Background The purpose of this study was to determine whether treatment with granulocyte colony-stimulating factor (G-CSF), which mobilizes endothelial progenitor cells from bone marrow, can safely improve the clinical outcomes of patients with atherosclerotic peripheral artery disease (PAD). Methods and Results Thirty-nine patients with intractable PAD were randomly assigned to 3 groups: a negative control group (n=12) treated with conventional drug therapy; a positive control group (n=13) treated with conventional drug therapy plus bone marrow transplantation (BMT); and a G-CSF group (n=14) treated with conventional therapy plus subcutaneous injection of 2-5 μg/kg of recombinant human G-CSF once daily for 10 days. One month after treatment, subjective symptoms improved significantly in the G-CSF and BMT groups. Ankle-brachial pressure index and transcutaneous oxygen pressure increased significantly in the BMT and G-CSF groups, but no such improvements were seen in the group receiving conventional therapy alone. Conclusions G-CSF improves the clinical signs and symptoms of patients with intractable PAD to the same degree as BMT does. This noninvasive treatment may thus represent a useful new approach to managing the disease. (Circ J 2006; 70: 1093 - 1098)

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Background Nicorandil in conjunction with percutaneous coronary intervention (PCI) has been reported to reduce reperfusion injury events and improve cardiac function in patients with acute myocardial infarction (AMI). This multicenter study was undertaken to determine the effectiveness and optimal administration of nicorandil in AMI patients. Methods and Results Ninety-two patients with first AMI were randomly assigned to 1 of 3 groups: intracoronary administration of nicorandil (Group A), combined intravenous and intracoronary administration of nicorandil (Group B), and no nicorandil administration (Group C). The primary endpoint was a composite of the incidence of reperfusion-induced arrhythmia, chest pain, and no-reflow/slow-reflow. The secondary endpoint was the combined rate of improvement in the Thrombolysis in Myocardial Infarction frame count (cTFC) and ST resolution (STR). A significant difference was observed in the primary endpoint for Group B as compared with Group C (p<0.05). In the meantime, a significant improvement was shown in the secondary endpoint for Group B compared with Group C (p=0.04 and 0.006 for cTFC and STR, respectively). Conclusions Combined intravenous and intracoronary administration of nicorandil reduces reperfusion injury during PCI and improves the cTFC and STR in AMI, and appears to be preferable to intracoronary administration alone. (Circ J 2006; 70: 1099 - 1104)

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Background The association of smoking with coronary heart disease (CHD) occurrence has been reported to be weaker for populations with lower plasma cholesterol levels. Recent studies suggest that low-density lipoprotein cholesterol (LDL-C) and smoking contribute to different stages of atherosclerosis, so the present study was designed to test the hypothersis that smoking is a stronger risk factor for CHD when LDL-C is high. Methods and Results The study group of 13,410 middle-aged adults who were initially free of stroke and CHD were followed and over 13.3 years there were 932 incident CHD events. Tests for multiplicative interaction were performed using proportional hazards models. Both smoking and increased LDL-C were risk factors for CHD incidence. The relative hazard (RH) of CHD in relation to smoking tended to be larger among higher LDL-C categories compared with lower LDL-C categories. For example, when the participants were dichotomized into 4 categories, using smoking ≥15 cigarettes per day and LDL-C ≥130 mg/dl as cutoffs, those with high LDL-C and heavier cigarette smoking showed a very high RH of CHD (RH =2.81) compared with that expected from the product of the RHs of high LDL-C (RH =1.15) only × heavy smoking only (RH =1.71) (p for interaction =0.04). Conclusions These results suggest positive multiplicative interactions between smoking and LDL-C for CHD incidence. (Circ J 2006; 70: 1105 - 1110)

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Background Although angiotensin II receptor blockers (ARB) have been found to reduce the coronary atherosclerotic plaque burden in animal models, it is unknown whether ARB have a similar effect on human coronary arteries. Methods and Results Serial intravascular ultrasound (IVUS) studies of the left main (LM) coronary artery were performed in 64 patients at baseline and after 7-month follow-up. All patients were divided into 2 groups (ARB group: 23 patients; non-ARB group: 41 patients). Three-dimensional volumetric analysis was done throughout the LM coronary artery, and the volume index (VI; volume/length) was calculated for the vessel (VVI), lumen (LVI), and plaque (PVI). No significant difference was found between the 2 groups in baseline clinical characteristics, including age, gender, blood pressure levels, serum cholesterol levels, the presence of diabetes and smoking status. At baseline VVI, LVI and PVI were similar between the groups. In the non-ARB group, VVI, LVI, and PVI did not change between baseline and follow-up. In the ARB group, PVI significantly decreased during follow-up (9.9 ±3.1 mm² vs 9.1±2.7 mm², p<0.01), whereas VVI and LVI were unaffected. Conclusions This preliminary IVUS study suggests that ARB could cause regression of coronary atherosclerosis in humans. (Circ J 2006; 70: 1111 - 1115)

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Background Previous studies have suggested that the lipid-lowering agents, statins, may help reduce blood pressure (BP). The goal of the present study was to characterize the effect of pravastatin on BP in hypercholesterolemic and hypertensive patients already receiving antihypertensive drugs. Methods and Results Eighty-two patients with hypercholesterolemia were retrospctively studied before and after 3 months of treatment with pravastatin. Forty-four patients had hypertension (HT group) and were receiving antihypertensive treatment, while the remaining 38 patients were normotensive (NT group). Patients in the HT group were further subdivided into those with uncontrolled or controlled BP. Pravastatin treatment significantly reduced systolic BP (SBP) in the HT group (134±16 to 130±13 mmHg, p<0.005) but not in the NT group (124±10 to 123±9 mmHg, p=0.52), despite the fact that treatment significantly reduced low-density lipoprotein cholesterol in both groups (HT group 178±27 to 132±17 mg/dl, p<0.0001; NT group 169±27 to 125±21 mg/dl, p<0.0001). Further, pravastatin significantly decreased SBP in the uncontrolled BP group (148±7 to 138±12 mmHg, p<0.005) but not in the controlled BP group (122±10 to 123±9 mmHg, p=0.72). Conclusion Concomitant use of statins and antihypertensive drugs could result in improved BP control in hypertensive patients with hypercholesterolemia. (Circ J 2006; 70: 1116 - 1121)

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Background The coronary artery calcification (CAC) score measured by multidetector row computed tomography (MDCT) has emerged as a marker for predicting coronary artery disease (CAD). To evaluate the clinical significance of the CAC score, coronary artery stenosis as assessed by coronary angiography (CAG) was compared with the CAC score determined by MDCT, risk factors and medications. Methods and Results Subjects included 374 consecutive patients who underwent ECG-gate CT angiography using MDCT. The accuracy in patients with a CAC score ≥400 was 84%, and significantly lower than that in patients with a CAC score =0. In addition 92 patients (68 males, 24 females; mean age, 63±11 years) who underwent both MDCT and CAG within a 1-month period were selected for further investigation. Patients with significant coronary stenosis had a significantly higher CAC score than those without stenosis. In addition, a higher number of stenosed vessels was associated with a higher CAC score. The subjects were divided into 3 groups according to the CAC score: low (0-12), intermediate (13-444) and high (≥445). The CAC score was significantly associated with age, and plasma levels of total cholesterol and hemoglobinA1c, and logistic regression analysis revealed that significant coronary stenosis as assessed by CAG was most closely correlated with the CAC score (p=0.03). Conclusions The CAC score determined by MDCT can predict CAD independent of other factors, such as age, metabolic diseases and medications, when coronary stenosis can not be diagnosed because of severe calcification. (Circ J 2006; 70: 1122 - 1127)

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Background Little is known about the long-term outcome of implantable cardioverter defibrillator (ICD) therapy in survivors of out-of-hospital cardiac arrest (OHCA). Methods and Results The frequency of lethal ventricular arrhythmias and whether ICD implantation can prevent recurrence of cardiac arrest were examined. Long-term (24.4±11.9 months) outcome was examined in 23 patients with OHCA who were treated with an ICD (OHCA group) and 35 patients without OHCA (non-OHCA group) who were treated with an ICD. Patients in both groups had same clinical backgrounds; however, those in the OHCA group showed a significantly lower incidence of induced ventricular arrhythmias (71%) than the non-OHCA group (96%). In the follow-up period, patients in the OHCA group had almost the same incidence of ICD discharge (30%) as patients in the non-OHCA group (40%). The rate of recurrence of ventricular fibrillation in the OHCA patients was 13%, and it was difficult to estimate the rate by induced ventricular arrhythmia. Conclusion The results suggest that ICD implantation for survivors of OHCA with favorable neurological recovery might be effective for preventing recurrence of cardiac arrest. (Circ J 2006; 70: 1128 - 1132)

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Background Previous studies have shown that both atrioventricular nodal reentrant tachycardia (AVNRT) and atrial flutter (AFL) have an area of slow conduction located in the low posterior right atrium near the ostium of the coronary sinus. The aim of this study was to evaluate the inducibility of AFL in patients with AVNRT. Methods and Results One hundred and seventy patients were prospectively evaluated for inducibility of tricuspid valve - inferior vena cava isthmus-dependent AFL. Two groups of patients were analyzed: 71 patients with inducible AVNRT and 99 control patients without a history of AFL. AFL was induced in a greater percentage of patients with AVNRT (53%) than of control patients (27%, p<0.02). In all 21 patients with AVNRT and inducible AFL before slow pathway ablation, AFL was also inducible after slow pathway ablation. There was no difference in the cycle length of induced AFL before and after ablation. Conclusions AFL was induced in a greater percentage of patients with AVNRT, suggesting that there may be a common area of posteroseptal perinodal atrium participating in the two-tachycardia circuits. However, radiofrequency ablation of the slow pathway of the AVNRT circuit does not influence the inducibility of AFL. (Circ J 2006; 70: 1133 - 1137)

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Background Suppression by antiarrhythmic drugs of the maintenance mechanisms could convert persistent atrial fibrillation (AF) to sinus rhythm (SR). Whether a history of drug-resistant paroxysmal AF (PAF) would affect the outcome of pharmacological conversion of persistent AF by bepridil or in combination with aprindine was evaluated in the present study. Methods and Results The study group comprised 51 consecutive patients (24 men, 61±8 years) undergoing pharmacological conversion of persistent AF lasting >1 month. Drug-resistant PAF was defined as AF and at least 2 ineffective antiarrhythmic drugs for suppression of AF recurrence. Fast Fourier transform analysis of fibrillation waves was used to measure fibrillation cycle length (FCL) from the peak frequency. Fifteen patients had a history of drug-resistant PAF (Group I), and the remaining 36 did not (Group II) before diagnosis of persistent AF. Ten patients (67%) in Group I and 26 patients (72%) in Group II were restored to SR by bepridil alone or in combination with aprindine after 29±15 days of drug administration. Before conversion to SR, bepridil increased the FCL more in Group II than in Group I. During a 12-month follow-up period, 4 of 10 patients in Group I and 2 of 26 patients in Group II (p<0.01) had recurrence of persistent AF with bepridil alone or in combination with aprindine. Conclusions A history of drug-resistant PAF does not affect the efficacy of pharmacological conversion by bepridil or in combination with aprindine. However, recurrence of AF was significantly higher in patients with such a history. (Circ J 2006; 70: 1138 - 1141)

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Background Although ventricular arrhythmia is critical for the prognosis of patients with severe congestive heart failure (CHF), it is difficult to control the arrhythmia using conservative therapies. However, many CHF patients also have sleep apnea syndrome (SAS) and oxygen supply improves their prognosis. The beneficial effects of oxygen treatment for ventricular arrhythmia have not yet been clarified, so the present study was designed to evaluate the effects of oxygen treatment for premature ventricular contraction (PVC). Methods and Results Patients with CHF and SAS were divided into 3 groups: (1) the "PVC declined" group that included patients who had frequent PVCs and oxygen treatment that suppressed the number of PVC; (2) the "PVC not affected" group that included patients who had frequent PVCs and oxygen treatment did not affect the number of PVC; and (3) the "few PVC" group that included patients who had no or few PVCs. The group 1 patients showed higher apnea-hypopnea index, standard deviation of all R-R intervals, left ventricular ejection fraction, and brain natriuretic peptide levels than the patients in group 2. Oxygen treatment in group 3 did not affect the PVC frequency. Conclusions Oxygen treatment may be useful for preventing ventricular arrhythmia in selected patients with CHF and SAS. (Circ J 2006; 70: 1142 - 1147)

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Background Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) in congestive heart failure (CHF) is generally considered a poor prognostic indicator, but treatment of CSR-CSA using an adaptive servo-ventilation (ASV) device has been developed. This is the first evaluation of its use in the management of CSR-CSA in Japanese CHF patients. Methods and Results Four CHF patients with CSR-CSA that was unresponsive to conventional positive airway pressure (CPAP) underwent 3 nights of polysomnography: baseline, CPAP or bi-level PAP, and on the ASV. The apnea - hypopnea index (AHI) and central-AHI (CAHI) were markedly improved on ASV (AHI 62.7±10.1 to 5.9±2.2 /h, p=0.0006, CAHI 54.5±6.7 to 5.6±2.3 /h, p=0.007). In addition, the sleep quality improved significantly on ASV, including arousal index (62.0±10.5 to 18.7 ±6.2 /h, p=0.012), percentage of slow-wave sleep (2.6±2.6 to 19.4±4.8 %, p=0.042). Conclusions ASV markedly improved CSR-CSA in patients with CHF. It is a promising treatment for Japanese patients with CHF. (Circ J 2006; 70: 1148 - 1154)

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Background Many large-scale clinical studies appear to be interpreted with bias and with hindsight. To select the best treatment, accurate evaluation of randomized controlled trials (RCTs) and fair comparison of the results using the concept of evidence-based medicine are critical. A scoring system has been developed to rate the scientific strength of evidence and thereby provide guidance for best clinical practice and for large-scale RCTs of angiotensin-receptor blockers (ARBs). Method and Results Positive evidence scores (ESs) were given based on whether specified study endpoints were proven and whether treatments tested made significant progress over current usual therapy. Retrospective ad hoc analyses data were not counted, in order to simplify the system and to avoid hindsight interpretations, even in cases that were medically significant. In fact, in more than half of the large-scale trials with ARBs examined, ad-hoc analyses had been retroactively performed. When such post-hoc analyses were not used, the ESs were positive with candesartan and valsartan for treatment of heart failure, irbesartan and losartan for nephropathy and losartan for hypertension. Applying the ES system, losartan was judged to be an ARB with the strongest evidence covering a wide range of clinical relevance. Conclusion ES is useful for quantifying and comparing the strength of evidence obtained in large-scale RCTs of ARBs. Several problems related to rating the evidence obtained from clinical trials were recognized in this study. (Circ J 2006; 70: 1155 - 1158)

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Background There are almost no reports on the physiological effects of the various electric massage devices available on the market. This report describes the effects on peripheral vascular circulation and autonomic-nervous system activity of a pulse-synchronized air-massage (PS-AM) device in which cuffs apply air pressure cyclically to the lower limbs only during the cardiac diastolic phase. Methods and Results The PS-AM device consists of a main unit with a pulse-wave detector that uses the pulse-wave to activate an air pump only during the cardiac diastolic phase. Pressure is applied sequentially from the feet to the thighs by 4 pairs of cuffs attached to the main unit. The study was carried out on 55 volunteers (19 males, 36 females). A laser Doppler flow-meter attached to the subjects' toes was used to measure blood flow (BF), while ECG, blood pressure and cardiac autonomic nerve activity [parasympathetic nerve activity (high-frequency component (HF))] were measured by a multibiomedical recorder (TM2425). The measurements were made for a total of 45 min consisting of three 15-min periods: before massage, during PS-AM, and after massage. BF increased 139±33 (SD) % in males and 154±44% in females during PS-AM, with a significant correlation being observed between BF and HF during PS-AM (p<0.01). Conclusions PS-AM significantly increased peripheral vascular BF in the lower extremities, a change that may affect venous return and cardiac parasympathetic nerve activity. (Circ J 2006; 70: 1159 - 1163)

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Background Non-invasive measurement of cardiac output (CO) may become an important modality for the treatment of heart failure. Among the several methods proposed, impedance cardiography (ICG) has gained particular attention. There are 2 basic technologies of ICG: thoracic and whole-body ICG whereby the electrodes are applied either to the chest or to the limbs. The present study is aimed to test the effectiveness of the Non-Invasive Cardiac System (NICaS), a new ICG device working with a wrist-to-ankle configuration. Methods and Results To evaluate the reliability of NICaS derived CO (NI-CO), 50 CO measurements were taken simultaneously with thermodilution (TD-CO) and modified Fick (Fick-CO) in 35 cardiac patients, with the TD-CO serving as the gold-standard for the evaluation. Overall, 2-tailed Pearson's correlation and Bland-Altman limits of agreement between NI-CO and TD-CO were r=0.91 and -1.06 and 0.68 L/min and between Fick-CO and TD-CO, r=0.80 and -1.52 and 0.88 L/min, respectively. Good correlation was observed in patients with loading conditions altered by nitroglycerin and also in patients with moderate valvular diseases. Conclusion Agreement between NI-CO and TD-CO is within the boundaries of the FDA guidelines of bio-equivalence. NI-CO is applicable for non-invasive assessment of cardiac function. (Circ J 2006; 70: 1164 - 1168)

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Background Trimetazidine is an anti-ischemic agent that is used to treat angina and it has cardioprotective effects without inducing any significant hemodynamic changes. It inhibits the long-chain mitochondrial 3-ketoacyl coenzyme A thiolase enzyme in the myocyte and can improve cardiac mitochondrial metabolism, as well as scavenge free radicals. The aim of this double-blind prospective randomized study was to investigate the effect of preoperative use of trimetazidine on the reduction of oxidative stress during coronary artery bypass grafting (CABG) under cardiopulmonary bypass (CPB). Methods and Results The study group (group T) and the control group (group C) each comprised 12 patients. Pretreatment began 2 weeks before CABG with trimetazidine (60 mg/day po); the control group did not receive any medication. Serial blood samples were collected before and after CPB for measurement of the serum concentrations of these major endogenous antioxidant enzyme systems, which are markers for oxidative degradation of the cellular membranes; postoperative levels were significantly different between the groups (p<0.05). There were no significant difference in hemodynamic values. Conclusion The findings suggest that pretreatment with trimetazidine alleviates malondialdehyde production and preserves endogenous antioxidant capacity during CABG with CPB and cardioplegic arrest. (Circ J 2006; 70: 1169 - 1173)

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Background Angiotensin-converting enzyme (ACE) plays an important role in vascular remodeling in pulmonary hypertension, and ACE gene polymorphism is associated with exercise-induced pulmonary hypertension in Japanese patients with chronic obstructive pulmonary disease. The present study was designed to investigate if ACE-insertion (I)/deletion (D) polymorphism might be related to the susceptibility, severity, and disease outcome in chronic thromboembolic pulmonary hypertension (CTEPH). Methods and Results ACE-I/D genotypes were determined in 95 consecutive CTEPH patients (46 underwent surgery, 49 received medical treatment) and 97 controls. The frequencies of genotypes and alleles were not significantly different between patients and controls. Clinical characteristics were compared among ACE genotypes (II, ID, DD). ACE D allele carrier (ID plus DD) was associated with a lower 6-min walk test distance compared with D allele non-carrier (II) (330±102 (mean ± SD) vs 381 ±85 m, p=0.046). Kaplan-Meier analysis in the medically treated group showed significantly deteriorated survival for D allele carriers compared with D allele non-carriers (p=0.0389). Multivariate analysis revealed that age (p=0.013), pulmonary vascular resistance (p=0.008), and D allele carrier status (p=0.021) were independent predictors of survival. Conclusion ACE D allele carrier is possibly one of the prognostic factors for medically treated CTEPH patients. (Circ J 2006; 70: 1174 - 1179)

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Background Despite recent improvements in the treatments of coronary artery disease (CAD), there are a considerable number of patients who can not receive complete revascularization because of severe or total arterial occlusion. Intramyocardial injection of autologous bone marrow mononuclear cells (ABMMCs) has been shown to induce neovascularization of ischemic myocardium. Methods and Results The study will investigate the safety and feasibility of intramyocardial injections of ABMMCs and test the hypothesis that this treatment would promote neovascularization and improve left ventricular (LV) global and/or regional function in patients with severe CAD who have no other option. ABMMCs (~10⁶ cells) will be injected into the area of ischemic myocardium where the coronary artery is not graftable, in combination with bypass surgery to the other coronary branches. Myocardial perfusion and LV global and regional function will be evaluated, based on the micromanometer-tipped catheter method, single-photon emission tomography, and myocardial enhanced and color tissue Doppler echocardiography at baseline and during 12 month follow-up. Conclusions This project will demonstrate that intramyocardial injection of ABMMCs with or without coronary artery bypass surgery could be a safe and effective method for therapeutic neovascularization, resulting in an improvement of cardiac function in patients with severe CAD. (Circ J 2006; 70: 1180 - 1183)

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Background Several clinical trials are underway to determine whether autologous skeletal myoblast transplantation is an effective and safe therapeutic strategy for severe heart failure due to myocardial infarction (MI). It remains unclear whether repeated skeletal myoblast implantation is a feasible and effective cell delivery method for the infarcted myocardium. Methods and Results Four weeks after a coronary ligation, male syngeneic Lewis rats were assigned to 3 treatment groups: 3 episodes of skeletal myoblasts (6×10⁶) transplantation (group I), a bolus transplantation of myoblasts (18×10⁶) (group II), or culture medium injection (group III). Eight weeks after the first treatment, echocardiography, cardiac catheterization and histological examination were performed to compare the therapeutic effects on left ventricular (LV) systolic and diastolic functions, and the engrafted myoblast volume. Repeated myoblast implantation significantly improved LV function and resulted in significantly larger engrafted volume and LV contractility compared with a bolus transplantation with the same number of myoblasts. Conclusions Repeated skeletal myoblast transplantation is a safe and effective therapeutic strategy for the infarcted myocardium. (Circ J 2006; 70: 1184 - 1189)

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Background The effectiveness of sustained-release basic fibroblast growth factor (bFGF) in potentiating arteriogenesis and angiogenesis was evaluated, as well as determining whether chronic oral administration of sarpogrelate, a serotonin blocker, would further increase collateral blood flow in the rabbit hindlimb following surgical induction of ischemia by femoral artery extraction. Methods and Results Two weeks after femoral artery removal, the rabbits were assigned to 1 of 4 experimental groups and treated for 4 weeks: group A, no treatment; group B, supplemented with diet containing sarpogrelate; group C, single intramuscular injection of sustained-release form of bFGF microspheres; group D: combined treatment with sustained-release bFGF and sarpogrelate. Endpoint measurements performed at 6 weeks found that the ischemic hindlimb blood flow was significantly improved in the rabbits that received sustained-release bFGF, with a further significant improvement in those with the additional administration of sarpogrelate. Angiographic assessment revealed augmented density of collateral vessels in the medial thigh region in the rabbits given the combined treatment. Conclusions The findings demonstrate that sustained-release bFGF stimulated the development of collateral vessels, and additional administration of sarpogrelate produced a further improvement in hindlimb blood flow in the rabbit hindlimb ischemia model. (Circ J 2006; 70: 1190 - 1194)

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Background Therapeutic angiogenesis for ischemic diseases has been successfully induced by the implantation of autologous bone marrow cells (BMCs). It is understood that interleukin (IL)-1β increases remarkably in ischemic tissue and has particular effects on angiogenesis. Thus, it is important to clarify how IL-1β would effect BMCs survival and angiogenic potential. Methods and Results The effect of IL-1β on BMCs survival, adhesion, and endothelial differentiation, as well as the production of angiogenic growth factors, was investigated using an in vitro assessment approach. BMCs were harvested from Zucker obese rats and cultured at a density of 3×10⁶ cells/ml with 5 ng/ml IL-1 β (IL-1β group) or without IL-1 β (control group). Survival and adhesion of BMCs were significantly increased in the IL-1β group than in the control group after 1, 3, and 7 days of culture (p<0.01). The release of vascular endothelial growth factor in supernatant was also significantly higher in the IL-1β group than in the control group after 3 and 7 days of culture (p<0.01). Furthermore, the number of differentiated endothelial cells derived from BMCs was significantly higher in the IL-1β group than in the control group after 7 days of culture (p<0.01). These results suggest that IL-1β has a positive effect on the angiogenic potential of BMCs in vitro. (Circ J 2006; 70: 1195 - 1199)

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Background Because nifekalant hydrochloride (NIF) displayed a superior defibrillating effect on ventricular tachycardia/fibrillation (VT/VF) in cardiopulmonary arrest (CPA) patients, despite some QT prolongation, its effect on transmural dispersion of repolarization (TDR) in the left ventricle (LV) in an animal model of CPA was investigated. Methods and Results Eight beagle dogs were created with a myocardial infarction under anesthesia, and then VT/VF induction by continuous stimulation and cardiopulmonary resuscitation (CPR) were repeated. NIF (0.3 mg/kg) was administered under acidotic conditions (pH 7.26). The QTc interval measured by Y-lead ECG showed no significant prolongation before and after NIF. The activation recovery interval (ARI) measured by 64-lead LV surface mapping showed minimum ARI prolongation (40%) by NIF without maximum ARI prolongation, and as a result the ARI dispersion decreased by 67%. The repolarization time (RPT) with the plunge electrode showed 13-19% prolongation in the subendocardium and subepicardium with CPR, but NIF prolonged the RPT in the middle layer alone (17%), and as a result Plunge-TDR decreased by 82% (n=8, p<0.05). Conclusions Administration of NIF during CPR decreased the TDR by RPT prolongation selectively in the middle layer. Because the subendocardial and subepicardial RPTs after CPR were already prolonged before NIF administration, it may have been the reason why the QT-prolonging effect of NIF was not reflected in the body surface ECG. (Circ J 2006; 70: 1200 - 1207)

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Background Left ventricular remodeling might be involved in the pathophysiology of right ventricular hypertrophy/failure due to pulmonary arterial hypertension (PAH), while the left ventricle is considered not under pressure/volume overload. Methods and Results Rats with monocrotaline-induced PAH were used in the present study to examine whether upregulated neurohumoral factors may induce left ventricular (LV) remodeling and(/or) contribute to prognosis. Morphological analysis revealed a significant increase in the weight of the free walls of both ventricles and the interventricular septum, indicating biventricular hypertrophy, although systemic blood pressure was not elevated. RNase protection assay demonstrated the activation of a fetal gene program in the cardiac muscle of the left and right ventricular free walls. Similar activation of the fetal gene program was observed in the LV of rats continuously infused with angiotensin (AT) II, although this was not the case for rats infused with isoproterenol. Measured plasma levels of ATII, noradrenaline, and brain natriuretic peptide (BNP) were all significantly elevated in the PAH rats. Furthermore, the plasma BNP level positively correlated with the ratio of heart weight to body weight and the plasma level of ATII. Not right but LV hypertrophy was significantly reduced by treatment with an AT II type 1 receptor blocker, valsartan, whereas the effect of an adrenergic α₁ and β_1,2 blocker, carvedilol, was borderline. Survival rate in the PAH rats was significantly improved when they were treated with valsartan or carvedilol. Conclusions Upregulated neurohumoral factors seem to play an important role in LV remodeling without mechanical overload, and are associated with impairment of prognosis in rats with PAH. (Circ J 2006; 70: 1208 - 1215)

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Background Recent evidence suggests that oxidative stress may play a role in the development of atherosclerosis. MCI-186 (3-methyl-1-phenyl-1-parazolin-5-one, edaravone) is a novel free radical scavenger, but it remains unclear whether free radical scavengers would be effective for the prevention of the disease. Methods and Results Experimental atherosclerosis was induced in apolipoprotein E-deficient mice fed a high-fat diet containing 0.3% cholesterol. Mice were treated with an intraperitoneal injection of either MCI-186 1 mg/kg per day or MCI-186 10 mg/kg per day on alternate days over 4 weeks. Fatty streak lesion was suppressed by MCI-186 10 mg/kg per day administration, but not by mg/kg per day. Immunohistochemical analysis showed that macrophage and CD4⁺ T-cell accumulation and oxidative stress overload in the fatty streak lesion were suppressed in mice that received MCI-186 treatment. Conclusions MCI-186 administration suppressed the development of atherosclerosis, associated with reduced expression of both immune-activated cells and oxidative stress in fatty streak plaques. (Circ J 2006; 70: 1216 - 1219)

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A young woman presented with takotsubo cardiomyopathy after a syncopal attack caused by torsades de pointes. Two-dimensional echocardiography on admission showed left ventricular apical akinesis (ballooning) and basal hyperkinesis, compatible with takotsubo cardiomyopathy. This gradually normalized in 2 months. ECG on admission showed remarkable QT prolongation, U waves, and negative T waves, which also gradually normalized. Coronary angiography revealed no organic stenosis; however, acetylcholine provocation test caused the QT interval to again become prolonged. During treadmill exercise stress testing, the QT interval shortened as heart rate increased. Therefore, without genetic analysis, this patient was considered to have sporadic long QT syndrome in which takotsubo cardiomyopathy developed after the syncopal attack caused by torsades de pointes. (Circ J 2006; 70: 1220 - 1222)

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We describe a case of dilated cardiomyopathy (DCM) caused by a coronary-pulmonary fistula and myocardial ischemia induced by the coronary steal phenomenon, which was successfully treated with coil embolization. Coronary fistulae and coronary-steal-induced ischemia are rare causes of DCM in adults with normal coronary arteries. Percutaneous treatment represents an alternative to surgery and may be offered as a relatively low-risk procedure. The choice between surgical and percutaneous treatment must take into account clinical and anatomical considerations. (Circ J 2006; 70: 1223 - 1225)

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Background Heart manipulation and displacement are common maneuvers during beating heart surgery to expose coronary arteries for revascularization. Effects of heart displacement on free radical generation, reactive oxygen species (ROS) have not been previously described. Methods and Results Seven adult male dogs were anesthetized, a left lateral thoracotomy performed to expose the heart, and the coronary sinus cannulated for ROS sampling during different manipulation protocols: (1) heart in normal position; (2) 90 degree manual heart displacement; (3) Trendelenburg position while the heart displaced 90 degrees and (4) return heart to normal resting anatomical position and plus the operating table returned to horizontal. Heart displacement followed by anatomical re-positioning significantly increased the ROS signal as measured by EPR (50-fold compared with control values; p<0.01). Conclusion Trendelenburg positioning and/or repositioning the heart during cardiac surgery may induce acute reperfusion injury and increase ROS. (Circ J 2006; 70: 1226 - 1228)

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