We performed a systematic review of the available evidence on the relationship between the individual clinical, echocardiographic and laboratory characteristics of patients with atrial fibrillation (AF) and the risk of stroke. A systematic review was also performed of all published stroke risk stratification models, as well as the accuracy of their discriminative ability between risk strata. Third, we reviewed the literature on cost-effectiveness analyses with oral anticoagulation in AF. From the systematic review on stroke risk factors, a prior stroke or transient ischemic attack (15/16 studies positive, risk ratio [RR] 2.86), hypertension (11/20 studies positive, RR 2.27), aging (9/13 studies positive, RR 1.46 per decade increase), structural heart disease (9/13 studies positive, RR 2.0) and diabetes (9/14 studies positive, RR 1.62) were found to be good independent predictors of stroke. Supportive evidence was found for sex (8/22 studies positive, RR 1.67), vascular disease (6/17 studies positive, RR 2.61) and heart failure (7/18 studies positive, RR 1.85). The various risk stratification schemes classified variable proportions as low, moderate and high risk, but the CHA₂DS₂–VASc score classified the smallest proportion of patients as ‘low risk’. Anticoagulation with vitamin K antagonists and dabigatran is cost-effective in patients at high risk of stroke, but not in patients without any other stroke risk factor beside AF. Continued efforts are warranted to improve the antithrombotic management of AF patients to identify, and challenge, risk factors and refine risk stratification models in order to realize an individualized tailored, risk factor-based approach.  (Circ J 2012; 76: 2289–2304)

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Sleep-disordered breathing (SDB) with predominant obstructive or central sleep apnea (OSA/CSA) with Cheyne-Stokes respiration (CSR) is a common, but underestimated and underappreciated, comorbidity in patients with heart failure (HF). Regardless of the type of HF (systolic or diastolic) or its etiology (ischemic, non-ischemic, valvular etc), the prevalence of SDB is remarkably high in this patient group, at 70–76%. Even more so in HF than in the general population, OSA and CSA in particular are independently associated with an impaired prognosis. This review details the pathophysiology of CSA-CSR in HF, highlights the challenges and tools available for diagnosis, explains the concept of adaptive servoventilation (ASV) therapy, and summarizes the existing literature on the use of ASV therapy in HF patients in general and HF with reduced ejection fraction in particular.  (Circ J 2012; 76: 2305–2317)

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To explore a novel strategy of preventing atrial fibrosis and atrial fibrillation (AF), we have established 3 appropriate experimental models of AF. Firstly, atrial fibrosis was induced by pressure overload by abdominal aortic constriction (AAC). AAC enhanced left atrial (LA) expression of monocyte chemoattractant protein-1. Scanning electron microscopy revealed that LA endothelial cells were irregularly hypertrophied, with disarrangement of lines of cells. Possible “arrested” leukocyte-derived cells were observed on the surface of LA endothelial cells. Treatment with pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, resulted in attenuation of pressure overload-induced LA fibrosis. Secondly, LA fibrosis was induced by continuous infusion of angiotensin II (AII). Repeated whole-body hyperthermia led to the induction of heat shock protein (HSP) 72, which resulted in attenuation of AII-induced LA fibrosis. Thirdly, atrial fibrosis was induced by 5/6 nephrectomy as a model of AF associated with chronic kidney disease. Because the amount of nicotinamide adenine dinucleotide phosphate oxidase was increased and the potent antioxidant agent was effective, oxidative stress may be involved in the pathogenesis of LA fibrosis and enhanced AF vulnerability in this model. These observations suggest that inflammatory profibrotic processes are essential for the development of atrial fibrosis in these 3 models. Pioglitazone, induction of HSPs and antioxidant agent could be novel therapeutic approaches to preventing atrial fibrosis and AF.  (Circ J 2012; 76: 2318–2326)

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Background: Periprocedural anticoagulation using uninterrupted warfarin could reduce the risk of thromboembolic complications of atrial fibrillation (AF) ablation. Few studies, however, have evaluated the efficacy and safety of periprocedural dabigatran in AF ablation. Methods and Results: A total of 211 consecutive patients who underwent AF ablation, including 110 patients who received 110mg dabigatran twice daily (group D) and 101 patients who received dose-adjusted warfarin (international normalized ratio, 2.0–3.0; group W), were evaluated. Dabigatran was discontinued on the morning of the procedure, and resumed on the next morning. Warfarin was continued throughout the procedure. During the procedure, heparin infusion was maintained to achieve an activated clotting time of >300s. Postprocedural cerebral magnetic resonance imaging (MRI) was performed in 60 patients (group D, n=31; group W, n=29). No periprocedural deaths or symptomatic thromboembolic complications were observed in either group. MRI indicated a silent cerebral infarction in 1 patient in each group. Five patients in group D and 11 in group W had minor bleeding (P=0.12). Cardiac tamponade occurred in 2 patients in group W, but in none in group D. Total bleeding complications occurred less frequently in group D (4.5%) than in group W (12.9%; P<0.05). Conclusions: Dabigatran at a dose of 110mg twice daily was safe for AF ablation in patients with a relatively low risk of thromboemboli, suggesting that it may become an alternative to warfarin in those patients.  (Circ J 2012; 76: 2337–2342)

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Background: Agents with α-2 adrenoreceptor (AR) agonistic action have reportedly suppressed tachyarrhythmias. Methods and Results: We hypothesized that α-2 AR agonists would have an inhibitory effect on abnormal repolarization-related ventricular tachyarrhythmias (VTs). To test this hypothesis, the effects of 2 clinically available α-2 AR agonists (dexmedetomidine and clonidine) on the occurrence of VTs were assessed in a methoxamine-sensitized rabbit model of acquired long QT syndrome (Study 1: n=45). In control rabbits, administration of methoxamine and nifekalant almost invariably caused VTs (14/15). In contrast, incidence of VT significantly decreased during the treatment with dexmedetomidine (1μg·kg^–1·min^–1: 5/12 [P<0.01 vs. control]) or with clonidine (33.3μg·kg^–1·min^–1: 10/18 [P<0.01]). To verify that VTs in this animal model are triggered by early afterdepolarization (EAD), the monophasic action potential on the left ventricular surface was recorded in 28 open-chest rabbits (Study 2). EAD-like hump was less frequently detected during treatment with clonidine or dexmedetomidine (2/14) than in saline-treated rabbits (9/10, P<0.005). Presence of a hump was significantly related to the advent of VTs (P<0.05). Conclusions: Agents with α-2 AR agonistic action have an inhibitory effect on VTs in a rabbit model of long QT syndrome. Alpha-2 AR agonists, especially dexmedetomidine, may be a therapeutic choice for abnormal repolarization-related VTs that are resistant to conventional treatment.  (Circ J 2012; 76: 2343–2347)

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Background: Cytochrome P450 (CYP) 2C19 polymorphism is associated with reduced responsiveness to clopidogrel and poor clinical outcome after drug-eluting stent (DES) implantation, but its contribution to lesion outcome after DES implantation is unclear. Methods and Results: The study included 160 Japanese patients who received clopidogrel and underwent DES implantation with follow-up angiography. Patients were divided into 3 groups by CYP2C19 polymorphism: extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). The incidence of major adverse cardiac events (MACE) and target lesion revascularization (TLR) were compared among the 3 groups. Optical coherence tomography (OCT) was performed for 120 patients to evaluate the incidence of intra-stent thrombi. Of the 160 patients, the proportion of EM, IM, and PM was 37.5%, 48.1%, and 14.4%, respectively. The incidence of TLR and MACE was more frequent in IM and PM than EM (TLR: 18.2% and 26.1% vs. 3.3%, P=0.008, MACE: 22.1% and 30.4% vs. 5.0%, P=0.005). Among the 120 patients who underwent follow-up OCT, intra-stent thrombi were more frequently detected in IM and PM than in EM (45.6% and 63.2% vs. 20.5%, P=0.005). The incidence of TLR was significantly higher in patients with than in those without intra-stent thrombi (27.7% vs. 6.8%, P=0.003). Conclusions: CYP2C19 loss-of-function polymorphism might be associated with the incidence of MACE and TLR in association with intra-stent thrombi.  (Circ J 2012; 76: 2348–2355)

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Background: A new concern in acute kidney injury (AKI) following coronary artery bypass grafting (CABG) is the elapsed time from coronary angiography (CAG) until subsequent surgery. This study aimed to retrospectively evaluate renal function following elective off-pump CABG (OPCAB). Methods and Results: Three hundred and seven patients were divided either into group A (elapsed time between CAG and surgery ≤5 days, n=138) or B (elapsed time >5 days, n=169). The estimated glomerular filtration rate (eGFR) was obtained on the 1st, 3rd and 7th day following CABG. The pre-, intra-and postoperative relevant data were analyzed. 51 patients (16.6%) developed postoperative AKI. Patients with shorter elapsed time were more likely to present postoperative AKI than those with a longer elapsed time (23.9% vs. 10.7%, P=0.003). Multivariate logistic regression analysis showed that elapsed time had an independent influence on the development of postoperative AKI (odds ratio 2.35, 95% confidence interval 1.45–5.26, P=0.009). The eGFR reduced gradually after surgery, dropped to a minimum within 3 days, and then increased slowly in both groups. Minimum eGFR following surgery in group B was significantly higher than that in group A (64.3±6.5ml/min vs. 59.2±9.3ml/min, P<0.0001). Conclusions: Beginning OPCAB early after CAG did affect postoperative renal function and increased the incidence of AKI.  (Circ J 2012; 76: 2356–2362)

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Background: This study assessed the effect on incident metabolic syndrome (MetS) of alcohol consumption status at baseline and changes in that status during a follow-up period. Methods and Results: 4,505 men without MetS at baseline were followed for an average of 3 years. Subjects were divided into 4 categories of alcohol consumption status at baseline and changes in that status in the follow-up period. The overall incidence of MetS was 10.6%: 7.0% in the non-drinkers, 10.3% in the light drinkers, 13.8% in the moderate drinkers, and 15.6% in the heavy drinkers (P<0.001). All of the 3 drinker groups at baseline had higher odds ratios for the incidence of MetS than the non-drinkers (OR [95% confidence interval]: 1.51 [1.06–2.13] in the light drinkers, 1.71 [1.14–2.55] in the moderate drinkers, and 2.11 [1.25–3.56] in the heavy drinkers). Comparison of the 4 categories of alcohol consumption at baseline and after follow-up showed that the ORs in the continuous drinkers showed a trend toward the risk of developing MetS (1.47 [0.99–2.19]) compared with the non-drinkers; the moderate and heavy drinkers in the continuous drinkers group had high ORs for incident MetS; however, new drinkers and ex-drinkers did not. Conclusions: Continuous drinking, especially moderate-to-heavy drinking, is associated with developing MetS in Korean men, suggesting that they should be advised to restrict their alcohol consumption to <15g/day to attenuate the risk for MetS.  (Circ J 2012; 76: 2363–2371)

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Background: Patients with heart failure (HF) have a high risk of cardiovascular (CV) death and re-hospitalization. The purpose of the present study was therefore to investigate predictors of CV death and re-hospitalization for acute decompensated HF (ADHF). Methods and Results: A total of 225 patients aged 67.2±15.2 years, including 134 men (59.6%), who were hospitalized for ADHF between 2008 and 2009, were followed up. After discharge, the relationship between clinical parameters and CV events (ie, CV death or re-hospitalization for HF) was examined. Follow-up was continued until 30 April 2011. The most important predictors of re-hospitalization were serum blood urea nitrogen (BUN; adjusted hazard ratio [HR], 1.02; 95% confidence interval [CI]: 1.00–1.03, P=0.01), plasma brain natriuretic peptide (BNP; adjusted HR, 1.85; 95% CI: 1.12–3.04, P=0.02), and diastolic blood pressure (DBP; adjusted HR, 0.97; 95% CI: 0.94–1.00, P=0.049). The only predictor of CV mortality was a high BUN (adjusted HR, 1.05; 95% CI: 1.01–1.09, P=0.01). Conclusions: High serum BUN (≥22.5mg/dl), high plasma BNP (≥250pg/ml), and low DBP (<60mmHg) predict CV events in patients hospitalized for ADHF. These factors may identify high-risk patients for CV events and provide therapeutic targets for managing HF.  (Circ J 2012; 76: 2372–2379)

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Background: Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). Myocardial dysfunction may occur in patients with diabetes mellitus (DM) in the absence of coronary artery disease or left ventricular (LV) hypertrophy. Although tissue Doppler imaging (TDI) is a highly effective means of quantifying myocardial diastolic function, its differences in ESRD patients with diabetes and without diabetes remain unclear. Methods and Results: A total of 101 ESRD patients on maintenance hemodialysis with normal LV systolic function were studied: 37 with type 2 DM and 64 without DM. Conventional echocardiography and TDI were performed to evaluate LV systolic and diastolic functions. The conventional LV systolic and diastolic echocardiographic parameters did not differ according to presence of DM, except for the left atrial size and volume index (P<0.001). The ESRD patients with DM, however, had significantly decreased mitral annular early diastolic peak velocity (e’) and ratio of early to late diastolic mitral annular velocity (e’/a’; both P<0.02). Additionally, the group with DM had markedly higher estimated LV end-diastolic filling pressure (E/e’; P=0.011). Conclusions: ESRD patients with DM had advanced LV diastolic dysfunction on TDI. In ESRD patients with DM, diabetic cardiomyopathy associated with advanced LV diastolic dysfunction is observed.  (Circ J 2012; 76: 2380–2385)

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Background: Patients with a normal stress image on technetium-99m (Tc-99m) single-photon emission computed tomography (SPECT) have a good prognosis for diagnosing coronary artery disease. However, current guidelines recommend stress and rest imaging to confirm that a stress image is normal. Methods and Results: We determined all-cause of cardiac events (acute coronary syndrome and sudden death) in 1,939 patients undergoing stress myocardial perfusion SPECT with Tc-99m radiotracers. Patients with an abnormal stress image were excluded, so we focused on 1,125 patients in whom the stress SPECT study was interpreted as normal. A stress-only protocol was used in 726 patients (adenosine=339; exercise=387), whereas 399 had both stress and rest imaging (adenosine=294; exercise=105). Mean follow-up was 1,252 days. At the end of follow-up, there were 39 cardiac events in the stress-only cohort and 19 in the stress-rest cohort. Kaplan-Meier analysis revealed that there were no differences for the entire cohort of cardiac events not only between the stress-only and stress-rest protocols but also for stressor modality, despite the fact that the stress-rest cohort showed higher coronary risk factors. Conclusions: Patients determined as having a normal SPECT on the basis of stress imaging alone have a similar cardiac event rate as those who have a normal SPECT on the basis of evaluation of both stress and rest images. This imaging strategy will significantly reduce radiation exposure in a substantial number of patients.  (Circ J 2012; 76: 2386–2391)

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Background: Although remote ischemic conditioning (RIC) by transient limb ischemia in percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) has shown favorable effects on myocardial (ischemia-reperfusion) injury, recent trials provide inconsistent results. The aim of the present study was to assess the effect of RIC in PCI or CABG. Methods and Results: Medline/Embase/conference reports were searched for randomized RIC trials and were included if they reported on biomarkers of myocardial injury (CK-MB/troponin T/I), after which, standardized mean differences (SMDs) were calculated (Hedges g statistic). Meta-analysis of 4 studies on PCI, involving 557 patients, indicated reduced biomarkers for myocardial injury with RIC compared to control (random effects model: SMD, –0.21; 95% confidence interval [CI]: –0.66 to 0.24). Analysis of primary PCI studies, involving 314 patients, indicated a highly significant positive effect of RIC on myocardial injury (SMD, –0.55; 95% CI: –0.77 to –0.32). The 13 CABG studies taken together, involving 891 patients, indicated a significant effect of RIC on myocardial injury (SMD, –0.34; 95% CI: –0.59 to –0.08). The statistical tests indicated moderate to high heterogeneity across the studies (Q-statistic: PCI, P=0.0006, I²=83%; CABG, P<0.0001, I²=69%). Conclusions: In patients undergoing PCI or CABG, RIC with transient episodes of limb ischemia is associated with lower biomarkers of myocardial injury compared to control, but this effect failed to reach statistical significance in the overall PCI analysis.  (Circ J 2012; 76: 2392–2404)

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Background: The question as to whether triple antiplatelet therapy is superior to dual antiplatelet therapy for patients with acute myocardial infarction (AMI) and renal dysfunction, who undergo percutaneous coronary intervention (PCI), is unresolved. Methods and Results: As part of the Korea Acute Myocardial Infarction Registry (KAMIR), 2,288 AMI patients with renal dysfunction (glomerular filtration rate <60ml/min·1.73m²) received either dual (aspirin plus clopidogrel; n=1,587) or triple (aspirin plus clopidogrel and cilostazol; n=701) antiplatelet therapy. Major adverse cardiac events (MACE) at 1 month and 1 year were compared between these 2 groups. On comparison with the dual therapy group, the triple therapy group had a similar incidence of major bleeding events but a significantly lower incidence of in-hospital mortality. The MACE rate at 1 month was significantly higher for the dual therapy group than for the triple therapy group (16.3% vs. 11.1%, P<0.05), and this difference was mainly attributed to death rather than repeat PCI (12.9% vs. 9.1%, P<0.05). The MACE rate at 1 year and the MACE-free survival time, however, did not differ between the groups. Conclusions: In AMI patients with renal dysfunction, triple antiplatelet therapy has a favorable in-hospital and short-term MACE impact, but it does not have an impact on the 1-year MACE-free survival.  (Circ J 2012; 76: 2405–2411)

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Background: Circulating monocytes can be divided into 2 subsets typically identified by the expression of CD14 and CD16. Although previous studies have shown that circulating monocytes contribute to the progression of coronary atherosclerotic lesions, the relationship between the severity of coronary artery disease (CAD) and the 2 distinct monocyte subsets has not previously been evaluated. We investigated the relationship between the monocyte subsets and the severity of CAD assessed by coronary angiography (CAG) in patients with stable angina pectoris (SAP). Methods and Results: We enrolled 125 patients who underwent diagnostic CAG. Patients were divided into 3 groups: those without CAD, those with single-vessel disease (SVD), and those with multiple-vessel disease (MVD). In addition, the severity of CAD was evaluated by Gensini score. The 2 monocyte subsets (CD14⁺CD16^– and CD14⁺CD16⁺) were measured by flow cytometry. Circulating CD14⁺CD16⁺ monocytes were more frequently observed in patients with MVD than in those with SVD or without CAD. The proportion of CD14⁺CD16⁺ monocytes positively correlated with Gensini score (r=0.618, P<0.001). Multivariate logistic regression analysis revealed that the proportion of CD14⁺CD16⁺ monocytes was an independent contributor to MVD (odds ratio: 1.475; 95% confidence interval: 1.273–1.708, P<0.001). Conclusions: A preferential increase in peripheral CD14⁺CD16⁺ monocytes may be closely related to the severity of CAD in patients with SAP.  (Circ J 2012; 76: 2412–2418)

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Background: Coronary computed tomography angiography (CTA) findings of positive vessel remodeling and low-attenuation plaque, referred to as computed tomography-verified high-risk plaque (CT-HRP), have been reported to be associated with the development of subsequent acute coronary syndromes. The aim of this study was to examine the usefulness of coronary CTA for coronary risk re-stratification of patients with asymptomatic and atypical chest symptoms. Methods and Results: A total of 1,139 subjects (M/F 602/537; mean age, 61.5±9.3 years) who were either asymptomatic or presented with atypical chest symptoms underwent coronary 64- or 320-slice multidetector computed tomography angiography and Agatston score. Age, sex, coronary risk factors, including hypertension, diabetes mellitus (DM), dyslipidemia, and smoking were investigated as predictors for CT-HRP on multivariate analysis using logistic regression analysis. CT-HRP was observed in 72 patients (6.3%). Based on Framingham risk scores (FRS), CT-HRP was observed in 0/94 subjects (0.0%) in the low-risk group, 35/806 (4.3%) in the intermediate-risk group, and 37/239 (15.5%) in the high-risk group. On logistic regression analysis significant predictors for CT-HRP in intermediate- and high-risk subjects were male sex (odds ratio [OR] 2.829; 95% confidence interval [CI] 1.460–5.479, P=0.0021), DM (OR 2.418; 95% CI 1.420–4.116, P=0.0011), and current smoking (OR 1.922; 95% CI 1.096–3.371, P=0.0160). CT-HRP prevalence for Agatston scores >500 and >250 was lower in the intermediate- and high-risk groups, respectively. Conclusions: In asymptomatic subjects and those presenting with atypical chest pain who have a more than an intermediate risk, coronary CTA is contributory to FRS. Male sex, DM and smoking were independent predictors of vulnerable plaque in the more than intermediate-risk group.  (Circ J 2012; 76: 2419–2425)

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Background: Because a close relationship between epicardial adipose tissue (EAT) and coronary artery disease (CAD) has been shown, the impact of functional, morphological and clinical parameters to identify potential determinants of EAT was investigated. Methods and Results: Clinical and cardiac magnetic resonance parameters were determined and correlated to the amount of EAT in 158 patients with CAD and 40 healthy subjects. Patients with CAD and left ventricular function (LVEF) ≥50% revealed significantly elevated EAT (36±11g/m²) compared to healthy controls (31±8g/m²) and to patients with LVEF <50% (26±8.0g/m²). In the whole study population, only LVEF (P=0.003), body mass index (BMI) (P=0.004) and left ventricular end diastolic diameter (LV-EDD) (P=0.004) remained significantly associated with EAT after multivariate analysis. Subgroup analysis in patients with CAD and LVEF ≥50% showed that BMI (P=0.03) was the only correlate of EAT. However, in patients with CAD and LVEF <50%, indexed LV end diastolic mass (LV-EDMI) (P=0.003) and the extent of late gadolinium enhancement (LGE %) (P=0.03) remained significantly correlated with EAT in multivariate analysis. Conclusions: The amount and the determinants of EAT differ according to the LVEF in patients with CAD. Thus, different amounts of EAT reflect different stages of CAD underlining the complex interaction of EAT in the pathogenesis and progression of ischemic cardiomyopathy.  (Circ J 2012; 76: 2426–2434)

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Background: Body fat percentage (BF%) determined by bioelectrical impedance analysis is widely used at home and in medical check-ups. However, the clinical significance of measuring BF% has not been studied in detail. Methods and Results: A cross-sectional study was carried out on a cohort of 10,774 middle-aged Japanese men who had undergone an annual check-up in 2008. Cut-off points were evaluated for body mass index (BMI), waist circumference (WC), and BF% for detecting participants with cardiovascular disease (CVD) risk factors (diabetes mellitus, hypertension, dyslipidemia), and effectiveness compared for each marker’s cut-off point. Additionally, the effects of smoking on cut-off points were evaluated. The cut-off points of BMI, WC, and BF% for detecting participants with 1 or more CVD risk factors were 22.7kg/m², 81.4cm, and 20.3%, respectively. The cut-off points of BF% for 1 or more CVD risk factors classified 3.43% more subjects into correct categories than those of BMI (P<0.001). The cut-off points of BMI, WC, and BF% for detecting individuals with 3 CVD risk factors in current smokers were 24.9kg/m², 87.8cm, and 23.7%, while those in non-smokers were 23.3kg/m², 83.9cm, and 22.3%, respectively. Conclusions: BF% could be more effective in detecting individuals with early stage CVD risk accumulation than BMI. The cut-off points for current smokers were lower than those for non-smokers in all markers.  (Circ J 2012; 76: 2435–2442)

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Background: It is controversial as to whether metabolic syndrome is a predictor of cardiovascular disease (CVD) independent of insulin resistance (IR). The aim of this study was to determine the independent and combined effects of metabolic syndrome and IR on the incidence of CVD in a prospective cohort study. Methods and Results: A total of 6,430 healthy subjects who underwent a health check-up were enrolled. Risk factors for atherosclerotic CVD (ASCVD) including ischemic heart disease (IHD) and stroke were measured. The prevalence of metabolic syndrome and IR were 24.4% and 25.6%, respectively. There were 644 incident cases (9.0%) of ASCVD diagnosed in the cohort. After adjusting for traditional confounders and IR, metabolic syndrome was related to the incidence of CVD. In the multivariate model, the hazard ratios (95% confidence intervals) of metabolic syndrome for IHD, stoke, and ASCVD were 1.66 (1.32–2.09), 1.60 (1.21–2.12), and 1.61 (1.36–1.90), respectively. The risk of IHD, stoke, and ASCVD increased with increasing number of metabolic syndrome components. Furthermore, the risk of CVD was stronger in those who had both metabolic syndrome and IR concurrently. Conclusions: Metabolic syndrome is related to the incidence of CVD independent of IR. Also, the combined effect of metabolic syndrome and IR contributes to the risk of CVD.  (Circ J 2012; 76: 2443–2448)

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Background: Application of immunoapheresis to eliminate pathogenic autoantibodies targeting the second extracellular loop of the β1-receptor (β1-AABs) is currently investigated in patients with cardiomyopathy. Aptamers (single short DNA or RNA strands) are a new class of molecules that bind to a specific target molecule. This property qualifies aptamers for potential use in the apheresis technique. We recently identified an aptamer that specifically binds to β1-AABs, so in the present study we tested whether this aptamer could be used as a binder to prepare an apheresis column suitable for clearing β1-AABs from rat’s blood. Methods and Results: An apheresis column was designed containing the β1-AAB-targeting-aptamer coupled to sepharose. As tested in vitro, this column (1) binds β1-AABs highly specifically without marked interference with common IgGs, (2) has a capacity for clearing of approximately 1L of β1-AAB-positive serum and (3) can be completely regenerated for subsequent use. Using the column for extracorporeal apheresis of spontaneously hypertensive rats (SHR) positive for both β1-AABs and muscarinic 2-receptor autoantibodies (M2-AABs), only β1-AABs were removed. In a follow-up of 9 weeks, recurrence of β1-AABs in the blood of SHR could not be detected. Conclusions: For the first time, a newly designed apheresis column with a β1-AAB specific aptamer as a binder was successfully used to eliminate β1-AABs from SHR blood.  (Circ J 2012; 76: 2449–2455)

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Background: Prostaglandin E₁ (PGE₁), via cAMP, dilates the ductus arteriosus (DA). For patients with DA-dependent congenital heart disease (CHD), PGE₁ is the sole DA dilator that is used until surgery, but PGE₁ has a short duration of action, and frequently induces apnea. Most importantly, PGE₁ increases hyaluronan (HA) production, leading to intimal thickening (IT) and eventually DA stenosis after long-term use. The purpose of this study was therefore to investigate potential DA dilators, such as phosphodiesterase 3 (PDE3) inhibitors, as alternatives to PGE₁. Methods and Results: Expression of PDE3a and PDE3b mRNAs in rat DA tissue was higher than in the pulmonary artery. I.p. milrinone (10 or 1mg/kg) or olprinone (5 or 0.5mg/kg) induced maximal dilatation of the DA lasting for up to 2h in rat neonates. In contrast, vasodilation induced by PGE₁ (10μg/kg) was diminished within 2h. No respiratory distress was observed with milrinone or olprinone. Most important, milrinone did not induce HA production, cell migration, or proliferation when applied to cultured rat DA smooth muscle cells. Further, high expression of both PDE3a and PDE3b was demonstrated in the human DA tissue of CHD patients. Conclusions: Because PDE3 inhibitors induced longer-lasting vasodilation without causing apnea or HA-mediated IT, they may be good alternatives to PGE₁ for patients with DA-dependent CHD.  (Circ J 2012; 76: 2456–2464)

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Background: Congenital left ventricular aneurysm (LVA) and diverticulum (LVD) are rare cardiac anomalies frequently associated with electrocardiogram (ECG) abnormalities. The aim of this study was to evaluate the long-term prognosis in such patients. Methods and Results: A total of 108 patients with LVA or LVD having ECG-abnormalities were assessed. The patients were classified into 2 groups according to ECG abnormalities: a distinct ECG group (8 ECG patterns known to be frequently associated with LVA/LVD); and a control group (all other ECG abnormalities). The primary endpoint was a composite of cardiac death, rhythm disturbances, syncope, embolic events, and hospitalization for cardiovascular events. Mean patient age was 64±10 years; 45 (42%) were male; median follow-up (FU) was 50 months. The primary endpoint occurred in 12/27 patients from the distinct ECG group and in 15/81 patients in the control group (44% vs. 19%; P=0.01). Cardiac event rate per year (CER) was 1.8% vs. 0.8%, respectively. There were no cardiac deaths during FU. Symptoms (arrhythmia-related symptoms, syncope, and embolic events) at time of diagnosis increased the incidence of adverse events during FU (70% vs. 28%; P=0.05; CER 2.9% vs. 1.1%). Age ≥64 years, presence of LVD, gender, and location of the anomaly did not affect the incidence of adverse events. Conclusions: The incidence of adverse events in symptomatic patients with isolated LVA or LVD and distinct abnormal ECG patterns is increased during long-term FU. None of the present patients, however, experienced cardiac death.  (Circ J 2012; 76: 2465–2470)

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Background: In Japan, the safety and efficacy of thrombolytic therapy using tissue-type plasminogen activator for acute pulmonary embolism (PE) in the real world remain unclear. Methods and Results: A total of 1,254 patients with acute PE covered by the post-marketing surveillance of thrombolytic therapy using monteplase were divided into 3 groups: cardiopulmonary arrest (CPA)/collapse group (n=85); massive group, patients with unstable hemodynamics without CPA/collapse (n=217); and submassive group, patients with stable hemodynamics and right ventricular dysfunction (RVD) (n=465). In the efficacy analysis of 767 cases, the response rate to monteplase was 94.6% according to pulmonary circulation assessment and 93.3% according to clinical efficacy judged by symptoms and signs. Overall survival rates at 30 days after monteplase administration were 89.2% overall, 41.2% for the CPA/collapse group, 93.0% for the massive group, and 96.3% for the submassive group. When the safety of monteplase was analyzed in 1,241 cases, severe bleeding complications occurred in 100 patients (8.1%). Intracranial hemorrhage (ICH) occurred in 21 patients (1.7%), but no significant independent predictors were found in multivariate analysis. Conclusions: Thrombolytic therapy is highly effective in Japanese acute PE patients and offers acceptable safety, but attention is needed regarding severe bleeding complications, including ICH.  (Circ J 2012; 76: 2471–2480)

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Background: Different influences of left ventricular (LV) remodeling on anterior and posterior mitral leaflet (AML and PML) tethering in ischemic mitral regurgitation (MR) has not been fully investigated. We hypothesized that progressive outward displacement of papillary muscles, including posterior vector, may cause greater tethering to PML compared to AML. Methods and Results: In 79 patients with LV ejection fraction <50% and 20 controls, LV sphericity, AML and PML tethering angles, apical and posterior displacement of coaptation, mitral annular area, and severity of MR (vena contracta width) were measured using 3-D echocardiography. To examine different influences of LV remodeling on AML and PML tethering, interaction between AML/PML and LV sphericity was tested using multiple regression analysis. Both AML and PML tethering significantly increased with increased LV sphericity (r=0.59 and 0.65, P<0.001). Multiple regression yielded a significant interaction term between AML vs. LV sphericity and PML vs. LV sphericity (t=3.69, P<0.001), indicating greater influence from LV remodeling on PML compared to that for the AML. Multivariate analysis demonstrated independent contributions to MR severity from PML tethering primarily along with posterior and apical displacement of coaptation. Conclusions: LV remodeling augments tethering of both AML and PML, with greater influence on PML.  (Circ J 2012; 76: 2481–2487)

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Background: Percutaneous edge-to-edge mitral valve repair with the MitraClip^® was shown to be a safe and feasible alternative compared to conventional surgical mitral valve repair. Herein is reported our experience on MitraClip^® for high-risk surgical candidates with severe mitral regurgitation (MR). Methods and Results: Patients with severe MR (3 or 4+) and high operative risk were considered for MitraClip^® implantation. Device success was defined as placement of 1 or more MitraClips^® with reduction of MR to ≤2+. Patients were followed up clinically and with echocardiography at 1 year. A total of 27 patients with severe MR (age, 74±12 years; 17 male; logistic EuroSCORE, 27±12; left ventricular ejection fraction, 40±17%) were treated. Fifty-six percent of MR was degenerative and 44% was functional. Device success was 93% with 14 patients receiving 2 clips. MR severity was reduced from 3.5±0.5 to 1.7±0.8 (P<0.001); New York Heart Association class improved from 3.1±0.4 to 2.0±0.8 (P<0.001). In 45% of functional and in 29% of degenerative MR patients, to avoid mitral stenosis, additional MitraClip^® implantation was not attempted, with resultant transmitral mean gradient of 4.9±1.6mmHg vs. 3.1±1.4mmHg, respectively (P=0.01). Conclusions: MitraClip^® was shown to be an effective and safe treatment for patients with both functional and degenerative MR. Inability to obtain a greater reduction of MR was the consequence of borderline transmitral gradient requiring a compromise to avoid mitral stenosis, particularly in the functional MR patients.  (Circ J 2012; 76: 2488–2493)

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