Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Volume 78 , Issue 4
Showing 1-46 articles out of 46 articles from the selected issue
Message From the Editor-in-Chief
Reviews
  • – A Cell Is Worth a Thousand Genes –
    Karim Sallam, Kazuki Kodo, Joseph C. Wu
    2014 Volume 78 Issue 4 Pages 784-794
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: March 17, 2014
    JOURNALS FREE ACCESS
    Advances in the understanding and treatment of cardiac disorders have been thwarted by the inability to study beating human cardiac cells in vitro. Induced pluripotent stem cells (iPSCs) bypass this hurdle by enabling the creation of patient-specific iPSC-derived cardiomyocytes (iPSC-CMs). These cells provide a unique platform to study cardiac diseases in vitro, especially hereditary cardiac conditions. To date, iPSC-CMs have been used to successfully model arrhythmic disorders, showing excellent recapitulation of cardiac channel function and electrophysiologic features of long QT syndrome types 1, 2, 3, and 8, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Similarly, iPSC-CM models of dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) have shown robust correlation of predicted morphologic, contractile, and electrical phenotypes. In addition, iPSC-CMs have shown some features of the respective phenotypes for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), LEOPARD syndrome, Pompe’s disease, and Friedriech’s ataxia. In this review, we examine the progress of utilizing iPSC-CMs as a model for cardiac conditions and analyze the potential for the platform in furthering the biology and treatment of cardiac disorders.  (Circ J 2014; 78: 784–794)
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  • Christian Waeber, Thomas Walther
    2014 Volume 78 Issue 4 Pages 795-802
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: March 17, 2014
    JOURNALS FREE ACCESS
    This review focuses on the role of sphingosine-1-phosphate (S1P) signaling in the heart, with particular emphasis on how it could be modulated therapeutically in the context of myocardial infarction (MI). After a brief general description of sphingolipid metabolism and signaling, this review will examine the relationship between S1P and the beneficial effects of high-density lipoprotein (HDL), and finally focus on the known actions of S1P on different mechanisms relevant to MI pathophysiology (cardiomyocyte protection, fibrosis, remodeling, arrhythmia, control of vascular tone and potential repair mechanisms). The potential of particular enzyme isoforms or receptor subtypes for the development of therapeutic agents for MI will also be explored.  (Circ J 2014; 78: 795–802)
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  • Rimpy Dhingra, Lorrie A. Kirshenbaum
    2014 Volume 78 Issue 4 Pages 803-810
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: March 20, 2014
    JOURNALS FREE ACCESS
    Though the mitochondrion was initially identified as a key organelle essentially required for energy production and oxidative metabolism, there is considerable evidence that mitochondria are intimately involved in regulating vital cellular processes, such as programmed cell death, proliferation and autophagy. Discovery of mitochondrial “shaping proteins” (Dynamin-related protein (Drp), mitofusins (Mfn) etc.) has revealed that mitochondria are highly dynamic organelles continually changing morphology by fission and fusion processes. Several human pathologies, including cancer, Parkinson’s disease, Alzheimer’s disease and cardiovascular diseases, have been linked to abnormalities in proteins that govern mitochondrial fission or fusion respectively. Notably, in the context of the heart, defects in mitochondrial dynamics resulting in too many fused and/or fragmented mitochondria have been associated with impaired cardiac development, autophagy, and contractile dysfunction. Understanding the mechanisms that govern mitochondrial fission/fusion is paramount in developing new treatment strategies for human diseases in which defects in fission or fusion is the primary underlying defect. Here, we provide a comprehensive overview of the cellular targets and molecular signaling pathways that govern mitochondrial dynamics under normal and disease conditions.  (Circ J 2014; 78: 803–810)
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  • – Nothing to Worry About Anymore? –
    Nikos Werner, Jan-Malte Sinning
    2014 Volume 78 Issue 4 Pages 811-818
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: March 14, 2014
    JOURNALS FREE ACCESS
    Paravalvular aortic regurgitation (AR) negatively affects prognosis following transcatheter aortic valve replacement (TAVR). As transcatheter heart valves (THV) are anchored using a certain degree of oversizing at the level of the aortic annulus, incomplete stent frame expansion because of heavily annular calcifications, suboptimal placement of the prosthesis, and/or annulus-prosthesis size-mismatch can contribute to paravalvular AR with subsequent increased mortality risk. Echocardiography is essential to differentiate between transvalvular and paravalvular AR and to further elucidate the etiology of AR during the procedure. However, because echocardiographic quantification of AR in TAVR patients remains challenging, especially in the implantation situation, a multimodal approach to the evaluation of AR with use of hemodynamic measurements and imaging modalities is useful to precisely quantify the severity of AR immediately after valve deployment. “Next-generation” THVs are already on the market and first results show that paravalvular AR related to design modifications (eg, paravalvular space-fillers, full repositionability) are rarely seen in these valve types.  (Circ J 2014; 78: 811–818)
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  • Jun-ichi Oyama, Koichi Node
    2014 Volume 78 Issue 4 Pages 819-824
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: March 07, 2014
    JOURNALS FREE ACCESS
    Type 2 diabetes mellitus (T2DM) is widely prevalent and a critical risk factor for cardiovascular disease that increases both morbidity and mortality. Recently, new therapies based on the actions of the incretin hormones have become widely used, offering advantages over conventional treatments by limiting hypoglycemia and achieving glycemic control. Moreover, many experimental studies have suggested that GLP-1 and related drugs exert cardioprotective effects on atherosclerosis and cardiac dysfunction both in vitro and in vivo. However, there is thus far little clinical evidence supporting the efficacy of incretin therapy in patients with cardiovascular disease. This review focuses on the effects of GLP-1-related therapy on cardiac function from the bench to the bed, with a discussion of possible underlying mechanisms.  (Circ J 2014; 78: 819–824)
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Editorials
Late Breaking Cohort Studies (JCS 2014)
  • – An Interim Result of Post-Marketing Surveillance in Japan –
    Koichiro Kinugawa, Naoki Sato, Takayuki Inomata, Toshiyuki Shimakawa, ...
    2014 Volume 78 Issue 4 Pages 844-852
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: March 21, 2014
    JOURNALS FREE ACCESS
    Supplementary material
    Background: Loop diuretics are commonly used in heart failure (HF) patients, but they are sometimes associated with insufficient response as well as adverse events. In such diuretics-resistant cases, tolvaptan, a vasopressin type 2 receptor antagonist, shows the improvement of volume overload without electrolyte imbalance. Tolvaptan was launched in Japan in 2010, and a post-marketing surveillance has been performed to evaluate the safety and efficacy of tolvaptan in real-world clinical settings. Methods and Results: HF patients with insufficient response to loop diuretics were enrolled: 1,053 to evaluate for efficacy and 1,057 patients for the safety assessment. Decreases in body weight from baseline were 1.0±1.6kg at day 2 and increases in urine volume were 631±1,179ml at day 1 (both P<0.0001 vs. baseline). Congestive symptoms were significantly improved within 14 days. Adverse drug reactions (ADR) were observed in 18.7%, with thirst being the most frequent ADR (10%). Hypernatremia was a complication in 40 patients (3.8%). Predictive factors for the occurrence of hypernatremia were the starting dosage of tolvaptan (15mg/day), baseline serum sodium level (≥142mEq/L) and serum potassium level (<3.8mEq/L) at baseline. Conclusions: In the real-world clinical setting, tolvaptan demonstrated aquaretic efficacy in HF patients with diuretic-resistant volume overload. We recommend a lower dose of tolvaptan in Japanese patients with normonatremia and hypokalemia to prevent hypernatremia.  (Circ J 2014; 78: 844–852)
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Original Articles
Arrhythmia/Electrophysiology
  • Wen-Yu Lin, Yenn-Jiang Lin, Fa-Po Chung, Tze-Fan Chao, Jo-Nan Liao, Sh ...
    2014 Volume 78 Issue 4 Pages 853-858
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 13, 2014
    JOURNALS FREE ACCESS
    Background: The impact of renal dysfunction has been investigated in patients with non-valvular atrial fibrillation (AF). The aim of this study was to assess its additive prognostic value in low thromboembolic risk AF patients with CHA2DS2-VASc score 0–1. Methods and Results: A total of 617 non-valvular AF patients were enrolled and baseline serum creatinine was measured. Estimated glomerular filtration rate and estimated clearance of creatinine were calculated using the Modification of Diet in Renal Disease equation and Cockcroft-Gault formula, respectively. The primary endpoint was cardiovascular death and systemic thromboembolic events, including acute ischemic stroke, transient ischemic attack, and peripheral artery embolism. Of these, 338 individuals had clinical CHA2DS2-VASc score 0–1. Among these individuals, 23 patients had impaired renal function. During the follow-up period of 53.6±32.1 months, the annual composite outcome rate in AF patients with CHA2DS2-VASc score 0–1 was 0.40%/year. As compared with patients with preserved renal function, the annual composite outcome rate was significantly higher in patients with impaired renal function (2.92%/year vs. 0.21%/year, P<0.001). Moreover, on multivariate Cox regression analysis, renal dysfunction was the only risk predictor in these low-risk patients. Conclusions: Impaired renal function has an additive prognostic value for thromboembolic events and cardiovascular mortality in low-risk AF patients with CHA2DS2-VASc score 0–1.  (Circ J 2014; 78: 853–858)
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  • Takeshi Machino, Hiroshi Tada, Yukio Sekiguchi, Yoshihisa Naruse, Kenj ...
    2014 Volume 78 Issue 4 Pages 859-864
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 14, 2014
    JOURNALS FREE ACCESS
    Background: Linear ablation of atrial flutter usually targets a 6 o’clock position on the cavotricuspid isthmus on left anterior oblique view, but the difficulty of the ablation often requires a variation in successful ablation line position from 5 to 7 o’clock. Methods and Results: This study included 94 patients without structural heart disease. A linear lesion was created in turn at the 6, 7, and 5 o’clock positions until bidirectional block of the isthmus was completed; the final lesion was defined as the successful ablation line. The degree of counterclockwise heart rotation (CCW-HR) was evaluated in a blinded fashion according to the angle between the vertical line crossing the His bundle catheter and the line connecting the His bundle catheter and coronary sinus ostium. Successful ablation lines were obtained at the 6 o’clock position in 59 patients (63%); the 7 o’clock position in 19 patients (20%; the oldest group with a moderate radiofrequency burden); and the 5 o’clock position in the remaining 16 (17%; the youngest group with the largest radiofrequency burden). Age-related increase in CCW-HR was the only independent predictor of a more septal successful ablation line (OR, 7.1; 95% CI: 3.3–14.3; P<0.01). Conclusions: Variation in successful ablation line position was affected by age-related CCW-HR; its evaluation might reduce radiofrequency burden, especially in the young and elderly.  (Circ J 2014; 78: 859–864)
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  • – 8-Year Follow-up Results –
    Ki-Hun Kim, Kyoung-Min Park, Gi-Byoung Nam, Dae-Kyeong Kim, Minkyung O ...
    2014 Volume 78 Issue 4 Pages 865-871
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: March 03, 2014
    JOURNALS FREE ACCESS
    Background: Long-term data on lead complication rates are limited for both the axillary and subclavian venous approaches for permanent pacemaker implantation. Methods and Results: We conducted a single-center, retrospective, nonrandomized comparison. We reviewed the patients who had consented to receiving a permanent pacemaker implant. A superficial landmark or radiographic contrast guiding was used for the axillary venous approach, whereas conventional landmarks were used for the subclavian venous approach. From January 1992 to December 2005, we analyzed 1,161 permanent pacemaker leads in 655 patients [subclavian venous approach (group I: 338 patients, 542 leads) and axillary venous approach (group II: 317 patients, 619 leads)]. Baseline characteristics of the patients did not differ. However, DDD-pacemakers and atrial leads were used more often in group II than in group I (94% vs. 62% and 49% vs. 40%, P<0.01). During the 8-year follow-up, lead complication rates were lower in group II (17 leads, 3%) than in group I (31 leads, 6%) (P=0.03), and group II had a better complication-free survival curve than group I with a 49% relative risk reduction in lead complication rates (hazard ratio =0.51; 95% confidence interval, 0.27–0.94; P=0.03). Conclusions: The axillary venous approach for permanent pacemaker implantation has better long-term efficacy and lower lead complication rates than the subclavian venous approach.  (Circ J 2014; 78: 865–871)
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  • Koichiro Ejima, Ken Kato, Kotaro Arai, Keiko Fukushima, Noritoshi Fuku ...
    2014 Volume 78 Issue 4 Pages 872-877
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 21, 2014
    JOURNALS FREE ACCESS
    Background: Both the left atrial volume index (LAVI) and estimated total atrial conduction time measured using tissue Doppler imaging of the atria (PA-TDI duration) are echocardiographic parameters reflecting atrial remodeling. We investigated their prognostic value for atrial tachyarrhythmia (AF/AT) recurrence after radiofrequency catheter ablation (RFCA) of paroxysmal atrial fibrillation (PAF). Methods and Results: We analyzed the data for 100 consecutive patients with drug-refractory PAF who underwent RFCA. The correlation between the LAVI and PA-TDI was extremely weak (r=0.26, P<0.01). We categorized the patients into 4 groups based on the median LAVI and PA-TDI duration: group 1 (LAVI <29ml/m2/PA-TDI duration <143ms), group 2 (LAVI ≥29ml/m2/PA-TDI duration <143ms), group 3 (LAVI <29ml/m2/PA-TDI duration ≥143ms), and group 4 (LAVI ≥29ml/m2/PA-TDI duration ≥143ms). With a mean follow-up of 20.2±8.9 months after a single RFCA procedure, 60 patients (60%) were in sinus rhythm without any antiarrhythmic drugs. Multivariate analysis using a Cox proportional hazards model demonstrated that the group was an independent predictor of AF/AT recurrence after RFCA (P=0.0017). The patients in groups 2, 3, and 4 had a 4.0-fold (P=0.048), 6.8-fold (P=0.0034) and 10.9-fold (P=0.0001) increase, respectively, in the probability of recurrent AF/AT as compared with group 1. Conclusions: Preprocedural echocardiographic estimation of atrial remodeling was a useful predictor of AF/AT recurrence following a single RFCA of PAF.  (Circ J 2014; 78: 872–877)
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Cardiovascular Surgery
  • Hiroaki Tanaka, Kayo Tanaka, Chizuko Kamiya, Naoko Iwanaga, Shinji Kat ...
    2014 Volume 78 Issue 4 Pages 878-881
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: January 24, 2014
    JOURNALS FREE ACCESS
    Background: Consensus has not been reached about the anticoagulant therapy to be used during pregnancy after mechanical valve replacement. Warfarin is a fetal toxicant, so we retrospectively examined anticoagulant therapy using unfractionated heparin. Methods and Results: Pregnancy after mechanical valve replacement occurred in 25 cases between 1983 and 2011. Targeted therapy using unfractionated heparin was administered in 9 pregnancies, which were divided into 3 groups: Group I received subcutaneous administration of heparin and APTT was measured twice weekly; Group II received heparin by constant rate infusion (CRI) and APTT was measured twice weekly; Group III received CRI of heparin and APTT was measured daily. Maternal complications consisted of valve thrombosis and perinatal bleeding in 1 pregnancy (Group I), intracranial hemorrhage in 2 pregnancies (Group II), and valve thrombosis and perinatal bleeding in 1 pregnancy (Group III). Two infants died in the neonatal period. Conclusions: Each group showed a high rate of maternal complications, so a review of current anticoagulant treatment strategies is necessary.  (Circ J 2014; 78: 878–881)
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  • Kenji Minakata, Shiro Tanaka, Yohei Okawa, Mitsuomi Shimamoto, Tatsuo ...
    2014 Volume 78 Issue 4 Pages 882-889
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: March 11, 2014
    JOURNALS FREE ACCESS
    Supplementary material
    Background: According to the Japanese Circulation Society guidelines, a bioprosthesis is recommended for aortic valve replacement (AVR) in patients aged ≥65 years who have no risk factors for thromboembolism. There are few data, however, regarding the actual durability of bioprosthetic valves in Japanese patients. The purpose of this study was to assess the long-term durability of Carpentier-Edwards pericardial (CEP) valves in Japanese AVR patients, and to assess the risk factors for reoperation due to structural valve deterioration (SVD). Methods and Results: From 1986 to 2001, a total of 591 patients underwent AVR with CEP valves in 9 hospitals. Of these, 574 patients (mean age, 71.9±8.5 years) were analyzed in this study. There were 26 in-hospital deaths (4.5%). The 10-year follow-up rate was 82.6% and the median follow-up time was 9.2 years. Freedom from reoperation due to SVD was 99.5%, 96.7%, and 87.5% at 5, 10, and 15 years, respectively. Factors that raised the risk of reoperation due to SVD included younger age at operation and history of prior operation. In patients aged ≥65 years, freedom from reoperation due to SVD was 94.4% at 15 years. Conclusions: The durability of CEP valves in patients with AVR was excellent, especially in elderly patients. Thus, it seems appropriate to follow the current Japanese Circulation Society recommendations for the use of bioprosthetic valves.  (Circ J 2014; 78: 882–889)
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Heart Failure
  • Yuichi Nakamura, Akiomi Yoshihisa, Mai Takiguchi, Takeshi Shimizu, Hir ...
    2014 Volume 78 Issue 4 Pages 890-895
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: January 23, 2014
    JOURNALS FREE ACCESS
    Background: Cardiac troponins are independent predictors of cardiac mortality in patients with heart failure (HF). Recently, elevation of troponins was described in non-cardiac diseases such as stroke and infection, among others, but it remains unclear whether high-sensitivity troponin T (hs-TnT) predicts non-cardiac mortality in HF patients. Methods and Results: Four-hundred and forty-four consecutive HF patients admitted to hospital for the treatment of decompensated HF were divided into 2 groups based on median hs-TnT: group L (<0.028ng/ml, n=220) and group H (≥0.028ng/ml, n=224). We compared all-cause mortality and echocardiographic findings between the 2 groups. In the follow-up period (mean 472 days), 77 deaths (49 cardiac deaths and 28 non-cardiac deaths) were observed. The event-free rate was significantly lower in group H than in group L for non-cardiac death (P=0.025), cardiac death (P<0.001), and all-cause mortality (P<0.001). On multivariate Cox proportional hazard analysis, high hs-TnT was found to be an independent predictor of non-cardiac death (P=0.042), cardiac death (P<0.001) and all-cause mortality (P<0.001) in HF patients after adjusting for risk factors. Regarding echocardiographic parameters, left ventricular wall thickness was higher (P<0.001), and ejection fraction was lower (P=0.011) in group H than in group L. Conclusions: Hs-TnT is an independent predictor not only of cardiac mortality, but also of non-cardiac mortality in HF patients.  (Circ J 2014; 78: 890–895)
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  • Masaaki Konishi, Yasushi Matsuzawa, Hiroyuki Suzuki, Eiichi Akiyama, N ...
    2014 Volume 78 Issue 4 Pages 896-902
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: January 29, 2014
    JOURNALS FREE ACCESS
    Supplementary material
    Background: Acute pulmonary edema (APE) often occurs without remarkable fluid retention, and the benefits of diuretics are unclear in such patients. Although aggressive diuresis induces an increase in intravascular substances including hemoglobin (Hb), acute changes in Hb level remain to be investigated. Methods and Results: We analyzed 237 consecutive acute heart failure patients (74±12 years; 60.8% men) without shock, hemodialysis, bleeding, or urgent coronary angiography. APE was defined as acute onset of dyspnea within the preceding 6h and radiographic alveolar edema requiring immediate airway intervention. At admission, Hb level was higher in APE (n=29) than non-APE patients (n=208; 13.4±2.2 vs 12.2±2.1g/dl, P<0.01). Although diuretic therapy was performed in 232 patients (97.9%), hemoconcentration (ie, any increase in Hb) was observed in only 64 patients (27.0%) at 24h after admission. Conversely, Hb level decreased in both groups and the difference was larger in APE patients (−1.8±1.1 in APE and −0.5±1.0g/dl in non-APE patients, P<0.001). APE was significantly related to a greater decrease in Hb after adjusting for baseline Hb (β=−1.08g/dl, SE=0.20, P<0.001, ANCOVA). Conclusions: APE patients had higher Hb level at admission and a more remarkable decline in 24h than did those without APE. Acute change in Hb might be caused by factors other than diuresis-induced hemoconcentration. The present findings may be useful in the selection of diuretic strategies.  (Circ J 2014; 78: 896–902)
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  • Shinsuke Hanatani, Yasuhiro Izumiya, Seiji Takashio, Yuichi Kimura, Sa ...
    2014 Volume 78 Issue 4 Pages 903-910
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 06, 2014
    JOURNALS FREE ACCESS
    Background: Thrombospondin-2 (TSP-2) is a matricellular protein found in human serum. Deletion of TSP-2 causes age-dependent dilated cardiomyopathy. We hypothesized that TSP-2 is a useful biomarker in patients with heart failure with reduced ejection fraction (HFrEF). Methods and Results: Serum TSP-2 was measured in 101 patients with HFrEF, and mortality and cardiovascular events were followed. Serum TSP-2 in the HFrEF group was significantly higher than in the non-HF group (n=17). Mean NYHA functional class was significantly higher in the high TSP-2 group (>median) than the low TSP-2 group (2.26 vs. 1.76, P=0.004). Circulating TSP-2 level was significantly associated with that of B-type natriuretic peptide (BNP; r=0.40, P<0.0001) on multivariate linear regression analysis. On Kaplan-Meier curve analysis the high TSP-2 group had a lower event-free rate than the low TSP-2 group (log-rank test, P=0.03). Multivariate Cox hazard analysis identified hemoglobin (hazard ratio [HR], 0.66; 95% confidence interval [CI]: 0.53–0.82, P<0.0001), and TSP-2 (ln[TSP-2]; HR, 3.34; 95% CI: 1.03–10.85, P=0.045) as independent predictors of adverse outcome. The area under the curve for 1-year events increased when TSP-2 was added to Framingham risk score (FRS; alone, 0.60) or BNP (alone, 0.69; FRS+TSP-2, 0.75; BNP+TSP-2, 0.76). Conclusions: TSP-2 is a potentially useful biomarker for assessment of disease severity and prognosis in HFrEF.  (Circ J 2014; 78: 903–910)
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  • Akihiro Shirakabe, Noritake Hata, Masanori Yamamoto, Nobuaki Kobayashi ...
    2014 Volume 78 Issue 4 Pages 911-921
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 18, 2014
    JOURNALS FREE ACCESS
    Background: Tolvaptan, an oral selective vasopressin 2 receptor antagonist that acts on the distal nephrons to cause a loss of electrolyte-free water, is rarely used during the acute phase of acute heart failure (AHF). Methods and Results: We investigated 183 AHF patients admitted to the intensive care unit and administered tolvaptan (7.5mg) with continuous intravenous furosemide, and then additionally at 12-h intervals until HF was compensated. When intravenous furosemide was changed to peroral use, the administration of tolvaptan was stopped. The patients were assigned to tolvaptan (n=52) or conventional treatment (n=131) groups. The amount of intravenous furosemide was significantly lower (35.4 [16.3–56.0] mg vs. 80.0 [30.4–220.0] mg), the urine volume was significantly higher on days 1 and 2 (3,691 [3,109–4,198] ml and 2,953 [2,128–3,592] ml vs. 2,270 [1,535–3,258] ml and 2,129 [1,407–2,906] ml) and the numbers of patients with worsening-AKI (step-up RIFLE Class to I or F) and Class F were significantly fewer (5.8% and 1.9% vs. 19.1% and 16.0%) in the tolvaptan group than in the conventional group, respectively. One of the specific medications indicated worsening-AKI and in-hospital mortality was tolvaptan (odds ratio [OR] 0.155, 95% confidence interval [CI] 0.037–0.657 and OR 0.191, 95% CI 0.037–0.985). The Kaplan-Meier curves showed that the death rate within 6 months was significantly lower in the tolvaptan group. The same result was found after propensity matching of the data. Conclusions: Early administration of tolvaptan could prevent exacerbation of AKI and improve the prognosis for AHF patients.  (Circ J 2014; 78: 911–921)
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Hypertension and Circulatory Control
  • Hung-Yu Chang, Li-Wei Lo, Yenn-Jiang Lin, Shih-Huang Lee, Chuen-Wang C ...
    2014 Volume 78 Issue 4 Pages 922-928
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 24, 2014
    JOURNALS FREE ACCESS
    Background: Spectral analysis of the left atrium can identify high dominant frequency (DF) sites, which might play a role in the perpetuation of atrial fibrillation (AF). Furthermore, the role of the cardiac autonomic nervous system (CANS) in the genesis of AF has been demonstrated. The relationship between CANS and the high-DF sites (AF nest) was the aim of the investigation. Methods and Results: In 12 dogs, high frequency stimulation was applied to locate 4 major left atrial (LA) ganglionated plexi (GPs). An Ensite Array and a mapping catheter were delivered into the left atrium for electroanatomical mapping. During sinus rhythm, spectral analysis was performed on the bipolar electrograms in the left atrium before and after epicardial GP ablation. The majority of AF nests were close to the GPs (52±18% of total AF nests). After GP ablation, the mean LA DF values decreased from 54±7Hz to 49±4Hz (P=0.023), and DF values of the AF nest decreased from 93±2Hz to 87±4Hz (P=0.001). Most of the previous AF nest sites close to the GPs disappeared (85±23%). The surface area of the AF nest decreased from 9±5cm2 to 3±2cm2 (P=0.001). Conclusions: Catheter ablation of the GP decreased the DF values, AF nest areas and diminished the number of AF nests; particularly those close to the GPs, indicating that the CANS might play an important role in the mechanism of the AF nest.  (Circ J 2014; 78: 922–928)
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Imaging
  • Yasuki Hen, Nobuo Iguchi, Yuko Utanohara, Kaori Takada, Haruhiko Machi ...
    2014 Volume 78 Issue 4 Pages 929-937
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 13, 2014
    JOURNALS FREE ACCESS
    Background: The prognostic value of late gadolinium enhancement (LGE) on contrast-enhanced cardiovascular magnetic resonance (CMR) in Japanese hypertrophic cardiomyopathy (HCM) patients in a large, single-center cohort was investigated. Methods and Results: A total of 345 HCM patients (mean age, 59±17 years; 214 male) underwent CMR with gadolinium enhancement, and were followed (mean duration, 21.8 months) for cardiovascular events. Patients were divided into event-positive and event-negative groups. The clinical and CMR characteristics were compared between the 2 groups, and predictors of cardiovascular events assessed on multivariate analysis. LGE was positive in 252 patients (73%). The annual cardiovascular events rate was significantly higher in patients with LGE than in those without (6.2%/year vs. 0.6%/year, P=0.003). On multivariate analysis, LGE (hazard ratio [HR], 7.436; 95% confidence interval [CI]: 1.001–55.228, P=0.050), increased myocardial mass index (HR, 1.013; 95% CI: 1.002–1.023, P=0.018), reduced left ventricular ejection fraction (HR, 0.965; 95% CI: 0.945–0.985, P=0.001), and atrial fibrillation (HR, 2.257; 95% CI: 1.024–4.976, P=0.043) were significantly associated with cardiovascular events. Conclusions: The presence of LGE, increased myocardial mass index, reduced left ventricular ejection fraction and atrial fibrillation were independent predictors of adverse prognosis in Japanese HCM patients.  (Circ J 2014; 78: 929–937)
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Molecular Cardiology
  • Jun Zhou, Wei-Guang Ding, Takeru Makiyama, Akashi Miyamoto, Yuichi Mat ...
    2014 Volume 78 Issue 4 Pages 938-942
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: January 31, 2014
    JOURNALS FREE ACCESS
    Background: Loss-of-function mutations in the HCN4 gene have been shown to be associated with sinus dysfunction, but there are no reports on HCN4-mediated atrioventricular (AV) block. A novel missense HCN4 mutation G1097W was identified in a 69 year-old Japanese male with AV block, and we characterized the functional consequences of If-like channels reconstituted with the heterozygous HCN4 mutation. Methods and Results: Wild-type (WT) HCN4 or/and HCN4-G1097W were expressed in a heterologous cell expression system. A functional assay using a whole-cell patch-clamp demonstrated that the mutant If-like currents were activated at more negative voltages compared to WT currents, while they retained the sensitivity to changes in intracellular cyclic adenosine monophosphate (cAMP) levels. Co-expression of G1097W with WT channels showed dominant-negative effects, including a reduction in peak currents and a negative voltage shifting on reconstituted currents. Conclusions: The HCN4-G1097W mutant channels displayed a loss-of-function type modulation on cardiac If channels and thus could predispose them to AV nodal dysfunction. These data provide a novel insight into the genetic basis for the AV block.  (Circ J 2014; 78: 938–942)
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Myocardial Disease
  • – Possible Markers for Severity of Myocardial Damage –
    Masato Shimizu, Mitsuhiro Nishizaki, Noriyoshi Yamawake, Hiroyuki Fuji ...
    2014 Volume 78 Issue 4 Pages 943-949
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 06, 2014
    JOURNALS FREE ACCESS
    Background: The J wave and fragmented QRS (fQRS) on electrocardiography are suggested to be closely related to cardiac arrhythmogenesis. Takotsubo cardiomyopathy (TTC) occasionally causes fatal cardiac conditions including life-threatening ventricular arrhythmia. There has been, however, only 1 case report describing the J wave in TTC, and fQRS has not been reported thus far in relation to clinical courses and prognosis. Methods and Results: J wave and fQRS formation were investigated in 31 consecutive patients with TTC. Nine patients (29%) had J waves and/or fQRS (group A), whereas the remaining 22 did not (group B). The J wave (4 patients), fQRS (4 patients), or both (1 patient) appeared transiently during the hyperacute phase. Left ventricular ejection fraction was significantly lower in group A. Summed defect score of single-photon emission computed tomography using iodine 123 beta-methyl-p-iodophenyl-pentadecanoic acid, and creatine kinase MB isozyme (CKMB) were significantly higher in group A. On multivariate analysis CKMB was a significant indicator of J wave or fQRS. Moreover, the J wave was a significant indicator for cardiac death and/or ventricular tachyarrhythmia (odds ratio, 11.5; P=0.026). Conclusions: Patients with TTC frequently had J waves and/or fQRS during the hyperacute phase, and which were associated with myocardial damage. J wave was also an indicator for cardiac death and/or ventricular tachyarrhythmia. J waves and fQRS may be useful markers for myocardial damage.  (Circ J 2014; 78: 943–949)
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Preventive Medicine
  • Masato Kajikawa, Ayumu Nakashima, Tatsuya Maruhashi, Yumiko Iwamoto, A ...
    2014 Volume 78 Issue 4 Pages 950-954
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 05, 2014
    JOURNALS FREE ACCESS
    Background: Poor oral health is an independent predictor of cardiovascular outcome. Endothelial dysfunction is the initial step of atherosclerosis, resulting in cardiovascular outcomes; but there is no information on the association between oral health and endothelial function. The purpose of this study was to determine the relationships between oral health and endothelial function. Methods and Results: A total of 190 subjects who underwent health examinations (mean age, 57±18 years), including patients with cardiovascular disease, completed a questionnaire on oral health and frequency of tooth brushing, and underwent measurement of vascular function, flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation. The subjects were divided into 2 groups according to frequency of tooth brushing (≥twice/day and <once/day). FMD was significantly lower in the <once/day tooth brushing group as compared to the ≥twice/day tooth brushing group (3.3±2.2% vs. 5.0±3.0%, P<0.001). There was no significant difference in nitroglycerine-induced vasodilation between the 2 groups. On multiple logistic regression analysis, tooth brushing <once/day remained independently associated with low FMD tertile. Conclusions: Poor oral health, that is, decreased frequency of tooth brushing, is associated with endothelial dysfunction.  (Circ J 2014; 78: 950–954)
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  • – The Circulatory Risk in Communities Study (CIRCS) –
    Fumihiko Sano, Tetsuya Ohira, Akihiko Kitamura, Hironori Imano, Renzhe ...
    2014 Volume 78 Issue 4 Pages 955-961
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 19, 2014
    JOURNALS FREE ACCESS
    Background: Evidence regarding the relationship between different levels of alcohol consumption and the risk of atrial fibrillation (AF) is currently limited in Asian populations. Methods and Results: Between 1991 and 1995, a total of 8,602 Japanese men and women aged 30–80 years took part in the first examination of the Circulatory Risk in Communities Study (CIRCS), a population-based cohort study in Japanese communities. An interviewer obtained detailed information on weekly alcohol intake. During the follow-up period, the incidence of AF was ascertained from annual ECG records, the subject’s medical history of AF, and cardiovascular disease surveillance. The hazard ratios (HRs) of incident AF and the 95% confidence intervals (CIs) relative to the never-drinking group were calculated with adjustment for potential confounding factors by using the Cox proportional hazard model. During a median follow-up period of 6.4 years, 296 incidents of AF occurred. A higher incidence of AF was observed among participants with an ethanol intake >69g/day, compared with never-drinkers. Compared with the never-drinkers, the multivariable-adjusted HRs (CIs) of past, light (<23g/day), light–moderate (23–46g/day), moderate (46–69g/day), and heavy (>69g/day) drinkers were 1.30 (0.68–2.49), 0.89 (0.60–1.32), 1.19 (0.73–1.95), 1.36 (0.79–2.35), and 2.90 (1.61–5.23), respectively. Conclusions: Heavy alcohol consumption is associated with a higher risk of AF.  (Circ J 2014; 78: 955–961)
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Pulmonary Circulation
  • Seitetsu L. Lee, Masao Daimon, Takayuki Kawata, Takahide Kohro, Koichi ...
    2014 Volume 78 Issue 4 Pages 962-966
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: January 29, 2014
    JOURNALS FREE ACCESS
    Background: Right atrial pressure (RAP) is commonly estimated using inferior vena cava (IVC) diameter and its respirophasic variations. Although a guideline has been provided for estimation of RAP due to variation in IVC dimensions based on studies in Western subjects, echocardiographic values in Asian subjects are unknown. Methods and Results: We studied 369 patients who underwent IVC ultrasound within 24h of right heart catheterization (RHC). The maximum and minimum IVC diameter during a respiratory cycle and the percent collapse after a sniff test were measured. These IVC parameters were compared with mean RAP measured on RHC. Receiver operating characteristic curves were generated for each IVC parameter to determine the optimal cut-off to detect RAP >10mmHg. The IVC maximum diameter cut-off for detecting RAP >10mmHg was 19mm (sensitivity, 75%; specificity, 78%) and the percent collapse cut-off was 30% (sensitivity, 75%; specificity, 83%). Both cut-offs were smaller than those previously reported in patients from Western countries. When the cut-off values from the existing guideline were applied to the present cohort, the sensitivity and specificity for normal RAP (0–5mmHg) were 38.6% and 74.2%, respectively, and 60.0% and 92.0% for elevated RAP (>10mmHg). Conclusions: The optimal IVC maximum diameter and percent collapse cut-offs to detect elevated RAP were smaller in Asian subjects than in a previously reported Western cohort.  (Circ J 2014; 78: 962–966)
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  • Md. Elias-Al-Mamun, Kimio Satoh, Shin-ichi Tanaka, Toru Shimizu, Suvd ...
    2014 Volume 78 Issue 4 Pages 967-976
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 18, 2014
    JOURNALS FREE ACCESS
    Supplementary material
    Background: Pulmonary hypertension (PH) is a fatal disease characterized by pulmonary artery (PA) remodeling, elevated PA pressure and right ventricular (RV) failure. It has been previously demonstrated that treatment with a Rho-kinase inhibitor, fasudil, ameliorates PH in animal models. Here, whether combination therapy with fasudil and sildenafil further ameliorates PH in rats was examined. Methods and Results: PH was induced in Sprague-Dawley rats by the use of a single subcutaneous monocrotaline (MCT) injection, which caused PA remodeling, elevated RV systolic pressure (RVSP), and RV hypertrophy (RVH). While fasudil and sildenafil monotherapy inhibited the development of MCT-induced PH in the prevention and treatment protocols, their combination therapy further improved RVSP and RVH. Moreover, a histological examination demonstrated significant improvements of PA remodeling in the combination group compared with the monotherapy groups. An echocardiographic examination also revealed significant reduction in RV diameter in the combination group compared with the monotherapy groups. Mechanistic experiments revealed significant inhibition of Rho-kinase activity in PA trunk, lung and RV tissues in the combination group as well as in the monotherapy groups. Finally, the combination therapy markedly improved the long-term survival compared with the monotherapy groups. Conclusions: These results indicate that the combination therapy with fasudil and sildenafil shows the synergistic effects through the inhibition of Rho-kinase activity for the treatment of PH.  (Circ J 2014; 78: 967–976)
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Regenerative Medicine
  • – Pathogenetic Implications –
    Francesca Graziani, Antonio Maria Leone, Eloisa Basile, Pio Cialdella, ...
    2014 Volume 78 Issue 4 Pages 977-985
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 27, 2014
    JOURNALS FREE ACCESS
    Background: The aim of this study was to assess the relationship among anthropometric indexes of adiposity (body mass index [BMI], waist circumference [WC]), endothelial progenitor cells (EPC) and carotid intima-media thickness (IMT) in patients with morbid obesity, and the effect of diabetes and weight loss. Methods and Results: BMI, WC, IMT and circulating EPC (defined as CD34+/KDR+/CD45- cells) were assessed in 100 patients (37 with diabetes). Fifty patients underwent bariatric surgery, and in 48 of them a complete re-assessment after an average follow-up of 252±108 days was carried out. In 29 of them subcutaneous and visceral adipose tissue samples were obtained at the time of intervention and analyzed for the presence and number of EPC. EPC were directly correlated with weight, BMI, WC and insulin level, and inversely with mean IMT. All correlations were confined to non-diabetic patients. EPC were found in both subcutaneous and visceral adipose tissue specimens. Circulating EPC significantly decreased after weight loss (P=0.002). Conclusions: EPC are positively related to markers of adiposity in severe obesity, when not complicated by diabetes. Weight loss is associated with decrease in EPC level. EPC are inversely correlated with IMT, confirming their protective role also in severe obesity. Diabetes has a negative modulating action.  (Circ J 2014; 78: 977–985)
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Renal Disease
  • Yoshitaka Kumada, Hideki Ishii, Toru Aoyama, Daisuke Kamoi, Yoshihiro ...
    2014 Volume 78 Issue 4 Pages 986-992
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 14, 2014
    JOURNALS FREE ACCESS
    Background: Although revascularization via coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) has been widely performed, there are limited data on which procedure is best in hemodialysis (HD) patients. Methods and Results: This 10-year follow-up study consisted of 997 HD patients electively undergoing coronary revascularization (CABG, n=210; PCI, n=787). With an adjustment for propensity scores with all baseline covariates, the incidence of major adverse cardiac events (MACE) was evaluated as a composite endpoint including all-cause death, non-fatal myocardial infarction (MI) and any revascularization. During the follow-up period, 465 MACE (death, n=325; non-fatal MI, n=45; revascularization, n=274) occurred. The 10-year freedom from MACE was higher in the CABG group compared to the PCI group (51.0% vs. 34.8%, adjusted hazard ratio [HR], 0.64; 95% confidence interval [CI]: 0.49–0.82, P=0.0003). On landmark analysis, adjusted HR of death was higher during the first 6 months after CABG compared to PCI (1.72; 95% CI: 1.04–2.79, P=0.036), but lower from 6 months onward (0.69; 95% CI: 0.48–0.97, P=0.033). When compared to patients treated with drug-eluting stent alone (n=345) in the PCI group, the CABG group still had an advantage for any revascularization (adjusted HR, 0.38; 95% CI: 0.22–0.62, P<0.0001), but not for MACE (adjusted HR, 0.86; 95% CI: 0.64–1.15, P=0.33). Conclusions: CABG was totally clinically advantageous compared to PCI in HD patients.  (Circ J 2014; 78: 986–992)
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Valvular Heart Disease
  • Tao Tu, Shenghua Zhou, Zhenjiang Liu, Xuping Li, Qiming Liu
    2014 Volume 78 Issue 4 Pages 993-1001
    Published: 2014
    Released: March 25, 2014
    [Advance publication] Released: February 19, 2014
    JOURNALS FREE ACCESS
    Background: The modification of cardiac energy metabolism during atrial fibrillation (AF) has been demonstrated in previous studies, indicating a close association between these 2 processes. The aim of the present study was to identify the underlying mechanisms via profiling of the expression of energy metabolism-related proteins in the left atrial appendage (LAA) of patients with AF. Methods and Results: Isobaric tag for relative and absolute quantification-coupled 2-D liquid chromatography-tandem mass spectrometry (iTRAQ-coupled 2-D LC-MS/MS) was used to profile the expression of energy metabolism-related proteins in the LAA from valvular disease patients with sinus rhythm (SR; n=6) and AF (n=8). Using ProteinPilot 4.0, 122 energy metabolism-related proteins, consisting of 39 carbohydrate metabolism-related proteins, 22 proteins involved in lipid metabolism, 49 biological oxidation-related proteins and 12 other kinds of proteins, were identified. Most of them were key enzymes involved in energy metabolism. Moreover, most of the proteins that were expressed differently in the LAA between the AF and SR patients, and which were related to energy metabolism, were downregulated. These results were further validated on western blot. Conclusions: Atrial myocardium energy production in valvular disease patients is impaired during permanent AF, and this impairment in energy production may be involved in the matrix of AF formation.  (Circ J 2014; 78: 993–1001)
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