Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Volume 83 , Issue 12
Showing 1-34 articles out of 34 articles from the selected issue
In Memoriam
JCS Statement
Reviews
  • Kenta Nakamura, Charles E. Murry
    Type: REVIEW
    2019 Volume 83 Issue 12 Pages 2399-2412
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: November 13, 2019
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    The investment of nearly 2 decades of clinical investigation into cardiac cell therapy has yet to change cardiovascular practice. Recent insights into the mechanism of cardiac regeneration help explain these results and provide important context in which we can develop next-generation therapies. Non-contractile cells such as bone marrow or adult heart derivatives neither engraft long-term nor induce new muscle formation. Correspondingly, these cells offer little functional benefit to infarct patients. In contrast, preclinical data indicate that transplantation of bona fide cardiomyocytes derived from pluripotent stem cells induces direct remuscularization. This new myocardium beats synchronously with the host heart and induces substantial contractile benefits in macaque monkeys, suggesting that regeneration of contractile myocardium is required to fully recover function. Through a review of the preclinical and clinical trials of cardiac cell therapy, distinguishing the primary mechanism of benefit as either contractile or non-contractile helps appreciate the barriers to cardiac repair and establishes a rational path to optimizing therapeutic benefit.

Editorials
Original Articles
Arrhythmia/Electrophysiology
  • Yasuo Okumura, Koichi Nagashima, Masaru Arai, Ryuta Watanabe, Katsuaki ...
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    2019 Volume 83 Issue 12 Pages 2418-2427
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 16, 2019
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    Background:The safety of discontinuing oral anticoagulant (OAC) after ablation for atrial fibrillation (AF) in Japanese patients has not been clarified.

    Methods and Results:A study based on the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) was conducted. Data were collected from 3,451 consecutive patients (74.1% men; age, 63.3±10.3 years) who had undergone AF ablation at any of 24 cardiovascular centers in Japan between August 2011 and July 2017. During a 20.7-month follow-up period, OAC therapy was discontinued in 1,836 (53.2%) patients; 51 patients (1.5%) suffered a stroke/transient ischemic attack (TIA), 71 (2.1%) suffered major bleeding, and 36 (1.0%) died. Patients in whom OAC therapy was discontinued were significantly younger than those in whom OACs were continued, and their CHA2DS2-VASc scores were significantly lower. The incidences of stroke/TIA, major bleeding, and death were significantly lower among these patients. Upon multivariate adjustment, stroke events were independently associated with relatively high baseline CHA2DS2-VASc scores but not with OAC status.

    Conclusions:Although the incidences of stroke/TIA, major bleeding, and death were relatively low among patients for whom OAC therapy was discontinued, stroke/TIA occurrence was strongly associated with a high baseline stroke risk rather than with OAC status. Thus, discontinuation of OAC therapy requires careful consideration, especially in patients with a high baseline stroke risk.

  • Makoto Ishizawa, Takahisa Noma, Takahiro Izumi, Ryosuke Tani, Tomoko I ...
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    2019 Volume 83 Issue 12 Pages 2428-2433
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: November 02, 2019
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    Supplementary material

    Background:Atrial fibrillation (AF), which contributes to an increased risk of stroke, frequently remains undetected, suggesting an unmet need for easier and more reliable AF screening. The reports on screening AF using an Omron blood pressure (BP) monitor with an irregular heartbeat (IHB) detector show inconsistent results, so the aim of this study was to develop a novel algorithm to accurately diagnose AF with 3 BP measurements using an Omron automated BP monitor with IHB detector.

    Methods and Results:In total, 303 general cardiac patients were included. Real-time single-lead ECG revealed AF in 44 patients. BP measurement was performed 3 times per patient using the Omron BP monitor HEM-907, and the number of IHBs detected was recorded. Based on these data, we developed the following algorithm: ≥1 IHB is detected during at least 2 of 3 BP measurements and the maximum number of IHBs detected is ≥2. Using this algorithm, we achieved a sensitivity of 95.5% and specificity of 96.5%, for diagnosing AF.

    Conclusions:The novel algorithm with 3 BP measurements using the Omron automated BP monitor with IHB detector showed high sensitivity and specificity for diagnosing AF in general cardiac patients.

  • Kazuo Miyazawa, Hisashi Ogawa, Michał Mazurek, Eduard Shantsila, Deird ...
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    2019 Volume 83 Issue 12 Pages 2434-2442
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: November 06, 2019
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    Supplementary material

    Background:Guideline-adherent antithrombotic treatment (ATT) reduces the risk of stroke and death in patients with atrial fibrillation (AF). However, the effect of ATT adherence among different ethnicities remains uncertain. We compared the prognosis of AF patients in Japan and the UK according to guideline adherence status.

    Methods and Results:We compared the clinical characteristics and outcomes of AF patients from the Fushimi AF registry (Japan; n=4,239) and the Darlington AF registry (UK; n=2,259). ATT adherence was assessed against the Japanese Circulation Society Guidelines and UK National Institute for Health and Care Excellence guidelines. The rates of guideline-adherent ATT were 58.6% and 50.8% in the Fushimi and Darlington registries, respectively. There was no significant difference in 1-year stroke rates between Fushimi and Darlington (2.6% vs. 3.0%, P=0.342). On multivariate logistic regression analysis, non-guideline adherent-ATT was significantly associated with an increased risk of stroke (odds ratio [OR]: 1.69, 95% confidence interval [CI]: 1.21–2.34, P=0.002 for undertreatment, OR: 2.13, 95% CI: 1.19–3.80, P=0.010 for overtreatment). No significant interaction for ATT and the 2 populations was found in the incidence of stroke, all-cause death, and the composite outcome.

    Conclusions:Approximately half of the AF patients received optimal ATT according to guideline recommendations, which was associated with a lower risk of stroke. Furthermore, there was no interaction for the 2 populations and the influence of ATT adherence.

  • Christian-H. Heeger, Huong-Lan Phan, Roza Meyer-Saraei, Thomas Fink, V ...
    Type: ORIGINAL ARTICLE
    Subject area: Arrhythmia/Electrophysiology
    2019 Volume 83 Issue 12 Pages 2443-2451
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: November 09, 2019
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    Background:Radiofrequency (RF)-based pulmonary vein isolation (PVI) results in a favorable clinical outcome, although its complexity demands a long learning curve. Balloon-based systems have been developed to possibly solve these limitations. The 2nd-generation laser balloon (LB2) offers optimized features for improved tissue contact and visibility. We determined the safety, efficacy and learning curve of the LB2 for PVI.

    Methods and Results:A total of 45 consecutive patients (89% persistent AF) were prospectively enrolled and divided into 3 groups (T1, T2, T3) of n=15 patients per group. All patients underwent PVI by 2 operators using the LB2. The operators were experienced in RF and cryothermal procedures, but not in laser ablations. A total of 174/177 PVs (98%) were successfully isolated. The median procedure time significantly declined from 132 (114, 158) to 119 (102, 127) and 91 (86, 105) min in T1–3, respectively (P=0.0009). Similarly, the median fluoroscopy time significantly decreased from T1 to T3 (22 (17, 27) vs. 21 (16, 24) vs. 13 (10, 17) min, respectively, P=0.045). Adverse events occurred in 6.7%, with a trend towards a lower complication rate with increasing experience.

    Conclusions:The LB2 was safe and effective for PVI, even for operators without any previous experience in laser balloon-based PVI. Procedure time, left atrial dwelling time and fluoroscopy time decreased after a learning curve of 15 cases.

Cardiovascular Intervention
  • Hiroshi Okamoto, Teruyoshi Kume, Ryotaro Yamada, Terumasa Koyama, Tomo ...
    Type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Intervention
    2019 Volume 83 Issue 12 Pages 2452-2459
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 22, 2019
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    Supplementary material

    Background:Healed plaques are identified as a layered pattern with optical coherence tomography (OCT) imaging, but the exact relationship between healed plaques and the development of significant coronary stenosis in stable angina pectoris (SAP) is not fully understood.

    Methods and Results:A retrospective clinincal study investigated the OCT characteristics of culprit lesions of SAP patients (n=205), and a prospective study examined the histopathological characteristics of layered plaque in directional coronary atherectomy (DCA) samples (42 samples from 18 SAP patients). In the retrospective study, layered plaque was observed in 36.6% of the SAP culprit lesions. Compared with patients with non-layered plaque, male sex and smoking were more frequent, and HbA1c level was significantly higher in the patients with layered plaque (81.3% vs. 65.9%, P<0.05; 62.7% vs. 41.8%, P<0.05; 6.6±1.3% vs. 6.2±1.0%, P<0.05, respectively). Furthermore, layered plaque was accompanied by higher plaque vulnerability and smaller minimal lumen area. In the histopathological study, the layered plaques had a significantly higher rate of intramural thrombus and macrophages infiltration than non-layered plaques (75.0% vs. 14.3%, P<0.05; 75.0% vs. 38.1%, P<0.05, respectively).

    Conclusions:Healed plaque containing intramural thrombus is identified as layered plaque by OCT, and was frequently observed, even in SAP patients. Intramural thrombus might play an important role in the development of coronary plaque with a high degree of stenosis in SAP patients.

  • Nobuaki Suzuki, Ken Kozuma, Sunao Nakamura, Kazuhiko Aramaki, Shigeru ...
    Type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Intervention
    2019 Volume 83 Issue 12 Pages 2460-2465
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: November 08, 2019
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    Background:The Japan post-marketing surveillance (PMS) for the Absorb GT1 bioresorbable vascular scaffold (BVS) mandated an intracoronary imaging-guided implantation technique.

    Methods and Results:We enrolled 135 patients who were planned to undergo PCI with THE Absorb GT1. Adequate lesion preparation, imaging-guided appropriate sizing, and high-pressure post-dilatation using a noncompliant balloon to minimize final diameter stenosis were recommended. The primary endpoint was the scaffold thrombosis rate at 3 months. All patients successfully received at least 1 Absorb GT1 at the index procedure and completed 1-year follow-up. All 139 lesions were predilatated: cutting/scoring balloon and noncompliant balloon were used in 48 (34.5%) and 58 (41.7%) lesions, respectively. Post-dilatation was performed in 137 (98.5%) lesions with mean high pressure of 18.8 atm. Optical coherence tomography (OCT) was used in 127 of 139 (91.4%) lesions, and revealed 56.7% of lesions had incomplete scaffold apposition (ISA) but only in 1.89% in the per strut analysis. All patients received adenosine diphosphate receptor antagonist at discharge, and 132 (97.8%) patients continued therapy through the year. No definite/probable scaffold thrombosis, cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization was reported up to 1 year follow-up.

    Conclusions:Appropriate OCT-guided BVS implantation may prevent incomplete strut apposition, thereby reducing the risk of target lesion failure and scaffold thrombosis.

Cardiovascular Surgery
  • Giuseppe Gatti, Antonio Fiore, Chiara Zilio, Sara Michelotti, Fiona Ec ...
    Type: ORIGINAL ARTICLE
    Subject area: Cardiovascular Surgery
    2019 Volume 83 Issue 12 Pages 2466-2478
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 29, 2019
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    Supplementary material

    Background:The use of bilateral internal thoracic artery (BITA) grafting concomitant with other cardiac operations is regarded as a risky strategy and the long-term advantages of BITA use remain unproven.

    Methods and Results:Pooled results from 3 series of patients (totaling 1,123 patients; mean age, 71.3 years; mean EuroSCORE II, 7.4%) undergoing combined coronary surgery using BITA were reviewed. Predictors of immediate and long-term adverse outcomes were identified by multivariable analyses. In-hospital and 30-day mortality was 7.9% and 6.3%, respectively. Diabetes on insulin (P=0.045), severe renal impairment (P<0.0001), extracardiac arteriopathy (P=0.0058), New York Heart Association class III−IV (P=0.017), recent myocardial infarction (P=0.0009), left ventricular dysfunction (P=0.0054), pulmonary hypertension (P=0.0016), active infective endocarditis (P=0.0011), and prolonged cross-clamp time (P=0.04) were predictors of in-hospital death. Multiple transfusions (27.3%), prolonged mechanical ventilation or reintubation (16.7%), acute kidney injury (11.5%), and sternal wound infections (10.4%) were relevant postoperative complications. Any neurological dysfunction occurred in 5.4% of cases. Median follow-up was 4.2 years. Female sex, chronic dialysis, extracardiac arteriopathy, and left ventricular dysfunction were predictors of both cardiac/cerebrovascular death and major adverse cardiac/cerebrovascular events (MACCE). The 10-year adjusted survival free of cardiac/cerebrovascular death, cerebrovascular accident after discharge, and MACCE was 84.2%, 94.8% and 54.6%, respectively.

    Conclusions:BITA grafting concomitant with other cardiac operations may be performed with satisfactory results. Long-term outcomes mostly depend on sex, preoperative comorbidities, and baseline cardiac function.

Critical Care
  • Keisuke Jinno, Toru Hifumi, Tomoya Okazaki, Yasuhiro Kuroda, Yoshio Ta ...
    Type: ORIGINAL ARTICLE
    Subject area: Critical Care
    2019 Volume 83 Issue 12 Pages 2479-2486
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 22, 2019
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    Supplementary material

    Background:This study examined the association between prehospital supraglottic airway (SGA) and/or epinephrine compared with bag-mask ventilation (BMV) and Glasgow–Pittsburgh cerebral performance category (CPC) 1 status in patients with out-of-hospital cardiac arrest (OHCA) using a large, nationwide, population-based registry dataset.

    Methods and Results:This was a post hoc analysis of the All-Japan Utstein Registry. We included patients with OHCA of cardiac origin aged ≥18 years with resuscitation performed by emergency medical services (EMS) between January 2011 and December 2015. The primary endpoint was favorable neurological outcome (CPC 1). The patients were divided into 4 groups according to the prehospital management performed by EMS: BMV group received only basic life support (BLS); epinephrine group received BLS plus epinephrine; SGA group received BLS plus SGA; and combined group received BLS plus epinephrine and SGA. Univariate and multivariable logistic regression analyses were performed for the primary endpoint. Among the 106,434 patients with OHCA, 48,847 received only BMV, 8,958 received BLS+epinephrine, 25,467 received BLS+SGA, and 15,551 received BLS+epinephrine+SGA. Using the BMV group as the reference, multivariable analysis showed that the epinephrine, SGA, and combined groups were independently associated with a reduced incidence of favorable neurological outcomes.

    Conclusions:Our results indicated that compared with BLS, patients in the prehospital SGA and/or epinephrine groups had a significantly reduced incidence of CPC 1 status.

Heart Failure
  • Kosuke Takahari, Takayuki Hidaka, Yusuke Ueda, Kanako Izumi, Yu Harada ...
    Type: ORIGINAL ARTICLE
    Subject area: Heart Failure
    2019 Volume 83 Issue 12 Pages 2487-2493
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: November 08, 2019
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    Background:Both the H2FPEF-score and nomogram-score, which consist of simple clinical parameters, can assist in diagnosing “early” heart failure with preserved ejection fraction (HFpEF) and only exertional dyspnea, but their these usefulness in Japanese remains unclear. We sought to investigate the correlation between these scores and exercise response, including the peak oxygen uptake (V̇O2), the pulmonary artery systolic pressure (PASP), the ratio of early diastolic transmitral flow velocity to early diastolic mitral annular velocity (E/e’) and stroke volume (SV) using exercise stress echocardiography (ESE) combined with cardiopulmonary exercise testing (CPET).

    Methods and Results:In this single-center, retrospective cross-sectional study the H2FPEF-score and nomogram-score were calculated in a total of 139 patients who underwent ESE combined with CPET. The scores correlated with peak V̇O2(r=−0.48, r=−0.44), PASP (r=0.23, r=0.29) and SV (r=−0.32, r=−0.19) at peak exercise. The nomogram-score correlated with E/e’ (r=0.24). The prevalence of exercise intolerance (percent predicted peak V̇O2<75% and <50%) increased as the H2FPEF-score increased and reached 88.9% and 22.2% among the patients with high H2FPEF-score (6–9 points).

    Conclusions:The H2FPEF-score may be useful as the initial step to diagnosing ‘early’ HFpEF. The nomogram-score may be more useful in Japanese because of its more universal association with exercise response than the H2FPEF-score.

Imaging
  • Takuma Nanno, Shigeki Kobayashi, Ryosuke Yoshitomi, Shohei Fujii, Tosh ...
    Type: ORIGINAL ARTICLE
    Subject area: Imaging
    2019 Volume 83 Issue 12 Pages 2494-2504
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 19, 2019
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    Supplementary material

    Background:Little is known about the pattern of isotope accumulation in the heart on 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography in patients with cardiac sarcoidosis (CS) complicated by ventricular aneurysm (VA).

    Methods and Results:We prospectively enrolled 82 consecutive patients with CS; 54 patients with active CS (presence of abnormal 18F-FDG accumulation in the heart) were subdivided into VA (n=17) and non-VA groups (n=37). Strong 18F-FDG accumulation surrounding the VA and its disappearance in the VA center was observed in all patients with VA, probably because of scar formation at the VA. Peak standardized uptake value was higher around the VA than in the VA center (5.1±2.1 vs. 2.2±0.6, P=0.0003) and the VA center had no 18F-FDG accumulation (VA center: 2.2±0.6 vs. control area: 2.1±0.6, P=0.37). On the other hand, in non-VA patients with LV wall thinning (n=28), 18F-FDG accumulation was significantly high, even in the area of LV wall thinning (LV wall thinning area: 3.1±0.8 vs. control area: 2.0±0.6, P=0.00002).

    Conclusions:A pattern of strong 18F-FDG accumulation surrounding the VA and its disappearance in the VA center might be characteristic in patients with CS complicated by VA. Careful attention to FDG uptake would further elucidate CS pathophysiology and aid in the early treatment of VA.

  • Hirofumi Ohashi, Hirohiko Ando, Hiroaki Takashima, Katsuhisa Waseda, M ...
    Type: ORIGINAL ARTICLE
    Subject area: Imaging
    2019 Volume 83 Issue 12 Pages 2505-2511
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 12, 2019
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    Background:The new 60-MHz high-resolution intravascular ultrasound (HR-IVUS) is the next-generation IVUS technology, providing higher image resolution than conventional IVUS. It gives clear images of plaque morphology and can discriminate the underlying mechanism of acute coronary syndrome (ACS). Our study aimed to evaluate the diagnostic performance of 60-MHz HR-IVUS in the detection of plaque rupture in patients with ACS.

    Methods and Results:Patients with ACS who underwent percutaneous coronary intervention for de novo native coronary artery lesions were enrolled. Both HR-IVUS and optical coherence tomography (OCT) were performed for the culprit lesions prior to interventions other than aspiration thrombectomy. Keeping plaque rupture detected by OCT as the gold standard, the diagnostic performance of HR-IVUS was evaluated. Overall, 70 patients underwent both HR-IVUS and OCT examinations. Of these, imaging assessments by HR-IVUS were available for all 70 patients (100%), and those by OCT were available for 54 patients (77.1%). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of HR-IVUS for identifying a plaque rupture were 84.8%, 57.1%, 75.7%, 70.6%, and 74.1%, respectively.

    Conclusions:HR-IVUS had high sensitivity, but modest specificity for identifying OCT-derived plaque rupture. Compared with results from previous conventional IVUS studies, HR-IVUS might have increased ability to detect OCT-derived plaque rupture, but there is still substantial scope for improvement, especially in the specificity.

  • Kenya Kusunose, Yuta Torii, Hirotsugu Yamada, Susumu Nishio, Yukina Hi ...
    Type: ORIGINAL ARTICLE
    Subject area: Imaging
    2019 Volume 83 Issue 12 Pages 2512-2519
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 12, 2019
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    Supplementary material

    Background:Whether preoperative echocardiography improves postoperative outcomes is not well established, so we examined the value of echocardiographic assessment on the onset of postoperative heart failure (HF), and determining which patients benefitted most from undergoing echocardiography prior to major elective non-cardiac surgery.

    Methods and Results:We identified all patients aged 50 years and older who had major elective non-cardiac surgery, and excluded patients with previously identified severe cardiovascular disease. The primary endpoint was the onset of HF during hospitalization. A total of 806 patients were included in the analysis. During hospitalization, 49 patients (6%) reached the primary endpoint. Within the matched cohort, preoperative echocardiography was associated with a statistically significant decrease in postoperative HF (hazard ratio: 0.46, P=0.01). In subgroup analyses, age, sex, body surface area, hypertension, diabetes mellitus, prior HF, surgical type, chronic kidney disease, pulmonary disease, and malignancy influenced the association of echocardiography with postoperative HF.

    Conclusions:The use of echocardiography in elderly patients with certain risk factors was associated with improved postoperative outcomes. The basis for this finding remains to be determined; particularly whether echocardiography is simply a marker of a population with better outcomes or whether it leads to better management that improves outcomes.

  • Junichi Taki, Anri Inaki, Hiroshi Wakabayashi, Ichiro Matsunari, Kyoko ...
    Type: ORIGINAL ARTICLE
    Subject area: Imaging
    2019 Volume 83 Issue 12 Pages 2520-2526
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 17, 2019
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    Background:Methionine uptake after myocardial infarction has been proven to reflect myocardial inflammation. The effect of postconditioning on the post-infarction inflammatory process, however, remains to be elucidated.

    Methods and Results:In control (n=22) and postconditioning rats (n=23), the left coronary artery was occluded for 30 min, followed by reperfusion for 1, 3, 7, and 14 days. Postconditioning was performed immediately following the reperfusion. 14C-methinine (0.74 MBq) and 201Tl (14.8 MBq) were injected 20 and 10 min prior to sacrifice, respectively. One minute before sacrifice, 150–180 MBq of 99 mTc-MIBI was injected immediately following the re-occlusion of the left coronary artery to verify the area at risk, and left ventricular triple-tracer autoradiography was performed. To examine the ventricular remodeling, echocardiography was performed 2 months after reperfusion in both groups (n=6 each). In the control rats, the methionine uptake ratios on days 1, 3, 7, and 14 were 0.74±0.12, 1.85±0.16, 1.48±0.10, 1.25±0.04, respectively. With postconditioning, methionine uptake was similar on day 3 (1.90±0.21), but was lower on day 7 (1.23±0.22, P<0.05) and day 14 (1.08±0.09, P<0.005). Echocardiography revealed that postconditioning reduced the ventricular end-diastolic (0.97±0.16 to 0.78±0.12 cm, P<0.05) and systolic (0.85±0.21 to 0.55±0.23 cm, P<0.05) dimensions and improved ventricular percentage fractional shortening (12±6.2 to 29±12 %, P=0.01).

    Conclusions: 14C-methinine imaging revealed that postconditioning accelerated resolution of inflammation and attenuated ventricular remodeling.

Pulmonary Circulation
  • Ayumi Goda, Kaori Takeuchi, Hanako Kikuchi, Mayumi Finger, Takumi Inam ...
    Type: ORIGINAL ARTICLE
    Subject area: Pulmonary Circulation
    2019 Volume 83 Issue 12 Pages 2527-2536
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 02, 2019
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    Background:Exercise-induced pulmonary hypertension (PH) is often seen in chronic thromboembolic PH (CTEPH) patients with normalized resting hemodynamics, but it is difficult to differentiate precapillary PH as pulmonary vascular dysfunction and post-capillary PH from occult-left ventricular dysfunction (LVD). The aim of this study was to examine whether the exercise-induced elevation of pulmonary arterial wedge pressure (PAWP) can be predicted by the echocardiographic index at rest.

    Methods and Results:A total of 71 CTEPH patients (67±11 years old, male/female=15/56) treated by pulmonary angioplasty with near-normal pulmonary arterial pressure (PAP) and normal PAWP at rest underwent symptom-limited exercise test using supine cycle ergometer with right heart catheterization. Exercise-induced elevation in PAWP of >20 mmHg during exercise was defined as occult-LVD. Resting echocardiography was performed within 3 months. In the occult-LVD (n=28), PAWP at rest after leg raising for exercise (14±4 vs. 11±3 mmHg, P<0.001), and mean PAP during exercise were higher compared with the non-LVD (n=43). Peak oxygen consumption, cardiac output, and pulmonary vascular resistance at peak exercise did not differ between groups. Left atrial volume index (LAVi) in the occult-LVD was significantly larger (39.7±8.1 vs. 34.4±9.6 mL/m2, P=0.017). LAVi correlated with exercise PAWP (r=0.356, P=0.002), but not resting PAWP (r=0.161, P=0.179).

    Conclusions:Larger left atrial volume may reflect the exercise-induced PAWP elevation as occult-LVD in CTEPH patients.

Regenerative Medicine
  • Wenhu Xu, Chenglin Yu, Limei Piao, Aiko Inoue, Hailong Wang, Xiangkun ...
    Type: ORIGINAL ARTICLE
    Subject area: Regenerative Medicine
    2019 Volume 83 Issue 12 Pages 2537-2546
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 24, 2019
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    Supplementary material

    Background:Given that cathepsin S (CatS) gained attention due to its enzymatic and non-enzymatic functions in signaling, the role of CatS in ischemia-induced angiogenesis of aged mice was explored.

    Methods and Results:To study the role of CatS in the decline in aging-related vascular regeneration capacity, a hindlimb ischemia model was applied to aged wild-type (CatS+/+) and CatS-deficient (CatS−/−) mice. CatS−/−mice exhibited impaired blood flow recovery and capillary formation and increased levels of p-insulin receptor substrate-1, Wnt5a, and SC35 proteins and decreased levels of phospho-endothelial nitric oxide synthase (p-eNOS), p-mTOR, p-Akt, p-ERK1/2, p-glycogen synthase kinase-3α/β, and galatin-3 proteins, as well as decreased macrophage infiltration and matrix metalloproteinase-2/-9 activities in the ischemic muscles. In vitro, CatS knockdown altered the levels of these targeted essential molecules for angiogenesis. Together, the results suggested that CatS−/−leads to defective endothelial cell functions and that CatS−/−is associated with decreased circulating endothelial progenitor cell (EPC)-like CD31+/c-Kit+cells. This notion was reinforced by the study finding that pharmacological CatS inhibition led to a declined angiogenic capacity accompanied by increased Wnt5a and SC35 levels and decreased eNOS/Akt-ERK1/2 signaling in response to ischemia.

    Conclusions:These findings demonstrated that the impairment of ischemia-induced neovascularization in aged CatS−/−mice is due, at least in part, to the attenuation of endothelial cell/EPC functions and/or mobilization associated with Wnt5a/SC35 activation in advanced age.

Stroke
  • Hyunjean Jung, Pil-Sung Yang, Eunsun Jang, Hee Tae Yu, Tae-Hoon Kim, J ...
    Type: ORIGINAL ARTICLE
    Subject area: Stroke
    2019 Volume 83 Issue 12 Pages 2547-2554
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 17, 2019
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    Supplementary material

    Background:Patients infected with human immunodeficiency virus (HIV) are at increased risk of cardiovascular diseases. However, little is known regarding the risk of ischemic stroke in HIV-infected individuals with atrial fibrillation (AF).

    Methods and Results:From the Korean National Health Insurance Service (NHIS) database from January 1, 2005 to December 31, 2016, we analyzed 962,116 patients with prevalent non-valvular AF aged ≥18 years. The overall HIV prevalence in AF patients was 0.17% (1,678 of 962,116). Oral anticoagulant (OAC)-naïve non-valvular AF (NVAF) patients with HIV had increased risks of ischemic stroke/systemic embolism (SE) [adjusted hazard ratio (HR) 1.37; 95% confidence interval (CI), 1.21–1.54], and major bleeding (adjusted HR 1.29; 95% CI, 1.15–1.46), compared with those without HIV. The incidence of ischemic stroke/SE in NVAF patients with HIV without any risk factors was similar to that of those without HIV at intermediate risk (i.e., male CHA2DS2-VASc score of 1) (2.04 vs. 2.18 events per 100 person-years). However, the use of OACs in AF patients with HIV was suboptimal, being only 8.9% at the time of AF diagnosis and 31.8% throughout the study period.

    Conclusions:The risks of ischemic stroke/SE and major bleeding were significantly higher in HIV-infected patients compared with non-HIV-infected patients with AF. Despite this, the actual use of OACs among AF patients with HIV was suboptimal.

Vascular Biology and Vascular Medicine
  • Hongchun Peng, Jianjun Tang, Shuiping Zhao, Li Shen, Danyan Xu
    Type: ORIGINAL ARTICLE
    Subject area: Vascular Biology and Vascular Medicine
    2019 Volume 83 Issue 12 Pages 2555-2566
    Published: November 25, 2019
    Released: November 25, 2019
    [Advance publication] Released: October 29, 2019
    JOURNALS FREE ACCESS FULL-TEXT HTML

    Background:Accumulation of foam cells in the neointima represents an early stage of atherosclerosis. 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl) urea (TPPU), a novel soluble epoxide hydrolase inhibitor (sEHi), effectively elevates epoxyeicosatrienoic acid (EET) levels. The effects of EETs on macrophages foam cells formation are poorly understood.

    Methods and Results:Incubation of foam cells with TPPU markedly ameliorate cholesterol deposition in oxidized low-density lipoprotein (oxLDL)-loaded macrophages by increasing the levels of EETs. Notably, TPPU treatment significantly inhibits oxLDL internalization and promotes cholesterol efflux. The elevation of EETs results in a decrease of class A scavenger receptor (SR-A) expression via downregulation of activator protein 1 (AP-1) expression. Additionally, TPPU selectively increases protein but not the mRNA level of ATP-binding cassette transporter A1 (ABCA1) through the reduction of calpain activity that stabilizes the protein. Moreover, TPPU treatment reduces the cholesterol content of macrophages and inhibits atherosclerotic plaque formation in apolipoprotein E-deficient mice. These changes induced by TPPU are dependent on heme oxygenase-1 (HO-1) activation.

    Conclusions:The present study findings elucidate a precise mechanism of regulating cholesterol uptake and efflux in macrophages, which involves the prevention of atherogenesis by increasing the levels of EETs with TPPU.

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