Three-dimensional (3D) echocardiography is one of the most promising methods for the diagnosis of cardiac disease. Left and right ventricular size and function are currently evaluated with 2D echocardiography. However, for unpredictable asymmetry of the chamber geometry, conventional 2D echocardiography cannot be used to accurately determine absolute chamber volumes and ejection fraction. As for valvular heart diseases, the 3D echo approach has proven to be the most unique, powerful, and convincing method for understanding the complicated anatomy of the valves and their dynamism. The method has been useful for surgical management, including robotic mitral valve repair. Moreover, this method has become indispensable for nonsurgical procedures such as edge-to-edge mitral valve repair. Color Doppler 3D echo has also been valuable to identify the location of the regurgitant orifice, and the severity and character of the valvular regurgitation. In addition, 3D echo is invaluable in the diagnosis and management of congenital heart disease and in certain other situations, such as evaluation of the aortic annulus for transcatheter aortic valve implantation or replacement. It is now clear that 3D echocardiography, especially with the continued development of real-time 3D transesophageal echo technology, will enhance the diagnosis and management of patients with heart diseases. (Circ J 2015; 79: 2287–2298)

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Acute Kawasaki disease (KD) is diagnosed and treated by pediatricians, but decades later, these individuals are presenting to adult cardiologists with a variety of cardiovascular sequelae, including myocardial ischemia and infarction, congestive heart failure secondary to myocardial fibrosis, and claudication because of vascular insufficiency from thrombosed peripheral arteries. There are no clinical trials to guide management, interventions, and medical therapy in this patient population. This review summarizes the emerging information regarding evaluation of the cardiovascular status of adults decades after childhood KD. (Circ J 2015; 79: 2299–2305)

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The Annual Congress of the European Society of Cardiology (ESC) was held in London from 29 August to 2 September 2015. It is the leading conference in cardiology in the world, with presentations on the latest scientific discoveries, innovations, technology, education, and clinical practices. More than 32,000 delegates and 5,000 exhibitors from 140 countries participated, sharing a number of scientific presentations, including 28 clinical hot lines, 18 clinical trial updates, 20 registry studies, 12 basic and translational science hot line studies, and 4,533 abstract studies. Japan had the highest number of accepted abstracts at the Congress, indicating the great contribution of Japanese scientists and the Japanese Circulation Society. (Circ J 2015; 79: 2306–2313)

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Background:The aim of this study was to identify the ECG features that might differentiate between anterior interventricular vein (AIV) and distal great cardiac vein (d-GCV) outflow tract-ventricular arrhythmias (OT-VAs).Methods and Results:Radiofrequency catheter ablation was performed in 13 of 375 patients (3.5%) for AIV or d-GCV OT-VAs. We grouped the 13 patients by the origin, d-GCV (n=9) or AIV (n=4), and compared their ECGs and electrophysiological data. The OT-VA ECGs had S waves in lead I in all 13 patients. The voltage in the inferior lead III and peak deflection index showed no significant between-group differences (2.3±0.7 vs. 2.5±0.3 mV and 0.65±0.04 vs. 0.68±0.04 mV, respectively) for the d-GCV and AIV groups. There were also no significant between-group differences in the QaVL/QaVR, where Q denotes the amplitude of the Q wave in the suffix lead. However, the R/S ratio in V1 (1.7±1.0 [n=5] vs. 0.2±0.05, P=0.04), and QRS duration (149±16.6 vs. 123±3.8 ms, P=0.012) were greater in the d-GCG group than in the AIV group. There were no significant between-group differences in the activation time or pace mapping score at the optimal ablation sites.Conclusions:A low R/S ratio in V1 and shorter QRS duration may help identify AIV sites of epicardial OT-VA origin. (Circ J 2015; 79: 2335–2344)

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Background:To clarify the effects of warfarin therapy in very old patients with non-valvular atrial fibrillation (NVAF), a post-hoc analysis was performed using the data of the J-RHYTHM Registry.Methods and Results:A consecutive series of AF outpatients was enrolled from 158 institutions. Of 7,937 patients, 7,406 with NVAF (men, 70.8%; 69.8±10.0 years) were followed for 2 years or until an event occurred. Patients were divided into 3 age groups (<70, 70–84, and ≥85 years) and 5 subgroups according to international normalized ratio (INR; <1.6, 1.6–1.99, 2.0–2.59, 2.6–2.99, and ≥3.0). Prevalence of female sex, permanent AF, hypertension, coronary artery disease, heart failure, and history of ischemic stroke/transient ischemic attack was higher in the older groups. In the oldest group, 79.7% of patients received warfarin and their time in therapeutic range, using the Japanese target INR of 1.6–2.6, was 67.1%. Rate of thromboembolic events was lower in the age groups <70 and 70–84 years (P=0.027 and P<0.001, respectively) for patients receiving warfarin compared with those who were not. In the oldest group, the rate of thromboembolism plus major hemorrhage was lower at INR 1.6–2.59.Conclusions:Warfarin could have beneficial effects even in very old NVAF patients if INR is kept between 1.6 and 2.59. (Circ J 2015; 79: 2345–2352)

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Background:Early recurrence of atrial fibrillation (ERAF) is common after pulmonary vein antrum isolation (PVAI); however, the definition, study population, and lesion set are not uniform in prior studies. We examined ERAF for paroxysmal AF while complying with the definition in the latest guidelines.Methods and Results:We included 471 patients undergoing empirical PVAI for paroxysmal AF. ERAF was observed in 180 patients (38.2%) including 49, 16, and 115 within 3, 4–7 days, and 8–90 days, respectively, after the index procedure. ERAF (hazard ratio 6.872; 95% confidence interval 4.803–9.382; P<0.0001) was the strongest factor associated with recurrence beyond 3 months (LR) in the multivariable model, and ERAF patients had worse outcomes than those without, regardless of the time to the first ERAF episode. There were no significant differences in the prevalence of PV reconnections and non-PV foci among 29 and 62 patients, respectively, who underwent redo procedures for ERAF within and more than 3 months after the index procedure, and 21 who underwent redo procedures for LR. Re-ablation was associated with a greater freedom from LR (HR 0.443; 95% CI 0.230–0.854; P=0.015).Conclusions:ERAF occurred in 38.2% of patients and was strongly associated with LR regardless of the time to the first ERAF episode. Re-ablation for ERAF significantly improved the freedom from recurrent atrial arrhythmias, regardless of the time to the first ERAF episode. (Circ J 2015; 79: 2353–2359)

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Background:The characteristics and prognostic value of the variability of premature ventricular contraction (PVC) coupling intervals (CIs) for cardiac mortality are not yet decisive.Methods and Results:In 133 consecutive patients (58±14 years old, 53 women) who had left ventricular dysfunction (LVD: ejection fraction <50%) and frequent PVCs (≥10/h) who underwent 24-h ambulatory electrocardiography (AECG) recording and ¹²³I-metaiodobenzylguanidine myocardial single-photon emission computed tomography simultaneously, the heart rate turbulence onset, slope, and T-wave alternans were analyzed from the 24-h AECG. The CI of the PVCs (MEAN_NV), standard deviation of the CI of the PVCs (SD_NV) as an index of the variability of the PVC CI, and their ratio to the preceding N-N intervals (SD_NV/SD_NN) were calculated from constructed Poincaré plots using the annotated 24-h AECG QRS data. The primary endpoint was cardiac mortality. The mean follow-up period was 63 months. Among 133 patients, 114 survived (group 1) and 19 (14%, group 2) died during the follow-up. The MEAN_NVand SD_NVwere higher in group 2 (539±104 vs. 599±114 ms, P=0.021; 64±34 vs. 83±37 ms, P=0.022, respectively). The SD_NV, PVC count, and delayed heart/mediastinum ratio remained as significant predictors of cardiac mortality in the binary logistic regression analysis.Conclusions:These results suggest that the SD_NVcould be another adjunctive parameter for predicting cardiac mortality in LVD. (Circ J 2015; 79: 2360–2366)

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Background:The aim of this study was to investigate the feasibility of static balloon atrial septostomy (BAS) with the double balloon technique for infants. TMP PED balloon catheter, newly designed for static BAS in small children, was used in 3 infants. The balloon catheter has a low profile, short and round shoulder, and smooth deflation without slippage.Methods and Results:Three infants (transposition of the great arteries, n=2; pulmonary atresia with intact ventricular septum, n=1) underwent static BAS with double balloon for restrictive interatrial communication between December 2014 and March 2015. Hemodynamic and echocardiographic assessment was done before and after the procedure. Pressure gradient between left and right atrium decreased from 6, 7 and 9 mmHg to 2, 2 and 1 mmHg, respectively. Oxygen saturation in systemic artery increased from 72, 68 and 73% to 78, 70 and 79%, respectively. Maximum defect diameter increased from 3.5, 3.0 and 3.3 mm to 6.6×5.2, 9.0×6.2 and 8.1×5.1 mm, respectively. No complication was recorded.Conclusions:Static BAS with double balloon technique using the novel TMP PED balloon catheter was safe and effective in producing sufficient interatrial communication for 8–20 weeks in infants. Static BAS is a promising procedure to create interatrial communication in infants. (Circ J 2015; 79: 2367–2371)

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Background:The incidence of late coronary artery abnormalities after arterial switch operation (ASO) for d-loop transposition of the great arteries may be underestimated.Methods and Results:We retrospectively reviewed coronary artery morphology in 40 of 97 patients who survived the first year after ASO. Seven asymptomatic patients developed significant late coronary artery abnormalities. One patient died suddenly at home with severe left coronary artery (LCA) ostial stenosis at age 3.8 years. The second patient collapsed during exercise at age 9.6 years due to ventricular fibrillation and severe LCA ostial stenosis despite prior negative exercise stress test (EST) and myocardial perfusion imaging (MPI). The third patient was found to have moderate ostial stenosis of the LCA with negative EST and MPI. The fourth patient with exercise-induced ST-T depression and myocardial perfusion defect was shown to have complete LCA occlusion with collateral vessel formation. Three other patients had complete proximal obliteration of either of the coronary arteries with collateral supply. An additional 4 asymptomatic patients had trivial-mild narrowing of the LCA on routine selective coronary angiogram.Conclusions:Incidence of late coronary stenosis or occlusion was not infrequent after ASO (11.3%) and presented usually without preceding symptoms and often after negative non-invasive screening. We advocate routine coronary imaging in all patients after ASO before they participate in competitive sports. (Circ J 2015; 79: 2372–2379)

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Background:Bioprostheses have become increasingly popular for aortic valve replacement (AVR) in recent years, but mechanical valves are still the standard choice, especially for younger patients. The aim of this study was to assess the very long-term outcomes in Japanese patients who underwent AVR with St. Jude Medical (SJM) mechanical valves.Methods and Results:From 1991 to 2001, a total of 816 patients underwent AVR with SJM mechanical valves in 5 hospitals. Of these, 801 patients (mean age, 58.3±11.7 years) were analyzed in this study. There were 24 in-hospital deaths (3.0%). Mean follow-up duration was 11.6±6.7 years and the 10-year follow-up rate was 84.1%. Freedom from valve-related death at 5, 10, 15, and 20 years was 96.2%, 92.7%, 88.8%, and 86.6%, respectively. The linearized ratio of major bleeding events and thromboembolic events was 1.1% per patient-year and 1.0% per patient-year, respectively. Freedom from reoperation for the aortic prosthesis was 98.0% and 94.8% at 10 and 20 years, respectively.Conclusions:The SJM mechanical valve provided excellent long-term freedom from valve-related death and reoperation in patients undergoing AVR. Therefore, this valve should be recommended to younger patients who wish to avoid reoperation. (Circ J 2015; 79: 2380–2388)

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Background:No study has examined the association between television (TV) viewing time and mortality from stroke and coronary artery disease (CAD) in Japanese.Methods and Results:A total of 35,959 men and 49,940 women aged 40–79 years without a history of cardiovascular disease (CVD) and cancer were followed from 1988–1990 until 2009. During 19.2 median years of follow-up, there were 2,553 deaths from stroke, 1,206 from CAD and 5,835 from total CVD. Compared with viewing TV for <2 h/day, mortality from stroke, CAD and total CVD were higher for ≥6 h/day of TV viewing. The multivariable hazard ratios (HRs) for ≥6 h/day of TV viewing were 1.15 (95% confidence interval: 0.96–1.37) for stroke, 1.33 (1.03–1.72) for CAD and 1.19 (1.06–1.34) for total CVD. The corresponding HRs for each 1-h/day increment in TV viewing time were 1.01 (0.99–1.04), 1.04 (1.01–1.08) and 1.02 (1.01–1.04), respectively. The excess risk of mortality from CAD and total CVD was somewhat attenuated after further adjustment for potential mediators such as history of hypertension and diabetes: the multivariable HRs for ≥6 h/day of TV viewing were 1.24 (0.96–1.61) and 1.14 (1.02–1.28). The corresponding HRs for each 1-h/day increment in TV viewing time were 1.03 (1.00–1.07) and 1.01 (1.00–1.03).Conclusions:Prolonged TV viewing was associated with a small but significant increase in mortality from CAD and total CVD in Japanese. (Circ J 2015; 79: 2389–2395)

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Background:Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure (HF) remain to be elucidated in Japan.Methods and Results:From the Chronic Heart Failure Analysis and Registry in the Tohoku District-1 (CHART-1; 2000–2005, n=1,278) and CHART-2 (2006-present, n=10,219) Studies, we enrolled 1,006 and 3,676 consecutive symptomatic stage C/D HF patients, respectively. As compared with the patients in the CHART-1 Study, those in the CHART-2 Study had similar age and sex prevalence, and were characterized by lower brain natriuretic peptide, higher prevalence of preserved left ventricular ejection fraction (LVEF) and higher prevalence of hypertension, diabetes mellitus and ischemic heart disease (IHD), particularly IHD with LVEF ≥50%. From CHART-1 to CHART-2, use of renin-angiotensin system inhibitors, β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was decreased. Three-year incidences of all-cause death (24 vs. 15%; adjusted hazard ratio [adjHR], 0.73; P<0.001), cardiovascular death (17 vs. 7%; adjHR, 0.38; P<0.001) and hospitalization for HF (30 vs. 17%; adjHR, 0.51; P<0.001) were all significantly decreased from CHART-1 to CHART-2. In the CHART-2 Study, use of β-blockers was associated with improved prognosis in patients with LVEF <50%, while that of statins was associated with improved prognosis in those with LVEF ≥50%.Conclusions:Along with implementation of evidence-based medications, the prognosis of HF patients has been improved in Japan. (Trial registration: clinicaltrials.gov identifier: NCT00418041) (Circ J 2015; 79: 2396–2407)

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Background:Several non-invasive methods for measuring pulmonary vascular resistance (PVR) have been proposed to date, but they remain empirical, lacking sufficient accuracy to be used in clinical practice. The aims of this study were to propose a novel echocardiographic measurement of PVR based on a theoretical formula and investigate the feasibilty and accuracy of this method in patients with heart failure.Methods and Results:Echocardiography was performed in 27 patients before right heart catheterization. Peak tricuspid regurgitation pressure gradient (TRPG), pulmonary regurgitation pressure gradient in end-diastole (PRPG_ed), and cardiac output derived from the time-velocity integral and the diameter in the left ventricular outflow tract (CO_LVOT) were measured. PVR based on a theoretical formula (PVR_theo) was calculated as (TRPG–PRPG_ed)/3CO_LVOTin Wood units (WU). The results were compared with PVR obtained by right heart catheterization (PVR_cath) using linear regression and Bland-Altman analysis. Mean PVR_cathwas 2.4±1.4 WU. PVR_theocorrelated well with PVR_cath(r=0.83, P<0.001). On Bland-Altman analysis the mean difference was 0.1±0.7 WU. The limits of agreements were smaller than for other non-invasive estimations previously reported.Conclusions:The new echocardiographic approach based on a theoretical formula provides a non-invasive and accurate assessment of PVR in patients with heart failure. (Circ J 2015; 79: 2408–2413)

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Background:We previously reported that cardiac resynchronization therapy with defibrillator (CRT-D) is not an appropriate rescue strategy in patients with advanced heart failure (HF), especially those dependent on inotrope infusion, and instead early ventricular assist device (VAD) implantation should be considered. Predictors of response to CRT in such populations, however, remain uncertain.Methods and Results:We studied 67 inpatients aged <65 years old with advanced HF, who received CRT-D between 2007 and 2014. Eleven patients (16%) were responders, in whom LVEF improved >10% at 6-month follow up. On logistic regression analysis, LA volume index (LAVI) <43 ml/m²(odds ratio (OR), 36.67; P=0.001) and complete left bundle branch block (CLBBB; OR, 6.663; P=0.032) were significant predictors of response to CRT-D among the baseline variables. Patients with both predictors were associated with improvements in LVEF and plasma B-type natriuretic peptide compared with those with none of these predictors during the 6-month follow up period (P<0.05 for both). VAD-free survival rate was significantly higher in the responders compared with the non-responders during the 2-year study period (86% vs. 52%, P=0.044).Conclusions:CLBBB and smaller LAVI are novel predictors of response in patients with advanced HF receiving CRT-D in real-world practice. Such responders may be better candidates for CRT-D and delay of cardiac replacement therapy. (Circ J 2015; 79: 2414–2421)

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Background:Patients with type 2 diabetes mellitus (T2DM) show a greater risk for coronary artery disease (CAD), but the risk stratification in asymptomatic CAD patients has not been established. This study investigated the prevalence and severity for asymptomatic CAD and predictors in T2DM patients.Methods and Results:In a multiclinic group, diabetic patients (320 men, 186 women) without known symptoms suggestive of CAD were recruited for multidetector computed tomography (MDCT). Patients were categorized according to severity of coronary atherosclerosis: Grade 1 (normal findings), Grade 2 (mild atherosclerosis without significant stenosis), Grade 3 (moderate stenosis/atherosclerosis, 50–74% stenosis), Grade 4 (moderate stenosis/atherosclerosis, 75–89% stenosis), Grade 5 (severe stenosis/atherosclerosis, ≥90% stenosis). The trend for severity grade of CAD was slightly higher in men than women (P=0.054). For critical lesions (combined Grades 3–5), the prevalence was almost equal (men 44% vs. women 37%; P=0.113). Multivariate models showed that in men, HbA_1c≥7.4%, dyslipidemia, duration of diabetes, retinopathy, and other type of cardiovascular diseases were predictors of critical lesions and in women, duration of diabetes and retinopathy were predictors.Conclusions:The prevalence and severity of asymptomatic CAD are comparably high in men and women with T2DM. Risk stratification by using MDCT might be useful to predict asymptomatic coronary lesions requiring coronary revascularization. (Circ J 2015; 79: 2422–2429)

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Background:Atherosclerotic plaque thrombogenicity is a critical factor that affects thrombus formation and the onset of acute myocardial infarction (AMI). The aim of this study was to identify the vascular factors involved in thrombus formation and AMI onset.Methods and Results:Culprit lesions in 40 coronary arteries with thrombi at autopsy after lethal AMI and non-cardiac death (asymptomatic plaque disruption) were analyzed on histology. Thrombus size, ratio of thrombus to lumen area, length of plaque disruption, and immunopositive areas for tissue factor (TF) and hexokinase (HK)-II were significantly larger in coronary arteries with AMI than with asymptomatic plaque disruption. The size of coronary thrombus positively correlated with the length of plaque disruption (r=0.80) and with immunopositive areas for TF (r=0.38) and HK-II (r=0.40). Because both M1 and M2 macrophages express TF and HK-II in symptomatic plaques, we assessed TF and HK-II expression in M1- and M2-polarized macrophages. The expression of TF was increased and that of HK-II was decreased in M2-, compared with M1-polarized THP-1 macrophages. Inhibiting glycolysis enhanced TF expression in the macrophages partly via hypoxia inducible factor-1α.Conclusions:The degree of plaque disruption and expression of TF and HK-II appear to be important vascular factors for AMI onset, and polarized macrophages make a distinct contribution to thrombogenicity and glucose metabolism. (Circ J 2015; 79: 2430–2438)

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Background:The pharmacodynamic effects of changing from standard-dose clopidogrel to low-dose (3.75 mg) prasugrel in Japanese patients are largely unknown.Methods and Results:A total of 53 consecutive Japanese patients with stable coronary artery disease (CAD) who received aspirin and clopidogrel were enrolled. Clopidogrel was switched to 3.75 mg prasugrel. At day 14, prasugrel was switched to 75 mg clopidogrel. Platelet reactivity was measured using the VerifyNow assay at baseline, day 14, and day 28. VerifyNow P2Y12 reaction units (PRU) >208 was defined as high on-treatment platelet reactivity (HPR). The prevalence of HPR (18.9% vs. 41.5% vs. 44.2%, P<0.001) and the PRU level (154.3±54.2 vs. 196.2±55.5 vs. 194.6±55.8, P<0.001) were significantly lower on prasugrel maintenance therapy compared with the clopidogrel therapy before and after switching. The CYP2C19 genotypes that account for the 3 phenotypes (ie, extensive metabolizer, intermediate metabolizer, and poor metabolizer) had a significant impact on platelet reactivity with clopidogrel (174.9±54.0 vs. 193.1±56.5 vs. 240.6±25.4 PRU, P<0.001) but not prasugrel (147.0±51.9 vs. 147.5±58.3 vs. 184.4±38.3 PRU, P=0.15).Conclusions:Low-dose prasugrel achieves stronger platelet inhibition than clopidogrel in Japanese patients with stable CAD. (Circ J 2015; 79: 2439–2444)

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Background:Coronary artery calcium score (CACS) is a well-recognized marker for subclinical coronary atherosclerosis, particularly in asymptomatic populations. To date, however, the added prognostic benefit of CACS compared with traditional risk factors in an Asian population remains unknown. This study therefore investigated the benefit of CACS over traditional risk factors for all-cause mortality in a large multicenter registry of asymptomatic Korean adults.Methods and Results:A total of 34,386 individuals were retrospectively enrolled to participate in a general health examination. The Framingham 10-year risk score (FRS) was calculated according to the traditional risk stratification algorithm and CACS was calculated in log(CACS+1) for continuous data and categorized as 0, 1–100, 101–400 and >400. During a median follow-up of 4.9 years (IQR, 3.0–7.1), there were 303 all-cause deaths (0.9%). Following adjustment, CACS was independently associated with all-cause death (hazard ratio, 1.10; 95% confidence interval (CI): 1.05–1.17; P<0.001). Notably, CACS added further prognostic value above and beyond FRS (likelihood ratio, χ²=75.42, P<0.001; continuous net reclassification improvement=0.40, 95% CI: 0.29–0.51, P≤0.001; improving C-statistic from 0.64, 95% CI: 0.61–0.67 to 0.68, 95% CI: 0.64–0.71; ∆C=0.04, 95% CI: 0.01–0.06, P=0.002).Conclusions:In an asymptomatic Korean population, CACS improved prediction of all-cause mortality over and above that of a conventional risk tool. (Circ J 2015; 79: 2445–2451)

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Background:Few data on the relative efficacy and safety of new P2Y₁₂inhibitors such as prasugrel and ticagrelor in Japanese, Taiwanese and South Korean patients with acute coronary syndromes (ACS) exist.Methods and Results:The multicenter, double-blind, randomized PHILO trial compared the safety and efficacy of ticagrelor vs. clopidogrel in 801 patients with ACS (Japanese, n=721; Taiwanese, n=35; South Korean, n=44; unknown ethnicity, n=1). All were planned to undergo percutaneous coronary intervention and randomized within 24 h of symptom onset. Primary safety and efficacy endpoints were time to first occurrence of any major bleeding event and to any event from the composite of myocardial infarction, stroke or death from vascular causes, respectively.At 12 months, overall major bleeding occurred in 10.3% of ticagrelor-treated patients and in 6.8% of clopidogrel-treated patients (hazard ratio (HR), 1.54; 95% confidence interval (CI): 0.94–2.53); the composite primary efficacy endpoint occurred in 9.0% and in 6.3% of ticagrelor- and clopidogrel-treated patients, respectively (HR, 1.47; 95% CI: 0.88–2.44). For both analyses, the difference between groups was not statistically significant.Conclusions:In ACS patients from Japan, Taiwan and South Korea, event rates of primary safety and efficacy endpoints were higher, albeit not significantly, in ticagrelor-treated patients compared with clopidogrel-treated patients. This observation could be explained by the small sample size, imbalance in clinical characteristics and low number of events in the PHILO population. (Circ J 2015; 79: 2452–2460)

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Background:The effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on arrhythmias remains unknown. The aim of this study was to investigate whether sitagliptin attenuates arrhythmias through inhibiting nerve growth factor (NGF) expression, focusing on cyclic adenosine monophosphate (cAMP) downstream signaling such as protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac).Methods and Results:Male Wistar rats were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after ligating the coronary artery. Post-infarction was associated with increased oxidative stress. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham. Compared with the vehicle, infarcted rats treated with sitagliptin had significantly increased cAMP levels, decreased DPP-4 activity, oxidative stress, NGF levels and immunofluorescence-stained sympathetic hyperinnervation. Arrhythmic scores were significantly lower in the sitagliptin-treated infarcted rats than in vehicle. Ex vivo studies showed that sitagliptin increased the phosphorylated cAMP response element-binding protein (CREB), which can be reversed by H-89 (a PKA inhibitor), not brefeldin A (an Epac inhibitor).Heme oxygenase-1(HO-1) expression was increased by a PKA agonist but not by an Epac agonist.HO-1expression was attenuated in KG-501 (a CREB inhibitor)-treated infarcted rats in the presence of a PKA agonist.Conclusions:Sitagliptin protects ventricular arrhythmias by attenuating NGF-induced sympathetic innervation via upregulation ofHO-1expression in a cAMP/PKA/CREB-dependent antioxidant pathway in non-diabetic infarcted rats. (Circ J 2015; 79: 2461–2470)

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Background:Although longitudinal strain (LS) is known to be reduced in patients with hypertrophic cardiomyopathy (HCM), it has not been elucidated whether or not circumferential strain (CS) is reduced. We aimed to determine whether multidirectional and layer-specific myocardial strain is reduced in patients with nonobstructive HCM.Methods and Results:Speckle-tracking echocardiography was performed in 41 HCM patients and 27 control subjects. Segmental and global LS and CS were measured in the inner, mid, and outer layers. Global LS was significantly lower in the HCM group than in controls in the inner (−10.3±2.9 vs. −14.8±2.0%, P<0.001), mid (−8.7±2.6 vs. −13.8±1.9%, P<0.001), and outer (−7.2±2.6 vs. −11.9±1.9%, P<0.001) layers. Global CS was preserved in the inner layer (−23.8±4.7 vs. −24.3±3.3%, P=0.69) but reduced in the mid (−10.3±3.1 vs. −13.3±2.5%, P<0.001) and outer layers (−6.7±2.3 vs. −8.6±2.3%, P=0.002). Differences in CS between the inner and outer layers correlated with segmental relative wall thickness (r=−0.20, P=0.002). Furthermore, only the absolute value of global CS in the inner layer positively correlated with left ventricular ejection fraction (r=0.32, P<0.01) among these multidirectional and layer-specific strains.Conclusions:In patients with HCM, not only the LS in all layers but also CS in the mid and outer layers was reduced, presumably reflecting impaired myocardial function. In contrast, CS in the inner layer was preserved, being associated with maintenance of chamber function. (Circ J 2015; 79: 2471–2479)

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Background:Kidney dysfunction is reportedly associated with adverse outcome in patients with peripheral artery disease (PAD). Estimated glomerular filtration rate (eGFR), a recently popularized index for assessing kidney function, is calculated using serum creatinine or cystatin C. Compared with creatinine-based eGFR (eGFRcr), cystatin C-based eGFR (eGFRcys) is less affected by age, gender, and muscle mass. We hypothesized that eGFRcys is a feasible prognostic biomarker despite muscle sarcopenia in patients with PAD.Methods and Results:We calculated both eGFRcr and eGFRcys according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline in 234 PAD patients who underwent endovascular therapy. Patients were prospectively followed during a median follow-up period of 964 days for the endpoint of major adverse cardiovascular and cerebrovascular events (MACCE). On multivariate Cox proportional hazard analysis eGFRcys, but not eGFRcr, was an independent predictor of MACCE. The C index was larger for eGFRcys than eGFRcr (0.69 vs. 0.57, P=0.0006). On Kaplan-Meier analysis the incidence of MACCE was increased with advancing chronic kidney disease stage based on eGFRcys, but not on eGFRcr, in patients with PAD. Net reclassification index was improved with the addition of eGFRcys to basic predictors.Conclusions:Compared with eGFRcr, eGFRcys may be a more reliable biomarker for MACCE and patient risk stratification. (Circ J 2015; 79: 2480–2486)

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Background:Angiogenesis is a critical component of many pathological conditions, and microRNAs (miRNAs) are indispensable in angiogenesis. It is unclear whether miRNAs regulate angiogenesis in the presence of high concentrations of uric acid (HUA), and the underlying mechanisms remain unknown.Methods and Results:It was found that HUA inhibited the angiogenic ability of endothelial cells. miRNA expression profiling was conducted using microarray assays in HUA-stimulated endothelial cells. Eighteen differentially expressed miRNAs were subjected to bioinformatic analyses. The results indicated that miR-92a was negatively regulated and was closely related to angiogenesis. Furthermore, the effects of miR-92a on HUA-stimulated endothelial cell angiogenesis and the underlying mechanisms were investigated in dual-luciferase reporter assays, electrophoretic mobility shift assays, immunoblot assays, and tube formation assays. It was determined that Krüppel-like factor 2 (KLF2) is a target gene of miR-92a, and KLF2 binds the vascular endothelial growth factor-A (VEGFA) promoter to inhibit its expression. miR-92a and VEGFA overexpression or KLF2 downregulation alleviates the HUA-mediated inhibition of angiogenesis in endothelial cells in vitro.Conclusions:This study reported that there is a novel pathway regulating angiogenesis under HUA conditions. In the presence of HUA, miR-92a downregulation increased KLF2 expression, subsequently inhibiting VEGFA, which resulted in decreased angiogenesis. Thus, this study reports a possible mechanism for cardiovascular injury caused by hyperuricemia and suggests that the miR-92a-KLF2-VEGFA axis may be a target for hyperuricemia treatment. (Circ J 2015; 79: 2487–2498)

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Background:Atherosclerosis is a progressive inflammatory disease that can lead to sudden cardiac events by plaque rupture and subsequent thrombosis. Factor Xa (FXa) not only occupies a crucial position in the coagulation cascade responsible for thrombin generation, but also has pro-inflammatory effects. The hypothesis that Fondaparinux, the selective FXa inhibitor, attenuates plaque progression and promotes stability of atherosclerotic lesions was assessed.Methods and Results:Fondaparinux (5 mg/kg body weight/day) or 0.9% saline was intraperitoneally administered for 4 weeks to apolipoprotein E-deficient mice (n=12 per group) with established atherosclerotic lesions in the innominate arteries. Fondaparinux did not remarkably decrease the progression of atherosclerosis development in apolipoprotein E-deficient mice, but increased the thickness of fibrous cap (P=0.049) and decreased the ratio of necrotic core (P=0.001) significantly. Moreover, Fondaparinux reduced the staining against Mac-2 (P=0.017), α-SMA (P=0.002), protease-activated receptor (PAR)-1 (P=0.001), PAR-2 (P=0.003), CD-31 (P=0.024), MMP-9 (P=0.000), MMP-13(P=0.011), VCAM-1 (P=0.041) and the mRNA expression of inflammatory mediators (P<0.05) significantly, such as interleukin (IL)-6, MCP-1, IFN-γ, TNF-α, IL-10 and Egr-1.Conclusions:Fondaparinux, the selective FXa inhibitor, can promote the stability of atherosclerotic lesions in apolipoprotein E-deficient mice, possibly through inhibiting expression of the inflammatory mediators in plaque and reduced synthesis of MMP-9 and MMP-13. (Circ J 2015; 79: 2499–2508)

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Background:Uptake of oxidized low-density lipoprotein (oxLDL) by macrophages is recognized as a crucial step in the development of atherosclerosis, whereas the precise molecular mechanisms involving it remain to be elucidated.Methods and Results:This study focused on determining the role of toll-like receptor 4 (TLR4) and Src kinase in macrophage lipid accumulation. oxLDL significantly enhanced Src kinase activity and intracellular lipid contents in RAW264.7 macrophages, whereas the small interference RNA-mediated knockdown of TLR4 and Src or chemical inhibition of Src activity blocked oxLDL-induced lipid accumulation. Immunoprecipitation and immunofluorescence studies demonstrated that TLR4 was associated with Src on the plasma membrane upon oxLDL stimulation.Conclusions:The results of the present study suggest an essential role of TLR4-Src signaling in macrophages in the pathogenesis of atherosclerosis. (Circ J 2015; 79: 2509–2516)

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