As a result of major achievements in pediatric cardiac care, a growing number of patients with congenital heart disease (CHD) are flourishing well into adulthood. This heterogeneous and aging population of patients, many of whom represent the first generation of middle-age survivors, faces unique issues and challenges. As a field, adult CHD has evolved markedly during the past decade on several fronts, including imaging, arrhythmia management, percutaneous interventions, surgical techniques, research, and multidisciplinary care that extends beyond the cardiac realm. This review highlights recent advances across the wide spectrum of key issues encountered by adults with CHD. (Circ J 2011; 75: 2287-2295)

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Congenital heart defects (CHD) are the most common type of human birth defect and result in significant mortality worldwide. Despite numerous epidemiologic studies in the past decades, few genetic causes have been identified until recently. CHD result from abnormal morphogenesis of the systematic cardiovascular construction during development. Recent advances in molecular embryology, including the discovery of a new source of cardiac progenitor cells termed the second heart field (SHF), have revealed that the heart arises from multiple distinct embryonic origins. Cells derived from the SHF contribute to the development of the cardiac outflow tract, together with the other progenitor cell lineage called cardiac neural crest cells. Numerous cardiac transcription factors regulate these progenitor cells during heart development. Elucidation of the transcriptional network for these cardiac progenitor cells is essential for further understanding cardiac development and providing new insights into the morphogenesis of CHD. This review outlines the recent discoveries of the molecular embryology of the normal heart and the genetic basis of CHD. (Circ J 2011; 75: 2296-2304)

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Atrial fibrillation (AF) is an arrhythmia associated with increased morbidity and mortality. Since the first report of catheter ablation curing AF, numerous techniques have evolved, from linear ablation to segmental pulmonary vein (PV) isolation, to extensive encircling PV isolation, to left atrial (LA) linear ablation, to ablation of complex fragmented atrial electrograms (CFAEs) and ablation of ganglionated plexi. A new approach for complete isolation of the posterior LA, including all PVs, is box isolation. PV isolation is associated with a high clinical success rate in paroxysmal AF. However, in persistent AF or longstanding persistent AF, PV isolation only may not be sufficient, so additional ablation at sites with CFAEs is needed to improve the clinical outcome. A hybrid approach of combining PV isolation plus CFAE ablation is highly effective in the majority of patients with persistent AF or longstanding persistent AF. Thus, AF ablation is an effective and established treatment for AF that offers an excellent chance of a lasting cure. It is about time that AF ablation became a first-line therapy for selected patients with AF. (Circ J 2011; 75: 2305-2311)

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Background: Renal dysfunction was reported to be associated with a higher recurrence rate after electric cardioversion of atrial fibrillation (AF). The aim of this study was to investigate the associations between renal function, atrial substrate properties and outcome of catheter ablation in paroxysmal AF patients. Methods and Results: A total of 232 paroxysmal AF patients that underwent catheter ablation were enrolled in the study. The estimated glomerular filtration rate (GFR) was calculated using the Cockcroft-Gaut equation normalized by the body surface area, and the patients were divided into 3 groups according to their GFR (group 1: ≥90ml·min^-1·1.73m^-2, group 2: 60-90ml·min^-1·1.73m^-2 and group 3: <60ml·min^-1·1.73m^-2). The left atrial (LA) voltage became lower and the activation time longer when the GFR decreased from group 1 to group 3. During a follow up of 25.4±13.3 months, 15.9% of the study population suffered from AF recurrences. The recurrence rates of those 3 groups were 6.9%, 14.5% and 38.9%, respectively. The LA dimension, LA voltage and groups of renal function were identified to be the independent predictors of an AF recurrence in the multivariate analysis. Conclusions: A decreased GFR was associated with an abnormal LA substrate and high recurrence rate of catheter ablation in patients with paroxysmal AF. (Circ J 2011; 75: 2326-2332)

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Background: Diacylglycerol kinase ζ (DGKζ) inhibited atrial tachyarrhythmias in a mouse model of heart failure (HF) in our study. However, whether DGKζ prevents the HF-induced ventricular tachyarrhythmia (VT) is unknown. Methods and Results: Effects of DGKζ on VT using transgenic mice with transient cardiac expression of activated G protein α_q (Gα_q-TG; model of HF) were elucidated and double transgenic mice with cardiac-specific overexpression of both DGKζ and the activated Gα_q (Gα_q/DGKζ-TG) were used. Premature ventricular contraction (PVC) and/or VT were frequently observed in Gα_q-TG mice but not in Gα_q/DGKζ-TG and wild-type (WT) mice (P<0.01). Protein expressions of canonical transient receptor potential (TRPC) channels 3 and 6 increased in Gα_q-TG hearts compared with WT and Gα_q/DGKζ-TG hearts. SK&F96365, a TRPC channel blocker, decreased the number of PVC and prevented VT in anesthetized Gα_q-TG mice (P<0.05). 1-oleoyl-2-acyl-sn-glycerol (OAG), a diacylglycerol analogue, increased the number of PVC in isolated Gα_q-TG hearts compared with WT hearts and induced VT in Gα_q-TG hearts (P<0.01). SK&F96365 decreased the number of PVC and prevented VT in isolated Gα_q-TG hearts (P<0.01) even in the presence of OAG. Early afterdepolarization (EAD)-induced triggered activity was frequently observed in single Gα_q-TG ventricular myocytes. Moreover, SK&F96365 prevented the EAD. Conclusions: These results demonstrated that DGKζ inhibited VT in a mouse model of HF and suggest that TRPC channels participate in VT induction in failing hearts. (Circ J 2011; 75: 2333-2342)

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Background: A low incidence of thromboembolic events after successful catheter ablation of atrial fibrillation (AF) during a mid-term follow-up period was recently reported. However, because the incidence of such events over the long term is unknown, we investigated the late incidence of thromboembolic events after catheter ablation. Methods and Results: Patients with paroxysmal and persistent AF undergoing catheter ablation and being followed up for at least 24 months formed the study group (n=524); 82 patients (16%) had CHADS₂ scores of at least 2. Mean follow-up was 44±13 months. Warfarin was discontinued in 400 (93%) of 429 patients (82% of 524 patients) without AF recurrence. None of the patients without AF recurrence suffered thromboembolic events, whereas 3 of 95 patients (3%) with AF recurrence did (P<0.001). One of the 3 was a late AF recurrence occurring >12 months after catheter ablation. There were 2 nonfatal major hemorrhagic events in patients with AF recurrence who continued on warfarin, but no hemorrhagic events were observed in patients free from AF (P=0.002). Conclusions: Maintenance of sinus rhythm after catheter ablation of AF was associated with a lower incidence of thromboembolic events during long-term follow-up >3 years. This result suggests that catheter ablation reduces thromboembolic events if patients continue anticoagulation regardless of the ablation outcome. (Circ J 2011; 75: 2343-2349)

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Background: The purpose of this study was to investigate the prognostic values of the E/e' ratio and other echocardiographic and clinical parameters in patients with non-valvular atrial fibrillation (AF) with preserved left ventricular (LV) systolic function. Methods and Results: A total of 488 patients (322 men, age: 66±11 years) with non-valvular AF with preserved LV systolic function (LV ejection fraction >50%) were included. The E and e' velocities were measured in 5 consecutive heart beats and averaged. Mean follow-up duration after enrollment was 17.7±5.3 months. All-cause deaths occurred in 45 patients (cardiovascular deaths: n=29). There were significant differences in age (65.6±11.3 vs. 71.5±9.1, P<0.001) and hemoglobin concentration (13.6±2.9 vs. 11.5±3.4g/dl, P<0.0001) between the deceased group and the survivors. E/e' ratio in the deceased group was significantly higher than that in the survivors (17.67±3.39 vs. 10.8±3.30, P<0.001). Survival analysis showed that a high E/e' ratio (>15.0) represents a poorer prognosis (P<0.001 by Log-Rank test) than an E/e' ratio of 15 and below. Multivariate analysis identified 2 significant variables that were predictive of all-cause deaths: hemoglobin (hazard ratio (HR)=0.806, 95% confidence interval (CI)=0.733-0.886, P<0.0001), and E/e'>15 (HR=3.064, 95%CI=1.38-6.804, P=0.006). Conclusions: E/e' ratio is a useful independent prognostic parameter for predicting mortality in patients with AF with preserved LV systolic function. (Circ J 2011; 75: 2350-2356)

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Background: Determinants of warfarin use and anticoagulation levels in atrial fibrillation (AF) patients have not been clarified thoroughly. Methods and Results: A total of 6,324 patients with non-valvular AF and congestive heart failure, hypertension, age, diabetes, prior stroke (CHADS₂) score ≥1 were used to investigate determinants of warfarin use, and 6,932 patients with AF receiving warfarin were used to investigate determinants of international normalized ratio (INR) of prothrombin time. Target INR levels for non-valvular AF patients were 1.6-2.6 for patients aged ≥70 years and 2-3 for patients aged <70 years. Those for patients with valvular AF were 2-3. Patients with non-valvular AF and CHADS₂ score ≥1 receiving warfarin (n=5,614) more frequently had permanent AF, congestive heart failure, and stroke or transient ischemic attack (TIA), and had higher CHADS₂ scores than those not receiving warfarin. Determinants of warfarin use were age (≥60 years), AF type (persistent and permanent), and comorbidities (congestive heart failure, diabetes mellitus, and prior stroke or TIA). Use of antiplatelet drugs was a negative determinant of warfarin use. Only 53% of patients met the target INR levels. Determinants for the meeting of the target INR level (vs. lower INR level) were age (≥60 years), permanent AF, hypertension, and prior stroke or TIA. Use of antiplatelet drugs was a negative determinant of the INR level. Conclusions: Currently in Japan, adherence to the guidelines regarding anticoagulation therapy is limited (UMIN Clinical Trials Registry UMIN000001569). (Circ J 2011; 75: 2357-2362)

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Background: Electrical isolation of the pulmonary veins (PV) is crucial for atrial fibrillation (AF) ablation. Conduction gaps on the circumferential PV antrum ablation (CPVA) line sometimes remain, which are sometimes difficult to identify. Methods and Results: CPVA of the ipsilateral superior and inferior PVs was performed during sinus rhythm or coronary sinus pacing using the NavX system in 22 AF patients, in whom 1 round of CPVA failed to disconnect 26 individual PVs (30%) in 18 patients. In these patients, a local activation map within the CPVA line (PV map) was created by a 20-pole circular mapping catheter with the use of the NavX, with 71±37 sampling points per PV antrum. The conduction gap was defined as a site on the CPVA line, from which the activation proceeded toward the entire PV. The mapped PV antra were comprised of the left superior PV in 11, right superior PV in 10, left inferior PV in 3, right inferior PV in 1 and a left common PV in 1 PV(s). The conduction gaps were identified at 1.4±0.7 sites per PV antrum, with an electrogram amplitude of 0.8±0.7mV. A point ablation at the gap completely isolated 24 out of 26PV antra (92%) with 1.9±1.3 applications. Conclusions: The PV map was useful for quickly and accurately identifying the conduction gap(s) after 1 round of CPVA. (Circ J 2011; 75: 2363-2371)

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Background: Low glomerular filtration rate (GFR) is associated with a worse outcome after coronary revascularization. Recently, a new specific equation to calculate the estimated GFR (eGFR) in Japanese populations has been reported, and it might be more accurate than the previously used equations. However, the relationship between a low GFR defined using the new equation for the Japanese population and the incidence of stroke following complete coronary revascularization is not yet known. Methods and Results: Consecutive patients who underwent complete coronary revascularization (percutaneous coronary intervention and bypass surgery) between 1984 and 1992 were enrolled. Patients on dialysis were excluded. Enrolled patients were divided into 2 groups: the preserved GFR group and the low GFR group. Low GFR was defined as eGFR<60ml·min^-1·1.73m^-2. The incidence of fatal and non-fatal stroke was compared between the groups. Among the 1,809 patients that were enrolled, 321 were placed in the low GFR group. During follow up (mean, 11.4 [2.9] years), there were 127 (7.0%) stroke events. Multivariable analysis using a Cox proportional hazards regression model revealed that the incidence of stroke was significantly higher in the low GFR group than in the preserved GFR group (hazard ratio, 1.66; 95% confidence interval, 1.10-2.48; P=0.008). Conclusions: Low GFR, defined as eGFR <60ml·min^-1·1.73m^-2, using a new specific equation for the Japanese population was associated with an increased risk of fatal and non-fatal stroke over a 10-year period after complete coronary revascularization. (Circ J 2011; 75: 2372-2378)

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Background: Exercise training (ET) after coronary stenting is considered to have a risk of stent thrombosis (ST). The present study investigated whether ET increases the incidence of ST in patients undergoing coronary stenting. Methods and Results: The current study was a prospective observational study. We enrolled 3,672 patients who underwent successful coronary stenting. Patients decided whether to participate in exercise and were divided into an ET group (n=1,592) and a control group (n=2,080). The primary endpoint was the incidence of ST. Secondary endpoints were major adverse cardiovascular events (MACE: death, myocardial infarction, and stroke) and unscheduled hospital visits for angina. The incidence of ST and MACE were similar in both groups (1.8% vs. 2.0%, P=0.73, 14.9% vs. 15.0%, P=0.97, respectively). Unscheduled hospital visits were significantly lower in the ET group (20.2% vs. 27.2%, P<0.0001). After adjusting for baselines, the ET group had no significant increase in ST (hazard ratio (HR) 0.86, adjusted P=0.56) and MACE (HR 0.98, adjusted P=0.83). The ET was effective to prevent an unscheduled hospital visits for worsening angina (HR 0.67, adjusted P<0.0001). Conclusions: Moderate ET after successful coronary stenting does not increase the incidence of ST and MACE, and was effective in reducing unscheduled hospital visits for angina. (Circ J 2011; 75: 2379-2386)

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Background: Redox aminothiols have been reported to modulate the activity of recombinant metalloproteinases (MMP). The aim of the present study was to investigate the effects of myocardial redox state on the activities of MMP-2 and -9 implicated in cardiac remodeling in end-stage heart failure patients supported by left ventricular assist device (LVAD). Methods and Results: During heart transplant (HT) surgery, myocardial specimens (MS) from right ventricular walls and LV walls were obtained from 7 LVAD recipients (LVAD group, MS n=35) and from 7 stable HT candidates on medical therapy (MT group, MS n=35). Myocardial MMP-2 and -9 activities and expression, tissue inhibitor of MMP (TIMP)-1 and -4, transforming growth factor (TGF)-β1 and aminothiol concentrations were measured. MMP-2 and -9 activities were evaluated also by incubating MS with different amounts of reduced and oxidized glutathione (GSH). MMP-2 and -9 activities and expression were lower in the LVAD group, whereas myocardial TIMP-1 and -4 concentrations were comparable to those of MT patients. Higher GSH and TGF-β1 concentrations were found in LVAD-recipients. Only GSH concentrations were inversely related to MMP-2 and -9 activities. In vitro, GSH had an inhibitory effect on MMP-2 and -9 activities. Conclusions: LVAD recipients show reduced myocardial MMP-2 and -9 activities and expression when compared to medically treated patients. Changes of myocardial redox state, predominantly GSH-dependent, appear to modulate MMP-2 and -9 activities by an inhibitory effect dependent on thiol content. These data support a role of GSH cycle in modulating the extracellular matrix in end-stage heart failure patients supported by LVAD. (Circ J 2011; 75: 2387-2396)

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Background: Hydroxyethyl starch (HES) solutions are often used for maintaining intravascular volume and improving microperfusion, while a large amount of HES can cause adverse effects on coagulation. As the indications for clopidogrel expand, an increasing number of patients undergoing off-pump coronary artery bypass surgery (OPCAB) are also undergoing dual antiplatelet therapy (DAPT), with its higher risk of bleeding complications. The aim of the present study was to determine whether a moderate dose of 6% HES 130/0.4 significantly increases perioperative blood loss in patients with continued DAPT within 5 days of OPCAB. Methods and Results: Patients who received clopidogrel and aspirin within 5 days of OPCAB were randomly allocated to receive HES 130/0.4 (≤30ml/kg) followed by crystalloid infusion (HES group, n=53), or crystalloid only (crystalloid group, n=53) perioperatively. The amount of perioperative blood loss (sum of bleeding during the intraoperative and postoperative 24-h period), transfusion requirements, modified thromboelastography and coagulation variables, hemodynamic parameters, and fluid balance were recorded. Perioperative blood loss and coagulation profiles were similar between the groups, but the postoperative hemoglobin level was higher in the crystalloid group. Conclusions: Up to 30ml·kg^-1·day^-1 of 6% HES 130/0.4 did not increase the perioperative blood loss compared to crystalloid in patients with recent exposure to DAPT undergoing OPCAB. HES 130/0.4 caused a similar degree and duration of coagulation impairment as observed when only crystalloid was given. (Circ J 2011; 75: 2397-2402)

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Background: Aging is associated with adverse outcomes in patients with cardiac diseases. Whether elderly patients hospitalized with heart failure (HF) had increased risks for mortality and rehospitalization compared with younger patients during the long-term follow-up was examined. The predictors of these adverse outcomes were also identified. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of 2,675 patients hospitalized with worsening HF and the outcomes were followed up. The majority of elderly patients were female, had lower body mass index (BMI), a higher rate of ischemic, valvular, and hypertensive heart disease as etiologies of HF, a lower estimated glomerular filtration rate (eGFR), lower hemoglobin, and higher left ventricular ejection fraction values. Even after adjustment for covariates, the elderly patients were associated with higher risks of adverse outcomes. The predictors for all-cause death were: lower eGFR, lower BMI, male sex, sustained ventricular tachycardia or fibrillation (VT/VF), and the use of diuretics at discharge. Conclusions: Among patients hospitalized with HF, elderly patients had a worse prognosis than younger patients. Lower eGFR, lower BMI, male sex, sustained VT/VF, and diuretic use were independent predictors for all-cause death in these patients with higher risk. (Circ J 2011; 75: 2403-2410)

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Background: The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the effects of candesartan and amlodipine on cardiovascular events in Japanese high-risk hypertensive patients. The aim of the present subanalysis was to evaluate the influence of coronary risk factors on coronary events in these patients as an observational study irrespective of allocated drugs. Methods and Results: The adjusted hazard ratios (HRs) of the association of baseline risk factors including gender, age, allocated drugs, body mass index, systolic/diastolic blood pressure (SBP/DBP), diabetes mellitus (DM), hyperlipidemia (HL), smoking, left ventricular hypertrophy, previous ischemic heart disease (IHD), previous cerebrovascular events, and chronic kidney disease (CKD) with coronary events in 4,703 patients who were enrolled in the CASE-J trial, were examined. The coronary events occurred in 83 patients, and were significantly associated with previous IHD, DM, male sex, CKD, and low DBP. Significant predictors were previous IHD (HR, 3.89), DM (HR, 3.10), male sex (HR, 1.81), CKD (HR, 1.60), and low DBP (HR, 1.36), respectively. In 4,107 patients without pre-vious IHD, DM (HR, 4.88), HL (HR, 2.67), and DBP (HR, 1.39) were significantly associated with the risk of coronary events, while male sex (HR, 3.03), CKD (HR, 2.44), and DM (HR, 2.15) were in 596 patients with previous IHD. Conclusions: DM is the important factor in both primary and secondary prevention of coronary events. Comprehensive risk management including surveillance of DM, CKD and HL is needed for preventing coronary events, in addition to blood pressure control. (Circ J 2011; 75: 2411-2416)

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Background: Myocardial perfusion imaging (MPI) has been used to estimate cardiac event risk. The aim of the present study is to achieve stable risk estimation based on perfusion scoring and a multi-center prognostic database. Methods and Results: Multivariate logistic regression analysis was performed to estimate cardiac event risk based on a J-ACCESS study. A stress-MPI was performed in 45 patients with coronary artery disease (CAD) and in 25 non-CAD patients. Perfusion defect scoring of summed stress score (SSS) was performed by 5 methods: (1) visual scoring; (2) automatic scoring of 3 short-axis and 1 vertical long-axis slices; (3) visual modification of Method 2; (4) automatic polar map scoring based on a Japanese multi-center database; and (5) visual modification of Method 4. Agreement of SSS between 2 observers was good (r=0.87-0.97). Agreement of estimated cardiac event risk between observers and among 5 methods was very good (r=0.99-1.00). Regarding diagnostic accuracy for CAD, Method 5 showed optimal diagnostic yields (sensitivity 84%, accuracy 77%). Conclusions: Estimation of cardiac event risk in conjunction with polar map segmentation and common normal databases resulted in stable risk values, and might be used for risk stratification in patients suspected of having CAD. (Circ J 2011; 75: 2417-2423)

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Background: Although the coronary artery calcium (CAC) score as measured with computed tomography (CT) is associated with cardiovascular mortality and morbidity in Western countries, little is known in Asian populations. Methods and Results: Three hundred and seventeen Japanese patients (205 men and 112 women) were followed in the study and they underwent both coronary angiography and CT for CAC measurements. The frequencies of angiographic coronary artery disease (CAD) were 5%, 36%, 76%, 80%, and 94% (P<0.001) and the needs for revascularization were 5%, 26%, 53%, 59%, and 69% (P<0.001) in patients with CAC scores of 0 (n=64), 1-100 (n=58), 101-400 (n=76), 401-1,000 (n=70), and >1,000 (n=49), respectively. In the average of 6.0 (range, 1-10) years follow-up period, 34 patients died including 13 from reasons of cardiac disease. In a Cox proportional hazard model after adjustment for age and sex, traditional coronary risk factors, previous myocardial infarction, and the need for revascularization, the hazard ratio for cardiac mortality in patients with a CAC score >1,000 was 2.98 (95% confidence interval: 1.15-9.40) compared with those with a CAC score=0-100. Conclusions: The CAC score has a predictive value for angiographical CAD and long-term mortality from cardiac disease in Japanese high-risk patients who undergo coronary angiography. (Circ J 2011; 75: 2424-2431)

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Background: A low ratio of serum eicosapentaenoic acid to arachidonic acid (EPA/AA) has been associated with cardiovascular events. Higher-grade yellow color coronary plaques are associated with higher plaque vulnerability and higher thrombogenic potential. Therefore, the association between EPA/AA ratio and yellow color grade of coronary plaques was examined. Methods and Results: Consecutive patients (n=54) who underwent percutaneous coronary intervention were enrolled in this study. The serum EPA/AA ratio was examined on admission. All patients underwent an angioscopic examination of the culprit vessel to examine the color grade of yellow plaques (0, white; 1, slight yellow; 2, yellow; and 3, intense yellow) and the presence of thrombus. Excluding 16 patients with acute coronary syndrome (ACS), 38 patients with stable angina were divided into 2 groups according to their EPA/AA ratio: the low EPA/AA group (n=19, EPA/AA ratio <0.37 [median]) and the high EPA/AA group (n=19, EPA/AA ratio ≥0.37). The maximum color grade (2.5±0.5 vs. 1.9±0.9; P=0.01) of yellow plaques was significantly higher and the number of non-culprit yellow plaques with thrombus (1.7±0.8 vs. 1.2±1.1; P=0.06) tended to be higher in low EPA/AA than in high EPA/AA stable angina patients. Multivariate analysis revealed that the serum EPA level (odds ratio=0.98, 95% confidence interval=0.96-0.99, P=0.03) was associated with the presence of grade-3 yellow plaques. Conclusions: A low serum EPA level and a low EPA/AA ratio was associated with high vulnerability of coronary plaques. (Circ J 2011; 75: 2432-2438)

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Background: Cystatin C, a marker for early stage chronic kidney disease, has been shown to be involved in cardiovascular disease. The relationship between serum cystatin C levels and coronary vasospastic angina (VSA), however, remains to be elucidated. The aim of the present study was to investigate whether elevated cystatin C levels predict the incidence of VSA. Methods and Results: One hundred and ten patients were referred to hospital due to suspected VSA. VSA was evoked in 59 patients by a vasospasm provocation test with administration of acetylcholine into the coronary arteries. The patients with VSA had lower levels of high-density lipoprotein cholesterol and a higher history of cigarette smoking, higher levels of triglyceride, high-sensitivity C-reactive protein, and higher cystatin C levels compared with those without VSA. There were no differences in serum creatinine or estimated glomerular filtration rate between patients with and without VSA. Multivariate logistic regression indicated that history of smoking (odds ratio, 2.956 P<0.05) and cystatin C levels (odds ratio, 2.285; P<0.01) were independently associated with the incidence of VSA. Conclusions: Elevated cystatin C levels were associated with higher incidence of VSA, suggesting that mild renal dysfunction may be implicated in the pathogenesis of coronary artery spasm. (Circ J 2011; 75: 2439-2444)

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Background: Toll-like receptors (TLRs) are expressed on cardiomyocytes and recognize pathogen-associated molecular patterns. Whether endogenous molecules produced by tissue injury (damage associated molecular patterns, DAMPs) can induce cardiomyocyte inflammation via TLR signalling pathways and/or reduce cardiomyocyte contractility is unknown. Methods and Results: Primary cardiomyocytes isolated from nuclear factor κ B (NFκB)-luciferase knock-in mice were used to assess NFκB signalling. DAMPs, HSP60, HSP70 and HMGB1, increased NFκB transcriptional activity compared to controls. HSP70 stood out compared to other DAMPs and even lipopolysaccharide (LPS). Subsequent experiments focused on HSP70. Cardiomyocytes exposed to HSP70 had a 58% decrease in contractility without a decrease in calcium flux. Exposure of cultured HL-1 cardiomyocytes to HSP70 resulted in increased expression of intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6) and keratinocyte-derived chemokine (KC) compared to controls. Knock-out mice for TLR2, TLR4 and MyD88, plus background strain controls (C57BL/6) were used to assess induction of cardiomyocyte inflammation by HSP70. The cardiomyocyte expression of ICAM-1 induced by HSP70 was significantly reduced in TLR2 and MyD88 knock-out mice but not TLR4 knock-out mice; implicating the TLR2 signalling pathway. Furthermore, blocking antibodies to TLR2 were able to abrogate HSP70-induced contractile dysfunction and cell death. Conclusions: Extracellular HSP70 acting via TLR2 and its obligate downstream adaptor molecule, MyD88, activate NFκB. This causes cardiomyocyte inflammation and decreased contractility. (Circ J 2011; 75: 2445-2452)

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Background: The dynamics of oxidation/reduction control system activities using reactive oxygen metabolites (ROM) and biological antioxidant potential (BAP) in acute stage patients was evaulated to understand the mechanism of vascular injury and remodeling in Kawasaki disease (KD). Methods and Results: ROM, BAP, high-sensitivity C-reactive protein (hs-CRP), interleukin-1,2,6, and tumour necrosis factor-α in 19 KD patients were measured. ROM decreased in good correlation only with hs-CRP (P<0.05) at 2 weeks after intravenous immunoglobulin (IVIG). Patients were further classified as responding well (Group A) or responding poorly (Group B) to IVIG. Both treatment groups had significantly higher ROM values than the control group (P<0.01). ROM decreased in Group A both immediately and 2 weeks after the IVIG treatment (P<0.05), but it did not decrease in Group B until 2 weeks post-treatment (P<0.01). BAP levels were unremarkable in Group A, but were significantly lower in Group B than in both other groups (P<0.05). BAP increased in Group A 2 weeks after IVIG treatment (P<0.01), but remained low in Group B (P<0.01). Conclusions: Acute stage KD patients suffer from obvious hyperoxidant stress, and improved in response to IVIG treatment in most patients. Blood BAP level might be a useful index for predicting responsiveness to IVIG the treatment. (Circ J 2011; 75: 2453-2459)

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Background: The results of paramalleolar distal bypass for critical limb ischemia in patients with peripheral arterial disease were reviewed to determine the factors affecting the long-term patency of this procedure in Japanese subjects. Methods and Results: A total of 65 legs from 60 consecutive Japanese patients with critical limb ischemia who underwent distal bypass to the ankle were retrospectively reviewed. Postoperative graft patency, morbidity and mortality were analyzed. All patients were monitored during a mean follow-up period of 2.2±1.7 years (median, 1.7 years). The accumulated primary and secondary patency rates were both 81.0% at 1 year and 78.7% at 3 and 5 years. The amputation-free rates and survival rates at 1 year, and 3 and 5 years were 94.5% and 82.6%, 82.6% and 88.1%, and 76.7% and 69.7%, respectively. The Cox proportional hazard model was used to determine factors contributing to long-term results. Age (odds ratio, 1.1; P<0.05) and diabetes (odds ratio, 18.0; P<0.05) were found to be the significant determinant factors of graft occlusion. No variables were found to be significant determinant factors of amputation-free or survival rates. Conclusions: Distal bypass to the paramalleolar tibial artery is an effective strategy for peripheral arterial disease with reasonable long-term reliability. Diabetes and old age were found to be the possible determinant factors of graft failure in Japanese patients. (Circ J 2011; 75: 2460-2464)

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Background: Several studies have suggested that depression poses a risk in cardiovascular patients. The aim of the present study was to evaluate the prevalence of depression and its effect on cardiovascular events and mortality in Japanese inpatients with cardiovascular disease. Methods and Results: A total of 505 patients hospitalized with cardiovascular disease (28% female; mean age, 61±14 years; 31% ischemic heart disease; 47% New York Heart Association [NYHA] class II-IV; 25% implantation of pacing devices) were enrolled in the present prospective observational study. The Zung Self-Rating Depression Scale (SDS) was used to screen for depression. The primary outcome was the time to death or cardiovascular event, and the secondary outcome was death. In total, 109 patients (22%) were diagnosed with depression (Zung SDS index score ≥60). NYHA class III/IV, defibrillator implantation, and being unmarried were independently associated with depression. During an average follow-up period of 38±15 months, 92 patients (18%) reached the primary outcome. There was a higher incidence of the primary outcome in patients with depression than in those who were not depressed (P<0.01). Depressed patients had a significantly higher rate of mortality than non-depressed patients (P<0.01). Depression was an independent predictor of the primary outcome (hazard ratio, 2.25; 95% confidence interval: 1.30-3.92, P<0.01). Conclusions: Depression was not uncommon in Japanese inpatients with cardiovascular disease and was associated with cardiovascular outcomes. (Circ J 2011; 75: 2465-2473)

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Background: There have been few reports regarding treatment selection and prognosis of symptomatic aortic valve stenosis (AS) in the elderly in Japan. Methods and Results: Sixty-one patients hospitalized between January 2000 and December 2007 for symptomatic severe AS were investigated. The average observation period was 27 months. Thirty-seven patients (61%) were diagnosed with AS for the first time on hospitalization. Thirty-six patients had onset of symptoms within 1 month before admission. Thirty-six patients received aortic valve replacement (group S) and 25 received medical therapy (group M). The patients in group M were older than those in group S (84.1±5.3 years vs. 74.2±4.6 years, P<0.001). Maximum flow velocity measured by echocardiography was lower in group M (4.5±0.3m/s vs. 4.9±0.5m/s, P<0 .01), but there was no difference in valve area between the 2 groups (0.62±0.19cm² vs. 0.57±0.15cm², P=0.12). One-year mortality rate derived from the Kaplan-Meier curve was higher in group M than group S (53.1% vs. 6.4%, respectively). On multivariate analysis, the only independent favorable prognostic factor was aortic valve replacement (HR: 0.02, 95%CI: 0.01-0.15, P<0.01). Conclusions: Medical therapy is often selected for treatment of symptomatic AS in the elderly, but the prognosis is very poor. Symptomatic severe aortic stenosis should be treated surgically, or with transcatheter aortic valve implantation in cases with high surgical risk. (Circ J 2011; 75: 2474-2481)

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Background: Tumor necrosis factor (TNF)-α, which is released as a soluble form by ectodomain shedding of TNF-α converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study. Methods and Results: Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-α expression in liver, and increased adipocyte size, macrophage infiltration and TNF-α and monocyte chemoattractant protein-1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1. Conclusions: Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders. (Circ J 2011; 75: 2482-2490)

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Background: Cadmium is a potential new risk factor for early atherosclerosis and cardiovascular diseases in humans, yet pathogenetic mechanisms are still a matter of debate. Methods and Results: In-depth histological analysis of 18 sections taken from 6 cadmium-fed ApoE-/- mice and 12 sections from 5 litter-mates not exposed to cadmium by light and scanning electron microscopy was performed. Cadmium-fed mice showed a marked increase in lesion load (plaque area) and severity as classified according to the American Heart Association vascular lesion grading. All inflammatory markers studied (CD68, CD3, CD25, vascular cell adhesion molecule 1 (VCAM-1), and heat shock protein 60 (Hsp60)) yielded a higher expression in cadmium-fed mice. Statistical difference was achieved for VCAM-1 and Hsp60 (P=0.03 and P=0.02). The shoulder region of atherosclerotic plaques in cadmium-fed mice showed a prominent retraction of endothelial cells on electron microscopy. Conclusions: Our data indicate that cadmium exposure amplifies the development of vessel pathology in atherosclerosis susceptible ApoE-/- mice and suggests upregulation of VCAM-1 and Hsp60 and endothelial leakage as potential pathomechanisms. (Circ J 2011; 75: 2491-2495)

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Background: Ezetimibe-plus-statin therapy has been reported to provide greater reduction in low-density lipoprotein cholesterol (LDL-C) level than statin monotherapy. The aim of the present study was to evaluate the relationship between LDL-C lowering effect and baseline cholesterol absorption and synthesis markers in patients with coronary artery disease (CAD). Methods and Results: A total of 171 patients with CAD whose LDL-C level was ≥100mg/dl after treatment with atorvastatin (10mg/day) or rosuvastatin (2.5mg/day) for 4 weeks were assigned to additionally receive ezetimibe (10mg/day) plus a statin or a double dose of statin for 12 weeks. The decreases in LDL-C (-30.0±15.6mg/dl vs. -19.2±14.2mg/dl) and the ratio of campesterol, an absorption marker, to total cholesterol levels (-1.35±0.90μg/mg vs. 0.33±0.74μg/mg) were greater in the ezetimibe-plus-statin group (P<0.05, respectively). The decrease in LDL-C level in the ezetimibe-plus-statin group was greatest in patients with baseline levels of higher absorption and lower synthesis markers and smallest in patients with baseline levels of lower absorption and higher synthesis markers (-34.3±15.6mg/dl vs. -21.5±16.7mg/dl, P<0.05). The decrease in LDL-C did not differ, irrespective of baseline levels of cholesterol absorption and synthesis markers, in the double-dose statin group, and was similar to that in patients with lower absorption and higher synthesis markers in the ezetimibe-plus-statin group. Conclusions: Ezetimibe-plus-statin therapy may be useful for lowering LDL-C level, irrespective of baseline levels of cholesterol absorption and synthesis markers. (Circ J 2011; 75: 2496-2504)

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