Stroke and coronary artery disease (CAD) are major causes of death throughout the world. As half of the world’s population lives in Asian countries, prevention of stroke and CAD in Asia is crucial. According to the vital statistics, East Asian countries have a lower mortality rate for CAD than for stroke. In contrast, CAD is a more common cause of death than stroke in other Asian countries and Western countries. Hypertension, diabetes, hypercholesterolemia, and smoking are major risk factors for stroke and CAD in Asia as well as in Western countries. In an observational study in Japan, the stroke incidence decreased as a result of improvements in blood pressure control and reduction in the smoking rate over the past half century, whereas the CAD incidence did not show a clear secular change, probably because the benefits of blood pressure control and smoking cessation were negated by increasing prevalence of both glucose intolerance and hypercholesterolemia. Although Asian populations have lower serum cholesterol levels than Western populations, the prevalence of hypercholesterolemia has increased during the past half century in Asia. In addition, the smoking rate among Asian men is higher than for Western men. These results underscore that, in addition to blood pressure control, smoking cessation and the management of metabolic risk factors are very important for prevention of stroke and CAD in Asia.  (Circ J 2013; 77: 1923–1932)

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Since its invention in the late 1990s, intravascular optical coherence tomography (OCT) has been rapidly adopted in clinical research and, more recently, in clinical practice. Given its unprecedented resolution and high image contrast, OCT has been used to visualize plaque characteristics and to evaluate the vascular response to percutaneous coronary intervention. In particular, OCT is becoming the standard modality to evaluate in vivo plaque vulnerability, including the presence of lipid content, thin fibrous cap, or macrophage accumulation. Furthermore, OCT findings after stent implantation, such as strut apposition, neointimal hyperplasia, strut coverage, and neoatherosclerosis, are used as surrogate markers of the vascular response. New applications for OCT are being explored, such as transplant vasculopathy or non-coronary vascular imaging. Although OCT has contributed to cardiovascular research by providing a better understanding of the pathophysiology of coronary artery disease, data linking the images and clinical outcomes are lacking. Prospective data are needed to prove that the use of OCT improves patient outcomes, which is the ultimate goal of any clinical diagnostic tool.  (Circ J 2013; 77: 1933–1940)

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The use of surgical lesion sets for the treatment of atrial fibrillation has been increasing, particularly in patients with complicated anatomical substrates and those undergoing concomitant surgery. Preferences in terms of lesion set, surgical approach and ablation technology vary by center. This review discusses both the surgical techniques and the outcomes for the most commonly performed procedures in the context of recent consensus guidelines. The Cox-Maze IV, pulmonary vein isolation, extended left atrial lesion sets, the hybrid approach and ganglionated plexus ablation are each reviewed in an attempt to provide insight into current clinical practice and patient selection.   (Circ J 2013; 77: 1941–1951)

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Chronic ischemic mitral regurgitation (IMR) is still a significant clinical problem. It is present in 10–20% of patients with coronary artery disease and is associated with a worse prognosis after myocardial infarction and subsequent revascularization. Currently, coronary artery bypass grafting combined with restrictive annuloplasty is the most commonly performed surgical procedure, although novel approaches have been used in limited numbers with varying degrees of success. The purpose of this review is to clarify the rationale for the surgical techniques applicable to IMR. In order to do so, the condition will be defined and the evolution of classic or traditional surgical approaches to repairing or replacing the mitral valve in the setting of IMR will be described. Finally, novel approaches to the repair of the ischemic mitral valve will be considered.  (Circ J 2013; 77: 1952–1956)

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The term “nonischemic cardiomyopathy” (NICM) designates a myocardial disease characterized by mechanical and/or electrical dysfunction in the absence of significant coronary artery disease, valvular heart disease, hypertension, or congenital heart disease. Although sustained ventricular tachycardia (VT) occurs in only 5% of patients with NICM, it is an important cause of sudden cardiac death. In this review we summarize the current understanding of the anatomic and electrophysiologic substrates of VT in the different types of NICM. In addition, we discuss recent progress and experience with catheter ablation of VT in these patients.  (Circ J 2013; 77: 1957–1966)

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Current evidence and guidelines support the strategy of ischemia-guided revascularization for treatment of patients with stable coronary symptoms. However, anatomical stenosis is often targeted in revascularization treatment using percutaneous coronary intervention or coronary artery bypass surgery without seriously considering objective evidence of myocardial ischemia. Particularly, for patients with multivessel disease, angiographic complete revascularization was traditionally considered an ideal objective of revascularization treatment. Recently, however, observational studies contradict the concept of angiographic complete revascularization and support the benefit of ischemia-guided selective revascularization based on noninvasive and invasive functional evaluation detecting ischemia-producing coronary lesions. In the absence of a trial specifically designed to assess the relative benefit of either strategy, the present review explores the current concepts about the strength and weakness of anatomical vs. functional revascularization.  (Circ J 2013; 77: 1967–1974)

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The goal of coronary plaque burden assessment is to detect vulnerable or high-risk atherosclerotic plaques that are prone to rupture and to stabilize them through pharmacologic and other types of interventions before the development of acute coronary syndrome. In this regard, a reliable, reproducible, and less invasive imaging modality capable of identifying plaque characteristics associated with plaque vulnerability would be immensely useful for evaluating plaque status and predicting future cardiovascular events. Recently, magnetic resonance imaging (MRI) has emerged as a novel modality for atherosclerotic plaque detection and characterization. This review will cover the developments in MRI for characterizing atherosclerosis in carotid and coronary arteries and its use in clinical diagnoses and longitudinal studies to understand the pathophysiology of atherosclerosis.  (Circ J 2013; 77: 1975–1983)

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Background: With respect to endovascular aneurysm repair (EVAR), the development of advanced techniques and devices, namely, Cook Zenith and Gore Excluder, has helped overcome device-related problems, including device migration. Deformities of abdominal aortic aneurysms (AAAs) can influence the long-term outcome of EVAR. The post-implantation behavior of stent grafts in AAAs with a severely angulated neck (SAN) was examined. Methods and Results: Among 190 AAA patients who underwent EVAR, 46 had SAN of more than 60 degrees. The post-implantation angle and adverse events were evaluated. Forty-one patients (89%) showed straightening of the neck angle immediately after the operation (early), with 2 types of subsequent (late) configuration changes — recoil and additional straightening. Among 34 Excluder patients, 29 showed immediate straightening, without additional straightening and 8 exhibited recoil. All 12 Zenith patients showed immediate straightening; 7 subsequently exhibited additional straightening, and none of them showed recoil. A difference (P=0.04) was noted between the 2 devices in the late angle changes. In all cases, no migration was observed at the proximal sites. Conclusions: The post-implantation configuration changes in stent placement in AAA patients with SAN were different for Excluder and Zenith. Appropriate device selection and proper planning of the procedure is necessary for EVAR.  (Circ J 2013; 77: 1996–2002)

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Background: According to the current guidelines, substitution of warfarin with heparin is recommended as perioperative management in patients with high risk of thromboembolism. Optimal management of oral anticoagulation in patients undergoing implantable cardioverter defibrillator (ICD) implantation, however, remains controversial. Methods and Results: Bleeding complications among 273 consecutive patients undergoing initial ICD implantation were retrospectively analyzed. Patients were grouped according to medication at the time of device implantation: neither antiplatelet nor anticoagulation (N group, n=121); antiplatelet only (AP group, n=59); warfarin (W group, n=59); and heparin bridging (H group, n=34). The rate of the major bleeding complications, defined as hematoma requiring reoperation, cardiac tamponade, and pericardial effusion requiring additional hospital stay, was 1.7% in the N group, 0% in the AP group, 5.1% in the W group, and 17.6% in the H group (P<0.001, N group vs. H group). After multivariate adjustment, heparin bridging was a significant predictor of major bleeding complications (odds ratio, 7.44; 95% confidence interval: 2.06–26.89; P=0.0022). The international normalized ratio of 3 patients in the W group with major bleeding complications was 1.98±0.10, and was significantly higher than in patients without them (1.31±0.05, n=26, P<0.001). Conclusions: Heparin bridging increased the risk of bleeding complications at the time of ICD implantation.  (Circ J 2013; 77: 2003–2008)

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Background: To gain further insights into mechanisms leading to atrial fibrillation (AF) recurrence after a first ablation procedure using cryoballoon technique, the data collected during redo procedure were analyzed. Methods and Results: From a total of 112 patients who underwent cryoballoon pulmonary vein isolation (PVI) for paroxysmal AF, 44 had a second ablation procedure using radiofrequency catheter, because of recurrent atrial arrhythmia. PV reconduction was observed in 109 of the 171 initially isolated veins (64%). Conduction recovery was found, respectively, at the left inferior PV, right inferior PV, right superior PV and left superior PV in 35 patients (80%), 26 patients (67%), 23 patients (52%) and 17 patients (39%). The mean number of reconnected PVs per patient was significantly lower with the 23-mm cryoballoon as compared to the 28-mm. Conduction gaps were focal and located at inferior parts of inferior veins and at the ridge between left atrial appendage and left veins. Mean procedure and fluoroscopy time were 109±32min and 14.7±8.3min, respectively. A 3-D mapping system was used in only 8 patients (18%). Conclusions: Atrial arrhythmia recurrences following cryoballoon PVI were associated with focal PV reconnections, occurring at preferential anatomical sites. These gaps were readily ablated with focal radiofrequency delivery, explaining the lack of need of 3-D mapping system and short procedure time. These results do not support the use of cryoballoon to perform redo procedures.  (Circ J 2013; 77: 2009–2013)

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Background: Dyspepsia is not uncommon in patients undergoing ablation of atrial fibrillation (AF). The purpose of this study was to investigate the change in gastric myoelectrical activity and its relationship to the outcome after ablation by electrogastrography (EGG). Methods and Results: The study prospectively enrolled 32 patients: 16 patients (Group 1) had AF and 16 (Group 2) had paroxysmal supraventricular tachycardia. The myoelectricity-like signals of the gastrointestinal tract were recorded using EGG before, immediately, and 3 months after ablation. Both fasting and postprandial abnormal gastric wave percentages increased immediately after ablation in Group 1 when compared with before ablation. Increased fasting (12.8±15.2% vs. 22.3±21.0%, P=0.04) and postprandial (10.4±6.2% vs. 21.2±14.5%, P=0.01) bradygastria percentages were noted immediately after ablation in Group 1 when compared with before ablation. These findings were not observed in Group 2. The normal gastric wave percentage returned to baseline 3 months after procedure. In total, 4 (25%) patients in Group 1 had a recurrence of AF after a follow-up of 18±3 months; those without recurrence had a significantly higher percentage of postprandial abnormal gastric waves immediately after ablation when compared with recurrence. Conclusions: Transient gastric dysrhythmias with bradygastria does occur in AF patients after ablation, which may indicate periesophageal vagal plexus damage after ablation. Careful application of radiofrequency energy to prevent esophageal injury is important.  (Circ J 2013; 77: 2014–2023)

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Background: The purpose of the present study was to compare the 5-year clinical outcomes after implantation of drug-eluting stent (DES) and bare-metal stent (BMS) in Japanese patients with acute myocardial infarction (AMI). Methods and Results: This study was a subgroup analysis of the Nagoya Acute Myocardial Infarction Study (NAMIS). It included 658 AMI patients, of which 280 were treated with a DES and 378 with a BMS. The major adverse cardiac event (MACE)-free rates during the 5-year follow-up period were similar between the 2 groups (95.7% vs. 96.8%, P=0.482). A significant difference was seen, however, in the target lesion revascularization (TLR) rates (7.9% vs. 17.7%, P<0.0001). Interestingly, there was no significant difference between the 2 groups from year 1 to 5 with regard to late TLR (2.5% vs. 2.1%, P=0.906), despite the markedly lower incidence of TLR within the first year in the DES group compared with the BMS group (5.4% vs. 15.6%, P<0.0001). Conclusions: In this long-term follow-up analysis of DES compared to BMS in Japanese patients with AMI, there was no significant difference in the incidence of MACE. Although a lower rate of TLR was observed in DES group within the first year, the superiority of DES in relation to the incidence of TLR disappeared after the first year following primary percutaneous coronary intervention.  (Circ J 2013; 77: 2024–2031)

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Background: Systematic long-term data on tricuspid valve (TV) endocarditis are limited. The aim of this study was to investigate the outcome of surgery for isolated TV endocarditis. Methods and Results: A total of 637 patients who underwent TV surgery between June 1996 and September 2012 at Hannover Medical School were retrospectively investigated. Of the 637 patients, 33 (14 female, mean age, 49±21 years) underwent isolated TV surgery for endocarditis: biological TV replacement, n=14; mechanical TV replacement, n=4; TV reconstruction, n=15. A total of 28 cases were associated with i.v. drug abuse (n=14) or pacemaker infection (n=14). Staphylococcus (S.) aureus was the most common microorganism detected on preoperative blood culture. Mean follow-up was 6.0±4.1 years (83% completed). Three patients (9%) died during the first 30 postoperative days. Survival at 1, 5 and 10 years was 88%, 73%, and 73%, respectively. Freedom from reoperation was 100%, 95%, and 88%, respectively. During follow-up New York Heart Association class improved significantly, and echocardiography identified remaining TV insufficiency grade ≥II° only in 2 patients. Statistical analysis identified advanced age, logistic EuroSCORE and positive blood culture for S. aureus as significant risk factors for long-term mortality. Conclusions: Isolated TV endocarditis is strongly associated with i.v. drug abuse or pacemaker infection. Long-term outcome is acceptable, independent of the surgical procedure.  (Circ J 2013; 77: 2032–2037)

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Background: After reports of cardiac impairment caused by mitral annuloplasty with rigid rings, several prosthetic rings with semi-rigidity were introduced. The influence of semi-rigid rings on postoperative cardiac function remains unknown. This study compared postoperative cardiac function between patients receiving a semi-rigid prosthetic ring and those receiving a flexible ring or band. Methods and Results: Transthoracic echocardiographic data of 305 patients who underwent mitral valve repair for degenerative mitral regurgitation (227 patients receiving a semi-rigid ring and 78 receiving a flexible ring or band) were retrospectively reviewed. The imbalance in the preoperative characteristics between groups was adjusted with propensity score matching. Left ventricular ejection fraction, end-diastolic dimension, and end-systolic dimension were compared at 1 week, 6 months, and 1 year after surgery. Propensity score matching yielded 68 matched pairs of patients for whom there were few group differences in preoperative covariates. Between patients receiving a semi-rigid ring and those receiving a flexible ring or band in the propensity-matched cohorts, there were no significant differences in ejection fraction (P=0.322), end-diastolic dimension (P=0.576), or end-systolic dimension (P=0.567). Conclusions: There was little difference in the influence on postoperative cardiac function between semi-rigid rings and flexible rings or bands.  (Circ J 2013; 77: 2038–2042)

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Background: Febuxostat has been reported to have a stronger effect on hyperuricemia than allopurinol. Methods and Results: Cardiac surgery patients with hyperuricemia (n=141) were randomized to a febuxostat group or an allopurinol group. The study was single-blind, so the treatment was not known by the investigators. The primary endpoint was serum uric acid (UA) level. Secondary endpoints included serum creatinine, urinary albumin, cystatin-C, oxidized low-density lipoprotein (LDL), eicosapentaenoic acid/arachidonic acid ratio, total cholesterol, triglycerides, LDL, high-density lipoprotein, high-sensitivity C-reactive protein, blood pressure, heart rate, pulse wave velocity (PWV), ejection fraction, left ventricular mass index (LVMI), and adverse reactions. UA level was significantly lower in the febuxostat group than the allopurinol group from 1 month of treatment onward. Serum creatinine, urinary albumin, cystatin-C and oxidized LDL were also significantly lower in the febuxostat group. There were no significant changes in systolic blood pressure, PWV, and LVMI in the allopurinol group, but these parameters all had a significant decrease in the febuxostat group. Conclusions: Febuxostat was effective for high-risk cardiac surgery patients with hyperuricemia because it reduced UA more markedly than allopurinol. Febuxostat also had a renoprotective effect, inhibited oxidative stress, showed anti-atherogenic activity, reduced blood pressure, and decreased PWV and LVMI.  (Circ J 2013; 77: 2043–2049)

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Background: We reviewed our 20-year experience of mitral valve (MV) repair for degenerative mitral regurgitation (MR) and analyzed the mechanisms and risk factors of reoperation. Methods and Results: Six hundred and fifty-four patients who underwent MV repair for degenerative MR between 1991 and 2010 were retrospectively reviewed. The mean follow-up duration was 7.5±4.9 years. Late echocardiography was obtained at a fixed schedule. Standard procedures for MV repair were resection and suture for posterior prolapse, artificial chordal reconstruction for anterior prolapse and a combination of them for prolapse of both. Ring annuloplasty was performed in most cases. We encountered 2 early and 23 late reoperations. Fifteen (60%) were valve-related failure, 9 (36%) were procedure-related failure and 1 was unknown. Valve-related failure was characterized with recurrence of MR due to new prolapse region and progression of mitral stenosis due to leaflet thickening. For them, reoperation was performed at 7.6 years and 14.3 years after the initial operation, respectively. Multivariate analysis identified preoperative left ventricular diastolic diameter and residual regurgitation at discharge as risk factors for reoperation. Conclusions: Valve-related failure occurred late due to slow progression of degenerative disease. Long-term follow-up after surgery is mandatory. Given that progression and severity of MR were identified as risk factors for reoperation, early surgical intervention is desirable for degenerative MR.  (Circ J 2013; 77: 2050–2055)

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Background: Heart transplantation (HTPL) is the effective treatment option to improve quality of life as well as survival of terminal heart failure patients. Shortage of donors, however, limits HTPL to all indicated cases. The temporal trend and clinical characteristics of HTPL donors in Korea were therefore investigated. Methods and Results: Among 2,001 brain-death donors registered in Korean Network for Organ Sharing from February 2000 to May 2012, a total of 28% of hearts (n=552) were utilized for HTPL. The mean age of Korean heart donors was 10 years younger than that of heart recipients (33.2±12 years vs. 43.2±17 years, respectively). The oldest was 56 years old, and donors aged over 50 accounted for only 6.2% (n=34) of total cases. Female donors were utilized less than male donors (23.6% vs. 29.6%, respectively). To determine characteristics of declined donor heart candidates, subgroup analysis of echocardiographic data was done, and 74.6% had normal ventricular function and structure, although only 42.3% were actually transplanted. The utilization rate of donor hearts with minor echocardiography abnormalities was only 15.2%. Clinical outcomes of marginal heart donors were not different from non-marginal donors. Conclusions: Although shortage of donor organs is an emerging issue, most donor hearts have been under-utilized in the past in Korea. In particular, aged and female donor hearts with minor echocardiographic abnormalities had a low rate of utilization.  (Circ J 2013; 77: 2056–2063)

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Background: The predictive factors for survival after percutaneous cardiopulmonary support (PCPS) are unknown. Methods and Results: Data for 105 patients with cardiovascular disease requiring PCPS were analyzed. The patients were divided into a survivor (n=21) or a non-survivor group (n=84). The age was significantly lower, and there were more patients with fulminant myocarditis and PCPS attempted before cardiac arrest (CA) in the survivor group. Additionally, there were fewer cases of out-of-hospital CA, and the mean time from CA to PCPS was shorter in the survivor group. On multivariate logistic regression it was found that the age and the time from CA to PCPS were independently associated with survival. A predictive scoring system was constructed that included the following: (1) age <50 years; (2) diagnosis of fulminant myocarditis; (3) no out-of-hospital CA; (4) PCPS attempted before CA; and (5) time from CA to PCPS <45min. The predictive score was significantly higher in the survivor than in the non-survivor group (2.33±1.32 vs. 1.06±1.02). The sensitivity and specificity for survival were 85.7% and 66.7% when the score was ≥2. Kaplan-Meier survival analysis showed that any-cause death was significantly higher in patients with PCPS survival score ≤1 than in those with a score ≥2. Conclusions: PCPS survival score is suitable for clinically predicting survival in patients with cardiovascular disease undergoing PCPS.  (Circ J 2013; 77: 2064–2072)

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Background: Weather conditions affect the occurrence of cardiovascular disease. The aim of this study was to investigate the associations between atmospheric conditions including temperature, pressure, and humidity, and the occurrence of out-of-hospital cardiac arrests (OHCAs) with cardiac etiology. Methods and Results: This study was a cross-sectional analysis of a prospective cohort that included all persons aged ≥18 years with OHCA in Osaka, from 1998 through 2007. The association between the number of daily OHCA events with various atmospheric conditions was analyzed using Poisson regression. A total of 28,806 adult OHCAs were presumed to be of cardiac etiology. The number of OHCAs in 1 day was inversely correlated with the day’s mean atmospheric temperature. The regression coefficient was greater on the days under 18°C (r=–0.317, P<0.001) than on days over 18°C (r=–0.088, P<0.001). A positive linear relation was found between the number of OHCAs in 1 day and the day’s mean atmospheric pressure (r=0.321, P<0.001). Under 18°C, every 5°C decrease in the daily mean temperature was associated with an 11% (95% confidence interval [CI]: 8–13%) increase in OHCA occurrence in the non-elderly group, and a 16% increase in the elderly group (95% CI: 14–19%). Conclusions: The occurrence of adult OHCA with cardiac etiology increases with decreasing temperature of the day. Elderly people are more susceptible to severe weather conditions.  (Circ J 2013; 77: 2073–2078)

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Background: Among patients with coronary artery disease (CAD), high-density lipoprotein cholesterol (HDL-C) is a cardiac protective factor. In contrast, body mass index (BMI) is inversely related to mortality, and this is known as the obesity-mortality paradox. The relationship of HDL-C and BMI to mortality, however, has not been clarified well. The aim of this study was to evaluate the impact of HDL-C and BMI on mortality among CAD patients. Methods and Results: A cohort of 1,114 angiographic CAD patients from the ET-CHD registry during 1997–2003 in Taiwan was studied. The subjects were categorized into 4 groups according to BMI ≥25kg/m² (overweight/obese) or BMI <25kg/m² (normal/underweight), and HDL-C higher or lower than the median of 40mg/dl in men and 45mg/dl in women. At a mean follow-up of 5.3 years, cardiac and all-cause death were the primary endpoints. On multivariate analysis, low HDL-C predicted higher cardiac and all-cause mortality in normal/underweight patients (hazard ratio [HR], 1.59; 95% confidence interval [CI]: 1.08–2.33; and 1.65, 95% CI: 1.25–2.19, respectively). In contrast, high BMI predicted lower cardiac and all-cause mortality in patients with low HDL-C (HR, 0.78; 95% CI: 0.54–1.14; and 0.66, 95% CI: 0.49–0.88, respectively). Conclusions: Among CAD patients in Taiwan, those with low HDL-C and normal/underweight had higher risk of mortality.  (Circ J 2013; 77: 2079–2087)

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Background: Beta-trace protein (BTP) and cystatin C (CysC) are novel biomarkers of renal function. We assessed the ability of both to predict major bleeding (MB) in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), compared to other renal function parameters and clinical risk scores. Methods and Results: We included 273 patients. Blood samples were obtained within 24h of admission. The endpoint was MB. During a follow-up of 760 days (411–1,098 days), 25 patients (9.2%) had MB. Patients with MB had higher concentrations of BTP (0.98mg/L; 0.71–1.16mg/L vs. 0.72mg/L, 0.60–0.91mg/L, P=0.002), CysC (1.05mg/L; 0.91–1.30mg/L vs. 0.90mg/L, 0.75–1.08mg/L, P=0.003), higher CRUSADE score (39±16 points vs. 29±15 points, P=0.002) and lower estimated glomerular filtration rate (eGFR; 66±27 vs. 80±30ml·min^–1·1.73m^–2, P=0.02) than patients without MB; there was no difference in creatinine level between the groups (P=0.14). After multivariable adjustment, both were predictors of MB, while eGFR and creatinine did not achieve statistical significance. Among subjects with eGFR >60ml·min^–1·1.73m^–2, those with elevated concentrations of both biomarkers had a significantly higher risk for MB. Net reclassification indexes from the addition of BTP and CysC to CRUSADE risk score were 38% and 21% respectively, while the relative integrated discrimination indexes were 12.5% and 3.8%. Conclusions: Among NSTE-ACS patients, BTP and CysC were superior to conventional renal parameters for predicting MB, and improved clinical stratification for hemorrhagic risk.  (Circ J 2013; 77: 2088–2096)

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Background: Serum N-terminal pro-brain natriuretic peptide (NTproBNP) is often elevated in patients with acute Kawasaki disease (KD), but the NTproBNP level in normal children is higher than in adults. Thus, characterization of the normal levels and cut-off values of NTproBNP according to age is warranted for proper diagnosis of acute KD in children. Methods and Results: Six hundred and fifty-five patients aged 1 month–15 years (median, 2.9 years) were included. Patients were admitted to the NTT East Japan Sapporo Hospital between October 2007 and October 2011. Serum NTproBNP level was examined in 149 patients with KD (median, 2.1 years) and 506 control patients with acute infectious disease (median, 3.2 years). In the control group, a Z-score curve of NTproBNP was generated for each age group using least mean square-based methods. The Z-score distribution of KD patients was then compared with that of the control group. The specificity and sensitivity of NTproBNP for diagnosing acute KD were 97.8% and 47.0%, respectively, at Z-score >2.0. Additionally, simple cut-offs every 100pg/ml according to age were established for more convenient use at the bedside. Conclusions: The Z-score curve for NTproBNP in children was characterized. A Z-score >2.0 or the cut-off for children may be used to diagnose acute KD.  (Circ J 2013; 77: 2097–2101)

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Background: The efficacy of stent-assisted endovascular therapy (EVT) in patients with critical limb ischemia (CLI) compared to bypass surgery (BSX) remains unclear. Methods and Results: This study was performed as a multicenter retrospective registry. Between January 2004 and December 2009, 460 CLI patients (460 first treated limbs) who underwent BSX (237 patients) or EVT (223 patients) for de novo infrainguinal lesions were identified retrospectively and analyzed. The main endpoints of this study were amputation-free survival (AFS), overall survival, limb salvage rate and freedom from major adverse limb events (MALE; includes any repeat revascularization and major amputation). Three-year AFS, limb salvage rate and overall survival were not different between the BSX and EVT groups (60.3% vs. 58.0%, P=0.43; 85.1% vs. 84.2%, P=0.91; 67.2% vs. 69.8%, P=0.96, respectively), but freedom from MALE was significantly lower in the EVT group during follow-up (69.1% vs. 51.1%, P=0.002). After adjusting endpoints with covariates, there was also no significant difference in AFS, limb salvage, and overall survival between EVT and BSX. Freedom from MALE, however, was still significantly lower in the EVT group (hazard ratio, 0.66; 95% confidence interval: 0.47–0.92, adjusted P=0.01). Conclusions: Serious adverse events with the exception of MALE after EVT seem to be acceptable compared to that after BSX in patients with CLI due to infrainguinal disease.  (Circ J 2013; 77: 2102–2109)

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Background: The surgical indication for chronic thromboembolic pulmonary hypertension (CTEPH) has been modified due to recognition of peripheral type CTEPH and changes in surgical methods and skill. Bosentan and sildenafil are used as modern oral therapy (mod Tx) in patients with inoperable CTEPH, although it remains unknown whether they have positive effects on survival. Methods and Results: A total of 202 patients were diagnosed with CTEPH at Chiba University Hospital between 1986 and 2010, 100 of whom underwent pulmonary endarterectomy. Seven medically treated patients with pulmonary vascular resistance (PVR) ≤300dyn·s·cm^–5 were regarded as having mild disease. Survival rate was stratified by date of diagnosis (group 1, 1986–1998; group 2, 1999–2004; group 3, 2005–2010), and prognostic factors in the remaining 95 medically treated patients were investigated. Group 3 included the most patients treated with mod Tx (group 1, 9.1%; group 2, 24.2%; group 3, 65.0%) and had significantly better survival than either group 1 or 2 (5-year survival: group 1, 54.6%; group 2, 69.7%; group 3, 87.3%). Patients receiving mod Tx had significantly better survival than those not on mod Tx (5-year survival: 88.9% vs. 60.2%). Multivariate analysis showed that mod Tx, lower PVR, and lack of comorbidity were significant predictors of better outcome. Conclusions: Medically treated patients with CTEPH had a better survival rate, and the use of mod Tx contributed to improved survival.  (Circ J 2013; 77: 2110–2117)

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Background: To investigate the possible role of sex hormones in the pathogenesis of pulmonary arterial hypertension (PAH), the effect of β-estradiol (E2) on bone morphogenetic protein (BMP) signaling, a key signaling pathway involved in PAH, was studied in human pulmonary arterial endothelial cells (HPAEC). Methods and Results: BMP signaling molecules, including BMP receptor, Smad1/5/8 and Id1, were studied in HPAEC under 1% O₂ (hypoxia) and 21% O₂ (normoxia) as well as the effect of hypoxia-inducible factor (HIF)-1α expression in the presence of E2 on BMP signaling. The effects of an estrogen receptor (ER) antagonist (ICI 182,780) and cycloheximide, and the interaction of ER with Smad or HIF-1α were also studied. In the presence of E2, BMP signaling was augmented under normoxia but suppressed under hypoxia. HIF-1α accumulation suppressed BMP signaling, whereas HIF-1α inhibition augmented signaling. These effects were cancelled by ICI 182,780. Moreover, binding between ER, HIF-1α and phosphorylated (p)-Smad1/5/8 proteins occurred only under hypoxia. On inhibition of de novo synthesis with cycloheximide, however, p-Smad1/5/8 expression was suppressed only under normoxia. Conclusions: The effects of E2 on BMP signaling in HPAEC altered depending on O₂ concentration and different mechanisms may be involved. BMP and sex hormones may play an important role in PAH development.  (Circ J 2013; 77: 2118–2126)

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Background: Continuous administration of prostacyclin has improved the survival of patients with pulmonary arterial hypertension (PAH). However, this treatment has some problems, including its short duration of activity and difficult delivery. Therefore, we developed ONO-1301, an orally active, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. Methods and Results: We investigated whether oral administration of ONO-1301 can both prevent and reverse monocrotaline (MCT)-induced PAH in rats. Rats were randomly assigned to receive repeated oral administration of ONO-1301 twice daily beginning either 1 or 8 days after subcutaneous injection of MCT. A control group received oral saline, and a sham group received a subcutaneous injection of saline instead of MCT. MCT-treated controls developed significant pulmonary hypertension. Treatment with ONO-1301 from day 1 or 8 significantly attenuated the increases in right ventricular systolic pressure and the increase in medial wall thickness of pulmonary arterioles. Kaplan-Meier survival curves demonstrated that the effect of ONO-1301 was equivalent to that of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. A single oral dose of ONO-1301 increased plasma cAMP levels for up to 6h. Treatment with ONO-1301 significantly decreased urinary 11-dehydro-thromboxane B₂ and increased the plasma hepatocyte growth factor concentration. Conclusions: Oral administration of ONO-1301 ameliorated PAH in rats, an effect that may occur through cAMP and hepatocyte growth factor.  (Circ J 2013; 77: 2127–2133)

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Background: Genetically modified mesenchymal stem cells (MSCs) are a promising approach to the treatment of cardiac injury after myocardial infarction (MI). Methods and Results: Rat MSCs were transduced with adenovirus containing human tissue kallikrein (TK) gene (TK-MSCs), and they secreted human TK into culture medium. Cultured TK-MSCs were more resistant to hypoxia-induced apoptosis and exhibited reduced caspase-3 activity compared to control GFP-MSCs. The effect of TK-MSC injection on cardiac injury was evaluated in rats at 1 and 14 days after MI. At 1 day after MI, human TK expression in the myocardium was associated with improved cardiac function and decreased inflammatory cell accumulation, proinflammatory gene expression and apoptosis. The beneficial effect of TK-MSCs against apoptosis was verified in cultured cardiomyocytes, as TK-MSC-conditioned medium suppressed hypoxia-induced apoptosis and caspase-3 activity, and increased Akt phosphorylation. At 2 weeks after MI, TK-MSCs improved cardiac function, decreased infarct size, attenuated cardiac remodeling, and promoted neovascularization, as compared to GFP-MSCs. Furthermore, the TK-MSC-conditioned medium, containing elevated vascular endothelial growth factor levels, stimulated the proliferation, migration and tube formation of cultured human endothelial cells. Conclusions: Our results indicate that TK-modified MSCs provide enhanced protection against cardiac injury, apoptosis and inflammation, and promote neovascularization after MI, leading to cardiac function improvement.  (Circ J 2013; 77: 2134–2144)

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Background: In recent decades, the prevention of vascular calcification (VC) by pyrophosphate (PPi), bisphosphonates, and polyphosphates has been extensively reported. However, the possibility of direct inhibition of calcium phosphate deposition (CPD) by nucleoside-associated polyphosphates has not been addressed. We analyzed the role of ATP as an inhibitor of calcification in 2 ways: by characterizing the extracellular hydrolysis of ATP as source of PPi in the aorta, and by demonstrating the ability of ATP to prevent CPD by acting as a polyphosphate. Methods and Results: In our study, both PPi and ATP hydrolysis in the rat aorta was kinetically characterized, thereby resulting in apparent Michaelis-Menten constants of 179 and 435μmol/l, respectively, with the corresponding maximal velocities of 55.1 and 6,177nmol·g^–1·min^–1. According to these kinetic parameters, the theoretical PPi concentration in the aortic wall was 0.4–3.5μmol/L (for an ATP concentration range of 0.1–1.0μmol/L). In addition, we showed that nonhydrolyzable molecules are more efficient as CPD inhibitors than endogenous compounds, in accordance with the IC₅₀ values: 1.2–2.4μmol/L for bisphosphonates vs. 8.8μmol/L for PPi, and 0.5–1.5μmol/L for nonhydrolyzable ATP analogs vs. 3.2μmol/L for ATP. Conclusions: Extracellular ATP can play an important role in the prevention of VC, not only as the source of PPi but also as a direct inhibitor of CPD.  (Circ J 2013; 77: 2145–2151)

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(Circ J 2013; 77: 1687–1688)

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