Background The benefits of percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) are limited by reperfusion injury. In animal models, atrial natriuretic peptide (ANP) reduces infarct size, so the Japan-Working groups of acute myocardial Infarction for the reduction of Necrotic Damage by ANP (J-WIND-ANP) designed a prospective, randomized, multicenter study, to evaluate whether ANP as an adjunctive therapy for AMI reduces myocardial infarct size and improves regional wall motion. Methods and Results Twenty hospitals in Japan will participate in the J-WIND-ANP study. Patients with AMI who are candidates for PCI are randomly allocated to receive either intravenous ANP or placebo administration. The primary end-points are (1) estimated infarct size (Σcreatine kinase and troponin T) and (2) left ventricular function (left ventriculograms). Single nucleotide polymorphisms (SNPs) that may be associated with the function of ANP and susceptibility of AMI will be examined. Furthermore, a data mining method will be used to design the optimal combinational therapy for post-MI patients. Conclusions J-WIND-ANP will provide important data on the effects of ANP as an adjunct to PCI for AMI and the SNPs information will open the field of tailor-made therapy. The optimal therapeutic drug combination will also be determined for post-MI patients. (Circ J 2004; 68: 95 - 100)

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Background The benefits of percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) are limited by reperfusion injury. In animal models, nicorandil, a hybrid of an ATP-sensitive K⁺ (KATP) channel opener and nitrates, reduces infarct size, so the Japan-Working groups of acute myocardial Infarction for the reduction of Necrotic Damage by a K-ATP channel opener (J-WIND-KATP) designed a prospective, randomized, multicenter study to evaluate whether nicorandil reduces myocardial infarct size and improves regional wall motion when used as an adjunctive therapy for AMI. Methods and Results Twenty-six hospitals in Japan are participating in the J-WIND-KATP study. Patients with AMI who are candidates for PCI are randomly allocated to receive either intravenous nicorandil or placebo. The primary end-points are (1) estimated infarct size and (2) left ventricular function. Single nucleotide polymorphisms (SNPs) that may be associated with the function of KATP-channel and the susceptibility of AMI to the drug will be examined. Furthermore, a data mining method will be used to design the optimal combined therapy for post-myocardial infarction (MI) patients. Conclusions It is intended that J-WIND-KATP will provide important data on the effects of nicorandil as an adjunct to PCI for AMI and that the SNPs information that will open the field of tailor-made therapy. The optimal therapeutic drug combination will also be determined for post-MI patients. (Circ J 2004; 68: 101 - 106)

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Background Data from Western comparative trials suggest that rosuvastatin is more effective than atorvastatin, simvastatin, and pravastatin in helping hypercholesterolemic patients achieve US and European lipid-lowering guidelines. The purpose of this analysis was to assess the comparative efficacy of rosuvastatin in reducing low-density lipoprotein cholesterol (LDL-C) to levels recommended by the Japan Atherosclerosis Society (JAS). Methods and Results A post hoc analysis of data from 6 randomized, double-blind, active-controlled trials was conducted to evaluate the relative efficacy of rosuvastatin and comparator statins in helping patients achieve the LDL-C goals established by the JAS. The first 5 trials, prospectively designed for pooling, were originally conducted to compare the effects of rosuvastatin with either atorvastatin, simvastatin, or pravastatin in reducing lipid levels and helping patients achieve the LDL-C goals established by the National Cholesterol Education Program. The 6th trial was conducted with similar objectives, but in patients with heterozygous familial hypercholesterolemia (HeFH). Data from 2,139 hypercholesterolemic patients in the first 5 trials were pooled for analysis: rosuvastatin 5 mg (n=390) or 10 mg (n=389) vs atorvastatin 10 mg (n=393); rosuvastatin 5 mg (n=240) or 10 mg (n=226) vs simvastatin 20 mg (n=249) or pravastatin 20 mg (n=252). In the studies with atorvastatin as the comparator, JAS-defined LDL-C goals were reached by 67.2% of the rosuvastatin 5-mg group, 82.3% of the rosuvastatin 10-mg group, and 58.0% of the atorvastatin 10-mg group (p<0.001 for both rosuvastatin groups vs atorvastatin) at 12 weeks. Similarly, in the trials with pravastatin and simvastatin as comparators, the JAS LDL-C goals were reached by 77.5% of the rosuvastatin 5-mg group, 86.7% of the rosuvastatin 10-mg group, 45.2% of the pravastatin 20-mg group and 65.5% of the simvastatin 20-mg group (p<0.001 for both rosuvastatin groups vs pravastatin and simvastatin). In the trial of HeFH patients (n=433 for rosuvastatin, n=187 for atorvastatin), 31.9% of patients treated with rosuvastatin 20 mg achieved JAS LDL-C goals, compared with 17.6% of patients treated with atorvastatin 20 mg (p<0.001). Conclusions Rosuvastatin has demonstrated clinical superiority over atorvastatin, pravastatin, and simvastatin in reducing LDL-C levels and in enabling patients to reach goals established by the JAS. (Circ J 2004; 68: 107 - 113)

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Background The dynamics of MCP-1 and neopterin and the relation between their concentrations in coronary circulation and the severity of coronary atherosclerosis were evaluated in patients with stable coronary artery disease (CAD). Methods and Results Blood samples were obtained from the aortic root (Ao) and coronary sinus (CS) of 78 patients who underwent coronary angiography. Plasma MCP-1 and neopterin concentrations were measured using an enzyme-linked immunosorbent assay method and the CS-Ao differences were calculated. The severity of coronary heart disease (CHD) was evaluated in 52 patients who had no history of coronary angioplasty, using 3 coronary scoring systems: the clinical 1- to 3-vessel disease score, the American Heart Association extension score (1-15 segments), and the Gensini score. The plasma MCP-1 and neopterin concentrations increased significantly with age. The CS-Ao differences for neopterin showed weak, but significant, positive correlation with the Gensini score (r=0.347, p=0.013). There were no correlations among the MCP-1 concentrations in the Ao or CS, or in the CS-Ao difference, with the severity of CHD. Conclusions The results indicate that neopterin is a useful marker of the severity of coronary atherosclerosis in patients with stable CAD, acting as an index of the activity of monocytes/macrophages. (Circ J 2004; 68: 114 - 120)

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Background There is evidence that statins induce the regression of cardiac hypertrophy in a transgenic rabbit model of hypertrophic cardiomyopathy. Methods and Results The association between treatment with statins and the regression of cardiac mass (left ventricular mass index, LVMI) was investigated in a case - control study using transthoracic echocardiography in 304 patients with angina who underwent coronary angiography. Those who received pravastatin or simvastatin were defined as cases (n=66), and age, sex and body mass index-matched controls (n=127) were selected. The cases showed a significant decrease in LVMI compared with the controls. Although the cases included a significantly higher percentage of patients with hypertension and calcium antagonist (CaA) treatment than the controls, there were no relationships between LVMI and either hypertension or CaA treatment. Because the cases had a significantly higher number of stenosed vessels than the controls, LVMI for each number of stenosed vessels was analyzed, and a significant interaction effect between the association of LVMI with statin and the number of stenosed vessels was found. Conclusions Treatment with statins was associated with a lower cardiac mass in patients with angina, suggesting that this is one of the drugs' pleiotropic effects. (Circ J 2004; 68: 121 - 125)

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Background Arrhythmia is a major late complication in adults with repaired tetralogy of Fallot, although a large-scale study has not been carried out in Japan. Methods and Results A nationwide multicenter study with 512 operative survivors was performed. Actuarial survival rate at 30 years (maximum follow-up) was 98.4%. Fifty-four patients (10.5%) had clinically important arrhythmias, including 23 patients with bradycardia caused by sick sinus syndrome or atrioventricular block (AVB). A patient with complete AVB (CAVB) without pacemaker implantation (PMI) died later. Two patients had sustained ventricular tachycardia (VT) and syncope was reported in 18 patients with ventricular arrhythmias (VA). Atrial tachyarrhythmias were observed in 13 patients. Older age at operation was a risk factor for atrial fibrillation/flutter, longer postoperative survival duration for VA, and QRS duration >120 ms for VT. Perimembranous ventricular septal defect was related to CAVB. Right ventricular outflow patch was not a risk factor. Importantly, 60% of the subjects had QRS duration <120 ms. Conclusion The prevalence of serious arrhythmias is low in Japanese TOF patients as compared with the results from Western countries. CAVB without PMI and VT are the major risk factors for late morbidity and mortality. The excellent result could be related to the narrow QRS after surgery. (Circ J 2004; 68: 126 - 130)

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Background Biatrial pacing has a significant problem with memory function that misinterprets normal sinus rhythm as atrial tachyarrhythmias and in addition estimation of the atrial pacing thresholds (biatrial and uniatrial pacing thresholds) is sometimes difficult because of small P waves. Methods and Results The intracardiac electrograms recorded by a pacemaker in 10 patients (age, 66.7±10.7 (SD) years) with implanted biatrial pacemakers were analyzed. Atrial sensing within the atrial refractory period after atrial pacing was counted in 6 of the 10 patients (timing of the double counting was 143±64 ms) when pacing failed in the left or right atrium. Atrial sensing within the atrial refractory period after atrial pacing disappeared when biatrial pacing was successfully performed. Atrial double-counts depend on interatrial conduction delay. The memory function of implanted pacemaker devices misinterpreted normal sinus rhythm as atrial tachyarrhythmias because of atrial double-counts. On the other hand, the biatrial pacing threshold was easily recognized using this phenomenon. Conclusions The memory function of pacemaker devices is unreliable because of atrial double-counting during sinus rhythm in patients with biatrial pacing. However, the biatrial pacing threshold is easily checked using this phenomenon. (Circ J 2004; 68: 131 - 134)

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Background It has been reported that recording electrocardiograms (ECGs) in the 3rd intercostal space (ICS) is one method that can be used for detecting Brugada syndrome; however, the prevalence of Brugada-type ECGs recorded in the 3rd ICS and the usefulness of recording the ECG in the 3rd ICS in accordance with recently established electrocardiographic criteria is unknown. Methods and Results ECGs were recorded in both the 4th and 3rd ICS in 17 Brugada-type ECG patients (group A) and in 206 consecutive male subjects (group B). Brugada-type ECGs were divided into 3 types. In group A, the prevalence of type 1 ECG, which is a coved-type ECG with ST-segment elevation of ≥2 mm, increased from 23.5% to 64.7% when ECG was recorded in the 3rd ICS. The conversion to type 1 ECG was found to be related to induction of ventricular arrhythmia. In group B, the prevalence of Brugada-type ECG increased from 1.5% to 5.8% when the ECG was recorded in the 3rd ICS. Conclusions Recording the ECG in the 3rd ICS is useful for identifying high-risk patients with Brugada-type ECG and for detecting concealed Brugada-type ECG. (Circ J 2004; 68: 135 - 138)

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Background The factors that may determine the evolution of right coronary cusp prolapse (RCCP) and regurgitation (AR) associated with a ventricular septal defect in the outlet septum (outlet VSD) have not been clarified. Methods and Results The Doppler echocardiograms of 316 patients were grouped according to both the development of RCCP, and the values of the right coronary cusp deformity index (RCCD) and the right coronary cusp imbalance index (R/L). All detected AR was ≤ slight, and not progressive in patients with both RCCD <0.30 and R/L <1.30. Moderate AR was detected in patients with either RCCD ≥0.30 or R/L ≥0.30. Rupture of the sinus of Valsalva was identified in patients with RCCD ≥0.30. A significantly large number of patients with both RCCD ≥0.30 and R/L ≥1.30 (p<0.01), and a few patients with either RCCD ≥0.30 or R/L ≥0.30 underwent aortic valvuloplasty or replacement. Operative outcome for AR ≤ slight was good. Conclusions There is no need to close an outlet VSD with RCCP when the RCCD <0.30 and R/L <1.30 as long as the AR remains trivial, but such defects should be closed when the RCCD is ≥0.30 or R/L ≥1.30. (Circ J 2004; 68: 139 - 143)

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Background The whole blood rapid troponin T test, used to determine the early diagnosis of acute myocardial infarction (AMI), is effective only for 3-4 h after onset. Methods and Results The present office cardiologists cooperative study compared the diagnostic efficacy of a newly developed whole blood rapid panel test for heart-type fatty acid-binding protein (H-FABP) with that of the rapid troponin T test in 129 consecutive patients with suspicious AMI according to certain time-frames from onset to presentation. Thirty-one patients (24.0%) had a final diagnosis of AMI. The respective sensitivities of the rapid H-FABP and troponin T tests were 100% vs 50% (p<0.05) for patients presenting within 3 h of onset; 75% vs 0% for those between 3 and 6 h; 100% vs 60% for those between 6 and 12 h; and 100% vs 100% for those presenting later than 12 h. The respective specificities were 63% vs 96.3% (p<0.05); 93.8% vs 93.8%; 72.7% vs 100%; and 75.0% vs 87.5%. Negative predictive value was 100% vs 86.7%; 93.8% vs 78.9%; 100% vs 84.6%; and 100% vs 100%, respectively. Patients with non-AMI myocardial damage associated with unstable angina or severe heart failure showed positive H-FABP test results and blunted the specificity. Conclusions When using the novel rapid H-FABP test, cardiac emergency triage to exclude non-AMI patients should be effectively organized within 3 h of onset. (Circ J 2004; 68: 144 - 148)

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Background Injecting various protein antigens conjugated to monomethoxypolyethylene glycol (mPEG) results in antigen-specific tolerance to subsequent immunization. In the present study the ability of mPEG-modified cardiac myosin (CM) to block the development of experimental autoimmune myocarditis (EAM) induced by CM immunization or by the transfer of lymphocytes from CM-immunized donors was studied. Methods and Results A/J mice were injected with mPEG-CM before active or passive EAM induction. We examined the suppressive mechanism by the transfer of lymphocytes from mPEG-CM-treated mice into naïve mice. To ascertain the cells responsible for suppressing EAM induction, in vivo or in vitro depletion of CD4⁺ or CD8⁺ T cells was performed. mPEG-CM administered before active or passive EAM induction markedly suppressed the incidence and severity of EAM and reduced CM-specific antibody responses. When lymphocytes from mPEG-CM treated mice were transferred into naïve mice that were then immunized with CM, the suppressive effect was recapitulated. Conclusions mPEG-CM treatment blocked the active and passive induction of EAM. (Circ J 2004; 68: 149 - 155)

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Background Recent studies have implicated the opening of mitochondrial K_ATP (mitoK_ATP) channels and the production of reactive oxygen species (ROS) in the cardioprotective mechanism of ischemic preconditioning (IPC). Methods and Results The involvement of mitoK_ATP channels and ROS in the cardioprotective effects of both IPC and the mitoK_ATP channel opener diazoxide (DZ) was investigated in ischemic/reperfused rat hearts. The effects of IPC and DZ on myocardial high-energy phosphate concentrations and intracellular pH (pH_i) were also examined using ³¹P nuclear magnetic resonance spectroscopy. Although both the mitoK_ATP channel inhibitor 5-hydroxydecanoate and the antioxidant N-acetylcysteine abolished the postischemic recovery of contractile function by DZ, neither of them inhibited that by IPC. IPC attenuated the decline in pHi during ischemia, but DZ did not (6.28±0.04 in IPC, p<0.05, and 6.02±0.05 in DZ vs 6.02 ±0.06 in control hearts). DZ, but not IPC, reduced the decrease in ATP levels during ischemia (ATP levels at 20-min ischemia: 26.3±3.4% of initial value in DZ, p<0.05, and 8.1±3.0% in IPC vs 15.1±1.3% in control hearts). Conclusions These results suggest that DZ-induced cardioprotection is related to ROS production and reduced ATP degradation during ischemia, whereas attenuated acidification during ischemia is involved in IPC-induced cardioprotection, which is not mediated through mitoK_ATP channel opening or ROS production. (Circ J 2004; 68: 156 - 162)

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Background Clinical methods for the early detection of doxorubicine (adriamycin; ADR) -induced cardiotoxicity have not been established. This study prospectively investigated whether atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and cardiac troponin T (TnT) are predictors for ADR-induced cardiotoxicity, and examined the correlations between the serum concentrations of these biomarkers and the functional alternations associated with ADR-induced myocardial damage. Methods and Results Male Wistar rats were injected weekly with 2 mg/kg of ADR via the tail vein for 8 weeks to induce cardiotoxicity. Echocardiograms of each ether anesthetized rat were taken at 6, 8, 10 and 12 weeks after the first administration of ADR, and blood samples collected from the tail vein were used to quantify plasma ANP and BNP, and serum TnT after echocardiography. Plasma BNP and serum TnT significantly increased from 6 to 12 weeks (81.5 to 173.3 pg/ml (p<0.001), <0.01 to 1.09 ng/ml (p<0.05), respectively) with deterioration of left ventricular % fractional shortening (%FS) (58.6% to 36.8%). The %FS significantly correlated with TnT (r=-0.51, p<0.001) and BNP (r=-0.75, p<0.0001); however, the increase of TnT was antecedent to the increase of BNP and the deterioration of %FS. Conclusion Plasma BNP and serum TnT concentrations, especially TnT, measured by this highly sensitive method are useful predictors for ADR-induced cardiomyopathy. (Circ J 2004; 68: 163 - 167)

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Atrial tachycardias after open heart surgery sometimes have complex reentrant circuits. A patient with a dual-loop atrial reentrant circuit occurring after mitral valve replacement was evaluated by entrainment mapping with a basket catheter. The position of the catheter was adjusted to obtain atrial electrograms of the anterior and posterior septal areas, the crista terminalis, the free wall, and the tricuspid annular region. Entrainment mapping identified a dual-loop reentry consisting of one circuit around the tricuspid annulus and another around the septal atriotomy scar. The reentrant circuit around the septal incision was eliminated by ablating the area between the septal incision and the inferior vena cava, and the circuit around the tricuspid annulus was terminated with an additional linear ablation between the tricuspid annulus and the inferior vena cava. Entrainment mapping using a multielectrode basket catheter is very useful for identifying complex atrial reentrant circuits. (Circ J 2004; 68: 168 - 171)

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Primary cardiac malignant lymphoma is extremely rare and almost all patients die within weeks. Monoclonal CD20 antibody (rituximab) was administered to a patient with primary cardiac B-cell non-Hodgkin's lymphoma expressing a CD20 molecule. The results suggest that rituximab may be a safe and effective new therapy for primary cardiac B-cell lymphoma. (Circ J 2004; 68: 172 - 173)

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A 60-year-old Japanese man with obstructive hypertrophic cardiomyopathy was found to have a mutation in the cardiac myosin binding protein C gene: a single base deletion of a thymidine residue at nucleotide 11645 (codon 593) in exon 18. He was diagnosed at the age of 43 and has been followed for 17 years. During this follow-up period, echocardiograms and mechanocardiograms revealed progressive hypertrophy until the age of 54, then gradual dilation of the left ventricle associated with a decrease in the obstruction. Paroxysmal atrial fibrillation occurred at the age of 52 and progressed to chronic atrial fibrillation at the age of 53. He had congestive heart failure at the age of 58. (Circ J 2004; 68: 174 - 177)

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A 55-year-old man had undiagnosed tetralogy of Fallot with the complications of decompensated heart failure and infective endocarditis, as well as pulmonic involvement secondary to the endocarditis. The patient had a massive hemoptysis and died. This case is a rare insight into the late outcome of this congenital heart disease.(Circ J 2004; 68: 178 - 180)

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