Heart failure (HF) is the major cause of mortality worldwide. For more than a decade, cell-based therapies have been developed as treatment for heart disease as an alternative to current therapies. Trials and systematic reviews have assessed the safety and efficacy of cell therapies in a diverse number of participants and clinical settings. The present study collated and synthesized evidence from all systematic reviews related to cell-based therapies and HF. A total of 11 systematic reviews were identified through searches of electronic databases up to June 2014. We set out to answer 2 key questions on the efficacy of cell therapies in HF: (1) What is the overall effect of cell therapies on primary outcomes such as left ventricular ejection fraction (LVEF) and mortality? (2) How important is it to define the clinical setting and length of follow-up when assessing cell therapies and HF? There seems to be enough evidence to suggest that cell therapies have a moderate, long-lasting effect on LVEF, but the reduction on the risk of mortality observed by some systematic reviews needs to be confirmed in larger, statistically powered clinical trials. Additionally, and in order to strengthen conclusions, it is important to assess clinical evidence for defined clinical settings and to standardize the length of follow-up when comparing outcome data across several trials and systematic reviews. (Circ J 2015; 79: 229–236)

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Heart failure is a growing epidemic, with more patients living longer and suffering from this disease. There is a growing segment of patients who have persistent symptoms despite pharmacologic therapy. In an era when transplants are rare, the need for devices and interventions that can assist ventricular function is paramount. This review goes through the devices used in heart failure, including left ventricular reconstruction, aortic counterpulsation, short-term mechanical circulatory support, long-term mechanical circulatory support, and right heart interventions. (Circ J 2015; 79: 237–244)

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Cardiac fibroblasts play critical roles in maintaining normal cardiac function and in cardiac remodeling during pathological conditions such as myocardial infarction (MI). Adult cardiomyocytes (CMs) have little to no regenerative capacity; damaged CMs in the heart after MI are replaced by cardiac fibroblasts that become activated and transform into myofibroblasts, which preserves the structural integrity. Unfortunately, this process typically causes fibrosis and reduces cardiac function. Directly reprogramming adult cardiac fibroblasts into induced CM-like cells (iCMs) holds great promise for restoring heart function. Direct cardiac reprogramming also provides a new research model to investigate which transcription factors and microRNAs control the molecular network that guides cardiac cell fate. We review the approaches and characterization of in vitro and in vivo reprogrammed iCMs from different laboratories, and outline the future directions needed to translate this new approach into a practical therapy for damaged hearts. (Circ J 2015; 79: 245–254)

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Platelets initiate the formation of a thrombus at the site of an arterial injury, and the clotting cascade is activated as the thrombus matures. After coronary stent placement, dual antiplatelet therapy (DAPT) with aspirin and ticlopidine dramatically reduces the risk of stent thrombosis, compared with anticoagulation therapy, and has become the standard of care for prevention of stent thrombosis. Clopidogrel is a second-generation thienopyridine that eliminates the serious side effects of ticlopidine, and new P2Y₁₂receptor blockers have emerged to overcome the limitations of clopidogrel. Current guidelines recommend DAPT with aspirin and clopidogrel for 1 month after implantation of bare-metal stents, and for 6–12 months after implantation of drug-eluting stents (DES). In patients with acute coronary syndrome (ACS), DAPT administration for 12 months was shown to be superior to aspirin alone for the prevention of recurrent events. Treatment with aspirin and new P2Y₁₂receptor blockers has further reduced the rate of cardiovascular death, myocardial infarction or stroke after ACS compared with aspirin and clopidogrel. Nonetheless, long-term DAPT increases the risk of major bleeding, requiring a delicate balance between anti-ischemic benefit and bleeding risk. In summary, DAPT should be maintained for at least 6–12 months after implantation of DES, and for at least 12 months after ACS, unless contraindicated. (Circ J 2015; 79: 255–262)

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Bioresorbable vascular scaffolds (BVS) represent a breakthrough technology for percutaneous coronary intervention (PCI). In this context, because of the unique properties of bioresorbable devices, ST-segment elevation myocardial infarction (STEMI) may represent the ideal scenario for BVS implantation. Consistently, 57% of physicians declare they currently use BVS in this group of patients. However, continuous and growing evidence on the good performance of these devices has been actually shown only in small studies with short- and mid-term follow-up. For these reasons, we need data from sufficiently large observational studies, with long-term follow-up, to confirm that BVS can deliver the same results as 2nd-generation drug-eluting stents when using an appropriate implantation technique. In this review, we discuss the potential advantages of BVS implantation in STEMI patients, together with the most recent evidence from clinical studies, highlighting safety and procedural concerns. (Circ J 2015; 79: 263–270)

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Many cardiac disorders and their treatment are associated with an increased risk for ischemic or hemorrhagic stroke, so it is important for cardiologists to be aware of recent advances in the field of stroke prevention. Atrial fibrillation (AF) is the most common cardiac disorder associated with a substantial risk for ischemic stroke (IS). The availability of implantable cardiac monitoring devices has substantially increased the detection rate of occult AF after IS. The 4 new oral anticoagulants have advantages when compared with warfarin, the standard therapy in AF to prevent IS, demonstrating a reduced risk for IS or intracerebral hemorrhage. Patients with cardiomyopathy, cardiac valve replacement, recent myocardial infarction, larger aortic arch atheroma and patent foramen ovale all have some level of increased risk for IS. The best approach for IS prevention in these disorders remains unsettled and varying approaches are recommended. (Circ J 2015; 79: 271–277)

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MicroRNAs (miRNAs; miRs) are small non-protein-coding RNAs that negatively regulate gene expression. They bind to the 3’ UTR of specific mRNAs and either inhibit translation or promote mRNA degradation. There is emerging evidence linking miR-33a/b to lipid homoeostasis, targetingABCA1,SREBF1, etc and it would appear that they have acted as “thrifty genes” during evolution to maintain cholesterol levels both at the cellular and whole body level. As we are now living in a period of “satiation”, miR-33a/b no longer seem to be useful and could be potential therapeutic targets for lipid disorders and/or atherosclerosis. In this review, we describe the current understanding of the function of miR-33a/b in lipid homeostasis, focusing on the “thrifty” aspect. (Circ J 2015; 79: 278–284)

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Background:Risk stratification in patients with Brugada syndrome for primary prevention of sudden cardiac death is still an unsettled issue. A recent consensus statement suggested the indication of implantable cardioverter defibrillator (ICD) depending on the clinical risk factors present (spontaneous type 1 Brugada electrocardiogram (ECG) [Sp1], history of syncope [syncope], and ventricular fibrillation during programmed electrical stimulation [PES+]). The indication of ICD for the majority of patients, however, remains unclear.Methods and Results:A total of 218 consecutive patients (211 male; aged 46±13 years) with a type 1 Brugada ECG without a history of cardiac arrest who underwent evaluation for ICD including electrophysiological testing were examined retrospectively. During a mean follow-up period of 78 months, 26 patients (12%) developed arrhythmic events. On Kaplan-Meier analysis patients with each of Sp1, syncope, or PES+ suffered arrhythmic events more frequently (P=0.018, P<0.001, and P=0.003, respectively). On multivariate analysis Sp1 and syncope were independent predictors of arrhythmic events. When dividing patients according to the number of these 3 risk factors present, patients with 2 or 3 risk factors experienced arrhythmic events more frequently than those with 0 or 1 risk factor (23/93 vs. 3/125; P<0.001).Conclusions:Syncope, Sp1, and PES+ are important risk factors and the combination of these risks well stratify the risk of later arrhythmic events. (Circ J 2015; 79: 310–317)

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Background:The clinical value of T-wave variability (T-var) for ventricular arrhythmia (VA) risk prediction was evaluated.Methods and Results:Three 20-min Holter-ECG-based T-var measurements (I1 at baseline, I2 after 6.5±1.6 months and I3 after 13.1±2.0 months) were done in 121 patients. T-var was defined as the amplitude variability of the T-wave with the maximum of T-wave oscillation. The endpoint was a fast, potentially fatal VA (>240 beats/min). During follow-up (20±4 months) 20/121 patients (55% ischemic heart disease, 15% preserved left ventricular ejection fraction [LVEF]) had fast VA terminated by ICD or external shock. Although T-var did not differ between patients with vs. without fast VA at baseline (I1: 10.7±7.3 µV vs. 7.8±4.1 µV, P=0.170), patients with fast VA had higher T-var compared to those without fast VA at 2 subsequent measurements (I2: 14.0±6.5 µV vs. 8.2±3.6 µV, P=0.030; I3: 17.0±5.4 µV vs. 8.8±4.6 µV, P=0.004). The increase in T-var between I1 and I2 was higher in patients with fast VA (∆T-var=7.0±9.3 µV), as compared to patients without (∆T-var=0.4±4.3 µV). After adjustment for LVEF in a multiple logistic regression model, the odds ratio for developing fast VA was 1.1 (P=0.056) for each 1-µV increment in T-var at I1.Conclusions:T-var is elevated in patients with fast VA, and both elevation of T-var and increase in T-var may complement LVEF in VA risk stratification. (Circ J 2015; 79: 318–324)

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Background:Warfarin is widely used for prevention of thromboembolism in patients with valvular atrial fibrillation (AF), and an international normalized ratio (INR) of prothrombin time between 2.0 and 3.0 is recommended. Optimal intensity of anticoagulation with warfarin in Japanese patients with valvular AF, however, has not been clarified thoroughly as yet.Methods and Results:We evaluated the status of anti-thrombotic therapy and incidence rates of events in 410 patients with mitral stenosis and/or mechanical valve replacement (valvular AF) among 7,816 patients with AF followed in the J-RHYTHM Registry. Patients were divided into 5 groups based on INR (<1.6, 1.6–1.99, 2.0–2.59, 2.6–2.99, and ≥3.0) at the time of event or at the end of follow-up in order to determine the target INR for patients with valvular AF. Warfarin was prescribed in 407 (99.3%) of valvular AF patients. During a 2-year follow-up period, thromboembolism and major hemorrhage occurred in 12 (2.9%) and in 15 (3.7%) patients, respectively. Among patients receiving warfarin, 2-year incidence rates of thromboembolism were 10.3%, 1.6%, 0.6%, 3.0%, and 0.0% (P=0.003 for trend), and those of major hemorrhage were 1.5%, 1.6%, 3.2%, 6.1%, and 21.1% (P<0.001 for trend), respectively.Conclusions:INR between 1.6 and 2.6 could be optimal to prevent thromboembolism without increasing major hemorrhage in Japanese patients with valvular AF. INR 2.6–2.99 would also be effective, but is associated with a modestly increased risk of major hemorrhage. (Circ J 2015; 79: 325–330)

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Background:Despite the good safety of rivaroxaban, there is limited information on strategies for urgent reversal of its antihemostatic effects.Methods and Results:Alterations of hemostasis induced by rivaroxaban (230 ng/ml) were assessed by using several tests applied to steady and circulating human blood. Effects on thrombin generation (TG) and thromboelastometry (TEM) parameters were measured. Modifications in platelet adhesive, aggregating and procoagulant activities were evaluated in studies with circulating blood. The potential reversal of prothrombin complex concentrates (PCCs; 50 IU/kg), activated PCCs (aPCCs; 75 IU/kg), or recombinant factor VIIa (rFVIIa; 270 μg/kg) was evaluated. Impairment of TG parameters induced by rivaroxaban were corrected by the different concentrates (aPCC≥PCC>rFVIIa). Prolonged clotting times and reduced clot firmness caused by rivaroxaban on TEM tests were improved by different concentrates (rFVIIa≥aPCC>PCC). Rivaroxaban significantly reduced platelets and fibrin interactions with damaged vascular surfaces in perfusion studies. While alterations of platelet interactions were favourably counteracted by rFVIIa or aPCCs, reductions in fibrin formation were only partially restored by the different factor concentrates (rFVIIa>aPCC≥PCC).Conclusions:Rivaroxaban-induced alterations on coagulation parameters measured through assays performed under static conditions were easily reversed by the different concentrates. Studies under flow conditions revealed that these concentrates normalized the action of rivaroxaban on platelets, and significantly improved fibrin formation; although in the later case, levels were not restored to the pre-treatment value. (Circ J 2015; 79: 331–338)

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Background:Non-vitamin K antagonist oral anticoagulants (NOAC) have been developed as alternatives to warfarin. Until recently, the latter was the standard oral anticoagulant for patients with non-valvular atrial fibrillation (NVAF). The efficacy and safety of NOAC in Japanese patients with NVAF has been investigated in small trials or subgroups from global randomized control trials (RCT).Methods and Results:We conducted a systematic review and meta-analysis of RCT, to compare the efficacy and safety of NOAC to those of warfarin in Japanese patients with NVAF. Published research was systematically searched for RCT that compared NOAC to warfarin in Japanese patients with NVAF. Random-effects models were used to pool efficacy and safety data across RCT. Three studies, involving 1,940 patients, were identified. Patients randomized to NOAC had a decreased risk for stroke and systemic thromboembolism (relative risk [RR], 0.45; 95% CI: 0.24–0.85), with a non-significant trend for lower major bleeding (RR, 0.66; 95% CI: 0.29–1.47), intracranial bleeding (RR, 0.46; 95% CI: 0.18–1.16) and gastrointestinal bleeding (RR, 0.52; 95% CI: 0.25–1.08).Conclusions:NOAC are more efficacious than warfarin for the prevention of stroke and systemic embolism in Japanese patients with NVAF. The present findings offer clinicians a more comprehensive picture of NOAC as a therapeutic option to reduce the risk of stroke in Japanese NVAF patients. (Circ J 2015; 79: 339–345)

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Background:Deep sedation or general anesthesia is generally used during atrial fibrillation (AF) ablation. The aim of this study was to report the safety and feasibility of minimal sedation during AF ablation.Methods and Results:One thousand and fifty-two AF ablation procedures in 819 patients (62±11 years, 621 men, 506 paroxysmal) were included. Boluses of intravenous hydroxyzine pamoate and pentazocine were administered, with a maximal dose of 100 mg of hydroxyzine and 60 mg of pentazocine in response to pain. If the pain was intolerable or patients requested deeper sedation, moderate sedation using dexmedetomidine or propofol was introduced. Among 819 consecutive first procedures, the procedure was completed under minimal sedation in 795 (97.1%) patients without inotropic drugs or respiratory support, whereas in 20 (2.4%) patients, anesthesia was switched to moderate sedation due to pain. Patients requiring a switch to moderate sedation were significantly younger than those without (53.6±2.3 vs. 62.6±10.4, P<0.01). No procedures were abandoned due to adverse effects of sedation. Significant intra-procedural blood pressure decreases requiring inotropic drugs were not observed in any patients. Among 233 patients who underwent repeat procedures, 6 (2.6%) requested moderate sedation before the procedure. The mean procedure time was 151±54 min. Cardiac tamponade, unrelated to sedation, was observed in 7 (0.66%) procedures.Conclusions:Minimal sedation might be acceptable anesthesia in the vast majority of AF ablation procedures performed in electrophysiological laboratories. (Circ J 2015; 79: 346–350)

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Background:Atherosclerotic renal artery stenosis (ARAS) causes renovascular hypertension (HTN) and impairs renal function, leading to chronic kidney disease (CKD). The J-RAS study was a prospective, multicenter study to assess the clinical outcome of renal artery stenting for up to 1 year in Japanese patients with ARAS.Methods and Results:One hundred and forty-nine patients were enrolled between November 2010 and January 2013. The patients were classified into an HTN (n=121) group and a CKD (n=108) group in the primary analysis. The primary efficacy endpoints were change in blood pressure for the HTN group and change in estimated glomerular filtration rate (eGFR) for the CKD group at 1 months. The primary safety endpoint was freedom from major cardiovascular or renal events at 12 months. In the HTN group, the mean systolic blood pressure (SBP) significantly decreased from 161.6±21 mmHg at baseline to 137.0±21 mmHg (P<0.0001). In the CKD group, there was no significant difference in eGFR from 40.7±10 ml·min⁻¹·1.73 m⁻²at baseline to 40.8±13 ml·min⁻¹·1.73 m⁻²(P=0.32). The primary safety endpoint was 89.4% at 12 months.Conclusions:In the J-RAS trial, significant SBP reduction was seen in the HTN group, and stabilization of renal function in the CKD group. Renal artery stenting for ARAS is safe and effective in Japanese patients. (Circ J 2015; 79: 351–359)

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Background:Patients at high bleeding risk would benefit from a shorter dual antiplatelet therapy after PCI. Compared to first-generation devices, the design of newer generation drug-eluting stents may facilitate more rapid anatomical and functional healing of stented vessel based on thinner stent platforms, biodegradable/biocompatible polymers and rapid drug elution.Methods and Results:Forty-four non-diabetic patients with acute coronary syndrome (ACS) and culprit lesion in the LAD were randomized to receive either biodegradable polymer sirolimus-eluting stent (BP-SES) or durable polymer zotarolimus-eluting stent (DP-ZES). Neointimal strut coverage was examined using optical coherence tomography, and vasodilator response on invasive thermodilution-derived coronary flow reserve (CFR) at 3-month follow-up. The primary endpoints were percent uncovered struts and CFR. A total of 425 cross-sections (4,897 struts) were analyzed in the BP-SES group, and 425 cross-sections (5,467 struts) in the DP-ZES group. The percent uncovered struts was lower in the BP-SES group compared with the DP-ZES group, both at strut level (3.9% vs. 8.9%, respectively, P<0.001), and stent level (3.9±3.2% vs. 8.9±6.9%, respectively, P=0.019). No significant difference was found between the 2 groups regarding CFR (3.0±1.3 vs. 3.2±1.0, respectively, P>0.05).Conclusions:In non-diabetic patients with ACS, BP-SES provided slightly better stent strut coverage at 3 months compared with DP-ZES, but neither stent was fully covered. No difference in vasodilator response was seen. (Circ J 2015; 79: 360–367)

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Background:Induction therapy with interleukin-2 receptor antagonists has been established as an effective immunosuppressive strategy in the management of heart transplant (HTx) recipients. We compared outcomes following HTx in patients receiving basiliximab, daclizumab, or no induction therapy.Methods and Results:We investigated post-transplant prognosis of patients receiving basiliximab (n=67), daclizumab (n=98) or no induction therapy (n=70). Patients treated with daclizumab (50.3±14.7 years) were younger than those receiving basiliximab (55.8±11.2 years) or no induction therapy (54.9±14.1 years; both P<0.05). Patients receiving either induction therapy showed better survival 1 year after HTx (95%) than those without induction therapy (82%; P<0.001). Survival was similar between patients receiving basiliximab and daclizumab. The incidence of acute cellular or antibody-mediated rejections did not differ among the groups. The main reason that patients did not receive induction therapy was ongoing infection (65.7%), which was more common in patients on ventricular assist device (VAD) support than those without VAD (76.1% vs. 45.8%; P=0.004). The VAD-related infection rate in the entire study cohort was 29.7% (35/118 VAD recipients).Conclusions:Survival following HTx was worse in patients not receiving induction therapy. No differences were noted in survival or the incidence of rejection between the daclizumab- and basiliximab-treated groups. Induction therapy was less used in patients with infection, which was related to prior VAD support. (Circ J 2015; 79: 368–374)

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Background:Patients with severe aortic stenosis (AS) are often found to have asymmetric septal hypertrophy (ASH). With low sensitivity of echocardiography for detecting dynamic left ventricular outflow tract (LVOT) obstruction in severe AS, we adopted a routine intraoperative inspection of LVOT strategy for aortic valve replacement (AVR), and performed concomitant septal myectomy (CSM) as necessary. We sought to (1) evaluate surgical outcomes of CSM, (2) suggest preoperative echocardiographic parameters that correlate with findings of ASH, and (3) determine the predictors of CSM.Methods and Results:A single surgeon performed AVR for moderate-to-severe AS in 301 patients from 2007 to 2012. CSM was performed in 35 (11.6%) patients, resulting in AVR vs. AVR+CSM groups. Echocardiographic parameters, including the ratio of LVOT to aortic annular diameter (LVOT/AA), were compared. Mortality rate was comparable between groups (P=0.37). There were no postoperative complications related to CSM. The AVR+CSM group had a smaller LVOT/AA ratio (P=0.0012). The predictor of CSM was implanted valve size ≤21 mm (odds ratio 3.2, confidence interval 1.54–6.65, P=0.002).Conclusions:CSM can be performed safely at the time of AVR. The preoperative echocardiographic LVOT/AA ratio may help in detecting ASH. As an implanted valve size ≤21 mm was the only risk factor for CSM, careful assessment of LVOT is important in patients with a small aortic annulus. (Circ J 2015; 79: 375–380)

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Background:The current status of primary prevention of sudden cardiac death (SCD) with implantable cardioverter defibrillator (ICD) in patients with heart failure with reduced ejection fraction remains to be fully elucidated in Japan.Methods and Results:In the chronic heart failure (CHF) cohort study, the CHART-2 Study, we enrolled 2,778 consecutive patients with NYHA class II–III. According to the Japanese Circulation Society guideline of prophylactic ICD, we divided them into 3 groups: group A, class I indication; B, class IIa; and C, no indication. During the (median) 3.2-year follow-up, 79 fatal arrhythmic events (FAE), defined as composite of sudden cardiac/arrhythmic death, ventricular tachycardia/fibrillation and appropriate ICD therapy, occurred. In the groups A, B and C, the prevalence of FAE was 16.1%, 8.9% and 1.9%, respectively; the use of prophylactic ICD among those with FAE, however, was only 44%, 9% and 6%, respectively. In the groups A and B combined, chronic atrial fibrillation (cAF) and left ventricular end-diastolic dimension (LVDd) ≥65 mm were independent predictors of FAE, and, when combined, their prognostic impact was highly significant (hazard ratio, 7.01; P<0.001).Conclusions:Primary prevention of SCD with ICD in CHF patients is validated but is still underused in Japan, and the combination of cAF and LVDd ≥65 mm may be a useful indication of prophylactic ICD implantation. (Circ J 2015; 79: 381–390)

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Background:The aim of the present study was to assess the efficacy of a non-invasive method, transient elastography (FibroScan), in measuring liver stiffness (LS), and whether LS can be used as a marker of cardiac – and hence perioperative – status.Methods and Results:Perioperative LS was prospectively measured using a FibroScan in 30 patients (21 male; 42.2±13.3 years old) who underwent left ventricular assist device (LVAD) implantation. LS was checked pre- and postoperatively, then analyzed in regard to perioperative status. Preoperative LS was 13.3±13.0 kPa (normal, <5.5 kPa), and was abnormal in 77% of patients. Four required bilateral VAD. LS in patients with bilateral VAD tended to be higher than in LVAD patients (25.1±22.7 vs. 11.5±10.5 kPa, P=0.051). No patient with LS ≤7.0 kPa required a right VAD. The incidence of major adverse events was lower in patients with LS ≤12.5 kPa (25% vs. 80%, P<0.05). There were also no mortalities among patients with LS ≤12.5 kPa.Conclusions:LS was correlated with preoperative severity in patients with severe heart failure and reflected liver congestion, and may be useful to predict the requirement of right VAD, as well as postoperative complications in patients with LVAD implantation. This novel modality may be a useful non-invasive assessment method for management of severe heart failure. (Circ J 2015; 79: 391–397)

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Background:Cold hemodynamic profile assessed on physical examination predicts survival, although it has low specificity and low reproducibility. We herein propose a new cold profile definition (Cold Modified 2014), including renal and hepatic damage. The aim of the study was to evaluate the additional prognostic value of clinical and laboratory identification of hypoperfusion over hypotension in the setting of advanced acute heart failure (AHF).Methods and Results:After preliminary analysis on derivation cohort, we studied 223 consecutive NYHA III–IV patients admitted with AHF requiring intensive care. Cold Modified 2014 definition included non-invasive hemodynamic assessment, renal and hepatic injury. Primary endpoint was a composite of cardiac death, urgent heart transplantation and mechanical circulatory support at 6 months. In the validation cohort (age, 60.5±12.8 years; ejection fraction 25.6±8.2%, systolic blood pressure [SBP] 104.3±26.1 mmHg) 77 reached the composite endpoint. Among SBP, ADHERE model, cold profile at admission and INTERMACS profile at 48 h, cold profile had the best diagnostic accuracy. On multivariate analysis only cold profile and INTERMACS predicted events, while SBP <115 mmHg and high risk on ADHERE did not. Cold Modified 2014 was more accurate than the old definition. Net reclassification improvement for Cold Modified 2014 over the old definition was 25.8%.Conclusions:This prospective study demonstrated the additional prognostic role of hypoperfusion assessment over hypotension in patients with AHF. Cold Modified 2014 improved risk stratification in advanced AHF patients. (Circ J 2015; 79: 398–405)

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Background:Recently, a non-invasive method using computational fluid dynamics to calculate vessel-specific fractional flow reserve (FFR_CT) from routinely acquired coronary computed tomography angiography (CTA) was described. The Analysis of Coronary Blood Flow Using CT Angiography: Next Steps (NXT) trial, which was a prospective, multicenter trial including 254 patients with suspected coronary artery disease, noted high diagnostic performance of FFR_CTcompared with invasive FFR. The aim of this post-hoc analysis was to assess the diagnostic performance of non-invasive FFR_CTvs. standard stenosis quantification on coronary CTA in the Japanese subset of the NXT trial.Methods and Results:A total of 57 Japanese participants were included from Okayama University (n=36), Kyoto University (n=17), and Keio University (n=4) Hospitals. Per-patient diagnostic accuracy of FFR_CT(74%; 95% confidence interval [CI]: 60–85%) was higher than for coronary CTA (47%; 95% CI: 34–61%, P<0.001) arising from improved specificity (63% vs. 27%, P<0.001). FFR_CTcorrectly reclassified 53% of patients and 63% of vessels with coronary CTA false positives as true negatives. When patients with Agatston score >1,000 were excluded, per-patient accuracy of FFR_CTwas 83% with a high specificity of 76%, similar to the overall NXT trial findings.Conclusions:FFR_CThas high diagnostic performance compared with invasive FFR in the Japanese subset of patients in the NXT trial. (Circ J 2015; 79: 406–412)

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Background:Although numerous studies have reported altered plasma levels of various microRNAs (miRNAs) in patients with cardiovascular disease, there are no data on the relationship between plasma miRNAs and vulnerable coronary plaque. In this study, we investigated whether plasma miRNAs might be a sensitive marker of coronary plaque vulnerability.Methods and Results:Integrated backscatter intravascular ultrasound (IB-IVUS) was performed in 32 consecutive patients with angina pectoris who underwent percutaneous coronary intervention. Three-dimensional analysis of IB-IVUS was performed to determine the percentage of lipid volume (%LV) and fibrous volume (%FV). Circulating miRNAs were measured in EDTA-plasma simultaneously obtained from the aorta and the coronary sinus (CS). Muscle-enriched (miR-133a, miR-208a, miR-499), vascular-enriched (miR-92a, miR-100, miR-126, miR-127, miR-145), and myeloid cell-enriched miRNAs (miR-155, miR-223) were measured. Plasma miR-100 was higher in the CS than in the aorta, but there were no significant differences in the levels of other miRNAs between the aorta and CS. Plasma miR-100 in the aorta was positively correlated with %LV (r=0.48, P<0.01) and negatively correlated with %FV (r=–0.41, P<0.05). Importantly, transcoronary concentration gradient of circulating miR-100 was more strongly correlated with %LV (r=0.53, P<0.01) and %FV (r=–0.56, P<0.01).Conclusions:miR-100 might be released into the coronary circulation from vulnerable coronary plaques. This study provides insights into the role of miRNAs in coronary atherosclerotic disease. (Circ J 2015; 79: 413–418)

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Background:The relationship between outcome of radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) and the severity of left ventricular (LV) diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM) remains unknown.Methods and Results:Twenty-two HCM patients (12 female, aged 65±11 years) with paroxysmal (n=5; 23%) or persistent (n=17; 77%) AF were enrolled. LV diastolic function was evaluated according to the ratio of the mitral inflow early filling velocity to the velocity of the early medial mitral annular ascent (E/e’) measured on pulsed wave and tissue Doppler assessments in all patients. Pulmonary vein isolation was performed in all patients. A second procedure was performed in 3 patients. During a follow-up of 21±12 months, sinus rhythm was maintained in 13 of 22 patients (59%). E/e’ was significantly higher in the patients with AF recurrence than in those without (18±7 vs. 11±3; P<0.01). On Kaplan-Meier analysis the prevalence of AF recurrence was significantly higher in patients with E/e’ ≥15 (n=6) than in those with E/e’ <15 (n=16; P<0.01). On multivariate Cox regression analysis the only significant and independent predictor for AF recurrence was E/e’ (hazard ratio, 1.16; 95% confidence interval: 1.01–1.37, P=0.03).Conclusions:LV diastolic dysfunction evaluated using E/e’ was associated with difficulty of rhythm control after RFCA in patients with HCM and AF. (Circ J 2015; 79: 419–424)

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Background:Dysfunction of the morphologic systemic right ventricle (RV) is a sequela in long-term survivors with transposition of the great arteries (TGA) after atrial switch operation (AtSO). Impairment of myocardial blood flow (MBF) and coronary flow reserve (CFR) are hypothesized as predisposing factors.Methods and Results:The study group comprised 20 patients after AtSO (22.7±5.03 years) and 15 individuals with congenitally corrected transposition (ccTGA) (30.6±19.4 years). MBF was quantified by positron emission tomography; controls for coronary flow were 11 healthy volunteers (26.2±5.1 years). Exercise capacity, ventricular mass, function and end-diastolic volume assessed by coronary magnetic resonance (CMR), hemodynamic parameters assessed by cardiac catheterization and echocardiography, and B-type natriuretic peptide levels correlated with MBF. At rest, MBF did not differ between patients and healthy volunteers (MBF_restml·100 g⁻¹·min⁻¹; ccTGA: 75±14 vs. AtSO: 73±16 vs. controls: 77±15; NS). After vasodilatation, MBF increased significantly, but was significantly lower in ccTGA and AtSO groups compared with controls (MBF_stressml·100 g⁻¹·min⁻¹; ccTGA: 198±38 vs. AtSO: 167±46 vs. controls 310±74; P<0.001). In ccTGA, CFR correlated significantly with clinical, CMR, echocardiographic and hemodynamic parameters, but for AtSO patients no significant correlation could be calculated.Conclusions:In patients with ccTGA, maximal coronary blood flow is attenuated and significantly correlated with ventricular function, whereas dysfunction of the morphologic systemic RV after AtSO is a multifactorial problem. (Circ J 2015; 79: 425–431)

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Background:The incidence rate of ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients without anticoagulation therapy remains unclear.Methods and Results:We performed a pooled analysis of 3,588 patients from the Shinken Database (n=1,099), J-RHYTHM Registry (n=1,002), and Fushimi AF Registry (n=1,487) to determine the incidence rate of ischemic stroke in Japanese NVAF patients without anticoagulation therapy. Average patient age was 68.1 years. During the follow-up period (total, 5,188 person-years; average, 1.4 years), 69 patients suffered from ischemic stroke (13.3 per 1,000 person-years; 95% confidence intervals [CI]: 10.5–16.8). The incidence rates of ischemic stroke were 5.4, 9.3, and 24.7 per 1,000 person-years and 5.3, 5.5, and 18.4 per 1,000 person-years in patients with low (0), intermediate (1), and high (≥2) CHADS2 and CHA2DS2-VASc scores, respectively. History of ischemic stroke or transient ischemic attack (hazard ratio [HR], 3.25; 95% CI: 1.86–5.67), age ≥75 years (HR, 2.31; 95% CI: 1.18–4.52), and hypertension (HR, 1.69; 95% CI: 1.01–2.86) were independent risk factors for ischemic stroke.Conclusions:A low incidence rate of ischemic stroke was observed in Japanese NVAF patients except for those with CHADS2 score ≥2. In this pooled analysis, history of ischemic stroke or transient ischemic attack, advanced age, and hypertension were identified as independent risk factors for ischemic stroke. (Circ J 2015; 79: 432–438)

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