Abnormal intracellular Ca²⁺ handling by the sarcoplasmic reticulum (SR) is a critical factor in the development of heart failure (HF). Not only decreased Ca²⁺ uptake, but also uncoordinated Ca²⁺ release plays a significant role in contractile and relaxation dysfunction. Spontaneous Ca²⁺ release through ryanodine receptor (RyR) 2, a huge tetrameric protein, during diastole leads to a decrease in the SR Ca²⁺ content, and also triggers delayed afterdepolarization that is a substrate for lethal arrhythmia. Several disease-linked mutations of RyR have been reported in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) or arrhythmogenic right ventricular cardiomyopathy type 2 (ARVC2). The unique distribution of these mutation sites has lead to the concept that an interaction among the putative regulatory domains within RyR may play a key role in regulating channel opening, and that there seems to be a common abnormality in the channel disorder of HF and CPVT/ARVC2. Recent knowledge gained from pathological conditions may lead to the development of a new therapeutic strategy for the treatment of HF or cardiac arrhythmia. (Circ J 2008; 72: 509 - 514)

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Background The benefits of coronary risk modification through medication and other methods have been shown in many clinical studies. Recently, aggressive lowering of low-density lipoprotein-cholesterol (LDL-C) has been shown to confer additive benefits in patients with coronary artery disease (CAD). However, it has not been shown in Japanese patients with CAD if multiple aggressive medical interventions for coronary risk factors are beneficial compared with standard regimens, so a prospective, randomized, open-label, blinded-endpoint (PROBE) multicenter study was designed to evaluate whether aggressive lowering of LDL-C and blood pressure in Japanese hypertensive, hypercholesterolemic CAD patients bestows additional benefits compared with regimens based on current Japanese guidelines. Methods and Results Seventeen hospitals in Japan are participating in the Japanese Coronary Artery Disease II (JCADII) study. Hypertensive and hypercholesterolemic patients who have ≥75% stenosis in at least one major coronary artery according to American Heart Association guidelines will be allocated randomly to receive either conventional or aggressive therapy. Standard therapy for hypertension and hypercholesterolemia aims to reduce blood pressure to <140/90 mmHg and LDL-C concentration to <100 mg/dl. Aggressive therapy aims for targets of <120/80 mmHg and <80 mg/dl, respectively. We plan to recruit 500 patients and follow them up for 3 years. Antihypertensive agents, when used, include the angiotensin receptor blockers candesartan and/or losartan. Antihypercholesterolemic agents, when used, include at least one of the following statins: pravastatin, simvastatin, and atorvastatin. Conclusion The JCADII study will provide important information concerning medical treatment of coronary risk factors in Japanese patients with CAD (UMIN-ID: UMIN000000571). (Circ J 2008; 72: 515 - 520)

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Background The impact of body mass index (BMI) on outcomes after primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) remains unclear. Methods and Results A total of 3,076 patients undergoing PCI for AMI within 48 h after symptom onset were studied. Patients were divided into 4 groups according to baseline BMI: lean (<20 kg/m²), normal weight (20.0-24.9 kg/m²), overweight (25.0-29.9 kg/m²) and obese (≥30.0 kg/m²). Obese patients were younger and had a higher frequency of diabetes mellitus, hyperlipidemia, hypertension and smoking. Lean patients were older, usually women and had a lower frequency of the aforementioned risk factors. Killip class on admission, renal insufficiency, and final Thrombolysis In Myocardial Infarction (TIMI) flow grade did not differ among the 4 groups. In lean, normal weight, overweight and obese patients, in-hospital mortality was 9.2%, 4.4%, 2.5% and 1.8%, respectively (p<0.01). Multivariate analysis showed that compared with normal weight patients, odds ratios for in-hospital death in lean, overweight and obese patients were 1.92, 0.79 and 0.40, respectively (p=NS). Independent predictors were age, Killip class on admission, renal insufficiency and final TIMI flow grade. Conclusion BMI itself had no impact on in-hospital mortality in patients undergoing primary PCI for AMI. The phenomenon `obesity paradox' may be explained by the fact that obese patients were younger at presentation. (Circ J 2008; 72: 521 - 525)

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Background Recent reports on facilitated reperfusion therapy re-address interests in coronary sinus interventions (CSI). Patients in whom short time results have been reported earlier were re-evaluated, with the aim of gathering the long-term results of pressure-controlled intermittent coronary sinus occlusion (PICSO) generated in patients with acute myocardial infarction (MI) and revascularization. Methods and Results Thirty-four patients with ST elevated MI, in whom complete revascularization was achieved, underwent primary thrombolysis with or without PICSO. Follow-up data from these patients were collected for at least 48 months. Immediate perioperative differences were observed for time to peak creatine kinase (CK), as well as cumulative CK. In addition, the time until reperfusion was considerably less than for the control group (p=0.014). Long-term data showed significant differences in reinfarction (p=0.015), as well as in major adverse cardiovascular events, between the 2 groups (p<0.0001). Conclusion These data, because of the wide interval between collection and current analysis, could have inherited historical bias. Nonetheless, they are also uniquely indicating the potential of CSI to induce not only immediate, but also clinically significant long-term, effects as an adjunct to reperfusion therapy. Therefore, CSI should be, once again, on the study agenda and be placed under contemporary and best-available scientific scrutiny. (Circ J 2008; 72: 526 - 533)

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Background Flow dynamics and shear stress may influence downstream vessel segments. The aim of this study was to investigate the potential impact of lumen narrowing within sirolimus-eluting stents (SES) on vessel response at adjacent reference sites. Methods and Results In 135 patients after SES implantation, minimal lumen area (MLA) within the stent and average lumen area at distal or proximal adjacent reference segments (5 mm) were obtained at baseline and follow up. In the smaller in-stent MLA group (MLA <3 mm²), lumen area decreased significantly at the distal reference compared with the larger in-stent MLA group (MLA ≥3 mm²), although no significant difference was seen at the proximal reference. Conclusion In-stent lumen patency may influence vascular responses at adjacent reference segments after SES implantation. (Circ J 2008; 72: 534 - 537)

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Background Hypercholesterolemia is a well-established risk factor for the development of vascular events. Statins have pleiotropic effects beyond reducing the low-density lipoprotein-cholesterol (LDL-C) concentration. This study sought to determine whether treatment with pitavastatin affects latent regional left ventricular (LV) systolic and diastolic dysfunction and carotid arterial stiffness in patients with hypercholesterolemia and preserved LV ejection fraction (LVEF), using newly developed ultrasonic strain imaging and carotid ultrasonography. Methods and Results A total of 30 patients with hypercholesterolemia (≥220 mg/dl for serum total cholesterol, and/or ≥140 mg/dl for LDL-C) were randomized to either administration of pitavastatin (1 or 2 mg/day; n=15) or no statin therapy (n=15) for 12 months. LV systolic and diastolic functions were evaluated by measuring transmitral flow velocity, mitral annular motion velocity, and the myocardial strain and strain rate profiles using pulsed Doppler, tissue velocity, and ultrasonic strain imaging. Subclinical atherosclerosis also was determined by measuring the intima - media thickness (IMT) and stiffness β of the left and right common carotid arteries using B- and M-mode ultrasonography. During the follow-up period, the mean peak systolic strains of the LV posterior and inferior walls increased from 39.2±15.9% to 51.5±17.7% (p<0.01) and 46.0±12.2% to 57.5±10.3% (p<0.01), respectively, in the pitavastatin group compared with the no statin group. The mean peak early diastolic strain rates of the LV posterior and inferior walls also increased from -6.5±2.9 s^-1 to -9.5±2.8 s^-1 (p<0.01) and -6.5±2.5 s^-1 to -9.1±2.7 s^-1 (p<0.01), respectively, in the pitavastatin group. The stiffness β decreased from 5.6±2.5 to 4.1±0.8 (p<0.05) in the pitavastatin group, whereas there was no significant change in IMT. Conclusions One year of pitavastatin treatment improved not only carotid arterial stiffness but also regional LV systolic and diastolic function in patients with hypercholesterolemia and preserved LVEF. Ultrasonic strain imaging has the potential to become a sensitive tool for detecting the effects of early medical intervention on latent regional LV myocardial dysfunction in this patient population. (Circ J 2008; 72: 538 - 544)

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Background Some studies focusing on low-risk profiles for cardiovascular disease have been reported in Western countries. Yet, few reports have examined, with substantial longevity, the low-risk profile for cardiovascular disease in the Japanese population. This study examines whether having a favorable risk factor profile yields lower all-cause mortality and whether the proportion of those with a low-risk profile is larger in the Japanese population. Methods and Results A total of 8,339 men and women aged 30-69 years without a history of cardiovascular diseases for 19 years, who had participated in the 1980 National Survey on Circulatory Disorders after being randomly selected from throughout Japan, were followed. Low risk was defined as having all of the following baseline characteristics: blood pressure (BP) <120/80 mmHg; no antihypertensive medication; serum cholesterol 160-240 mg/dl (4.14-6.22 mmol/L); no history of diabetes; and non-smoker. The long-term mortality of the low-risk group was compared with that of others using the Cox proportional hazard model. The prevalence of low risk was 9.4% of all participants. The multivariate-adjusted hazard ratios for low-risk individuals compared with others were as follows: 0.33 (95% confidence intervals (CI), 0.15-0.74) for cardiovascular disease and 0.63 (95% CI, 0.46-0.88) for all-cause mortality. The most attributable risk factor for all-cause mortality was high BP (≥120/80 mmHg). Conclusion Japanese individuals with favorable cardiovascular disease risk profiles had lower mortality from cardiovascular disease and all-causes than those without. (Circ J 2008; 72: 545 - 550)

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Background Peroxisome proliferator-activated receptor γ (PPARγ) is involved mainly in adipocyte differentiation and has been suggested to play an important role in the pathogenesis of insulin resistance (IR) and atherosclerosis. The frequencies of 2 common polymorphisms of the PPARγ gene, Pro12Ala single nucleotide polymorphism (SNP) in exon B and C161T SNP in exon 6, were investigated in 792 subjects and the correlations between the different genotypes, IR and metabolic syndrome (MS) were analyzed. Methods and Results Anthropometric measurements, fasting glucose, insulin and lipid profiles were measured in 792 people of the Han population in Beijing, China. Homeostatic model assessments and quantitative insulin sensitivity check indices were calculated. MS was diagnosed according to the IDF guidelines (2005) for a Chinese population. Polymerase chain reaction - restriction fragment length polymorphism were performed for DNA genotyping. For the C161T polymorphism, allele frequencies were 0.804 for the C allele and 0.196 for the T allele. For Pro12Ala, allele frequencies were 0.947 for proline and 0.053 for alanine. There was no Ala12Ala homozygote in the population. No differences were seen in the mean values of age, body mass index (BMI), blood pressure or fasting blood glucose level among different genotypes when analyzed as a whole. Subjects with an A or T allele had lower fasting insulin levels, HOMA-IR levels, and a lower level QUICKI trend. Further analysis by age was conducted, and A or T allele carriers in the <60 year group showed a trend of lower triglyceride and a higher high-density lipoprotein-cholesterol level, but this was not statistically significant. When subjects were divided into 4 groups according to the combination of genetic alleles of the 2 polymorphisms, the subjects with Pro12Ala and a T allele simultaneously showed a significantly higher BMI than those without the Ala allele. The presence of a T allele in the C161T polymorphism and Pro12Ala polymorphism seems to affect body weight, which is similar to the results found in previous studies. Conclusions Both polymorphisms showed a significant association with IR, but failed to show an association with MS components. Those with an A allele of Pro12Ala and a T allele of the C161T polymorphism showed a higher BMI, which requires further investigation. (Circ J 2008; 72: 551 - 557)

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Background Mutation T/C inside codon 131 of the gene encoding the α subunit of Gs protein (GNAS1) causes the increased activation of adenyl cyclase, which plays an important role in cardiovascular regulation. The aim of the present study was to evaluate GNAS1 T/C,Ile 131 mutation's manifestation in syncopal patients regarding head-up tilt test (HUTT) results. Methods and Results In 137 syncopal patients (without any other diseases) the silent T/C,Ile 131 mutation within the GNAS1 codon on chromosome 20 q was identified. This mutation consists of the presence (+) or absence (-) of a target site for endonuclease FokI (Promega). Ninety-six patients (70%) with positive HUTT had a higher FokI+ allele frequency compared with those with negative tilting results (49% vs 27%, X²=12.05; p<0.001). In positive tilted patients, the studied mutation had significant influence on blood pressure (p<0.05). When comparing positive HUTT with vasodepressore component, cardioinhibition results and negative HUTT, the frequencies of the FokI+ allele were decreased among these groups: 53%, 36% and 27%, respectively. Conclusions An association between positive tilting and mutation C/T,Ile 131 within the GNAS1 codon was found. The predisposition to vasovagal syncope seems to be associated with the GNAS1 FokI+ allele. (Circ J 2008; 72: 558 - 562)

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Background Adiponectin, which is an adipocyte-specific cytokine that has a beneficial effect in cardiovascular disease, may be downregulated by oxidative stress in patients with chronic heart failure (CHF). Plasma levels of both adiponectin and biomarkers of oxidative stress are increased and have a prognostic impact on CHF patients. Methods and Results The plasma adiponectin level was measured in 116 patients with CHF (left ventricular ejection fraction <45%) who underwent cardiac catheterization, and these findings were compared with the atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) levels, hemodynamic parameters and plasma oxidized low-density lipoprotein (oxLDL) level as a marker of oxidative stress. There was no correlation between the plasma adiponectin level and hemodynamic parameters, but there was a positive correlation with the cardiac natriuretic peptides [ANP (r_s=0.464, p<0.0001) or BNP (r_s=0.489, p<0.0001)]. There was a significant negative correlation between plasma adiponectin level and oxLDL (r=-0.245, p=0.0079). In the stepwise multivariate analysis, a high level of natriuretic peptide (log BNP) (p=0.0098), and a low level of oxLDL (p=0.0105) were independent predictors of a high adiponectin level in CHF patients. Conclusions The plasma adiponectin level is regulated not only by cardiac natriuretic peptides but also by oxidative stress in patients with CHF. (Circ J 2008; 72: 563 - 568)

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Background Recent studies have shown the presence of ongoing myocardial damage in patients with chronic heart failure (CHF) detected by myofibril and membrane damage markers, cardiac troponin T (TnT) and heart-type fatty acid-binding protein (H-FABP), which identifies patients at increased risk of a future cardiac event (CE: death or rehospitalization because of worsening CHF). There is a difference between TnT and H-FABP in their release kinetics following myocardial damage. Methods and Results TnT and H-FABP were measured in 103 patients with CHF and in 31 controls. Patients were classified into 4 groups based on detectable (≥0.01 ng/ml) or undetectable TnT (TnT+ or TnT-) and H-FABP ≥ or <4.5 ng/ml (mean + 2 standard deviations in controls) (high-H-FABP or low-H-FABP). Kaplan-Meier analysis showed that the CE-free rate (n=43) was significantly lower in patients with TnT+ and high-H-FABP than in patients in the other 3 groups (patients with TnT+ and low-H-FABP, TnT- and high-H-FABP, and TnT- and low-H-FABP; p=0.02, p=0.001 and p=0.0002, respectively). In stepwise multivariate Cox proportional hazard analysis, TnT+ (p=0.01) and high-H-FABP (p=0.04) were independent predictors of future CE. Conclusions Elevated levels of both TnT and H-FABP predict adverse outcomes in CHF patients. (Circ J 2008; 72: 569 - 574)

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Background It is well-known that both B-type natriuretic peptide (BNP) and peak oxygen uptake (VO₂) are independent predictors of mortality in patients with heart failure. This study investigates the predictive power of BNP and peak VO₂ for survival in cardiac patients. Methods and Results A total of 609 patients with cardiac disease participated in the study. They underwent cardiopulmonary exercise testing to determine peak VO₂, with BNP being measured before exercise testing During 502.5 median follow-up days, 29 patients died of cardiovascular disease. In the univariate Cox proportional hazards analysis, peak VO₂ and BNP were both found to be significant prognostic indices for survival. The time-dependent ROC curve analysis (Heagerty 2006) was applied to 3 predictors: peak VO₂, BNP, and then both, with gender and age as adjusted variables. The area under the curve (AUC) compared with the follow-up period curves of peak VO₂ and the 2 combined variables (ie, BNP and peak VO₂) were consistently over that of BNP. The integrated AUC indices were 0.80 (peak VO₂), 0.81 (peak VO₂ and BNP) and 0.70 (BNP), respectively. Conclusions These results indicate that peak VO₂ is more potent than BNP for predicting the mortality in patients with mixed cardiac disease. (Circ J 2008; 72: 575 - 581)

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Background The current study aimed to investigate the effect of ablation therapy on the quality of life (QOL) in patients with atrial fibrillation (AF) by using a questionnaire specific for AF. Methods and Results A total of 86 patients (paroxysmal/chronic, 61/25) with drug-resistant AF undergoing extensive pulmonary vein isolation were recruited for the study. The QOL was quantitatively assessed by the Atrial Fibrillation Quality of Life Questionnaire at baseline, and 1, 3 and 6 months after the ablation. Sinus rhythm was maintained in 48/61 (79%) of the paroxysmal AF group, and 15/25 (60%) of those in the chronic AF group during 6 months after the initial ablation procedure. Among the patients without any AF recurrences, patients with chronic AF exhibited a substantial improvement in the QOL at 1 month after the procedure, and it remained unchanged until the end of the follow-up period. However, in the patients with paroxysmal AF, the QOL level gradually increased over a 6-month period. The patients with recurrent AF exhibited no improvement in the QOL. Conclusion Although the clinical course of the QOL improvement was different, both paroxysmal and chronic AF patients gained better QOL to maintain sinus rhythm by means of catheter ablation. (Circ J 2008; 72: 582 - 587)

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Background Arrhythmias following cardiovascular surgery lead to unstable hemodynamics, along with myocardial ischemia and decreased cardiac output. The purpose of the present case cohort study compared the control group with no carvedilol administered and the other group of patients given carvedilol and determined whether postoperative treatment with carvedilol, a β-adrenergic blocker, prevents paroxysmal atrial fibrillation after coronary artery bypass grafting (CABG). Methods and Results Of 160 patients who underwent scheduled isolated CABG, 80 received postoperative carvedilol and 80 did not. Postoperative paroxysmal atrial fibrillation was defined as episodes of atrial fibrillation persisting for over 10 min and confirmed by 12-lead electrocardiography. The incidence of paroxysmal atrial fibrillation was significantly lower in patients given carvedilol (12/80:15%) than in those who were not (27/80:34%) (p=0.0094). Logistic regression analysis showed that only postoperative carvedilol was significantly associated with the development of postoperative atrial fibrillation (95% confidence interval, 0.169-0.832; p=0.0159). Conclusion Postoperative treatment with carvedilol prevented paroxysmal atrial fibrillation after CABG. (Circ J 2008; 72: 588 - 591)

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Background Mutations of human cardiac sodium channel α subunit gene (SCN5A) have been implicated in risk of various cardiac arrhythmias. The present study aimed to investigate whether SCN5A polymorphism was related to the occurrence of idiopathic ventricular arrhythmia (IVA) in Chinese Han patients. Methods and Results Genotyping for polymorphic variance of SCN5A was performed by polymerase chain reaction and automated gene scan sequencing analysis in 31 unrelated Chinese patients with IVA (IVA group) and 103 healthy controls (control group). The allele frequencies of c.87G>A (p.Ala29Ala) and c.1673A>G (p.His558Arg) were higher in men than in women for control group (p=0.023 and p=0.027, respectively). For women, patients with IVA had higher allele frequency of c.87G>A than controls (0.455 vs 0.198, p=0.013, odds ratio (OR) 3.382), whereas for men, minor allele c.1673A>G was significantly less prevalent in IVA patients compared with controls (0.025 vs 0.175, p=0.017, OR 0.121). Significant difference existed in occurrence of ventricular arrhythmia between female patients with 87GA/AA and those with 87GG genotypes (0.348 vs 0.097, p=0.039, OR 4.978) and between male patients with 1673AA and those with 1673AG/GG genotypes (0.311 vs 0.053, p=0.031, OR 8.143). The frequency of haplotype GG (87G-1673G) was significantly lower in IVA patients than in controls (0.016 vs 0.128, p=0.009, OR 0.109). Conclusions The present study indicates that Chinese Han people have significant difference in distribution of 2 single nucleotide polymorphisms (c.87G>A and c.1673A>G) between healthy male and females. The 87A allele might be associated with an increased risk of IVA in females, whereas 1673G allele might have been positively selected because of its protective effects against ventricular arrhythmia in males. (Circ J 2008; 72: 592 - 597)

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Background Recently, arterial stiffness parameter called cardio-ankle vascular index (CAVI) has been developed. In the current study, using coronary angiographic (CAG) findings, the usefulness of CAVI as a marker of the severity of coronary atherosclerosis was compared with that of carotid atherosclerosis parameters obtained from high-resolution B-mode ultrasonography. Method and Result A total of 109 participants who underwent CAG were enrolled in the current study. They were divided into 4 groups according to the number of stenotic vessels on CAG; no lesion (0VD), 1-vessel (1VD), 2-vessel (2VD) and 3-vessel (3VD) groups. CAVI was significantly higher in 1VD group compared with the 0VD group (p<0.05), and was significantly higher in 2VD and 3VD group compared with the 1VD group. In single regression analysis, CAVI correlated positively with maximum intima-media thickness (IMT) (p<0.01) and plaque score (p<0.0001). A stepwise ordinal logistic regression analysis using mean IMT, maximum IMT, plaque score and CAVI as independent variables identified only CAVI as positively related to the severity of coronary atherosclerosis. The area under the receiver operating characteristic curve defined by CAVI was the greatest. Conclusion CAVI might be more useful for discriminating the probability of coronary atherosclerosis than findings of carotid atherosclerosis by high-resolution B-mode ultrasonography. (Circ J 2008; 72: 598 - 604)

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Background The aim of the present study was to prospectively evaluate the sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-) of the ankle - brachial index (ABI), using conventional digital subtraction angiography (DSA) as the reference standard, in the assessment of lower extremity arteries, and to research the threshold value of the ABI in diagnosing periphery arterial disease (PAD), as well as the relationship between the ABI value and stenosis in the artery of the lower extremity in Chinese high-risk cardiovascular patients. Methods and Results A total of 298 consecutive patients (199 men, 99 women, 64.9±11.3 years old) underwent conventional DSA and ABI measurement. Receiver operator characteristics (ROC) analysis was performed to assess possible threshold values that predict PAD in these patients. The greater the stenosis in the artery of the lower extremity, the lower the measured ABI value. DSA was used as the gold standard in defining lesions ≥30%, ≥50%, and ≥70% and the respective areas under the ROC curve were 0.786 (95% confidence interval (CI) 0.712, 0.860), 0.927 (95% CI 0.869, 0.984), and 0.963 (95% CI 0.927, 0.999). Conventional DSA was the gold standard in defining ≥50% luminal stenosis for the diagnosis of lower extremity PAD. The 0.95 is the overall cutoff of the ABI that was associated with 91% sensitivity, 86% specificity, 6.5 LR+ and 0.1 LR- for detection of hemodynamically significant stenosis (lesions ≥50%) in all 298 subjects (p<0.001). Conclusion The ABI value shows a decreasing tendency with increasing severity of stenosis in patients with PAD. ABI measurement is an accurate and reliable noninvasive alternative to conventional DSA in the assessment of lower extremity arteries and the cut-off of 0.95 is the threshold ABI value for detecting PAD in Chinese patients. (Circ J 2008; 72: 605 - 610)

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Background In Japan, Diagnosis Procedure Combination (DPC) of hospitalization health-care costs has been introduced since 2004, and its introduction has been recently expanded also to general hospitals. In such situations, the role of nuclear cardiology as a gatekeeper for the diagnosis of ischemic heart disease is increasingly important. Thus, the present study was designed to determine which clinical risk for hard events after normal single-photon emission computed tomography (SPECT) images, identify the predictors of increased risk in patients with normal SPECT images based on the J-ACCESS study. Methods and Results A total of 4,629 consecutively tested patients who underwent stress ^99mTc-tetrofosmin SPECT at hospitals in Japan were included in the study. Based on SPECT image data, 1,862 participants had a summed stress score of ≤3, which was considered normal (selection criteria I; normal perfusion). Myocardial perfusion was normal in 46.2% of the study population. Among normal SPECT subjects, cardiac function, as assessed by quantitative gated SPECT software, showed 1,786 participants were considered normal, based on left ventricular end-systolic volume (ESV) (ESV ≤60 ml in men, ESV ≤40 ml in women), which is defined as selection criteria II (normal perfusion and ESV). In addition, 1,742 participants were found to be normal based on ejection fraction (EF) (EF ≥49% in men, EF ≥55% in women), which is defined as selection criteria III (normal perfusion, ESV and EF). During the 3-year follow-up period, there was a total of 211 cardiac events (11.3%) in patients grouped in selection criteria I, 196 cardiac events (11.0%) in patients grouped in selection criteria II, and 189 cardiac events in patients grouped in selection criteria III (10.8%). The annual hard event rates were 0.81%, 0.67% and 0.63% in selection criteria I, II and III, respectively. Cox proportional hazard analysis showed that diabetes mellitus, age and hypertension were independent predictors of all cardiac events in all selection criteria. Conclusion Normal stress myocardial perfusion imaging in the Japanese population is associated with a low cardiac event risk. The prognosis results of a normal SPECT scan would be useful for better patient management. (Circ J 2008; 72: 611 - 617)

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Background Multislice computed tomography (MSCT) permits direct visualization of not only coronary artery stenosis but also the characteristics of plaques in patients with coronary artery disease (CAD). Also, because of its potential to be a novel risk factor for cardiovascular disease, interest in non-alcoholic fatty liver disease (NAFLD) is increasing. Methods and Results Participants comprised 298 consecutive patients who received MSCT to diagnose CAD. Patients with an alcohol intake exceeding 20 g/day or with a history of known liver disease were excluded from the study. Liver steatosis and 4 coronary artery findings, including remodeling lesions, lipid core plaques, calcified plaques and narrowing of lumen, were assessed. Liver steatosis was evaluated by computed tomography density of the liver and spleen. In the study, NAFLD was defined as having a liver and spleen (L:S) ratio of <1.1. The L:S ratios of patients with remodeling lesions or lipid core plaques were significantly lower than those without. NAFLD was related significantly to those findings, but there was no correlation between calcified plaques, narrowing of lumen and L:S ratios. Adjusted odds ratio of NAFLD for remodeling lesions was 2.41 (95% confidence interval (CI), 1.24-4.67; p=0.009), and those for lipid core lesions was 2.29 (95% CI, 1.15-4.56; p=0.018). Conclusion NAFLD is a novel risk factor for vulnerable plaques. (Circ J 2008; 72: 618 - 625)

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Background Clopidogrel has become standard treatment after urgent percutaneous coronary revascularization. Due to its enhanced and irreversible platelet inhibition, patients undergoing urgent surgical revascularization have a higher risk of bleeding complications and transfusions. Therefore, the effect of preoperative continuous administration of clopidogrel on the incidence of hemorrhagic complications in patients undergoing off-pump coronary artery bypass surgery with acute coronary syndrome was evaluated. Methods and Results From March 2004 to September 2006, 172 patients with acute coronary syndrome underwent isolated off-pump coronary artery bypass surgery; 70 (40.7%) and 102 (59.3%) of these patients did or did not take clopidogrel before surgery respectively. Seventy patients in each group were matched using propensity scores and associations between preoperative continuous administration of clopidogrel and postoperative bleeding, hemostatic reoperation, blood products received, the need for multiple transfusions and early graft patency by coronary computed tomography were assessed. Univariate analysis showed the continuous clopidogrel group had similar levels of postoperative bleeding for 24 h (601.4±312.6 ml vs 637.2±452.4 ml, p=0.616) and rates of reexploration (1.4% vs 1.4%), perioperative blood transfusion (33.3% vs 34.3%, p>0.05) and platelet transfusion (2.9% vs 7.1%, p=0.44) compared with the non-continuous group. Conclusions Preoperative continuous administration of clopidogrel did not increase the risk of hemorrhagic complications in patients with acute coronary syndrome undergoing isolated off-pump coronary artery bypass surgery. These findings indicate that surgery after clopidogrel treatment in patients with acute coronary syndrome should not be delayed until platelet function returns to normal because they may have a higher risk of recurrent myocardial ischemic events. (Circ J 2008; 72: 626 - 632)

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Background The combined treatment of sustained-release basic fibroblast growth factor (Sr-bFGF) and a 5-hydroxytryptamine_2A blocker, sarpogrelate, was evaluated to see whether it reversed the impaired collateral circulation in diabetic (DM) mouse hindlimb ischemia. Method and Results Diabetic and normal mice with ischemic hindlimb were randomly assigned to 1 of 5 experimental groups (no treatment, sarpogrelate 50 mg · kg^-1 · day^-1, 20 μg or 50 μg Sr-bFGF and a combined treatment of 20 μg Sr-bFGF and sarpogrelate), and treated for 4 weeks. Tissue blood perfusion (TBP), vascular density (angiogenesis) and the number of mature vessels (arteriogenesis) were checked by the use of standard methods. Although angiogenesis was comparable (161±14 vs 154±12 vessels/mm²), the laser Doppler perfusion image index (LDPII) (0.43±0.11 (SD) vs 0.63±0.08, p<0.05) and arteriogenesis (8±3 vs 12±4 vessels/mm², p<0.05) were significantly lower in DM mice than those in normal mice. The dose of Sr-bFGF for the sufficient number of mature vessels (≥45 vessels/mm²) and LDPII (≥0.9) was 20 μg for the normal mice, and 50 μg for the DM mice, which was reduced with the aid of sarpogrelate. Conclusions A combined therapy of Sr-bFGF and sarpogrelate is effective for neovascularization to reverse the impaired arteriogenesis and TBP in DM mice. (Circ J 2008; 72: 633 - 640)

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Background Left ventricular (LV) function provides prognostic information regarding the morbidity and mortality of patients. An automated cardiac phase selection algorithm has the potential to support the assessment of LV function with computed tomography (CT). This algorithm is clinically evaluated for 64-slice cardiac CT. Methods and Results Examinations of twenty consecutive patients were selected. Electrocardiogram gated contrast-enhanced CT was performed. Reconstructions were performed using an automated and a manual method, followed by the determination of the global LV function. Significances were tested using 2-sided Student's t-tests. Reduction in post processing time and storage capacity were estimated. A slightly smaller mean end-systolic volume was found with the automated method (52±18 ml vs 54±17 ml, p=0.02, r=0.99). The mean LV ejection fraction was slightly larger with the automated method (65±8% vs 64±8%, p=0.004, r=0.99). The estimated reduction in post processing time was maximal 5 min per patient with a potential 80% data storage reduction. Conclusions Results of the automated phase selection algorithm are similar to the manual method. The automated tool reduces post processing time, reconstruction time and transfer time. (Circ J 2008; 72: 641 - 646)

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Background The high affinity receptor for interleukin (IL)-13, IL-13 receptor α2 (IL-13Rα2), acts as a decoy receptor for IL-13, modulates fibrosis and has an anti-tumor effect. Recently, IL-13Rα2 has been considered as a therapeutic target for fibrosis and tumor growth. However, the mechanism of IL-13Rα2 expression in cardiomyocytes is unclear. Methods and Results The mechanism of IL-13Rα2 expression was examined using cultured rat neonatal cardiomyocytes. Cyclical mechanical stretch induced IL-13Rα2 mRNA expression in rat cardiomyocytes. Treatment with angiotensin II, which plays a pivotal role in mechanical stretch-induced cardiomyocyte hypertrophy, upregulated IL-13Rα2 mRNA expression in rat cardiomyocytes. IL-13Rα2 mRNA expression was also upregulated through IL-13 treatment. Furthermore, mechanical stretch and angiotensin II treatment caused IL-13 secretion from rat cardiomyocytes, which was suppressed by angiotensin type1 receptor (AT1R) RNA interference. Upregulation of IL-13Rα2 mRNA expression through mechanical stretch, angiotensin II treatment and IL-13 treatment was inhibited by anti-IL-13Rα1 antibody and STAT6 depletion through RNA interference. Positive immunohistochemical staining for IL-13Rα2 was observed in the myocardium of endomyocardial biopsy specimens from the failing human heart, but not in autopsy specimens from control subjects. Conclusion IL-13 might act in an autocrine and paracrine fashion to upregulate IL-13Rα2 expression in cardiomyocytes. (Circ J 2008; 72: 647 - 653)

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Background Smoking impairs neovascularization, possibly, through the impaired function of peripheral blood-derived mononuclear cells (PB-MNCs). Thus, the mechanism of impaired function of PB-MNCs caused by chronic smoking was examined, and whether vitamin C reversed the malfunction of PB-MNCs in smokers was investigated. Methods and Results The cohort comprised 27 healthy male volunteers (16 smokers and 11 age-matched non-smokers). For evaluation of the colony-forming activity of PB-MNCs, the number of endothelial colony-forming units (e-CFUs) was counted in a culture assay. Migration activity of PB-MNCs was evaluated by the modified Boyden chamber method. In smokers, the number of e-CFUs was reduced to 56% and migratory activity of PB-MNCs to 40% compared with non-smokers (p<0.01). The urinary level of 8-isoprostane, an oxidative stress marker, was greater in smokers than in non-smokers (p<0.05). There was an inverse correlation between migratory activity of PB-MNCs but not between the number of e-CFUs and urinary level of 8-isoprostane. Furthermore, oral administration of vitamin C for 2 weeks ameliorated the impaired migratory activity of PB-MNCs in smokers. Conclusion Chronic smoking impairs the function of PB-MNCs. Smoking-induced oxidative stress may be involved in impaired migratory activity of PB-MNCs. (Circ J 2008; 72: 654 - 659)

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Background In the present study, nitric oxide (NO) was investigated to see if it mediated effects of nebivolol on apoptosis in the rat myocardial infarction (MI) model. Methods and Results Rats were divided into 3 groups: sham operated (sham-control), MI-induced (MI-control) and nebivolol treated (MI-nebivolol). The initial dose of nebivolol was administrated intravenously (iv) within 10 min of post-MI reperfusion and continued orally for 28 days. NO mediated effects of nebivolol were assessed either in the early (2^nd day) or sub-acute (28^th day) period of MI by histologic, hemodynamic and biologic studies. Left ventricular (LV) pressure changes were prevented with nebivolol (the increase in LV end-diastolic pressure and the decrease in maximum rise and fall rate of LV pressure (+dp/dt and -dp/dt) was significantly less in MI-nebivolol). Total and regional apoptotic indexes were significantly lower in the MI-nebivolol group (10.2 vs 7.1%, respectively on the 2^nd day; p=0.004). Although plasma nitrite/nitrate, cyclic guanylate cyclase and peroxynitrite concentrations were high both in MI-control and MI-nebivolol groups on the 2^nd day, these concentrations were decreased to the basal value on the 28^th day in the MI-nebivolol group. Conclusion As a result, nebivolol treatment (initially by iv within 10 min of reperfusion and continued orally) reduced the myocardial apoptosis after MI. This beneficial effect of nebivolol is mediated by NO regulation. (Circ J 2008; 72: 660 - 670)

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Background There is no post-processing technique that can display an overview image of the lumen and vessel wall of a whole heart in one image. A merging coronary lumen view (Angiographic View) with a plaque image can provide a single, comprehensive image of plaque distribution. Methods and Results A color-coded plaque image is assigned to different computed tomography attenuation ranges in the coronary artery to visualize plaques. This plaque image is re-formatted into a maximum intensity projection image and loaded onto the Angiographic View image. Conclusions The integrated image of the coronary lumen and vessel wall of a whole heart is feasible. This image (Plaque-loaded Angiographic View) will give effective information in explaining the distribution of coronary lesions in patients as well as providing opportunities to discuss treatment strategies. (Circ J 2008; 72: 671 - 673)

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A 42-year-old man suffering from massive aortic valve regurgitation with mild stenosis because of a bicuspid valve underwent surgery in May 2007. The surgical procedure was performed through a right anterolateral thoracotomy using the peripheral cannulation method. Cardiac arrest was achieved by direct aortic cross-clamping and selective cardioplegia delivery. The aortic valve was replaced with a bioprosthesis. The operation and aortic cross-clamping periods were 265 and 117 min, respectively. The patient's recovery was uneventful, and he was discharged from hospital 8 days after surgery. (Circ J 2008; 72: 674 - 675)

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Isolated noncompaction of the ventricular myocardium (INVM) was diagnosed with delayed enhancement cardiac magnetic resonance imaging (MRI) in a 12-year-old boy, who developed dyspnea and syncope while running. Chest radiograph showed no marked cardiomegaly, but revealed bilateral consolidation caused by aspiration pneumonia. Laboratory findings showed plasma level of brain natriuretic peptide (BNP) of 768 pg/dl. Echocardiography showed a slightly thickened myocardium, but the trabecular meshwork region was unclear. He was given a diagnosis of unknown heart failure. His dyspnea and cyanosis improved in response to inotropic agents, oxygen and steroid therapy. However, the plasma BNP levels could not be decreased to normal. Cardiac MRI was performed and delayed-enhancement demonstrated hyperenhancement of prominent trabeculation in the lateral and apical regions of the left ventricle, suggesting fibrosis. The patient was given a diagnosis of INVM, but his status was New York Heart Association Class I heart failure. The diagnosis of INVM in children is difficult because heart failure symptoms are present in only 30% of the cases at diagnosis. Delayed-enhancement MRI is a more precise method of assessment. (Circ J 2008; 72: 676 - 678)

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The use of automated external defibrillators (AEDs) has increased the number of survivors of out-of-hospital cardiac arrest. The AED has a high specificity and moderately high sensitivity in detecting rhythms appropriately treated by defibrillation. However, a few shockable rhythms are misdiagnosed by the AED. Two cases of inappropriate analyses by AEDs in patients with in-hospital ventricular fibrillation are presented. In the first case, the AED failed to recognize ventricular fibrillation because of the presence of pacemaker spikes. In the second case, the fine ventricular fibrillation and the presence of artifacts were suspected as the causes of inappropriate analysis by the AED. Both patients were resuscitated by advanced cardiovascular life support with a manual defibrillator. Trained healthcare providers should be aware of the limitations of AED in specific situations. (Circ J 2008; 72: 679 - 681)

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Doppler sonography has gained considerable recognition as a noninvasive method of detecting carotid artery disease, and power Doppler sonography achieves good color-filling of all the examined vessels. Dolichoarterial disease of the internal carotid artery occurs in 10-25% of the population; these alterations are characterized by atypical elongation of the vessel, which predisposes it to tortuosity, coiling, and kinking, which is the most frequent morphologic anomaly and is characterized by sharp angulation (single and double Z-shaped). A patient with double Z-shaped angulation (kinking) of the left internal carotid artery was incidentally diagnosed in an asymptomatic state because of the broad use of these noninvasive investigations. (Circ J 2008; 72: 682 - 683)

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