Although there is general agreement on the favorable effect of immunosuppression in eosinophilic, granulomatous, giant-cell myocarditis and in lymphocytic myocarditis associated with connective tissue disorders and with rejection of a transplanted heart, its therapeutic role in lymphocytic inflammatory cardiomyopathy (ICM) is still debated. Previous retrospective studies reported a relevant clinical benefit in 90% of patients with virus-negative ICM and no response or cardiac impairment in 85% of those with virus-positive ICM following immunosuppression. Other studies identified cardiomyocyte HLA upregulation as an additional indicator of ICM susceptibility to immunosuppressive therapy. Recently in a single-center randomized prospective double-blind trial using a combination of prednisone and azathioprine in addition to supportive treatment in 85 virus-negative ICM patients, a significant improvement in left ventricular (LV) ejection fraction and a significant reduction in LV dimensions in 88% of 43 treated patients compared with 42 patients receiving placebo who showed a cardiac impairment in 83% of cases (TIMIC study) was reported. These data confirm the efficacy of immunosuppression in virus-negative ICM. Lack of response in 12% of cases suggests the presence of unscreened viruses or mechanisms of damage and inflammation not susceptible to immunosuppression. Recovery of cardiac function in responders to immunosuppression was associated with inhibition of cardiomyocyte death, increased cell proliferation and with newly synthesized contractile material. (Circ J 2015; 79: 4–7)

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Coronary artery disease (CAD) is the most common cause of death and physical disabilities in developed countries, even though efforts to identify and target causal factors such as hypertension and dyslipidemia have brought tremendous improvements in prevention and treatment. A rapid advance in technology has unraveled new genetic variants associated with CAD and also provided great opportunities to identify novel pathogenic mechanisms and to develop new drugs with higher specificity. Whole-genome sequencing and whole-exome sequencing has made it possible to find rare alleles that are responsible for CAD in small, affected families and case-control studies in a very efficient manner. At present, genome-wide association studies have identified more than 50 loci that explain approximately 10% of the heritability of CAD, most of which is unrelated to traditional risk factors. Mendelian randomization studies enable identification of causal factors among numerous biomarkers and to narrow down promising therapeutic targets. This review highlights new genetic approaches and demonstrates the extent to which the outcome contributes to the finding of new therapeutic targets. (Circ J 2015; 79: 8–14)

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Coronary artery disease (CAD) is a major cause of death in Japan. Coronary angiography is useful to assess the atherosclerotic burden in CAD patients, but its ability to predict whether patients will respond favorably to optimal medical therapy and revascularization is limited. The measurement of the fractional flow reserve with angiography is a well-validated method for identifying ischemic vessels. However, neither an anatomical assessment nor a functional assessment can delineate microvasculature or estimate its function. The quantitative coronary flow reserve (CFR) estimated from sequential myocardial perfusion images obtained by positron emission tomography (PET) during stress provides an accurate index of hyperemic reactivity to vasodilatory agents in the myocardium. In fact, there is growing evidence that the CFR reflects disease activity in the entire coronary circulation, including epicardial coronary artery stenosis, diffuse atherosclerosis, and microvascular dilatory function. Importantly, reduced CFR is observed even in patients without flow-limiting coronary stenosis, and its evaluation can improve the risk stratification of patients at any stage of CAD. This review focuses on the application of CFR estimated by cardiac PET for the diagnosis and risk stratification of patients with CAD. (Circ J 2015; 79: 15–23)

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Both intravascular ultrasound (IVUS) and optical coherence tomography (OCT) can provide critical information that facilitates pre-interventional lesion assessment and post-interventional stent assessment and both have the potential to influence treatment strategy. Meta-analyses of randomized trials and observational studies comparing IVUS-guided percutaneous coronary intervention (PCI) with angiography-guided PCI revealed that IVUS-guided procedures reduce the incidence of target vessel revascularization, stent thrombosis, and myocardial infarction. Several IVUS criteria have been proposed to optimize stent implantation. Whether these criteria can be directly used to facilitate OCT-guided stent implantation needs to be clarified. Recent studies revealed several IVUS- and OCT-derived predictors of adverse events during PCI. Attenuated coronary plaque on IVUS might be related to deterioration of coronary flow after PCI, whereas tissue characterization on IVUS radiofrequency signal analysis can also detect coronary plaques at high risk for distal embolization. Thin-cap fibroatheroma on OCT has been proposed as a useful characteristic for predicting the no-reflow phenomenon. Furthermore, ostial plaque distribution as assessed by IVUS is reported to be a useful predictor of side-branch occlusion after PCI, whereas the severity of calcified lesions may be better assessed by OCT. Although IVUS and OCT each have inherent strengths and weaknesses, these techniques can complement each other, and selective utilization in appropriate patient subgroups or combined usage is expected to be beneficial during PCI procedures. (Circ J 2015; 79: 24–33)

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The American Heart Association (AHA) Scientific Sessions were held in Chicago on November 15–19, 2014. The meeting attracted more than 17,000 participants, including physicians, research scientists, students, and paramedical personnel, from more than 100 countries. Sessions over the 5 days included comprehensive and unparalleled education delivered via more than 5,000 presentations, with 1,000 invited faculty members and 4,000 abstract presentations from world leaders in cardiovascular (CV) disease. There were 16 trials scheduled in 4 late-breaking clinical trial sessions. The Dual Antiplatelet Therapy study revealed that aspirin plus a thienopyridine beyond 1 year subsequent to placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced stent thrombosis and major CV and cerebrovascular events but was associated with increased risk of bleeding. The IMPROVE-IT research showed that, relative to simvastatin with placebo, simvastatin with 10 mg of ezetimibe daily led to a significantly lower primary combined endpoint in moderate- to high-risk patients, who stabilized following acute coronary syndrome. This was the first trial to demonstrate incremental clinical benefit by adding a nonstatin agent to statin therapy and reaffirmed the low-density lipoprotein (LDL) hypothesis stating that reducing LDL-cholesterol prevents CV events. Summaries and overviews of both the late-breaking trials and the sessions to which members of the Japanese Circulation Society contributed are presented. (Circ J 2015; 79: 34–40)

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Background:The epidemiology of traumatic thoracic aortic injury has not been reported in many countries, so we investigated the current trends in Japan.Methods and Results:Patients with traumatic thoracic aortic injury from July 2007 to March 2013 were identified using a Japanese nationwide administrative database, the Diagnosis Procedure Combination inpatient database. The trends in crude in-hospital mortality and proportion of endovascular repair use among patients with repair were evaluated over time. A total of 617 incident cases of thoracic aortic injury were identified at 234 hospitals, and categorized into endovascular repair (n=126), open repair (n=76), and non-repair (n=415) groups. The in-hospital mortality rate for each of these groups was 5.6%, 15.8%, and 45.3%, respectively. The in-hospital survival rate was higher in the endovascular repair group than in the open repair group (log-rank χ²=4.9; P=0.03). Although the crude in-hospital mortality did not change significantly during the study period (Mantel-Haenszel trend test, P=0.10), the proportion of endovascular repair use among all repair cases increased significantly (P<0.001).Conclusions:The results of the present nationwide study suggest that the endovascular approach to treatment of thoracic aortic injury in Japan gained in popularity from 2007 to 2012. (Circ J 2015; 79: 55–60)

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Background:The difference between left atrial (LA) and systemic coagulation activity in paroxysmal atrial fibrillation (PAF) is unclear.Methods and Results:We enrolled 100 patients with PAF who underwent AF ablation. Warfarin was stopped 1 day before the procedure. LA volume index and LA emptying fraction were measured by 64-slice multidetector computed tomography. Immediately after transseptal puncture, blood samples were simultaneously collected from the LA and systemic circulation (SC). In addition, to evaluate the effect of warfarin on D-dimer levels we recruited an additional 27 PAF patients on continuous warfarin. Even in patients with low CHADS₂scores (mean 0.59±0.68) and during sinus rhythm, the prevalence of positive LA-D-dimer (≥0.5 µg/ml) was greater than that of SC-D-dimer (23% vs. 10%, P<0.01). The LA-D-dimer-positive patients had a larger mean LA volume index and reduced LA emptying fraction than the LA-D-dimer-negative patients. Multiple logistic regression analysis revealed that LA volume index was independently correlated with positive LA-D-dimer (odds ratio 2.245, 95% confidence interval 1.194−4.626, P=0.0112). The prevalence of positive LA-D-dimer was significantly lower in patients taking continuous warfarin, than in those on discontinuous warfarin (3.7% vs. 23%, P=0.025).Conclusions:An enlarged LA volume index was associated with high LA coagulation status in patients with paroxysmal AF. Adequate warfarin control during AF catheter ablation may reduce the prevalence of positive LA-D-dimer. (Circ J 2015; 79: 61–69)

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Background:Little is known about mid-term (3-month) postoperative atrial fibrillation (MT-POAF) in patients treated with bioprosthetic aortic valve replacement (BAVR). The aim of this study was to describe the natural history, identify the predictors and investigate the potential consequences in terms of anti-thrombotic therapy.Methods and Results:During a longitudinal, prospective study, 219 patients were treated with BAVR early (7 days) and at mid-term postoperatively (30 and 90 days). POAF was monitored and risk factors were identified on logistic regression analysis. History of previous AF (OR, 3.08; 95% CI: 1.35–6.98), early POAF (OR, 5.93; 95% CI: 2.96–11.8), and BMI (per 5 kg/m²: OR, 1.46; 95% CI: 1.03–2.09), were independent predictors for MT-POAF whereas sex, age and Euroscore were not. Results were identical when restricted to the 176 patients free from preoperative AF. In this subgroup, 36 patients (20.4%) had MT-POAF; 33 out of 174 (18.7%) would have required anticoagulation (CHA2DS2VASc score ≥1). Conversely, patients with BMI <27.7 and sinus rhythm at early follow-up had a very low risk of MT-POAF (OR, 0.16; 95% CI: 0.06–0.42).Conclusions:There was a higher than expected occurrence of MT-POAF in patients treated with BAVR, particularly in overweight patients with early POAF. This raises the question of implementing an anti-thrombotic therapy in these patients at higher risk of delayed atrial arrhythmia. (Circ J 2015; 79: 70–76)

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Background:Defibrillation testing (DT) is considered a standard procedure during implantable cardioverter-defibrillator (ICD) implantation. However, little is known about the factors that are significantly related to patients with high defibrillation threshold (DFT) using the present triad system.Methods and Results:We examined 286 consecutive patients who underwent ICD implantation with a transvenous dual-coil lead and DT from December 2000 to December 2011. We defined patients who required 25 J or more by the implanted device as the high DFT group, and those who required less than 25 J as the normal DFT group. For each patient, assessment parameters included underlying disease, comorbidities, NYHA functional class, drugs, and echocardiographic measures. The high DFT group consisted of 12 patients (4.2%). Multivariate analysis identified 3 independent predictors for high DFT: atrial fibrillation (odds ratio (OR) 4.85, 95% confidence interval (CI) 1.24–22.33, P=0.023), hypertension (OR 4.01, 95% CI 1.08–15.96, P=0.039), thickness of interventricular septum (IVS) >12 mm (OR 4.82, 95% CI 1.17–20.31, P=0.030).Conclusions:Atrial fibrillation, hypertension and IVS hypertrophy were significantly associated with high DFT. Identification of such patients could help to lower the risk of complications with DT. (Circ J 2015; 79: 77–84)

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Background:The loss-of-function genotype of cytochrome P450 2C19 (CYP2C19) has been proposed as a risk factor for stent thrombosis in patients with drug-eluting stent implantation. The aim of this study was to clarify the clinical features of patients with angioscopically-detected in-stent mural thrombi (ISMT).Methods and Results:Enrolled were 100 stented segments in 55 patients with stable angina (20 bare-metal stents; 39 Cypher sirolimus-eluting stents [SES]; 26 Endeavor zotarolimus-eluting stents [ZES]; 13 Xience V everolimus-eluting stents; and 2 Nobori biolimus-eluting stents). Dual antiplatelet therapy (100 mg aspirin+75 mg clopidogrel once daily) had been continued since stenting. A poor metabolizer (PM) of clopidogrel was defined as a homozygote of CYP2C19 loss-of-function alleles. Coronary angioscopy revealed ISMT in 6 patients (5 SES, 1 ZES). Between the ISMT group and control group (n=49), there were no significant differences with regards to the VerifyNow P2Y₁₂platelet function assay or in-stent endothelial coverage grade. Exact logistic regression analyses with stepwise forward selection at a significance level of 0.10 were performed to reveal predictive variables for ISMT (respectively: odds ratio, 95% confidence interval, P value: CYP2C19 PM genotype (3.28, 0.88–24.80, 0.09), SES implantation (3.37, 0.90–28.09, 0.08), and presence of yellow plaque (3.69, 1.14–25.70, 0.02).Conclusions:Patients with ISMT were characterized by SES implantation, poor clopidogrel metabolism, and in-stent yellow plaque. (Circ J 2015; 79: 85–90)

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Background:A strategy of deferred percutaneous coronary intervention for coronary stenosis with fractional flow reserve (FFR) 0.75–0.80, termed the gray zone, remains a matter of debate. The aim of this study was to assess the safety of deferring revascularization for patients with FFR 0.75–0.80 compared with those with FFR >0.80.Methods and Results:We assessed 3-year clinical outcome in 150 patients with angiographically intermediate stenosis who had revascularization deferred on the basis of FFR ≥0.75 (FFR 0.75–0.80, n=56; FFR >0.80, n=94). Target vessel failure (TVF), defined as a composite of cardiac death, target vessel-related myocardial infarction (MI), and ischemia-driven target vessel revascularization (TVR) was evaluated during follow-up. Cardiac death was observed in 1 patient with FFR 0.75–0.80. There was no target vessel-related MI in either group. The incidence of ischemia-driven TVR was higher in patients with FFR 0.75–0.80 than in those with FFR >0.80 (14% vs. 3%, P=0.020). TVF-free survival was significantly worse for the patients with FFR 0.75–0.80 than those with FFR >0.80 (hazard ratio, 5.2; 95% confidence intervals: 1.4–19.5; P=0.015).Conclusions:Patients with FFR 0.75–0.80 were at higher risk of TVF mainly due to TVR than those with FFR >0.80. (Circ J 2015; 79: 91–95)

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Background:This study evaluated the safety and efficacy of the RESOLUTE^TMzotarolimus-eluting stent (R-ZES; Medtronic, Inc, Santa Rosa, CA, USA) in Japanese patients for the treatment of de novo native coronary lesions.Methods and Results:Both RESOLUTE Japan (R-Japan) and RESOLUTE Japan Small Vessel Study (R-Japan SVS) were prospective, multicenter, single-arm observational studies. R-Japan enrolled 100 patients (reference vessel diameter, 2.5–3.5 mm) and R-Japan SVS enrolled 65 patients (at least 1 lesion suitable for 2.25-mm stent) treated with R-ZES. In R-Japan, in-stent late lumen loss (LLL; the primary endpoint) at 8 months was 0.12±0.22 mm and volume obstruction on intravascular ultrasound was 2.33±3.51%. At 4 years, there were no cases of clinically driven target lesion revascularization (TLR); the target lesion failure (TLF; composite of cardiac death, target vessel myocardial infarction, and clinically driven TLR) was 5.6% (5/90). In R-Japan SVS, in-stent LLL at 9 months was 0.27±0.33 mm, TLF (primary endpoint) was 4.6% (3/65), without incidence of TLR. At 3 years, TLF was 7.9% (5/63) and clinically driven TLR, 3.2% (2/63).Conclusions:R-Japan and R-Japan SVS demonstrate substantial suppression of neointimal hyperplasia, low LLL, and excellent and sustained long-term clinical outcome with R-ZES in Japanese patients. (Circ J 2015; 79: 96–103)

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Background:Predicting the occurrence of aortic insufficiency (AI) during left ventricular assist device (LVAD) support has remained unsolved.Methods and Results:We enrolled 52 patients who had received continuous flow LVAD (14 axial and 38 centrifugal pumps) and who been followed for ≥6 months between Jun 2006 and Dec 2013. Native aortic valve (AV) opening was observed in 18 patients (35%) with improved LV systolic function, and none of them had AI. On multivariate logistic regression analysis preoperative shorter heart failure duration was the only independent predictor of postoperative native AV opening (P=0.042; odds ratio [OR], 0.999). Of the remaining 34 patients (65%) with closed AV, 11 had AI with enlargement of the aortic root and narrow pulse pressure. Among those with closed AV, axial pump use (n=13) was the only significant predictor of the development of AI (P=0.042; OR, 4.950). Patients with AI had lower exercise capacity and a higher readmission rate than those without AI during 2-year LVAD support (55% vs. 8%; P<0.001).Conclusions:Native AV opening during LVAD support is profoundly associated with reversal of LV systolic function, especially in patients with preoperative shorter heart failure duration. Among those in whom the native AV remains closed, low pulsatility of axial flow pump may facilitate aortic root remodeling and post-LVAD AI development that results in worse clinical outcome. (Circ J 2015; 79: 104–111)

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Background:Postoperative atrial fibrillation (AF) is a common complication following coronary artery bypass grafting (CABG). We investigated the risk factors for postoperative AF and analyzed the relationship between blood sugar concentration (BS) and AF after CABG.Methods and Results:A total of 199 consecutive patients who underwent isolated CABG were retrospectively examined and classified according to the presence (n=95) or absence (n=104) of postoperative AF. On univariate analysis mean postoperative BS (P<0.001), postoperative drainage volume (P<0.001), age (P=0.034), presence of diabetes mellitus (DM; P=0.004), and postoperative estimated glomerular filtration rate (P=0.032) were significant risk factors for postoperative AF. On multivariate analysis mean postoperative BS (OR, 1.041; 95% CI: 1.008–1.079; P<0.001), postoperative drainage volume (OR, 1.003; 95% CI: 1.001–1.006; P=0.001), and age (OR, 1.040; 95% CI: 1.002–1.083; P=0.041) were significant risk factors for postoperative AF. Postoperative AF often occurred in patients with high postoperative BS, irrespective of DM. The BS cut-off that predicted postoperative AF occurrence was 180 mg/dl. A strong positive correlation existed between the time of the maximum postoperative BS and AF onset time (ρ=0.746).Conclusions:Mean postoperative BS and postoperative drainage volume are risk factors for AF after CABG. AF was strongly associated with maximum postoperative BS. Intensive glycemic control could reduce AF occurrence after CABG. (Circ J 2015; 79: 112–118)

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Background:Different mechanisms of acute kidney injury (AKI) may exist for acute heart failure (AHF) patients compared with other patients.Methods and Results:We analyzed data from 282 patients with AHF. The biomarkers were measured within 30 min of admission. Patients were assigned to a no-AKI (n=213) or AKI group (Class R (n=49), Class I (n=15) or Class F (n=5)) using the RIFLE classifications on admission. We evaluated the relationships between the biomarkers and AKI, in-hospital mortality, all-cause death and HF events (HF re-admission, all-cause death) within 90 days. The serum heart-type fatty acid-binding protein (s-HFABP) levels were significantly higher in the AKI than in the no-AKI group, and the predictive biomarker for AKI was s-HFABP (odds ratio: 6.709; 95% confidence interval: 3.362–13.391). s-HFABP demonstrated an optimal balance between sensitivity and specificity (71.0%, 79.3%; area under the receiver-operating characteristic curve [AUC]=0.790) at 22.8 ng/ml for AKI, at 22.8 ng/ml for Class I/F (90.0%, 71.4%; AUC=0.836) and at 21.0 ng/ml for in-hospital mortality (74.3%, 70.0%; AUC=0.726). The Kaplan-Meier survival curves showed a significantly poorer prognosis in the high s-HFABP group (≥22.9 ng/ml) than in other groups.Conclusions:The s-HFABP level can indicate AKI on admission, and a high s-HFABP level is associated with a poorer prognosis for AHF patients. (Circ J 2015; 79: 119–128)

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Background:Several reports have evaluated the association between seasonal variation and acute heart failure (AHF) onset. Cold weather may induce AHF, but the clinical characteristics of patients susceptible to AHF during winter have not been established. Clinical Scenario (CS) is used in the early clinical management of AHF, so we investigated the relationship between CS classification and winter onset of AHF in Japan.Methods and Results:We enrolled 582 patients hospitalized for AHF and compared the frequency of AHF among the 4 seasons in each CS group to clarify the clinical characteristics of the winter onset group. Significant increase of AHF during winter was seen in CS1 (systolic blood pressure [SBP] (>140 mmHg) (P=0.01) but not in CS2 (SBP ≥100 and ≤140 mmHg) or CS3 (SBP <100 mmHg). CS1 patients were divided into winter and other season admission groups. In multivariate analysis, only lack of loop diuretic use was associated with winter admission of CS1 patients (odds ratio 0.562, 95% confidence interval: 0.256–0.798, P=0.006).Conclusions:Winter predominance of AHF was seen only in CS1, and lack of loop diuretic use was a risk factor for winter onset. Future studies are necessary to confirm whether loop diuretics are useful in preventing AHF with CS1 in winter. (Circ J 2015; 79: 129–135)

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Background:Although fragmented QRS complex (frag-QRS) reflecting intra-ventricular conduction delay has been shown to be a prognostic marker for cardiac events, few data exist regarding the impact of frag-QRS on cardiac events in hypertrophic cardiomyopathy (HCM).Methods and Results:Ninety-four HCM patients (56 male; mean age, 58±17 years) were retrospectively investigated. Frag-QRS was defined as the presence of various RsR’ patterns in at least 2 contiguous ECG leads. Major arrhythmic events (MAE) were defined as sudden cardiac death, and combined sustained ventricular tachycardia/ventricular fibrillation. New-onset atrial fibrillation (AF) was diagnosed based on ECG during provisional or routine medical examination. Heart failure (HF) with hospitalization was defined as hospital admission due to subjective or objective symptoms. Frag-QRS was detected in 31 patients (33%).TNNI3was the most frequent disease-causing gene. Median follow-up was 4.6 years. The 4-year cumulative survival rates of cardiac death, MAE, new-onset AF and HF with hospitalization were 97.6%, 94.6%, 87.5% and 89.3%, respectively. On multivariate analysis, frag-QRS was significantly associated with HF with hospitalization (adjusted hazard ratios [95% confidence intervals]: 5.4 [1.2–36], P=0.03). Moreover, HF-free survival was significantly lower in the frag-QRS (+) group compared to the frag-QRS (–) group (79.0% vs. 95.1%, P=0.03).Conclusions:Frag-QRS is associated with HF with hospitalization in HCM patients who had a unique distribution of gene mutations. (Circ J 2015; 79: 136–143)

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Background:The intra-left atrial (LA) blood flow from pulmonary veins (PVs) to the left ventricle (LV) changes under various conditions and might affect global cardiac function. By using phase-resolved 3-dimensional cine phase contrast magnetic resonance imaging (4D-Flow), the intra-LA vortex formation was visualized and the factors affecting the intra-LA flow dynamics were examined.Methods and Results:Thirty-two patients with or without organic heart diseases underwent 4D-Flow and transthoracic echocardiography. The intra-LA velocity vectors from each PV were post-processed to delineate streamline and pathline images. The vector images revealed intra-LA vortex formation in 20 of 32 patients. All the vortices developed during the late systolic and early diastolic phases and were directed counter-clockwise when viewed from the subjects’ cranial side. The flow vectors from the right PVs lengthened predominantly toward the mitral valves and partly toward the LA appendage, whereas those from the left PVs directed rightward along the posterior wall and joined the vortex. Patients with vortex had less organic heart diseases, smaller LV and LA volume, and greater peak flow velocity and volume mainly in the left PVs, although the flow directions from each PV or PV areas did not differ.Conclusions:4D-Flow can clearly visualize the intra-LA vortex formation and analyze its characteristic features. The vortex formation might depend on LV and LA volume and on flow velocity and volume from PVs. (Circ J 2015; 79: 144–152)

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Background:The severity of impaired fatty acid utilization in the myocardium can predict cardiac death in asymptomatic patients on hemodialysis. However, interpretive variability and its impact on the prognostic value of myocardial fatty acid imaging are unknown.Methods and Results:A total of 677 patients who received hemodialysis for ≥20 years and had one or more cardiovascular risk factors underwent ¹²³I-labeled β-methyl iodophenyl-pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT) at 48 hospitals across Japan. SPECT images were interpreted by experts at the nuclear core laboratory and by readers with varying skill levels at clinical centers, based on the standard 17-segment model and 5-point scoring systems, independently. The κ values only reached fair agreement both for overall impression (κ=0.298, normal vs. abnormal) and for categorical impression (κ=0.244, normal vs. mildly abnormal vs. severely abnormal). The normalcy rate was lower in readers at the clinical centers (60.9%) than in experts (69.9%). In contrast to the results assessed by experts, a Kaplan-Meier analysis based on the interpretation by readers at the clinical centers failed to distinguish the risk of events in patients with normal scans from that of patients with mildly abnormal scans.Conclusions:Considerable variability and its impact on prognostic value were observed in the visual interpretation of BMIPP SPECT images between experts and readers at the clinical centers. (Circ J 2015; 79: 153–160)

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Background:Statins reduce the incidence of cardiovascular events, but no randomized trial has investigated the best statins for secondary prevention. We compared the efficacy of hydrophilic pravastatin with that of lipophilic atorvastatin in patients with acute myocardial infarction (AMI).Methods and Results:A prospective, multicenter study enrolled 508 patients (410 men; mean age, 66.0±11.6 years) with AMI who were randomly assigned to atorvastatin (n=255) or pravastatin (n=253). The target control level of low-density lipoprotein cholesterol (LDL-C) was <100 mg/dl, and patients were followed for 2 years. The primary endpoint was the composite of death due to any cause, non-fatal myocardial infarction, non-fatal stroke, unstable angina or congestive heart failure requiring hospital admission, or any type of coronary revascularization. The primary endpoint occurred in 77 patients (30.4%) and in 80 patients (31.4%) in the pravastatin and atorvastatin groups, respectively (hazard ratio, 1.181; 95% confidence interval: 0.862–1.619; P=0.299), whereas greater reductions in serum total cholesterol and LDL-C were achieved in the atorvastatin group (P<0.001 for each). Changes in hemoglobin A1c, brain natriuretic peptide, and creatinine were not significant between the 2 regimens, and safety and treatment adherence were similar.Conclusions:On 2-year comparison of hydrophilic and lipophilic statins there was no significant difference in prevention of secondary cardiovascular outcome. (Circ J 2015; 79: 161–168)

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Background:Clinical prognosis is critically poor in fulminant myocarditis, while it’s initiation or progression is fated, in part, by T cell-mediated autoimmunity. Adiponectin (APN) and associated adipokines were shown to be immune tolerance inducers, although the clinically relevant delivery method into target pathologies is under debate. Whether the cell sheet-based delivery system of adipokines might induce immune tolerance and functional recovery in experimental autoimmune myocarditis (EAM) was tested.Methods and Results:Scaffold-free-induced adipocyte cell-sheet (iACS) was generated by differentiating adipose tissue-derived syngeneic stromal vascular-fraction cells into adipocytes on temperature-responsive dishes. Rats with EAM underwent iACS implantation or sham operation. Supernatants of iACS contained a high level of APN and hepatocyte growth factor (HGF), and reduced proliferation of CD4-positive T cells in vitro. Immunohistolabelling showed that the iACS implantation elevated the levels of APN and HGF in the myocardium compared to the sham operation, which attenuated the immunological response by inhibiting CD68-positive macropharges and CD4-positive T-cells and activating Foxp3-positive regulatory T cells. Consequently, left ventricular ejection fraction was significantly greater after the iACS implantation than after the sham operation, in association with less collagen accumulation.Conclusions:The targeted delivery of adipokines using tissue-engineered iACS ameliorated cardiac performance of the EAM rat model via effector T cell suppression and induction of immune tolerance. These findings might suggest a potential of this tissue-engineered drug delivery system in treating fulminant myocarditis in the clinical setting. (Circ J 2015; 79: 169–179)

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Background:There is currently a well-established network for the allocation of donor organs for transplantation in Japan, and emergency patients are often transported by the “Doctor Helicopter”. However, interhospital transfer of patients, which can require aircraft with specialized equipment, depends on arrangement by each responsible hospital.Methods and Results:Since 2009 there were 41 interhospital aviation transfers of pediatric patients with intractable cardiac or airway diseases seeking surgical treatment at Sakakibara Heart Institute. Of these, 22 were newborns, 21 were on continuous drip infusion and 14 on mechanical ventilator support. In 15 cases (36.6%), a commercial airliner was used, with the remaining using chartered emergency aircraft (eg, local fire department helicopter, Self-Defense-Forces of Japan and the Doctor Helicopter). The median transfer time was 239 min for commercial airliners, 51 min for chartered aircraft departing directly from the referring hospital and 120.5 min for chartered aircraft departing from a nearby location. The efficiency of the transfer exemplified by the percentage of the time on board the aircraft was significantly lower for commercial airliners compared with chartered emergency aircraft.Conclusions:Further efforts and cooperation with government are required to obtain geographically uniform availability of carriers with optimal medical equipment to improve pediatric patient outcomes. (Circ J 2015; 79: 180–184)

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Background:Improvements in life expectancy among adults with congenital heart disease (ACHD) provide them with unique challenges throughout their lives and age-related psychosocial tasks in this group might differ from those of healthy counterparts. This study aimed to clarify age-related differences in psychosocial functioning in ACHD patients and determine the factors influencing anxiety and depression.Methods and Results:A total of 133 ACHD patients (aged 20–46) and 117 reference participants (aged 20–43) were divided in 2 age groups (20 s and 30 s/40 s) and completed the Hospital Anxiety and Depression Scale, Independent-Consciousness Scale, and Problem-Solving Inventory. Only ACHD patients completed an illness perception inventory. ACHD patients over 30 showed a significantly greater percentage of probable anxiety cases than those in their 20 s and the reference group. Moreover, ACHD patients over 30 who had lower dependence on parents and friends, registered higher independence and problem-solving ability than those in their 20 s, whereas this element did not vary with age in the reference participants. Furthermore, ACHD patients may develop an increasingly negative perception of their illness as they age. The factors influencing anxiety and depression in patients were aging, independence, problem-solving ability, and NYHA functional class.Conclusions:Although healthy people are psychosocially stable after their 20 s, ACHD patients experience major differences and face unique challenges even after entering adulthood. (Circ J 2015; 79: 185–192)

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Background:Proton pump inhibitors (PPI) are frequently prescribed in combination with aspirin for preventing peptic ulcer in patients with atherosclerotic diseases. In contrast, long-term use of PPI has been suggested to be associated with iron or vitamin B₁₂deficiency. The effect of PPI on hemoglobin (Hb) concentration, however, has not been clarified in cardiovascular outpatients.Methods and Results:We retrospectively investigated the clinical characteristics of 278 continuous outpatients who received blood test including complete blood count and serum creatinine concentration (mean age, 69.9±10.8 years; male, 68.7%). The frequency of anemia was 51% in patients receiving PPI and 19% in those not receiving PPI (chi-squared test, P<0.001). On multivariate analysis female sex (P<0.001), peripheral artery disease (P=0.003), PPI (P=0.003), low white blood cell count (P=0.004), old age (P=0.007), and low estimated glomerular filtration rate (P=0.010) were independently associated with low Hb. Among these patients, we investigated the change in Hb after the initiation of PPI in 36 patients for whom data on Hb level within 1 year before and within 1 year after the initiation of PPI were available. Mean decrease in Hb after the initiation of PPI was 0.38±0.87 g/dl (95% confidence interval: –0.67 to –0.09 g/dl).Conclusions:Use of PPI was associated with anemia in Japanese cardiovascular outpatients. (Circ J 2015; 79: 193–200)

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Background:Endothelial-mesenchymal transition (EndMT) plays a pivotal role in cardiac fibrosis. However, it is unclear whether EndMT is involved in dyssynchronous heart failure (DHF).Methods and Results:Twelve dogs received 3-week rapid right ventricular pacing (RVP) to develop DHF and then were randomly divided into a RVP group (n=6; RVP for another 3 weeks) and a biventricular pacing (BiVP) group (n=6; BiVP for 3 weeks), and another 6 dogs were in the control group. Contractile function in BiVP group was a little better than that in RVP group (P<0.05), but significant heart failure remained in 2 groups. RVP induced more significant cardiac fibrosis and higher collagen 1A2 expression in the left ventricular lateral wall (late-contracting and high-stress) than that in the anterior wall, and for those in the BiVP group, it was much lower. CD31, S100A4, α-smooth muscle actin and collagen 1A2 were used to evaluate EndMT. EndMT levels, transforming growth factor-β (TGF-β)/snail signaling, collagen 1A2 and integrin β1 expression were much higher in the endothelial cells from the RVP lateral wall than that from BiVP. In this in vitro study, cyclic stretch could independently induce EndMT and enhance the pro-EndMT effect of TGF-β in HUVECs, which could be partly blocked by integrin β1 siRNA.Conclusions:RVP-induced DHF could aggravate fibrosis due to regional heterogeneity of mechanical stress, and it was better in the BiVP group where mechanical stress-induced EndMT might play a pivotal role through the integrin β1 pathway. (Circ J 2015; 79: 201–209)

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Background:Microalbuminuria is significantly associated with long-term prognosis in the general population as well as in diabetic patients. It is well known that insulin resistance (IR) can induce microalbuminuria, but an elevated fasting insulin level, which is an early clinical manifestation of IR, as a risk factor for microalbuminuria has not been clarified, so we investigated the association between fasting insulin level and the development of microalbuminuria in a general population.Methods and Results:A total of 1,192 non-diabetic Korean men without microalbuminuria in 2005 were followed until 2010. They were categorized into 3 groups according to their fasting insulin levels and monitored for the development of microalbuminuria. The incidence of microalbuminuria was compared among groups, and Cox proportional hazards models were used to calculate the hazard ratios for microalbuminuria according to the fasting insulin levels. During 4,013.0 person-years of follow-up, 51 incident cases of microalbuminuria developed between 2006 and 2010. The incidence of microalbuminuria increased in proportion to the fasting insulin levels (tertile 1: 1.8%, tertile 2: 4.5%, tertile 3: 6.5%, P<0.001). Hazard ratios for microalbuminuria also increased in proportion to the fasting insulin levels [tertile 1: reference, tertile 2: 2.44 (1.01–5.89), tertile 3: 3.30 (1.40–7.78), respectively, P for trend 0.013].Conclusions:Elevated fasting insulin level was associated with the future development of microalbuminuria. (Circ J 2015; 79: 210–215)

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