Over the years there has been considerable improvement in the clinical outcomes of patients treated for acute coronary syndrome (ACS). Despite a significant reduction in acute mortality, a large percentage of patients post ACS continue to experience adverse cardiovascular (CV) events, with high long-term mortality rates and overall suboptimal medical management. Long-term risk prediction tools rely on traditional CV risk factors and are developed and validated in specific populations. Established CV risk factors, however, only explain half or fewer of CV events. These risk models may thus not be optimal in determining individual risk for long-term adverse outcomes or in helping to identify individual patients who do not respond to therapy. Identifying the specific plaque characteristics associated with increased likelihood for thrombotic complications and rapid progression has led to the concept of the vulnerable plaque. Recently, "vulnerable myocardium" (ie, myocardium that is prone to myocardial ischemia and fatal arrhythmia) has been shown to play an important role in outcome. Both vulnerable plaque and vulnerable myocardium are associated with functional vascular abnormalities, such as endothelial dysfunction, which are considered a key event in the initiation, progression and complications of coronary artery disease. Endothelial dysfunction may serve as an underlying unifying mechanism that would independently predict long-term outcome in patients with ACS undergoing revascularization. (Circ J 2012; 76: 778-783)

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The optimal strategy for coronary revascularization remains controversial. Currently, most surgical revascularizations are performed with the use of cardiopulmonary bypass (ONCAB), yet over the past 20 years off-pump coronary artery bypass grafting (OPCAB) has been increasingly used because of the increased awareness of the deleterious effects of cardiopulmonary bypass (CPB) and aortic manipulation. Small, prospective, randomized controlled trials have lacked sufficient sample size to demonstrate differences in early and long-term outcomes. Larger observational studies that are better powered to statistically compare outcomes have shown more favorable in-hospital outcomes and equivalent long-term outcomes with OPCAB and ONCAB. The benefits of OPCAB techniques may be more apparent for patients at high risk for complications associated with CPB and aortic manipulation. Recent studies have demonstrated improved outcomes in higher-risk patients undergoing OPCAB, as well as improved neurological outcomes. The purpose of this review is to outline the recent literature comparing OPCAB with ONCAB, and to demonstrate efficacy of OPCAB as a useful technique for coronary revascularization. (Circ J 2012; 76: 784-790)

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The aortic root is at the center of the heart. Each of the aortic sinuses of Valsalva, positioned at the base of the aortic root, is in contact with the atrial myocardium and/or ventricular myocardium at their bases, which enables mapping and ablating of some ventricular arrhythmias with an outflow tract origin and supraventricular tachycardias (ie, atrial tachycardia, accessory pathways) from the aortic sinuses of Valsalva. These arrhythmias have characteristic electrocardiographic findings associated with their origins, and almost all are difficult to ablate from an atrial or ventricular endocardial site. Site-specific and potential complications, such as a coronary artery occlusion or atrioventricular block, can occur with catheter ablation at the aortic sinuses of Valsalva. Therefore, accurate diagnosis and proper ablation at the aortic sinuses of Valsalva are required for a cure. This review describes the anatomic features of the aortic sinuses of Valsalva and focuses on the diagnosis and radiofrequency catheter ablation of arrhythmias that can be ablated from this site. (Circ J 2012; 76: 791-800)

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MitraClip^® therapy is a percutaneous edge-to-edge plication of the mitral leaflets, mimicking the Alfieri surgical technique. MitraClip^® implantation is a safe procedure, and survival outcomes in high-surgical-risk patients are superior to historical controls. Despite these results, questions remain concerning long-term efficacy and durability. The MitraClip^® device has been studied in a safety and feasibility trial in the USA, a randomized pivotal trial against surgical mitral valve repair. Moreover, MitraClip^® now has over 2 years of CE-mark approval and a rapidly expanding clinical experience in Europe, primarily in patients at high risk for surgery. A dedicated multidisciplinary team is necessary, as well as thoughtful patient selection, familiarity with the technical aspects of the procedure, including transesophageal ultrasound imaging and post-procedure monitoring. Currently available clinical data and procedural steps are herein reviewed. Because the MitraClip^® procedure is still relatively new, continued investigation is required to further better define the patient populations that will benefit most. (Circ J 2012; 76: 801-808)

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Background: The JAPAN-ACS study demonstrated that statins significantly reduced coronary plaque volume in patients with acute coronary syndrome (ACS). The clinical implications of plaque regression for clinical outcomes in ACS patients has not been established. The Extended JAPAN-ACS study was conducted to evaluate the relationship between coronary plaque regression and long-term clinical outcome, and to explore the factors associated with cardiovascular events. Methods and Results: Patients with intravascular ultrasound (IVUS) data at both enrollment and follow-up in the JAPAN-ACS study were enrolled and observed for at least 3 years. Patients were divided into lesser and greater coronary plaque regression groups. The primary endpoint was defined as a composite of the following events: cardiovascular death, nonfatal myocardial infarction, nonfatal cerebral infarction, and unstable angina. The median value of the percent change in plaque volume, 18.0%, was used as a cutoff point. There were 4 primary events (3.4%) in the lesser regression group, and 2 events (1.7%) in the greater regression group (P=0.4). Cumulative secondary cardiovascular events did not differ between the 2 groups. Multivariate analysis identified the high-density lipoprotein cholesterol (HDL-C) at baseline and the % change of the external elastic membrane volume as independent risk factors of cardiovascular events. Conclusions: Coronary plaque regression induced by an intensive statin regimen did not predict future cardiovascular events in ACS patients. Rather, the baseline HDL-C level and reverse vessel remodeling might serve as predictors for cardiovascular events. (Circ J 2012; 76: 825-832)

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Background: Diuretics are the most prescribed drug in heart failure (HF) patients. However, clinical evidence about their long-term effects is lacking. The purpose of this study was to compare the therapeutic effects of furosemide and azosemide, a short- and long-acting loop diuretic, respectively, in patients with chronic heart failure (CHF). Methods and Results: In this multicenter, prospective, randomized, open, blinded endpoint trial, we compared the effects of azosemide and furosemide in patients with CHF and New York Heart Association class II or III symptoms. 320 patients (160 patients in each group, mean age 71 years) were followed up for a minimum of 2 years. The primary endpoint was a composite of cardiovascular death or unplanned admission to hospital for congestive HF. During a median follow-up of 35.2 months, the primary endpoint occurred in 23 patients in the azosemide group and in 34 patients in the furosemide group (hazard ratio [HR], 0.55, 95% confidence interval [CI] 0.32-0.95: P=0.03). Among the secondary endpoints, unplanned admission to hospital for congestive HF or a need for modification of the treatment for HF were also reduced in the azosemide group compared with the furosemide group (HR, 0.60, 95%CI 0.36-0.99: P=0.048). Conclusions: Azosemide, compared with furosemide, reduced the risk of cardiovascular death or unplanned admission to hospital for congestive HF. (Circ J 2012; 76: 833-842)

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Background: The purpose of this study was to analyze the effect of valsartan on abnormal adipocyte metabolism and prothrombotic state in hypertensive patients with metabolic syndrome (MetS). Methods and Results: We conducted a multicenter, prospective, randomized, parallel-group controlled trial in 150 hypertensive patients with MetS. They were randomly assigned to receive either 80-160mg valsartan per day (valsartan group, n=79) or other conventional treatment without a renin-angiotensin system (RAS) inhibitor (non-RAS inhibitor group, n=71). After 1 year, there were no significant differences between the 2 groups in the changes in systolic and diastolic blood pressures (valsartan: 153±15/86±15 to 138±16/77±12mmHg; non-RAS inhibitor: 150±14/82±15 to 137±15/76±10mmHg). There was a significant difference in the change in the levels of plasminogen activator inhibitor-1 (PAI-1) between the 2 groups after 1 year (valsartan: 3.7±3.2ng/ml; non-RAS inhibitor: 5.8±3.3ng/ml, P=0.04). There was no significant difference between groups in the change in the concentration of adiponectin after 1 year (valsartan: 0.3±0.4μg/ml; non-RAS inhibitor: 0.9±0.4μg/ml, P=0.22). The animal study showed aortic PAI-1 protein expression was reduced in double knockout mice of angiotensin II type 1a receptor and apolipoprotein E (apoE) compared with the apoE knockout mice. Conclusions: Valsartan reduced plasma PAI-1 levels compared to non-RAS inhibitor in hypertensive patients with MetS, which suggests it may be useful for improving fibrinolytic function. (Circ J 2012; 76: 843-851)

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Background: The pulmonary veins (PV) and posterior left atrium (LA) may contribute to the occurrence and maintenance of atrial fibrillation (AF). We evaluated whether simple epicardial electrophysiological mapping can predict elimination of chronic AF after the box PV isolation procedure. Methods and Results: Using a computerized 48-channel mapping system, we performed intraoperative atrial mapping in 16 patients with chronic AF associated with mitral valve (MV) disease. Patients' ages ranged from 48 to 76 years (mean, 61.4 years). AF duration ranged from 1 to 16 years (mean, 7.5±5.4 years). Simple box PV isolation was performed during the MV operation. Regular and repetitive activation was found in the LA of 12 of 16 patients, and irregular and chaotic activation was found in both atria in 4 of 16 patients; 12 patients with regular and repetitive activation of the LA were treated by box PV isolation and the other 4 patients with irregular and chaotic activation in both atria did not recover sinus rhythm after this procedure. AF-free rate was significantly higher in patients with regular and repetitive activation of the LA (P<0.01). Conclusions: Box PV isolation was effective in the treatment of chronic AF associated with MV disease. Epicardial atrial mapping may predict elimination of AF after the box PV isolation. (Circ J 2012; 76: 852-859)

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Background: The impact of the right atrial (RA) anatomical remodeling on outcomes of atrial fibrillation (AF) after radiofrequency ablation (RFA) is unclear. Methods and Results: Sixty-three patients (50 men, 57±10 years, 23 persistent AF [PeAF]) who underwent RFA for AF were enrolled. Both RA and left atrial (LA) volumes, measured with multidetector computed tomography, as well as echocardiographic parameters were compared between subjects with early (<3 months, n=13) or 1-year (n=19) recurrence after RFA and without recurrence. The RA volume index (RAVI) was larger (98±21 vs. 77±22ml/m²) and PeAF was more common (62% vs. 30%) in the early recurrence group (P<0.05 for all), whereas the LA volume index (LAVI) was similar between the 2 groups (78±15 vs. 72±19ml/m², P=0.23). Notably, RAVI was the only independent predictor of early recurrence (for each 10ml/m² increase, OR: 1.650, 95%CI: 1.017-2.677, P=0.04). PeAF was the only independent predictor of 1-year recurrence after RFA (OR: 4.496, 95%CI: 1.110-18.211, P=0.04), whereas RAVI and LAVI were not. Conclusions: RA anatomical remodeling might affect the early recurrence of AF after RFA. However, the chronicity of AF, rather than RA and LA anatomical remodeling, is a determinant of 1-year recurrence of AF after RFA. (Circ J 2012; 76: 860-867)

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Background: Limited data are available regarding the direct comparison of angiographic and clinical outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) for chronic total occlusion (CTO). Methods and Results: A prospective, randomized, multicenter trial was conducted to evaluate the non-inferiority of a zotarolimus-eluting stent (ZES; Endeavor Sprint^®, n=80) to a sirolimus-eluting stent (SES; Cypher^®, n=80) in patients with CTO lesion with a reference vessel diameter ≥2.5mm. The primary endpoint was in-segment binary restenosis rate at 9-month angiographic follow-up. Key secondary endpoints included target vessel failure (TVF; including cardiac death, myocardial infarction, and target vessel revascularization) and Academic Research Consortium-defined definite/probable stent thrombosis (ST) within 12 months. The ZES was non-inferior to the SES with respect to the primary endpoint, which occurred in 14.1% (95% confidence interval [CI]: 6.0-22.2) and in 13.7% (95%CI: 5.8-21.6) of patients, respectively (non-inferiority margin, 15.0%; P for non-inferiority <0.001). There were no significant between-group differences in the rate of TVF (10.0% vs. 17.5%; P=0.168) nor in the rate of ST (0.0% vs. 1.3%; P=0.316) during the 12-month clinical follow-up. Conclusions: The effectiveness and safety of ZES are similar to those of SES and therefore it is a good treatment option in patients undergoing PCI for CTO with DESs. (Circ J 2012; 76: 868-875)

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Background: Transient increases (overshoot) in respiratory gas variables have been observed during exercise recovery, but their clinical significance is not clearly understood. Our group evaluated the relationship between the presence of overshoot of respiratory gas variables and the parameters obtained from cardiopulmonary exercise testing (CPX). Methods and Results: In total, 227 patients with various cardiac diseases underwent CPX. The overshoot phenomena of O₂ uptake (VO₂), VO₂/heart rate (O₂-pulse), and CO₂ output (VCO₂) were analyzed by respiratory gas analysis during recovery after maximal exercise. The overshoot of VO₂, O₂-pulse, and VCO₂ were recognized in 11 (5%), 43 (19%), and 12 (5%) patients, respectively. Compared with the patients without a VO₂ overshoot, those with a VO₂ overshoot had a significantly lower peak VO₂ (12.3±3.7 vs. 17.9±6.2ml·min^-1·kg^-1, P=0.003), lower anaerobic threshold (9.4±1.7 vs. 12.4±3.3ml·min^-1·kg^-1, P=0.001), higher VE-VCO₂ slope (38.0±5.2 vs. 33.2±9.6, P=0.013), and lower left ventricular ejection fraction (LVEF) (39.9±22.8 vs. 55.8±16.8%, P=0.003). Similar findings were obtained for the patients with an O₂-pulse overshoot and those with a VCO₂ overshoot. Conclusions: The overshoot phenomena of respiratory gas variables during recovery after maximal exercise are correlated with impaired cardiopulmonary function during exercise in cardiac patients. (Circ J 2012; 76: 876-883)

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Background: Myocardial injury is associated with an adverse outcome after off-pump coronary artery bypass graft surgery (OPCAB). The authors conducted a randomized controlled trial to evaluate whether remote ischemic preconditioning (RIPC) with remote ischemic postconditioning (RIPostC) reduces myocardial injury in patients undergoing OPCAB. Methods and Results: Seventy patients scheduled for OPCAB were randomly assigned to an RIPC+RIPostC group (n=35) or a control group (n=35). In the RIPC+RIPostC group, 4 cycles of 5-min ischemia and 5-min reperfusion were done on a lower limb before anastomoses (RIPC) and after anastomoses (RIPostC). RIPC+RIPostC significantly reduced postoperative serum troponin I levels (P=0.001). The area under the curve for postoperative troponin I was 48.7% lower in the RIPC+RIPostC group (median [interquartile range], 21.3h·ng^-1·ml^-1, 16.5-53.1h·ng^-1·ml^-1 vs. 41.5h·ng^-1·ml^-1, 24.6-90.2h·ng^-1·ml^-1, P=0.020). There was no significant difference in creatinine levels and PaO₂/F_iO₂ ratios between the 2 groups. Conclusions: RIPC+RIPostC by lower limb ischemia decreased postoperative myocardial enzyme elevation by almost half postoperatively in patients undergoing OPCAB. (Circ J 2012; 76: 884-890)

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Background: Although studies have shown there is a correlation between increased blood ammonia level and hepatic encephalopathy, little information is available for patients with out-of-hospital cardiac arrest. Methods and Results: We did a prospective study of 357 adult patients with out-of-hospital cardiac arrest whose venous blood ammonia levels were measured on arrival at the emergency room. The primary endpoint was favorable of neurological outcome to hospital discharge. Of the 357 patients, 25 (7%) had a favorable neurological outcome. The venous ammonia levels were lower in the favorable neurological outcome group than in the unfavorable neurological outcome group (median, 50μg/dl vs. 210μg/dl, P<0.0001). The adjusted odds ratio of ammonia levels for favorable neurological outcome was 0.98 (95% confidence interval, 0.96-0.99; P<0.0001). The ammonia cutoff value of 93.0μg/dl for the identification of favorable neurological outcome had the highest combined sensitivity and specificity, and higher ammonia levels were associated with more accurate negative predictive values (for ammonia levels of 192.5μg/dl, the negative predictive value was 100%). Hyperammonemia was significantly related to patient variables that had a poor outcome (R=0.439, P<0.001). In addition, there was a significant correlation between venous ammonia level and arterial pH on emergency room arrival (R=0.633, P<0.0001). Conclusions: The measurement of ammonia was found to provide valuable information regarding neurological outcome to hospital discharge in adult patients with out-of-hospital cardiac arrest. (Circ J 2012; 76: 891-899)

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Background: The Seventh Report of The Joint National Committee has recently introduced the prehypertension category of blood pressure (BP) status that needs monitoring and intervention. Little is known about the epidemiology of prehypertension in urban China, so this study aimed at estimating the prevalence of prehypertension and identifying risk factors in urban Chinese adults. Methods and Results: Using a multistage cluster and random sampling method, a representative sample of 25,196 urban adults aged 18-74 years in northeast of China was selected from 2009 to 2010. The survey of BP and associated risk factors was carried out in 33 communities. Multiple logistic regression methods were used to identify risk factors for prehypertension. Overall, 40.5% of urban Chinese adults had prehypertension, with a prevalence of 47.7% and 33.6% in men and women, respectively. Multivariate logistic regression analysis revealed the risk factors of being overweight (adjusted odds ratio [aOR]=1.38, 95% confidence interval [CI]: 1.26-1.52), obesity (aOR=3.94, 95%CI: 2.99-5.20), central obesity (aOR=2.13, 95%CI: 1.96-2.32). Being female, and having a higher education level, higher family income and diet control were protective factors. Conclusions: Prehypertension is common among urban residents in China, and is associated with many risk factors. Comprehensive lifestyle modifications need to be taken to decrease the incidence of prehypertension and to prevent prehypertension progressing to hypertension and cardiovascular disease. (Circ J 2012; 76: 900-906)

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Background: Hypertension (HT) is caused by complex interactions between genetic and environmental factors. Despite evidence for an association between short sleep duration and the development of HT, genetic factors associated with this effect have not been defined. Here we prospectively investigated the incidence of HT in subjects with short sleep duration over a 6-year follow-up period, and identified associated genetic variants in a genome-wide association study. Methods and Results: Sleep duration was determined by questionnaire and 3 categories were established: <5h, 5-7h, and >7h. Genotyping was carried out using the Affymetrix Genome-Wide Human Single Nucleotide Polymorphism (SNP) Array 5.0. Of the 4,965 individuals included in our study, 1,071 (543 of 2,330 men, 528 of 2,635 women) developed HT. The cumulative incidence of HT during the 6-year study period was 21.6%. Sleep duration <5h was associated with an increased risk of incident HT only in premenopausal women (adjusted hazard ratio 2.43, 95% confidence interval 1.36-4.35). The SNPs of rs6691577, rs2226284 and rs12756253 were associated with this increased risk. Conclusions: This prospective communitywide study showed that premenopausal women with short sleep duration had an increased risk of incident HT, and found associations with specific genomic markers. (Circ J 2012; 76: 907-913)

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Background: To determine the prevalence and signal intensity (SI) characteristics of late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI) in takotsubo cardiomyopathy (TC). Methods and Results: Cine, black-blood T2-weighted and LGE MR images were acquired in 23 patients with TC within 72h of onset. Wall motion abnormality (WMA), edema and LGE were evaluated with a 16-segment model. The SI characteristics of LGE were analyzed using SI distribution in remote normal segments as reference. Follow-up MRI was performed 3 months later. Retrospective analysis of LGE MRI was also performed in 10 patients with acute myocardial infarction (AMI) to compare the SI characteristics between TC and AMI. In acute phase, WMA and edema were observed in 236 (64%) and 205 (56%) of 368 segments. LGE was observed in 10 (2.7%) of 368 segments and in 5 (22%) of 23 patients. All LGE lesions in TC exhibited transmural enhancement. The contrast-to-noise ratio (CNR) in TC was significantly lower than that of AMI (3.1±0.3 standard deviations (SD) vs. 6.1±1.2 SD, P<0.01), and CNR value of 4 was useful for distinguishing TC from AMI. Both LGE and WMA disappeared within 12 months. Conclusions: Grey myocardial signal on LGE MRI may be observed in patients with TC. However, the extent of LGE is substantially less than that of WMA and edema, and disappears within 12 months. (Circ J 2012; 76: 914-921)

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Background: Although an intracoronary frequency-domain optical coherence tomography (FD-OCT) system overcomes several limitations of the time-domain OCT (TD-OCT) system, the former requires injection of contrast media for image acquisition. The increased total amount of contrast media for FD-OCT image acquisition may lead to the impairment of renal function. The safety and usefulness of the non-occlusion method with low-molecular-weight dextran L (LMD-L) via a guiding catheter for TD-OCT image acquisition have been reported previously. The aim of the present study was to compare the image quality and quantitative measurements between contrast media and LMD-L for FD-OCT image acquisition in coronary stented lesions. Methods and Results: Twenty-two patients with 25 coronary stented lesions were enrolled in this study. FD-OCT was performed with the continuous-flushing method via a guiding catheter. Both contrast media and LMD-L were infused at a rate of 4ml/s by an autoinjector. With regard to image quality, the prevalence of clear image segments was comparable between contrast media and LMD-L (97.9% vs. 96.5%, P=0.90). Furthermore, excellent correlations were observed between both flushing solutions in terms of minimum lumen area, mean lumen area, and mean stent area. The total volumes of contrast media and of LMD-L needed for OCT image acquisition were similar. Conclusions: FD-OCT image acquisition with LMD-L has the potential to reduce the total amount of contrast media without loss of image quality. (Circ J 2012; 76: 922-927)

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Background: It is unclear whether facilitated percutaneous coronary intervention (PCI) via a transradial approach therapy is preferable to primary PCI, with improved ventricular synchrony performance (VS), in Chinese patients. Methods and Results: The 152 patients with their first anterior acute myocardial infarction (AMI) were randomized to a primary PCI group or facilitated PCI group. In the 1^st week and 6^th month after AMI onset, the parameters of VS were measured by equilibrium radionuclide angiography with ventricular phase analysis. The rate of TIMI grade-3 flow in the infarct-related artery pre-PCI in the facilitated PCI group was higher than that in the primary PCI group (30.56% vs. 8.45%, P=0.001). At the 6^th month post-AMI, the parameters of time to peak ejection rate, phase shift and peak phase standard deviation were lower than in the primary PCI group (P<0.05, respectively). The incidence of recurrent ischemia and new or worsening congestive heart failure post-AMI in the facilitated PCI group was significantly lower than that in the primary PCI group (2.78% vs. 9.86%, P=0.043; 2.78% vs. 12.68%, P=0.028). Conclusions: Facilitated PCI via a transradial approach might significantly inhibit left ventricular remodeling and improve left ventricular function because of the complete, persistent patency of the infarct-related artery with few complications of vessel access and bleeding. (Circ J 2012; 76: 928-935)

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Background: Coronary slow flow phenomenon (CSFP) is defined as delayed coronary opacification in the absence of obstructive coronary artery disease. In the present study, we sought to define its prevalence and clinical features. Methods and Results: The 1,741 consecutive patients who underwent coronary angiography (CAG) were identified. Those with normal left ventricular ejection fraction and normal coronary arteries were included in the study (n=158). TIMI frame counts were calculated, and data on demographics, comorbidities, and medication use were collected. CSFP was defined as frame count >27. Multivariate logistic regression analysis was used to identify independent predictors of CSFP. CSFP was identified in 96 (5.5%) subjects referred for CAG. Subjects with CSFP were more obese (body mass index [BMI] 33.9 vs. 29.8kg/m², P=0.003) and had lower high-density lipoprotein levels (39.7 vs. 45.7mg/dl, P=0.04). In the CSFP group, total cholesterol, low-density lipoprotein and frame counts increased significantly with increasing vessel involvement (1-, vs. 2-, vs. 3-vessel involvement; P<0.05 for each variable). By multivariate analysis, male sex (odds ratio 3.36, 95% confidence interval 1.17-8.61, P=0.02) and higher BMI independently predicted the presence of CSFP (odds ratio 1.09, 95% confidence interval 1.03-1.15, P=0.003). Conclusions: CSFP is associated with male sex and obesity. Multivessel involvement may be a marker of more severe, diffuse disease. Further studies are needed to investigate this hypothesis. (Circ J 2012; 76: 936-942)

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Background: In recent studies, the inhibition of protein kinase C (PKC) β has been shown to improve diabetic vascular complications. However, the effect on angiogenesis in myocardial ischemia with diabetes mellitus (DM) is still unknown. Methods and Results: Mice were divided into 3 groups: control, DM and DM+PKC-I groups (n=8, respectively). In the DM and DM+PKC-I groups, diabetes was induced by streptozotocin (STZ) (1.5mg/body i.p.) for 5 days. Next, left anterior descending artery (LAD) ligation was performed in all groups. In the DM+PKC-I group, PKC β inhibitor (Cat. No. 539654; 10nmol/L) was administered from days 1 to 10. After 4 weeks of LAD ligation, the animals were killed. Microvascular density was significantly improved by PKC β inhibitor (control: 87.9±5.2/high-power field (HPF); DM: 51.4±6.9/HPF; PKC-I: 80.3±4.9/HPF; P<0.05). Expression of both vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS), which was decreased in the DM group, were significantly improved by inhibition of PKC β [VEGF (DM: 0.36±0.11-fold and DM+PKC-I: 0.77±0.07-fold vs. control), eNOS (DM: 0.35±0.06-fold and DM+PKC-I: 0.73±0.08-fold vs. control); both P<0.05)]. Conclusions: Inhibition of PKC β ameliorated impaired angiogenesis by hyperglycemia in STZ-induced DM mice complicated by myocardial infarction. These results suggest a new possible indication of PKC β inhibitor for myocardial ischemia with DM. (Circ J 2012; 76: 943-949)

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Background: Chromosome 9p21 single nucleotide polymorphisms (SNPs) have been shown to be associated with coronary heart disease in multiple studies. The aim of the present study was to identify whether these SNPs are associated with recurrent myocardial infarction (MI), revascularization, or death in acute coronary syndrome (ACS) patients or in those undergoing coronary artery bypass grafting (CABG). Methods and Results: TexGen registry participants with ACS (n=2,067) or CABG (n=1,176) were evaluated, to assess whether 9p21 SNPs (rs1333049, rs2383206, rs10757278, rs10757274) were associated with recurrent MI (primary outcome), recurrent revascularization, or death (secondary outcomes) at approximately 3.2 years of follow-up. Carriers of risk allele (C) for rs1333049 presented at an earlier age (62 vs. 63.5 years in non-carriers, P=0.0004) with more extensive disease (number of vessels with significant stenosis: 1.9 vs. 1.7 in non-carriers, P=0.001) in the ACS group. In adjusted models, the C allele was not associated with recurrent MI (hazard ratio [HR], 1.01; 95% confidence interval [CI]: 0.74-1.38), recurrent revascularization (HR, 0.98; 95%CI: 0.78-1.23), or death (HR, 0.91; 95%CI: 0.69-1.18) in the ACS or CABG groups (recurrent MI: HR, 0.64; 95%CI: 0.40-1.05; recurrent revascularization: HR, 0.98; 95%CI: 0.61-1.55; death: HR, 0.89; 95%CI: 0.61-1.30). Results were similar for the other 3 SNPs. Conclusions: 9p21 SNPs were not associated with recurrent MI, revascularization, or mortality after ACS or CABG. Individuals with the rs1333049 C allele, however, may present with earlier and more extensive disease. (Circ J 2012; 76: 950-956)

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Background: Improved medical techniques have allowed most women with repaired tetralogy of Fallot (TOF) to reach childbearing age. The predictors of adverse events and the effects of pregnancy on cardiac function have not been clearly described in these patients. Methods and Results: In the present study we retrospectively reviewed 40 deliveries in 25 patients with repaired TOF. There were 23 patients in New York Heart Association (NYHA) class I, and 2 in classes II-III before pregnancy. The mean age at delivery was 29.1 years and the mean gestational period was 37.8 weeks. Seven pregnancies (17.5%) in 7 patients were complicated with cardiac events such as a decline in NYHA class and arrhythmia. History of ablation and the baseline cardiothoracic ratio on chest radiography were predictors of adverse events. Peak plasma brain natriuretic peptide (BNP) level after the second trimester was higher in patients with cardiac events. Left ventricular size and contraction did not change from before to after pregnancy, but the right ventricle was enlarged at 6 months after delivery. Conclusions: Many of the pregnancies in women with repaired TOF were successful. However, careful management is required for some patients and the BNP level may be a useful marker to identify these patients. Because the right heart tended to be enlarged in the late postpartum period, pregnancy may also affect the long-term prognosis of patients with repaired TOF. (Circ J 2012; 76: 957-963)

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Background: The objectives of this study were to clarify the details of pediatric vasculitic diseases on the basis of Japanese autopsy reports and determine whether there were cases of probable Kawasaki disease (KD) even before KD came to be widely recognized as a disease entity. Methods and Results: Systemic vasculitis autopsy cases aged 15 years or less were selected from the total of 1,335,045 autopsy cases listed in the Annual of Pathological Autopsy Cases in Japan from 1958 through 2008. Those cases were classified into 14 disease groups and then analyzed with regard to various details. There were 380 autopsy cases of vasculitis in children (0.03% of the total autopsy cases). More than half were KD, and other diseases included unclassified vasculitis, polyarteritis nodosa, purpuric vasculitis, Takayasu arteritis, etc. The first recorded case of KD autopsy occurred in 1969. Up until 1976 there was a great difference in the number of autopsies between pediatric vasculitis and KD. However, after 1977 their numbers were in close agreement. The autopsy findings for 24 of 125 child vasculitis autopsies performed before 1976 and diagnosed as non-KD were consistent with KD. Conclusions: Although autopsies of pediatric vasculitis cases are extremely rare, the majority consists of KD. Moreover, it is likely that autopsy cases that were probably KD first appeared in the early 1960s. (Circ J 2012; 76: 964-970)

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Background: Although the acute effect of intermittent pneumatic compression (IPC) therapy had been documented for patients with symptomatic peripheral arterial obstructive disease (PAOD), its efficacy in improving quality of life (QOL), especially for those with infrapopliteal diffuse lesions, remains unclear. Methods and Results: Thirty-one patients with infrapopliteal diffuse or multiple segmental lesions were enrolled in the study. Based on receipt of IPC therapy (3h daily for 3 months), patients were allocated to a study (n=23) or control (n=8) group. The 6-min walking test, transcutaneous oxygen tension (TcPO₂), and QOL evaluated with the Short-Form 36 questionnaire were measured at the beginning and end of the study. In the QOL analysis, scores for physical functioning, physical and emotional role functioning, bodily pain, and general and mental health showed significant changes after IPC therapy. In the 6-min walking test, duration, and the initial and absolute claudication distances were significantly increased in the study group. The TcPO₂ also significantly increased in the distal end of the target limb after IPC therapy. Conclusions: Patients at high risk for amputation with infrapopliteal diffuse or multiple segmental lesions can improve their walking ability, TcPO₂ of the target limb and QOL after IPC therapy. (Circ J 2012; 76: 971-976)

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Background: We investigated the safety and feasibility of intratracheal administration of autologous bone marrow-derived mononuclear cells (ABM-MNCs) and observed the effects in a canine model of pulmonary hypertension (PH). Methods and Results: The PH model was induced by intravenous injection of 3mg/kg dehydromonocrotaline (DMCT) via the right atrium. Two weeks after DMCT administration, the animals received 4 different treatments (n=10 in each group): (I) negative control group; (II): ABM-MNCs group; (III) PH group; (IV) PH+ABM-MNCs group. Six weeks after injection of cells (10⁷), the hemodynamic data were significantly improved in group IV compared with group III (P<0.05). The ratio of right ventricular weight to left ventricular plus septal weight was significantly decreased in group IV compared with group III (P<0.05). The mRNA levels of vascular endothelial growth factor, preproendothelin-1, interleukin-6 and tumor necrosis factor-α were significantly improved in group IV compared with group III (P<0.05). The immunofluorescence result showed that 6 weeks after administration ABM-MNCs could differentiate into pulmonary vascular endothelial cells. Conclusions: Six weeks after intratracheal administration, ABM-MNCs significantly improved the impairment caused by DMCT in a canine model of PH (ie, decreased pulmonary arteriolar narrowing, alveolar septum thickening and right ventricular hypertrophy, enhanced angiogenesis) and this provides a firm foundation for a clinical trial. (Circ J 2012; 76: 977-985)

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Background: Hypoxic preconditioning of bone marrow cells (BMCs) from young healthy individuals can enhance the cells' therapeutic potential. Considering that the response to hypoxia may differ according to the quality of the cells, we assessed the effect of hypoxic preconditioning on BMCs from aged mice and compared the difference in response between BMCs from aged and young mice. Methods and Results: BMCs from young (3 months) and aged (20-22 months) mice were subjected to hypoxic preconditioning by culture for 24h in 2% O₂. Compared with BMCs from young mice, those from aged mice showed significantly fewer CD34- or c-kit-positive stem cells, higher expression of p53, and lower telomerase activity. Adhesion, survival and angiogenic potency were also lower in BMCs from aged mice, indicating an aging-related impairment. Hypoxia-preconditioned BMCs from aged mice showed enhanced adhesion, survival, and angiogenic potency with the in vitro assessments, as well as the in vivo implantation into ischemic hindlimbs. All the enhancements by hypoxic preconditioning were comparable between BMCs from aged and young mice, although the angiogenic potential of BMCs with and without hypoxic preconditioning was lower in old mice compared with young mice. Conclusions: Similar responses to hypoxia by BMCs from both aged and young mice suggest that hypoxic preconditioning could be a useful method of enhancing the angiogenic potential of BMCs. (Circ J 2012; 76: 986-994)

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Background: Corosolic acid (CRA) is a pentacyclic triterpene acid that has been shown to exhibit an anti-atherosclerotic effect when added to diets of low-density lipoprotein-deficient mice, but the mechanisms are unclear. The purpose of the present study was to investigate the molecular mechanisms by which CRA ameliorates atherosclerosis. Methods and Results: The anti-atherosclerosis effect of CRA in apolipoprotein E-deficient mice fed a Western-type diet was evaluated using atherosclerosis lesion area, serum profiles, gene expression and histological lesions. In vitro, the mechanisms responsible for the anti-inflammatory effect of CRA were investigated on a lipopolysaccharide-induced inflammation model. This model was also used to investigate in detail the effects of CRA on gene expression and nuclear factor (NF)-κB activation. Compared with the control group, the CRA-treated group exhibited a significant decrease in atherosclerotic lesion area, as well as expression of monocyte chemoattractant protein-1 (MCP-1) and CCR2. In vitro studies showed that CRA treatment downregulated the mRNA levels of MCP-1, and inhibited monocyte adhesion and migration, together with suppression of NF-κB signaling pathway. Conclusions: CRA is capable of ameliorating atherosclerosis in apolipoprotein E-deficient mice by, partly at least, inhibition of NF-κB activity along with decreased MCP-1 expression. (Circ J 2012; 76: 995-1003)

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Background: We aimed to describe the recent clinical characteristics of Takayasu arteritis (TA). Methods and Results: We enrolled 106 consecutive TA patients and compared the clinical characteristics of patients with TA onset before 1999 and after 2000, patients with onset at age less than 39 years and more than 40 years, patients with monophasic and relapsing-remitting clinical course, and patients with and without human lymphocyte antigen (HLA)-B52 allele. Among the patients with TA onset after 2000, the time from onset to diagnosis had decreased; the frequency of occlusion in aortic arch branches and the complication of moderate or severe aortic regurgitation (AR) had decreased, and the maximum dose of prednisolone and the use of immunosuppressive agents had increased. In patients with onset at age more than 40 years, the complications of coronary artery lesions and hypertension had increased, and the incidence of moderate or severe AR had decreased. In the relapsing-remitting group, the maximum dose of prednisolone and the use of immunosuppressive agents had increased, and the mean dose reduction rate of prednisolone was significantly high. There was no significant difference between patients with and without HLA-B52 allele. Conclusions: The prognosis of TA patients has improved over the past decade, which may be related to early diagnosis because of the development of noninvasive diagnostic imaging tools and improved medical treatments. (Circ J 2012; 76: 1004-1011)

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Background: The potential biological significance of hydrogen sulfide (H₂S) has attracted growing interests in recent years, but its role in the myogenic response of rat cerebral arterioles has not been explored. Methods and Results: Rats were injected with NaHS (an H₂S donor, 2-200μmol·kg^-1·day^-1, i.p.) or saline for 3 weeks. MBP was measured with a tail-cuff method. Cerebral arterioles were isolated and cannulated in an organ bath system, and vessel diameters were measured with an image-shearing device. Changes in diameter in response to stepwise increases in intravascular pressure (20-120mmHg) were investigated under no-flow conditions. After the treatments, plasma H₂S increased and MBP decreased significantly. NaHS reduced the myogenic response in a dose-dependent manner. This effect was markedly attenuated by glibenclamide, a K_ATP channel blocker. Blockade of nitric oxide (NO) production with NG-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor) enhanced, whereas removal of the endothelium abolished the inhibitory role of NaHS on the myogenic response. Conclusions: For the first time it has been demonstrated that H₂S decreases the myogenic response of cerebral arterioles in vivo, and this effect is endothelium-dependent and partially mediated by K_ATP channels. (Circ J 2012; 76: 1012-1019)

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Background: The characteristics and prognosis of patients with first-detected atrial fibrillation (AF) in Japan remain unclear. Methods and Results: First-detected AF patients without structural heart disease (n=289) were reviewed with regard to 2 symptom classifications (CCS-SAF and EHRA). In both classifications, asymptomatic patients comprised ≈40% of the patients, and patients in the most symptomatic class (≈6%) had peculiar characteristics and poor prognosis. In other symptomatic classes, symptoms affected the treatment strategy without a significant difference in the patients' backgrounds and prognosis. Conclusions: This is the first report to describe the distribution, characteristics and outcomes of first-detected AF patients according to symptom classifications. (Circ J 2012; 76: 1020-1023)

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Appendix
Chair:
· Toyoaki Murohara, Department of Cardiology, Nagoya University Graduate School of Medicine
Members:
· Tadayuki Ahiko, Health and Welfare Department, Yamagata Prefecture/Yamagata Prefectural Institute of Public Health
· Yoshinori Doi, Department of Medicine and Geriatrics, Kochi Medical School
· Takashi Hanioka, Department of Preventive and Public Health Dentistry, Fukuoka Dental Colledge
· Jitsuo Higaki, Department of Integrated Medicine and Infomatics, Ehime University Graduate School of Medicine
· Takashi Hirano, Toda Chuo General Hospital
· Mami Iida, Department of Internal Medicine, Gifu Prefectural General Medical Center
· Masahiro Ishii, Department of Pediatrics, Kitasato University, School of Medicine
· Masayuki Kaji, Shizuoka City Public Health Center
· Katsuyuki Kinoshita, Seijo Kinoshita Hospital
· Yumiko Mochizuki-Kobayashi, Division of Tobacco Policy and Education, National Cancer Center Research Institute
· Atsushi Nagai, First Department of Medicine, Tokyo Women's Medical University School of Medicine
· Keijiro Saku, Department of Cardiology, Fukuoka University School of Medicine
· Yuko Takahashi, Health Administration Center, Nara Women's University
· Teruo Takano, Nippon Medical School
· Masanobu Yanase, Department of Organ Transplantation, National Cerebral and Cardiovascular Center
· Nobuo Yosizawa, Yamagata University
Collaborators:
· Yukari Kamiyama, Divisions of Thoracic Diseases, Tochigi Cancer Center
· Masahiko Kawakami, Ryokufuso Hospital
· Hiroshi Kawane, Japanese Red Cross Hiroshima College of Nursing
· Yoshihisa Matsumura, Department of Medicine and Geriatrics, Kochi Medical School
· Masakazu Nakamura, Department of Health Promotion and Education, Osaka Medical Center for Health Science and Promotion
· Yasushi Nakamura, Department of Fetal Medicine, Chigasaki Tokushukai General Hospital
· Yuri Nakata, Department of Health Development, Institute of Industrial Ecological Science, University of Occupational and Environmental Health
· Toshiyuki Shibata, Department of Oral and Maxillofacial Sciences, Division of Organ Pathobiology, Gifu University School of Medicine
· Jun Sono, Nishinomiya City Public Health Center
· Masahiro Tsuboi, Department of Thoracic Surgery, Kanagawa Cancer Center Hospital
· Hiroshi Yamato, Department of Health Development, Institute of Industrial Ecological Science, University of Occupational and Environmental Health
Independent Assessment Committee:
· Hiroyuki Daida, Division of Cardiology, Department of Internal Medicine, Juntendo University School of Medicine
· Takayuki Ito, Department of Internal Medicine, Division of Cardiology, Aichi Medical University School of Medicine
· Hisao Ogawa, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
· Kazuaki Shimamoto, Sapporo Medical University
(The affiliations of the members are as of September 2011)

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