Despite increasing competition from percutaneous interventions and other novel methods of non-surgical coronary revascularization, coronary artery bypass grafting (CABG) remains one of the most definitive and durable treatments for coronary artery disease, especially for those patients with extensive and diffuse disease. In recent years the CABG procedure itself has undergone innovation and evolution. This review article provides a brief historical perspective on the procedure, and examines the current state of modern variations including off-pump, limited-access, and robotic-assisted CABG.  (Circ J 2010; 74: 1031 - 1037)

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Electrical device therapy began 50 years ago with the external defibrillator, and was followed subsequently with the introduction of implantable cardiac pacemakers, defibrillators, and resynchronization devices to prevent bradycardia, sudden arrhythmic death, and heart failure. During the past 20 years the Multicenter Automatic Defibrillator Implantation Trial (MADIT) research group has carried out a series of trials, including the MADIT-I, MADIT-II, and MADIT-III (MADIT-CRT), that have focused on improving the outcomes for patients with ischemic and nonischemic cardiac disease. The most recent MADIT-CRT trial showed that a cardiac resynchronization therapy device with defibrillator (CRT-D) was effective in reducing the risk of heart failure or death, whichever came first, in cardiac patients who were asymptomatic or minimally symptomatic (New York Heart Association class I or II) with reduced ejection fraction ≤0.30 and wide QRS complex ≥130 ms when compared with an implantable cardiac defibrillator (ICD) device. The family of MADIT ICD and CRT-D trials have provided a firm foundation for improving the clinical management of at-risk cardiac patients as the second decade of the 21^st century begins.  (Circ J 2010; 74: 1038 - 1041)

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Stromal cells, composed of fibroblasts, microvascular endothelial cells, immune cells and inflammatory cells, are critical determinants of the mechanical properties and function of the heart and vasculature, and the mechanisms whereby these types of cells are activated are important to understand the progression of cardiovascular diseases. Emerging studies have suggested that the activation of autocrine and paracrine signaling pathways by stromal cell-derived growth factors, cytokines and bioactive molecules contributes to disease progression. Disruption of the stromal network will result in alterations in the geometry and function in these organs. Interventions targeting the stromal cells (eg, myofibroblasts, microvascular endothelial cells, inflammatory cells) by pharmacological agents or direct gene delivery/small interfering RNA would be potential novel therapeutic strategies to prevent/attenuate the progression of cardiovascular disorders.  (Circ J 2010; 74: 1042 - 1050)

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Pulmonary vein (PV) isolation is a cornerstone of atrial fibrillation (AF) ablation. This technique is now widely spread all over the world. Numerous studies have demonstrated that complete PV isolation with circular lesions has a better outcome in patients with paroxysmal and persistent AF. In contrast, it may lead to iatrogenic left atrial tachycardia (AT) as an adverse effect of the ablation. Three mechanisms of AT can develop after AF ablation, including macro-reentrant AT, focal AT and PV tachycardia. AT after AF ablation is predominantly related to the arrhythmogenicity of the PVs, lesions created by the ablation procedure and damaged atrial tissue from the persistent tachyarrhythmias. The 3-dimensional maps play an important role in clarifying the mechanism of the tachycardia and the optimal ablation site for ATs.  (Circ J 2010; 74: 1051 - 1058)

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Hypertensive heart disease and post-myocardial-infarction heart failure (HF) are leading causes of cardiovascular mortality in industrialized countries. To date, pharmacological agents that block cell surface receptors for neurohormonal factors have been used, but despite such conventional therapy, HF is increasing in incidence worldwide. During the development and deterioration process of HF, cardiomyocytes undergo maladaptive hypertrophy, which markedly influences their gene expression. Regulation of histone acetylation by histone acetyltransferase (eg, p300) and histone deacetylase plays an important role in this process. Increasing evidence suggests that the excessive acetylation of cardiomyocyte nuclei is a hallmark of maladaptive cardiomyocyte hypertrophy. Curcumin inhibits p300-mediated nuclear acetylation, suggesting its usefulness in HF treatment. Clinical application of this natural compound, which is inexpensive and safe, should be established in the near future.  (Circ J 2010; 74: 1059 - 1066)

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Background: Transesophageal echocardiography (TEE) is useful for detecting left atrial (LA) thrombus prior to percutaneous LA catheter ablation in patients with atrial fibrillation (AF). This study was designed to evaluate clinical predictors of LA thrombus and determine indications for TEE screening prior to LA ablation. Methods and Results: The study consisted of 446 patients with drug-resistant AF who were scheduled to undergo initial LA ablation (age 59±11 years, 312 males, 136 persistent AF). TEE was performed in all cases within 24 h before ablation. We assessed clinical parameters including CHADS₂ score and echocardiographic parameters. LA thrombus was detected in 13 cases (2.9%) prior to LA ablation (67±8 years, 10 males, 12 persistent AF). In multiple logistic regression analysis, advanced age (odds ratio (OR) 1.1, 95% confidence interval (CI) 1.0-1.2; P<0.05), persistent AF (OR 38.1, 95%CI 1.4-988; P<0.05) and structural heart diseases (OR 29.8, 95%CI 2.8-383; P<0.01) were independent positive predictors of LA thrombus prior to ablation, while CHADS₂ score and LA volume were not significant predictors. None of the 136 patients with paroxysmal lone AF whose age was below 60 years had LA thrombus prior to ablation. Conclusions: It might be reasonable to omit TEE as a screening examination for LA thrombus prior to LA ablation in younger paroxysmal lone AF patients.  (Circ J 2010; 74: 1081 - 1086)

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Background: Connexin-43 (Cx43) expression is reduced or redistributed in heart disease. Restraint or other emotional stressors might cause sudden death in persons with such diseases, but the mechanism of death and its connection to Cx43 during restraint remain unknown. Whether Cx43 distribution or gap junction (GJ) function during restraint is involved in sudden arrhythmic death in rats is addressed in this study. Methods and Results: Male Sprague - Dawley rats underwent immobilization (IMO), and individual electrocardiographic responses were monitored by telemetry. Heart sections were used to examine ventricular Cx43 distribution, and GJ intercellular communication (GJIC) activity was assessed using a dye-transfer assay. IMO induced the translocation of Cx43 into to the GJ-rich fraction, with a peak at 60 min. During IMO, Cx43 immunofluorescence was enhanced at intercalated discs, in association with GJIC activation, and premature ventricular contractions (PVCs) increased. In the presence of the GJ inhibitor, carbenoxolone (0.25 mg·kg^-1·h^-1), IMO induced lethal ventricular tachycardia or fibrillation in 21.7% of rats, in association with QRS prolongation and increased PVCs. Conclusions: IMO causes Cx43 translocation to intercalated discs, thereby reducing vulnerability to lethal arrhythmias via enhancing GJ coupling.  (Circ J 2010; 74: 1087 - 1095)

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Background: Complete isolation of the posterior left atrium, including all pulmonary veins (box isolation), is a feasible and safe atrial fibrillation (AF) treatment method. Data on long-term effects of box isolation on autonomic function, however, remain limited. Methods and Results: A total of 92 patients (paroxysmal AF, n=76; persistent AF, n=16) undergoing box isolation with non-contact mapping were studied. Twenty-four-hours ambulatory electrocardiograms and transthoracic echocardiography were done at baseline and after 2 days, and at 3, 6 and 12 months. Autonomic functions were evaluated by means of heart rate variability (HRV). During a mean follow up of 16±5 months, no AF episodes were detected in 76 patients while AF recurred in 16. Significant long-term HRV attenuations were observed in all patients without AF recurrence, but not in those with AF recurrence. In patients without AF recurrence, the natural logarithm (Ln) high-frequency (HF) decreased significantly from 5.5±1.3 ms² (before) to 4.2±0.9 ms² (after 12 months, P<0.001) and the ratio of the low-frequency to HF power increased significantly from 2.4±2.0 (before) to 3.4±2.3 (after 12 months, P=0.05). LnHF was significantly lower in patients without than in those with AF recurrence during the 12-month period after ablation. Cardiac function improved significantly in patients without AF recurrence after box isolation. Conclusions: Changes in the sympathovagal balance with box isolation may contribute to AF prevention.  (Circ J 2010; 74: 1096 - 1103)

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Background: In previous studies, the minimal luminal diameter (MLD) of lesions treated with a bare metal stent (BMS) was shown to improve from 6 months to 3 years. However, the long-term response to a sirolimus-eluting stent (SES) implantation remains unclear. Methods and Results: To evaluate 6-month, 12-month and 3-year outcomes, clinical and angiographic follow-up data were analyzed for 367 consecutive patients (506 de novo lesions) who underwent successful SES implantation compared to follow-up data for 617 consecutive patients (802 de novo lesions) who underwent BMS implantation. Clinical follow-up information was obtained for 363 SES-treated patients (98.9%) and 581 BMS-treated patients (94.2%) at 1 year, and 334 SES-treated patients (91.0%) and 566 BMS-treated patients (91.7%) at 3 years. At 3 years, there were no significant differences in the cumulative cardiac death and myocardial infarction. Target lesion revascularization (TLR) rates were significantly higher in BMS-treated patients than in SES-treated patients. In BMS-treated patients, most TLR was performed within 450 days, however, after 450 days, the TLR rate was significantly lower than that for the SES-treated patients. In quantitative coronary angiographic data, among lesions that required no revascularization at the initial 12-month follow up, MLD increased significantly from the 12-month to the 3-year follow-up angiography in BMS-treated lesions. However, MLD decreased significantly in SES-treated lesions. Conclusions: From a 12-month follow-up to a 3-year follow-up, stenosis in BMS-treated lesions regressed, but stenosis in SES-treated lesions progressed. And late TLR was more frequently required in the SES-treated patients.  (Circ J 2010; 74: 1104 - 1110)

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Background: Concerns exist regarding the long-term efficacy and safety of drug-eluting stents (DES) in patients with ST-segment elevation myocardial infarction (STEMI). The study aimed to compare the mid- to long-term outcomes of DES vs bare metal stents (BMS) in patients with STEMI in a real-world setting. Methods and Results: Six hundred and eighty four consecutive patients with STEMI who underwent percutaneous coronary intervention from January 2003 to December 2006 were analyzed; 539 patients (78.8%) with DES and 145 (21.2%) with BMS. Patients were followed for the occurrence of target vessel failure (TVF); a composite of cardiac death, non-fatal myocardial infarction, or target vessel revascularization (TVR). After a follow-up duration of 36 months, the TVF rate was significant lower in the DES group compared with the BMS group (17.8% vs 34.5%, P<0.01), which was mainly driven by a decrease in TVR (9.1% vs 22.8%, P<0.01). Diabetic patients, those with multivessel disease and those treated with smaller or longer stents benefited more from DES implantation. Propensity score matching concordantly indicated a benefit of DES with regard to TVF (13.5% vs 34.2%; P<0.01). The overall incidence of stent thrombosis (ST) in each group was comparable (3.9% vs 4.1%, P=0.47). Conclusions: Compared to BMS, the mid- to long-term outcome was better in patients receiving DES for acute STEMI. This was driven mainly by a reduction in repeat revascularization.  (Circ J 2010; 74: 1111 - 1120)

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Background: Metabolic syndrome (MetS) is a clustering of risk factors, including dyslipidemia, hypertension, and increased plasma glucose levels, which increase the risk of cardiovascular disease and renal impairment. We retrospectively analyzed the relationship between MetS and acute kidney injury (AKI) after off-pump coronary artery bypass surgery (OPCAB). Methods and Results: Patients who underwent isolated OPCAB between January 2006 and December 2008 were identified. Patients were grouped by using the National Cholesterol Education Program-Adult Treatment Panel III criteria with body mass index instead of waist circumference. From a total of 740 patients, 320 patients (43.2%) were in the MetS group, and 420 patients (56.8%) were in the non-MetS group. Postoperative AKI occurred in 84 patients (26.2%) in the MetS group and 44 patients (10.5%) in the non-MetS group (P<0.05). Multivariate logistic regression identified diabetes mellitus (odds ratio (OR), 1.83; 95% confidence interval (CI), 1.12-3.00; P=0.02), chronic kidney disease (OR, 4.79; 95%CI, 2.85-8.07; P<0.001), MetS (OR, 3.14; 95%CI, 1.79-5.49; P=0.001), and emergency surgery (OR, 5.08; 95%CI, 1.01-25.6; P=0.05) as independent risk factors for AKI after OPCAB. Conclusions: MetS is a prevalent risk factor for postoperative AKI after OPCAB, and aggressive treatments of its components could have reduced operative morbidity.  (Circ J 2010; 74: 1121 - 1126)

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Background: Although carvedilol and bisoprolol are effective medicines for the treatment of patients with heart failure (HF), only a few reports have compared their effects. This study was designed to compare the effects of them in patients with severe HF. Methods and Results: A total of 655 consecutive patients with HF, categorized as New York Heart Association Class 3 or 4, were retrospectively investigated. Of these patients, 217 were administered β-blockers after admission and were divided into 2 groups (carvedilol, n=110; bisoprolol, n=107). No significant differences were observed in their characteristics between the 2 groups prior to the introduction of the β-blockers. After 18 months of follow-up, there were no significant differences in the survival and cardiac event-free rates between the 2 groups. In contrast, there were several significant differences in patients with atrial fibrillation (AF) (carvedilol, n=40; bisoprolol, n=43). The percent changes in heart rate and brain natriuretic peptide level improved significantly in the bisoprolol group than in the carvedilol group. Furthermore, more patients in the bisoprolol group were defibrillated from AF to sinus rhythm than those in the carvedilol group (48% vs 16%; P=0.03). Conclusions: Our data suggest that the 2 β-blockers are equally effective in the improvement of severe HF, but bisoprolol shows favorable effects in patients with AF.  (Circ J 2010; 74: 1127 - 1134)

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Background: The exaggerated blood pressure response to exercise (EBPR) is an independent predictor of hypertension. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide inhibitor and higher plasma levels of ADMA are related to increased cardiovascular risk. The aim of this study is to identify the relationship between ADMA and EBPR. Methods and Results: A total of 66 patients (36 with EBPR and 30 as controls) were enrolled in the study. EBPR is defined as blood pressure (BP) measurements ≥200/100 mmHg during the treadmill test. All the subjects underwent 24-h ambulatory BP monitoring. L-arginine and ADMA levels were measured using a high performance lipid chromatography technique. The serum ADMA levels were increased in the EBPR group compared to the healthy controls (4.0±1.4 vs 2.6±1.1 μmol/L respectively, P=0.001), but L-arginine levels were similar in the 2 groups (P=0.19). The serum ADMA levels were detected as an independent predictor of EBPR (odds ratio 2.28; 95% confidence interval 1.22-4.24; P=0.002). Conclusions: Serum ADMA levels might play a role in EBPR to exercise.  (Circ J 2010; 74: 1135 - 1141)

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Background: It is not well known which plaque components are associated with the development of plaque prolapse (PP) and what are the major components in prolapsed plaque. The relationship between pre-stenting plaque components and post-stenting PP was assessed and the plaque components of prolapsed plaque were evaluated in patients who underwent drug-eluting stent (DES) implantation using virtual histology - intravascular ultrasound (VH-IVUS). Methods and Results: The study group consisted of 132 patients who underwent DES implantation and pre- and post-stenting VH-IVUS. Of these patients, 68 patients had 76 PP lesions and 64 patients had 76 non-PP lesions. Intra-stent PP volume was 3.6±1.5 mm³. Plaque volume was significantly greater and absolute fibrotic (FT) and necrotic core (NC) volumes were significantly greater in PP lesions compared with non-PP lesions. On multivariate analysis, absolute NC (odds ratios [OR]=1.14, P<0.001) and FT volume (OR =1.09, P<0.001) were independently associated with the development of PP. In intra-stent prolapsed plaque the FT component was greatest, but the NC component was also large, and %NC volume correlated positively with Δcreatine kinase-MB (r=0.489, P<0.001) and Δtroponin-I (r=0.679, P<0.001), and %FT volume correlated negatively with ΔCK-MB (r=-0.539, P<0.001) and Δtroponin-I. Conclusions: NC and FT components were associated with development of PP; and NC and FT components in prolapsed plaque were associated with cardiac enzyme elevation after DES implantation.  (Circ J 2010; 74: 1142 - 1151)

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Background: Predictors of in-hospital outcome after primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) requiring mechanical support devices such as intra-aortic balloon pumping (IABP) and/or percutaneous cardiopulmonary support (PCPS) remain unclear. Methods and Results: Using the AMI-Kyoto Multi-Center Risk Study database, clinical background, angiographic findings, results of primary PCI, and in-hospital prognosis were retrospectively compared between primary PCI-treated AMI patients requiring mechanical assist devices (with-IABP/PCPS patients, n=275) and those without (without-IABP/PCPS patients, n=1,510). The with-IABP/PCPS patients were more likely to have a larger number of diseased vessels, lower Thrombolysis In Myocardial Infarction (TIMI) grade in the infarct-related artery (IRA) before/after primary PCI, and a significantly higher in-hospital mortality rate than the without-IABP/PCPS patients. On multivariate analysis, the number of diseased vessels ≥2 or diseased left main trunk (LMT) at initial coronary angiography (CAG) was the independent positive predictor of the in-hospital mortality in the with-IABP/PCPS patients, not in the without-IABP/PCPS patients, whereas acquisition of TIMI 3 flow in the IRA immediately after primary PCI was the negative predictor in the without-IABP/PCPS patients, not in the with-IABP/PCPS patients. Conclusions: The number of diseased vessels ≥2 or diseased LMT at initial CAG is an independent risk factor of in-hospital death in primary PCI-treated AMI patients requiring mechanical support devices.  (Circ J 2010; 74: 1152 - 1157)

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Background: Inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) can suppress left ventricular (LV) remodeling after acute myocardial infarction (AMI), possibly through the modifications of matrix metalloproteinase (MMP)-9. Whether LV remodeling is suppressed in association with MMP-9 suppression in post-AMI/-percutaneous coronary intervention (PCI) patients treated with ACE inhibitor and/or ARB was examined. The presence of any differences in LV remodeling and MMP-9 levels across the groups was also investigated. Methods and Results: Sixty-five patients were initiated into each of 3 treatments; trandolapril, valsartan or a combination of both (half-dose-trandolapril plus half-dose-valsartan). Changes in MMP-9, LV end-diastolic and end-systolic volume index (LVEDVI and LVESVI) after 12 months were assessed. Overall, MMP-9 significantly decreased, although neither LVEDVI nor LVESVI increased significantly. ΔMMP-9 was significantly correlated with ΔLVEDVI (r=0.36) or ΔLVESVI (r=0.39). In comparison, across groups, it was found that MMP-9, LVEDVI and LVESVI at 12 months were significantly lower in the combination therapy group than in the trandolapril group. There were no significant differences between the valsartan group and combination therapy group, or between the valsartan group and the trandolapril group. Conclusions: LV remodeling might be suppressed in association with MMP-9 suppression in AMI patients treated with PCI and regular dose or half-dose-combination of RAS inhibitors. Furthermore, a half-dose-combination might suppress LV remodeling more effectively than trandolapril alone.  (Circ J 2010; 74: 1158 - 1164)

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Background: The Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS) trial has found that early aggressive statin therapy in patients with acute coronary syndrome (ACS) significantly reduces the plaque volume (PV) of non-culprit coronary lesions. The purpose of the present study was to evaluate clinical factors that have an impact on plaque regression using statin therapy. Methods and Results: Serial intravascular ultrasound observations over 8-12 months were performed in 252 ACS patients receiving pitavastatin or atorvastatin. Linear regression analysis identified the presence of diabetes mellitus (DM) and PV at baseline as inhibiting factors, and serum remnant-like particle-cholesterol level at baseline as a significant factor significantly affecting the degree of plaque regression. Significant correlation between % change of PV and low-density lipoprotein cholesterol (LDL-C) level was found in patients with DM (n=73, P<0.05, r=0.4), whereas there was no significant correlation between the 2 parameters in patients without DM (n=178). Conclusions: The regression of coronary plaque induced by statin therapy after ACS was weaker in diabetic patients than their counterparts. Moreover, vigorous reduction of the LDL-C levels might induce a greater degree of plaque regression in ACS patients with DM.  (Circ J 2010; 74: 1165 - 1174)

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Background: The presence of microvascular obstruction (MVO) after primary ST-segment elevation acute myocardial infarction (STEMI) is associated with a poor outcome. The aim of the paper was to examine the relationship between distinct monocyte subsets and gadolinium-enhanced cardiovascular magnetic resonance (CMR) characteristics of MVO after STEMI. Methods and Results: Seventy-one patients with primary STEMI successfully treated with stenting were enrolled in the study. Two monocyte subsets (CD14⁺CD16^- and CD14⁺CD16⁺) were measured on flow cytometry on admission and 2, 3, 4, 5, 8 days after the onset of STEMI. CMR was performed 7 days after revascularization to determine MVO on late gadolinium-enhanced imaging. The peak levels of CD14⁺CD16^- monocytes, but not those of CD14⁺CD16⁺ monocytes, were significantly higher in patients with MVO than in those without MVO. A multivariate logistic regression model showed that the post-perfusion peak levels of CD14⁺CD16^- monocytes remained an independent factor for the presence of MVO (odds ratio=1.53; 95% confidence interval: 1.01-2.32; P=0.04). The absence of MVO was significantly associated with improvement in left ventricular ejection fraction. Conclusions: Post-reperfusion enhancement of CD14⁺CD16^- monocytes was associated with MVO in patients with STEMI. The pathophysiologic and therapeutic implications of this association require further study.  (Circ J 2010; 74: 1175 - 1182)

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Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) is known as a cytoprotective polypeptide. PACAP and its receptors are expressed in the heart, but it is unclear whether PACAP exerts its protective effect on the myocardium in vivo. The aim of the present study was to investigate whether endogenous PACAP has a cardioprotective effect on Doxorubicin (Dox)-induced cardiomyopathy. Methods and Results: Dox was intraperitoneally injected to induce cardiomyopathy in wild type (WT) and PACAP knockout (ie, PACAP+/- and PACAP-/-) mice. The survival rates up to 15 days of PACAP+/- mice and PACAP-/- mice were significantly less than that of WT mice. Cardiac function, measured by echocardiography, was significantly lower in PACAP+/- mice than in WT mice at day 10. Morphological examination of sections of myocardium showed degenerative change and fibrosis in PACAP+/- mice at day 10. Serum reactive oxygen metabolites (a marker of oxidative stress), the number of 8-hydroxy-deoxyguanosine-positive nuclei and TdT-mediated dUTP nick end-labeling (TUNEL) positive nuclei in the myocardium were higher in PACAP+/- mice than WT mice. However, continuous subcutaneous administration of PACAP38 was able to prevent the myocardial damage typically caused by Dox injection in PACAP+/-. Conclusions: These results suggest that endogenous PACAP might attenuate Dox-induced myocardial damage and that its mechanism of action is likely to be associated with the reduction of oxidative stress and mediated via anti-apoptotic effects.  (Circ J 2010; 74: 1183 - 1190)

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Background: The impact of matrix metalloproteinase (MMP) on left ventricular (LV) remodeling and heart failure events is unresolved in patients with hypertrophic cardiomyopathy (HCM). Methods and Results: Plasma levels of MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and clinical findings and heart failure events were evaluated in 41 HCM patients, including 8 with LV systolic impairment. Plasma B-type natriuretic peptide (BNP) levels were also measured. MMP-2 levels in patients with severe symptoms were higher than that in those with no or mild symptoms. The levels of MMP-2 and TIMP-1 were positively related to LV end-systolic and left atrial dimensions, and inversely related to LV ejection fraction. MMP-2 levels were positively related to BNP levels (r=0.52, P=0.0009). However, MMP-9 levels were not related to echocardiographic parameters and plasma BNP levels. Six patients had complicated heart failure events during the follow-up period of 3.2±0.7 years. Patients with high plasma MMP-2 levels (>1,170 ng/ml) revealed a poorer prognosis than those with low MMP-2 levels. Conclusions: Elevated levels of MMP-2 were related to LV remodeling and poor prognosis in patients with HCM. These results suggest that regulation of the extracellular collagen matrix might be one of the therapeutic targets in patients with HCM.  (Circ J 2010; 74: 1191 - 1196)

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Background: Regional heterogeneity of left ventricular (LV) hypertrophy may contribute to arrhythmic vulnerability in patients with hypertrophic cardiomyopathy (HCM). The aim of the present study was to investigate the relationship between LV wall thickness (LVWT) and microvolt T-wave alternans (TWA), a surrogate risk marker of ventricular tachyarrhythmias (VTAs). Methods and Results: A total of 157 consecutive HCM patients underwent 2-D echocardiography and TWA-exercise testing, and assessment of arrhythmic burden in a follow up of a median 3.7 years. VTAs were commoner in the non-negative groups (NN-TWA: n=72, TWA+ and indeterminate outcome; 29 events, P<0.02; TWA+: n=34; 14 events, P=0.01), than in the negative TWA group (n=85, 16 events). TWA+ patients were older (P<0.04) and had greater maximal LVWT and LV mass (P=0.02 and P=0.05, respectively), whereas NN-TWA linked only with increased LV mass (P=0.05). Regionally, the TWA+ group had greater inferior LVWT (P<0.05). TWA+ outcome positively correlated with maximal LVWT (r=0.2, P=0.05), and basal/equatorial/apical inferior LVWT (BA6: r=0.2, P=0.05 and EQ6: r=0.2 P=0.03, AP6: r=0.2, P=0.04). Multivariate analysis identified left atrium size, max LVWT and EQ6 with predictive association for TWA+ outcome. Conclusions: Positive and NN-TWA outcomes are associated with increased LV mass. Moreover, TWA+ is associated with maximal and regional LVWT in HCM patients at risk of arrhythmic events. The present findings support the complementary role of key regional LVWTs in a risk stratification model.  (Circ J 2010; 74: 1197 - 1204)

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Background: The aim of our study was to assess longitudinal (L), circumferential (C) and radial (R) strain (S) of the left ventricle (LV) in patients with acute myocarditis and preserved LV wall motion. Methods and Results: Of the 26 male patients that were enrolled, 13 patients (26±8 years) suffered from acute myocarditis and 13 (25±2 years) were healthy participants (controls). Both patients and controls underwent cardiac magnetic resonance (CMR) and 2-dimensional S imaging (2D-S) echocardiography on the same day. Myocardial strains (RS, LS and CS) were quantified by 2D-S. In patients with myocarditis, a delayed enhancement (DE) CMR study was performed to identify damaged myocardial segments. In the myocarditis group there was a significant LS reduction compared with controls (-25±7 vs -20±7, P<0.0001), whereas no difference was found between the 2 groups concerning CS and RS. Subepicardial DE areas were found in 12 of 13 patients. Segments with DE showed a significantly lower LS in comparison with segments without DE (-19±4 vs -23±6, P<0.0001). In contrast, no difference in CS and RS was found when comparing segments with DE vs segments without DE. Conclusions: In patients with acute myocarditis, evidence of subepicardial damage and no wall motion abnormalities, longitudinal deformation is diffusely impaired, whereas circumferential impairment is regionally sited in the areas of subepicardial damage.  (Circ J 2010; 74: 1205 - 1213)

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Background: The arterial switch operation (ASO) may be infeasible in patients with transposition of the great arteries (TGA) and left ventricular outflow tract obstruction (LVOTO). Methods and Results: Patients with LVOTO were identified among the 229 patients with TGA repaired between 1991 and 2006. Dynamic LVOTO was defined as LVOTO without LVOT abnormalities requiring resection (group I, receiving ASO). Fixed LVOTO was defined as LVOTO with LVOT abnormalities that could (group IIa, receiving ASO) or could not be resected (group IIb, receiving operations other than ASO). Preoperative echocardiography parameters were compared to identify criteria predicting the surgical findings of LVOTO. LVOTO was found in 63 patients (27.5%): 39 with dynamic and 24 with fixed (14 group IIa and 10 IIb) LVOTO. Late, severe neo-aortic regurgitation occurred more frequently in group IIa patients. Echocardiography evidence of isolated subvalvular stenosis, pulmonary to aortic valvular annulus ratio >0.98 or LVOT pressure gradient <22 mmHg predicted dynamic LVOTO (sensitivity 86.3%, specificity 94.7%), whereas that of an annulus ratio <0.85 and a pressure gradient >35 mmHg predicted fixed and non-resectable LVOTO (sensitivity 100%, specificity 100%). Conclusions: Approximately one-fourth of TGA patients had LVOTO. Echocardiography criteria identified those with dynamic or fixed but resectable (ASO) LVOTO with satisfactory sensitivity and specificity.  (Circ J 2010; 74: 1214 - 1218)

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Background: Cell transplantation therapy for heart failure is hindered by poor differentiation into cardiomyocytes and arrhythmias caused by the poor expression of connexin 43 (Cx43). A new stem cell source for cardiac regeneration is needed. Methods and Results: Tongue muscle-derived Sca-1(+) cells (TDSCs) were isolated from normal and green fluorescence protein (GFP)-transgenic mouse tongues using surface antigen Sca-1. Cardiomyogenic differentiation was confirmed by measuring the calcium transient and the expression of cardiac-specific genes. The formation of gap junctions was confirmed by the expression of Cx43 and the dye transfer method. The contraction of regenerated cells was demonstrated by the calcium transients. GFP mouse-derived TDSCs were transplanted into hearts in a model of acute myocardial infarction. Three months after transplantation, LV remodeling was attenuated and the survival rate was improved compared with the control group. Conclusions: TDSCs form gap junctions and improve cardiac function and long-term survival after myocardial infarction.  (Circ J 2010; 74: 1219 - 1226)

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Background: Aspirin is an antiplatelet drug widely used for the prevention of cardiovascular diseases. It has been reported that some patients who exhibit a reduced antiplatelet effect of aspirin have higher cardiovascular risk. It is still controversial whether the antiplatelet effect of aspirin diminishes after a few years of treatment. This study aimed to evaluate the antiplatelet effect of aspirin and its 2-year change in Japanese patients. Methods and Results: Collagen-induced platelet-aggregability was measured at enrollment by conventional optical aggregometer in 239 patients undergoing antiplatelet therapy with aspirin alone. Among them, 167 patients were evaluated after 2 years. Whole blood aggregability based on the screen-filtration method was also evaluated. Optical aggregometer studies showed that 27% of patients were low-responders. Multivariate analyses revealed that female sex and non-use of calcium-channel blockers were associated with low responsiveness. The antiplatelet effect of aspirin did not decrease after 2 years. Similar data were obtained with the whole blood aggregometer. Conclusions: In this Japanese patient group, 27% were low-responders to aspirin, and the antiplatelet effect of aspirin did not decrease after a 2-year interval.  (Circ J 2010; 74: 1227 - 1235)

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Background: Vessel wall inflammation, atherosclerosis and hypercoagulability may be responsible for ischemic events in Takayasu arteritis (TA). No study has evaluated the effect of antiplatelet therapy for the prevention of ischemic events in TA. Methods and Results: Forty-eight patients who met the ACR Classification Criteria for TA under follow-up at the Vasculitis Unit of Universidade Federal de São Paulo were evaluated retrospectively for clinical manifestations, therapy and arterial ischemic events. The mean age at study was 38.0 years and the mean age at TA diagnosis was 29.1 years. Women comprised for 89.6% of patients and 60.4% were Caucasian. Risk factors for cardiovascular disease were found in 44 patients (91.7%) The most common comorbidities for TA patients were hypertension (77.1%), high low-density lipoprotein (45.8%) and obesity (16.7%). Antiplatelet therapy was used by 62.5% of patients whereas anticoagulants were used by 12.5%. Acute ischemic events occurred in 29.2% of patients. TA patients with ischemic events used significantly less antiplatelet agents (14.3%) than those without ischemic events (82.4%), P<0.0001. No difference concerning ischemic events was observed in patients on anticoagulant therapy (P=0.339). The 3 deaths of TA patients were observed only in those who had presented ischemic events (P=0.021). Antiplatelet agents had a protective effect against ischemic events (hazard ratio =0.055, 95% confidence interval: 0.06-0.514; P=0.011). Conclusions: Antiplatelet therapy is associated with a lower frequency of ischemic events in patients with TA.  (Circ J 2010; 74: 1236 - 1241)

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Background: Diabetic patients are frequently afflicted with medial artery calcification, a predictor of cardiovascular mortality. Diabetes induced the expression of osteopontin in arterial vasculature, which is an indicator of disease progression in artery calcification and vascular stiffness. Signal transduction and strategies that suppress high glucose-induced osteopontin expression in arterial vascular smooth muscle cells is investigated. Methods and Results: The incubation of rat aortic smooth muscle cells under high glucose concentration increased osteopontin protein secretion and mRNA expression. Treatment with dipyridamole decreased high glucose-induced osteopontin expression and secretion. Dipyridamole decreased glucose-induced osteopontin through inhibition of phosphodiesterase, thereby increasing intracellular levels of adenosine-3',5'-cyclic monophosphate (cAMP) and guanosine-3',5'-cyclic monophosphate (cGMP), and increased thioredoxin expression to inhibit the reactive oxygen species (ROS) system. Induction of osteopontin was reversed when cells were pretreated with N-[2-bromocinnamyl(amino)ethyl]-5-isoquinolinesulfonamide (H89, cAMP-dependent protein kinase inhibitor), KT5823 (cGMP-dependent protein kinase inhibitor), or dinitrochlorobenzene (thioredoxin reductase inhibitor). The antioxidant, N-acetyl-L-cysteine, suppressed glucose-induced osteopontin expression by decreasing ROS concentration. Both H89 and KT5823 downregulated thioredoxin expression. Conclusions: These results suggest a novel effect for dipyridamole to suppress high glucose-induced osteopontin protein secretion and mRNA expression. Dipyridamole has antioxidant properties and a phosphodiesterase inhibitor activity, which might be useful to ameliorate diabetic vasculopathy and its cardiovascular complications.  (Circ J 2010; 74: 1242 - 1250)

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Background: Doppler imaging of ophthalmic artery (OA), the first major branch of the internal carotid artery, provides anatomical advantages due to the vertical angle to the body surface and absence of ultrasonic obstacles. It was hypothesized that the Doppler waveform indices of OA correlate with severity of systemic atherosclerosis. Methods and Results: The study subjects were 180 patients who underwent cardiac catheterization and OA Doppler imaging (90 patients with coronary artery disease (CAD) and 90 control patients). The ratio of stroke volume to pulse pressure, an index of arterial compliance, was closely associated with the ratio of systolic to diastolic mean velocity (Sm/Dm) in OA. The level of Sm/Dm increased in proportion with the increase in number of stenosed coronary arteries (0-vessel disease 2.1±0.3, 1-vessel disease 2.3±0.3, multi-vessel disease 2.6±0.5, P<0.0001). The Sm/Dm level in OA correlated positively with age, pulse pressure, pulse wave velocity, resistive index and pulsatility index in OA. The best Sm/Dm cut-off to predict CAD was 2.3, and patients with Sm/Dm >2.3 had 8.0-fold risk for CAD. Conclusions: The waveform indices of OA are clinically useful for evaluating the severity of CAD and may help explain the missing link between OA circulation and systemic arterial compliance.  (Circ J 2010; 74: 1251 - 1256)

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Background: Although peri-strut low-intensity area (PLIA) is frequently observed on post-stenting optical coherence tomography (OCT) images, the histology associated with PLIA is undocumented. Methods and Results: The 36 porcine coronary lesions treated with bare-metal (BMS: n=16) or drug-eluting (DES: n=20) stents were assessed by OCT and histology at 28 days. DES showed a significantly higher incidence of PLIA than BMS. Also, +PLIA stents had greater neointima than PLIA stents. Histological analysis revealed the existence of fibrinoid and proteoglycans at the site of PLIA. Conclusions: PLIA might be represented by the presence of fibrinoid and proteoglycans, and associated with neointimal proliferation after stenting.  (Circ J 2010; 74: 1257 - 1259)

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