Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Volume 86, Issue 6
Displaying 1-27 of 27 articles from this issue
Focus on issue: Vascular Disease
Reviews
  • Shinsuke Yuasa
    Article type: REVIEW FOR THE 2020 SATO AWARD
    2022 Volume 86 Issue 6 Pages 919-922
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: February 19, 2022
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    Cardiovascular disease (CVD) is a major global health concern. Several therapeutic strategies for CVDs are available, such as medicine, cardiac assist devices, and heart transplantation. However, they are insufficient for the treatment of severe CVD. To develop novel, innovative treatment approaches for CVDs, it is imperative to understand the underlying pathophysiology and to undertake basic research on this facet. The generation of induced pluripotent stem (iPS) cells has opened avenues for developing new strategies for disease analysis and drug development. This technology has made it possible to obtain pluripotent stem cells from patients with genetic disorders, model the disease in a dish, and use such cells for future regeneration therapy. Meanwhile, artificial intelligence (AI), which is widely used for big data analysis in basic research, has potential in various applications in medicine. New tools such as iPS cells and AI can provide much needed novel insights into CVDs. This review focuses on the recent progress in cardiovascular research using these new technologies.

Original Articles
Vascular Disease
  • Nobuhiro Hara, Tetsumin Lee, Toshihiro Nozato, Mao Terui Matsuyama, Sh ...
    Article type: ORIGINAL ARTICLE
    2022 Volume 86 Issue 6 Pages 923-933
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: October 12, 2021
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    Supplementary material

    Background: The efficacy of direct oral anticoagulants (DOACs) compared with warfarin for the treatment of venous thromboembolism (VTE), and the recurrence of VTE after discontinuation of anticoagulation therapy in research are limited.

    Methods and Results: This retrospective study enrolled 893 patients with acute VTE between 2011 and 2019. The cohort was divided into the transient risk, unprovoked, continued cancer treatment, and cancer remission groups. The following were compared between DOACs and warfarin: composite outcome of all-cause death, VTE recurrence, bleeding and composite outcome of VTE-related death, recurrence and bleeding. In the continued cancer treatment group, more bleeding was seen in warfarin-treated patients than in patients treated with DOACs (53.2% vs. 31.2%, [P=0.048]). In addition, composite outcome of VTE-related death and recurrence after discontinuation of anticoagulation therapy (n=369) was evaluated. The continued cancer treatment group (multivariate analysis: HR: 3.62, 95% CI: 1.84–7.12, P<0.005) and bleeding-related discontinuation of therapy (HR: 2.60, 95% CI: 1.32–5.13, P=0.006) were independent predictors of the event after discontinuation of anticoagulation therapy. VTE recurrence after discontinuation of anticoagulation therapy in the cancer remission group was 1.6% and a statistically similar occurrence was found in the transient risk group (12.4%) (P=0.754).

    Conclusions: DOACs may decrease bleeding incidence in patients continuing to receive cancer treatment. In patients with bleeding-related discontinuation of anticoagulation therapy, VTE recurrence may increase. Discontinuation of anticoagulant therapy might be a treatment option in patients who have completed their cancer treatment.

  • Norimichi Koitabashi
    Article type: EDITORIAL
    2022 Volume 86 Issue 6 Pages 934-935
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: November 13, 2021
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  • Yuki Yamagata, Satoshi Ikeda, Sanae Kojima, Yuki Ueno, Tomoo Nakata, S ...
    Article type: ORIGINAL ARTICLE
    2022 Volume 86 Issue 6 Pages 936-944
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: March 12, 2022
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    Supplementary material

    Background: Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are characterized by elevated pulmonary arterial pressure resulting in right heart failure. Right ventricular (RV) dyssynchrony may be associated with early-stage RV dysfunction; however, the differences in RV dyssynchrony between CTEPH and PAH and the factors contributing to RV dyssynchrony remain unclear.

    Methods and Results: Forty-four patients (CTEPH, 26; PAH, 18) were enrolled in this study. RV dyssynchrony was assessed by determining the standard deviation of the intervals from the peak QRS to peak systolic strain for 6 segments of the RV free and septal wall by using 2-dimensional speckle-tracking echocardiography (RV-6SD). The RV-6SD, pulmonary hemodynamics, echocardiographic findings, and patient demographics in CTEPH and PAH patients were compared and their correlations with RV-6SD were investigated. CTEPH patients were older and had significantly higher pulse pressure of the pulmonary artery (PP), tricuspid valve regurgitation pressure gradient, and RV-6SD, and lower pulmonary arterial compliance (PAC), despite showing comparable pulmonary arterial pressures. Age-adjusted multiple logistic analysis showed that RV-6SD and PAC were predictors of CTEPH rather than PAH. RV-SD6 was positively correlated with PP and RV dimension and negatively correlated with PAC.

    Conclusions: CTEPH patients showed more evident RV dyssynchrony than PAH patients. Low PAC and a widened PP may delay RV free wall motion and cause RV dyssynchrony.

  • Shiro Adachi, Yoshihisa Nakano, Kenji Furusawa
    Article type: EDITORIAL
    2022 Volume 86 Issue 6 Pages 945-946
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: April 16, 2022
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  • Hiromasa Hayama, Masao Moroi, Satomi Adachi-Akahane, Tokuhisa Uejima, ...
    Article type: ORIGINAL ARTICLE
    2022 Volume 86 Issue 6 Pages 947-955
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: November 20, 2021
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    Supplementary material

    Background:Several non-invasive methods for pulmonary vascular resistance (PVR) measurement are proposed, but none are sufficiently accurate for use in clinical practice. This study proposes a new echocardiographic method of pulmonary artery wave reflection and investigates its efficacy in managing patients with pulmonary hypertension.

    Methods and Results:In total, 83 patients with left heart disease, pulmonary arterial hypertension, and chronic thromboembolic pulmonary hypertension (CTEPH), who underwent Doppler echocardiography and right heart catheterization, were included in the study. Pulmonary artery wave reflection was characterized by separating the pulmonary artery pressure waveform into forward and backward (Pb) waves, based on wave intensity. Pulmonary artery pressure waveforms were estimated from continuous Doppler tracings of tricuspid regurgitation velocity, and flow velocity was measured using pulsed Doppler of the right ventricular outflow tract. Pb-peak was compared with catheter hemodynamic indices, and with PVR by Abbas 2003, 2013 and Haddad in relation to increased catheter PVR. Catheter PVR and Pb were strongly correlated (r=0.77, P<0.001). The areas under the receiver operator characteristic curve for Pb-peak, PVR by Abbas 2003, 2013 and Haddad were 0.91, 0.72, 0.80, and 0.80, respectively, and were used to detect an increase in PVR (>3 Woods units).

    Conclusions:This study describes a novel, simple, and non-invasive echocardiography method to assess pulmonary wave reflected pressure to identify patients with pulmonary hypertension due to increased PVR.

  • Yoshihisa Nakano, Shiro Adachi
    Article type: EDITORIAL
    2022 Volume 86 Issue 6 Pages 956-957
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: December 21, 2021
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  • Keisuke Tokunaga, Masahiro Yasaka, Kazunori Toyoda, Etsuro Mori, Teruy ...
    Article type: ORIGINAL ARTICLE
    2022 Volume 86 Issue 6 Pages 958-963
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: November 17, 2021
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    Background: The present observational study aimed to clarify the association between bridging therapy with heparin before starting rivaroxaban and clinical outcomes after ischemic stroke or transient ischemic attack (TIA) in patients with non-valvular atrial fibrillation (NVAF).

    Methods and Results: Patients with NVAF who experienced acute ischemic stroke or TIA of the middle cerebral artery territory and started rivaroxaban within 30 days after onset were enrolled and were followed up for 90 days. Outcome measures were ischemic events, major bleeding, their composite, and death or disability 90 days after onset. Ischemic events were defined as ischemic stroke, TIA, and systemic embolism. Of 1,308 analyzed patients, 638 received bridging therapy with unfractionated or low-molecular-weight heparin with a median of 10,000 IU/day. Associations between bridging therapy and ischemic events or major bleeding were not statistically significant individually, but the association between bridging therapy and their composite was statistically significant (multivariable-adjusted hazard ratio, 1.80; 95% confidence interval, 1.01–3.29). The association between bridging therapy and death or disability 90 days after onset was not statistically significant.

    Conclusions: The composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin than in those who started treatment directly with rivaroxaban after ischemic stroke or TIA.

  • Shigeru Fujimoto
    Article type: EDITORIAL
    2022 Volume 86 Issue 6 Pages 964-965
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: December 25, 2021
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  • Pilar Jimenez-Quevedo, Esther Bernardo, Maria del Trigo, Shuji Otsuki, ...
    Article type: ORIGINAL ARTICLE
    2022 Volume 86 Issue 6 Pages 966-974
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: December 02, 2021
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    Background: The role of circulating progenitor cells (CPC) in vascular repair following everolimus-eluting stent (EES) implantation is largely unknown. The aim of the study was to investigate the relationship between temporal variation in CPC levels following EES implantation and the degree of peri-procedural vascular damage, and stent healing, as measured by optical coherence tomography (OCT).

    Methods and Results: CPC populations (CD133+/KDR+/CD45low) included patients with stable coronary artery disease undergoing stent implantation, and were evaluated using a flow cytometry technique both at baseline and at 1 week. OCT evaluation was performed immediately post-implantation to quantify the stent-related injury and at a 9-month follow up to assess the mid-term vascular response. Twenty patients (mean age 66±9 years; 80% male) with EES-treated stenoses (n=24) were included in this study. Vascular injury score was associated with the 1-week increase of CD133+/KDR+/CD45low (β 0.28 [95% CI 0.15; 0.41]; P<0.001) and with maximum neointimal thickness at a 9-month follow up (β 0.008 [95% CI 0.0004; 0.002]; P=0.04). Inverse relationships between numbers of uncoated and apposed struts for the 9-month and the 1-week delta values of CD133+/KDR+/CD45low (β −12.53 [95% CI −22.17; −2.90]; P=0.011), were also found.

    Conclusions: The extent of vessel wall injury influences early changes in the levels of CPC and had an effect on mid-term vascular healing after EES implantation. Early CPC mobilisation was associated with mid-term strut coverage.

  • Setsu Nishino, Masashi Sakuma, Shichiro Abe, Shigeru Toyoda, Teruo Ino ...
    Article type: EDITORIAL
    2022 Volume 86 Issue 6 Pages 975-976
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: January 14, 2022
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  • Kenichi Watanabe, Hiroshi Suzuki, Meizi Jiang, Shinya Tsukano, Satoshi ...
    Article type: ORIGINAL ARTICLE
    2022 Volume 86 Issue 6 Pages 977-983
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: September 16, 2021
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    Background: Intimal smooth muscle cells (SMCs) play an important role in the vasculitis caused by Kawasaki disease (KD). Lipoprotein receptor 11 (LR11) is a member of the low-density lipoprotein receptor family, which is expressed markedly in intimal vascular SMCs and secreted in a soluble form (sLR11). sLR11 has been recently identified as a potential vascular lesion biomarker. sLR11 is reportedly elevated in patients with coronary artery lesions long after KD, but there is no description of sLR11 in acute KD. Our aim was to determine the sLR11 dynamics in acute KD and to assess its usefulness as a biomarker.

    Methods and Results: 106 acute KD patients and 18 age-matched afebrile controls were enrolled. KD patients were classified into the following subgroups: intravenous immunoglobulin (IVIG) responders (n=85) and non-responders (n=21). Serum sLR11 levels before IVIG therapy were higher in non-responders (median, 19.6 ng/mL; interquartile range [IQR], 13.0–24.9 ng/mL) than in controls (11.9 ng/mL, 10.4–14.9 ng/mL, P<0.01) or responders (14.3 ng/mL, 11.7–16.5 ng/mL, P<0.01). Using a cutoff of >17.5 ng/mL, non-responders to initial IVIG therapy were identified with 66.7% sensitivity and 78.8% specificity.

    Conclusions: sLR11 can reflect the state of acute KD and might be a biomarker for patient response to IVIG therapy.

  • Taichi Kato
    Article type: EDITORIAL
    2022 Volume 86 Issue 6 Pages 984-985
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: November 02, 2021
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  • Fumihiko Takeuchi, Kozue Takano, Masaya Yamamoto, Masato Isono, Wataru ...
    Article type: ORIGINAL ARTICLE
    2022 Volume 86 Issue 6 Pages 986-992
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: February 01, 2022
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    Supplementary material

    Background: Tobacco smoking is a leading preventable cause of morbidity and mortality worldwide; still, the success rate of smoking cessation is low in general. From the viewpoint of public health and clinical care, an objective biomarker of long-term smoking behavior is sought.

    Methods and Results: This study assessed DNA methylation as a biomarker of smoking in a hospital setting through a combination of molecular approaches including genetic, DNA methylation and mRNA expression analyses. First, in an epigenome-wide association study involving Japanese individuals with chronic cardiovascular disease (n=94), genome-wide significant smoking association was identified at 2 CpG sites on chromosome 5, with the strongest signal at cg05575921 located in intron 3 of the aryl-hydrocarbon receptor repressor (AHRR) gene. Highly significant (P<1×10−27) smoking–cg05575921 association was validated in 2 additional panels (n=339 and n=300). For the relationship of cg05575921 methylation extent with time after smoking cessation and cumulative cigarette consumption among former smokers, smoking-related hypomethylation was found to remain for ≥20 years after smoking cessation and to be affected by multiple factors, such as cis-interaction of genetic variation. There was a significant inverse correlation (P=0.0005) between cg05575921 methylation extent and AHRR mRNA expression.

    Conclusions: The present study results support that reversion of AHRR hypomethylation can be a quantifiable biomarker for progress in and observance of smoking cessation, although some methodological points need to be considered.

  • Seitaro Nomura, Hiroyuki Morita
    Article type: EDITORIAL
    2022 Volume 86 Issue 6 Pages 993-994
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: April 02, 2022
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  • Akio Kodama, Kimihiro Komori, Akio Koyama, Tomohiro Sato, Shuta Ikeda, ...
    Article type: ORIGINAL ARTICLE
    2022 Volume 86 Issue 6 Pages 995-1006
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: March 26, 2022
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    Supplementary material

    Background: Zinc (Zn) has been reported to play an important role in wound healing (WH). Nevertheless, the effect of Zn in chronic limb-threatening ischemia (CLTI) patients is unclear. This study investigated the effect of Zn on the clinical outcomes of CLTI patients undergoing bypass surgery.

    Methods and Results: This study reviewed 111 consecutive patients who underwent an infrainguinal bypass from 2012 to 2020. Patients with Zn deficiency (serum Zn level <60 μg/dL) received oral Zn supplementation and maintained a normal level until WH. This study aimed to explore: (1) the effect of Zn deficiency; and (2) Zn supplementation in Zn-deficient patients on the clinical outcomes of this cohort. Patients with Zn deficiency, Zn supplementation, and no Zn supplementation despite Zn deficiency accounted for 48, 21, and 42 patients, respectively. (1) Zn deficiency was associated with WH (HR, 0.47; 95% CI, 0.29–0.78: P=0.003), major adverse limb events (MALE) (HR, 2.53; 95% CI, 1.26–5.09: P=0.009), and major amputation or death (HR, 3.17; 95% CI, 1.51–6.63: P=0.002). (2) Zn supplementation was positively related to WH (HR, 2.30; 95% CI, 1.21–4.34: P=0.011). This result was confirmed using propensity score matching (HR, 2.24; 95% CI, 1.02–4.87: P=0.043).

    Conclusions: The current study revealed that Zn level was associated with clinical outcomes in CLTI patients after bypass surgery. Oral Zn supplementation could improve WH in these patients.

  • Fushuo Zhou, Zhi Zheng, Zhengbiao Zha, Tianxin Xiong, Youmin Pan
    Article type: ORIGINAL ARTICLE
    2022 Volume 86 Issue 6 Pages 1007-1018
    Published: May 25, 2022
    Released on J-STAGE: May 25, 2022
    Advance online publication: December 09, 2021
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    Supplementary material

    Background: Nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be involved in the progression of many cancers; however, the role and mechanisms underlying NEAT1 in abdominal aortic aneurysm (AAA) remain unclear.

    Methods and Results: The expression of NEAT1, miR-30d-5p and A disintegrin and metalloprotease 10 (ADAM10) was measured by qRT-PCR and western blot. Functional experiments were conducted by using a CCK-8 assay, EDU assay, flow cytometry, western blot, ELISA, and commercial kits. The target relation was confirmed by dual-luciferase reporter assay and the RIP assay. It was then found that NEAT1 was upregulated in peripheral blood of AAA patients ~3.46-fold, smooth muscle cells (SMCs) isolated from AAA tissues ~2.6-fold and in a hydrogen peroxide (H2O2)-induced injury model of human vascular SMC (HVSMCs) ~2.0- and 3.9-fold at 50 µmol/L and 200 µmol/L H2O2treatment, respectively. NEAT1 deletion attenuated H2O2-induced cell proliferation promotion (40.0% vs. 74.3%), apoptosis inhibition (25.0% vs. 13.5%), and reduction of inflammatory response and oxidative stress in HVSMCs. Mechanistically, NEAT1 targeted miR-30d-5p to prevent the degradation of its target, ADAM10, in HVSMCs. Further rescue experiments suggested miR-30d-5p inhibition mitigated the effects of NEAT1 deletion on H2O2-induced HVSMCs. Moreover, ADAM10 overexpression counteracted the inhibitory functions of miR-30d-5p on H2O2-evoked HVSMC injury.

    Conclusions: NEAT1 promoted H2O2-induced HVSMC injury by inducing cell apoptosis, inflammation and oxidative stress through miR-30d-5p/ADAM10 axis, indicating the possible involvement of NEAT1 in the pathogenesis of AAA.

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