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Reviews
  • Masahide Harada, Jonathan Melka, Yoshihiro Sobue, Stanley Nattel
    Type: REVIEW
    Volume 81 (2017) Issue 12 Pages 1749-1757
    Released: November 24, 2017
    [Advance publication] Released: October 24, 2017
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    Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and is associated with morbidity and mortality. Over the past 2 decades, there have been major advances in understanding AF pathophysiology, but important knowledge gaps, particularly about targetable basic mechanisms, remain. Recent metabolomic and proteomic studies have shown changes in the expression of molecules involved in metabolic pathways in human and experimental AF, indicating a role for metabolic alterations in AF pathophysiology. AF is characterized by irregular high-frequency excitation and contraction that affect atrial energy demands, circulation and oxygen supply, and change the balance between metabolic demand and supply, causing metabolic stress. Here, we review the information available about AF-induced metabolic changes and their pathophysiological contribution. We also discuss the possibilities of developing novel therapeutic strategies that act by modulating cardiac metabolic processes during AF.

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2017 ESC Report
  • Kimio Satoh, Jun Takahashi, Yasuharu Matsumoto, Shunsuke Tatebe, Tatsu ...
    Type: 2017 ESC REPORT
    Volume 81 (2017) Issue 12 Pages 1758-1763
    Released: November 24, 2017
    [Advance publication] Released: November 02, 2017
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    From August 26th to 30th, the 2017 Annual Congress of the European Society of Cardiology (ESC 2017) was held in Barcelona, Spain. Despite the terrorism tradegy just before the ESC congress, the congress attracted many medical professionals from all over the world to discuss the recent topics in cardiovascular medicine in more than 500 sessions, including COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS Trial), CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), and ORION (which assessed the effect of a novel siRNA inhibitor to PCSK9 on reductions in low-density lipoprotein cholesterol). Japanese cardiologists and the Japanese Circulation Society greatly contributed to the congress. This report briefly introduces some late-breaking registry results, late-breaking clinical trials, and ESC Guidelines from the ESC 2017 Congress.

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Editorials
Original Articles
Aortic Disease
  • Yuta Tajima, Hitoshi Goto, Masato Ohara, Munetaka Hashimoto, Daijiro A ...
    Type: ORIGINAL ARTICLE
    Subject area: Aortic Disease
    Volume 81 (2017) Issue 12 Pages 1774-1782
    Released: November 24, 2017
    [Advance publication] Released: June 30, 2017
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    Background:The maximum axial diameter (MAD) of a fusiform abdominal aortic aneurysm (AAA) is an indicator of the risk of expansion or rupture. Apart from smoking and MAD itself, few expansion risk factors have been reported. In this study, we investigated expansion risk factors for AAA.

    Methods and Results:This retrospective cohort study included 176 patients who attended Tohoku University Hospital with infrarenal fusiform AAA. AAA expansion rate was determined on multidetector computed tomography, and the correlations between expansion rate and the clinical data were analyzed. The median expansion rate was 2.405 mm/year. On univariate analysis, a significant positive correlation with expansion rate was observed for the initial MAD (P<0.001) and significant negative correlations for oral angiotensin receptor blocker usage (P=0.025), height (P=0.005), body weight (P=0.017), total cholesterol (P=0.007), low-density lipoprotein cholesterol (P=0.004), and HbA1c (P=0.037). On logistic regression analysis, significant positive associations with expansion rate were observed for initial MAD (P<0.001) and oral steroid usage (P=0.029) and a negative association for height (P=0.041).

    Conclusions:Oral steroid usage is an important risk factor for AAA expansion, independent of other risk factors of atherosclerosis and MAD.

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Arrhythmia/Electrophysiology
  • Mamoru Hayano, Takeru Makiyama, Tsukasa Kamakura, Hiroshi Watanabe, Ke ...
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    Volume 81 (2017) Issue 12 Pages 1783-1791
    Released: November 24, 2017
    [Advance publication] Released: June 20, 2017
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    Background:TheSCN5Agene encodes the α subunit of the cardiac voltage-gated sodium channel, NaV1.5. The missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced NaV1.5 function, including cardiac conduction disease and dilated cardiomyopathy. Curiously, the reported biophysical properties ofSCN5A-D1275N channels vary with experimental system.

    Methods and Results:First, using a human embryonic kidney (HEK) 293 cell-based heterologous expression system, theSCN5A-D1275N channels showed similar maximum sodium conductance but a significantly depolarizing shift of activation gate (+10 mV) compared to wild type. Second, we generated human-induced pluripotent stem cells (hiPSCs) from a 24-year-old female who carried heterozygousSCN5A-D1275N and analyzed the differentiated cardiomyocytes (CMs). AlthoughSCN5Atranscript levels were equivalent between D1275N and control hiPSC-CMs, both the total amount of NaV1.5 and the membrane fractions were reduced approximately half in the D1275N cells, which were rescued by the proteasome inhibitor MG132 treatment. Electrophysiological assays revealed that maximum sodium conductance was reduced to approximately half of that in control hiPSC-CMs in the D1275N cells, and maximum upstroke velocity of action potential was lower in D1275N, which was consistent with the reduced protein level of NaV1.5.

    Conclusions:This study successfully demonstrated diminished sodium currents resulting from lower NaV1.5 protein levels, which is dependent on proteasomal degradation, using a hiPSC-based model forSCN5A-D1275N-related sodium channelopathy.

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  • Wei-Syun Hu, Cheng-Li Lin
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    Volume 81 (2017) Issue 12 Pages 1792-1797
    Released: November 24, 2017
    [Advance publication] Released: June 16, 2017
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    Background:The aim of this study was to assess the accuracy of CHA2DS2-VASc score in predicting new-onset atrial fibrillation (AF) in patients with chronic obstructive pulmonary disease (COPD).

    Methods and Results:A total of 50,430 COPD patients were enrolled in this study. The area under the receiver operating characteristic curve (AUC) and the Cox model c-statistic were used to assess the association between new-onset AF risk and CHA2DS2-VASc score in COPD patients. After adjustment for comorbidities other than the components of CHA2DS2-VASc score, risk of new-onset AF in COPD patients increased from 1.24 (95% confidence interval (CI): 1.01–1.52) for a score of 1, to 2.15 (95% CI: 1.62–2.86) for score ≥6 (trend test, P<0.001), compared with CHA2DS2-VASc score 0. The AUC for CHA2DS2-VASc score in predicting new-onset AF in COPD patients was 0.69 (95% CI: 0.68–0.70). The c-statistic of Cox model in predicting incident AF was 0.73.

    Conclusions:Risk of new-onset AF in COPD patients increased with increasing CHA2DS2-VASc score. The predictive ability of the score was moderate. CHA2DS2-VASc score might be used as a screening tool for AF in COPD patients.

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  • Hisashi Yokoshiki, Akihiko Shimizu, Takeshi Mitsuhashi, Hiroshi Furush ...
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    Volume 81 (2017) Issue 12 Pages 1798-1806
    Released: November 24, 2017
    [Advance publication] Released: June 13, 2017
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    Background:Randomized control trials comparing the effectiveness of cardiac resynchronization therapy devices, with (CRT-D) or without (CRT-P) a defibrillator, are scarce in heart failure patients with no prior sustained ventricular tachyarrhythmias.

    Methods and Results:The Japan Cardiac Device Treatment Registry (JCDTR) has data for 2714 CRT-D and 555 CRT-P recipients for primary prevention with an implantation date between January 2011 and August 2015. Of these patients, follow-up data were available for 717. Over the mean follow-up period of 21 months, Kaplan-Meier curves of survival free of combined events for all-cause death or heart failure hospitalization (whichever came first) diverged between the CRT-D (n=620) and CRT-P (n=97) groups with a rate of 22% vs. 42%, respectively, at 24 months (P=0.0011). However, this apparent benefit of CRT-D over CRT-P was no longer significant after adjustment for covariates. With regard to mortality, including heart failure death or sudden cardiac death, there was no significant difference between the 2 groups.

    Conclusions:In patients without sustained ventricular tachyarrhythmias enrolled in the JCDTR, there was no significant difference in mortality between the CRT-D and CRT-P groups, despite a lower trend in CRT-D recipients. This study was limited by large clinical and demographic differences between the 2 groups.

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  • Yoshiaki Yui, Yukio Sekiguchi, Akihiko Nogami, Hiro Yamasaki, Takeshi ...
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    Volume 81 (2017) Issue 12 Pages 1807-1815
    Released: November 24, 2017
    [Advance publication] Released: June 23, 2017
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    Background:Idiopathic ventricular arrhythmias (VAs) rarely arise from the epicardium at the crux of the heart. However, the electrophysiological characteristics of VAs successfully ablated from the ostium of the coronary sinus (CSO) have not yet been documented.

    Methods and Results:Electrocardiographic and electrophysiological data were analyzed in patients with idiopathic VAs successfully ablated from the CSO.Among 309 patients with idiopathic VAs treated with radiofrequency catheter ablation (RFCA), 6 (1.94%; 3 men; age: 66.3±9.7 years) had VAs successfully ablated from the CSO. Only 1 patient had sustained ventricular tachycardia. The morphology of the QRS showed a left superior axis and QS pattern in leads III and aVF. Furthermore, the precordial maximum deflection index was >0.55 in all patients and a right bundle branch block pattern was recorded in 5 of 6 patients. All VAs were successfully eliminated by RFCA within the CSO. Intracardiac ECGs at sites where VAs were eliminated by RFCA showed clear atrial and ventricular potentials (atrial amplitude: 0.21±0.11 mV; ventricular amplitude: 0.43±0.24 mV), except in 1 case of atrial fibrillation. No patients had recurrence during the 3.4±1.8-year follow-up period.

    Conclusions:The idiopathic VAs in our study were eliminated by RFCA within the CS, where a clear atrial amplitude was recorded.

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Cardiovascular Intervention
  • Eisuke Usui, Taishi Yonetsu, Tadashi Murai, Yoshihisa Kanaji, Junji Ma ...
    Type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Intervention
    Volume 81 (2017) Issue 12 Pages 1816-1823
    Released: November 24, 2017
    [Advance publication] Released: June 16, 2017
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    Background:The relationship between the features of morphologically unstable plaque and physiological lesion severity remains elusive. We aimed to investigate this relationship using optical coherence tomography (OCT)-derived high-risk plaque characteristics and fractional flow reserve (FFR) as the degree of anatomical and physiological stenosis severity.

    Methods and Results:We investigated 286 de novo intermediate and severe coronary lesions in 248 patients who underwent OCT and FFR examinations. Lesions were divided into tertiles based on either FFR or quantitative coronary angiographic diameter stenosis (QCA-%DS). The OCT findings were compared among the tertiles of FFR and QCA-%DS. FFR and QCA tertiles were defined as follows: FFR-T1 (FFR <0.74), FFR-T2 (0.74≤FFR≤0.81), and FFR-T3 (FFR >0.81); and QCA-T1 (%DS ≥61%), QCA-T2 (51%≤%DS<61%), and QCA-T3 (%DS <51%). The prevalence of thin-cap fibroatheroma (TCFA) was significantly greater in FFR-T1 (20.0%) than in FFR-T2 and FFR-T3 (7.0%, P=0.03 and 7.7%, P=0.04, respectively), although no significant differences were observed among the QCA tertiles.

    Conclusions:Physiological severity of coronary stenosis evaluated by FFR correlated with plaque instability in terms of TCFA. Preferable clinical outcomes for lesions with negative FFR based on the existing clinical evidence might be attributable to less likelihood of TCFA.

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Cardiovascular Surgery
  • Takashi Kunihara, Niklas Neumann, Steffen Daniel Kriechbaum, Ryota Nom ...
    Type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Surgery
    Volume 81 (2017) Issue 12 Pages 1824-1831
    Released: November 24, 2017
    [Advance publication] Released: June 23, 2017
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    Background:Valve-preserving aortic surgery is increasingly used in acute aortic dissection type A (AADA). The object of this study was to compare the long-term results of aortic root remodeling (remodeling) for patients with and without AADA.

    Methods and Results:Between October 1995 and December 2013, 776 patients underwent valve-preserving root replacement, of whom 59 patients with AADA (<2 weeks from onset, 56±16 years, 48 male) underwent remodeling (the remodeling-group); 7 patients had bicuspid anatomy (12%), 3 had Marfan syndrome (5%), and 1 had undergone previous cardiac surgery (2%). For this analysis the control group of patients who underwent remodeling for stable aneurysm (n=59) was generated using a propensity score matching. The long-term outcomes regarding survival and reoperation on the aortic valve were compared between the 2 groups. Pre- and intraoperative patients’ characteristics were comparable between groups. Early death was 7% in the AADA group and 3% in the control group (P=0.40). Actuarial survival at 10 years of the AADA group (72±6%) was insignificantly lower than that of the control group (83±5%) (P=0.16). Freedom from reoperation at 10 years was similar (AADA group: 98±2%, control group: 97±3%, P=0.99). Multivariable Cox’s proportional hazards model could not identify an independent predictor for late reoperation but advanced age for late death.

    Conclusions:Long-term stability of remodeling was comparable between patients with and without AADA.

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  • Satoshi Kainuma, Kazuhiro Taniguchi, Koichi Toda, Toshihiro Funatsu, H ...
    Type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Surgery
    Volume 81 (2017) Issue 12 Pages 1832-1838
    Released: November 24, 2017
    [Advance publication] Released: June 28, 2017
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    Background:There are few reports of the determinants of “functional” mitral stenosis in terms of a residual mitral valve (MV) pressure gradient >5 mmHg following restrictive mitral annuloplasty (RMA) or the effect on long-term outcome in patients with functional mitral regurgitation (MR).

    Methods and Results:Serial cardiac catheterization and echocardiographic studies were performed in 55 patients with functional MR who underwent RMA using a 24/26-mm semi-rigid complete ring. The mean postoperative (1 month) catheter-measured MV gradient was 3.4±1.6 mmHg, which was independently associated with corresponding cardiac output [standardized partial regression coefficient (SPRC)=0.59] and indexed effective orifice area (SPRC=−0.25). Body surface area (BSA) had the greatest contribution to MV gradient (SPRC=0.38), followed by use of a 24-mm ring (SPRC=0.33) and hemodialysis (SPRC=0.26). Receiver-operating characteristic curve analysis demonstrated an optimal BSA cutoff value of 1.86 m2to predict post-MV stenosis (21% for <1.86 m2vs. 86% for ≥1.86 m2, P=0.002). During follow-up (75±32 months), freedom from adverse events did not differ between patients with (n=16) and without (n=39) an MV gradient ≥5 mmHg (log-rank P=0.24).

    Conclusions:Post-RMA MV gradient was determined not only by the degree of annular reduction but also by patients’ hemodynamic factors (e.g., cardiac output). Implantation of a 24/26-mm annuloplasty ring for patients with BSA ≥1.86 m2indicated a high likelihood of post-MV stenosis. However, mild MV stenosis did not adversely affect late outcome after RMA.

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Critical Care
  • SOS-KANTO 2012 Study Group
    Type: ORIGINAL ARTICLE
    Subject area: Critical Care
    Volume 81 (2017) Issue 12 Pages 1839-1845
    Released: November 24, 2017
    [Advance publication] Released: July 04, 2017
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    Background:Initial blood ammonia level is associated with neurologic outcomes in out-of-hospital cardiac arrest (OHCA). We tested the usefulness of blood ammonia for prediction of long-term neurological outcome of OHCA.

    Methods and Results:A total of 3,011 hospitalized adult OHCA patients were enrolled. Blood samples were obtained at the ED. Cut-offs (ammonia <100 μmol/L and lactate <12 mmol/L) were determined in a previous study. Neurological outcomes in survivors were assessed at 3 months. A logistic regression model with adjustment for within-hospital clustering and other risk factors was used to evaluate the association between biomarkers and outcomes. Of 3,011 patients, 380 (13.8%) had favorable neurological outcomes. Ammonia and lactate predicted neurological outcome with an AUC of 0.80 (95% CI: 0.76–0.84) and 0.77 (95% CI: 0.72–0.82), respectively. Adjusted OR for ammonia <100 μmol/L (4.55; 95% CI: 2.67–7.81) was higher than that for lactate <12 mmol/L (2.63; 95% CI: 1.61–4.28) and most other risk factors, such as cardiac etiology (3.47; 95% CI: 2.55–4.72), age<80 years (3.16; 95% CI: 2.17–4.61), bystander CPR (2.39; 95% CI: 1.70–3.38), and initial rhythm shockable (1.66; 95% CI: 1.16–2.37). The combination of ammonia and lactate had an increased predictive value (AUC, 0.86; 95% CI: 0.85–0.87) compared with that without biomarkers (AUC, 0.81; 95% CI: 0.80–0.82).

    Conclusions:Initial blood ammonia level is as useful as other traditional prognostic indicators such as lactate. Measurement of both initial blood ammonia and lactate helped accurately predict neurological outcomes after OHCA.

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Epidemiology
  • Kunihiro Kudo, Jun Hata, Koichiro Matsumoto, Yuki Shundo, Satoru Fukuy ...
    Type: ORIGINAL ARTICLE
    Subject area: Epidemiology
    Volume 81 (2017) Issue 12 Pages 1846-1853
    Released: November 24, 2017
    [Advance publication] Released: June 06, 2017
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    Background:There has been no large-scale observational study examining the association between chronic obstructive pulmonary disease (COPD) or airflow limitation and carotid atherosclerosis in the general population across a wide range of generations in Asia. In the present study we assessed the association between airflow limitation and carotid intima-media thickness (IMT) in a general Japanese population, with consideration of a comprehensive array of cardiovascular risk factors.

    Methods and Results:In all, 2,099 community-dwelling Japanese subjects were included in the study. Airflow limitation was defined by spirometry. Maximum and mean IMT values were measured using carotid ultrasonography. Among the subjects, 352 (16.8%) had airflow limitation. The geometric mean values of maximum IMT and mean IMT were significantly higher in subjects with than without airflow limitation (1.27 vs. 1.18 mm, respectively, for maximum IMT; 0.73 mm vs. 0.72 mm, respectively, for mean IMT) and increased with the severity of airflow limitation after adjustment for conventional risk factors, including smoking habits and serum high-sensitivity C-reactive protein. It should be noted that the magnitude of these associations was greater in the middle-aged (40–64 years) than elderly (≥65 years) subgroup.

    Conclusions:The findings of the present study suggest that airflow limitation is a significant risk factor for carotid atherosclerosis, especially in midlife, in the general Japanese population.

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  • Motoyuki Nakamura, Fumitaka Tanaka, Toshie Segawa, Tomohiro Takahashi, ...
    Type: ORIGINAL ARTICLE
    Subject area: Epidemiology
    Volume 81 (2017) Issue 12 Pages 1854-1861
    Released: November 24, 2017
    [Advance publication] Released: July 01, 2017
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    Background:Recent temporal trends in the incidence and clinical features of acute myocardial infarction (MI) in the Japanese population are not well known.

    Methods and Results:This study used comprehensive registration for first-ever MI during the 9-year period from 2006 to 2014 in a rural area of northeastern Japan. The study period was divided into three 3-year terms (T1, 2006–2008; T2, 2009–2011; T3, 2012–2014). During the study period, a total of 814 patients with MI were registered. Although the age-adjusted incidence rate (100,000 person-years) in the middle-aged group (<70 years) was relatively stable, the rate for the elderly group (≥70 years) in T3 was significantly lower than that in T1 in both men (368 vs. 279; P<0.01) and women (204 vs. 108; P<0.01). In the general population of the study area, the rate of prescribed anticholesterol drugs was significantly increased during the study period, especially in the elderly population (P<0.01). From a clinical perspective, although the performance rate of primary percutaneous coronary intervention significantly increased with a shortened duration of hospital stay, the in-hospital mortality rate, especially in the elderly, did not significantly decrease during the study period.

    Conclusions:The present study is the first to demonstrate a decreased age-adjusted incidence of MI during the period from 2006 to 2014 in a Japanese rural population, especially in the elderly.

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Heart Failure
  • Dimitar P. Zankov, Akira Sato, Akio Shimizu, Hisakazu Ogita
    Type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    Volume 81 (2017) Issue 12 Pages 1862-1870
    Released: November 24, 2017
    [Advance publication] Released: June 28, 2017
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    Background:Pressure overload induces cardiac hypertrophy, which often ends in heart failure. Afadin is an adaptor protein that is ubiquitously expressed and, in the heart, it localizes at intercalated disks. The current study aimed to examine the afadin-mediated cardiac phenotype in mice exposed to different types of pressure overload: transverse aortic constriction (TAC) burden and angiotensin II (Ang II) stimulation.

    Methods and Results:Conditional knockout mice with selective deletion of afadin (afadin cKO) in cardiomyocytes were generated. TAC-operated and Ang II-infused mice at 4 weeks had a similar degree of pressure overload and cardiac hypertrophy in the heart. In afadin cKO mice, TAC operation caused progressive left ventricular dysfunction and heart failure, while Ang II infusion did not deteriorate cardiac function. Furthermore, TAC operation produced more fibrosis and apoptosis in the heart than Ang II infusion, and the expression of growth differentiation factor 15, which can promote apoptosis, in the afadin cKO heart was higher in TAC-operated mice than Ang II-infused ones.

    Conclusions:In the 2 pressure overload models, myocardial afadin is involved in mechanical stress-induced, but not pharmacological Ang II-related, compensated cardiac hypertrophy.

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  • Yuki Saito, Tomohito Ohtani, Hidetaka Kioka, Toshinari Onishi, Yasumas ...
    Type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    Volume 81 (2017) Issue 12 Pages 1871-1878
    Released: November 24, 2017
    [Advance publication] Released: July 04, 2017
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    Background:Advanced left heart failure (HF) often accompanies post-capillary pulmonary hypertension related to RV afterload. Although pulmonary arterial capacitance (PAC), a measure of pulmonary artery compliance, reflects right ventricular (RV) afterload, the clinical utility of PAC obtained by echocardiography (echo-PAC) is not well established in advanced HF.

    Methods and Results:We performed right heart catheterization in advanced HF patients (n=30), calculating echo-PAC as stroke volume/(tricuspid regurgitation pressure gradient-pulmonary regurgitation pressure gradient). The difference between the echo-PAC and catheter-measured PAC values was insignificant (0.21±0.17 mL/mmHg, P=0.23). Echo-PAC values predicted both pulmonary arterial wedge pressure (PAWP) ≥18 mmHg and pulmonary vascular resistance ≥3 Wood units (P=0.02, area under the curve: 0.88, cutoff value: 1.94 mL/mmHg). Next, we conducted an outcome study with advanced HF patients (n=72). Patients with echo-PAC <1.94 mL/mmHg had more advanced New York Heart Association functional class, higher B-type natriuretic peptide plasma levels, larger RV and lower RV fractional area change than those with echo-PAC ≥1.94 mL/mmHg. They also had a significantly higher rate of ventricular assist device implantation or death, even after adjustment for indices related to HF severity or RV function during a 1-year follow-up period (P<0.01).

    Conclusions:Decreased PAC as measured by echocardiography, indicating elevated PAWP and RV dysfunction, predicted poorer outcomes in patients with advanced HF.

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Imaging
  • Masahito Michikura, Masatsune Ogura, Masahiro Yamamoto, Masahiko Sekim ...
    Type: ORIGINAL ARTICLE
    Subject area: Imaging
    Volume 81 (2017) Issue 12 Pages 1879-1885
    Released: November 24, 2017
    [Advance publication] Released: June 23, 2017
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    Background:Difficulty in detecting and measuring Achilles tendon (AT) xanthomas may be responsible for underdiagnosis of familial hypercholesterolemia (FH). We aimed to determine a cutoff value for AT thickness (AT-T) using ultrasonography to diagnose FH, and to investigate the relationship between AT-T and atherosclerosis.

    Methods and Results:Ultrasonographic AT-T and carotid intima-media thickness (IMT) were evaluated in 130 genetically diagnosed FH patients and 155 non-FH patients. The outline and internal properties of the AT could be clearly determined using ultrasonography, and a good correlation in AT-T was observed between ultrasonography and the conventional method of X-ray radiography (r=0.924, P<0.001). Cutoff values for the diagnosis of FH derived from receiver-operating curves were 5.8 mm (sensitivity 71%, specificity 78%) in men, and 5.5 mm (sensitivity 80%, specificity 81%) in women. Importantly, increased AT-T was positively associated with carotid IMT only in the FH group. Additionally, increased AT-T was associated with the presence of coronary artery disease in a logistic regression analysis adjusted for traditional cardiovascular risk factors.

    Conclusions:This is the first study to determine a cutoff value for AT-T based on ultrasonography for the diagnosis of FH in Japanese subjects. Clearer detection and easier measurement of AT-T using ultrasonography would encourage clinicians to diagnose FH more actively, and could solve the problem of underdiagnosis of FH.

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  • Yasumi Uchida, Yasuto Uchida, Takanobu Kobayashi, Seiichiro Shirai, No ...
    Type: ORIGINAL ARTICLE
    Subject area: Imaging
    Volume 81 (2017) Issue 12 Pages 1886-1893
    Released: November 24, 2017
    [Advance publication] Released: June 30, 2017
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    Background:The presence of ceramide in human coronary plaques is a risk factor for ischemic heart disease, but its visualization in the human vessel wall is currently beyond the scope of any available imaging techniques.

    Methods and Results:Deposition of ceramide was examined by fluorescent angioscopy (FA) and microscopy (FM) using golden fluorescence (Go) as a specific marker of ceramide in yellow plaques, which were obtained from 23 autopsy subjects and classified by conventional angioscopy and histology. Ceramide was observed by FM in 34 of the 41 yellow plaques with a necrotic core (NC) but rarely in the 28 without. Ceramide and macrophages/foam cells co-deposited mainly in the border zone of the NC and fibrous cap (FC). The Go of ceramide was seen when the fibrous cap thickness was ≤100 µm. FA was performed to detect coronary plaques exhibiting Go in patients with coronary artery disease. Ceramide was also detected by FA in 6 of 18 yellow plaques (33.3%) in 8 patients with stable angina and in 18 of 24 yellow plaques (75.0%, P<0.05 vs. stable angina) in 8 patients with old myocardial infarction.

    Conclusions:The Go of ceramide in human coronary plaques is detectable by FA and Go could be used as a marker of vulnerable plaque (i.e., thin FC with NC).

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  • Signe Helene Forsdahl, Ian S. Rogers, Ingela Schnittger, Shigemitsu Ta ...
    Type: ORIGINAL ARTICLE
    Subject area: Imaging
    Volume 81 (2017) Issue 12 Pages 1894-1900
    Released: November 24, 2017
    [Advance publication] Released: July 07, 2017
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    Background:Myocardial bridges (MB) are commonly seen on coronary CT angiography (CCTA) in asymptomatic individuals, but in patients with recurrent typical angina symptoms, yet no obstructive coronary artery disease (CAD), evaluation of their potential hemodynamic significance is clinically relevant. The aim of this study was to compare CCTA to invasive coronary angiography (ICA), including intravascular ultrasound (IVUS), to confirm MB morphology and estimate their functional significance in symptomatic patients.

    Methods and Results:We retrospectively identified 59 patients from our clinical databases between 2009 and 2014 in whom the suspicion for MB was raised by symptoms of recurrent typical angina in the absence of significant obstructive CAD on ICA. All patients underwent CCTA, ICA and IVUS. MB length and depth by CCTA agreed well with length (0.6±23.7 mm) and depth (CT coverage) as seen on IVUS. The product of CT length and depth (CT coverage), (MB muscle index (MMI)), ≥31 predicted an abnormal diastolic fractional flow reserve (dFFR) ≤0.76 with a sensitivity and specificity of 74% and 62% respectively (area under the curve=0.722).

    Conclusions:In patients with recurrent symptoms of typical angina yet no obstructive CAD, clinicians should consider dynamic ischemia from an MB in the differential diagnosis. The product of length and depth (i.e., MMI) by CCTA may provide some non-invasive insight into the hemodynamic significance of a myocardial bridge, as compared with invasive assessment with dFFR.

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Ischemic Heart Disease
  • Ching-Hui Huang, Chen-Ling Kuo, Ching-San Huang, Chin-San Liu, Chia-Ch ...
    Type: ORIGINAL ARTICLE
    Subject area: Ischemic Heart Disease
    Volume 81 (2017) Issue 12 Pages 1901-1910
    Released: November 24, 2017
    [Advance publication] Released: June 16, 2017
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    Background:Left ventricular (LV) shape influences LV systolic function. It is possible to assess LV shape using 3-D echocardiography sphericity index (SI). Maintaining mitochondrial DNA copy number (MCN) is important for preserving mitochondrial function and LV systolic function after acute myocardial infarction (AMI). Information is limited, however, regarding the relationship between leukocyte MCN and the subsequent change in LV shape after AMI.

    Methods and Results:Fifty-five AMI patients undergoing primary angioplasty were recruited. Plasma MCN was measured before primary angioplasty using quantitative polymerase chain reaction. 3-D echocardiography measurement of SI was performed at baseline, and at 1-, 3-, and 6-month follow-up. AMI subjects with MCN lower than the median had a higher 6-month SI and LV volume compared with those with higher MCN. Baseline echocardiographic parameters were similar between the 2 groups. MCN was negatively correlated with 3- and 6-month SI, and 3- and 6-month LV volume. On multiple linear regression analysis, baseline plasma MCN could predict LV SI and LV volume at 6 months after primary angioplasty for AMI, even after adjusting for traditional prognostic factors.

    Conclusions:In AMI patients, higher plasma leukocyte MCN at baseline was associated with favorable LV shape and remodeling at 6-month follow-up. Plasma leukocyte MCN may provide a novel prognostic biomarker for LV remodeling after AMI.

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Metabolic Disorder
  • Akihiro Tokushige, Shinichiro Ueda, Hirofumi Tomiyama, Mituru Ohishi, ...
    Type: ORIGINAL ARTICLE
    Subject area: Metabolic Disorder
    Volume 81 (2017) Issue 12 Pages 1911-1918
    Released: November 24, 2017
    [Advance publication] Released: July 07, 2017
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    Background:Waist circumference (WC), waist-to-height ratio (WHtR) and body mass index (BMI) are known as easy anthropometric markers of abnormal obesity and screening tools for predicting cardiovascular outcomes, but which indices are best is unclear. We therefore investigated the superiority and association between each index and low flow-mediated dilatation (FMD) as a surrogate marker for cardiovascular outcomes in patients with morbidity in a large Japanese prospective cohort.

    Methods and Results:A total of 1,645 Japanese patients who had coronary artery disease and hypertension or diabetes mellitus were enrolled, and 1,087 of them were analyzed. The high-WHtR group (≥0.5) showed greater morbidity and increased inflammation in association with atherosclerosis compared with the low-WHtR group. High WHtR and advanced age were identified as predictors of low FMD (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.02–1.88, P=0.037 and OR 1.55, 95% CI 1.19–2.01, P=0.001, respectively). However, WC was not associated with that risk in either sex (male: OR 1.37, 95% CI 0.97–1.93, P=0.076; female: OR 1.08, 95% CI 0.68–1.73, P=0.74), and no association was evident between high BMI and low FMD (OR 0.92, 95% CI 0.71–1.19, P=0.54).

    Conclusions:WHtR offers a superior predictor of decreased FMD than other anthropometric indices, and progression of arteriosclerosis might be detected more sensitively. Further study is needed to investigate the relationship between cardiovascular mortality and WHtR.

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Peripheral Vascular Disease
  • Kentaro Jujo, Katsumi Saito, Issei Ishida, Yuho Furuki, Eiji Shibahash ...
    Type: ORIGINAL ARTICLE
    Subject area: Peripheral Vascular Disease
    Volume 81 (2017) Issue 12 Pages 1919-1926
    Released: November 24, 2017
    [Advance publication] Released: July 01, 2017
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    Background:Sensory disturbance (SD) is a common consequence of peripheral nerve damage associated with diabetes and severe ischemia. Progression of SD places patients at high risk for lower extremity ulcers and amputations. SD has been thought to be progressive and irreversible, and possibly caused by microvascular dysfunction. The aim of this study was to determine whether endovascular revascularization (EVR) induces quantifiable changes in SD in chronic critical limb ischemia (CLI) patients with neuropathy.

    Methods and Results:In all, 36 legs from 28 chronic CLI patients who underwent elective EVR were prospectively enrolled in this study (64% with diabetes and 54% on maintenance hemodialysis). The current perception threshold (CPT), an established diagnostic parameter for SD, was measured before and 3 months after EVR. Of the target lesions, 11%, 47%, and 81% were in the aortoiliac, femoropopliteal, and below-the-knee arteries, respectively, and 58% were totally occluded. Overall CPT in the target foot had improved significantly 3 months after EVR (from 53 to 30 µA; P=0.010); however, EVR did not change CPT in the non-target foot (from 44 to 33 µA; P=0.33). Patients with improved SD after EVR had a significantly higher 180-day survival rate (94% vs. 63%; P=0.040).

    Conclusions:EVR improved CPT in target limbs of patients with CLI, and may be a promising option to improve SD associated with peripheral ischemic sensory neuropathy.

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Valvular Heart Disease
  • Hiroki Matsuzoe, Kensuke Matsumoto, Hidekazu Tanaka, Yutaka Hatani, Ke ...
    Type: ORIGINAL ARTICLE
    Subject area: Valvular Heart Disease
    Volume 81 (2017) Issue 12 Pages 1927-1935
    Released: November 24, 2017
    [Advance publication] Released: June 28, 2017
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    Background:Although aortic valve intervention is recommended for virtually all symptomatic patients with aortic stenosis (AS), how urgently the intervention should be performed remains controversial. The aim of this study was thus to determine whether the preload reserve in response to leg-positive pressure (LPP) maneuver could serve for decision-making for AS patients awaiting aortic valve intervention.

    Methods and Results:Sixty-eight patients with symptomatic AS, who were referred for aortic valve intervention, were recruited. Stroke volume (SV) was assessed by means of pulsed-wave Doppler, and the ratio between transmitral E wave and mitral annular velocity (e’) was calculated to estimate ventricular filling pressure. While waiting for intervention, 11 patients experienced preoperative cardiac events. During acute preload stress, forward SV for patients without cardiac events increased significantly (from 43±9 to 49±10 mL/m2, P<0.01) along with a minimal change in filling pressure (E/e’: from 20±8 to 21±9, NS). For patients with cardiac events, the Frank-Starling mechanism was significantly impaired (SVi: from 40±9 to 38±7 mL/m2, NS), while filling pressure increased to the critical level (E/e’: from 24±8 to 31±8, P<0.001). Both the patients without flow reserve (∆SVi <4.5 mL/m2) and those without diastolic reserve (∆E/e’ ≥2.9) exhibited significantly worse event-free survival than the others (P<0.05, respectively).

    Conclusions:Assessment of preload reserve during LPP stress could facilitate risk stratification of patients with severe AS waiting for aortic valve intervention.

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Vascular Biology and Vascular Medicine
  • Yugo Yamashita, Hiroki Shiomi, Takeshi Morimoto, Tomoya Yoneda, Chinat ...
    Type: ORIGINAL ARTICLE
    Subject area: Vascular Biology and Vascular Medicine
    Volume 81 (2017) Issue 12 Pages 1936-1944
    Released: November 24, 2017
    [Advance publication] Released: June 27, 2017
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    Background:The prognosis of asymptomatic deep vein thrombosis (DVT) is uncertain and there is no consensus on the necessity of detection and treatment.

    Methods and Results:We retrospectively evaluated 300 patients with asymptomatic lower extremity DVT screened from 4,514 consecutive patients on ultrasound at Kyoto University Hospital between January 2010 and September 2015. The subjects had concomitant active cancer in 40%, unprovoked DVT in 59%, and distal DVT in 70%. The cumulative 5-year incidences of symptomatic recurrent venous thromboembolism (VTE); major bleeding; and all-cause death were 14.5%, 16.6%, and 34.1%, respectively. Among 232 patients (77%) with prolonged anticoagulant therapy, anticoagulants were discontinued in 48.4% at 1 year. Anticoagulant therapy was associated with a significantly higher incidence of major bleeding compared with the non-anticoagulant group (20.5% vs. 1.5%, P=0.01) with no significant effect on the incidence of VTE. In patients with active cancer, the favorable effect of anticoagulants relative to no anticoagulants for VTE was significant (HR, 0.22; 95% CI: 0.05–0.95).

    Conclusions:Prolonged anticoagulants therapy was implemented in the majority of patients with asymptomatic DVT, but was associated with a significantly higher risk for major bleeding. On subgroup analysis in patients with active cancer, however, there appeared to be a benefit of prolonged anticoagulant therapy in decreasing the rate of symptomatic recurrent VTE.

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  • Leif Å. Söderström, Hong Jin, April S. Caravaca, Maria L. Klement, Yuh ...
    Type: ORIGINAL ARTICLE
    Subject area: Vascular Biology and Vascular Medicine
    Volume 81 (2017) Issue 12 Pages 1945-1952
    Released: November 24, 2017
    [Advance publication] Released: July 26, 2017
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    Background:Increased inflammatory activity destabilizes the atherosclerotic lesion and may lead to atherothrombosis and symptomatic cardiovascular disease. Co-stimulatory molecules, such as CD137, are key regulators of inflammation, and CD137 activity regulates inflammation in experimental atherosclerosis. Here, we hypothesized that CD137 activation promotes carotid artery inflammation and atherothrombosis.

    Methods and Results:In a model of inducible atherothrombosis with surgical ligation of the right carotid artery and a subsequent placement of a polyethene cuff, elevated levels of CD137 and CD137 ligand mRNA in atherothrombotic vs. non-atherothrombotic murine carotid lesions was observed. Mice treated with the CD137 agonistic antibody 2A showed signs of increased inflammation in the aorta and a higher proportion of CD8+T cells in spleen and blood. In carotid lesions of 2A-treated mice, significantly higher counts of CD8+and major histocompatibility (MHC)-class II molecule I-Ab+cells were observed. Treatment with the CD137 agonistic antibody 2A did not significantly affect the atherothrombosis frequency in 16-week-old mice in this model.

    Conclusions:Levels of CD137 and CD137 ligand mRNA were higher in advanced atherosclerotic disease compared to control vessels, and treatment with the CD137 agonistic antibody 2A, in a murine model for inducible atherothrombosis promoted vascular inflammation, but had no significant effect on atherothrombosis frequency at this early disease stage.

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