This essay summarizes 30 years of work attempting to understand why regenerated endothelium becomes dysfunctional. It focuses on the activation of endothelial nitric oxide synthase (eNOS) and the production of NO in response to platelet products and thrombin, which represents a first-line protection against vasospasm and atherosclerosis. Serotonin and adenosine diphosphate released by aggregating platelets are coupled to the activation of eNOS by different G-proteins. The endothelium-dependent relaxation that they cause is modulated non-selectively by the lipid content in the diet. When the endothelium regenerates after mechanical disruption, the newly formed endothelial cells selectively lose their G_i-mediated coupling and become less responsive to serotonin and thrombin. Accelerated senescence and the emergence of adipocyte-fatty acid binding protein leading to increased oxidative stress play a key role in the genesis of the dysfunction of regenerated endothelium. The consequent local NO deficiency not only favors the occurrence of vasospasm but sets the stage for the occurrence of atherosclerosis. (Circ J 2016; 80: 783–790)

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Diabetes mellitus (DM) is a key risk factor for recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI). The prothrombotic milieu that characterizes patients with DM underscores the importance of oral antithrombotic therapy for secondary prevention of recurrent events in these patients. Indeed, dual antiplatelet therapy (DAPT) with aspirin and the P2Y₁₂inhibitor clopidogrel, which has represented the mainstay of treatment for many years, has significantly reduced the incidence of recurrent atherothrombotic events. However, recurrence rates in DM patients still remain high despite this treatment regimen, which may be partly related to inadequate platelet inhibition induced by standard DAPT with aspirin and clopidogrel. This underpins the need for more potent antithrombotic treatment regimens for secondary prevention of atherothrombotic events in DM patients following ACS or PCI. The development of antiplatelet therapies associated with more potent oral platelet P2Y₁₂receptor inhibition, including prasugrel and ticagrelor, as well as platelet inhibitors blocking alternative pathways, such as thrombin-mediated platelet inhibition with vorapaxar, may represent potential treatment options in DM patients. Moreover, with the introduction of the target-specific oral anticoagulants, there has been a reappraisal of the use of anticoagulation in addition to antiplatelet therapy for secondary prevention in patients with ACS. This review provides an update on the recent advances and limitations of oral antithrombotic agents used for secondary prevention in DM patients following ACS or PCI. (Circ J 2016; 80: 791–801)

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The major guidelines on stable coronary artery disease recommend revascularizing patients with large areas of myocardium at risk. The algorithms on how to prove that such high risk is present differ considerably. The opinions on the use of coronary CT (calcium scoring and angiography) vary widely. This review aims to summarize the recommendations of the major guidelines, commenting on differences between the guidelines and discussing whether extending the role of coronary CT angiography should be considered in the light of new CT data. (Circ J 2016; 80: 802–810)

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Background:Waon therapy improves heart failure (HF) symptoms, but further evidence in patients with advanced HF remains uncertain.Methods and Results:In 19 institutes, we prospectively enrolled hospitalized patients with advanced HF, who had plasma levels of B-type natriuretic peptide (BNP) >500 pg/ml on admission and BNP >300 pg/ml regardless of more than 1 week of medical therapy. Enrolled patients were randomized into Waon therapy or control groups. Waon therapy was performed once daily for 10 days with a far infrared-ray dry sauna maintained at 60℃ for 15 min, followed by bed rest for 30 min covered with a blanket. The primary endpoint was the ratio of BNP before and after treatment. In total, 76 Waon therapy and 73 control patients (mean age 66 years, men 61%, mean plasma BNP 777 pg/ml) were studied. The groups differed only in body mass index and the frequency of diabetes. The plasma BNP, NYHA classification, 6-min walk distance (6MWD), and cardiothoracic ratio significantly improved only in the Waon therapy group. Improvements in NYHA classification, 6MWD, and cardiothoracic ratio were significant in the Waon therapy group, although the change in plasma BNP did not reach statistical significance. No serious adverse events were observed in either group.Conclusions:Waon therapy, a holistic soothing warmth therapy, showed clinical advantages in safety and efficacy among patients with advanced HF. (Circ J 2016; 80: 827–834)

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Background:Inhaled iloprost is approved for pulmonary arterial hypertension (PAH) in many countries. IBUKI was a phase III, non-randomized, open-label study of the efficacy and safety of inhaled iloprost in Japanese patients with PAH.Methods and Results:Adults with PAH who were treatment-naïve or administered endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 inhibitors (PDE5-Is) and in NYHA/WHO functional class (FC) III/IV had inhaled iloprost (2.5 µg, increased to 5.0 µg if tolerated) 6–9 times daily for 12 weeks. Eligible patients entered a 40-week extension phase. Endpoints included change from baseline to week 12 in pulmonary vascular resistance (PVR; primary endpoint), other efficacy parameters, and safety. Data were compared with new subgroup analyses of treatment-naïve Western PAH patients from the global phase III AIR study. 27 patients received iloprost: 89% were treated with an ERA and/or PDE5-I; 70% with both. At week 12, PVR improved from baseline by –124 dyn·sec·cm⁻⁵(95% CI, –177 to –72) and 6-min walking distance increased by 36.0 m (95% CI, 14.9 to 57.1). NYHA/WHO FC improved in 62%; none worsened. Common drug-related adverse events were headache (37%) and cough (15%); 1 patient experienced hypotension; none reported syncope or hemoptysis. There were no deaths and no unexpected long-term safety findings. AIR PAH subgroup analyses showed similar results.Conclusions:Inhaled iloprost appeared effective and safe in Japanese PAH patients, including ERA- and PDE5-I-treated patients, consistent with findings of the AIR PAH subpopulation and previous iloprost studies. (Circ J 2016; 80: 835–842)

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Background:The J-RHYTHM Registry 2 was a multicenter, prospective observational study that extended the follow-up period of the J-RHYTHM Registry in order to investigate long-term outcomes and effects of non-vitamin K antagonist oral anticoagulants (NOACs) in Japanese patients with atrial fibrillation (AF).Methods and Results:Among 6,616 patients with nonvalvular AF (NVAF) (men 71.0%, 69.7±9.9 years, CHADS₂score 1.7±1.2), event rates were compared among patients receiving warfarin (n=3,964), NOACs (n=923), and no anticoagulation therapy (No-OAC, n=753) at the end of follow-up, except for 976 patients lacking anticoagulant data. During the 5-year follow-up period, thromboembolism occurred in 196 (4.9%), 19 (2.1%), and 45 (6.0%) patients, respectively; major hemorrhage in 233 (5.9%), 22 (2.4%), and 36 (4.8%); all-cause death in 230 (5.8%), 13 (1.4%), and 105 (13.9%), (P<0.001 for each). After adjusting for the components of the CHA₂DS₂-VASc score and antiplatelet drug use, the odds ratio (OR) in the Warfarin group was significantly lower for all-cause death compared with that in the No-OAC group (OR 0.30, 95% confidence interval [CI] 0.23–0.39, P<0.001), whereas ORs in the NOACs group were significantly lower for all events (OR 0.42, 95% CI 0.24–0.74, P=0.003 for thromboembolism; OR 0.53, 95% CI 0.31–0.93, P=0.027 for major hemorrhage; and OR 0.10, 95% CI 0.06–0.18, P<0.001 for all-cause death, respectively).Conclusions:NOACs could be beneficial for reducing event rates of all types in Japanese NVAF patients. (Circ J 2016; 80: 843–851)

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Background:There are little data about cardiovascular shock caused by various diseases. We evaluated the characteristics and predictors of 30-day mortality in patients with cardiovascular shock in Japan.Methods and Results:The Japanese Circulation Society Cardiovascular Shock registry was a prospective, observational, multicenter, cohort study. Between May 2012 and June 2014, 979 patients with cardiovascular shock were analyzed. The primary endpoint was 30-day all-cause mortality. The mean systolic blood pressure on hospital arrival was 78±18 mmHg. The main causes of shock were acute coronary syndrome (51.0%), non-ischemic arrhythmia (16.4%), and aortic disease (14.9%). The 30-day all-cause mortality was 34.3%. After adjustment for independent predictors of 30-day mortality, the odds ratios for systolic blood pressure (per 10-mmHg decrease), consciousness disturbance, congestive heart failure, out-of-hospital cardiac arrest, estimated glomerular filtration rate (per 10-ml/min/1.73 m²decrease), and causes of shock (non-ischemic arrhythmia, aortic disease, and myocarditis) were 1.15 (95% confidence interval [CI], 1.08–1.22), 2.62 (95% CI, 1.80–3.82), 2.58 (95% CI, 1.67–3.99), 1.62 (95% CI, 1.05–2.51), 1.20 (95% CI, 1.10–1.30), and 0.48 (95% CI, 0.30–0.77), 3.98 (95% CI, 2.32–6.81), and 3.25 (95% CI, 1.20–8.84), respectively.Conclusions:The 30-day mortality for cardiovascular shock was still high at 34%. Primary predictors of mortality were cardiorenal function on hospital arrival and shock etiology. (Circ J 2016; 80: 852–859)

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Background:In the multinational, double-blind, double-dummy ENGAGE AF-TIMI 48 phase 3 study, once-daily edoxaban was non-inferior to warfarin for prevention of stroke or systemic embolism event (SEE) in patients with non-valvular atrial fibrillation (AF). Here, we evaluated the efficacy and safety of edoxaban in patients from East Asia.Methods and Results:Patients aged ≥21 years with documented AF and CHADS score ≥2 were randomized to receive once-daily edoxaban higher-dose (60 mg) or lower-dose (30 mg) regimen or warfarin dose-adjusted to an international normalized ratio of 2.0–3.0. Patients with a creatinine clearance of 30–50 ml/min, weighing ≤60 kg, or receiving strong p-glycoprotein inhibitors at randomization or during the study received a 50% dose reduction of edoxaban or matched placebo. This prespecified subanalysis included 1,943 patients from Japan, China, Taiwan, and South Korea. The annualized rate of stroke/SEE for higher-dose edoxaban was 1.34% vs. 2.62% for warfarin (hazard ratio [HR], 0.53; 95% confidence interval [CI]: 0.31–0.90, P=0.02) and 2.52% for lower-dose edoxaban (HR, 0.98; 95% CI: 0.63–1.54, P=0.93). Compared with warfarin (4.80%), major bleeding was significantly reduced for the higher-dose (2.86%; HR, 0.61; 95% CI: 0.41–0.89, P=0.011) and lower-dose regimens (1.59%; HR, 0.34; 95% CI: 0.21–0.54, P<0.001).Conclusions:Once-daily edoxaban provided similar efficacy to warfarin while reducing major bleeding risk in the East Asian population. (Circ J 2016; 80: 860–869)

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Background:The aim of this study was to identify the predictors of silent cerebral ischemic lesions (SCIL) after catheter ablation of atrial fibrillation (AF) and to determine whether SCIL develop into cerebral infarcts in patients with 5 types of oral anticoagulants (OAC).Methods and Results:We retrospectively studied 286 consecutive patients (median, 67 years; 208 male; paroxysmal/persistent/long-standing persistent AF [LSP-AF], 147/90/49) who received periprocedural OAC and underwent MRI after the procedure. Warfarin (n=46) was continued, while dabigatran (n=47), rivaroxaban (n=89), apixaban (n=87), and edoxaban (n=17) were discontinued on the day of the procedure. I.v. heparin was infused to maintain an activated clotting time of 300–350 s during the procedure. Fifty-eight SCIL in 40 patients (14.0%) were identified on diffusion-weighted MRI. On multivariate logistic analysis, LSP-AF and dabigatran use were significant positive predictors of SCIL (OR, 2.912 and 2.287; P=0.006 and 0.042, respectively). Among 34 patients with 49 SCIL undergoing follow-up MRI, 45 (91.8%) of the lesions disappeared and 4 lesions developed into chronic cerebral infarcts. The SCIL with development into infarcts had a larger lesion diameter than those without (median, 6.55 mm vs. 4.2 mm; P=0.002).Conclusions:LSP-AF and dabigatran use were independent risk factors for post-ablation SCIL in patients with uninterrupted warfarin and interrupted non-vitamin K antagonist OAC, but the majority of SCIL disappeared. (Circ J 2016; 80: 870–877)

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Background:To reduce myocardial damage caused by implantable cardioverter defibrillator (ICD) shock, the left axilla was studied as an alternative pulse generator implantation site, and compared with the traditional implantation site, the left anterior chest.Methods and Results:Computer simulation was used to study the defibrillation conduction pattern and estimate the simulated defibrillation threshold (DFT) and myocardial damage when pulse generators were placed in the left axilla and left anterior chest, respectively; pulse generators were also newly implanted in the left axilla (n=30) and anterior chest (n=40) to compare the corresponding DFT. On simulation, when ICD generators were implanted in the left axilla, compared with the left anterior chest, the whole heart may be defibrillated with a lower defibrillation energy (left axilla 6.4 J vs. left anterior chest 12.0 J) and thus the proportion of cardiac myocardial damage may be reduced (2.1 vs. 4.2%). Clinically, ventricular fibrillation was successfully terminated with a defibrillation output ≤5 J in 86.7% (26/30) of the left axillary group, and in 27.5% (11/40) of the left anterior group (P<0.001).Conclusions:Clinically and theoretically, the left axilla was shown to be an improved ICD implantation site that may reduce DFT and lessen myocardial damage due to shock. Lower DFT also facilitates less myocardial damage, as a result of the lower shock required. (Circ J 2016; 80: 878–886)

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Background:The clinical efficacy of catheter ablation (CA) for paroxysmal atrial fibrillation (PAF) in patients with sick sinus syndrome (SSS) and the mechanism and predictors of recurrence are not yet completely elucidated.Methods and Results:Of 963 consecutive patients who underwent PAF ablation during the study period, a total of 108 patients with SSS (SSS group) and 108 matched controls without SSS (non-SSS group) were followed up. During the follow-up period (mean, 32.8±17.5 months), the SSS group had significantly higher AF recurrence rate since the last procedure than the non-SSS group (26.9% vs. 12.0%; P=0.02). The SSS group had significantly higher prevalence of non-pulmonary vein (non-PV) foci than the non-SSS group (25.9% vs. 13.9%; P=0.027). On multivariate analysis congestive heart failure (HR, 13.7; 95% CI: 1.57–119; P=0.02) and non-PV foci (HR, 5.75; 95% CI: 1.69–19.6; P=0.005) were independent predictors of recurrence following CA in the SSS group. In the SSS group, 88 patients had bradycardia-tachycardia syndrome without prior permanent pacemaker implantation. Of these, 6 required pacemaker implantation because of AF and sinus pause recurrence.Conclusions:Patients with SSS are at higher risk of AF recurrence after CA. Non-PV foci are associated with AF recurrence following PAF with SSS. (Circ J 2016; 80: 887–894)

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Background:The role of culprit plaque and related atherothrombotic components on incomplete stent apposition (ISA) occurrence after primary percutaneous coronary intervention (p-PCI) is unknown.Methods and Results:ST-segment elevation myocardial infarction (STEMI) patients undergoing p-PCI with an everolimus-eluting stent were prospectively investigated with optical coherence tomography (OCT) of the infarct-related artery before, after stenting and at 9 months. OCT data, aspirated thrombus and serum inflammatory biomarkers were analyzed. 114 patients with 114 lesions were evaluated. Acute ISA occurred in 82 lesions (71.9%), preferentially in larger vessels with a median area of 0.2 mm². The presence of thrombus before stent implantation (odds ratio (OR) 5.5, 95% confidence interval (CI) [1.1–26.9], P=0.04) and the lipid content in the target segment (OR 1.3, 95% CI [1.0–1.5], P=0.04) independently predicted acute ISA. At 9-month follow-up, ISA persisted in 46 lesions (56.1%). The volume of acute ISA significantly predicted persistent ISA (OR 1.3, 95% CI [1.1–1.5], P=0.01). Late-acquired ISA occurred in 39 lesions (34.2%) with a median area of 0.3 mm². Red/mixed thrombus before stent implantation (OR 3.7, 95% CI [1.0–13.3], P=0.05) and length of the underlying ruptured plaque (OR 1.7, 95% CI [1.1–2.8] P=0.02) were independently associated with late-acquired ISA.Conclusions:In STEMI patients, culprit plaque and atherothrombotic components of the infarct-related artery significantly contribute to the onset of acute and late ISA. ISA persistence at follow-up depends on the initial volume of acute ISA. (Circ J 2016; 80: 895–905)

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Background:The Cobalt-Chromium Everolimus-Eluting Stent (CoCr-EES) Post-marketing Surveillance (PMS) is a prospective multicenter registry designed to evaluate the safety and efficacy of XIENCE V/PROMUS everolimus-eluting stents in routine clinical practice at 47 centers representative of the clinical environment in Japan.Methods and Results:We enrolled 2,010 consecutive patients (2,649 lesions) who underwent PCI using CoCr-EES. Clinical outcomes were evaluated for up to 3 years. Clinical follow-up was available in 1,930 patients (96%) at 3 years. Major adverse cardiovascular events (MACE) occurred in 6.8% of patients, including cardiac death (1.7%), myocardial infarction (1.5%), and clinically driven target lesion revascularization (CD-TLR, 4.2%). Late CD-TLR rate was 0.8% from 1 to 2 years, and 0.5% from 2 to 3 years. Definite or probable stent thrombosis occurred in 7 patients (0.3%) up to 1 year. There was no very late definite or probable stent thrombosis from 1 to 3 years. Significant independent predictors for MACE were hemodialysis, prior coronary intervention, triple-vessel coronary artery disease, and age >70 years.Conclusions:Three-year clinical outcomes from the CoCr-EES PMS demonstrated a low incidence of clinical events. There was no major concern about very late stent thrombosis or late catch-up phenomenon in patients treated with EES in routine clinical practice in Japan. (Circ J 2016; 80: 906–912)

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Background:There are limited studies regarding the prognostic value of coagulation abnormalities in heart failure patients. The clinical significance of prothrombin time international normalized ratio (INR), a widely accepted marker assessing coagulation abnormalities, in acute decompensated heart failure (ADHF) remains unclear.Methods and Results:Among 561 consecutive patients admitted for ADHF, INR was assessed in 294 patients without prior anticoagulation therapy, acute coronary syndrome, liver disease, or overt disseminated intravascular coagulation. Increased INR on admission was positively associated with increased levels of thrombin-antithrombin complex, C-reactive protein, total bilirubin, γ-glutamyl transpeptidase, inferior vena cava diameter, tricuspid regurgitation severity, markers of neurohormonal activation, and also negatively associated with decreased albumin, cholinesterase, and total cholesterol. In contrast, there was no significant association with left ventricular ejection fraction, serum sodium or blood urea nitrogen. Multivariate analysis showed that increased INR was independently associated with increased all-cause mortality (hazard ratio 1.89 per 0.1 increase, 95% confidence interval 1.14–3.13, P=0.013) during the median follow up of 284 days. Increased INR also had a higher prognostic value compared to risk score models including the Model for End-Stage Liver Disease (MELD) score or the MELD excluding INR (MELD-XI) score.Conclusions:Increased INR is an independent predictor of all-cause mortality in ADHF patients without anticoagulation, reflecting coagulation abnormalities and hepatic insufficiency, possibly through systemic inflammation, neurohormonal activation and venous congestion. (Circ J 2016; 80: 913–923)

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Background:Data on the prognostic value of the shock index in patients with ST-elevation myocardial infarction (STEMI) are scarce. Furthermore, the relationship of the shock index with myocardial damage is unknown. The aim of this study was to evaluate the association of the shock index with markers of myocardial damage and clinical outcome in patients with STEMI.Methods and Results:This multicenter study analyzed 791 patients. Patients were categorized in 2 groups according to the admission shock index (optimized cut-off=0.62). Infarct severity was determined by cardiac magnetic resonance (CMR) imaging. Patients with cardiogenic shock that were unable to undergo CMR acquisition were excluded. Major adverse cardiac events (MACE) were defined as a composite of death, reinfarction and congestive heart failure within 12 months. Patients with elevated admission shock index (n=321 [40.6%]) had a significantly larger area-at-risk (37.6 [27.8–50.4] % of left ventricular volume [LV] vs. 34.3 [24.5–46.0] % LV, P=0.02), larger infarct size (19.5 [10.7–28.0] % LV vs. 14.9 [7.7–22.3] % LV, P<0.001), lower myocardial salvage index (46.2 [27.9–64.5] vs. 53.5 [36.5–75.2], P<0.001), and a larger extent of microvascular obstruction (0.3 [0.0–2.2] % LV vs. 0.0 [0.0–1.4] % LV, P=0.01). An elevated shock index was associated with reduced MACE-free survival (P<0.001). Furthermore, the admission shock index was identified as an independent predictor of MACE (hazard ratio=2.92 [1.24–4.22], P<0.01).Conclusions:STEMI patients with an elevated admission shock index had more pronounced myocardial and microvascular damage. Moreover, the shock index was independently associated with MACE at 12 months. (Circ J 2016; 80: 924–930)

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Background:Co-existence of vulnerable plaque and pro-thrombotic state may provoke acute coronary events. It was hypothesized that elevated serum levels of fibrin and fibrinogen degradation products (FDP) are associated with larger total plaque and necrotic core (NC) areas.Methods and Results:Seventy-five patients presenting with stable anginal symptoms (69%) or stabilized acute coronary syndrome (ACS; 31%), and found to have non-obstructive coronary artery disease (CAD) with a fractional flow reserve >0.8, were studied. Invasive virtual histology intravascular ultrasound (VH-IVUS) was performed in 68 LAD arteries, 6 circumflex arteries, and 1 right coronary artery. Serum FDP levels were measured using ELISA technique. Plaque volumetrics and composition were assessed in each VH-IVUS frame and averaged. The median age of patients was 56 (47–63) years; 52% were men and 23% had diabetes. The average length of coronary artery studied was 62 mm. After adjustment for systemic risk factors, medications, CRP levels and ACS, male gender (P<0.001) and serum FDP levels (P=0.02) were independent predictors of a larger NC area. Older age (P<0.001), male gender (P<0.0001) and increased serum FDP level (P=0.03) were associated with a larger plaque area.Conclusions:In patients with CAD, a higher serum level of FDP is independently associated with larger plaques and greater plaque NC. (Circ J 2016; 80: 931–937)

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Background:Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited disorder; mutations in at least 20 genes have been associated. Brugada syndrome (BrS) is an autosomal dominant inherited disorder caused by mutations mainly in theSCN5Agene. A new clinical entity that consists of HCM, typical electrical instability of BrS and sudden death (SD), is described.Methods and Results:The family was constituted by 7 members, 4 of who presented clinical features of HCM and electrical instability of BrS. The clinical presentation of proband was ventricular fibrillation. All members were clinically evaluated by physical examination, 12-lead electrocardiography, 2-dimensional echocardiography, stress test, electrocardiogram Holter, flecainide test, and electrophysiological study. An integrated linkage analysis and next generation sequencing (NGS) approach was used to identify the causative mutation. Linkage with the α-tropomyosin (TPM1) gene on chromosome 15q22 was identified. The NGS study identified a missense mutation within theTPM1gene (c.574G>A; p.E192K), exactly located in a binding domain with polycystin-2 protein. No other pathogenic mutations were identified.Conclusions:This is the first report of an association between HCM and BrS, and the first to use a combined approach of linkage and NGS to identify a causative mutation in SD. The present study expands the clinical spectrum of disorders associated with theTPM1gene and may be useful to report novel mechanisms of electrical instability in HCM and BrS. (Circ J 2016; 80: 938–949)

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Background:In addition to the presence of late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR), the extent of LGE is considered clinically important in hypertrophic cardiomyopathy (HCM). We evaluated the extent of LGE on CMR in a large series of Japanese HCM patients.Methods and Results:CMR was performed in 317 HCM patients (147 male). The extent of LGE was scored as the sum of LGE-positive segments in a left ventricle (LV) 17-segment model. LGE was present in 246 patients (77.6%). LGE was detected in 3.5±3.1 segments on average. When the patients were divided according to maximum wall thickness (mild, <20 mm; moderate, 20–29 mm; severe, ≥30 mm), median LGE score increased as wall thickness increased (mild, 2 vs. moderate, 4 vs. severe, 5; P=0.000). When the patients were divided according to ejection fraction (EF) (reduced, <50%; low-normal, 50–65%; normal, >65%), median LGE score increased as EF decreased (reduced, 7 vs. low-normal, 4 vs. normal, 2; P=0.000). On multivariate analysis, reduced EF (OR, 0.947, P=0.015), pressure gradient <30 mmHg (OR, 0.359, P=0.000) and increased maximum wall thickness (OR, 1.236, P=0.000) were independent factors associated with extensive LGE.Conclusions:Progression of LGE was related to increased wall thickness, decreased contractility, and reduced intraventricular pressure gradient. (Circ J 2016; 80: 950–957)

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Background:Small-for-gestational-age (SGA) children have increased cardiovascular risk, but the mediating factors are poorly understood. We hypothesized that birth size could affect the cardiovascular system since childhood in the absence of other risk factors. We investigated endothelial and myocardial function in SGA children with regular catch-up growth.Methods and Results:Biochemical markers, blood pressure, flow-mediated vasodilation (FMD), common carotid intima-media thickness (cIMT), anteroposterior diameter of the infrarenal abdominal aorta (APAO) and echocardiographic parameters of left and right ventricular (LV and RV) function were studied in 27 SGA and 25 appropriate-for-gestational-age (AGA) subjects. SGA subjects had a higher homeostasis model assessment index than controls (2.61±1.27 vs. 1.56±0.40, P=0.01), higher cIMT (0.51±0.04 mm vs. 0.45±0.07 mm, P=0.007) and APAO (1.31±1.35 cm vs. 1.30±0.16 cm, P=0.005), and lower FMD (10.11±4.17% vs. 12.34±4.28, P=0.04) than controls. On echocardiography SGA had higher Tei index both at LV and RV than controls (P=0.001). Reduced RV systolic function was also observed in SGA subjects.Conclusions:SGA subjects had vascular morphological and function abnormalities compared with AGA, which increase their cardiovascular risk profile. Furthermore, a subtle cardiac alteration in both RV and LV functions was seen in SGA patients compared with AGA. (Circ J 2016; 80: 958–963)

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Background: Although common femoral artery endarterectomy (CFE) is the standard treatment for occlusive disease of the common femoral artery (CFA), several studies have noted encouraging results for endovascular therapy in this anatomical area.Methods and Results: A retrospective multi-center study of 118 consecutive limbs from 111 symptomatic patients undergoing CFE between April 1998 and December 2014 was performed. Seventy-five CFE were performed on limbs for intermittent claudication and 43 CFE were performed for critical limb ischemia (CLI). The prevalence of perioperative complications was higher in patients with CLI than in the claudication patients. The technical success rate was 99% in all cases. The 1- and 5-year primary patency rates were 100% and 100% for claudication and 95% and 95% for CLI, respectively. The assisted-primary patency rates were 100% at both time points in both groups. Freedom from major amputation at 1 and 5 years was 100% and 100% in the claudication patients and 93% and 82% in the CLI patients, respectively. The 1- and 5-year overall survival rates were 97% and 89% in the claudication patients and 69% and 33% in the CLI patients, respectively.Conclusions: CFE is a safe, effective and durable procedure for occlusive disease of the CFA. This procedure should remain the standard treatment for this anatomical region. (Circ J 2016; 80: 964–969)

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Background:The postoperative changes in the coagulation-fibrinolysis system and the association between the system and postoperative course of patients with chronic thromboembolic pulmonary hypertension (CTEPH) who have undergone pulmonary endarterectomy (PEA) remain unclear.Methods and Results:Between 1986 and 2013, 117 patients (55.1±11.2 years, preoperative mean pulmonary arterial pressure 46.5±10.5 mmHg) underwent PEA, and 15 patients died during the perioperative period. We studied the association between the preoperative coagulation-fibrinolysis markers and surgical outcomes of all patients, and the long-term outcomes of the 102 survivors from the date of PEA. We also investigated the postoperative changes in coagulation-fibrinolysis markers and their association with residual pulmonary hypertension (PH) in 20 consecutive patients. Only an elevated factor VIII level was associated with perioperative death. Thrombomodulin and plasminogen values were significantly increased after PEA. Univariate logistic regression analysis revealed that D-dimer positivity at follow-up was a risk factor for residual PH. Patients with both an elevated fibrinogen level (≥291 mg/dl [median]) and decreased plasminogen activity (<100% [median]) had significantly worse disease-specific survival than the other patients (5-year disease-specific survival: 84.0% vs. 100%, respectively; P=0.0041 [log-rank test]).Conclusions:Preoperatively high fibrinogen and low plasminogen values in patients with CTEPH are associated with poor long-term postoperative outcome. PEA benefited not only the pulmonary hemodynamics but also the coagulation-fibrinolysis system of patients. (Circ J 2016; 80: 970–979)

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Background:Pulmonary arterial hypertension with systemic dysfunctions, including metabolic disorders and renal dysfunction, has a poor prognosis. However, it remains to be elucidated whether chronic thromboembolic pulmonary hypertension (CTEPH) is also associated with systemic dysfunctions, and if so, whether balloon pulmonary angioplasty (BPA) improves them.Methods and Results:Fifty-five consecutive patients who underwent BPA from March 2012 to December 2014 for systemic dysfunctions, including glycemic control, lipid profiles, renal and vascular function, and nutritional status were examined. The analyses were performed before and after BPA (mean, 3.5 sessions/patient) and changes in hemodynamic parameters were compared. The average follow-up period was 474±245 days. Baseline prevalence of hypertension, diabetes mellitus, dyslipidemia and advanced chronic kidney disease was 58, 7, 33 and 36%, respectively. BPA caused marked hemodynamic improvements in the CTEPH patients. Importantly, BPA also significantly improved dysglycemia (fasting blood sugar, hemoglobin A1c and homeostatic assessment model of insulin resistance), renal (creatinine and estimated glomerular filtration rate) and vascular (cardio-ankle vascular index) functions and nutritional status (albumin, cholesterols, and body mass index). Importantly, there were positive correlations between the degrees of the hemodynamic improvements and those of other improvements.Conclusions:These results indicate that BPA may exert multiple beneficial effects in CTEPH patients, not only in terms of hemodynamics but also in other systemic functions, with positive correlations among them. (Circ J 2016; 80: 980–988)

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Background:The expression of vasopressin type 2 receptor (V2R) in the lung, and the long-term effects of tolvaptan, a selective V2R antagonist, on pulmonary circulation and right ventricular (RV) remodeling in a pulmonary arterial hypertension (PAH) rat model were evaluated.Methods and Results:Six-week-old male Sprague-Dawley rats were injected subcutaneously with 20 mg/kg of SU5416 and were exposed to hypoxia for 3 weeks followed by re-exposure to normoxia for 7 weeks. These rats showed signs of RV failure and upregulation of V2R and cAMP in the lung tissue at 10 weeks after SU5416 injection. They were then treated with either 0.05% tolvaptan in diet (SUHx+Tolv) or normal diet (SUHx) during 5–10 weeks of SU5416 injection. Normal control rats (Cont) were also used for comparison. SUHx+Tolv had significantly higher pulmonary arterial pressure, more progressive pulmonary arterial remodeling, and more severe myocyte hypertrophy and interstitial myocardial fibrosis in the right ventricle compared with SUHx despite achieving successful preload reduction.Conclusions:Chronic vasopressin V2R antagonism may contribute to the worsening of PAH and the development of RV remodeling. (Circ J 2016; 80: 989–997)

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Background:Although stem cells have been regarded as a promising therapeutic option, the marginal therapeutic effects of stem cells are limitations that must be overcome for the development of effective cell therapy. This study sought to identify the angio-vasculogenic properties of endothelial differentiated mesenchymal stem cells (MSCs) and to determine whether these cells are effective for vascular repair.Methods and Results:Adipose MSCs were cultured for 10 days under endothelial cell (EC) culture conditions. These endothelial cell differentiated adipose MSCs (EA) and undifferentiated adipose MSCs (UA) were characterized via angiogenesis and adhesion assays. These cells were transplanted into a hindlimb ischemia (HLI) model to determine therapeutic effects and their underlying mechanisms. EA displayed low adhesion and angiogenic properties in vitro compared with UA. When implanted into mouse HLI models, EA exhibited the decreased recovery of blood perfusion in limb ischemia than uncultured UA. Histology data showed that injected EA exhibited lower retention, angiogenic cytokine levels, and neovascularization in vivo than did UA. Short-term differentiated EA display less cell engraftment and angio-vasculogenic potential, and are less effective for peripheral vascular repair than UA.Conclusions:EC differentiation of MSCs may not present an effective strategy for the promotion of therapeutic neovascularization. (Circ J 2016; 80: 998–1007)

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Background:There is a paucity of studies on whether early referral (ER) to nephrologist could reduce cardiovascular mortality on dialysis, and the length of pre-dialysis nephrological care needed to reduce mortality on dialysis.Methods and Results:A total of 604 consecutive patients who started dialysis between 2001 and 2009 in Senshu region, Osaka, Japan were analyzed. Non-linear associations between mortality and pre-dialysis duration of nephrological care were assessed using restricted cubic spline function, and predictors for death analyzed on Cox modeling. A total of 31.6%, 18.2%, 11.3% and 6.1% of patients had >12, 24, 36 and 48 months of pre-dialysis care, respectively. A total of 258 patients (42.7%) were categorized as ER (≥6 months pre-dialysis duration). During the follow-up period (median, 31.1 months), 218 patients died (cardiovascular, n=70; infection, n=69). Although patients with late referral (LR) had a proxy of inappropriate pre-dialysis care compared with the ER group, Cox multivariate analysis failed to show a favorable association between ER and cardiovascular outcome. In contrast, a deleterious effect of LR on overall survival was observed but was limited only to the first 12 months of dialysis (HR, 1.957; 95% CI: 1.104–3.469; P=0.021), but not observed thereafter.Conclusions:Current pre-dialysis nephrological care may reduce short-term mortality but may not improve cardiovascular mortality after dialysis initiation. (Circ J 2016; 80: 1008–1016)

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Background:Acute kidney injury (AKI) is associated with morality and repeated hospitalization, and is frequently encountered in patients with acute decompensated heart failure (ADHF). However, few effective tools exist for early AKI identification and risk stratification.Methods and Results:This was a prospective observational study conducted in the coronary care unit (CCU) of a tertiary care university hospital. Patients with a diagnosis of ADHF and who were using diuretics were enrolled.Samples collected between December 2013 and February 2015 were tested for serum cystatin C (Cys-C), urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (KIM-1). Demographic, clinical, and laboratory data were evaluated. A total of 103 adult patients with a mean age of 68 years were investigated. AKI was diagnosed in 49 patients (47.6%). For predicting intrinsic AKI on the first day of CCU admission, a combination of Cys-C and urine KIM-1 yielded an excellent area under the receiver operating characteristic curve of 0.828, a sensitivity of 71.0%, and specificity of 43.0%, for an overall accuracy of 78%.Conclusions:In this study, we found that combinations of the biomarker (Cys-C and KIM-1) were an effective clinical model for predicting AKI in patients with ADHF. The biomarker was also useful for differentiating subclinical AKI in patients with ADHF. (Circ J 2016; 80: 1017–1023)

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Background:Previous work has demonstrated that the volume-regulated chloride channel is activated during foam cell formation, and inhibition of chloride movement prevents intracellular lipid accumulation. However, the mechanism explaining how chloride movement promotes foam cell formation is not clear.Methods and Results:Foam cell formation was determined by Oil Red O staining. Western blotting and co-immunoprecipitation were used to examine protein expression and protein-protein interaction. [Cl⁻]_iwas measured using 6-methoxy-N-ethylquinolinium iodide dye. The results showed that [Cl⁻]_iwas decreased in monocytes/macrophages from patients with hypercholesterolemia and from apoE^−/−mice fed with a high-fat diet. Lowering [Cl⁻]_iupregulated scavenger receptor A (SR-A) expression, increased the binding and uptake of oxLDL, enhanced pro-inflammatory cytokine production and subsequently accelerated foam cell formation in macrophages from humans and mice. In addition, low Cl⁻solution stimulated the activation of JNK and p38 mitogen-activated protein kinases. Inhibition of JNK and p38 blocked Cl⁻reduced medium-induced SR-A expression and lipid accumulation. In contrast, reduction of [Cl⁻]_ipromoted the interaction of SR-A with caveolin-1, thus facilitating caveolin-1-dependent SR-A endocytosis. Moreover, disruption of caveolae attenuated SR-A internalization, JNK and p38 activation, and ultimately prevented SR-A expression and foam cell formation stimulated by low Cl⁻medium.Conclusions:This data provide strong evidence that reduction of [Cl⁻]_iis a critical contributor to intracellular lipid accumulation, suggesting that modulation of [Cl⁻]_iis a novel avenue to prevent foam cell formation and atherosclerosis. (Circ J 2016; 80: 1024–1033)

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Background:The aim of this study was to assess the role of clinically available vascular function tests as predictors of cardiovascular events and decline in kidney function.Methods and Results:One hundred and fourteen patients who had at least 2 cardiovascular risk factors were recruited for vascular function assessment including ankle-brachial blood pressure index (ABI), brachial-ankle pulse wave velocity (baPWV), cardio-ankle vascular index (CAVI) and flow-mediated vasodilatation (%FMD). During a median period of 51 months, 35 patients reached the primary endpoint (29 cardiovascular events and 6 cardiac deaths), and 30 patients reached the secondary endpoint (decline in kidney function: defined as a 5% per year decline of estimated glomerular filtration rate). In sequential Cox models, a model on the basis of the Framingham risk score, hemoglobin, and high-sensitivity C-reactive protein (chi-squared, 16.6) was improved by the ABI (chi-squared: 21.5; P=0.047). The baPWV (hazard ratio: 1.42 per 1 SD increase; P=0.025) and the CAVI (hazard ratio: 1.52 per 1 SD increase; P=0.040) were associated with the secondary endpoint. The %FMD was only slightly associated with the primary and secondary endpoints.Conclusions:Both ABI and baPWV are significantly associated with future cardiovascular events in high-risk patients with cardiovascular disease. The predictive capabilities of these parameters are greater than that of other parameters in this cohort. (Circ J 2016; 80: 1034–1040)

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Background:Pulmonary valve replacement (PVR) is a common reoperation, typically required approximately 10 years following right ventricular outflow tract reconstruction and especially true in cases of tetralogy of Fallot. However, an improved prosthetic valve is required.Methods and Results:A fresh decellularized pulmonary allograft was used for PVR to correct pulmonary valve regurgitation in a 35-year-old man 33 years following tetralogy of Fallot repair. The postoperative course and short-term valve function were excellent. This is the first case of a decellularized pulmonary allograft in Japan.Conclusions:Fresh decellularized pulmonary allografts have the potential to become a new source of material for PVR in patients who have undergone right ventricular outflow tract reconstruction. (Circ J 2016; 80: 1041–1043)

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