Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Volume 78, Issue 11
Displaying 1-39 of 39 articles from this issue
Message From the Editor-in-Chief
Reviews
  • Christian Riehle, E. Dale Abel
    Article type: REVIEW
    2014 Volume 78 Issue 11 Pages 2569-2576
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: October 20, 2014
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    Autophagy is a conserved cellular process that plays an important role in cardiovascular homeostasis. Basal levels of autophagy are required for the maintenance of organellar quality control. Autophagy is dynamically regulated in the heart in the fasting to re-feeding transition. Insulin signaling plays an important role in the regulation of myocardial fuel metabolism, mitochondrial function and cellular growth. Recent studies have suggested an important role for insulin signaling in the regulation of myocardial autophagy. This dynamic regulation of autophagy induction during fasting may contribute to organellar homeostasis and if perturbed under conditions of hyperinsulinemia could contribute to accelerated cardiac aging. (Circ J 2014; 78: 2569–2576)
  • – SERCA2a as a Therapeutic Target –
    Carl Hayward, Hitesh Patel, Alexander Lyon
    Article type: REVIEW
    2014 Volume 78 Issue 11 Pages 2577-2587
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: October 18, 2014
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    The treatment of heart failure (HF) may be entering a new era with clinical trials currently assessing the value of gene therapy as a novel therapeutic strategy. If these trials demonstrate efficacy then a new avenue of potential treatments could become available to the clinicians treating HF. In principle, gene therapy allows us to directly target the underlying molecular abnormalities seen in the failing myocyte. In this review we discuss the fundamentals of gene therapy and the challenges of delivering it to patients with HF. The molecular abnormalities underlying HF are discussed along with potential targets for gene therapy, focusing on SERCA2a. We discuss the laboratory and early clinical evidence for the benefit of SERCA2a gene therapy in HF. Finally, we discuss the ongoing clinical trials of SERCA2a gene therapy and possible future directions for this treatment. (Circ J 2014; 78: 2577–2587)
  • Lin Y. Chen, David G. Benditt, Alvaro Alonso
    Article type: REVIEW
    2014 Volume 78 Issue 11 Pages 2588-2593
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 26, 2014
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    Evidence is emerging to indicate that atrial fibrillation (AF) is independently associated with an increased risk of sudden cardiac death (SCD). This association has been consistently observed in specific patient subgroups such as patients with myocardial infarction (MI), heart failure, and hypertension, and importantly, in the general population. Data from studies of implantable cardioverter-defibrillator recipients suggest that the rapid and irregular rhythm of AF and the short-long-short cycles that are highly prevalent in AF increase susceptibility to ventricular tachycardia and ventricular fibrillation. An alternative explanation for the association between AF and SCD includes confounding or mediation by shared risk factors such as coronary artery disease and heart failure. Possible risk factors for SCD in patients with AF include black race, left ventricular hypertrophy, history of MI, and diabetes. Additional research is needed to confirm the inherent proarrhythmic nature of AF, identify patients’ characteristics or clinical conditions that potentiate SCD risk, and define effective SCD prevention strategies for patients with AF. (Circ J 2014; 78: 2588–2593)
  • Tatsuya Shimizu
    Article type: REVIEW FOR THE 2013 SATO AWARD
    2014 Volume 78 Issue 11 Pages 2594-2603
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: October 16, 2014
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    In addition to stem cell biology, tissue engineering is an essential research field for regenerative medicine. In contrast to cell injection, bioengineered tissue transplantation minimizes cell loss and has the potential to repair tissue defects. A popular approach is scaffold-based tissue engineering, which utilizes a biodegradable polymer scaffold for seeding cells; however, new techniques of cell sheet-based tissue engineering have been developed. Cell sheets are harvested from temperature-responsive culture dishes by simply lowering the temperature. Monolayer or stacked cell sheets are transplantable directly onto damaged tissues and cell sheet transplantation has already been clinically applied. Cardiac cell sheet stacking produces pulsatile heart tissue; however, lack of vasculature limits the viable tissue thickness to 3 layers. Multistep transplantation of triple-layer cardiac cell sheets cocultured with endothelial cells has been used to form thick vascularized cardiac tissue in vivo. Furthermore, in vitro functional blood vessel formation within 3-dimensional (3D) tissues has been realized by successfully imitating in vivo conditions. Triple-layer cardiac cell sheets containing endothelial cells were layered on vascular beds and the constructs were media-perfused using novel bioreactor systems. Interestingly, cocultured endothelial cells migrate into the vascular beds and form perfusable blood vessels. An in vitro multistep procedure has also enabled the fabrication of thick, vascularized heart tissues. Cell sheet-based tissue engineering has revealed great potential to fabricate 3D cardiac tissues and should contribute to future treatment of severe heart diseases and human tissue model production. (Circ J 2014; 78: 2594–2603)
Report of Heart Transplantation in Japan
2014 ESC Report
  • Takashi Muramatsu, Yukio Ozaki
    Article type: 2014 ESC REPORT
    2014 Volume 78 Issue 11 Pages 2610-2618
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: October 15, 2014
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    The Annual Congress of the European Society of Cardiology (ESC) was held in Barcelona from 30th August to 3rd September 2014. More than 30,300 attendees from around the world shared the latest original research, including 27 clinical Hot Line studies, 12 basic science Hot Lines, 15 clinical trial updates, 19 registry studies, and 4,597 abstracts. Many important issues were presented, including novel treatment strategies for heart failure, acute coronary syndrome, interventional treatment for structural heart disease, renal denervation, novel anticoagulant therapies, atrial fibrillation and so on. In addition, 5 new ESC clinical practice guidelines (ie, myocardial revascularization, non-cardiac surgery, acute pulmonary embolism, hypertrophic cardiomyopathy, and aortic disease) were launched. It should be noted that Japan has recently been ranked in the top position in terms of the number of abstract submissions. Based on these activities, the ESC Congress has been recognized as the dominant scientific and educational forum for healthcare professionals in cardiology. We report the highlights and several key presentations of the ESC Congress 2014. The scientific activities and growing contributions of Japanese cardiologists or cardiovascular surgeons enhance the favorable relationship between the ESC and the Japanese Circulation Society. (Circ J 2014; 78: 2610–2618)
Editorials
Original Articles
Arrhythmia/Electrophysiology
  • – Validation and Utility After Catheter Ablation –
    Takamitsu Takagi, Shinsuke Miyazaki, Shigeki Kusa, Hiroshi Taniguchi, ...
    Article type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    2014 Volume 78 Issue 11 Pages 2637-2642
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 22, 2014
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    Background:Clinical outcomes after atrial fibrillation (AF) ablation are evaluated using standard 24-h Holter monitoring, and the large spontaneous variability of AF episodes and incidence of silent AF are major limitations. Further, symptoms generally decrease after AF ablation.Methods and Results:Newly developed extended external auto-trigger loop recorders (ELR) were used for 14-day consecutive monitoring to detect atrial tachyarrhythmia (ATa). Continuous tracings were stored for the initial 24h. Among 500 examinations after AF ablation in 342 patients, 40 ATa episodes were manually detected in 25 patients during the initial 24h. All episodes including 27 asymptomatic episodes (67.5%) were successfully identified using ELR. Recurrent ATa after AF ablation were detected in 83 patients, and a median monitoring duration of 4.0 days (IQR, 1.0–7.75 days) was required to detect the first episode of recurrence. The sensitivity of 24-h monitoring in detecting arrhythmia recurrence was 27.7% relative to the 14-day monitoring. The diagnostic yield gradually improved with longer monitoring duration regardless of the period after the ablation procedure. Longer follow-up, however, was required to obtain similar diagnostic yield >1 year after as compared to <1 year after the procedure.Conclusions:Twenty-four-hour monitoring detected a part of the ATa recurrences after ablation procedures. Extended ELR enabled arrhythmia monitoring for longer, with higher diagnostic yield of recurrence, regardless of patient symptoms. (Circ J 2014; 78: 2637–2642)
  • – Primary Results of the SATISFACTION Study –
    Tetsuya Watanabe, Koichi Inoue, Kazunori Kashiwase, Takanao Mine, Keij ...
    Article type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    2014 Volume 78 Issue 11 Pages 2643-2650
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 27, 2014
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    Background:Anti-tachycardia pacing (ATP) delivered by implantable cardioverter defibrillators (ICD) safely avoids painful shocks with minimum risk of tachycardia acceleration. The etiology of ventricular tachycardia (VT) in those studies, however, was predominantly coronary artery disease (CAD). Patient etiology differs by geography and could affect ATP efficacy rate. The primary objective of this study was to examine how often the first ATP therapy terminates fast VT (FVT) in Japanese ICD patients with regional etiologies.Methods and Results:Seven hundred and fifteen patients received ICD or cardiac resynchronization therapy defibrillator with the function of ATP during capacitor charging. The primary endpoint was the first ATP success rate for terminating FVT with cycle length 240–320 ms. During a mean follow-up of 11.3 months, 888 spontaneous VT episodes were detected, including 276 FVT (31.1%) in 42 patients. The first-ATP success rate for FVT in the overall group (41% CAD, 59% non-CAD including 23% idiopathic VT) was 62.1% (61.7% adjusted). Success rate was not different between non-CAD and CAD patients (61.4% adjusted and 57.5% adjusted, respectively, P=0.75). Eight FVT episodes (2.9%) accelerated after the first ATP attempt, all of which were terminated by subsequent device therapy (additional ATP or shock).Conclusions:ATP efficacy for FVT was similar between ICD patients with and without CAD etiology. (Circ J 2014; 78: 2643–2650)
  • – Single Center Cohort Study –
    Masashi Kanemoto, Hiroko Kuhara, Toru Ueda, Takahiro Shinohara, Takama ...
    Article type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    2014 Volume 78 Issue 11 Pages 2651-2656
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 25, 2014
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    Background:This study evaluated whether measuring prothrombin time (PT) using particular reagents of interest predicted apixaban-associated anticoagulant activity in Japanese patients with non-valvular atrial fibrillation (NVAF).Methods and Results:Two reagents, Shinplastin Excel S and Coagpia PT-N, were used to evaluate PT under apixaban therapy. From June 2013 to February 2014, 103 NVAF patients were recruited, and PT was measured at 3 time points: (1) anytime in the outpatient clinic, (2) at peak, and (3) at trough. In spike-in experiments using pooled citrated normal human platelet-poor plasma with these PT reagents, apixaban prolonged PT values in a concentration-dependent manner. PT values significantly correlated between both reagents (r=0.97) in outpatients. PT values in outpatients taking 5-mg apixaban bid were significantly prolonged and had wide inter- and intraindividual variability. Peak values were significantly higher than trough values, with both values higher than normal. The dose change of apixaban from 5 mg bid to 2.5 mg bid in outpatients halved the degree of PT prolongation in each NVAF patient.Conclusions:The PT value measured by these specific reagents can predict apixaban-associated anticoagulant activity, although there is significant interpatient variability. (Circ J 2014; 78: 2651–2656)
Cardiovascular Intervention
  • – Serial Intravascular Ultrasound Study From the Late Incomplete Stent Apposition Evaluation (LISA) Trial –
    Shuji Otsuki, Yoshitaka Shiratori, Salvatore Brugaletta, Clarissa Cola ...
    Article type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Intervention
    2014 Volume 78 Issue 11 Pages 2657-2664
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 22, 2014
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    Background:It is unknown if lack of polymer can provoke a different edge response in drug-eluting stents. The aim of this study was to compare edge vascular response between polymer-free paclitaxel-eluting stent (PF-PES) and polymer-based paclitaxel-eluting stents (PB-PES).Methods and Results:A total of 165 eligible patients undergoing percutaneous coronary intervention were prospectively randomized 1:1 to receive either PF-PES or PB-PES. Those patients with paired intravascular ultrasound (IVUS) after procedure and at 9-month follow-up were included in this analysis.Seventy-six patients with 84 lesions, divided into PB-PES (38 patients, 41 lesions) and PF-PES groups (38 patients, 43 lesions) had paired post-procedure and 9-month follow-up IVUS and were therefore included in this substudy. There was a significant lumen decrease at the proximal edge of PF-PES (from 9.02±3.06 mm2to 8.47±3.05 mm2; P=0.040), and a significant plaque increase at the distal edges of PF-PES (from 4.39±2.73 mm2to 4.78±2.63 mm2; P=0.004). At the distal edge there was a significant plaque increase in the PF-PES compared to PB-PES (+8.0% vs. –0.6%, respectively; P=0.015) with subsequent lumen reduction (–5.2% vs. +6.0%, respectively; P=0.024).Conclusions:PF-PES had significant plaque increase and lumen reduction at the distal edge as compared to PB-PES, probably due to difference in polymer-based drug-release kinetics between the 2 platforms. (Circ J 2014; 78: 2657–2664)
  • Noritoshi Hiranuma, Toshiro Shinke, Gaku Nakazawa, Hiromasa Otake, Dai ...
    Article type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Intervention
    2014 Volume 78 Issue 11 Pages 2665-2673
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 27, 2014
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    Background:This study directly compared optical coherence tomography (OCT) and histopathology for the assessment of vascular response to first- and second-generation drug-eluting stents.Methods and Results:Sirolimus-, everolimus-, and biolimus-eluting stents (SES, EES, and BES, respectively) were randomly implanted into the coronary arteries of 12 porcine. OCT was conducted after implantation: at 1, 3, and 6 months; histopathology was assessed at 3 and 6 months. At 1-month OCT, EES had the highest neointimal area (NA) and lowest neointimal unevenness score (NUS). At 6 months, NA and NUS were equivalent among the stent types. ∆NA from 1 to 6 months was lowest for EES, and ∆NA correlated with the histopathological inflammation score at 6 months, which was highest for SES (P<0.001). The mean signal intensity (MSI) and the attenuation were different for the stent types at 3 months, and were associated with inflammation score. Moderate diagnostic efficiency for measuring MSI was found, with an optimal cut-off of 6.88 predicting a high (≥grade 3) inflammation score.Conclusions:EES had the greatest uniformity and the least neointimal proliferation and were associated with less persistent inflammation. OCT provides accurate morphometric data; furthermore, quantitative measurement of the optical properties may help assess histological inflammation, which was more predominantly associated with SES than with EES and BES. (Circ J 2014; 78: 2665–2673)
  • – Insights From the AFCAS Registry –
    Tuomas Kiviniemi, Marja Puurunen, Axel Schlitt, Andrea Rubboli, Pasi K ...
    Article type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Intervention
    2014 Volume 78 Issue 11 Pages 2674-2681
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: October 09, 2014
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    Background:We explored 12-month clinical outcomes of 929 patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) with bare-metal stents (BMS) vs. drug-eluting stents (DES) from the prospective multicenter AFCAS (Atrial Fibrillation undergoing Coronary Artery Stenting) registry.Methods and Results:Endpoints included the first occurrence of major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of all-cause death, myocardial infarction (MI), target vessel revascularization, definite/probable stent thrombosis (ST), transient ischemic attack or stroke. Bleeding events were defined according to the Bleeding Academic Research Consortium criteria. Altogether, 673 (72.4%) patients received BMS and 220 (23.7%) at least one DES. Patients treated with DES more often had diabetes and prior ischemic events, and a longer stent length (P<0.05 for all), whereas patients treated with BMS more often had heart failure and were more likely to present with acute ST-elevation MI (P<0.05 for both). At 12-month follow-up, rates and risks of MACCE and total bleeding events were comparable between the groups (22.0% with BMS vs. 19.5% with DES, P=0.51, hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.63–1.25 for DES) and (19.5% vs. 15.0%, respectively, P=0.16, HR 0.75, 95% CI 0.51–1.09 for DES). Definite/probable ST was more frequent in the BMS group (1.9% vs. 0%, respectively, P=0.046).Conclusions:In real-world patients with AF undergoing PCI, DES use was associated with outcomes comparable to those with BMS without excess bleeding complications. More ST was seen in BMS-treated patients. (Circ J 2014; 78: 2674–2681)
Cardiac Rehabilitation
  • Akira Takashima, Takayuki Ise, Shusuke Yagi, Takashi Iwase, Sahika Kim ...
    Article type: ORIGINAL ARTICLE
    Subject area: Cardiac Rehabilitation
    2014 Volume 78 Issue 11 Pages 2682-2687
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 22, 2014
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    Background:Oxidized low-density lipoprotein (oxLDL) levels have been found to play an important role in the progression of atherosclerosis. However, methods for effectively reducing oxLDL levels have not been established. Comprehensive cardiac rehabilitation (CR) with exercise training prevents the progression of atherosclerosis, and might reduce oxLDL levels.Methods and Results:We measured the serum levels of malondialdehyde-modified LDL (MDA-LDL), a marker of oxLDL, in 136 patients who were enrolled in a 6-month CR program. Peak oxygen consumption (V̇O2) and MDA-LDL levels were analyzed, before and 6 months after enrolment. In total, 67 patients completed the CR program (CR group) and 69 patients failed to complete the program (non-CR group). Peak V̇O2increased significantly in the CR group (P<0.01). The levels of MDA-LDL decreased significantly in the CR group (P<0.01) but not in the non-CR group. ∆V̇O2(peak V̇O2after CR–peak V̇O2before CR) was negatively associated with ∆MDA-LDL (MDA-LDL after CR–MDA-LDL before CR) (R2=0.11, P=0.01). Multiple regression analysis showed that continuing CR was an independent determining factor for lowering MDA-LDL levels.Conclusions:CR decreases oxLDL levels in patients with cardiovascular diseases. Moreover, CR may prevent cardiovascular events through an antioxidative effect. (Circ J 2014; 78: 2682–2687)
Cardiovascular Surgery
  • Takahiro Nishida, Hiromichi Sonoda, Yasuhisa Oishi, Hideki Tatewaki, Y ...
    Article type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Surgery
    2014 Volume 78 Issue 11 Pages 2688-2695
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 27, 2014
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    Background:The long-term results of aortic valve replacement (AVR; n=737) with bileaflet mechanical prosthesis (MP) or Carpentier-Edwards Perimount bioprostheses (BP) were evaluated in different age groups.Methods and Results:Since 1981, a total of 737 prostheses (424 bileaflet MP vs. 313 BP) were implanted for AVR in 278 patients aged ≥70 years (79 MP vs. 199 BP), in 191 patients aged 60–69 years (128 MP vs. 63 BP) and in 268 patients aged <60 years (217 MP vs. 51 BP). Follow-up was completed for 6,523 patient-years in 98.5% of cases. Among the patients ≥70 years, both the actuarial survival rate (P=0.0434) and freedom from valve-related morbidity (P=0.0205) were better in the BP group than in the MP group without any difference in occurrence of structural valve deterioration in both groups. Among the patients aged 60–69, anticoagulant-related complications occurred less often in the BP group (P=0.0134) without any difference in long-term survival. Among the patients aged <60, long-term survival was significantly better in the MP group, whereas freedom from anticoagulant-related events did not differ.Conclusions:The use of BP is suitable in patients aged ≥70 years, while the use of bileaflet MP is preferable in patients aged <60 years. Among patients aged 60–69 years, the use of BP is acceptable because of the lower incidence of anticoagulant-related events and the equivalent long-term survival. (Circ J 2014; 78: 2688–2695)
  • Naoto Fukunaga, Yukikatsu Okada, Yasunobu Konishi, Takashi Murashita, ...
    Article type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Surgery
    2014 Volume 78 Issue 11 Pages 2696-2703
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: October 01, 2014
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    Background:Long-term survival and incidence of late tricuspid regurgitation (TR) were studied in patients who underwent tricuspid annuloplasty (TAP) during redo valve surgery.Methods and Results:We retrospectively analyzed 125 patients (mean age, 64.5±10.4 years) who underwent TAP using suture (n=54, group S) or ring (n=71, group R) implantation during redo surgery in a 20-year period. There was a significant difference in prevalence of preoperative atrial fibrillation (P=0.0199). More group S patients were in New York Heart Association functional class III or IV than group R patients (P=0.0066). Mean follow-up was 6.6±5.3 years. Mortality rate for group S was 9.3%, and for group R, 7.0% (P=0.6508). Survival at 5 and 10 years was 72.2±6.6% vs. 88.1±4.0%, and 66.4±7.3% vs. 61.0±7.2%, respectively (log-rank, P=0.7235). Less than moderate TR (hazard ratio [HR], 0.113; P=0.0198) before discharge was a predictor of late survival. There was no statistically significant difference in freedom from valve-related events (log-rank, P=0.5196). A predictor of freedom from valve-related events was less than moderate TR before discharge (HR 0.428; P=0.0100). It was also a positive predictor of freedom from late TR more than mild (HR 0.070; P<0.0001).Conclusions:Less than moderate TR before discharge after TAP during redo valve surgery was an independent risk factor for better long-term outcome. (Circ J 2014; 78: 2696–2703)
Heart Failure
  • Tadafumi Sugimoto, Kaoru Dohi, Katsuya Onishi, Tomomi Yamada, Masahide ...
    Article type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    2014 Volume 78 Issue 11 Pages 2704-2710
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 25, 2014
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    Background:Secondary hyperparathyroidism develops as a compensatory response to chronic heart failure (HF) and renal failure. The role of parathyroid hormone (PTH) level in acute decompensated HF remains unclear. The aim of this study was therefore to investigate the relationships among mortality, renal function, and serum PTH level in acute decompensated HF patients.Methods and Results:A total of 266 consecutive patients admitted for acute decompensated HF without acute coronary syndrome (78±12 years; 48% male) were enrolled. Demographic, clinical, and laboratory characteristics were obtained on admission.During 1-year follow-up, 65 patients (24%) died. Serum PTH level on admission was within the normal range (10–65 pg/ml) in 108 patients (41%), of whom 39 (15%) had low-normal PTH (10–40 pg/ml). On Kaplan-Meier analysis all-cause mortality was significantly higher in patients with low-normal PTH than in those with high-normal (40–65 pg/ml) or high (>65 pg/ml) PTH (log-rank test). On univariate and multivariate Cox regression analysis, low-normal PTH was significantly associated with increased all-cause mortality (unadjusted HR, 2.88; 95% CI: 1.69–4.91; P<0.001; adjusted HR, 3.84; 95% CI: 1.54–9.57; P=0.004).Conclusions:In patients with acute decompensated HF resulting in hospitalization, low-normal PTH on admission is associated with increased all-cause mortality, regardless of renal function. (Circ J 2014; 78: 2704–2710)
  • Shaukat Khan, Jennifer Joyce, Kenneth B. Margulies, Takeshi Tsuda
    Article type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    2014 Volume 78 Issue 11 Pages 2711-2718
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: October 09, 2014
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    Supplementary material
    Background:Transforming growth factor (TGF)-β activation is known to play a central role in progressive ventricular remodeling in advanced heart failure in animal models, but there has been no direct evidence of increased TGF-β activity in the myocardium of patients with advanced human heart failure.Methods and Results:Using a recently developed bioassay that measures TGF-β bioactivity rather than TGF-β abundance, we measured bioactive TGF-β in human myocardium from control non-failing donors (NF), and patients with ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). Both free and total soluble TGF-β were significantly increased in ICM and DCM compared with NF. Free TGF-β had an excellent correlation with phosphorylated Smad2 (R2=0.55, P<0.0001), a downstream marker of TGF-β signaling. Collagen type I and type III were significantly upregulated in DCM compared with NF, consistent with histological evidence of myocardial fibrosis. Expression of fibulin-2, a positive modulator of TGF-β, was significantly increased in DCM compared with NF, and the free TGF-β level was correlated with fibulin-2 mRNA (R2=0.24, P<0.006).Conclusions:Although both free and total soluble TGF-β are significantly increased in ICM and DCM compared with NF, the superior correlation of free TGF-β with downstream signaling suggests that this is the most functionally relevant form. The present findings suggest that sustained TGF-β activation in both ICM and DCM contributes to excess myocardial fibrosis. (Circ J 2014; 78: 2711–2718)
Hypertension and Circulatory Control
  • – Randomized Multicenter Trial –
    Takuma Sawa, Yukihito Sato, Mitsuo Matsuda, Masaru Tanaka, Shunichi Mi ...
    Article type: ORIGINAL ARTICLE
    Subject area: Hypertension and Circulatory Control
    2014 Volume 78 Issue 11 Pages 2719-2726
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 30, 2014
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    Background:In hypertensive patients, left ventricular hypertrophy (LVH) may persist despite satisfactory blood pressure (BP) control. The efficacy of thiazide diuretics in Western countries has been reported, but whether this applies to hypertensive Japanese patients is uncertain.Methods and Results:We randomly assigned 94 patients whose BP was poorly controlled with usual doses of angiotensin-II receptor blockers (ARB), to losartan/hydrochlorothiazide (HCTZ) fixed-dose combination vs. maximum doses of ARB. After 6 months follow-up, decrease in BP, regression of electrocardiographic LVH, and changes in laboratory measurements were examined. Although a similar decrease in BP was observed in both groups, the decrease in LV Sokolow-Lyon voltage, from 34.4±9.2 to 29.4±8.8 mm in the losartan/HCTZ vs. from 29.9±10.2 to 29.1±8.4 mm in the ARB group (P=0.0003), and the decrease in serum B-type natriuretic peptide (BNP) level, from 30.1±28.5 to 26.8±28.0 pg/ml vs. from 23.7±14.8 to 29.8±29.3 pg/ml (P=0.045) were greater in the losartan/HCTZ group. By single variable logistic regression analysis, ∆BNP (P=0.012) and treatment with losartan/HCTZ (P<0.0001) correlated with the regression of LVH. By multiple variable logistic regression analysis, both ∆BNP (P=0.035) and treatment with losartan/HCTZ (P=0.0003) remained significant. No major adverse effects were observed.Conclusions:Greater regression of LVH was safely achieved with losartan/HCTZ in patients whose BP was poorly controlled with an ARB. (Circ J 2014; 78: 2719–2726)
Imaging
  • Hirokazu Tanaka, Taishiro Chikamori, Nobuhiro Tanaka, Satoshi Hida, Yu ...
    Article type: ORIGINAL ARTICLE
    Subject area: Imaging
    2014 Volume 78 Issue 11 Pages 2727-2734
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 22, 2014
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    Background:Although the novel cadmium-zinc-telluride (CZT) camera system provides excellent image quality, its diagnostic value using thallium-201 as assessed on coronary angiography (CAG) and fractional flow reserve (FFR) has not been validated.Methods and Results:To evaluate the diagnostic accuracy of the CZT ultrafast camera system (Discovery NM 530c), 95 patients underwent stress thallium-201 single-photon emission computed tomography (SPECT) and then CAG within 3 months. Image acquisition was performed in the supine and prone positions after stress for 5 and 3 min, respectively, and in the supine position at rest for 10 min. Significant stenosis was defined as ≥90% diameter narrowing on visual estimation, or a lesion with <90% and ≥50% stenosis and FFR ≤0.75. To detect individual coronary stenosis, the respective sensitivity, specificity, and accuracy were 90%, 64%, and 78% for left anterior descending coronary artery stenosis, 78%, 84%, and 81% for left circumflex stenosis, and 83%, 47%, and 60% for right coronary artery (RCA) stenosis. The combination of prone and supine imaging had a higher specificity for RCA disease than supine imaging alone (65% vs. 47%), with an improvement in accuracy from 60% to 72%.Conclusions:Using thallium-201 with short acquisition time, combined with prone imaging, CZT SPECT had a high diagnostic yield in detecting significant coronary stenosis as assessed using FFR. (Circ J 2014; 78: 2727–2734)
Ischemic Heart Disease
  • Hideki Kawai, Sadako Motoyama, Masayoshi Sarai, Hajime Ito, Hiroshi Ta ...
    Article type: ORIGINAL ARTICLE
    Subject area: Ischemic Heart Disease
    2014 Volume 78 Issue 11 Pages 2735-2740
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: October 09, 2014
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    Background:The additive value of plaque characteristics determined by computed tomography angiography (CTA) in patients undergoing invasive coronary angiography (ICA) has not been established.Methods and Results:We studied 676 patients undergoing ICA and CTA within 3 months. The luminal diameter narrowing based on ICA and the presence of high risk plaque (HRP) based on CTA were assessed in all coronary artery segments except for those after or before scheduled treatment. We followed their cardiac events including cardiac death, acute coronary syndrome (ACS), and revascularization for de novo lesions ≥3 months after ICA. The incidence of coronary events was higher in the segments including >25% luminal narrowing than in those without (2.94% vs. 0.31%, P<0.0001), and higher in the segments containing HRP than in those without (12.6 vs. 0.46%, P<0.0001). Greater than 25% residual luminal narrowing and the presence of HRP were identified as independent predictors of cardiac events after risk adjustment for age, gender, and history of ACS (hazard ratio [HR], 3.22; 95% confidence interval [CI]: 1.29–10.76; P=0.0092, HR, 2.64; 95% CI: 1.59–4.35; P=0.0002, respectively). Adding the presence of HRP to a model including age, gender, ACS history, and >25% residual stenosis improved the prediction of cardiac events.Conclusions:Assessment of coronary plaque characteristics on CTA improves the prediction of cardiac events in patients undergoing ICA. (Circ J 2014; 78: 2735–2740)
Valvular Heart Disease
  • Jan Vecera, Jozef Bartunek, Marc Vanderheyden, Martin Kotrc, Radka Koc ...
    Article type: ORIGINAL ARTICLE
    Subject area: Valvular Heart Disease
    2014 Volume 78 Issue 11 Pages 2741-2749
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: October 03, 2014
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    Background:This study assessed the independent significance of color Doppler 3-D vena contracta area (VCA) at rest and during exercise as a predictor of clinical outcome in mild-moderate functional mitral regurgitation (FMR).Methods and Results:The subjects consisted of 62 patients (age, 68±11 years; 76% male) with chronic systolic heart failure and mild-moderate FMR (<2+/4) at rest. All patients underwent VCA assessment at rest and during semi-supine bicycle exercise. During median follow-up of 17 months (IQR, 13–20 months), 15 patients (24%) had composite endpoint of all-cause death (n=3), heart failure admission (n=11), and heart transplantation (n=1). At baseline, patients with vs. without endpoint had significantly larger VCA at rest (17±6 mm2vs. 13±7 mm2, P=0.002) and at peak exercise (35±16 mm2vs. 21±12 mm2, P<0.001). On Cox regression analysis, large (≥15-mm2) resting VCA (HR, 7.6; 95% CI: 1.93–13.02; P=0.004) and large (≥20-mm2) exercise-induced increase of VCA (HR, 5.1; 95% CI: 1.39–15.21; P=0.014) were independently associated with composite endpoint. Concomitant presence of large VCA at rest and its large increase during exercise occurred in 53% of patients with, vs. in only 8% without, endpoint (negative predictive value, 86%).Conclusions:The presence of relatively large VCA at rest and its significant increase during exercise is independently associated with adverse clinical outcome in patients with mild-moderate FMR at rest. (Circ J 2014; 78: 2741–2749)
  • Kimi Sato, Yoshihiro Seo, Tomoko Ishizu, Masaaki Takeuchi, Masaki Izum ...
    Article type: ORIGINAL ARTICLE
    Subject area: Valvular Heart Disease
    2014 Volume 78 Issue 11 Pages 2750-2759
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 30, 2014
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    Background:To assess whether global longitudinal strain (GLS) can discriminate high-risk patients with adverse outcome in paradoxical low-flow, low-gradient (LFLPG) severe aortic stenosis (AS).Methods and Results:We enrolled 204 patients with severe AS (indexed aortic valve area [iAVA] <0.6 cm2/m2) and preserved left ventricular ejection fraction (LVEF >50%). Patients were divided into 4 groups according to flow state (stroke volume index < or > 35 ml/m2) and mean pressure gradient (< or > 40 mmHg). LV GLS was measured by 2-dimensional speckle-tracking analysis. The primary endpoint consisted of major cardiovascular events, including aortic valve replacement. During a mean 399-day follow-up, 51 (25%) patients met the primary endpoint. Among the 98 LFLPG AS patients, GLS was significantly reduced in patients with any event (−15.6±4.5% vs. −19.4±3.6%, P=0.002). Using receiver-operating characteristic analysis, we classified LFLPG AS patients as impaired GLS (GLS ≥−17%, n=24) or preserved GLS (GLS <−17%, n=74). The impaired GLS group had smaller iAVA, higher LV mass index, higher E/E’, and lower overall 2-year event-free survival (57% vs. 97%; P<0.001) than the preserved GLS group.Conclusions:Longitudinal function was severely impaired in patients with LFLPG AS and they had poor prognosis. GLS could stratify the high-risk group for future adverse outcomes. Patients with paradoxical LFLPG AS comprised a mixed group with different LV mechanical properties associated with different prognoses. (Circ J 2014; 78: 2750–2759)
Vascular Biology and Vascular Medicine
  • Zhong-Cheng Mo, Ji Xiao, Shi-Lin Tang, Xin-Ping Ouyang, Ping-ping He, ...
    Article type: ORIGINAL ARTICLE
    Subject area: Vascular Biology and Vascular Medicine
    2014 Volume 78 Issue 11 Pages 2760-2770
    Published: October 24, 2014
    Released on J-STAGE: October 24, 2014
    Advance online publication: September 26, 2014
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    Supplementary material
    Background:Both clinical data and basic science studies suggest that advanced oxidation protein products (AOPPs) may contribute to the progression of atherosclerosis. The aim of this study was to investigate the effects of AOPPs on ATP-binding cassette transporter (ABC) A1 and ABCG1 expression, lipid accumulation and atherosclerotic lesions in apolipoprotein E knockout (apoE-KO) mice.Methods and Results:Male 8-week-old apoE-KO mice were fed a high-fat/high-cholesterol diet. Mice received intraperitoneal injections of AOPPs (5 mg/kg) and/or Janus Kinase (JAK) inhibitor AG-490 (5 mg/kg) once every other day for 8 weeks. As shown in our data, AOPPs increased lipid levels of plasma, and promoted advanced lesions in the aortic regions in apoE-KO mice. The ABCA1, ABCG1 and liver X receptor alpha (LXRα) expression were downregulated in apoE-KO mice treated with AOPPs, whereas the lesions in the aortas were decreased, and the ABCA1, ABCG1 and LXRα expression were upregulated in mice treated with AOPPs plus AG-490, compared to the mice treated with AOPPs only. The ABCA1 and LXRα expressions of aortas, liver and intestine were downregulated in the AOPPs group, while the expressions were upregulated in the AOPPs-plus-AG-490 group when compared to the AOPPs group. The same results can be also observed in peritoneal macrophages.Conclusions:AOPPs increase accumulation of lipids and exacerbate atherosclerosis through downregulation of ABCA1 and ABCG1 expression, and the JAK-LXRα signaling pathway in apoE-KO mice. (Circ J 2014; 78: 2760–2770)
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