocardium, skeletal muscle, and brain tissues were stained with hematoxylin-eosin, and Masson trichrome for histopathology. Target nuclei taken from the myocardial and skeletal muscles and brain tissue were purified after removing debris by the modified Hedley method. These nuclei were stained with propidium iodide (PI) for analysis by flow cytometry. The number of nuclei in the G2M phase was bigger in myocytes of MELAS than in normal myocytes (Control) (MELAS myocyte: Control myocyte=24.9 ±7.3: 6.1±1.6%, p<0.005), but there was no significant increase in the G2M phase in brain tissue. The G1 phase was far more reduced in MELAS myocytes and skeletal muscle than in Controls (MELAS myocyte: Control myocyte=65.8 ±9.1: 88.0±3.2%, p<0.005; MELAS skeletal muscle: Control skeletal muscle=85.1±2.2: 90.1±3.2%, p<0.05), while there was no significant decrease of nuclei in the G1 phase in brain tissue. Increased amount of nuclei in the G2M phase in cardiac myocytes and skeletal muscle cells compared with that in neurons might depend on the capacity for proliferation and differentiation of these cells as compared with brain tissue. It was concluded that the mitochondrial DNA mutation (3271T-to-C) of MELAS may influence the nuclear DNA synthesis of cells in various tissues depending on their level of mitotic activity. (Jpn Circ J 1998; 62: 695 - 699)

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Scheie's syndrome (mucopolysaccharidosis type I-S) is a rare genetic lysosomal storage disease affecting mucopolysaccharide metabolism, and is known to include cardiovascular disease. Surgical treatment was carried out in 2 patients with Scheie's syndrome. Patient 1 was a 56-year-old man with triple-vessel coronary artery disease, who successfully underwent coronary artery bypass grafting. Patient 2 was a 52-year-old man with aortic and mitral valve stenosis, who successfully underwent combined aortic and mitral valve replacement. The literature on Scheie's syndrome associated with valvular and coronary artery disease is also reviewed. (Jpn Circ J 1998; 62: 700 - 703)

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A 72-year-old woman was admitted to our hospital for evaluation of chest pain. Coronary angiography showed a left coronary artery-left ventricle fistula. An acetylcholine provocation test induced vasoconstriction of the right but not the left coronary artery. Her chest pain was not relieved by combined therapy with isosorbide dinitrate, diltiazem and nicorandil. Because of the coronary spasm, beta-blockers could not be used. However, her chest pain was relieved after the administration of a minor tranquilizer. Thus, the patient's chest pain was unlikely to be associated with either the fistula or the coronary spasm. (Jpn Circ J 1998; 62: 704 -706)

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The effect of oral amiodarone (AMD) therapy on left ventricular (LV) function was evaluated retrospectively in Japanese patients with ventricular tachyarrhythmias and congestive heart failure. Seventeen patients were treated with oral AMD (maintenance dose 191±52 mg/day) for more than 12 months. Fractional shortening (FS) on echocardiography revealed a trend towards an increase in the short-term (3 months) (p=0.06), but was not significant in the long-term follow-up period (more than 12 months) after AMD therapy. In 8 patients with 1 episode of myocardial infarction, FS revealed a trend towards an increase (p=0.09). In all of the 4 patients with dilated cardiomyopathy whose LV end-diastolic diameter was increased, FS was decreased in the long-term follow-up. Neither hospitalization frequency nor New York Heart Association classification were reduced by AMD therapy. In conclusion,oral AMD therapy did not cause LV function to recover significantly and could not improve the clinical course in patients with ventricular tachyarrhythmias. However, if the underlying disease is not progressive, AMD therapy may improve LV function. (Jpn Circ J 1998; 62: 707 - 709)

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The levels of circulating monocyte chemoattractant protein-1 (MCP-1) and tissue factor (TF) were examined on admission in 46 consecutive patients with acute coronary syndromes (ACS) and 30 patients with stable exertional angina (SEA). The plasma levels of both MCP-1 and TF were higher in the ACS patients than in the SEA patients (MCP-1: p<0.001; TF: p<0.001). Only the circulating TF level related to the number of diseased vessels. A positive correlation between plasma MCP-1 and TF levels was found (r=0.476, p<0.001). These results suggest that circulating MCP-1 plays an important role in the pathogenesis and/or development of ACS. (Jpn Circ J 1998; 62: 710 - 712)

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