Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease, and is now predominantly among patients with uncorrected left-to-right shunts. A growing population is characterized by persistent or recurrent PAH after surgical or interventional correction of left-to-right shunts; the latter having a worse prognosis than other forms of PAH associated with congenital heart disease. New treatments for PAH have been shown to be effective in improving PAH exercise capacity and hemodynamics, raising the hope for making previously inoperable congenital heart defects operable and shifting the framework for the assessment of operability. This review focuses on current methods for assessing operability in PAH associated with congenital heart disease, and the possibility of “treat-and-repair” vs. “repair-and-treat” strategies for patients with inoperable or borderline PAH.  (Circ J 2014; 78: 4–11)

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The development of vascular bioengineering has led to a variety of novel treatment strategies for patients with cardiovascular disease. Notably, combining biodegradable scaffolds with autologous cell seeding to create tissue-engineered vascular grafts (TEVG) allows for in situ formation of organized neovascular tissue and we have demonstrated the clinical viability of this technique in patients with congenital heart defects. The role of the scaffold is to provide a temporary 3-dimensional structure for cells, but applying TEVG strategy to the arterial system requires scaffolds that can also endure arterial pressure. Both biodegradable synthetic polymers and extracellular matrix-based natural materials can be used to generate arterial scaffolds that satisfy these requirements. Furthermore, the role of specific cell types in tissue remodeling is crucial and as a result many different cell sources, from matured somatic cells to stem cells, are now used in a variety of arterial TEVG techniques. However, despite great progress in the field over the past decade, clinical effectiveness of small-diameter arterial TEVG (<6mm) has remained elusive. To achieve successful translation of this complex multidisciplinary technology to the clinic, active participation of biologists, engineers, and clinicians is required.  (Circ J 2014; 78: 12–19)

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Approximately half of patients with heart failure (HF) have a preserved ejection fraction (HFpEF), and with the changing age and comorbidity characteristics in the adult population, this number is growing rapidly. The defining symptom of HFpEF is exercise intolerance, but the specific mechanisms causing this common symptom remain debated and inadequately understood. Although diastolic dysfunction was previously considered to be the sole contributor to exercise limitation, recent studies have identified the importance of ventricular systolic, chronotropic, vascular, endothelial and peripheral factors that all contribute in a complex and highly integrated fashion to produce the signs and symptoms of HF. This review will explore the mechanisms underlying objective and subjective exercise intolerance in patients with HFpEF.  (Circ J 2014; 78: 20–32)

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Patients with diabetes mellitus have increased atherothrombotic risk and elevated rates of recurrent cardiac events, which may be in part attributable to abnormalities of platelet function resulting in increased platelet reactivity. Despite improved clinical outcomes with an antiplatelet strategy of aspirin plus clopidogrel in patients with acute coronary syndrome (ACS), diabetic patients continue to experience relatively high rates of adverse events during follow-up. Thus, strategies using more potent antiplatelet drugs are warranted in diabetic patients with ACS, especially in the presence of an increased coronary angiographic risk profile. The relative benefit of prasugrel has been described as higher in diabetic vs. nondiabetic patients, without increase in the bleeding risk, whereas a reduction in ischemic events was similar with ticagrelor in patients with and without diabetes. Glycoprotein IIb/IIIa inhibitors are indicated in high-risk patients with ACS, but diabetic patients do not benefit from routine administration of such agents.  (Circ J 2014; 78: 33–41)

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Patients with some progeroid syndromes, such as Werner syndrome, exhibit atherosclerotic cardiovascular disease (CVD) at a young age as a manifestation of premature aging. Recent studies have revealed that most progeroid syndromes are caused by genetic defects in specific molecules involved in the DNA damage response, a cornerstone of genome stability. Ionizing radiation is one of the most potent genotoxic stimuli and causes various kinds of DNA damage. Further, there is increasing evidence that therapeutic radiation treatments can cause cardiovascular complications. Here, we describe the DNA damage and subsequent response, review recent advances in the understanding of the molecular basis of progeroid syndromes (especially those syndromes that involve CVD), review the pathological and epidemiological analysis of radiation-induced CVD, and discuss the possible role of DNA damage and the DNA damage response in the pathogenesis of atherosclerotic CVD.  (Circ J 2014; 78: 42–50)

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The American Heart Association (AHA) Scientific Sessions were held in Dallas on November 16–20, 2013. The meeting is one of the most leading conferences of cardiology in the world, with over 18,000 professional attendees from more than 105 countries. There were 315 invited sessions and 443 abstract sessions, comprising more than 5,000 presentations. The sessions were expanded to 26 program tracks, which included and integrated basic, translational, clinical, and population science. In the series of late-breaking sessions, updates of results from 20 clinical trials were disclosed. Japanese scientists submitted the second most abstracts to the Scientific Sessions in 2013. We appreciate the significant contribution to the sessions by Japanese cardiologists as well as the Japanese Circulation Society.  (Circ J 2014; 78: 51–56)

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Background: Little is known about predictors of response to cardiac resynchronization therapy (CRT) in patients with intraventricular conduction delay (IVCD). The purpose of this study was to investigate the benefits of CRT and significant variables on surface electrocardiogram (ECG) to predict response to CRT in those patients. Methods and Results: Among the cohort of 152 CRT patients, 40 patients with IVCD were evaluated. Sixteen patients (40%) were responders. At baseline, responders had a wider QRS duration (158±18 vs. 144±18ms, P=0.02) and a higher frequency of left axis deviation (LADEV; 75% vs. 29%, P=0.004) compared with non-responders. After CRT, greater shortening of QRS duration (ΔQRS; 26±24 vs. 7±24ms, P=0.02), axis shift from LADEV to right axis deviation (RADEV; 69% vs. 13%, P<0.001), and both rightward forces in lead I and anterior forces in V1 (56% vs. 13%, P=0.003) were found more frequently in responders. Multivariable logistic regression analysis showed that LADEV at baseline, or ΔQRS and axis shift from LADEV to RADEV after CRT were independent predictors of response to CRT. Conclusions: Patients with IVCD may not respond to CRT, but LADEV at baseline and reversal of ventricular activation after CRT on surface ECG could be important to predict response to CRT.  (Circ J 2014; 78: 71–77)

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Background: Although atrial fibrillation (AF) termination has been reported as a predictor of clinical outcome after persistent AF (PsAF) ablation, the relationship between AF termination site and mode and clinical outcome has not been fully evaluated. Methods and Results: A total of 135 patients (62±9 years) underwent their first ablation procedure for PsAF (76 longstanding PsAF). With an endpoint of AF termination, the ablation procedure was performed sequentially in the following order: pulmonary vein (PV) antrum isolation, and left atrial and right atrial substrate modification. AF termination was achieved in 69 patients (51%; 24 at the PV antrum, and 45 in the atrium; direct conversion to sinus rhythm in 21, and atrial tachycardia [AT] in 48). With a mean of 1.7±0.7 procedures/patient, 100 patients (74%) were free from atrial tachyarrhythmia (ATa) during a median of 15.0 months of follow-up. During the initial procedure, the AF termination site (atrium vs. PV antrum, hazard ratio [HR], 1.38; 95% confidence interval [CI]: 0.72–3.77; no termination vs. PV antrum, HR, 2.32; 95% CI: 1.26–6.30; P=0.023) and mode (AT vs. sinus rhythm, HR, 1.47; 95% CI: 0.77–4.01; no termination vs. sinus rhythm, HR, 2.38; 95% CI: 1.26–6.46; P=0.017) were independent predictors of ATa recurrence after the last ablation procedure. Conclusions: The site and mode of AF termination during the index ablation procedure predict ATa recurrence following multiple catheter ablation procedures for PsAF.  (Circ J 2014; 78: 78–84)

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Background: To evaluate the incidence and clinical predictors of contrast-induced acute kidney injury (CI-AKI) in patients with ST-segment elevation myocardial infarction (STEMI), unstable angina pectoris/non-STEMI (UAP/NSTEMI), and stable AP (SAP) undergoing percutaneous coronary intervention (PCI). Methods and Results: We enrolled 1,954 patients (SAP, n=1,222; UAP/NSTEMI, n=277; STEMI, n=455) who underwent PCI. Patients were categorized according to contrast media volume/estimated glomerular filtration rate ratio (CV/eGFR low: <2.0, mid: 2.0–2.9, high: ≥3.0). CI-AKI was defined as an increase in serum creatinine of 0.5mg/dl or 25% within 1 week from contrast-medium injection. The incidence of CI-AKI was highest among the STEMI patients (SAP, 4.24%; UAP/NSTEMI, 10.7%; STEMI, 16.1%, P<0.01). Significant predictors of CI-AKI were emergency PCI (odds ratio [OR] 3.70; 95% confidence interval [CI] 2.55–5.37; P<0.001), ejection fraction <40% (OR 2.04; 95% CI 1.24–3.36; P=0.005), and hemoglobin <10g/dl (OR 0.02; 95% CI 1.17–4.55; P=0.02) after multivariate logistic regression analysis. In the SAP group, a CV/eGFR ratio ≥3.0 was a significant predictor of CI-AKI (P=0.048), but not in UAP/NSTEMI and STEMI patients. Conclusions: UAP/NSTEMI and STEMI patients undergoing emergency PCI were at high risk for CI-AKI regardless of CV/eGFR ratio. Minimizing the dose of contrast medium based on eGFR might be valuable in reducing the risk of CI-AKI in SAP patients.  (Circ J 2014; 78: 85–91)

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Background: Although both optical coherence tomography (OCT) and angioscopy are robust tools for detecting intrastent thrombi and neoatherosclerosis in vivo, whether OCT findings are comparable with angioscopy findings remains unclear. Methods and Results: 22 patients presenting with de novo lesions underwent 26 sirolimus-eluting stent (SES) implantations, with follow-up OCT and angioscopy at 10 months post-implantation for segmental assessment of the proximal, mid-, and distal SES segments (66 segments). The mean signal intensity index (signal intensity of the neointima/signal intensity of fibrous intimal hyperplasia) was quantified for angioscopically detected in-stent yellow and white segments. The detection rate for red thrombi was numerically higher with angioscopy than with OCT (17% vs. 9%; P=0.053). Angioscopically detected in-stent yellow segments were categorized into 3 OCT patterns: “high-attenuation tissue covering struts” (OCT-defined neoatherosclerosis), “high-attenuation tissue underneath struts,” and “low-attenuation and low-intensity tissue covering struts”; further, macrophage-like appearance was most frequently observed with OCT-defined neoatherosclerosis (56%, 6.3%, and 0%, respectively, P<0.001). The mean signal intensity index of neoatherosclerosis was significantly lower than that of angioscopically detected in-stent white segments (0.929 vs. 0.997, P=0.004). Conclusions: Current OCT-based definitions for thrombus detection may underestimate the presence of subclinical red thrombi. Qualitative and quantitative OCT assessments of the neointima may enhance the detection of neoatherosclerosis over SES in vivo.  (Circ J 2014; 78: 92–100)

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Background: Differences in long-term outcome between early stent thrombosis (EST), late stent thrombosis (LST), and very late stent thrombosis (VLST) are unknown. Methods and Results: A total of 152 patients who had undergone percutaneous coronary intervention for stent thrombosis between January 2001 and October 2011 were enrolled, and the clinical outcome compared between EST (55 patients), LST (34 patients), and VLST (63 patients) after drug-eluting stent (DES) and bare-metal stent (BMS) implantation. Major adverse cardiac events (MACE), including cardiac death, recurrent stent thrombosis, non-fatal myocardial infarction, and target lesion revascularization (TLR), were evaluated at 5 years. The in-hospital mortality was similar between EST, LST, and VLST (P=0.37). The incidence of MACE was significantly lower in VLST (21.9%) than in EST (66.9%, P<0.001) and LST (66.6%, P<0.001), mainly because of a lower TLR rate after VLST (11.1%) than after EST (50.8%, P<0.001) and LST (52.2%, P<0.001). The 5-year mortality rate was also significantly lower in VLST (14.7%) than in EST (29.3%, P=0.049) and LST (41.6%, P=0.025). The incidence of MACE was similar between DES and BMS (46.2% vs. 50.0%, P=0.82), and this finding was observed in EST (P=0.83), LST (P=0.77), and VLST (P=0.57). Conclusions: Compared with EST and LST, long-term outcome was markedly better in VLST, mainly because of a lower TLR rate, whether after DES or BMS implantation.  (Circ J 2014; 78: 101–109)

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Background: The advantages of the final kissing balloon technique (FKB) in a provisional 1-stent approach are under debate. Long-term clinical outcomes remain unclear due to limited data. Methods and Results: Of 2,132 patients (2,502 lesions) enrolled in the TAXUS Japan Postmarket Surveillance Study at 56 centers between July 2007 and December 2008, patients having coronary bifurcation treated with a single cross-over stenting with FKB (FKB-group: 132 patients/137 lesions) were compared to those treated without FKB (no-FKB-group: 121 patients/124 lesions). The no-FKB-group was also compared with non-bifurcation patients who had a single-stent implantation (814 patients/937 lesions). The primary outcome was MACE (major adverse clinical events), defined as cardiac death, myocardial infarction and target vessel revascularization (TVR) at 3 years. Higher late loss and binary restenosis were found in the main vessel (MV) of the FKB-group at the 9-month angiogram compared to the no-FKB-group. At 3 years, MACE was numerically higher (14.6% vs. 6.9%, P=0.07) and TVR was significantly higher (14.6% vs. 5.9%, P<0.05) in the FKB-group compared with the no-FKB-group. The rate of MACE (6.9% vs. 10.4%, P=0.34) and TVR (5.9% vs. 7.7%, P=0.57) were similar between the no-FKB and non-bifurcation patients. Conclusions: In a 1-stent approach, FKB was associated with worse angiographic outcomes in the MV, and did not demonstrate any clinical benefit over the long-term follow-up period. Cross-over stenting without FKB showed similar clinical outcomes to patients without bifurcation.  (Circ J 2014; 78: 110–121)

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Background: Peri-stent contrast staining (PSS) has been recognized as a predictor of late stent thrombosis following drug-eluting stent (DES) implantation. However, the intravascular conditions at PSS sites remain unclear. Methods and Results: We evaluated 10 patients (median age 72 years, 80% male) with stable angina pectoris by coronary angioscopy. The patients had a total of 11 DES implantations (5 sirolimus-eluting stents; 4 paclitaxel-eluting stents; 2 everolimus-eluting stents) that showed PSS. Neointimal coverage (NIC), presence of thrombus, and yellow plaques underneath the stent were compared between PSS and non-PSS sites for each stent. NIC was graded as: grade 0, struts exposed; grade 1, struts bulging into the lumen, although covered; grade 2, struts embedded by neointima, but translucent; grade 3, struts fully embedded and invisible. Mean follow-up was 394±206 days (median: 289). NIC grade was lower at PSS sites (P=0.021) with 8 out of 11 stents (73%) having grade 0. Angioscopy detected a thrombus more frequently at PSS sites than at non-PSS sites (64% vs. 9%, P=0.012). Yellow plaques tended to be more significant at PSS sites than at non-PSS sites (82% vs. 45%, P=0.091). Conclusions: The angioscopic findings suggest high thrombogenicity at PSS sites.  (Circ J 2014; 78: 122–127)

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Background: The J wave is an ECG marker of ventricular fibrillation. However, the prevalence and clinical implications of J waves in hypothermic patients remain unclear. Methods and Results: We evaluated the clinical characteristics and ECGs of patients who were admitted for accidental hypothermia (<35.0°C). J waves were defined as notches or slurs in the terminal part of the QRS complex with an amplitude ≥0.1mV. We analyzed the prevalence of J waves and the relationship between body temperature (BT) and J wave amplitude. We also examined the augmentation of J waves following variable R-R intervals in patients with atrial fibrillation. Furthermore, we assessed the incidence of ventricular arrhythmias. A total of 60 hypothermic patients were recruited (mean age, 64±9 years; 97% male). The mean BT was 31.3°C (range, 29.4–33.5°C). J waves, which disappeared after rewarming, were observed in 30 patients (50%), with a higher frequency in patients with lower BT. Higher amplitude of J waves was associated with lower BT (P<0.001). Of the 8 patients with J waves and atrial fibrillation, 4 exhibited an augmentation of J waves following a short R-R interval. Only 1 patient with J waves developed ventricular tachycardia during rewarming. Conclusions: The prevalence of J waves and their amplitude increased with the severity of hypothermia. The temporal development of J waves might not be associated with fatal arrhythmic events.  (Circ J 2014; 78: 128–134)

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Background: Tamoxifen is used for breast cancer treatment and has been reported to be beneficial for the cardiovascular system, but it is unclear whether tamoxifen exhibits a favorable cardiovascular effect in Asian patients. Methods and Results: From January, 1998 to December, 2006, a breast cancer cohort study was conducted using the Taiwan National Health Insurance database. Patients were divided according to whether tamoxifen was used. Study endpoints were occurrence of acute myocardial infarction (AMI), ischemic or hemorrhagic stroke and total cardiovascular events. A total of 3,690 female subjects were enrolled (mean age 50.1±11.3), 2,056 of whom received tamoxifen and 1,634 did not. During a mean follow-up of 6.9 years, the tamoxifen group had a significantly lower incidence of AMI (0.15% vs. 0.67%, P=0.008), ischemic stroke (1.99% vs. 3.30%, P=0.008), hemorrhagic stroke (0.15% vs. 0.55%, P=0.029), and total cardiovascular events (2.24% vs. 4.16%, P<0.001) than the non-exposed group. After adjusting for comorbidities, tamoxifen was independently associated with a reduced risk of myocardial infarction (hazard ratio [HR] 0.22; 95% confidence interval [CI] 0.07–0.70, ischemic stroke (HR 0.52; 95% CI 0.35–0.78), hemorrhagic stroke (HR 0.25; 95% CI 0.07–0.92), and total cardiovascular events (HR 0.54; 95% CI 0.37–0.78). Conclusions: In Asian female breast cancer patients, tamoxifen use was associated with reduced risks of AMI, ischemic, hemorrhagic stroke and total cardiovascular events.  (Circ J 2014; 78: 135–140)

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Background: The detection of significant coronary artery disease (CAD) in patients with heart failure (HF) from left ventricular (LV) systolic dysfunction is crucial. We evaluated the usefulness of LV mechanical dyssynchrony as assessed by phase analysis compared with conventional gated single-photon emission computed tomography to identify ischemic etiology in patients with HF. Methods and Results: Forty-one consecutive patients who were initially admitted to hospital due to HF resulting from systolic dysfunction were evaluated. All patients underwent cardiac catheterization. LV mechanical dyssynchrony was evaluated using SyncTool™ to obtain the phase SD and histogram bandwidth. The changes in phase SD and histogram bandwidth with stress were calculated. The summed stress score, summed difference score, and changes in phase SD and histogram bandwidth with stress were greater in 26 patients with CAD than in 15 patients without CAD (P=0.001 and P=0.01). On multivariate analysis a phase SD of >14° (odds ratio [OR], 16.7) and a summed stress score of >17 (OR, 8.0) best differentiated LV dysfunction of ischemic and non-ischemic etiologies, with a sensitivity of 89% and a specificity of 87% (χ²=20), compared with summed stress score only (sensitivity, 46%; specificity, 87%; χ²=4.5). Conclusions: The addition of phase analysis to conventional perfusion analysis enables better differentiation of the etiology of HF in patients with systolic dysfunction.  (Circ J 2014; 78: 141–150)

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Background: Ultrasound assessment of either intima-media thickness (IMT) or plaque echolucency of the carotid artery provides prognostic information on coronary events. This study examined the hypothesis that IMT and plaque echolucency of the carotid artery may remain useful for prediction of coronary events in patients with coronary artery disease (CAD) after achievement of LDL-C goals on statin therapy. Methods and Results: Ultrasound assessment of carotid maximum IMT (maxIMT) and plaque echolucency with integrated backscatter (IBS) analysis was performed in 357 chronic CAD patients with LDL-C <100mg/dl on statin therapy. All patients were prospectively followed up until the occurrence of one of the following coronary events: cardiac death, non-fatal myocardial infarction, or unstable angina pectoris requiring unplanned revascularization. During a mean follow-up of 32±18 months, 33 coronary events occurred. On multivariate Cox proportional hazards analysis, plaque echolucency (lower IBS value) was a significant predictor of coronary events (HR, 0.44; 95% CI: 0.29–0.73; P=0.009), whereas maxIMT was not. The addition of plaque echolucency to traditional risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI; NRI, 0.59; P=0.0013; and IDI, 0.075; P=0.0009). Conclusions: Measurement of echolucency of the carotid artery was useful for assessment of residual coronary risk in CAD patients after LDL-C goal attainment on statin treatment.  (Circ J 2014; 78: 151–158)

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Background: We aimed to assess the relationships of pentraxin-3 (PTX3) with coronary plaque components and myocardial perfusion after percutaneous coronary intervention (PCI) in order to clarify the mechanisms underlying the prognostic function of PTX3 in ST-elevation acute myocardial infarction (STEMI) patients. Methods and Results: We enrolled 75 STEMI patients who underwent pre-PCI virtual histology (VH)-intravascular ultrasound. Relationships of the systemic pre-PCI PTX3 level with coronary plaque components and post-PCI myocardial blush grade (MBG) were evaluated. Lesions with elevated pre-PCI PTX3 (median ≥3.79ng/ml) had higher frequencies of VH-derived thin-cap fibroatheroma (65.8% vs. 24.3%, P<0.0001), plaque rupture (63.2% vs. 24.3%, P=0.001), and post-PCI MBG (0–1) (65.8% vs. 40.5%, P=0.03) than those with PTX3 <3.79ng/ml. In multivariate analysis, pre-PCI PTX3 level was independently related to post-PCI MBG (0–1) (odds ratio, 11.385; 95% confidence interval (CI), 1.346–96.289; P=0.026). At 9-month follow-up, cardiac event-free survival was poorer for patients with post-PCI MBG (0–1) (log-rank test χ²=8.6; P=0.003). Cox proportional-hazards analysis showed post-PCI MBG (0–1) (hazard ratio, 4.109; 95% CI, 1.372–12.309; P=0.012) and Killip class >2 on admission (hazard ratio, 5.356; 95% CI, 1.409–20.359; P=0.014) as independent predictors of adverse cardiac events during follow-up. Conclusions: Systemic pre-PCI PTX3 was associated with high-risk plaque components and impaired post-PCI myocardial perfusion. Thus, PTX3 may be a reliable predictor of outcome in STEMI patients.  (Circ J 2014; 78: 159–169)

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Background: It remains unclear whether glycemic fluctuation immediately after acute myocardial infarction (AMI) can affect myocardial damage. This study investigated the impact of glucose fluctuation on myocardial salvage following successful recanalization of primary AMI. Methods and Results: A total of 36 consecutive patients with AMI were studied. Glycemic variability, as indicated by the mean amplitude of glycemic excursion (MAGE), was measured on a continuous glucose monitoring system. Three subsets (CD14⁺CD16⁻, CD14⁺⁺CD16⁺ and CD14⁺⁻CD16⁺) were measured on flow cytometry 1, 2, 3, 4 and 5 days after AMI onset. A 2-h oral glucose test was performed in 23 patients who had no previous diagnosis of diabetes and/or glycated hemoglobin <6.5%, after the onset of AMI at 2 weeks. Plasma active glucagon-like peptide (GLP)-1 level was measured in each sample. The extent of myocardial salvage 7 days after AMI was evaluated on cardiovascular magnetic resonance imaging. MAGE and the peak CD14⁺CD16⁻ monocyte level were significantly negatively correlated with myocardial salvage index (MSI). MAGE was significantly correlated with peak CD14⁺CD16⁻ monocyte level. Of interest, plasma GLP-1 level was significantly positively correlated with MSI and significantly negatively correlated with MAGE. Conclusions: Glucose fluctuations during the acute phase of AMI affect MSI, indicating that manipulation of glucose variability from peak to nadir might be a potential therapeutic target for salvaging ischemic damage.  (Circ J 2014; 78: 170–179)

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Background: The prevalence of contraindications/special warnings and precautions (CON/SWP) for clopidogrel, prasugrel and ticagrelor use is not adequately studied and might affect P2Y12 inhibitor choice in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Methods and Results: In the context of the GReek AntiPlatelet rEgistry (GRAPE) a detailed recording of CON/SWP for use of clopidogrel, prasugrel and ticagrelor was done for 1,280 consecutive, moderate–high-risk ACS patients undergoing PCI. At least 1 CON for use of clopidogrel, prasugrel and ticagrelor was present in 5 (0.4%), 49 (3.8%) and 12 patients (0.9%), respectively. Prevalence of at least 1 CON/SWP to clopidogrel (45.8%) was less frequent compared to prasugrel (49.1%) or ticagrelor (49.1%; P=0.02 and P=0.04, respectively), while 34% of patients had at least 1 CON/SWP to all the 3 P2Y12 inhibitors. At discharge, 482 (38.6%), 301 (24.1%) and 464 patients (37.2%) received clopidogrel, prasugrel and ticagrelor, respectively. Age ≥75 years, co-medication related to increased bleeding risk, and history of asthma/chronic obstructive pulmonary disease favored clopidogrel vs. prasugrel or ticagrelor use as discharge medication, while geographic region also affected this choice (C-statistic, 0.81; 95% CI: 0.78–0.83). Conclusions: In patients with ACS undergoing PCI the prevalence of CON to antiplatelet agents is low, whereas that of SWP is high. Certain SWP, along with regional trends may affect the choice of newer P2Y12 inhibitors vs. clopidogrel.  (Circ J 2014; 78: 180–187)

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Background: Little is known about the platelet dynamics and the effect of antiplatelet therapy in Kawasaki disease (KD). The aim of this study was to clarify platelet activation dynamics in acute-phase KD patients by assaying platelet-derived microparticles (PDMPs). Methods and Results: The PDMP level in 18 patients with acute KD was measured on ELISA. Of the 18 patients, 14 were receiving oral aspirin and i.v. immunoglobulin (IVIG) and 4, oral aspirin alone. Blood samples were drawn before, immediately after, and 10–14 days after IVIG infusion; thereafter, at 1, 2, and 3 months after the onset of disease. PDMP level before aspirin treatment was significantly higher in acute-phase KD patients than in the control subjects with common febrile diseases (P<0.01). In the acute-phase KD patients, IVIG significantly decreased PDMP level; the PDMP level was not lower on the similar day of KD in the patients who did not receive IVIG. Eight patients’ PDMP level rebounded after aspirin was discontinued. Conclusions: Platelets are activated during acute-phase KD, which confirms the importance of antiplatelet therapy. In addition, platelet activation continues as long as 2 or 3 months after the acute phase, the time at which aspirin is commonly discontinued, and the timing of aspirin discontinuation should therefore be evaluated in each individual patient.  (Circ J 2014; 78: 188–193)

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Background: A prospective, 3-year comparative observational study compared the risk of cardiovascular events in patients with osteoarthritis or rheumatoid arthritis prescribed celecoxib or a nonsteroidal antiinflammatory drug (NSAID). Methods and Results: Patients prescribed celecoxib (n=5,470) or NSAIDs (n=5,059) between November 1, 2007, and July 31, 2008 in 1,084 hospitals and clinics in Japan were eligible for safety analysis. Mean (standard deviation) observation for the celecoxib group was 716 (420) days and 692 (426) days for the NSAID group (P=0.004). Composite I (adjudicated cardiovascular adverse events of myocardial infarction, angina pectoris, heart failure, cerebral infarction, cerebral hemorrhage) number of events (percentage) and rate/1,000 person years was 66 (1.2%) and 6.2 (10,745 person years), respectively, for the celecoxib and 65 (1.3%) and 6.8 (9,601 person years) for the NSAID (P=0.58) groups. Composite II (all cardiovascular events) number of events (percentage) and rate/1,000 person years was 79 (1.4%) and 7.4, respectively, for the celecoxib and 84 (1.7%) and 8.8 for the NSAID (P=0.26) group. Adjusted Cox hazards ratio (95% confidence interval) was 0.89 (0.63–1.27; P=0.52) for Composite I, 0.87 (0.63–1.19; P=0.39) for Composite II and 1.03 (0.75–1.41; P=0.87) for death from all causes. Conclusions: After adjustment for confounding variables, celecoxib was not associated with an increase of cardiovascular risk in comparison with nonselective NSAID in Japanese patients with rheumatoid arthritis or osteoarthritis in an observational setting.  (Circ J 2014; 78: 194–205)

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Background: Endothelial microparticles (EMPs) are vehicles released from activated or apoptotic endothelium. The aim of this study was to establish a new cytometric bead assay for EMPs and investigate the prognostic value of EMPs in chest pain patients. Methods and Results: We invented and verified the cytometric bead assay to quantify EMP level in vitro. A total of 80 healthy volunteers and 350 chest pain patients were recruited and the EMPs measured. The major adverse cardiovascular events (MACE) of documented coronary artery disease patients were recorded in the follow-up period. The level of EMPs statistically correlated with those of endothelin-1 (ET-1) and intercellular adhesion molecule-1 (ICAM-1) in vitro. The EMP level in healthy subjects was <300.10. The patients had a remarkably higher EMP level than healthy subjects. Diabetes mellitus, EMP, and ET-1 levels were significantly associated with future cardiovascular events in chest pain patients. There was a significantly higher event incidence in the top tertile EMP level than in the lower tertile in the acute coronary syndrome (ACS) patient group. Conclusions: A novel EMP quantification assay has been successfully established. The EMPs in vitro and in patients were significantly correlated with ET-1 and ICAM-1 level. The patients with a higher EMP level had a higher risk of MACE. EMP level is a predictor for MACE in ACS patients.  (Circ J 2014; 78: 206–214)

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Background: Nearly all clinical trials investigating patients with pulmonary arterial hypertension (PAH) have used the 6-min walk test (6MWT) to evaluate exercise tolerance. The incremental shuttle walk test (SWT), however, has been proposed as a more valid and reproducible alternative to the 6MWT in the evaluation of exercise tolerance in patients with chronic obstructive pulmonary disease. The efficacy of SWT in clinical practice to evaluate the exercise capacity of patients with PAH was investigated. Methods and Results: The peak oxygen consumption (pVO₂) and oxygen consumption at anaerobic threshold (VO₂ at AT), the gold standard for measurement of exercise tolerance, 6MWT and SWT were measured in 19 clinically stable PAH patients (WHO functional class II–III) and the data compared. There was a higher correlation between SWT walk distance and pVO₂ than between 6MWT walk distance and pVO₂ (r=0.866 and 0.765, respectively; P<0.05), and a higher correlation between SWT walk distance and VO₂ at AT than between 6MWT walk distance and VO₂ at AT (r=0.775 and 0.587, respectively; P<0.05). No adverse events occurred during the exercise tests. Conclusions: SWT is a better reflection than 6MWT of exercise tolerance in PAH patients, and thus is a preferable alternative for assessment of exercise tolerance in PAH patients.  (Circ J 2014; 78: 215–221)

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Background: Because human cardiac stem cells (CSC) have regeneration potential in damaged cardiac tissue, there is increasing interest in using them in cell-based therapies for cardiac failure. However, culture conditions, by which CSCs are expanded while maintaining their therapeutic potential, have not been optimized. We hypothesized that the plating cell-density would affect proliferation activity, differentiation and therapeutic potential of CSCs through the Notch signaling pathway. Methods and Results: Human CSCs were plated at 4 different densities. The population doubling time, C-KIT positivity, and dexamethasone-induced multidifferentiation potential were examined in vitro. The therapeutic potential of CSCs was assessed by transplanting them into a rat acute myocardial infarction (AMI) model. The low plating density (340cells/cm²) maintained the multidifferentiation potential with greater proliferation activity and C-KIT positivity in vitro. On the other hand, the high plating density (5,500cells/cm²) induced autonomous differentiation into endothelial cells by activating Notch signaling in vitro. CSCs cultured at low or high density with Notch signal inhibitor showed significantly greater therapeutic potential in vivo compared with those cultured at high density. Conclusions: CSCs cultured with reduced Notch signaling showed better cardiomyogenic differentiation and therapeutic potentials in a rat AMI model. Thus, reducing Notch signaling is important when culturing CSCs for clinical applications.  (Circ J 2014; 78: 222–231)

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Background: Many symptomatic patients with severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF) are denied surgery and have a grim prognosis with medical management. Methods and Results: Between 2003 and 2012, among 550 patients with severe isolated AS and preserved LVEF on transthoracic echocardiography, 241 did not undergo aortic valve replacement (mean age, 83.2±7.6 years; 54% female; aortic valve area index, 0.40±0.13cm²/m²; mean LVEF, 64.8±7.6%) and 67% presented with cardiac symptoms. At a mean follow-up of 25.5±25.1 months, 134 patients (56%) had died. Survival at 1, 5 and 9.5 years was 71%, 28% at 12%, respectively. Median survival was 36.3 months (95% confidence interval [CI]: 27.2–42.4 months). In unadjusted analyses, age, heart failure, hypertension, renal insufficiency, left atrial size, pulmonary artery systolic pressure (PASP), relative wall thickness and LV mass/LV end diastolic volume ratio were associated with mortality. On multivariate analysis adjusted for all significant univariate predictors, age ≥78 years, history of hypertension, left atrial diameter ≥40mm and PASP ≥42mmHg gave a joint area under the curve of 0.80 (95% CI: 0.73–0.86) for mortality. Conclusions: In medically treated patients with severe isolated AS and preserved LVEF, older age, history of hypertension, and echo-Doppler variables reflecting LV diastolic dysfunction are independent predictors of death.  (Circ J 2014; 78: 232–239)

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Background: Telmisartan has unique pleiotropic effects in addition to renin-angiotensin system (RAS)-inhibition effects. The aim of this study was to evaluate the effects of telmisartan on the coronary plaque component and local inflammatory cytokines. Methods and Results: A total of 50 patients with hypertension were randomized to 2 groups: the telmisartan group (additional treatment with telmisartan 80mg/day, n=25) or the control group (additional treatment with other anti-hypertensive drugs except RAS blockers, n=25) for 6 months. Tissue characteristics of target coronary plaque were analyzed using integrated backscatter intravascular ultrasound (IB-IVUS) before and after treatment. Plasma levels of inflammatory cytokines sampled in the coronary sinus (CS) and peripheral vein were also measured. Significant increases in fibrous volume (51.2±10.4 to 58.3±7.7%, P=0.03) and reductions in lipid volume (38.4±12.4 to 32.8±9.7%, P=0.03) were observed on IB in the telmisartan group, while there were no significant changes in the plaque component in the control group. CS levels of inflammatory cytokines (matrix metalloproteinase [MMP]3, tumor necrosis factor-α, high-sensitivity C-reactive protein and MMP9) were lower after than before treatment in the only telmisartan group (7.7±6.1 to 5.5±4.9ng/ml, 3.1±1.9 to 2.3±2.0pg/ml, 5.6±6.0 to 2.2±2.4mg/L, 36.1±39.3 to 19.9±27.5ng/ml, P=0.02, P=0.03, P=0.04, P=0.07, respectively). Conclusions: Decreased local inflammatory response and plaque stabilization on IB imaging were observed after 6 months of telmisartan treatment. These findings might be associated with local anti-inflammatory and anti-arteriosclerotic effects of telmisartan.  (Circ J 2014; 78: 240–247)

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Background: Studies have shown that repeated post-prandial hyperglycemia may play an important role in the development of atherosclerosis by suppressing endothelial function. α-Glucosidase inhibitors (α-GIs), which reduce post-prandial hyperglycemia without stimulating insulin secretion, significantly reduce the risk of coronary artery disease (CAD), whereas glinides, which improve post-prandial hyperglycemia through post-prandial insulin secretion, do not appear to affect CAD. Methods and Results: A total of 104 diabetic patients with CAD were randomly divided into 2 groups: those treated with miglitol (M-group; n=52) and those treated with nateglinide (N-group; n=52). After 4 months’ treatment, although hemoglobin A1c and 1,5-anhydroglucitol were significantly improved in both groups, only the M-group had significant reductions in insulin resistance index and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C; a beneficial index for assessing the presence of small dense low-density lipoprotein, and a marker of atherogenic dyslipidemia). Furthermore, only the M-group had improvement in percentage flow-mediated dilatation (%FMD) and reactive oxygen metabolites. In the M-group, multiple regression analysis showed that improvement in TG/HDL-C, in addition to 1,5-anhydroglucitol, was an independent predictor of improvement in %FMD. Conclusions: The ameliorating effect of α-GI on post-prandial hyperglycemia without stimulating insulin secretion may improve atherogenic dyslipidemia by reducing insulin resistance. These effects are associated with its beneficial impact on oxidative stress, consequently leading to an improvement in endothelial dysfunction.  (Circ J 2014; 78: 248–255)

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Background: It remains to be elucidated whether brain activity is altered in takotsubo cardiomyopathy. Methods and Results: We measured cerebral blood flow (CBF) in 3 consecutive patients with takotsubo cardiomyopathy using ^99mTc ethyl cysteinate dimmer single photon-emission computed tomography (SPECT) in the acute and chronic phases. In all patients, CBF was significantly increased in the hippocampus, brainstem and basal ganglia and significantly decreased in the prefrontal cortex in the acute phase, which changes subsided in the chronic phase with full recovery of cardiac wall motion. Conclusions: These results provide the first direct evidence for brain activation in takotsubo cardiomyopathy.  (Circ J 2014; 78: 256–258)

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