Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Volume 77 , Issue 9
Showing 1-37 articles out of 37 articles from the selected issue
Message From the Editor-in-Chief
Cardiovascular Epidemiology in Asia
  • Yasuhiko Sakata, Hiroaki Shimokawa
    2013 Volume 77 Issue 9 Pages 2209-2217
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: August 14, 2013
    JOURNALS FREE ACCESS
    Heart failure (HF) is a global epidemic in health care and a leading cause of mortality and morbidity worldwide. In Asian countries, causes of mortality and morbidity have shifted or have been shifting from infectious diseases and/or nutritional deficiencies to lifestyle-related diseases, such as cardiovascular disease, cancers and diabetes, in conjunction with the transition from developing to developed countries during the past decades (so-called “the epidemiologic transition”). Because the effect of this epidemiologic transition varies among countries, the etiology, prevalence, management and outcomes of HF also differ among the countries. Thus, we need to assemble and comprehensively analyze the available evidence to date for daily HF practice in Asia and to systematically conduct future epidemiologic approaches to establishing appropriate prevention programs against the burden of HF in Asia. This review article will briefly update the epidemiology of HF in Asia.  (Circ J 2013; 77: 2209–2217)
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Reviews
  • Osamu Tsukamoto, Masafumi Kitakaze
    2013 Volume 77 Issue 9 Pages 2218-2225
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: July 18, 2013
    JOURNALS FREE ACCESS
    Cardiac-specific myosin light chain kinase (cMLCK) is the kinase predominantly responsible for the maintenance of the basal level of phosphorylation of cardiac myosin light chain 2 (MLC2), which it phosphorylates at Ser-15. This phosphorylation repels the myosin heads from the thick myosin filament and moves them toward the thin actin filament. Unlike smooth muscle cells, MLC2 phosphorylation in striated muscle cells appears to be a positive modulator of Ca2+ sensitivity that shifts the Ca2+-force relationship toward the left and increases the maximal force response and thus does not initiate muscle contraction. Recent studies have revealed an increasing number of details of the biochemical, physiological, and pathophysiological characteristics of cMLCK. The combination of recent technological advances and the discovery of a novel class of biologically active nonstandard peptides will hopefully translate into the development of drugs for the treatment of heart diseases.  (Circ J 2013; 77: 2218–2225)
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  • Katsuyuki Miura, Masato Nagai, Takayoshi Ohkubo
    2013 Volume 77 Issue 9 Pages 2226-2231
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: July 30, 2013
    JOURNALS FREE ACCESS
    Analyses of data from national surveys of the Japanese population have shown a clear decreasing tendency in mean systolic blood pressure (BP) level over the past 50 years in all age groups of men and women; however, mean diastolic BP level clearly did not decrease in men. Hypertension prevalence is high among older people and may increase in the future, especially in men aged ≥50 years. The treatment and control rates of hypertension are not sufficiently high, although they have been continuously improving. Recent epidemiological studies also showed that the burden of cardiovascular diseases and total mortality because of the adverse BP level of the nation is still the highest among other preventable risk factors. To overcome this epidemic, the first priority should be primary prevention of a lifetime increase in BP through lifestyle improvement. Lowering the distribution of BP in the whole population and maintaining BP at optimal levels contributes to the achievement of this goal.  (Circ J 2013; 77: 2226–2231)
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  • Minoru Tabata, Toshihiro Fukui, Shuichiro Takanashi
    2013 Volume 77 Issue 9 Pages 2232-2239
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: August 03, 2013
    JOURNALS FREE ACCESS
    With the development of techniques and technologies in the past decade, minimally invasive valve surgery (MIVS) has become a well-established surgical option for heart valve disease. Unlike emerging transcatheter valves, MIVS still requires cardiopulmonary bypass and cardiotomy. The only difference between minimally invasive and conventional valve operations is whether a full sternotomy is avoided or not. The minimally invasive approach has been shown to have some beneficial effects such as reduced blood transfusion and faster postoperative recovery. However, these could be limited and outweighed by the potential adverse effects of small access. Careful selection of patient, approach and perfusion strategy based on thorough preoperative assessment and each surgical team experience is necessary to perform MIVS safely.  (Circ J 2013; 77: 2232–2239)
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Editorials
Original Articles
Arrhythmia/Electrophysiology
  • Hee-Sun Mun, Changyu Shen, Hui-Nam Pak, Moon-Hyoung Lee, Shien-Fong Li ...
    2013 Volume 77 Issue 9 Pages 2255-2263
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 04, 2013
    JOURNALS FREE ACCESS
    Background: The mechanisms underlying amiodarone-induced sinoatrial node (SAN) dysfunction remain unclear, so we used 3-dimensional endocardial mapping of the right atrium (RA) to investigate. Methods and Results: In a matched-cohort design, 18 patients taking amiodarone before atrial fibrillation (AF) ablation (amiodarone group) were matched for age, sex and type of AF with 18 patients who had undergone AF ablation without taking amiodarone (no-amiodarone group). The amiodarone group had a slower heart rate than the no-amiodarone group at baseline and during isoproterenol infusion. Only the amiodarone group had sick sinus syndrome (n=4, 22%, P=0.03) and abnormal (>550ms) corrected SAN recovery time (n=5, 29%; P=0.02). The median distance from the junction of the superior vena cava (SVC) and RA to the most cranial earliest activation site (EAS) was longer in the amiodarone group than in the no-amiodarone group at baseline (20.5 vs. 10.6mm, P=0.04) and during isoproterenol infusion (12.8 vs. 6.3mm, P=0.03). The distance from the SVC-RA junction to the EAS negatively correlated with the P-wave amplitudes of leads II (r=–0.47), III (r=–0.60) and aVF (r=–0.56) (P<0.001 for all). Conclusions: In a quarter of the AF patients, amiodarone causes superior SAN dysfunction, which results in a downward shift of the EAS and reduced P-wave amplitude in leads II, III and aVF at baseline and during isoproterenol infusion.  (Circ J 2013; 77: 2255–2263)
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  • Hiroshi Inoue, Ken Okumura, Hirotsugu Atarashi, Takeshi Yamashita, Hid ...
    2013 Volume 77 Issue 9 Pages 2264-2270
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: May 25, 2013
    JOURNALS FREE ACCESS
    Background: Target anticoagulation levels for warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF) are unclear. Methods and Results: Of 7,527 patients with NVAF, 1,002 did not receive warfarin (non-warfarin group), and the remaining patients receiving warfarin were divided into 5 groups based on their baseline international normalized ratio (INR) of prothrombin time (≤1.59, 1.6–1.99, 2.0–2.59, 2.6–2.99, and ≥3.0). Patients were followed-up prospectively for 2 years. Primary endpoints were thromboembolic events (cerebral infarction, transient ischemic attack, and systemic embolism), and major hemorrhage requiring hospital admission. During the follow-up period, thromboembolic events occurred in 3.0% of non-warfarin group, but at lower frequencies in the warfarin groups (2.0, 1.3, 1.5, 0.6, and 1.8%/2 years for INR values of ≤1.59, 1.6–1.99, 2.0–2.59, 2.6–2.99, and ≥3.0, respectively; P=0.0059). Major hemorrhage occurred more frequently in warfarin groups (1.5, 1.8, 2.4, 3.3, and 4.1% for INR values ≤1.59, 1.6–1.99, 2.0–2.59, 2.6–2.99, and ≥3.0, respectively; P=0.0041) than in non-warfarin group (0.8%/2 years). These trends were maintained when the analyses were confined to patients aged ≥70 years. Conclusions: An INR of 1.6–2.6 is safe and effective at preventing thromboembolic events in patients with NVAF, particularly patients aged ≥70 years. An INR of 2.6–2.99 is also effective, but associated with a slightly increased risk in major hemorrhage. (UMIN Clinical Trials Registry UMIN000001569)  (Circ J 2013; 77: 2264–2270)
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  • Maciej Wójcik, Alexander Berkowitsch, Harald Greiss, Sergey Zal ...
    2013 Volume 77 Issue 9 Pages 2271-2279
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 12, 2013
    JOURNALS FREE ACCESS
    Background: Pre-procedural predictors (PP) of atrial fibrillation (AF) recurrence (AFR) after repeated catheter ablation of AF (RCAF) are unknown. The aim of this study was identification of PP of outcome after RCAF. Methods and Results: In 213 patients (73% male) with drug-refractory AF (47% paroxysmal AF; PAF) RCAF was performed. CHADS2, CHA2DS2-VASc and ALARMEc (AF type, Left Atrium size, Renal insufficiency, MEtabolic syndrome, cardiomyopathy) scores were calculated for each patient. Complete success was defined as no AFR. After RCAF, 125 patients (59%) were free of atrial flutter or atrial tachycardia (AFLAT) on long-term follow-up (FU). The univariate predictors of AFR were: type of AF (non-PAF vs. PAF, P=0.001), normalized left atrium area (NLA ≥10.25 vs. NLA <10.25, P=0.012) and estimated glomerular filtration rate (<68ml/min vs. ≥68ml/min, P=0.048). The independent predictors of AFLAT-free survival after RCAF were non-PAF (P=0.002) and NLA ≥10.25 (P=0.018). Among combined predictors, only ALARMEc score, and neither CHADS2 or CHA2DS2-VASc, predicted outcome after RCAF (P<0.0001). Conclusions: RCAF results in a moderate success rate on very long-term FU. Lower success was observed in patients with non-PAF and enlarged LA. ALARMEc score allows for clear description of expected outcome after RCAF.  (Circ J 2013; 77: 2271–2279)
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  • Maciej Wójcik, Damir Erkapic, Alexander Berkowitsch, Sergey Zal ...
    2013 Volume 77 Issue 9 Pages 2280-2287
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 26, 2013
    JOURNALS FREE ACCESS
    Background: Predictors of long-term outcome of atrial fibrillation (AF) ablation are unknown. The predictors of 5-year follow-up (FU) after single ipsilateral circumferential antrum pulmonary vein isolation (PVI) with irrigated tip catheter were investigated. Methods and Results: In 356 patients (74% male) with AF (44% paroxysmal AF [PAF]) PVI was performed. Success was defined as absence of AF, atrial flutter or tachycardia (AFLAT) recurrence. A total of 161 patients (45%) were free of AFLAT. The univariate predictors of AFLAT recurrence were: type of AF (non-PAF vs. PAF, P=0.0001), size of LA (normalized left atrium area [NLA] ≥11.5 vs. NLA <11.5, P=0.0001), renal function (glomerular filtration rate [GFR] <68ml/min vs. GFR ≥68ml/min, P=0.001) and hypertension (HT vs. no HT, P=0.025). The independent predictors of AFLAT-free survival were non-PAF (hazard ratio [HR], 1.67; 95% confidence interval [CI]: 1.23–2.26, P=0.0005), NLA ≥11.5 (HR, 1.40; 95% CI: 1.03–1.90, P=0.007) and GFR <68ml/min (HR, 1.70; 95% CI: 1.21–2.37, P=0.008). Conclusions: Single PVI results in a moderate success rate in patients with AF during 5-year FU without the use of a 3-D mapping system. Higher success was observed in patients with PAF, non-enlarged LA and good renal function.  (Circ J 2013; 77: 2280–2287)
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Cardiovascular Surgery
  • Takashi Murashita, Yukikatsu Okada, Hideo Kanemitsu, Naoto Fukunaga, Y ...
    2013 Volume 77 Issue 9 Pages 2288-2294
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: May 25, 2013
    JOURNALS FREE ACCESS
    Background: The issue of whether functional tricuspid regurgitation (TR) should be repaired at the time of mitral valve surgery is controversial, and the long-term durability of tricuspid valve (TV) annuloplasty remains unknown. Methods and Results: We retrospectively reviewed 654 patients who underwent mitral valve repair for degenerative mitral regurgitation between 1991 and 2010. Preoperative TR was classed as mild, trivial or absent in 479 (73.2%) patients, moderate in 125 (19.1%) patients and severe in 50 (7.7%) patients. Concomitant TV annuloplasty was performed in 162 patients (24.8%). The mean follow up duration was 7.5±4.9 years. Postoperative transthoracic echocardiography was performed according to a fixed schedule. The long-term survival rate and freedom from re-admission for congestive heart failure were affected by the severity of TR. Although the durability of ring annuloplasty was excellent up to 10 years after surgery, the mean TR grade started to increase after 10 years. Sixteen out of 492 patients who did not undergo TV annuloplasty (3.2%) revealed progression to severe TR. Preoperative atrial fibrillation (odds ratio (OR), 4.85; 95% confidence interval (CI), 1.38–17.1; P=0.014) and preoperative TR grade (OR, 5.16; 95% CI, 1.78–14.9; P=0.003) were predictors for progression to severe TR. Conclusions: Aggressive treatment with concomitant TV annuloplasty should be advocated in cases with atrial fibrillation and more than moderate TR.  (Circ J 2013; 77: 2288–2294)
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  • Hiroshi Munakata, Alexander Assmann, Bhawana Poudel-Bochmann, Kim Hors ...
    2013 Volume 77 Issue 9 Pages 2295-2302
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: May 29, 2013
    JOURNALS FREE ACCESS
    Background: The objective of this study was to describe a small animal aortic conduit model that could analyze long-term conduit valve (CV) function by echocardiography. Methods and Results: Recipient Wistar rats (200–250g, n=20) underwent aortic leaflet injury of their native aortic valve under echocardiographic control. After 2 weeks, U-shaped decellularized CVs obtained from other rats were implanted onto the abdominal aorta. Implanted CVs were analyzed via pulsed-wave echocardiography at day 0, 4 and 12 weeks. CV stenosis was assessed as systolic flow velocity (post-pre CV)/flow velocity in the ascending aorta. CV regurgitation was assessed as the ratio of the amount of reversed diastolic flow to forward systolic flow in post-pre CV. The endpoint was set at 12 weeks. Three rats died immediately after aortic valve injury and all surviving rats received CV implantation (n=17, 85%). The survival rate after conduit implantation was 100% at 4 weeks and 88% (15/17) at 12 weeks. Regarding the CV function at 0, 4 and 12 weeks, the average observed value of CV stenosis was 3.8±7.9%, 3.1±4.1% and 14±10% (P<0.01), respectively. The average value of CV regurgitation was 0%, 12±27% and 52±43%, respectively (P<0.001). Conclusions: By using this model, the degeneration of implanted CV could be assessed not only qualitatively, but also quantitatively.  (Circ J 2013; 77: 2295–2302)
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  • Su-Kiat Chua, Kou-Gi Shyu, Ming-Jen Lu, Huei-Fong Hung, Jun-Jack Cheng ...
    2013 Volume 77 Issue 9 Pages 2303-2310
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 15, 2013
    JOURNALS FREE ACCESS
    Background: Renal dysfunction is associated with a higher rate of atrial fibrillation in clinical practice. This study investigated the associations between renal function, left ventricular (LV) diastolic dysfunction, and postoperative atrial fibrillation (POAF). Methods and Results: A total of 265 consecutive patients who underwent cardiac surgery were prospectively enrolled in the study. Echocardiography was performed before cardiac surgery. The patients were divided into 3 groups based on estimated glomerular filtration rate (eGFR) (group 1, ≥90ml·min–1·1.73m–2; group 2, 60–90ml·min–1·1.73m–2; and group 3, <60ml·min–1·1.73m–2). POAF occurred in 83 of 265 patients (31.3%). The rate of new-onset POAF increased from 15.2% (12/79) in group 1 to 27.8% (27/97) in group 2 and 49.4% (44/89) in group 3 (P<0.001). Further, with increasing renal dysfunction from groups 1 to 3, the rate of LV diastolic dysfunction – defined as E/e’ >15 – also increased (group 1, 19.0%; group 2, 38.1%; and group 3, 48.3%; P<0.001). Absolute eGFR was significantly correlated with E/e’ ratio (r=−0.39, P<0.001). Renal function remained as the independent predictor of POAF on multivariate analysis (odds ratio, 1.90; 95% confidence interval: 1.26–2.87; P=0.002). Conclusions: In patients undergoing cardiac surgery, decreased eGFR was associated with an increased rate of LV diastolic dysfunction with a subsequent increase in the rate of POAF.  (Circ J 2013; 77: 2303–2310)
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Epidemiology
  • Tomoko Usui, Toshiharu Ninomiya, Masaharu Nagata, Otowa Takahashi, Yas ...
    2013 Volume 77 Issue 9 Pages 2311-2317
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 04, 2013
    JOURNALS FREE ACCESS
    Background: Angiopoietin-like protein 2 (Angptl2) is an adipokine that promotes inflammation and endothelial dysfunction of the vessels. The aim of this study was to investigate the relationship between serum Angptl2 level and chronic kidney disease (CKD). Methods and Results: A total of 3,169 community-dwelling subjects aged ≥40 years were divided into quintiles by Angptl2 level. CKD was defined as the presence of albuminuria (urine albumin-creatinine ratio ≥30.0mg/g) or decreased estimated glomerular filtration rate (eGFR <60ml·min–1·1.73m–2). The odds ratio (OR) for the presence of CKD was calculated using a logistic regression model. The overall prevalence of CKD was 37.5%. The age- and sex-adjusted ORs for the presence of CKD increased with higher serum Angptl2 level. This trend remained significant after adjusting for known cardiovascular risk factors (<2.01ng/ml: OR, 1.00 (reference); 2.01–2.48ng/ml: OR, 1.67, 95% confidence interval [CI]: 1.24–2.24; 2.49–2.99ng/ml: OR, 1.70, 95% CI: 1.27–2.28; 3.00–3.65ng/ml: OR, 1.78, 95% CI: 1.32–2.39; ≥3.66ng/ml: OR, 1.79, 95% CI: 1.32–2.43; P-value for trend=0.001). Multivariate-adjusted ORs for the presence of albuminuria increased significantly with elevated serum Angptl2 (P-value for trend=0.004), while there was no evidence of a significant relationship between serum Angptl2 level and decreased eGFR (P-value for trend=0.08). Conclusions: Elevated serum Angptl2 is associated with the likelihood of CKD in the general population.  (Circ J 2013; 77: 2311–2317)
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  • Kotaro Nochioka, Yasuhiko Sakata, Jun Takahashi, Satoshi Miyata, Masan ...
    2013 Volume 77 Issue 9 Pages 2318-2326
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 26, 2013
    JOURNALS FREE ACCESS
    Background: The prognostic impact of nutritional status is poorly understood in asymptomatic patients with structural and/or functional heart diseases, classified as stage B in the ESC/AHA/ACC chronic heart failure (HF) guidelines. Methods and Results: We evaluated the impact of nutrition, using the controlling nutritional status (CONUT) score, calculated by the serum albumin and total cholesterol levels,and lymphocyte number, in 3,421 stage B patients from the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 Study (mean age: 66.9±12.7 years, male: 71.6%). During a median follow-up of 2.89 years, 224 patients died from cardiovascular (45%, n=102) and noncardiovascular (55%, n=123) causes and 139 experienced hospitalization for HF. Survival at 3 years in patients with CONUT 0–1 (reference, n=2,121), 2 (n=693) and ≥3 (n=607) was 95.5, 92.3, and 73.2%, respectively (P<0.001). The adjusted Cox hazard analyses revealed that the CONUT score was significantly associated with increased incidence of all-cause death (hazard ratio 1.27 per point increase; 95% confidence interval, 1.16–1.39, P<0.001). Subgroup analysis showed that per point increase in the CONUT score was significantly associated with a 17% increase in HF hospitalization in patients ≥70 years old (P=0.049), but not in those aged <70 years. Conclusions: In the current stage B patients, poor nutritional status was associated with increased incidence of death for the overall population and of HF hospitalization for the elderly proportion.  (Circ J 2013; 77: 2318–2326)
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Imaging
  • Takashi Muramatsu, Hector M. García-García, Yoshinobu On ...
    2013 Volume 77 Issue 9 Pages 2327-2333
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 15, 2013
    JOURNALS FREE ACCESS
    Background: The prevalence and clinical sequelae of optical frequency domain imaging (OFDI)-detected intimal flaps caused by vessel trauma or plaque rupture in the proximal native coronary arteries have not been described. Methods and Results: OFDI investigation was performed following stent implantation in patients with ST-segment elevation myocardial infarction (STEMI). We defined a flap-like structure (FS) as a disruption or discontinuation of the endoluminal vessel surface, and classified as actual flap or artifact. FS in the left main stem, or maximally 20mm distal to the guiding catheter in the proximal right coronary artery were assessed. A total of 8,931 frames in 97 patients were analyzed in a frame-by-frame fashion (0.125-mm interval). OFDI identified 8 FS in 7 patients, none of which was evident angiographically. All FS were left untreated because the operators per protocol were blinded to the OFDI images. A total of 5 FS in 5 patients (5.1%) appeared to be actual flaps in which only the intima was involved (mean distance from guiding catheter: 4.8±2.7mm). The remaining 3 FS in 3 patients were artifacts; namely, residual blood and interface light reflectivity. There were no adverse cardiac events during 6-months follow-up. Conclusions: In 5.1% of STEMI patients, post-procedural OFDI identified flaps with minimal involvement of the intima in the proximal coronary arteries. A precise interpretation of FS may help decision making to avoid unnecessary procedures. (Clinical Trial Registration Information: ClinicalTrials.gov identifier: NCT01271361.)  (Circ J 2013; 77: 2327–2333)
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  • Emile Mehanna, Hiram G. Bezerra, David Prabhu, Eric Brandt, Daniel Cha ...
    2013 Volume 77 Issue 9 Pages 2334-2340
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 19, 2013
    JOURNALS FREE ACCESS
    Background: Coronary artery calcification (CAC) presents unique challenges for percutaneous coronary intervention. Calcium appears as a signal-poor region with well-defined borders by frequency-domain optical coherence tomography (FD-OCT). The objective of this study was to demonstrate the accuracy of intravascular FD-OCT to determine the distribution of CAC. Methods and Results: Cadaveric coronary arteries were imaged using FD-OCT at 100-μm frame interval. Arteries were subsequently frozen, sectioned and imaged at 20-μm intervals using the Case Cryo-Imaging automated systemTM. Full volumetric co-registration between FD-OCT and cryo-imaging was performed. Calcium area, calcium-lumen distance (depth) and calcium angle were traced on every cross-section; volumetric quantification was performed offline. In total, 30 left anterior descending arteries were imaged: 13 vessels had a total of 55 plaques with calcification by cryo-imaging; FD-OCT identified 47 (85%) of these plaques. A total of 1,285 cryo-images were analyzed and compared with corresponding co-registered 257 FD-OCT images. Calcium distribution, represented by the mean depth and the mean calcium angle, was similar, with excellent correlation between FD-OCT and cryo-imaging respectively (mean depth: 0.25±0.09 vs. 0.26±0.12mm, P=0.742; R=0.90), (mean angle: 35.33±21.86° vs. 39.68±26.61°, P=0.207; R=0.90). Calcium volume was underestimated in large calcifications (3.11±2.14 vs. 4.58±3.39mm3, P=0.001) in OCT vs. cryo respectively. Conclusions: Intravascular FD-OCT can accurately characterize CAC distribution. OCT can quantify absolute calcium volume, but may underestimate calcium burden in large plaques with poorly defined abluminal borders.  (Circ J 2013; 77: 2334–2340)
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Ischemic Heart Disease
  • Hisao Ogawa, Shinya Goto, Masunori Matsuzaki, Shintaro Hiro, Daisuke S ...
    2013 Volume 77 Issue 9 Pages 2341-2348
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 07, 2013
    JOURNALS FREE ACCESS
    Background: Concomitant anticoagulant therapy may further reduce the risk of thrombotic events in patients with acute coronary syndrome (ACS) when given in addition to current standard antiplatelet therapies. This Phase II, randomized, double-blind, placebo-controlled study in Japanese patients with ACS assessed the bleeding risk of apixaban compared with placebo when given in combination with standard antiplatelet therapy, and followed a similar design to APPRAISE-1, the larger global Phase II study. Methods and Results: Patients with recently diagnosed ACS were randomized to receive apixaban 2.5mg twice daily (BID; n=49), apixaban 5mg BID (n=50), or placebo (n=52) in addition to standard antiplatelet therapy for 24 weeks. The composite primary endpoint of major or clinically relevant nonmajor bleeding occurred in 2 patients (4.1%) in each apixaban treatment group and 1 patient (2.0%) in the placebo group, and a dose-dependent increase was seen in all bleeding events. No hemorrhagic strokes occurred in either apixaban treatment group. This study was terminated before completion because the APPRAISE-2 global Phase III trial was stopped based on the recommendation of the Data Monitoring Committee, following an increase in bleeding events without a counterbalancing reduction in ischemic events. Conclusions: The bleeding profile of apixaban in Japanese patients with ACS was similar to that found in the global APPRAISE-1 study, supporting the safety of apixaban in Japanese patients.  (Circ J 2013; 77: 2341–2348)
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Metabolic Disorder
  • Shigemasa Tani, Ken Nagao, Michiaki Matsumoto, Atsushi Hirayama
    2013 Volume 77 Issue 9 Pages 2349-2357
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 26, 2013
    JOURNALS FREE ACCESS
    Background: The purpose of this study was to evaluate the effect of highly purified eicosapentaenoic acid (EPA) in increasing low-density lipoprotein (LDL) particle size, as one of the possible mechanisms by which intake of EPA may prevent coronary events. Methods and Results: Hypertriglyceridemic subjects were randomly assigned to a control group (n=72) or an EPA group (n=72; EPA regimen 1,800mg/day for 6 months). In the EPA group, the serum LDL-cholesterol and high-density lipoprotein cholesterol levels remained unchanged, but there was a significant increase in LDL particle size based on LDL-relative mobility measured on lipoprotein polyacrylamide-gel electrophoresis, and a significant decrease in serum triglyceride-rich lipoproteins (TRLs) level. None of these changes were observed in the control group. After adjustments for coronary risk factors, multivariate logistic regression analysis identified elevation of serum EPA-related markers (6-month EPA, 6-month EPA/arachidonic acid [AA] ratio, change in [Δ] EPA, and EPA/AA), and treatment with statins and EPA as independent variables associated with increase in LDL particle size. Negative correlations were found between ΔTRLs and ΔLDL particle size, suggesting that improvement in triglyceride metabolism was associated with an increase in LDL particle size. Conclusions: EPA increases LDL particle size by improving triglyceride metabolism; and serum EPA level and EPA/AA ratio after EPA treatment may be useful markers of increased LDL particle size.  (Circ J 2013; 77: 2349–2357)
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Molecular Cardiology
  • Lucía Núñez, Juan Ramón Gimeno-Blanes, Mar ...
    2013 Volume 77 Issue 9 Pages 2358-2365
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 19, 2013
    JOURNALS FREE ACCESS
    Background: Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous genetic heart disease characterized by left ventricular hypertrophy in the absence of another disease that could explain the wall thickening. Elucidation of the genetic basis of HCM lead to the identification of several genes encoding sarcomeric proteins, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3. Sarcomeric genes are mutated in approximately 40% of HCM patients and a possible explanation for the incomplete yield of mutation-positive HCM may be somatic mutations. Methods and Results: We studied 104 unrelated patients with non-familial HCM. Patients underwent clinical evaluation and mutation screening of 5 genes implicated in HCM (MYH7, MYBPC3, TPM1, TNNT2, and TNNI3) in genomic DNA isolated from resected cardiac tissue; 41 of 104 were found to carry a mutation, but as several patients carried the same mutations, the total amount of different mutations was 37; 20 of these mutations have been previously described, and pathogenicity has been assessed. To determine the effect of the 17 new mutations an in silico assay was performed and it predicted that 4 variants were damaging mutations. All identified variants were also seen in the DNA isolated from the corresponding blood, which demonstrated the absence of somatic mutations. Conclusions: Somatic mutations in MYH7, MYBPC3, TPM1, TNNT2, and TNNI3 do not represent an important etiologic pathway in HCM.  (Circ J 2013; 77: 2358–2365)
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Myocardial Disease
  • Georgios K. Efthimiadis, Efstathios D. Pagourelias, Despoina Parcharid ...
    2013 Volume 77 Issue 9 Pages 2366-2374
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: May 31, 2013
    JOURNALS FREE ACCESS
    Background: The prevalence, clinical characteristics and natural history of patients with hypertrophic cardiomyopathy (HCM) and midventricular obstruction (MVO) have not been adequately studied. Methods and Results: A single-center cohort consisting of 423 patients (mean age, 49.3±17.2 years; 66.2% male) was thoroughly followed up for a median of 84 months (7 years; range, 6–480 months). MVO, characterized by the echocardiographic appearance of midventricular muscular apposition with a simultaneous mid-cavitary gradient ≥30mmHg, was identified in 34 patients (8%). Patients with MVO tended to be more symptomatic during their initial evaluation (>90% presented with NYHA class ≥II) compared to the rest of the HCM cohort. Apical aneurysm formation was identified in more than one-fourth of patients with MVO (26.5%), being a characteristic of the group. On multivariate Cox regression hazard analysis, presence of MVO strongly predicted progression to end-stage (burnt out) HCM and related heart failure (HF) deaths (hazard ratio, [HR], 2.62; 95% confidence interval [CI]: 1.2–8.8; P=0.047), as well as sudden death and associated lethal arrhythmic events (HR, 3.3; 95% CI: 1.26–8.85; P=0.016). Conclusions: MVO is a distinct phenotype of HCM associated with unfavorable prognosis in terms of end-stage HCM, sudden death and lethal arrhythmic events. The high adverse outcome rate necessitates early recognition of MVO and appropriate therapeutic interventions.  (Circ J 2013; 77: 2366–2374)
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Pediatric Cardiology and Adult Congenital Heart Disease
  • Satoshi Masutani, Hirofumi Saiki, Clara Kurishima, Hirotaka Ishido, Ma ...
    2013 Volume 77 Issue 9 Pages 2375-2382
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: May 31, 2013
    JOURNALS FREE ACCESS
    Background: There is no information on heart failure (HF) with preserved ejection fraction (HFpEF, EF >50%) in children. Methods and Results: Through a retrospective review of 3,907 pediatric patients with cardiovascular disease, we examined the characteristics of pediatric HFpEF over a 10-year period. We identified 18 patients with HFpEF (0.5%). They were predominantly young children (1.1±0.9 years, no sex preponderance), who had undergone surgery for congenital heart disease. They also had concentric hypertrophy and diastolic dysfunction with elevated blood pressure. Notably, HFpEF patients had more pronounced elevation of serum aldosterone but less pronounced elevation of plasma brain natriuretic peptide (BNP) than 22 systolic HF patients (SHF, EF ≤50%) (aldosterone: 1,375±1,200 vs. 511±563pg/ml, P<0.05, and BNP: 101±141 vs. 749±818pg/ml, P<0.005). Consequently, the aldosterone/BNP ratio was significantly higher in HFpEF (38±63) than in SHF (1.7±1.9, P<0.05), and an aldosterone/BNP ratio of 10.3 or higher best predicted HFpEF (area under the curve=0.89). The HF mortality rate was significantly lower in the HFpEF than in the SHF cases, and HF symptoms showed amelioration in 61% of patients during the follow-up period of 4.2±2.6 years. Conclusions: HFpEF does exist in children. A common pathophysiology underlies childhood and adult HFpEF despite considerable epidemiological and etiological differences. Future controlled studies are warranted to assess the cause-effect relationship between unique hormonal profiles and HFpEF.  (Circ J 2013; 77: 2375–2382)
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Pulmonary Circulation
  • Yu Taniguchi, Noriaki Emoto, Kazuya Miyagawa, Kazuhiko Nakayama, Hirot ...
    2013 Volume 77 Issue 9 Pages 2383-2389
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 12, 2013
    JOURNALS FREE ACCESS
    Background: Right heart catheterization (RHC) is the gold standard for the diagnosis of pulmonary hypertension (PH) and a useful tool for monitoring PH. However, there are some disadvantages in the regular use of RHC because it is invasive. Noninvasive methods for monitoring hemodynamics are needed to manage patients with PH. In this study, we aimed to evaluate the reliability of noninvasive hemodynamic assessment with whole-body impedance cardiography (Non-Invasive Cardiac System [NICaS]) for PH. Methods and Results: We investigated 65 consecutive patients undergoing RHC. Two-thirds of them had pulmonary arterial hypertension and one-third had chronic thromboembolic PH; 25% of the patients were receiving medical therapy. Cardiac output (CO) was estimated by NICaS (NI-CO), thermodilution (TD-CO), and the Fick method (Fick-CO). There was a strong correlation between NI-CO and TD-CO (r=0.715, P<0.0001) and Fick-CO (r=0.653, P<0.0001). Noninvasive pulmonary vascular resistance (PVR) was estimated using a conventional invasive equation with NI-CO, mean pulmonary arterial pressure was calculated by echocardiographic measurement, and pulmonary capillary wedge pressure was estimated at 10mmHg in all cases. NICaS-derived PVR was very strongly correlated with invasive PVR (TD-PVR: r=0.704, P<0.0001; Fick-PVR: r=0.702, P<0.0001). Conclusions: Noninvasive measurement of CO and PVR using NICaS and echocardiography is a useful tool for the assessment of PH.  (Circ J 2013; 77: 2383–2389)
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Valvular Heart Disease
  • Sung-Ji Park, Maurice Enriquez-Sarano, Jung-Eun Song, Yung-Joo Lee, Mi ...
    2013 Volume 77 Issue 9 Pages 2390-2398
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 12, 2013
    JOURNALS FREE ACCESS
    Background: The aim of this study was to assess contractile reserve (CR) in patients with severe aortic regurgitation (AR), and potential clinical applications of CR in minimally symptomatic patients. Methods and Results: Symptom-limited treadmill exercise echocardiography was performed in 58 asymptomatic or mildly symptomatic patients with chronic severe AR (male 69%, 50±14 years). Patients with increased ejection fraction (EF) after exercise were denoted as having CR (+) and those without increased EF were categorized as CR (−). CR (+) was found in 31 and CR (–) in 27 patients. Compared with CR (+), the CR (–) group had lower EF, larger effective regurgitant orifice, regurgitant volume, left ventricular (LV) end-diastolic dimension, LV end-systolic dimension (LVESD), and LV mass index. On multiple logistic regression analysis LVESD index (LVESDI; odds ratio –0.354, P<0.0001) was an independent predictor of CR. One-third of patients with LVESD >50mm, however, were found to be CR (+), while one-third of patients with smaller LVESD were CR (–). Conclusions: Although CR is best related to baseline resting LVESDI, one-third of patients were found to have discordance between the presence of CR and the LV dimension recommended for aortic valve replacement (AVR) in minimally symptomatic patients with severe AR, suggesting that exercise test may be able to further stratify the current guideline for AVR.  (Circ J 2013; 77: 2390–2398)
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Vascular Biology and Vascular Medicine
  • Qian Lu, Shi-Lin Tang, Xiao-Yan Liu, Guo-Jun Zhao, Xin-Ping Ouyang, Yu ...
    2013 Volume 77 Issue 9 Pages 2399-2408
    Published: 2013
    Released: August 23, 2013
    [Advance publication] Released: June 05, 2013
    JOURNALS FREE ACCESS
    Background: Tert-butylhydroquinone (tBHQ), a synthetic phenolic antioxidant, is commonly used as a food preservative because of its potent antilipid peroxidation activity. Several lines of evidence have demonstrated that dietary supplementation with antioxidants has an antiatherogenic function through reducing cholesterol uptake or promoting reverse cholesterol transport. In this study, we investigated whether tBHQ affects expression of ATP-binding cassette transporter A1 (ABCA1) and the potential subsequent effect on cellular cholesterol homeostasis. Methods and Results: tBHQ increased ABCA1 protein levels and markedly enhanced cholesterol efflux from THP-1 macrophage-derived foam cells. Furthermore, tBHQ reduced calpain-mediated ABCA1 proteolysis via activation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Inhibition of HO-1 with a pharmacological inhibitor or siRNA and knockdown of Nrf2 suppressed the stimulatory effects of tBHQ on ABCA1 expression and calpain activity. Conclusions: Nrf2/HO-1 signaling is required for the regulation by tBHQ of ABCA1 expression and cholesterol efflux in macrophage-derived foam cells and an antiatherogenic role of tBHQ is suggested.  (Circ J 2013; 77: 2399–2408)
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