Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
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Message From the Editor-in-Chief
Reviews
  • Aiko Ogawa, Hiromi Matsubara
    Type: REVIEW
    Volume 82 (2018) Issue 5 Pages 1222-1230
    Released: April 25, 2018
    [Advance publication] Released: April 17, 2018
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    In the past 5 years, balloon pulmonary angioplasty (BPA) for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are deemed inoperable has undergone significant refinement. As a result, the procedure is now used worldwide and has become a promising therapeutic option for those patients. However, pulmonary endarterectomy remains the gold standard treatment for patients with CTEPH because the techniques and strategies for BPA are not yet unified. The best therapeutic option for each patient should be determined based on discussion among a multidisciplinary team of experts. For BPA to become an established treatment for CTEPH, further data are needed. This review summarizes the techniques and strategies of BPA at present and discusses the future development of the procedure.

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  • Koh Ono, Yasuhide Kuwabara, Takahiro Horie, Takeshi Kimura
    Type: REVIEW
    Volume 82 (2018) Issue 5 Pages 1231-1236
    Released: April 25, 2018
    [Advance publication] Released: March 10, 2018
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    Protein-coding genes account for less than 2% of the whole genome. However, the advances in RNA sequencing and genome-wide analysis have demonstrated that most of the genome is capable of being transcribed. Moreover, recent studies have suggested that long non-coding RNAs (lncRNAs) are critical regulators of gene expression and epigenesis in both physiological and disease states. Several lncRNAs are functionally involved in cardiovascular diseases and may be potential therapeutic targets. Here, we review the current strategies for the discovery of functional lncRNAs and recently discovered lncRNAs in the cardiovascular field, focusing on cardiac development, hypertrophy, heart failure, and atherosclerosis. We also discuss the therapeutic potentials of synthetic RNAs to modulate these lncRNAs and future directions in this research field.

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  • Yung-Kuo Lin, Yi-Ann Chen, Ting-I Lee, Yao-Chang Chen, Shih-Ann Chen, ...
    Type: REVIEW
    Volume 82 (2018) Issue 5 Pages 1237-1244
    Released: April 25, 2018
    [Advance publication] Released: September 14, 2017
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    Aging plays a critical role in the genesis of atrial fibrillation (AF) and also increases the risks of cardiac dysfunction and stroke in AF patients. AF is caused by increased AF triggering from abnormalities of the thoracic vein and/or modulated substrate (atrial) with enhancement of AF maintenance. Clinical and laboratory evidence indicates that aging is significant in the creation of atrial electrical and structural remodeling that leads to increased susceptibility to AF occurrence. Aging is commonly associated with cardiovascular comorbidities, oxidative stress, calcium dysregulation, atrial myopathy with apoptosis, and fibrosis, which all contribute to the genesis of AF. This review updates the current understanding of the effects of aging on the pathophysiology of AF.

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Editorials
Late Breaking Cohort Studies (JCS 2018)
  • Yugo Yamashita, Takeshi Morimoto, Hidewo Amano, Toru Takase, Seiichi H ...
    Type: LATE BREAKING COHORT STUDY (JCS 2018)
    Volume 82 (2018) Issue 5 Pages 1262-1270
    Released: April 25, 2018
    [Advance publication] Released: March 23, 2018
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    Background:Venous thromboembolism (VTE) has a long-term risk of recurrence, which can be prevented by anticoagulation therapy.

    Methods and Results:The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic VTE between January 2010 and August 2014. The entire cohort was divided into the transient risk (n=855, 28%), unprovoked (n=1,477, 49%), and cancer groups (n=695, 23%). The rate of anticoagulation discontinuation was highest in the cancer group (transient risk: 37.3% vs. unprovoked: 21.4% vs. cancer: 43.5% at 1 year, P<0.001). The cumulative 5-year incidences of recurrent VTE, major bleeding and all-cause death were highest in the cancer group (recurrent VTE: 7.9% vs. 9.3% vs. 17.7%, P<0.001; major bleeding: 9.0% vs. 9.4% vs. 26.6%, P<0.001; and all-cause death: 17.4% vs. 15.3% vs. 73.1%, P<0.001). After discontinuation of anticoagulation therapy, the cumulative 3-year incidence of recurrent VTE was lowest in the transient risk group (transient risk: 6.1% vs. unprovoked: 15.3% vs. cancer: 13.2%, P=0.001). The cumulative 3-year incidence of recurrent VTE beyond 1 year was lower in patients on anticoagulation than in patients off anticoagulation at 1 year in the unprovoked group (on: 3.7% vs. off: 12.2%, P<0.001), but not in the transient risk and cancer groups (respectively, 1.6% vs. 2.5%, P=0.30; 5.6% vs. 8.6%, P=0.44).

    Conclusions:The duration of anticoagulation therapy varied widely in discordance with current guideline recommendations. Optimal duration of anticoagulation therapy should be defined according to the risk of recurrent VTE and bleeding as well as death.

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Original Articles
Arrhythmia/Electrophysiology
  • Kenshi Hayashi, Toyonobu Tsuda, Akihiro Nomura, Noboru Fujino, Atsushi ...
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    Volume 82 (2018) Issue 5 Pages 1271-1278
    Released: April 25, 2018
    [Advance publication] Released: March 01, 2018
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    Background:B-type natriuretic peptide (BNP) may be a predictor of stroke risk in patients with nonvalvular atrial fibrillation (NVAF); because heart failure is associated with the incidence of stroke in AF patients. However, limited data exist regarding the association between BNP at baseline and risks of thromboembolic events (TE) and death in NVAF patients.

    Methods and Results:We prospectively studied 1,013 NVAF patients (725 men, 72.8±9.7 years old) from the Hokuriku-plus AF Registry to determine the relationship between BNP at baseline and prognosis among Japanese NVAF patients. During the follow-up period (median, 751 days); 31 patients experienced TE and there were 81 cases of TE/all-cause death. For each endpoint we constructed receiver-operating characteristic curves that gave cutoff points of BNP for TE (170 pg/mL) and TE/all-cause death (147 pg/mL). Multivariate analysis with the Cox-proportional hazards model indicated that high BNP was significantly associated with risks of TE (hazard ratio [HR] 3.86; 95% confidence interval [CI] 1.83–8.67; P=0.0003) and TE/all-cause death (HR 2.27; 95% CI 1.45–3.56; P=0.0003). Based on the C-index and net reclassification improvement, the addition of BNP to CHA2DS2-VASc statistically improved the prediction of TE.

    Conclusions:In a real-world cohort of Japanese NVAF patients, high BNP was significantly associated with TE and death. Plasma BNP might be a useful biomarker for these adverse clinical events.

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  • Wei-Syun Hu, Fung-Chang Sung, Cheng-Li Lin
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    Volume 82 (2018) Issue 5 Pages 1279-1285
    Released: April 25, 2018
    [Advance publication] Released: February 16, 2018
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    Background:This retrospective cohort study sought to follow up patients with aplastic anemia (AA) to evaluate their risk of developing atrial fibrillation (AF).

    Methods and Results:From the National Health Insurance Research Database of Taiwan, this study identified an AA cohort (n=3,921), a general population cohort (n=17,617,843) and a propensity score-matched none AA cohort (PSM non-AA cohort in brief, n=15,684) in 2000–2010. By the end of 2011, the incident AF was higher in the AA cohort than in the general population and PSM non-AA cohorts (8.94 vs. 1.14 and 6.47 per 1,000 person-years, respectively). The adjusted hazards ratio of AF for the AA cohort was 2.12 (95% confidence interval 1.46–3.08) compared with the PSM non-AA cohort, after controlling for covariates. However, after further controlling for the competing risk of death, adjusted subhazard ratio was 1.21 (95% CI 0.97–1.50). Among those who developed AF, the AA cohort had a higher mortality rate (83.7 vs. 51.1 per 100), but a lower rate of incident stroke (26.0 vs. 41.5 per 100), compared with the PSM non-AA cohort.

    Conclusions:Patients with AA could have an elevated risk for AF. The mortality risk increased further for those who develop AF.

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  • Daniele Pastori, José Miguel Rivera-Caravaca, María Asunción Esteve-Pa ...
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    Volume 82 (2018) Issue 5 Pages 1286-1292
    Released: April 25, 2018
    [Advance publication] Released: March 16, 2018
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    Background:Two risk scores have been developed to predict composite outcomes in atrial fibrillation (AF): the 2MACE and TIMI-AF scores. The aim of this study was to compare the predictive ability of these scores in 2 separate warfarin-treated cohorts (one ‘real world’, one clinical trial) of AF patients.

    Methods and Results:The 2MACE and TIMI-AF scores were calculated in the ‘real-world’ ATHERO-AF cohort (n=907), and in the randomized controlled AMADEUS trial (n=2,265). Endpoints were major adverse cardiovascular events (MACEs), net clinical outcomes (NCO) and a combination of them, namely “clinically relevant events” (CREs). ROC curves showed similar predictive ability for MACE for 2MACE and TIMI-AF, in both the ATHERO-AF (0.698 vs. 0.688, respectively P=0.783) and AMADEUS (0.657 vs. 0.569, respectively P=0.057) cohorts. Similarly, the TIMI-AF showed a comparable c-index with 2MACE for NCOs in the ATHERO-AF (0.676 vs. 0.667, P=0.737), and AMADEUS (0.666 vs. 0.663, P=0.859) cohorts. No differences were found between the 2 scores for the prediction of CREs (0.675 vs. 0.684, P=0.740 in ATHERO-AF and 0.669 vs. 0.667, P=0.889 in AMADEUS for 2MACE and TIMI-AF, respectively).

    Conclusions:This study showed that the 2MACE and TIMI-AF scores had modest but significant predictive ability for composite outcomes in AF. The clinical usefulness of both scores was similar, but the 2MACE score may be simpler and easy to use.

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Cardiovascular Intervention
  • Seung Hwa Lee, Young Bin Song, Joo Myung Lee, Taek Kyu Park, Jeong Hoo ...
    Type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Intervention
    Volume 82 (2018) Issue 5 Pages 1293-1301
    Released: April 25, 2018
    [Advance publication] Released: March 23, 2018
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    Background:Whether side branch (SB) predilation before main vessel (MV) stenting is beneficial is uncertain, so we investigated the effects of SB predilation on procedural and long-term outcomes in coronary bifurcation lesions treated using the provisional approach.

    Methods and Results:A total of 1,083 patients with true bifurcation lesions undergoing percutaneous coronary intervention were evaluated. The primary outcome was a major adverse cardiovascular event (MACE): cardiac death, myocardial infarction, or target lesion revascularization. SB predilation was performed in 437 (40.4%) patients. Abrupt (10.5% vs. 11.3%; P=0.76) or final SB occlusion (2.7% vs. 3.9%; P=0.41) showed no differences between the predilation and non-predilation groups. The rates of angiographic success (69.1% vs. 52.9%, P<0.001) and SB stent implantation (69.1% vs. 52.9%, P<0.001) were significantly higher in the predilation group. During a median follow-up of 36 months, we found no significant difference between the groups in the rate of MACE (9.4% vs. 11.5%; P=0.67) in a propensity score-matched population. In subgroup analysis, patients with minimal luminal diameter of the parent vessel ≤1 mm benefited from SB predilation in terms of preventing abrupt SB occlusion (P for interaction=0.04).

    Conclusions:For the treatment of true bifurcation lesions, SB predilation improved acute angiographic and procedural outcomes, but could not improve long-term clinical outcomes. It may benefit patients with severe stenosis in the parent vessel.

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Epidemiology
  • Sumiyo Yasukawa, Eri Eguchi, Keiki Ogino, Akiko Tamakoshi, Hiroyasu Is ...
    Type: ORIGINAL ARTICLE
    Subject area: Epidemiology
    Volume 82 (2018) Issue 5 Pages 1302-1308
    Released: April 25, 2018
    [Advance publication] Released: April 03, 2018
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    Background:Nulliparity is associated with an excess risk of cardiovascular disease (CVD). “Ikigai”, subjective wellbeing in Japan, is associated with reduced risk of CVD. The impact of ikigai on the association between parity and the risk of CVD, however, has not been reported.

    Methods and Results:A total of 39,870 Japanese women aged 40–79 years without a history of CVD, cancer or insufficient information at baseline in 1988–1990, were enrolled and followed until the end of 2009. They were categorized into 7 groups according to parity number 0–≥6. Using Cox regression hazard modeling, the associations between parity and mortality from stroke, coronary artery disease, and total CVD were investigated. During the follow-up period, 2,121 total CVD deaths were documented. No association was observed between parity and stroke and CVD mortality in women with ikigai, but there was an association in those without ikigai. The multivariable hazard ratios of stroke and total CVD mortality for nulliparous women without ikigai vs. those with 1 child were 1.87 (95% CI: 1.15–3.05) and 1.46 (95% CI: 1.07–2.01), respectively, and that for stroke mortality in high parity women without ikigai was 1.56 (95% CI: 1.00–2.45).

    Conclusions:Nulliparous or high parity women without ikigai had higher mortality from stroke and/or total CVD, suggesting that ikigai attenuated the association between parity and CVD mortality in Japanese women.

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Heart Failure
  • Rashad Zayat, Mohammad Amen Khattab, Oliver Grottke, Markus Honickel, ...
    Type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    Volume 82 (2018) Issue 5 Pages 1309-1318
    Released: April 25, 2018
    [Advance publication] Released: December 12, 2017
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    Background:In long-term left ventricular assist device (LVAD) therapy, recurrent bleeding events may justify cessation of anticoagulation therapy (AT). However, data about THE safety and risks of AT cessation in LVAD patients are scarce.

    Methods and Results:Between 2010 and 2015, 128 patients received a HeartMate II (HMII). Following recurrent bleeding events, we ceased vitamin K antagonist (VKA) therapy in 13 patients (10%) (no-VKA group). To characterize the hemostatic profile, we performed von Willebrand factor (vWF), platelet function (PF), and other hemostatic tests in all HMII patients. The incidence of pump thrombosis (PT), ischemic stroke (IS) and bleeding events in this HMII population was 4.7 %, 6.2% and 36.7%, respectively. Median survival without VKA was 435 days. No cases of PT and only 1 of IS occurred after AT discontinuation. All patients had impaired PF and acquired von Willebrand syndrome (AvWS). However, the vWF collagen-binding activity to antigen ratio before and after VKA cessation was significantly lower in the no-VKA group compared with the HMII population (0.60±0.12 vs. 0.73±0.14, P=0.006). The thrombin-antithrombin III complex (TAT) value was significantly higher in the no-VKA group (P=0.0005).

    Conclusions:We experienced good results with AT cessation in specific HMII patients. The simultaneous onset of AvWS and high TAT values could explain at least in part the low thromboembolic rate in HMII patients without VKA.

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  • Yujiro Kinomura, Toshiki Tanaka, Takuma Aoyama, Masanori Hatasa, Shing ...
    Type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    Volume 82 (2018) Issue 5 Pages 1319-1326
    Released: April 25, 2018
    [Advance publication] Released: February 28, 2018
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    Background:The role of endogenous adenosine in cardiac patients is still unclear, so we investigated the relationship between the plasma adenosine concentration and left ventricular (LV) function, LV dilation and LV wall thinning in cardiac patients.

    Methods and Results:In 97 cardiac patients, with angina pectoris, old myocardial infarction, dilated or hypertrophic cardiomyopathy, and valvular heart disease, plasma adenosine concentrations were measured using the LC-MS/MS system, and the LV function, LV end-diastolic dimension (LVDd), LV posterior wall thickness (LVPWth), and interventricular septum thickness (IVSth) were assessed by echocardiography. The plasma adenosine concentration was significantly higher in patients with a LV ejection fraction (EF), an indicator of the LV systolic function, <47% compared with those with LVEF ≥47% (P=0.027). There was no difference between the plasma adenosine concentration and E/e’, an indicator of LV diastolic function. The plasma adenosine concentration was significantly higher in patients with LVDd ≥50 mm than in those with LVDd <50 mm (P=0.030). The plasma adenosine concentration was inversely correlated with IVSth (P=0.003) and LVPWth (P=0.0007). The plasma adenosine concentration was significantly higher in patients with IVSth <8 mm than in those with IVSth ≥8 mm (P=0.015), and was significantly higher in patients with LVPWth <8 mm than in those with LVPWth ≥8 mm (P=0.020).

    Conclusions:Endogenous adenosine may be related to LV dysfunction, dilation, and wall thinning in cardiac patients.

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  • Moritake Iguchi, Yuji Tezuka, Hisashi Ogawa, Yasuhiro Hamatani, Daisuk ...
    Type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    Volume 82 (2018) Issue 5 Pages 1327-1335
    Released: April 25, 2018
    [Advance publication] Released: March 09, 2018
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    Background:Heart failure (HF) is a heterogeneous syndrome, but the effect of the type and severity of HF on the incidence of stroke or systemic embolism (SE) in atrial fibrillation (AF) patients is unclear.

    Methods and Results:The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. Follow-up data were available for 3,749 patients. We defined pre-existing HF as having one of the following: prior hospitalization for HF, presence of HF symptoms (NYHA ≥2), or reduced ejection fraction (<40%). At baseline, 1,008 (26.9%) patients had pre-existing HF. On multivariate analysis, the incidence of stroke/SE was not associated with pre-existing HF (hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.92–1.64) or each criterion for the definition of pre-existing HF, but was associated with high B-type natriuretic peptide (BNP) or N-terminal proBNP levels (above the median of the pre-existing HF group) at baseline (HR, 1.65; 95% CI, 1.06–2.53). Stroke/SE was markedly increased in the initial 30-day period following hospital admission for HF (HR, 12.0; 95% CI, 4.59–31.98).

    Conclusions:The effect of HF on the incidence of stroke/SE may depend on the stage or severity of HF in patients with AF. The incidence of stroke/SE was markedly increased in the 30 days after admission for HF, but compensated ‘stable’ HF did not appear to confer an independent risk.

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  • Takashi Kuragaichi, Yuma Kurozumi, Shogo Ohishi, Yasuo Sugano, Akihiro ...
    Type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    Volume 82 (2018) Issue 5 Pages 1336-1343
    Released: April 25, 2018
    [Advance publication] Released: March 10, 2018
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    Background:Palliative care for heart failure (HF) patients is recommended in Western guidelines, so this study aimed to clarify the current status of palliative care for HF patients in Japan.

    Methods and Results:A survey was sent to all Japanese Circulation Society-authorized cardiology training hospitals (n=1,004) in August 2016. A total of 544 institutions (54%) returned the questionnaire. Of them, 527 (98%) answered that palliative care is necessary for patients with HF. A total of 227 (42%) institutions held a palliative care conference for patients with HF, and 79% of the institutions had <10 cases per year. Drug therapy as palliative care was administered at 403 (76%) institutions; morphine (87%) was most frequently used. Among sedatives, dexmedetomidine (33%) was administered more often than midazolam (29%) or propofol (20%). Regarding the timing of end-of-life care, most institutions (84%) reported having considered palliative care when a patient reached the terminal stage of HF. Most frequently, the reason for the decision at the terminal stage was “difficulty in discontinuing cardiotonics.” A major impediment to the delivery of palliative care was “difficulty predicting an accurate prognosis.”

    Conclusions:This large-scale survey showed the characteristics of palliative care for HF in Japan. The present findings may aid in the development of effective end-of-life care systems.

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  • Koichiro Kinugawa, Naoki Sato, Takayuki Inomata, Moriyoshi Yasuda, Yos ...
    Type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    Volume 82 (2018) Issue 5 Pages 1344-1350
    Released: April 25, 2018
    [Advance publication] Released: March 31, 2018
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    Background:It has been 7 years since tolvaptan was approved in Japan for the indication of heart failure in patients with volume overload; the drug can be used in patients with normonatremia. Hypernatremia was identified as a significant adverse event to be prevented.

    Methods and Results:We compiled and analyzed data from 3,349 patients over 5 years to identify patients at high risk of hypernatremia with tolvaptan treatment. The incidence of hypernatremia, defined as serum sodium ≥150 mEq/L, was 3.65%. Baseline serum sodium concentrations, serum potassium concentrations, blood urea nitrogen : creatinine ratio, initial tolvaptan dose, and age were identified as risk factors for hypernatremia. A hypernatremia risk score was developed using the odds ratios for these factors. The high-risk population was defined as patients with a risk score ≥17.80.

    Conclusions:To prevent the occurrence of hypernatremic events in patients taking tolvaptan, we recommend a very low starting dose (i.e., 3.75 mg/day) in patients identified as being at high risk of hypernatremia using our new scoring process.

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  • Grecia M. Marrón-Liñares, Lucía Núñez, María G. Crespo-Leiro, Eloy Álv ...
    Type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    Volume 82 (2018) Issue 5 Pages 1351-1359
    Released: April 25, 2018
    [Advance publication] Released: April 03, 2018
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    Background:Heart transplantation (HT) is a well-established lifesaving treatment for endstage cardiac failure. Antibody-mediated rejection (AMR) represents one of the main problems after HT because of its diagnostic complexity and the poor evidence for supporting treatments. Complement cascade and B-cells play a key role in AMR and contribute to graft damage. This study explored the importance of variants in genes related to complement pathway and B-cell biology in HT and AMR in donors and in donor-recipient pairs.

    Methods and Results:Genetic variants in 112 genes (51 complement and 61 B-cell biology genes) were analyzed on next-generation sequencing in 28 donor-recipient pairs, 14 recipients with and 14 recipients without AMR. Statistical analysis was performed with SNPStats, R, and EPIDAT3.1. We identified one single nucleotide polymorphism (SNP) in donors in genes related to B-cell biology,interleukin-4 receptor subunitα (p.Ile75Val-IL4Rα), which correlated with the development of AMR. Moreover, in the analysis of recipient-donor genotype discrepancies, we identified another SNP, in this case inadenosine deaminase(ADA; p.Val178(p=)), which was related to B-cell biology, associated with the absence of AMR.

    Conclusions:Donor polymorphisms and recipient-donor discrepancies in genes related to the biology of B-cells, could have an important role in the development of AMR. In contrast, no variants in donor or in donor-recipient pairs in complement pathways seem to have an impact on AMR.

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Imaging
  • Konstantinos C. Koskinas, Masato Nakamura, Lorenz Räber, Roisin Coller ...
    Type: ORIGINAL ARTICLE
    Subject area: Imaging
    Volume 82 (2018) Issue 5 Pages 1360-1368
    Released: April 25, 2018
    [Advance publication] Released: March 15, 2018
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    Background:This study evaluated the views of the cardiology community on the clinical use of coronary intravascular imaging (IVI).

    Methods and Results:A web-based survey was distributed to 31,893 individuals, with 1,105 responses received (3.5% response rate); 1,010 of 1,097 respondents (92.1%) self-reported as interventional cardiologists, 754 (68.7%) with >10 years experience. Overall, 96.1% had personal experience with IVI (95.5% with intravascular ultrasound [IVUS], 69.8% with optical coherence tomography [OCT], and 7.9% with near-infrared spectroscopy); 34.7% of respondents were from Europe and 52.0% were from Asia (45.4% from Japan). The most commonly reported indications for IVI were optimization of stenting (88.5%), procedural/strategy guidance (79.6%), and guidance of left main interventions (77.0%). Most respondents reported perceived equipoise regarding choice between IVUS and OCT for guidance of coronary intervention. High cost (65.9%) and prolongation of the procedure (35.0%) were the most commonly reported factors limiting use. IVI was used more frequently (>15% of cases guided by IVI) in Japan than Europe (96.6% vs. 10.4%, respectively; P<0.001) and by operators with longer interventional experience.

    Conclusions:In a sample of predominantly experienced interventional cardiologists, there was a high rate of personal experience with IVI in clinical practice. The most commonly identified indications for IVI were optimization of stenting, procedural/strategy guidance, and guidance of left main interventions. Variability in practice patterns is substantial according to geographic region and interventional experience.

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  • Gulinu Maimaituxun, Michio Shimabukuro, Daiju Fukuda, Shusuke Yagi, Yu ...
    Type: ORIGINAL ARTICLE
    Subject area: Imaging
    Volume 82 (2018) Issue 5 Pages 1369-1378
    Released: April 25, 2018
    [Advance publication] Released: March 21, 2018
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    Background:Compared with global cardiac adiposity, the local accumulation of fat surrounding coronary arteries might have a more direct impact on coronary artery disease (CAD). Here, we compared the local epicardial adipose tissue (EAT) thickness and global cardiac adiposity volumes for predicting CAD.

    Methods and Results:A total of 197 consecutive subjects underwent 320-slice multi-detector computed tomography coronary angiography and were segregated into CAD (≥1 coronary artery branch stenosis ≥50%) and non-CAD groups. EAT thickness was measured at the right coronary artery (EATRCA), the left anterior descending artery (EATLAD), and the left circumflex artery (EATLCX). Although EATRCAand EATLCXwere similar between the 2 groups, EATLADwas larger in the CAD group than in the non-CAD group (5.45±2.16 mm vs. 6.86±2.19 mm, P<0.001). EATLAD, after correcting for confounding factors, was strongly associated with CAD (r=0.276, P<0.001) and Gensini score (r=0.239, P<0.001). On multiple regression analysis, Framingham risk score combined with EATLADwas a strong predictor of CAD (adjusted R2=0.121; P<0.001).

    Conclusions:The local fat thickness surrounding the LAD is a simple and useful surrogate marker for estimating the presence, severity, and extent of CAD, independent of classical cardiovascular risk factors.

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Ischemic Heart Disease
  • Léo Cuenin, Sophie Lamoureux, Mathieu Schaaf, Thomas Bochaton, Jean-Pi ...
    Type: ORIGINAL ARTICLE
    Subject area: Ischemic Heart Disease
    Volume 82 (2018) Issue 5 Pages 1379-1386
    Released: April 25, 2018
    [Advance publication] Released: September 23, 2017
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    Background:Up to 25% of patients with ST elevation myocardial infarction (STEMI) have ST segment re-elevation after initial regression post-reperfusion and there are few data regarding its prognostic significance.

    Methods and Results:A standard 12-lead electrocardiogram (ECG) was recorded in 662 patients with anterior STEMI referred for primary percutaneous coronary intervention (PPCI). ECGs were recorded 60–90 min after PPCI and at discharge. ST segment re-elevation was defined as a ≥0.1-mV increase in STMax between the post-PPCI and discharge ECGs. Infarct size (assessed as creatine kinase [CK] peak), echocardiography at baseline and follow-up, and all-cause death and heart failure events at 1 year were assessed. In all, 128 patients (19%) had ST segment re-elevation. There was no difference between patients with and without re-elevation in infarct size (CK peak [mean±SD] 4,231±2,656 vs. 3,993±2,819 IU/L; P=0.402), left ventricular (LV) ejection fraction (50.7±11.6% vs. 52.2±10.8%; P=0.186), LV adverse remodeling (20.1±38.9% vs. 18.3±30.9%; P=0.631), or all-cause mortality and heart failure events (22 [19.8%] vs. 106 [19.2%]; P=0.887) at 1 year.

    Conclusions:Among anterior STEMI patients treated by PPCI, ST segment re-elevation was present in 19% and was not associated with increased infarct size or major adverse events at 1 year.

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Metabolic Disorder
  • Kyong Yeun Jung, Kyoung Min Kim, Sun Kyoung Han, Han Mi Yun, Tae Jung ...
    Type: ORIGINAL ARTICLE
    Subject area: Metabolic Disorder
    Volume 82 (2018) Issue 5 Pages 1387-1395
    Released: April 25, 2018
    [Advance publication] Released: September 22, 2017
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    Background:Quality and quantity of high-density lipoprotein cholesterol (HDL-C) may be associated with cardiovascular risk. We investigated the effect of rosuvastatin on cholesterol efflux (CE) for HDL function and vascular health.

    Methods and Results:We enrolled 30 dyslipidemic patients with type 2 diabetes mellitus and 20 healthy subjects as controls. Vascular health was assessed on flow-medicated dilation (FMD), nitroglycerin-induced dilatation of the brachial artery and carotid artery intima-media thickness (cIMT). These parameters were compared between patients and controls, and between baseline and at 12 weeks of treatment with rosuvastatin 20 mg. Age and body mass index were 49.8±11.3 years and 25.8±3.7 kg/m2in the patients, and 28.8±3.2 years and 22.4±2.4 kg/m2in the controls, respectively. The biomarkers related to lipid and glucose metabolism and lipoprotein (a), high-sensitivity C-reactive protein, and cIMT were significantly higher, and CE and FMD were significantly lower in the patients than in the controls. In the patients, rosuvastatin 20 mg decreased low-density lipoprotein cholesterol by 54.1% and increased HDL-C by 4.8%. The CE increased significantly after rosuvastatin treatment (12.26±2.72% vs. 14.05±4.14%). FMD also increased, and lipoprotein (a) and cIMT decreased significantly and were associated with changes of CE.

    Conclusions:Rosuvastatin-induced changes in HDL function are significantly associated with cardiovascular benefit.

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Molecular Cardiology
  • Min Zhang, Guo-Jun Zhao, Kai Yin, Xiao-Dan Xia, Duo Gong, Zhen-Wang Zh ...
    Type: ORIGINAL ARTICLE
    Subject area: Molecular Cardiology
    Volume 82 (2018) Issue 5 Pages 1396-1404
    Released: April 25, 2018
    [Advance publication] Released: April 03, 2018
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    Background:It has previously been demonstrated that apolipoprotein A-1 (apoA-1) binding protein (AIBP) promotes apoA-1 binding to ATP-binding cassette transporter A1 (ABCA1) and prevents ABCA1 protein degradation so as to inhibit foam cell formation. Because apoA-1 inhibits inflammatory signaling pathways, whether AIBP has an inhibitory effect on inflammatory signaling pathways in THP-1-derived macrophages is investigated.

    Methods and Results:Analysis of inflammation-related gene expression indicated that AIBP decreased lipopolysaccharide (LPS)-mediated macrophage inflammation. AIBP significantly prevented NF-κB nuclear translocation. Further, AIBP prevented the activation of mitogen-activated protein kinases (MAPKs), including p38 MAPK, extracellular-signal regulated kinase and c-Jun N-terminal kinase. AIBP decreased MyD88 expression at both mRNA and protein levels, but did not have any effect on TLR4 expression. Moreover, treatment with both AIBP and apoA-1 decreased the abundance of TLR4 in the lipid raft fraction. AIBP lacking 115-123 amino acids (∆115-123), however, did not have such effects as described for intact AIBP. In addition, knockdown of ABCA1 inhibited the effects of AIBP on inflammatory factor secretion.

    Conclusions:These results suggest that AIBP inhibits inflammatory signaling pathways through binding to apoA-1 and stabilizing ABCA1, and subsequent alteration of lipid rafts and TLR4 in the cell membrane.

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Myocardial Disease
  • Stephen A. McCullough, Michael A. Fifer, Pouya Mohajer, Patricia A. Lo ...
    Type: ORIGINAL ARTICLE
    Subject area: Myocardial Disease
    Volume 82 (2018) Issue 5 Pages 1405-1411
    Released: April 25, 2018
    [Advance publication] Released: March 09, 2018
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    Background:The clinical characteristics associated with elevated right atrial pressure (RAP) in hypertrophic cardiomyopathy (HCM) are unknown. Few data exist as to whether elevated RAP has prognostic implications in patients with HCM. This study investigated the clinical correlates and prognostic value of elevated RAP in HCM.

    Methods and Results:This retrospective cohort study was performed on 180 patients with HCM who underwent right heart catheterization between 1997 and 2014. Elevated RAP was defined as >8 mmHg. Baseline characteristics, mean pulmonary artery pressure, and mean pulmonary capillary wedge pressure (PCWP) were assessed for association with elevated RAP. The predictive value of elevated RAP for all-cause mortality and the development of atrial fibrillation (AF), ventricular tachycardia/fibrillation (VT/VF), and stroke was evaluated. Elevated RAP was associated with higher New York Heart Association class, dyspnea on exertion, orthopnea, edema, jugular venous distention, larger left atrial size, right ventricular hypertrophy, higher pulmonary artery pressure, and higher PCWP. RAP independently predicted all-cause mortality (adjusted hazard ratio [aHR] 2.18 per 5-mmHg increase, 95% confidence interval [CI] 1.05–4.50, P=0.04) and incident AF (aHR 1.85 per 5-mmHg increase, 95% CI 1.20–2.85, P=0.005). Elevated RAP did not predict VT/VF (P=0.36) or stroke (P=0.28).

    Conclusions:Elevated RAP in patients with HCM is associated with left-sided heart failure and is an independent predictor of all-cause mortality and new-onset AF.

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Peripheral Vascular Disease
  • Naoya Kurata, Osamu Iida, Tatsuya Shiraki, Masashi Fujita, Masaharu Ma ...
    Type: ORIGINAL ARTICLE
    Subject area: Peripheral Vascular Disease
    Volume 82 (2018) Issue 5 Pages 1412-1417
    Released: April 25, 2018
    [Advance publication] Released: December 21, 2017
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    Background:Although stent-to-vessel (S/V) diameter ratio has been described as a restenotic factor after superficial femoral artery (SFA) stenting, the reference vessel diameter is commonly measured distally at a healthy site. It remains unclear whether S/V ratio assessed at the lesion site would be more predictive than that assessed distally at a healthy site.

    Methods and Results:A total of 117 patients (mean age, 73±7 years; 74% male) who underwent successful nitinol stent implantation in SFA lesions (mean lesion length, 172±104 mm) on intravascular ultrasound (IVUS) were retrospectively analyzed. S/V ratio at the proximal and distal healthy site, and at the smallest lesion site, was evaluated on IVUS. One-year restenosis predictors were evaluated on multivariate analysis. Mean S/V diameter ratio on IVUS at proximal and distal healthy sites, and at the lesion site, was 0.98±0.11, 1.02±0.11 and 1.15±0.16, respectively. One-year primary patency was 77%. On multivariate analysis, lesion length (OR, 1.06 per 10-mm increment; P=0.046) and S/V ratio measured at the lesion site (OR, 1.34 per 0.1 increment; P=0.032), but not that at the distal healthy site (OR, 1.05 per 0.1 increment; P=0.705), were significantly associated with 1-year restenosis.

    Conclusions:S/V ratio assessed on IVUS at the lesion site, but not at the distal healthy site, was independently associated with 1-year restenosis after SFA stenting.

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Preventive Medicine
  • Keiichi Kohashi, Akihiro Nakagomi, Taichirou Morisawa, Ikuko Endoh, Na ...
    Type: ORIGINAL ARTICLE
    Subject area: Preventive Medicine
    Volume 82 (2018) Issue 5 Pages 1418-1427
    Released: April 25, 2018
    [Advance publication] Released: December 09, 2017
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    Background:Smoking increases the risk of atherothrombotic events. Tissue factor (TF) mainly expressed on monocytes plays an important role in thrombosis and atherosclerosis. Metabolic syndrome (MetS) is being increasingly recognized as a major atherothrombotic risk factor, but the effects of smoking on monocyte TF activity (MTFA), carotid atherosclerosis estimated on carotid intima-media thickness (CIMT), and long-term prognosis in MetS remain unclear.

    Methods and Results:A total of 301 MetS patients lacking any known cardiovascular disease were prospectively investigated and classified into 4 groups according to smoking status at entry and at 12 months as follows: never smokers, past smokers, quitters, and persistent smokers. Peripheral blood mononuclear cells (PBMC) were isolated, and MTFA was measured using a coagulation assay. Linear trends for higher baseline MTFA and CIMT were observed among persistent smokers, quitters, and past smokers compared with never smokers. At 12 months, MTFA and CIMT decreased in never and past smokers and quitters but increased in persistent smokers. Six acute myocardial infarctions and 8 strokes occurred during a median follow-up of 66.0 months. Persistent smoking was associated with an increased risk of events (P<0.001).

    Conclusions:Smoking is associated with upregulated MTFA and progression of CIMT, which may be related to the risk of atherothrombotic events in MetS patients.

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Pulmonary Circulation
  • Hideki Miwa, Nobuhiro Tanabe, Takayuki Jujo, Fumiaki Kato, Rie Anazawa ...
    Type: ORIGINAL ARTICLE
    Subject area: Pulmonary Circulation
    Volume 82 (2018) Issue 5 Pages 1428-1436
    Released: April 25, 2018
    [Advance publication] Released: March 13, 2018
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    Background:Several new treatments for chronic thromboembolic pulmonary hypertension (CTEPH) have appeared in recent years, which have led to changes in the treatment algorithm. Changes in survival rates and prognostic factors, however, have not been estimated so far.

    Methods and Results:Two hundred and eighty patients were diagnosed with CTEPH at Chiba University Hospital between June 1986 and June 2016. Survival rate was investigated by date of treatment initiation (group 1, 1986–1998; group 2, 1999–2008; group 3, 2009–2016). Survival rates were also evaluated by treatment strategy: balloon pulmonary angioplasty (BPA), pulmonary endarterectomy (PEA), and medical treatment. Group 3 had significantly better disease-specific survival than groups 1 and 2 (5-year survival: 91.9% vs. 67.1%, 77.0%, respectively). For the non-PEA (BPA+medication) strategy, group 3 had better disease-specific survival than groups 1 and 2 (5-year survival: 94.9% vs. 54.6%, 74.2%, respectively). The PEA strategy had significantly better survival than the medication strategy in groups 1 and 2, whereas no difference was observed between the BPA, PEA, and medication strategies in group 3.

    Conclusions:Survival in CTEPH in the recent era has significantly improved, especially in non-PEA patients. BPA and selective pulmonary vasodilators could improve survival in the non-PEA group. In the present study, no difference in survival was found between PEA and non-PEA.

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Stroke
  • Yuki Sakamoto, Seiji Okubo, Chikako Nito, Satoshi Suda, Noriko Matsumo ...
    Type: ORIGINAL ARTICLE
    Subject area: Stroke
    Volume 82 (2018) Issue 5 Pages 1437-1442
    Released: April 25, 2018
    [Advance publication] Released: December 21, 2017
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    Background:Insufficient anticoagulant intensity on admission is common in stroke patients with atrial fibrillation (AF) on vitamin K antagonist (VKA) therapy. Nevertheless, the effects of VKA under-treatment on stroke severity or arterial occlusion are not well known. The aim of the present study was to investigate the relationship between insufficient VKA therapy and stroke severity, or the site of arterial occlusion in patients with acute ischemic stroke (AIS) and AF.

    Methods and Results:From March 2011 through July 2016, 446 consecutive patients with AF and AIS were recruited. Of the 446 patients, 364 (167 women; median age, 79 years; IQR, 71–86 years) with anterior-circulation stroke were assessed to investigate the effects of insufficient VKA. Of these, 281 were on no anticoagulant, 53 were undertreated with a VKA, and 30 were sufficiently treated with VKA on admission (PT-INR ≥2.0 for patients <70 years and PT-INR ≥1.6 for ≥70 years old). On multivariate analysis, insufficient VKA was independently associated with severe stroke (i.e., initial NIHSS score ≥10; OR, 2.70, P=0.022) and higher prevalence of proximal artery occlusion (OR, 1.91; P=0.039) compared with no anticoagulant therapy.

    Conclusions:Insufficient VKA therapy on admission was associated with higher severity of stroke and higher prevalence of proximal artery occlusion in patients with AF and acute anterior-circulation stroke compared with no anticoagulant medication.

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  • Kazunori Toyoda, Masatoshi Koga, Hiroshi Yamagami, Chiaki Yokota, Shoi ...
    Type: ORIGINAL ARTICLE
    Subject area: Stroke
    Volume 82 (2018) Issue 5 Pages 1443-1450
    Released: April 25, 2018
    [Advance publication] Released: March 31, 2018
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    Background:Seasonal variations in the severity and outcomes of stroke remain unclarified.

    Methods and Results:A total of 2,965 acute ischemic stroke patients from a single-center prospective registry were studied. Among the total patients, stroke onset did not vary by season, though it varied with a peak in winter when limited to patients >75 years old (P=0.026), when limited to patients with moderate-to-severe initial neurological deficits (National Institutes of Health Stroke Scale Score ≥10, P=0.014), and when limited to those with cardioembolic stroke (n=1,031, P=0.010). In 1,934 patients with noncardioembolic stroke, stroke onset did not vary by season. After multivariable adjustment, moderate-to-severe neurological deficits were more common in winter (odds ratio 1.37, 95% confidence interval 1.10–1.72) and spring (1.27, 1.01–1.60), and death at 1 year was more common in summer than in fall (1.55, 1.03–2.36); death or dependency (modified Rankin Scale score 3–6) and death or bedridden (score of 5–6) were not differently common among the seasons.

    Conclusions:Overall ischemic stroke showed a fairly even distribution among the 4 seasons. Cardioembolic stroke was more common in winter. Ischemic stroke patients had more moderate-to-severe initial neurological deficits in winter and spring. Poor clinical outcomes at 1 year were generally similar among the seasons. Ischemic stroke is not necessarily a winter-dominant disease.

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Valvular Heart Disease
  • Yukio Abe, Kanako Akamatsu, Kazato Ito, Yoshiki Matsumura, Kenji Shime ...
    Type: ORIGINAL ARTICLE
    Subject area: Valvular Heart Disease
    Volume 82 (2018) Issue 5 Pages 1451-1458
    Released: April 25, 2018
    [Advance publication] Released: March 16, 2018
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    Background:We investigated the prevalence and prognostic significance of functional mitral regurgitation (MR) and tricuspid regurgitation (TR) in patients with atrial fibrillation (AF) and preserved left ventricular ejection fraction (LVEF).

    Methods and Results:We retrospectively studied the cases of 11,021 consecutive patients who had undergone transthoracic echocardiography. AF appeared in 1,194 patients, and we selected 298 with AF and LVEF ≥50% but without other underlying heart diseases. Moderate or greater (significant) degree of functional MR and of TR was seen in 24 (8.1%) and in 44 (15%) patients, respectively (P=0.0045). In contrast, significant MR and TR were more frequently seen in patients with AF duration >10 years (28% vs. 25%, respectively). During the follow-up period of 24±17 months, 35 patients (12%) met the composite endpoint defined as cardiac death, admission due to heart failure, or mitral and/or tricuspid valve surgery. On Cox proportional hazard ratio analysis, both MR and TR grading predicted the endpoint, independently of other echocardiographic parameters. On Kaplan-Meyer analysis, presence of both significant functional MR and TR was associated with poor prognosis, with an event-free rate of only 21% at the mean follow-up period of 24 months.

    Conclusions:Significant functional MR and TR are seen in a substantial proportion of patients with longstanding AF, despite preserved LVEF. This MR/TR combination predicts poor outcome for AF patients, who may have to be treated more intensively.

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Vascular Biology and Vascular Medicine
  • Yoshihiro Hata, Masayoshi Iwasaki, Keisuke Fujitaka, Haengnam Park, Da ...
    Type: ORIGINAL ARTICLE
    Subject area: Vascular Biology and Vascular Medicine
    Volume 82 (2018) Issue 5 Pages 1459-1465
    Released: April 25, 2018
    [Advance publication] Released: September 21, 2017
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    Background:We previously identified circulating mesoangioblasts (cMABs), a subset of mesenchymal stem cells that express cardiac mesodermal markers, in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). We also found that hepatocyte growth factor (HGF) is upregulated during cardiac surgery with CPB in humans, and induces MAB-like cell mobilization in rodents. These results strongly suggest that heparin induced MAB mobilization via HGF upregulation. Here, we tested this hypothesis in patients undergoing cardiac surgery or cardiac catheterization. We also examined whether human cMABs are derived from the heart.

    Methods and Results:Plasma HGF levels were determined by ELISA. Mononuclear cells isolated from blood samples were cultured on fibronectin-coated dishes, and outgrowing cMAB colonies were counted. We first confirmed that HGF upregulation and cMAB mobilization were observed before the start of CPB, excluding the possibility that CPB is the primary inducer of cMAB mobilization. We then examined patients undergoing cardiac catheterization and found that heparin significantly increased plasma HGF levels and the number of cMAB colonies in a dose-dependent manner. The results of simultaneous blood sampling from the aortic sinus, coronary sinus, and right atrium were consistent with the notion that human cMABs are derived from the heart.

    Conclusions:Human cMABs are mobilized by heparin injection during cardiac surgery or cardiac catheterization, presumably via HGF upregulation.

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Rapid Communications
  • Sarasa Isobe, Masaharu Kataoka, Takashi Kawakami, Keiichi Fukuda
    Type: RAPID COMMUNICATION
    Volume 82 (2018) Issue 5 Pages 1466-1468
    Released: April 25, 2018
    [Advance publication] Released: March 21, 2018
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    Background:The correlation between serum adiponectin concentration and hemodynamics or certain metabolic markers in patients with chronic thromboembolic pulmonary hypertension (CTEPH) is unknown.

    Methods and Results:We enrolled 30 CTEPH patients who underwent interventional therapy of balloon pulmonary angioplasty or pulmonary endarterectomy. Serum adiponectin concentrations positively correlated with B-type natriuretic peptide (BNP) concentrations, pulmonary vascular resistance, and mean pulmonary arterial pressure. After the therapeutic interventions, serum adiponectin concentrations improved and changes in serum adiponectin concentrations significantly correlated with changes in BNP concentrations.

    Conclusions:Adiponectin can be a useful marker for the severity of CTEPH.

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