An early repolarization (ER) pattern in the ECG, distinguished by J-point elevation, slurring of the terminal part of the QRS and ST-segment elevation has long been recognized and considered to be a benign electrocardiographic manifestation. Experimental studies conducted over a decade ago suggested that some cases of ER may be associated with malignant arrhythmias. Validation of this hypothesis was provided by recent studies demonstrating that an ER pattern in the inferior or inferolateral leads is associated with increased risk for life-threatening arrhythmias, termed ER syndrome (ERS). Because accentuated J waves characterize both Brugada syndrome (BS) and ERS, these syndromes have been grouped under the term "J wave syndromes". ERS and BS share similar ECG characteristics, clinical outcomes and risk factors, as well as a common arrhythmic platform related to amplification of I_to-mediated J waves. Although BS and ERS differ with respect to the magnitude and lead location of abnormal J wave manifestation, they can be considered to represent a continuous spectrum of phenotypic expression. Although most subjects exhibiting an ER pattern are at minimal to no risk, mounting evidence suggests that careful attention should be paid to subjects with "high risk" ER. The challenge ahead is to be able to identify those at risk for sudden cardiac death. Here I review the clinical and genetic aspects as well as the cellular and molecular mechanisms underlying the J wave syndromes. (Circ J 2012; 76: 1054-1065)

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Although epidemiological studies in the US and Europe have confirmed that type 2 diabetes mellitus (DM) is associated with an increased risk of cardiovascular disease (CVD) events, evidence is limited in Japan. Earlier studies in Japan showed that hypertension has a major effect on atherosclerosis in relatively lean subjects, with type 2 DM contributing more to CVD events, because of a decline in blood pressure levels in both sexes and an increase in body mass index in men. Recent cohort studies in Japan using baseline assessments carried out during the 1990s have confirmed that type 2 DM is associated with an increased risk of coronary heart disease (CHD) and all types of stroke, except hemorrhagic stroke. In addition, the metabolic syndrome, a constellation of metabolic risk factors, was shown to predict CVD events in Japanese people, independent of the presence or absence of obesity. The strong association of type 2 DM with CHD (hazard ratio: 1.5-4) and ischemic stroke (hazard ratio: 2-4) events was confirmed in Japanese adults. Individuals with impaired glucose tolerance or impaired fasting glucose were also shown to have an increased risk of a CHD event, but not a stroke. (Circ J 2012; 76: 1066-1073)

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Because ischemic heart diseases (IHDs) are a major cause of mortality and heart failure, novel therapeutic approaches are expected to improve the clinical outcomes of patients with IHDs such as acute myocardial infarction and ischemic heart failure. Brief episodes of nonlethal ischemia and reperfusion before sustained ischemia or at the onset of reperfusion can reduce ischemia-reperfusion injury. These ischemic conditioning phenomena are termed "ischemic preconditioning" and "ischemic postconditioning", respectively. Furthermore, brief episodes of nonlethal ischemia and reperfusion applied to the organ or tissue distal to the heart reduce myocardial infarct size, known as "remote ischemic conditioning". The cardioprotection afforded by these ischemic conditionings can be used to treat patients with acute myocardial infarction or cardiac operations. Extensive research has determined that autacoids (eg, adenosine, bradykinin opioid) and cytokines, their respective receptors, kinase signaling pathways and mitochondrial modulation are involved in ischemic conditioning. Modification of these factors by pharmacological agents mimics the cardioprotection by ischemic conditioning and provides a novel therapeutic intervention for IHDs. Here, the potential mechanisms of ischemic conditioning and its "proof-of-concept" translational studies are reviewed. In the near future, large, multicenter, randomized, placebo-controlled, clinical trials will be required to determine whether pharmacological and ischemic conditioning can improve the clinical outcomes of patients with IHDs. (Circ J 2012; 76: 1074-1082)

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Background: In typical atrioventricular nodal reentrant tachycardia, radiofrequency (RF) ablation of the slow pathway (SP) is known to change the effective refractory period of the fast pathway (ERP_FP) after successful RF ablation of the SP. The purpose of this study was to ascertain the mechanism of the ERP_FP changes after SP ablation by comparing the results of both cryo- and RF ablation. Methods and Results: A total of 112 patients were enrolled prospectively and their electrophysiological properties analyzed before and after successful SP ablation. Patients were grouped into cryoablation (n=54) and RF ablation (n=58) groups and each group was subdivided into complete ablation (CG) and modification (MG) based on the presence of the SP after successful ablation. CG was performed in 64 patients: 30 by cryoablation and 34 by RF ablation. In patients who underwent complete SP ablation, the ERP_FP was shortened significantly after cryoablation (375±74 vs. 281±39ms, P<0.01), without significant change in the atrio-His (AH) or sinus cycle length (SCL) interval. Similarly, the ERP_FP was shortened significantly (358±106 vs. 289±84ms, P=0.01) also after RF ablation without change in AH or SCL interval. Conclusions: ERP_FP shortening was observed after complete SP ablation with both cryo- and RF ablation without significant changes in indices of autonomic activity. (Circ J 2012; 76: 1091-1096)

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Background: Recent studies have suggested that esmolol is the first choice for rate control in patients with postoperative atrial fibrillation (AF) after coronary artery bypass surgery, but side-effects of esmolol such as hypotension are problematic. To overcome this problem, landiolol, an ultra-short-acting β₁-blocker with a less negative inotropic effect than esmolol, has been developed. The aim of the present study was to investigate whether landiolol was effective for both rate control and conversion to normal sinus rhythm (NSR). Methods and Results: A prospective, randomized, open-label comparison between i.v. landiolol and diltiazem in patients with postoperative AF was undertaken between January 2008 and June 2009 in Japan. Of 335 patients included in the analysis, 71 patients went into AF. Among these 71 patients, conversion to NSR within 8h after onset of AF occurred in 19 of 35 patients (54.3%) in the landiolol group vs. 11 of 36 patients (30.6%) in the diltiazem group (P<0.05). The incidence of hypotension was lower in the landiolol group (4/35, 11.4%) compared with the diltiazem group (11/36, 30.6%; P<0.05). The incidence of bradycardia was also lower in the landiolol group (0%) compared with the diltiazem group (4/36, 11.1%; P<0.05). Conclusions: Landiolol is more effective and safer than diltiazem for patients with postoperative AF after open heart surgery. (Circ J 2012; 76: 1097-1101)

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Background: Positive peri-stent vascular remodeling (PPVR) after drug-eluting stent (DES) implantation is an important mechanism of late-acquired stent malapposition (LASM). Methods and Results: A total of 226 patients (sirolimus-eluting stent [SES], n=105; paclitaxel-eluting stent [PES], n=121) from the Poststent Optimal Stent Expansion Trial who underwent a post-intervention and 9-month follow-up intravascular ultrasound were followed clinically for 5 years. PPVR was arbitrarily defined as a >10% increase in the external elastic membrane volume index at follow-up. PPVR and LASM occurred more frequently with SESs than with PESs. The 5-year rate of major adverse cardiac events was lower with SES than with PES (10.7% vs. 23.2%, P=0.002). The late and very late stent thrombosis (ST) rate was similar between the 2 DES types, but it was higher in patients with PPVR than in those without PPVR (8.8% vs. 1.3%, P=0.009) regardless of the DES type. Early discontinuation (<1 year) of dual antiplatelet therapy (DAPT; hazard ratio [HR], 24.14; 95% confidence interval [CI]: 4.90-118.87; P<0.001), PPVR (HR, 14.94; 95%CI: 1.85-120.46; P=0.011), LASM (HR, 8.01; 95%CI: 1.93-33.16; P=0.004), and stent length (HR, 1.14; 95%CI: 0.98-1.32 per mm; P=0.078) were associated with increased risk of late and very late ST. Conclusions: PPVR and LASM development after DES implantation, along with early discontinuation of DAPT and longer stent length, are important risk factors of late and very late ST. (Circ J 2012; 76: 1102-1108)

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Background: Statins have anti-inflammatory and antiproliferative properties irrespective of their cholesterol-lowering effects. The aim of the present study was to evaluate a simvastatin-eluting stent (SimvES) in the treatment of de novo coronary lesions. Methods and Results: Forty-two patients with de novo coronary artery lesions were assigned to SimvES, bare-metal stent (BMS) or everolimus-eluting stent (EES) implantation followed by intravascular ultrasound (IVUS) for neointimal quantitative analysis. Six months later, quantitative coronary angiography (QCA) and IVUS were repeated. QCA showed no binary restenosis, a mean in-stent late loss of 1.05±0.25mm (BMS, 1.12±0.48mm; EES, 0.20±0.16mm) and a diameter stenosis of 33.5±7.1% (BMS, 35.5±15.30%; EES, 7.2±3.12%). Control IVUS showed a mean in-stent obstruction of 18.3±9.4% (BMS, 32.8±19.1%; EES, 9.8±2.4%) and a neointimal volume index of 1.58±0.75mm³/mm (BMS, 2.93±1.76mm³/mm; EES, 0.80±0.16mm³/mm). Thrombus, late incomplete apposition and major adverse cardiac events were not observed. Conclusions: In this sample of patients with de novo coronary lesions, the use of a SimvES was not related to major adverse cardiac events, but it was associated with a higher level of neointimal proliferation than expected. (Circ J 2012; 76: 1109-1114)

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Background: Perioperative risk during coronary artery bypass grafting (CABG) is reportedly high in patients with chronic renal disease. We aimed to determine postoperative mortality and morbidity and identify the perioperative risk factors of mortality during CABG in hemodialysis (HD)-dependent patients. Methods and Results: From the Japan Adult Cardiovascular Surgery Database, we compared 1,300 HD-dependent chronic renal failure patients with 18,387 non-HD patients who all underwent isolated CABG between January 2005 and December 2008. The operative mortality and mortality, including major morbidity, was 4.8% vs. 1.4% and 23.1% vs. 13.7% in the HD and non-HD groups, respectively. Preoperative predictors of operative mortality included age, chronic obstructive pulmonary disease, peripheral arterial disease, congestive heart failure, arrhythmia, preoperative inotropic agent requirement, New York Heart Association class IV, urgent or emergency operation, poor left ventricular function, aortic valve regurgitation (>2), and mitral valve regurgitation (>3). Postoperative predictors of operative mortality included stroke, infection, prolonged ventilation, pneumonia, heart block, and gastrointestinal complications. Conclusions: Compared with non-HD patients, CABG in HD patients was associated with high mortality and morbidity rates. An appropriate surgical strategy and careful perioperative assessment and management for prevention of respiratory and gastrointestinal complications might contribute to improved clinical outcomes after CABG in these patients. (Circ J 2012; 76: 1115-1120)

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Background: We aimed to evaluate if the use of an intra-aortic balloon pump (IABP) during cardioplegic arrest improves organ function and reduces endothelial activation in patients undergoing coronary artery bypass graft (CABG). Methods and Results: Five-hundred and one CABG patients were randomized into 2 groups: (Group A n=270) linear cardiopulmonary bypass (CPB); and (Group B n=231) automatic 80beats/min IABP-induced pulsatile CPB. We evaluated hemodynamic response, coagulation and fibrinolysis, transaminase, bilirubin, amylase, lactate, renal function (estimated glomerular filtration rate [eGFR], creatinine and any possibility of renal insufficiency or failure), respiratory function and endothelial markers (vascular endothelial growth factor [VEGF] and monocyte chemotactic protein-1 [MCP-1]). IABP, which induced surplus hemodynamic energy, was 21,387±4,262ergs/cm³. Group B showed lower chest drainage, transfusions, international normalized ratio, and antithrombin III, together with higher platelets, activated partial thromboplastin time, fibrinogen and D-dimer. Transaminases, bilirubin, amylase, lactate were lower in Group B; there were better results for eGFR in Group B from ICU-arrival to 48h, resulting in lower creatinine from ICU-arrival to 48h. The necessity for renal replacement therapy was lower in Group B Stage-3. Group B P_aO₂/F_iO₂ and lung compliance improved with aortic de-clamping on the first day with shorter intubation time. Group B showed lower VEGF and MCP-1. Conclusions: Pulsatile flow by IABP improves whole-body perfusion and reduces endothelial activation during CPB. (Circ J 2012; 76: 1121-1129)

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Background: Early initiation of bystander cardiopulmonary resuscitation (CPR) improves the chances of successful resuscitation and survival. The aim of the present study was to identify the attitudes of Japanese subjects toward bystander CPR and to compare them with those observed in previous studies in 1998 and 2006. Methods and Results: Participants were asked about their willingness to perform CPR in 5 different scenarios and their willingness to perform chest compression (CC) plus mouth-to-mouth ventilation (MMV) versus CC alone. A total of 2,785 individuals completed the questionnaire, including high school students, teachers, medical nurses, and medical students, whose characteristics were not statistically different from those in the previous studies. Only 15-30% of participants were likely to perform CC plus MMV, especially on a stranger or a trauma victim; these percentages in nurses and medical students were significantly lower than those in the previous studies. But 50-100% of them were likely to perform CC alone, consistent with the results obtained in 2006. The reasons for the unwillingness among laypeople to perform CC plus MMV were inadequate knowledge and/or doubt regarding whether they could perform the techniques effectively, while health-care providers reported a fear of disease transmission. Conclusions: Most participants are unlikely to perform CC plus MMV, especially on a stranger or trauma victim, but are more likely to perform CC alone, as also found in the previous studies. (Circ J 2012; 76: 1130-1135)

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Background: It remains to be examined whether urbanization and lifestyle changes are associated with the incidence and mortality from acute myocardial infarction (AMI) in Japan. Methods and Results: A total of 19,921 AMI patients (male/female 14,290/5,631) registered by the MIYAGI-AMI Registry Study from 1988 to 2009 were divided into 2 groups according to their residences; inside (urban area, n=7,316) and outside (rural area, n=11,402) of Sendai City. From 1988 to 2009, the incidence of AMI (/100,000 persons/year) increased more rapidly in the rural area (24.2 to 51.4) than in the urban area (31.3 to 40.8) (P<0.001), with rapid aging in both areas. Moreover, from 1998 to 2009, the age-adjusted incidence of AMI in young (<44 years) and middle-aged (45-64 years) male patients (both P<0.05) in the rural area increased significantly, along with a markedly increased prevalence of dyslipidemia (P<0.001). Although in-hospital mortality from AMI decreased in both areas over the last 20 years (both P<0.001), it remained relatively higher in female than in male patients and was associated with higher age of the onset, longer elapsing time for admission and lower prevalence of primary coronary intervention in female patients in both areas. Conclusions: These results demonstrate that urbanization and lifestyle changes have been associated with the incidence and mortality from AMI, although sex differences still remain to be improved. (Circ J 2012; 76: 1136-1144)

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Background: Early (e')/late (a') diastolic mitral annular velocity ratio is a powerful independent predictor of poor prognosis in patients with left ventricular (LV) dysfunction. Doppler tissue imaging, however, may change over time according to intervention and medical treatment. The aim of the present study was to prospectively evaluate whether, in clinically stable patients with chronic heart failure (CHF), the decrease of an initially high e'/a' ratio on long-term therapy predicts a more favorable outcome. Methods and Results: One hundred and eighty-one adult patients with CHF and high e'/a' ratio (≥0.74) underwent repeat echocardiography 6 months after the initial examination, and were then followed up for a mean period of 20 months. After 6 months, e'/a' ratio did not change in 95 patients, whereas it was significantly decreased (<0.74) in the remaining 86 patients. During follow-up, 55 participants (30%) had cardiac events. According to multivariate Cox regression analysis, decrease in e'/a' ratio, initial New York Heart Association class III or IV, and change in LV mass index as well as in systolic mitral annular velocities emerged as independent predictors of survival. Conclusions: The decrease of an initially high e'/a' ratio on long-term therapy predicts a more favorable outcome in clinically stable patients with CHF. (Circ J 2012; 76: 1145-1150)

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Background: There is a paucity of data on the effects of adherence to treatment on outcomes for patients with acute heart failure (HF) in Korea. We used HF performance measures to evaluate overall adherence and whether this affects clinical outcomes. Methods and Results: Among 3,466 patients in the Korean Heart Failure Registry, 1,527 patients with left ventricular systolic dysfunction (LVSD) who survived hospitalization were evaluated. Modified validated performance measures were defined as follows: use at discharge of angiotensin-converting enzyme inhibitor (ACEI), angiotensin-receptor II blocker (ARB), β-blocker or aldosterone receptor antagonist. Adherence to performance measures were as follows: ACEI or ARB at discharge, 68.0%; β-blocker at discharge, 40.9%; aldosterone receptor antagonist at discharge, 37.5%. On multivariate analysis, adherence to the measure of ACEI or ARB use at discharge was significantly associated with mortality (odds ratio (OR), 0.344; 95% confidence interval (CI), 0.123-0.964), readmission (OR, 0.180; 95%CI, 0.062-0.522) and mortality/readmission (OR, 0.297; 95%CI, 0.125-0.707) at 60 days and that for β-blocker with mortality (OR, 0.337; 95%CI, 0.147-0.774) at 1 year. Conclusions: For patients with LVSD in Korea, adherence to treatment performance measures, including prescription of an ACEI/ARB and β-blocker use at discharge, is associated with improved clinical outcomes. (Circ J 2012; 76: 1151-1158)

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Background: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are widely used to lower plasma cholesterol levels, have been reported to have various pleiotropic effects such as protective effect of endothelial cells, angiogenic effect, antioxidant effect and anti-inflammatory effect. It is unclear, however, whether statins have any effects on the progression from left ventricular (LV) hypertrophy to heart failure in the established hypertrophied heart. Methods and Results: C57BL/6 mice were treated with pitavastatin (pitava) or vehicle (control) from 2 weeks (established hypertrophy stage) after transverse aortic constriction (TAC) and the treatment was continued for 4 weeks. Pitavastatin significantly inhibited the progression from LV hypertrophy to heart failure as assessed on echocardiography. The cardiomyocyte cross-sectional area was significantly increased in the control group compared to the sham-operated mice (sham group), but it was not significantly different between the control group and the pitava group at 6 weeks after TAC. Moreover, pitavastatin induced myocardial angiogenesis (ratio of number of endothelial cells to cardiomyocytes) and decreased the myocardial fibrosis and oxidative stress. The expression of angiopoietin-1 in the heart was significantly increased by pitavastatin at 6 weeks after TAC. Conclusions: Pitavastatin has preventive effects on the progression of heart failure even in the hypertrophied heart. (Circ J 2012; 76: 1159-1168)

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Background: Acute heart failure syndrome (AHFS) remains a major clinical challenge because of its poor prognosis. Nicorandil, a hybrid compound of a potassium-channel opener and nitric oxide donor, has been reported to improve the prognosis of ischemic heart disease. We sought to evaluate the effect of intravenous nicorandil on the mid-term prognosis of AHFS. Methods and Results: A total of 402 consecutive patients who were hospitalized for AHFS were divided into 2 groups according to the use of intravenous nicorandil: 78 patients in the Nicorandil group and 324 patients in the Control group. During the 180-day follow-up, death or rehospitalization for heart failure occurred in 7 patients in the Nicorandil group (9.0%) and in 75 patients (23.2%) in the Control group. Event-free survival rates were significantly higher in the Nicorandil group than in the Control group (P=0.006). Multivariate Cox hazard analysis revealed that age (hazard ratio (HR)=1.066, P<0.0001), systolic blood pressure (HR=0.983, P=0.0023), New York Heart Association class III/IV (HR=6.550, P<0.0001), log creatinine (HR=3.866, P=0.0106), and use of intravenous nicorandil (HR=0.179, P<0.0001) were significant predictive factors for the occurrence of death or rehospitalization for heart failure. Conclusions: Intravenous nicorandil treatment from the urgent phase of AHFS may improve the prognosis. (Circ J 2012; 76: 1169-1176)

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Background: The recently developed real-time 3-dimensional echocardiography (RT3DE) is a promising imaging method to quantify cardiac chamber volumes and their functions in clinical practice. However, normal reference values of RT3DE parameters have not been fully investigated in a large, healthy Japanese population. Methods and Results: This study consisted of 410 healthy subjects aged from 20 to 69 years who had a RT3DE at one of the 23 collaborating institutions. All subjects had no history of cardiac disease and no risk factors. The mean values in men and women were as follows: 50±12ml/m² and 46±9ml/m² for left ventricular (LV) end-diastolic volume index, 19±5ml/m² and 17±4ml/m² for end-systolic volume index, 61±4% and 63±4% for ejection fraction, 64±12g/m² and 56±11g/m² for mass index, 23±6ml/m² and 24±6ml/m² for left atrial (LA) maximum volume index, 10±3ml/m² and 10±3ml/m² for minimum volume index, and 58±6% and 58±6% for percent volume change. LV sizes decreased with age, whereas LV mass index did not change. LA sizes slightly increased with age. Conclusions: This multicenter investigation determined normal reference values for LV and LA sizes, and their functional parameters on RT3DE in a large, healthy Japanese population. The results of the present study support the use of RT3DE for the diagnosis and management of cardiovascular disease. (Circ J 2012; 76: 1177-1181)

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Background: To clarify multidetector computed tomography (MDCT) findings of attenuated plaque detected by intravascular ultrasound (IVUS). Methods and Results: One hundred and fifty-four patients with stable angina underwent MDCT before IVUS. The attenuated plaque was identified in the targeted artery with IVUS, and the same artery was analyzed with MDCT for the presence of a high density area (HDA) >130 Hounsfield units (HU), and a low density area (LDA) <30HU. A HDA in attenuated plaque was compared with that in calcified plaque. Ten attenuated plaques and 15 calcified plaques were identified in 9 of 154 patients (males=9, 66.2±9.5 years). Eight of the 10 attenuated plaques and all 15 calcified plaques were accompanied with a HDA on MDCT. The HDA ranged from 174 to 667HU (mean 389.0±148.3HU) in the 8 attenuated plaques, and from 545 to 1,205HU (mean 920.9±215.9HU) in 15 calcified plaques. There was a significant difference in CT density of the HDA between the attenuated and calcified plaque (P<0.001). All attenuated plaques contained LDA <30HU in the portions without HDA. Conclusions: MDCT has the ability to demonstrate attenuated plaque as the combination of HDA (approximately 400HU on average) and LDA <30HU. The HDA can be differentiated from calcified plaque by its lower CT density value. (Circ J 2012; 76: 1182-1189)

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Background: Advancement in chemotherapy has significantly improved the prognosis of cancer patients. However, many anticancer drugs have serious cardiovascular side effects. We assessed doxorubicin-induced cardiac toxicity (DCT) during and after preoperative chemotherapy using gated ^99mTc-hexakis-2-methoxyisobutylisonitrile (MIBI) single photon emission computed tomography (SPECT) in patients with malignant bone and soft tissue tumors. Methods and Results: Gated ^99mTc-MIBI SPECT was performed before, and after the middle and final courses of preoperative chemotherapy. Gated ^99mTc-MIBI SPECT was quantitatively analyzed with QGS/QPS software. We also assessed the reproducibility of measurements of global and regional functions from gated SPECT images. Twenty-eight patients (19 males and 9 females), eligible for preoperative chemotherapy, were included. All patients had normal myocardial perfusion images based on QPS during preoperative chemotherapy. Wall thickening (WT) and motion (WM) decreased after the middle course of preoperative chemotherapy compared to baseline. After the final course of preoperative chemotherapy, significant decreases of ejection fraction, WT and WM, and one-third mean filling rate were observed compared to baseline. By regression analysis, correlation coefficients of inter- and intra-observer reproducibility of global and regional functions were excellent (r≥0.95). Conclusions: Gated ^99mTc-MIBI SPECT can monitor the deterioration of cardiac function in asymptomatic patients with possible DCT. WT and WM might be useful as early markers of ventricular dysfunction due to DCT. (Circ J 2012; 76: 1190-1196)

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Background: Previously the stabilization of coronary plaque with atorvastatin was demonstrated in the TWINS (evaluaTion With simultaneous angIoscopy and iNtravascular ultraSound) study. The influence of the low-density lipoprotein cholesterol (LDL-C) level on plaque stabilization was analyzed. Methods and Results: Patients (n=29) with hypercholesterolemia and coronary artery disease (CAD) were analyzed. They received atorvastatin (10-20mg/day) for 80 weeks and were divided into low (<91mg/dl) and high (≥91mg/dl) LDL-C groups based on their 80-week LDL-C level. Angioscopy was performed before and after treatment. Yellow coronary plaques were classified into six grades (grades 0 to 5) and mean grade was determined for each patient. The LDL-C levels at week 28 and 80 were reduced in both low LDL-C groups (n=14, 140.3 to 77.9 and 75.9mg/dl; P<0.001 both groups) and high LDL-C groups (n=15, 151.7 to 93.0 and 99.1mg/dl; P<0.001 both groups). Significant improvement in the mean grade was shown in the low LDL-C groups (1.44 to 1.00 and 1.05; P=0.003 both groups) at week 28 and 80 vs. no significant change in high LDL-C groups (1.43 to 1.23 and 1.28; P=0.032 and P=0.169 respectively). Conclusions: Adequate reduction of LDL-C is important for the stabilization of coronary plaques. (Circ J 2012; 76: 1197-1202)

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Background: Carbon dioxide (CO₂) baths have been used to treat a variety of diseases, but developing an artificial bath of highly concentrated CO₂ is difficult. Here, we tried the efficacy of a novel device instead of a CO₂ bath. Methods and Results: Using a device equipped with double fluid nozzles, CO₂ gas and H₂O were compounded and compressed at 4 barometric pressures. As a result, CO₂ gas was dissolved in H₂O, which contained a few micrometers of CO₂ particles, namely, a CO₂ mist. Wistar rats with myocardial infarction (MI) by ligation of the left coronary artery were percutaneously administered CO₂ mist or CO₂ gas alone or no treatment for 30min daily. With regard to tissue blood flow during treatment, the group treated with CO₂ mist had significantly increased tissue oxygenated hemoglobin levels and tissue saturation levels, and significantly decreased deoxygenated hemoglobin levels compared with the group treated with CO₂ gas. After 4 weeks treatment, the group treated with CO₂ mist had a significantly improved ejection fraction by echocardiography compared with the untreated group. Interestingly, the group treated with CO₂ mist had significantly increased nitrate concentrations in serum and vascular endothelial growth factor mRNA expression levels in the myocardium compared with the untreated group. Conclusions: Our new mist production device may be potentially useful for the treatment of heart failure caused by MI. (Circ J 2012; 76: 1203-1212)

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Background: The correlations between circulating angiogenic cell mobilizations and improvement of microvascular integrity were investigated in patients (n=110) with acute myocardial infarction (AMI) during an 8-month follow up. Methods and Results: Coronary flow reserve (CFR) was measured at baseline and at 8 months by using an intracoronary Doppler wire. Serial changes in the absolute numbers of circulating angiogenic cells such as CD34+, CXCR4+, CD117+, CD133+ and C-met+ were measured at baseline, day 1, day 5 and at 8 months. The absolute numbers of circulating angiogenic cells at day 1 were significantly higher than those at baseline. A positive correlation was found between the numbers of circulating angiogenic cells of CD34+, CXCR4+, CD117+ and CD133+ cells at day 1 and the CFR changes from baseline. The cut-off value of CFR changes at 8 months by a receiver operating characteristic curve between a circulating CD34+ cell at day 1 and changes of CFR at 8 months was 0. Late-loss showed the positive correlation with the absolute number of C-met+ cells and the negative correlation with the absolute number of CXCR4+ cells after AMI. The negative correlation was found between changes in high-sensitive C-reactive protein and soluble intercellular adhesion molecule-1 and changes in CFR at 8 months. Conclusions: The recovery of microvascular integrity after acute ischemic injury was expedited by the increases in circulating angiogenic cell mobilization together with the greater decreases in inflammatory cytokines. The improvement in CFR could be predicted by the measurement of circulating angiogenic cells after AMI. (Circ J 2012; 76: 1213-1221)

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Background: Myocarditis (MC) is an important cause of cardiac dysfunction in children. Fulminant MC is sometimes fatal, and sequelae may develop during follow-up. We conducted a nationwide survey to determine the clinico-epidemiological features of MC in Japanese children and adolescents. Methods and Results: Survey questionnaires were mailed to 627 hospitals, which were asked if they had treated MC patients aged between 1 month and 17 years during the period from January 1997 through December 2002. Responses were collected until December 2005, and data were collected and analyzed until January 2008. A total of 169 patients were reported: 64 fulminant cases, 89 acute cases, and 8 chronic cases. Incidence was 43.5 cases/year and 0.26 cases/100,000. Pathogens were identified in 37 patients; coxsackie virus accounted for 60%. Major cardiovascular manifestations at onset were congestive heart failure, refractory arrhythmia, and syncope in 70, 37, and 17 patients, respectively. Intravenous immunoglobulin was administered to 73 patients. Mechanical support seemed to be effective and life-saving. Among the 169 patients, 123 survived. Cardiovascular sequelae were reported in 49 patients. Conclusions: The survival rate for children with fulminant MC was disappointing. Overall, two-thirds of survivors had no sequelae. Mechanical support may reduce the mortality and the risk of clinical worsening. (Circ J 2012; 76: 1222-1228)

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Background: Transcatheter closure of atrial septal defects (ASDs) has become an alternative to open surgical procedures. The Amplatzer septal occluder (ASO) has been approved since 2005 in Japan, but there are still many concerns about adverse events, and information about outcomes and complications is limited. The objective of this study was to assess the immediate and mid-term outcomes of device closure of secundum ASDs. Methods and Results: From August 2005 to July 2011, 208 consecutive patients with a significant secundum ASD underwent percutaneous closure with the ASO [72 males, 136 females; median age, 7.3 years (range, 3.3-21.9 years)]. Follow-up was available for 206 (99%) patients. Device closure was successful in 203 (98%) patients. Device embolization occurred in 1 case within 1h of device implantation, but the device was surgically retrieved without any neurological sequelae. During the follow-up period, complete closure was observed in 202 of 203 patients. There were no cases of erosions, late embolization, thrombus formation, or death. Conclusions: Transcatheter closure of ASDs using the ASO is safe and effective, with excellent results during mid-term follow-up. Appropriate patient selection and accurate device selection is mandatory to avoid serious complications. (Circ J 2012; 76: 1229-1234)

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Background: Post-capillary pulmonary hypertension (pc-PH) is a disorder with elevated pulmonary arterial pressure and pulmonary vascular resistance (PVR) because of left heart disease (LHD), and is classified as reactive (PVR >2.5 WU) or passive (PVR ≤2.5 WU). However, the clinical significance of these pc-PH subtypes remains to be elucidated. Methods and Results: We examined 676 consecutive patients with chronic heart failure (CHF) (NYHA ≥2), and found that 158 (23%) had pc-PH: reactive pc-PH in 58 and passive pc-PH in 100. Univariate analysis showed that 4 factors were significantly associated with reactive pc-PH and multivariate analysis showed that female sex was the only independent predictor of reactive pc-PH (odds ratio 2.12, 95% confidence interval (CI) 1.05-4.30, P=0.03). During the mean follow-up period of 2.6 years, 125 CHF patients (18%) died, including 22 with reactive pc-PH and 24 with passive pc-PH (P<0.001). Multivariate Cox regression analysis showed that elevated PVR was independently associated with higher mortality (hazard ratio 1.18, 95%CI 1.03-1.35, P=0.02). Kaplan-Meier analysis demonstrated that the prognosis of patients with reactive pc-PH was significantly worse than for those with no PH or passive pc-PH. Reactive pc-PH was a significant prognostic factor regardless of CHF etiology (ischemic vs. non-ischemic) or reduced/preserved LV ejection fraction (HFrEF vs. HFpEF). Conclusions: Reactive pc-PH is characterized by predominant female sex and is a significant prognostic factor of LHD with PH. (Circ J 2012; 76: 1235-1244)

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Background: Sildenafil has been demonstrated as effective for the treatment of pulmonary arterial hypertension (PAH). The purpose of this study was to investigate the occurrence of clinical events after sildenafil monotreatment as a first-line therapy in patients with PAH over a long-term observation period. Methods and Results: Sildenafil was administered as a first-line drug to 46 patients with PAH (including 24 patients with idiopathic PAH) during 2003-2010. We investigated subsequent clinical events such as the addition of epoprostenol, hospitalization for right-side heart failure, and death. All the hemodynamic parameters and the 6-min walk distance improved significantly in the enrolled patients as a whole receiving sildenafil treatment; 15 (33%) of the 46 patients required the addition of epoprostenol during follow-up. Kaplan-Meier analysis demonstrated that more than 60% of the patients receiving first-line sildenafil treatment did not require the addition of epoprostenol for a 5-year period. Furthermore, the 5-year survival rate after first-line sildenafil treatment was 81%. Finally, more than 75% of the enrolled patients did not reach the composite endpoint of hospitalization for right-side heart failure and death for a 5-year period. Conclusions: This study describes the long-term outcome of patients with PAH receiving sildenafil monotreatment as a first-line therapy and suggests that it is a promising therapeutic strategy. (Circ J 2012; 76: 1245-1252)

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Background: The incidence of inferior vena cava anomalies in patients with horseshoe kidney is higher than that reported in the general population. As far as we know, no studies have reported the incidence and variations of superior vena cava (SVC) anomalies using multidetector-row computed tomography (MDCT) in patients with horseshoe kidney. Methods and Results: Using MDCT, 71 patients with a horseshoe kidney (group A: 45 males, 26 females; mean age, 60.1±10.2 years) and 2,292 patients without a horseshoe kidney (group B: 1,385 males, 907 females; mean age, 61.1±13.5 years) were retrospectively evaluated for the incidence and variations of SVC anomalies, and the incidence of an anomalous SVC was compared between groups. An anomalous SVC was identified in 3 group A patients (4.2%) (double SVC, n=2; persistent left SVC without a right SVC, n=1) and 5 group B patients (0.22%) (double SVC, n=3; persistent left SVC without a right SVC, n=2). MDCT revealed a significantly higher incidence of anomalous SVC in patients with a horseshoe kidney than in those without a horseshoe kidney (P<0.001). Conclusions: Patients with horseshoe kidney frequently have an anomalous SVC. Although the incidence of horseshoe kidney is related in some way to that of an anomalous SVC, the reasons for their coexistence remain unclear. (Circ J 2012; 76: 1253-1258)

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Background: Several clinical trials have reported inconsistent findings for the effects of rosuvastatin (RSV) and atorvastatin (ATV) on renal function. The aim of this meta-analysis was to investigate the effects of these 2 statins on glomerular filtration rate (GFR) and proteinuria respectively, and determine which is better. Methods and Results: PubMed, CENTRAL, Web of Knowledge, and ClinicalTrials.gov website were searched for randomized controlled trials. Eligible studies reported GFR and/or proteinuria during treatment with RSV or ATV compared with control (placebo, no statins, or usual care), or RSV compared with ATV head to head. Trials that enrolled dialysis participants and teenagers were excluded. Statistical heterogeneity was assessed using the I² statistic, and pooled results using the random-effects model. The standardized mean differences (SMD) and ratio of means (ROM) were measured, respectively, to analyze GFR and proteinuria. Sixteen trials with a total number of 24,278 participants were identified. Compared with control, changes in the SMD of GFR were 0.04 (95% confidence interval [CI]: 0.01-0.07) and 0.59 (95%CI: 0.12-1.06) for RSV and ATV, respectively. The ROMs of proteinuria were 0.59 (95%CI: 0.46-0.74) for RSV vs. the control group, and 1.23 (95%CI: 1.05-1.43) in the head-to-head comparison. Conclusions: Both RSV and ATV improve GFR, and ATV seems to be more effective in reducing proteinuria. The validity and clinical significance require high-quality intensive studies with composite clinic endpoints of kidney and death. (Circ J 2012; 76: 1259-1266)

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Background: The adventitia plays an important role in and is considered to be the initiating site for vascular remodeling. Urotensin II (UII) and angiotensin II (Ang II) are the two most important vascular peptides involved in vascular remodeling in the adventitia. Nevertheless, little is known about their effect on the expression of vascular endothelial growth factor (VEGF). It was hypothesized that both UII and Ang II could induce VEGF expression in adventitial fibroblasts and VEGF may play a role in cell proliferation and collagen I synthesis induced by UII or Ang II. Methods and Results: Growth-arrested adventitial fibroblasts were incubated in serum-free medium with UII and/or Ang II and inhibitors of the mitogen-activated protein kinase (MAPK) pathway or VEGF-neutralizing antibodies. The VEGF expression was evaluated using enzyme-linked immunosorbent assay (ELISA), while the proliferation and collagen I synthesis were detected using methyl thiazol tetrazolium (MTT) assay and ELISA. It was found that: (1) both UII and Ang II could stimulate VEGF expression in adventitial fibroblasts and they had a synergistic effect; (2) MAPK pathway inhibitors could inhibit VEGF secretion induced by UII and/or Ang II; and (3) VEGF-neutralizing antibodies could inhibit UII/Ang II-induced cell proliferation and collagen synthesis in adventitial fibroblasts. Conclusions: Induction of VEGF expression may be a new mechanism involved in vascular remodeling for UII and Ang II. (Circ J 2012; 76: 1267-1273)

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Background: Most atherosclerotic lesions are vascularized, so neovessels may also contribute to plaque progression and vulnerability, but their precise role of neovessels in atherosclerosis is still unknown. The aim of this study was to analyze the possible relationships among neovascularization, relevant angiogenic factors, and plaque vulnerability in patients with advanced carotid artery stenosis. Methods and Results: The study group comprised 56 patients (stable: n=28, unstable: n=28) with advanced carotid artery stenosis (>70%). Immunohistochemistry was performed for smooth muscle, endothelial, and inflammatory cells, macrophages, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), platelet-derived growth factor (PDGF), and angiopoietin-1,-2 (Ang-1,-2). Furthermore, the concentrations of angiogenic factors were measured in serum. Quantitative expression analysis was performed by SYBR-Green-based real-time polymerase chain reaction. Compared with stable carotid lesions, unstable carotid lesions showed 1.8-fold increase in neovascularization (P=0.013), which significantly correlated with accumulation of inflammatory cells (factor 1.9, P<0.001). In unstable lesions, compared with stable lesions, VEGF was 1.7-fold increased (P=0.032) and Ang-1 was 1.9-fold reduced (P=0.029). Furthermore, VEGF was higher in the blood of patients with unstable plaques than in stable plaques (0.32±0.22 vs. 0.22±0.16ng/ml; P=0.002). Significant correlations were observed between plaque vulnerability, VEGF, neovascularization and inflammatory cells. Conclusions: Our results show a close association between neovascularization, expression of angiogenic factors, inflammation, and plaque vulnerability in patients with advanced carotid stenosis. (Circ J 2012; 76: 1274-1282)

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Background: After the East Japan Earthquake disaster there may have been a deterioration of patients with cardiovascular diseases. Methods and Results: We examined the data from 189 consecutive patients implanted with cardiovascular devices for the 6-month period before and after the Earthquake. In 170 patients with defibrillators, the number who experienced tachyarrhythmias increased significantly after the Earthquake (28±5 vs. 34±3 patients/month, P<0.05). In 74 patients with biventricular pacemakers, the number of heart failure hospitalizations significantly increased after the Earthquake (1.2±1.0 vs. 2.7±1.2 patients/month, P<0.05). Conclusions: The East Japan Earthquake disaster unfavorably affected patients implanted with defibrillators or biventricular pacemakers. (Circ J 2012; 76: 1283-1285)

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(Circ J 2012; 76: 891-899)

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