Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
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Focus on issue: Vascular Disease
Reviews
  • Masafumi Takahashi
    Type: REVIEW
    2021 Volume 85 Issue 12 Pages 2129-2136
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: April 20, 2021
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    Atherosclerosis and abdominal aortic aneurysm (AAA) are multifactorial diseases characterized by inflammatory cell infiltration, matrix degradation, and thrombosis in the arterial wall. Although there are some differences between atherosclerosis and AAA, inflammation is a prominent common feature of these disorders. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic multiprotein complex that activates caspase-1 and regulates the release of proinflammatory cytokines interleukin (IL)-1β and IL-18, as well as the induction of lytic cell death, termed pyroptosis, thereby leading to inflammation. Previous experimental and clinical studies have demonstrated that inflammation in atherosclerosis and AAA is mediated primarily through the NLRP3 inflammasome. Furthermore, recent results of the Canakinumab Anti-inflammatory Thrombosis and Outcome Study (CANTOS) showed that IL-1β inhibition reduces systemic inflammation and prevents atherothrombotic events; this supports the concept that the NLRP3 inflammasome is a promising therapeutic target for cardiovascular diseases, including atherosclerosis and AAA. This review summarizes current knowledge with a focus on the role of the NLRP3 inflammasome in atherosclerosis and AAA, and discusses the prospects of NLRP3 inflammasome-targeted therapy.

Original Articles
Endovascular Treatment
  • Masato Nakamura, Munenori Takata, Hiroyoshi Yokoi, Takafumi Ueno, Yuka ...
    Type: ORIGINAL?ARTICLE
    Subject area: Endovascular Treatment
    2021 Volume 85 Issue 12 Pages 2137-2145
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: April 29, 2021
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    Supplementary material

    Background:The effect of treatment with paclitaxel-containing devices (PTXD) on mortality in patients with peripheral artery disease remains controversial.

    Methods?and?Results:An independent patient-level meta-analysis of 12 clinical trials (1,389 PTXD patients and 1,192 non-PTXD patients) was conducted. This study included 7 pivotal trials and 5 post-marketing surveillance studies on endovascular treatment for femoropopliteal artery by 6 companies. The primary endpoint was all-cause death, and 5-year cumulative mortality was estimated by a Kaplan-Meier curve. Cox proportional hazard model was used to calculate the hazard ratio (HR) and confidential interval (CI). During the median follow up of 3.0 years, 459 patients died. The cumulative 5-year mortality for the entire cohort was significantly lower in the PTXD than in the non-PTXD group (24.4% vs. 27.4%, respectively; HR, 0.81; 95% CI, 0.67–0.97; P=0.023), but this difference was no longer significant after adjustment for relevant covariates (HR, 1.01; 95% CI, 0.39–2.58; P=0.987). The Cox proportional hazard model revealed that sex, hyperlipidemia, Type 2 diabetes, hemodialysis, Rutherford category, and age above 75 years were significantly associated with 5-year mortality, but treatment with PTXD was not.

    Conclusions:This large individual meta-analysis of patients with femoropopliteal artery disease found that the use of PTXD does not have a negative effect on 5-year mortality.

  • Eitaro Kodani
    Type: EDITORIAL
    2021 Volume 85 Issue 12 Pages 2146-2148
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: May 26, 2021
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  • Yoshimitsu Soga, Osamu Iida, Masahiko Fujihara, Daizo Kawasaki, Shiger ...
    Type: ORIGINAL?ARTICLE
    Subject area: Endovascular Treatment
    2021 Volume 85 Issue 12 Pages 2149-2156
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: October 06, 2021
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    Supplementary material

    Background:To confirm the safety and efficacy of the IN.PACT Admiral drug-coated balloon (DCB) based on the indication approved by the Pharmaceuticals and Medical Devices Agency Japan in real-world patients with femoropopliteal artery disease.

    Methods?and?Results:IN.PACT PMS Japan was a prospective, multicenter, single-arm, post-market surveillance (PMS) study conducted in Japan that enrolled 304 participants (mean age 75.3±7.9 years). The primary endpoint was primary patency at 6 months following the index procedure, defined as freedom from clinically driven target lesion revascularization (CD-TLR) and freedom from restenosis as determined by duplex ultrasound (DUS) peak systolic velocity ratio (PSVR) ≤2.4 (assessed by the independent DUS core laboratory). Secondary endpoints included acute outcomes, primary patency at 12 months post-index procedure, freedom from CD-TLR, and major adverse events at 12 months. The mean lesion length was 97.81±58.97 mm. The primary endpoint, 6-month primary patency, was 91.3% (240/263). Kaplan-Meier estimates of primary patency and freedom from CD-TLR through 12 months were 91.5% and 94.1%, respectively. The CD-TLR rate was 5.8% (14/240) with low rates of thrombosis (0.8%) and target limb amputation (0.4%) at 12 months.

    Conclusions:The results of this real-world PMS study were consistent with outcomes from previous IN.PACT DCB studies, confirming the safety and efficacy of the IN.PACT Admiral DCB for broader use in patients seen in everyday practice.

  • Eiji Shibahashi, Kentaro Jujo
    Type: EDITORIAL
    2021 Volume 85 Issue 12 Pages 2157-2158
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: October 28, 2021
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  • Yusuke Tomoi, Shoichi Kuramitsu, Tomohiro Shinozaki, Seiichi Hiramori, ...
    Type: ORIGINAL?ARTICLE
    Subject area: Endovascular Treatment
    2021 Volume 85 Issue 12 Pages 2159-2165
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: March 12, 2021
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    Supplementary material

    Background:Limited data are available regarding the vascular response after fluoropolymer paclitaxel-eluting stent (FP-PES) implantation. This study sought to assess the vascular response at 6 and 12 months after FP-PES implantation for femoropopliteal artery lesions using serial optical coherence tomography (OCT) examination.

    Methods?and?Results:From the IMPERIAL trial, this study evaluated 10 de novo femoropopliteal lesions treated with FP-PES. The primary study endpoint was neointimal tissue coverage at a 6- and 12-month follow up, as assessed by serial OCT examination. The incidence of peri-strut low-intensity area (PLIA) and extra-stent lumen (ESL) was also assessed. A total of 203 matched cross-sectional images were evaluated at 6 and 12 months (5,615 and 5,763 struts, respectively). From 6 to 12 months, the mean neointimal thickness tended to increase from 198 μm to 233 μm, with a significant reduction in the incidence of malapposed struts (0.59% vs. 0.28%, P=0.039). Conversely, uncovered struts and PLIA were more frequently observed at 12 months (4.4% vs. 7.8%, P=0.01; 12.7% vs. 21.0%, P<0.001, respectively). The ESL area significantly increased over time without any difference in its incidence (0.24±0.32 mm2vs. 0.38±0.36 mm2, P=0.009).

    Conclusions:Neointimal proliferation was markedly inhibited from 6 to 12 months after FP-PES implantation, whereas the incidence of uncovered struts and PLIA significantly increased over time with the enlargement of ESL.

  • Hiroshi Banno, Masayuki Sugimoto, Tomohiro Sato, Shuta Ikeda, Yohei Ka ...
    Type: ORIGINAL?ARTICLE
    Subject area: Endovascular Treatment
    2021 Volume 85 Issue 12 Pages 2166-2171
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: October 21, 2021
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    Supplementary material

    Background:Not every elderly person is frail, and whether it would be beneficial to perform endovascular aneurysm repair (EVAR) solely because a patient is older is unclear. This study aimed to compare the results of EVAR and open surgical repair (OSR) in elderly individuals.

    Methods?and?Results:From May 1998 to March 2021, 828 EVAR patients and 886 OSR patients with abdominal aortic aneurysm (AAA) were reviewed. Patients aged ≥80 years were included among them. After propensity score matching by age, sex, and American Society of Anesthesiologists (ASA) classification, the outcomes were compared between patients who underwent EVAR and OSR. The study cohort was composed of 351 EVAR patients and 90 OSR patients. The groups had similar comorbidities, except that EVAR patients were significantly older and had higher ASA classifications. After propensity score matching, 79 pairs of patients were selected. The 30-day mortality (0 vs. 1.2%) and aneurysm-related death (ARD) rates during follow up (2.3% vs. 2.3%, respectively) were similar between the groups. Kaplan-Meier curves revealed that estimated overall survival and freedom from ARD were also similar.

    Conclusions:This study suggests that EVAR cannot improve survival outcomes compared with OSR if applied solely because a patient is aged ≥80 years. Not only age but also other risk factors and quality of life after surgery need to be further studied.

Aortic Aneurysm
  • Masao Yamaguchi, Taishi Yonetsu, Masahiro Hoshino, Tomoyo Sugiyama, Yo ...
    Type: ORIGINAL?ARTICLE
    Subject area: Aortic Aneurysm
    2021 Volume 85 Issue 12 Pages 2172-2180
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: April 24, 2021
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    Supplementary material

    Background:Recent imaging studies reported an association between vascular inflammation and progression of abdominal aortic aneurysm (AAA). This study investigated the clinical significance of periaortic adipose tissue inflammation derived from multidetector computed tomography angiography (MDCTA).

    Methods?and?Results:Patients with asymptomatic AAA (n=77) who underwent an index and >6 months follow-up MDCTA examinations were retrospectively investigated. MDCTA analysis included AAA diameter and the periaortic adipose tissue attenuation index (PAAI). The PAAI was defined as the mean CT attenuation value within a predefined range from ?190 to ?30 Hounsfield units of adipose tissue surrounding the AAA. The growth rate of the AAA was calculated as the change in diameter. AAA progression (AP) was defined as an AAA growth rate ≥5 mm/year. Univariate and multivariate logistic regression analysis were performed to determine the predictors of AP. AP was observed in 19 patients (24.7%), the median baseline AAA diameter was 38.9 mm (interquartile range [IQR] 32.7–42.9 mm), and the median growth rate was 3.1 mm/year (IQR 1.5–4.9 mm/year). Baseline AAA diameter (odds ratio [OR] 1.16; 95% confidence interval [CI] 1.05–1.28; P=0.001) and PAAI (OR 1.12; 95% CI 1.05–1.20; P=0.004) were independent predictors of AP.

    Conclusions:PAAI was an independent and significant predictor of AP, supporting the notion that local adipose tissue inflammation may contribute to aortic remodeling.

  • Shigeo Okuda, Yoshitake Yamada, Takehiro Nakahara, Masahiro Jinzaki
    Type: EDITORIAL
    2021 Volume 85 Issue 12 Pages 2181-2183
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: June 18, 2021
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  • Tatsuo Ueda, Hiromitsu Hayashi, Takahiro Ando, Kotomi Iwata, Hidemasa ...
    Type: ORIGINAL?ARTICLE
    Subject area: Aortic Aneurysm
    2021 Volume 85 Issue 12 Pages 2184-2190
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: October 28, 2021
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    Supplementary material

    Background:Although the high-attenuating crescent (HAC) sign can indicate aortic aneurysm (AA) impending rupture, the relation of its computed tomography (CT) value to the aneurysmal status remains unclear. This study compared the HAC sign CT-attenuation values among rupture, impending rupture, and non-rupture AA cases.

    Methods?and?Results:This included 76 patients (mean age: 77.0 years) diagnosed with HAC sign-associated AA between January 2005 and July 2015. The CT-attenuation values of the HAC sign (H) and aortic lumen (A) using region-of-interest methodology were measured and the H/A ratio was calculated. The study classified patients into the rupture group (R-G, n=36), impending rupture group (IR-G, n=16), and non-rupture group (NR-G, n=24); the H and the H/A ratio were compared among them. Additionally, the H and the H/A ratio cut-offs between the IR-G and NR-G groups were evaluated. The H and the H/A ratio were significantly higher in the R-G and IR-G than in the NR-G (both P<0.001); the H/A ratio was significantly higher in the R-G than in the IR-G (P=0.038). The optimal cut-off for H between the IR-G and NR-G was 50.3 Hounsfield units (area under the curve [AUC]=0.875; sensitivity=87.5%; specificity=87.5%), and that for the H/A ratio was 1.3 (AUC=0.909; sensitivity=91.7%; specificity=87.5%).

    Conclusions:Among patients with AA, the H and the H/A ratio were significantly higher in cases of rupture and impending rupture than in those of non-rupture.

Aortic Dissection
  • Kenichi Hagiya, Kazuyuki Ozaki, Mamoru Nanasato, Nobuo Iguchi, Morimas ...
    Type: ORIGINAL?ARTICLE
    Subject area: Aortic Dissection
    2021 Volume 85 Issue 12 Pages 2191-2200
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: March 30, 2021
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    Supplementary material

    Background:Resting heart rate (HR) at discharge is an important predictor of mortality after acute myocardial infarction. However, in patients with Stanford type A acute aortic dissections (TA-AADs), the relationship between HR and long-term outcomes is unclear. Therefore, this relationship was investigated in the present study.

    Methods?and?Results:Surgically treated consecutive patients with TA-AAD (n=721) were retrospectively categorized according to HR quartiles, recorded within 24 h before discharge (<70, 70–77, 78–83, and ≥84 beats/min). The study endpoints included aortic aneurysm-related deaths, sudden deaths, aortic surgeries, and hospitalizations for recurrence of acute aortic dissections. The mean (±SD) patient age was 65.8±13.0 years. During a median observation period of 5.8 years (interquartile range 3.9–8.5 years), 17.2% of patients (n=124) experienced late aortic events. Late aortic surgery was performed in 14.0% of patients. After adjusting for potential confounders, including β-blocker use, HR at discharge remained an independent predictor of long-term aortic outcomes. Patients with discharge HR ≥84 beats/min had a higher risk (hazard ratio 1.86; 95% confidence interval 1.06–3.25; P=0.029) of long-term aortic events than those with HR <70 beats/min; the cumulative survival rates were similar among the groups (log-rank, P=0.905).

    Conclusions:In surgically treated patients with TA-AAD, HR at discharge independently predicted long-term aortic outcomes. Consequently, HR in patients with TA-AAD should be optimized before discharge, particularly if the HR is ≥84 beats/min.

Venous Thromboembolism
  • Norikazu Yamada, Makoto Mo, Ako Ohsawa, Motoki Sato, Michiaki Umeyama, ...
    Type: ORIGINAL?ARTICLE
    Subject area: Venous Thromboembolism
    2021 Volume 85 Issue 12 Pages 2201-2207
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: May 15, 2021
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    Supplementary material

    Background:A post-marketing surveillance study (STANDARD-VTE) evaluated the real-world safety and effectiveness of apixaban in Japanese patients prescribed for either the treatment of venous thromboembolism (VTE) or prevention of recurrent VTE.

    Methods?and?Results:Patients newly initiated on apixaban were followed up for 52 weeks or 28 days post-discontinuation. Subgroup analysis was performed on patients with and without active cancer, and on patients with provoked VTE and with unprovoked VTE. A total of 1,119 patients were enrolled. Of these, 43.1% were aged ≥75 years, 46.4% had body weight ≤60 kg, and 21.3% had active cancer; mean serum creatinine was 0.76 mg/dL. The incidence of adverse drug reactions (ADRs) was 8.85%, and that of severe ADRs was 3.22%. Incidence of any bleeding, major bleeding, and recurrent VTE was 6.70%, 3.40%, and 0.80%, respectively. In patients starting apixaban 10 mg twice daily, THE incidence of any bleeding and major bleeding was 7.72% and 3.86%, respectively. In patients with active cancer, THE incidence of any bleeding and major bleeding was 16.81% and 9.24%, respectively.

    Conclusions:No new safety signals of apixaban were identified in Japanese patients with VTE. In this study, the safety and effectiveness of apixaban in real-world practice was consistent with the results of the apixaban phase III trial.

  • Yugo Yamashita, Yuuki Maruyama, Hirono Satokawa, Yuji Nishimoto, Ichiz ...
    Type: ORIGINAL?ARTICLE
    Subject area: Venous Thromboembolism
    2021 Volume 85 Issue 12 Pages 2208-2214
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: May 20, 2021
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    Background:Coronavirus disease 2019 (COVID-19) reportedly causes venous thromboembolism (VTE), but the status of this complication in Japan was unclear.

    Methods?and?Results:The VTE and COVID-19 in Japan Study is a retrospective, multicenter cohort study enrolling hospitalized patients with COVID-19 who were evaluated with contrast-enhanced computed tomography (CT) examination at 22 centers in Japan between March 2020 and October 2020. Among 1,236 patients with COVID-19, 45 (3.6%) were evaluated with contrast-enhanced CT examination. VTE events occurred in 10 patients (22.2%), and the incidence of VTE in mild, moderate, and severe COVID-19 was 0%, 11.8%, and 40.0%, respectively. COVID-19 patients with VTE showed a higher body weight (81.6 vs. 64.0 kg, P=0.005) and body mass index (26.9 vs. 23.2 kg/m2, P=0.04), and a higher proportion had a severe status for COVID-19 compared with those without. There was no significant difference in the proportion of patients alive at discharge between patients with and without VTE (80.0% vs. 88.6%, P=0.48). Among 8 pulmonary embolism (PE) patients, all were low-risk PE.

    Conclusions:Among a relatively small number of patients undergoing contrast-enhanced CT examination in Japanese real-world clinical practice, there were no VTE patients among those with mild COVID-19, but the incidence of VTE seemed to be relatively high among severe COVID-19 patients, although all PE events were low-risk without significant effect on mortality risk.

Population Science
  • Kawser Khan, Sachiko Tanaka-Mizuno, Tanvir C Turin, Naoyuki Takashima, ...
    Type: ORIGINAL?ARTICLE
    Subject area: Population Science
    2021 Volume 85 Issue 12 Pages 2215-2221
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: July 28, 2021
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    Supplementary material

    Background:Using a population-based stroke registry system, we evaluated the relationship between ambient temperature parameters and stroke incidence in a Japanese population.

    Methods?and?Results:We analyzed data from the Takashima Stroke Registry, which records all stroke occurrences in Takashima City, Japan. The study period of 8,401 days was divided into quintiles of daily weather parameters, and the middle quintile was used as the reference category. Incidence rates (IR per 100,000 person-years) were calculated across the quintiles. Poisson regression analysis was used to calculate the effect of temperature parameters on stroke incidence. There were 2,405 first-ever strokes (1,294 men), including 1,625 ischemic, 545 cerebral hemorrhages, 213 subarachnoid hemorrhages, and 22 unclassified strokes. The stroke IR was higher in the middle quintile of average temperature, 357.3 (328.4–388.8), and for other parameters. After adjustment for age and sex, for all stroke, the incidence rate ratio (IRR) in the highest (Q5: IRR 0.81, 95% confidence interval (CI) 0.71–0.92) and the second-highest (Q4: IRR 0.80, 95% CI 0.71-0.91) quintile was lower than that in the middle quintile (Q3: Reference). Analogous results were observed for the minimum, maximum, and lag-days temperatures, also in the subtypes and across ≥65 years of age, also in females.

    Conclusions:Higher temperatures, irrespective of the parameter (average, minimum, or maximum), had a protective effect against stroke occurrence in Japan.

  • Yoichiro Otaki, Tetsu Watanabe, Tsuneo Konta, Masafumi Watanabe, Shoui ...
    Type: ORIGINAL?ARTICLE
    Subject area: Population Science
    2021 Volume 85 Issue 12 Pages 2222-2231
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: September 03, 2021
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    Supplementary material

    Background:Aortic diseases (ADs), including aortic dissection, aortic aneurysm, and aortic rupture, are fatal diseases with extremely high mortality rates. Hypertension has been reported to be associated with AD development; however, it remains unclear whether a 1-year change in diastolic blood pressure (DBP) is a risk factor for AD-related mortality in the general population.

    Methods?and?Results:This study used a nationwide database of 235,076 individuals (aged 50–75 years) who participated in the annual “Specific Health Check and Guidance in Japan” for 2 consecutive years between 2008 and 2010. There were 55 AD-related deaths during the follow-up period of 1,770 days. All subjects were divided into 4 groups based on the baseline DBP and change in DBP at 1 year: persistent high DBP, increasing DBP, decreasing DBP, and normal DBP. Kaplan-Meier analysis demonstrated that the persistent high DBP group had the greatest risk among the 4 groups. Multivariate Cox proportional hazard regression analysis demonstrated that both DBP and 1-year change in DBP were significantly associated with AD-related deaths. The prediction capacity was significantly improved by the addition of 1-year change in DBP to confounding risk factors.

    Conclusions:This study demonstrated for the first time that a 1-year change in DBP was associated with AD-related deaths in the general population. Monitoring changes in DBP are of critical importance in the primary prevention of AD-related deaths in apparently healthy subjects aged 50–75 years.

Basic Science
  • Yuichi Kimura, Yasuhiro Izumiya, Satoshi Araki, Satoru Yamamura, Shins ...
    Type: ORIGINAL?ARTICLE
    Subject area: Basic Science
    2021 Volume 85 Issue 12 Pages 2232-2240
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: March 05, 2021
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    Background:Sirt7 is a recently identified sirtuin and has important roles in various pathological conditions, including cancer progression and metabolic disorders. It has previously been reported that Sirt7 is a key molecule in acute myocardial wound healing and pressure overload-induced cardiac hypertrophy. In this study, the role of Sirt7 in neointimal formation after vascular injury is investigated.

    Methods?and?Results:Systemic (Sirt7?/?) and smooth muscle cell-specific Sirt7-deficient mice were subjected to femoral artery wire injury. Primary vascular smooth muscle cells (VSMCs) were isolated from the aorta of wild type (WT) and Sirt7?/?mice and their capacity for cell proliferation and migration was compared. Sirt7 expression was increased in vascular tissue at the sites of injury. Sirt7?/?mice demonstrated significant reduction in neointimal formation compared to WT mice. In vitro, Sirt7 deficiency attenuated the proliferation of serum-induced VSMCs. Serum stimulation-induced upregulation of cyclins and cyclin-dependent-kinase 2 (CDK2) was significantly attenuated in VSMCs of Sirt7?/?compared with WT mice. These changes were accompanied by enhanced expression of the microRNA 290-295 cluster, the translational negative regulator of CDK2, in VSMCs of Sirt7?/?mice. It was confirmed that smooth muscle cell-specific Sirt7-deficient mice showed significant reduction in neointima compared with control mice.

    Conclusions:Sirt7 deficiency attenuates neointimal formation after vascular injury. Given the predominant role in vascular neointimal formation, Sirt7 is a potentially suitable target for treatment of vascular diseases.

  • Kimio Satoh
    Type: EDITORIAL
    2021 Volume 85 Issue 12 Pages 2241-2242
    Published: November 25, 2021
    Released: November 25, 2021
    [Advance publication] Released: March 23, 2021
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