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Background: Low-gradient (LG) aortic stenosis (AS) has not been fully characterized compared with high-gradient (HG) AS in terms of cardiac damage, frailty, aortic valve calcification, and clinical outcomes., Objectives: The aim of this study was to compare the clinical characteristics and outcomes between each hemodynamic type of LG AS and HG AS., Methods: The current study included 3,363 patients in the CURRENT AS (Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis) Registry-2 after excluding patients without indexed stroke volume or left ventricular ejection fraction (LVEF) data. Patients were divided into 4 groups (LG AS with reduced LVEF: n = 285; paradoxical low flow, low gradient [LFLG]: n = 220; normal flow, low gradient [NFLG]: n = 872; HG: n = 1,986)., Results: Compared with HG AS, LG AS with reduced LVEF more often had cardiovascular comorbidities, advanced cardiac damage, and frailty with less severe valve calcification and paradoxical LFLG AS more often had atrial fibrillation, advanced cardiac damage, and frailty with less severe valve calcification, while NFLG AS had comparable cardiac damage and frailty with less severe valve calcification. Cumulative 3-year incidence of death or heart failure hospitalization was higher in LG AS with reduced LVEF and paradoxical LFLG than in HG AS. After adjusting for confounders, LG AS with reduced LVEF and paradoxical LFLG compared with HG AS were independently associated with higher risk for death or heart failure hospitalization (HR: 1.82; 95% CI: 1.49-2.23; P < 0.001; and HR: 1.43; 95% CI: 1.13-1.82; P = 0.003, respectively) but NFLG AS was not (HR: 1.03; 95% CI: 0.88-1.21; P = 0.68)., Conclusions: Clinical outcomes were significantly worse in LG AS with reduced LVEF and paradoxical LFLG AS and comparable in NFLG AS compared with HG AS., Competing Interests: Funding Support and Author Disclosures This work was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan). Dr Shirai has served as a clinical proctor for Edwards Lifesciences, Medtronic, and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025. Published by Elsevier Inc.)

There was a scarcity of data evaluating variations in treatment approaches and clinical outcomes for severe aortic stenosis (AS) between medical centers with and without availability of transcatheter aortic valve implantation (TAVI). Current study population was 2993 patients with severe AS enrolled in the CURRENT AS Registry-2 (2581 patients from 10 TAVI centers; 412 patients from 10 non-TAVI centers). TAVI centers more frequently opted for the initial aortic valve replacement (AVR) strategy compared to non-TAVI centers (60% and 40%, P < 0.001). Among patients with the initial AVR strategy, TAVI centers disproportionately favored the initial TAVI strategy compared to non-TAVI centers (71% and 23%, P < 0.001). No significant differences were observed in the risk of a composite of all-cause death or heart failure hospitalization between TAVI and non-TAVI centers in the entire study population (cumulative 3-year incidence: 32.0% and 31.0%, P = 0.37; adjusted hazard ratios: 0.92, 95% confidence intervals: 0.74-1.15, P = 0.45) or in conservative, initial AVR, initial surgical AVR, and initial TAVI strata. A substantial disparity exists in the treatment strategies for patients with severe AS between TAVI and non-TAVI centers. TAVI centers tended to perform AVR, particularly TAVI, earlier and more frequently. However, there was no discernible distinction in the risk of the composite of all-cause death or HF hospitalization between TAVI and non-TAVI centers. UMINID: UMIN000034169., Competing Interests: Declarations. Conflict of interest: K. Ono and K. Minatoya are members of Circulation Journal’s Editorial Team. S.S. reports clinical proctoring for Edwards Life Science, Medtronic, and Abbott Vascular. H.S. reports receiving personal fees from Abbott Vascular, Boston Scientific, and Daiichi Sankyo. T.M reports receiving lecturer fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray and manuscript fees from Bristol-Myers Squibb and Kowa, as well as being on the advisory board for Sanofi. T. Kimura reports being on the advisory board for Abbott Vascular and receiving grants from Edwards Lifescience, Daiichi Sankyo, Takeda Pharmaceutical, Bayer, Otsuka Parmaceutical, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Sumitomo Dainippon Pharma, Kowa, Abiomed, Japan Academic Research Forum, NIPRO, W.L. Gore & Associates G.K., RPM Co., Ltd., CSL Behring, Pfizer R&D Japan G.K., and EP- CRSU Co., Ltd; and honoraria from MSD, Eisai, Edwards Lifescience, Ono Pharmaceutical, Tsumura, Medical Review, Kowa, Sanofi, Pharmaceuticals and Medical Devices Agency, Bristol-Myers Squibb, Boston Scientific, Lifescience, Toray, Astellas Amgen Biopharma, Astellas, AstraZeneca, OrbusNeich, MSD Life Science Foundation, Public Health Research Foundation, Chugai Pharmaceutical, Japan Society for the Promotion of Science, Interscience, Philips, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Terumo, Novartis Pharma, HeartFlow Japan G.K., and CROSSCO Co. The remaining authors have no conflicts of interest to disclose. IRB information: The present study was approved by Kyoto University Graduate School and Faculty of Medicine Ethics Committee, Reference number: R1501., (© 2024. The Author(s) under exclusive licence to Japanese Association of Cardiovascular Intervention and Therapeutics.)

Background: There is a paucity of data on safety of calcium channel blockers (CCB) in patients with severe aortic stenosis (AS) and hypertension., Methods and Results: Among 2,460 patients with severe AS and hypertension receiving antihypertensive therapy in the CURRENT AS registry-2, we compared the clinical outcomes between patients taking antihypertensive therapy with CCB (CCB group) and without CCB (no CCB group). In the entire study population, CCB was prescribed in 1,763 patients (71.7%), which was the most commonly prescribed antihypertensive agents. The prescription rates of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and thiazides were 61.9%, 25.6%, and 7.3% in the CCB group, and 75.8%, 54.4%, and 6.0% in the no CCB group. In the propensity score matched cohort, the cumulative 3-year incidence of all-cause death or hospitalization for heart failure was not different between the CCB and no CCB groups (38.3% vs. 38.7%, log-rank P=0.65; HR, 0.94; 95%CI, 0.77-1.15; P=0.56). The cumulative 3-year incidence of syncope was low regardless of CCB prescription (1.1% vs. 1.0%, P=0.74)., Conclusions: Among patients with severe AS and hypertension, CCB was the most commonly prescribed antihypertensive agents, and antihypertensive therapy with CCB was associated with comparable clinical outcomes to antihypertensive therapy without CCB. Syncope was rarely seen in patients with severe AS and hypertension receiving antihypertensive therapy regardless of CCB prescription.

Background: Data on concomitant mitral regurgitation (MR) in patients with severe aortic stenosis (AS) are scarce., Methods and results: We investigated the risk of concomitant MR in patients with severe AS in the CURRENT AS Registry-2 according to initial treatment strategy (transcatheter aortic valve implantation [TAVI], surgical aortic valve replacement [SAVR], or conservative). Among 3,365 patients with severe AS, 384 (11.4%) had moderate/severe MR (TAVI: n=126/1,148; SAVR: n=68/591; conservative: n=190/1,626). The cumulative 3-year incidence for death or heart failure (HF) hospitalization was significantly higher in the moderate/severe than no/mild MR group in the entire population (54.6% vs. 34.3%, respectively; P<0.001) and for each treatment strategy (TAVI: 45.0% vs. 31.8% [P=0.006]; SAVR: 31.9% vs. 18.7% [P<0.001]; conservative: 67.8% vs. 41.6% [P<0.001]). The higher adjusted risk of moderate/severe MR relative to no/mild MR for death or HF hospitalization was not significant in the entire population (hazard ratio [HR] 1.15; 95% confidence interval [CI] 0.95-1.39; P=0.15); however, the risk was significant in the SAVR (HR 1.92; 95% CI 1.04-3.56; P=0.04) and conservative (HR 1.30; 95% CI 1.02-1.67; P=0.04) groups, but not in the TAVI group (HR 1.03; 95% CI 0.70-1.52; P=0.86), despite no significant interaction (P interaction =0.37)., Conclusions: Moderate/severe MR was associated with a higher risk for death or HF hospitalization in the initial SAVR and conservative strategies, while the association was less pronounced in the initial TAVI strategy.

Background: This study aimed to evaluate the association of COVID-19 preventive behavior and job-related stress with sleep quality among healthcare workers (HCWs). We conducted a cross-sectional survey using a questionnaire at the National Center of Neurology and Psychiatry, Tokyo, Japan., Methods: A total of 586 participants who completed the questionnaire were eligible for the study. The Pittsburgh Sleep Quality Index was used to evaluate sleep quality. We examined the level of engagement between poor sleep and COVID-19-related infection preventive behaviors, such as avoiding closed spaces, crowded places, and close contact (three Cs), a distance of at least one meter from others, wearing a face mask regularly, washing hands regularly, and working remotely, as well as job-related stress in the work environment, exposure to patients, potential risk of infection, fear of infecting others, need for social confinement, and financial instability. We conducted a hierarchical logistic regression analysis to examine the relationship between poor sleep and COVID-19 preventive behavior, job-related stress, and other covariates, including age, sex, and the Kessler Psychological Distress Scale (K6), which was used to measure non-specific psychological distress., Results: Poor sleep was observed in 223 (38.1%) participants. Adherence to COVID-19 preventive measures was relatively high: 84.1% of participants answered "always" for wearing a face mask regularly and 83.4% for washing hands regularly. In the multivariate logistic regression analysis, stress in the work environment (odds ratio [OR] = 2.09, 95% confidence interval [CI], 1.37-3.20; p < 0.001), financial instability (OR = 1.73, 95% CI, 1.12-2.67; p < 0.05), and low adherence to working remotely (OR = 1.65, 95% CI, 1.06-2.57; p < 0.05) were independently and significantly associated with poor sleep after controlling for the covariates., Conclusions: One year into the COVID-19 pandemic, the poor sleep rates of HCWs remained high. These results emphasize the need to protect HCWs from work environment stress and financial concerns., (© 2024. The Author(s).)

Background: The average sleep duration of Japanese people is shorter than that of people from other countries, and bedtime procrastination is suspected to be one of the factors contributing to this issue. This study aimed to develop and validate the Japanese version of the Bedtime Procrastination Scale (BPS-J)., Methods: The BPS-J was developed through procedures including the translation and back-translation of the scale, cognitive interviews with 100 participants who reported having experiences of being diagnosed with insufficient sleep syndrome (ISS) or receiving treatment for ISS using open-ended online questionnaires, and expert checking. To investigate the scale's validity and reliability, an online survey was conducted with daytime workers aged 20 - 65 years without a history of sleep disorders other than ISS. Half the participants were retested using the same survey after 14 days. Participants' responses to the Brief Self-Control Scale (BSCS), General Procrastination Scale (GPS), and Munich ChronoType Questionnaire (MCTQ), and data on sleep-related variables such as sleep duration on workdays and the days per week of fatigue or sleep loss, sex, and age, were collected., Results: We analyzed data from 574 participants to assess scale validity. We then analyzed data from 280 participants to determine test-retest reliability. Confirmatory factor analyses revealed that the two-factor model without Item 2 was most suitable for the BPS-J, unlike other language versions. Regardless of the full-item model or the model with Item 2 eliminated, sufficient reliability and significant correlations with the BSCS, GPS, MCTQ, and sleep-related variables such as sleep duration per night on work days, days per week of feeling fatigued, and days per week of sleep loss were observed. Logistic and linear regressions showed that the relationships between the BPS-J, sleep-related variables, and MCTQ were maintained after adjusting for sex and age., Conclusion: The BPS-J had sufficient validity and reliability. Further, eliminating Item 2 from the original version of the BPS strengthened the ability to survey Japanese daytime workers., (© 2024. The Author(s).)

There were no data comparing the in-hospital outcomes after transcatheter aortic valve implantation (TAVI) with those after surgical aortic valve replacement (SAVR) in Japan. Among consecutive patients with severe AS between April 2018 and December 2020 in the CURRENT AS Registry-2, we identified 1714 patients who underwent aortic valve replacement (TAVI group: 1134 patients, and SAVR group: 580 patients). Patients in the TAVI group were much older (84.4 versus 73.6 years, P < 0.001) and more often had comorbidities than those in the SAVR group. In-hospital death rate was numerically lower in the TAVI group than in the SAVR group (0.6% versus 2.2%). After excluding patients with dialysis, in-hospital death rate was very low and comparable in the TAVI and SAVR groups (0.6% versus 0.8%). The rates of major bleeding and new-onset atrial fibrillation during index hospitalization were higher after SAVR than after TAVI (72% versus 20%, and 26% versus 4.6%, respectively), while the rate of pacemaker implantation was higher after TAVI than after SAVR (8.1% versus 2.4%). Regarding the echocardiographic data at discharge, the prevalence of patient-prosthesis mismatch was lower in the TAVI group than in the SAVR group (moderate: 9.0% versus 26%, and severe: 2.6% versus 4.8%). In this real-world data in Japan, TAVI compared with SAVR was chosen in much older patients with more comorbidities with severe AS. In-hospital death rate was numerically lower in the TAVI group than in the SAVR group., (© 2023. The Author(s).)

Introduction: Sleep enhances the antibody response to vaccination, but the relationship between sleep and mRNA vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not fully understood., Methods: In this prospective observational study, we investigated the influence of sleep habits on immune acquisition induced by mRNA vaccines against SARS-CoV-2 in 48 healthy adults (BNT-162b2, n=34; mRNA-1273, n=14; female, n=30, 62.5%; male, n=18, 37.5%; median age, 39.5 years; interquartile range, 33.0-44.0 years) from June 2021 to January 2022. The study measured sleep duration using actigraphy and sleep diaries, which covered the periods of the initial and booster vaccinations., Results: Multivariable linear regression analysis showed that actigraphy-measured objective sleep duration 3 and 7 days after the booster vaccination was independently and significantly correlated with higher antibody titers (B=0.003; 95% confidence interval, 0.000-0.005; Beta=0.337; p=0.02), even after controlling for covariates, including age, sex, the type of vaccine, and reactogenicity to the vaccination. Associations between acquired antibody titer and average objective sleep duration before vaccination, and any period of subjective sleep duration measured by sleep diary were negligible., Discussion: Longer objective, but not subjective, sleep duration after booster vaccination enhances antibody response. Hence, encouraging citizens to sleep longer after mRNA vaccination, especially after a booster dose, may increase protection against SARS-CoV-2., Study Registration: This study is registered at the University Hospital Medical Information Network Center (UMIN: https://www.umin.ac.jp) on July 30, 2021, #UMIN000045009., Competing Interests: MI reports personal fees from Eisai outside the submitted work. KM reports personal fees from Eisai, Meiji Seika Pharma, Mochida, MSD, Otsuka Pharmaceutical Co., Ltd, and Yoshitomi Pharmaceutical outside the submitted work. TY reports personal fees outside the submitted work from MSD and Takeda Pharmaceutical Co. AK reports personal fees from Otsuka Pharmaceutical Co., Ltd, and Takeda Pharmaceutical Co., Ltd, outside the submitted work. TU reports personal fees from Eisai outside the submitted work. KN reports personal fees from Dainippon Sumitomo and Takeda Pharmaceutical Co., Ltd, outside the submitted work. AT reports personal fees from MSD outside the submitted work. KK reports research grants from Otsuka Pharmaceutical Co., Ltd, and Shionogi Pharma, research grants and personal fees from Meiji Seika Pharma, Eisai, MSD, Takeda Pharmaceutical Co., Ltd, and Tsumura, and personal fees from Yoshitomi Pharmaceutical and Sumitomo Pharma outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Izuhara, Matsui, Yoshiike, Kawamura, Utsumi, Nagao, Tsuru, Otsuki, Kitamura and Kuriyama.)

Objective: Health anxiety (HA), defined as excessive worry about having a serious medical condition, may affect preventive behaviors during the coronavirus disease 2019 (COVID-19) pandemic. We examined the distinct role of two dimensions of HA-perceived likelihood (probability dimension) and awfulness of illness (awfulness dimension)-in self-protection, as reflected in preventive behaviors during the pandemic., Methods: Participants comprised 657 healthcare workers. Data were collected between February 24 and 26, 2021. The Short Health Anxiety Inventory determined the HA dimensions. Adherence to the government's recommendations for COVID-19 preventive behaviors was self-rated. An independent association between each HA dimension and participants' adherence to the recommendations was examined using multivariable regression., Results: Within the analyzed sample of 560 subjects, severe HA was observed in 9.1 %. The more the participants felt awful, the less frequently they engaged in the recommended preventive behaviors (adjusted odds ratio = 0.993, 95 % confidence interval: 0.989, 0.998, p = 0.003) regardless of their profession, working position, psychological distress, sleep disturbance, and current physical diseases. However, the probability dimension was not associated with their preventive behaviors., Conclusion: The awfulness dimension of HA could be a more sensitive marker of preventive behaviors than the probability dimension. Paying particular attention to the awfulness dimension may help optimize self-protection strategies during the COVID-19 pandemic. A two-dimensional understanding of HA may be useful for the maintenance of the healthcare system and public health as well as healthcare workers' own health., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Takeshi Miyama reports financial support was provided by Japan Health Research Promotion Bureau. Kentaro Nagao reports a relationship with 10.13039/501100002975Dainippon Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Kentaro Nagao reports a relationship with 10.13039/100008373Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Takuya Yoshiike reports a relationship with MSD that includes: speaking and lecture fees. Takuya Yoshiike reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with 10.13039/501100003769Eisai Co Ltd that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with 10.13039/501100004169Meiji Seika Pharma Co Ltd that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with MSD that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with 10.13039/501100007132Otsuka Pharmaceutical Co Ltd that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with 10.13039/100008373Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Kentaro Matsui reports a relationship with Yoshitomi Pharmaceutical that includes: speaking and lecture fees. Aoi Kawamura reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: speaking and lecture fees. Aoi Kawamura reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees. Muneto Izuhara reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Tomohiro Utsumi reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Ayumi Tsuru reports a relationship with MSD that includes: speaking and lecture fees. Hideki Oi reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants. Hideki Oi reports a relationship with Sumitomo Pharma Co Ltd that includes: funding grants. Hideki Oi reports a relationship with Japan Society of Clinical Trials and Research that includes: board membership. Hideki Oi reports a relationship with Japanese Association of Pharmaceutical Medicine that includes: board membership. Kenichi Kuriyama reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants. Kenichi Kuriyama reports a relationship with 10.13039/501100005612Shionogi Pharma that includes: funding grants. Kenichi Kuriyama reports a relationship with 10.13039/501100004169Meiji Seika Pharma Co Ltd that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with Eisai Co Ltd that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with MSD that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with Takeda Pharmaceutical Company Limited that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with 10.13039/501100013420Tsumura & Co that includes: funding grants and speaking and lecture fees. Kenichi Kuriyama reports a relationship with Yoshitomi Pharmaceutical that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Kenichi Kuriyama reports a relationship with Igaku-Shoin Ltd that includes: consulting or advisory. Kazuyuki Nakagome reports a relationship with SHIONOGI that includes: funding grants. Kazuyuki Nakagome reports a relationship with Sumitomo Pharma Co Ltd that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with Meiji Seika Pharma Co Ltd that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with 10.13039/100008897Janssen Pharmaceuticals Inc that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with 10.13039/501100012351Mitsubishi Tanabe Pharma Corporation that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with Nippon Boehringer Ingelheim Co Ltd that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with Mochida Pharmaceutical Co Ltd that includes: funding grants, speaking and lecture fees, and travel reimbursement. Kazuyuki Nakagome reports a relationship with Takeda Pharmaceutical Company Limited that includes: speaking and lecture fees and travel reimbursement. Kazuyuki Nakagome reports a relationship with 10.13039/501100013327Lundbeck Japan that includes: speaking and lecture fees. Kazuyuki Nakagome reports a relationship with Viatris that includes: speaking and lecture fees. Kazuyuki Nakagome reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees., (© 2023 The Authors.)

Background: There is scarce data evaluating the current practice pattern and clinical outcomes for patients with severe aortic stenosis (AS), including both those who underwent surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) and those who were managed conservatively in the TAVI era., Methods and results: The Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis (CURRENT AS) Registry-2 is a prospective, physician-initiated, multicenter registry enrolling consecutive patients who were diagnosed with severe AS between April 2018 and December 2020 among 21 centers in Japan. The rationale for the prospective enrollment was to standardize the assessment of symptomatic status, echocardiographic evaluation, and other recommended diagnostic examinations such as computed tomography and measurement of B-type natriuretic peptide. Moreover, the schedule of clinical and echocardiographic follow up was prospectively defined and strongly recommended for patients who were managed conservatively. The entire study population consisted of 3,394 patients (mean age: 81.6 years and women: 60%). Etiology of AS was degenerative in 90% of patients. AS-related symptoms were present in 60% of patients; these were most often heart failure symptoms. The prevalence of high- and low-gradient AS was 58% and 42%, respectively, with classical and paradoxical low-flow low-gradient AS in 4.6% and 6.7%, respectively., Conclusions: The CURRENT AS Registry-2 might be large and meticulous enough to determine the appropriate timing of intervention for patients with severe AS in contemporary clinical practice.

This study investigated the difference in the severity of mental distress and factors contributing to mental distress in frontline and non-frontline healthcare professionals during the coronavirus disease (COVID-19) pandemic. A cross-sectional web-based survey of medical staff collected by snow-ball sampling was performed in Japan in October 2020 using the Kessler Psychological Distress Scale (K6) as an outcome measure for mental distress. Originally developed items asking about the degree of change in psychological and physical burdens, COVID-19-related fear, and experience of discrimination were obtained. The median score of the K6 was 7 in the frontline staff group (n = 86) and 6 in the non-frontline staff group (n = 504), without a statistically significant difference. Multiple regression analyses showed that among the participants, an increase in psychological burden and COVID-19-related fear was significantly associated with mental distress in both groups. Experience of discrimination was significantly associated with mental distress only in the frontline staff group. However, an increase in physical burden was significantly associated with mental distress only in the non-frontline staff group. The results indicate that the factors contributing to mental distress between frontline and non-frontline staff can be different, although the severity of mental distress is comparable between them., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Vaccinations are the main tool being used to control the COVID-19 pandemic. When the Japanese Ministry of Health approved the Moderna mRNA-1273 vaccination in May 2021, it was limited to patients over 18 years old; however, using the additional data of efficacy and safety from clinical trials, vaccination was approved for 12- to 17-year-olds in Japan in July 2021. A previous study reported that myocarditis after the mRNA-1273 vaccination was more prevalent in young men; however, no patients under 18 years old with myocarditis diagnosed by cardiovascular magnetic resonance (CMR) findings after mRNA-1273 vaccination have been reported in Japan. In the present case, a 17-year-old healthy male developed arthralgia and had fever on the day of the second mRNA-1273 vaccination for severe acute respiratory syndrome coronavirus 2. Three days after the vaccination, the patient felt severe chest pain with broad ST elevations on electrocardiography and troponin T elevations. Symptoms and findings rapidly improved; however, on CMR, myocarditis remained. Thus, it is necessary to be vigilant of potential acute myocarditis in young men following mRNA-1273 vaccination., Learning Objective: Although it is very rare, acute myocarditis after mRNA-1273 (Moderna) vaccination developed within 3-5 days following the second dose of the vaccine.Most reported cases were mild or moderate in severity, but there were cases of cardiogenic shock. We need to be vigilant of acute myocarditis in young men following mRNA-1273 vaccination., Competing Interests: The authors declare that there is no conflict of interest., (© 2022 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: The ventral tegmental area (VTA; a dopaminergic nucleus) plays an important role in the sleep-wake regulation system including orexin system. In addition to neuronal activity, there is increasing evidence for an important role of glial cells (i.e., astrocytes and microglia) in these systems. The present study examined the utility of magnetic resonance spectroscopy (MRS) for detecting neural and/or glial changes in the VTA to distinguish responders from non-responders before treatment with the orexin receptor antagonist suvorexant. Methods: A total of 50 patients were screened and 9 patients were excluded. The remaining 41 patients with insomnia who have or not a psychiatric disease who were expected to receive suvorexant treatment were included in this study. We compared MRS signals in the VTA between responders to suvorexant and non-responders before suvorexant use. Based on previous reports, suvorexant responders were defined as patients who improved ≥3 points on the Pittsburgh Sleep Quality Index after 4 weeks of suvorexant use. MRS data included choline (reflects non-specific cell membrane breakdown, including of glial cells) and N-acetylaspartate (a decrease reflects neuronal degeneration). Results: Among 41 examined patients, 20 patients responded to suvorexant and 21 patients did not. By MRS, the choline/creatine and phosphorylcreatine ratio in the VTA was significantly high in non-responders compared with responders ( p = 0.039) before suvorexant treatment. There was no difference in the N-acetylaspartate/creatine and phosphorylcreatine ratio ( p = 0.297) between the two groups. Conclusions: Changes in glial viability in the VTA might be used to distinguish responders to suvorexant from non-responders before starting treatment. These findings may help with more appropriate selection of patients for suvorexant treatment in clinical practice. Further, we provide novel possible evidence for a relationship between glial changes in the VTA and the orexin system, which may aid in the development of new hypnotics focusing on the VTA and/or glial cells., Competing Interests: MIn received grants from the Research for Promotion of Cancer Control Programs during this study. He has also received lecture fees from Technomics, Fuji Keizai, Novartis, Yoshitomiyakuhin, Pfizer, MSD, Meiji Seika Pharma, Eisai, Otsuka, Sumitomo Dainippon Pharma, Mochida, Janssen, Takeda, and Eli Lilly. His institute has received research funds from Otsuka, Eisai, Daiichi-Sankyo, Pfizer, Astellas, MSD, Takeda, Fujifilm, Shionogi, and Mochida. HK has received lecture fees from Eisai, FUJIFILM Toyama Chemical Co., Ltd, Guerbet Japan, and Bayer. His institute has received research funds from Fuji Pharma Co., Ltd., Eisai, Guerbet Japan, Daiichi-Sankyo, Nihon Medi-Physics Co., Ltd., and FUJIFILM Toyama Chemical Co., Ltd. MIz has received lecture fee from Eisai. This study has NOT supported any institute including MSD, Merck unit in Japan, which sells suvorexant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Izuhara, Miura, Otsuki, Nagahama, Hayashida, Hashioka, Asou, Kitagaki and Inagaki.)

Patients with delayed sleep-wake phase disorder (DSWPD) suffer from difficulties in sleep initiation at night, difficulties in waking up at the socially required time, and daytime somnolence. About half of the patients resist conventional light therapy and melatonin therapy. Therapy using hypnotics is not recommended due to its adverse effects. Recently, suvorexant, an orexin receptor antagonist, has become available for clinical use. The drug is relatively safer than traditional hypnotics such as benzodiazepines. We report three DSWPD patients who were successfully treated by the combination therapy of suvorexant and ramelteon. The first case was a 19-year-old woman who was experiencing difficulties in sleep initiation, difficulty in waking up in the morning, and daytime somnolence. She showed a prompt response to the combination therapy of suvorexant and ramelteon. Her sleep phase advanced, and her daytime somnolence reduced. The second and third cases were 21-year-old and 17-year-old men, respectively, who also showed significant sleep phase advances. Although case 2 was resistant to ramelteon treatment, his sleep phase advanced after suvorexant started. His difficulty in falling asleep and his habit of daytime napping disappeared after the combination therapy of suvorexant and ramelteon was started. Case 3 also showed a prompt response. His difficulties in falling asleep and waking up in the morning were ameliorated immediately after suvorexant with ramelteon was started. No obvious side effects were observed. Therapy using the combination therapy of suvorexant and ramelteon might be a reasonable option for DSWPD patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone (PTH). PHPT presents with a complex set of renal, skeletal, and neuropsychological symptoms. Parathyroidectomy (PTX) is a radical treatment that is recommended for all physically symptomatic patients with PHPT. However, psychiatric symptoms are not considered as an indication for surgery. There remains an important issue from the view of perioperative management of whether PTX should be performed with the presence of uncontrolled psychiatric symptoms or deferred until severe psychiatric symptoms have been controlled. We report a case of mild hypercalcemia that caused severe psychosis in PHPT, which improved dramatically following PTX and resulted in successful postoperative management., Patient Concern: Our patient was a 68-year-old Japanese woman. She was diagnosed with PHPT, which was triggered by mild hypercalcemia. She was due to receive an operation for osteoporosis and kidney stones. She had severe psychosis, despite medication. Blood examinations revealed mild hypercalcemia (10.4 mg/dL, 8.8-10.1 mg/dL) and elevated serum levels of intact PTH (184.0 pg/mL, 10-65 pg/mL)., Diagnosis: She was diagnosed with severe psychosis caused by mild hypercalcemia in PHPT., Interventions: Although she was treated with 37.5 mg quetiapine and 2 mg risperidone daily, she was excessively sedated and rejected oral treatment. Therefore, we decided to perform the operation., Outcomes: Immediately following surgery, serum levels of calcium, and intact PTH were normalized. Her psychotic symptoms ceased completely 5 days after surgery., Conclusion: We emphasize that PHPT presents with various severe psychiatric symptoms, even in mild hypercalcemia. Psychiatric symptoms may be the only salient symptoms in PHPT, and thus clinicians should suspect PHPT in patients with psychiatric symptoms and mild hypercalcemia. Furthermore, PTX is recommended for PHPT-even in the presence of severe uncontrolled psychiatric symptoms, which carries risks for postoperative management-because psychiatric symptoms are expected to improve and good postoperative management is possible., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study aimed to examine the effects of suvorexant on delirium prevention in a real-world setting. Previous studies have demonstrated the efficacy of suvorexant for delirium prevention in limited randomized clinical trial settings; however, its effectiveness in everyday clinical settings remains unknown., Methods: A single-center, retrospective cohort study was conducted in the intensive care unit of an academic hospital. Patients (aged ≥ 3 years) admitted from January 2016 to December 2018 were eligible if they stayed in the intensive care unit for at least 72 hours. Suvorexant was prescribed by the attending physician for insomnia as part of everyday clinical practice. A Cox proportional hazards regression analysis was conducted on delirium-free survival for suvorexant users, adjusting for delirium-related covariates. As part of routine clinical practice, the Confusion Assessment Method for the Intensive Care Unit was used to detect the existence of delirium at least twice daily throughout the intensive care unit stay., Results: There were 699 patients-84 suvorexant users and 615 suvorexant nonusers. Delirium was detected in 214 patients. Delirium prevalence was significantly lower in suvorexant users than in nonusers (17.9% vs 32.4%, respectively; P = .007). Cox regression analysis revealed a significantly lower hazard ratio (0.472; 95% CI, 0.268-0.832; P = .009) of delirium in suvorexant users than in nonusers. Trazodone also had a preventive effect on delirium (hazard ratio 0.345; 95% CI, 0.149-0.802; P = .013)., Conclusions: The present study extends to real-world settings previous findings that suvorexant is effective for delirium prevention., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Recent high-throughput approaches have revealed a vast number of transcripts with unknown functions. Many of these transcripts are long noncoding RNAs (lncRNAs), and intergenic region-derived lncRNAs are classified as long intergenic noncoding RNAs (lincRNAs). Although Myosin heavy chain 6 (Myh6) encoding primary contractile protein is down-regulated in stressed hearts, the underlying mechanisms are not fully clarified especially in terms of lincRNAs. Here, we screen upregulated lincRNAs in pressure overloaded hearts and identify a muscle-abundant lincRNA termed Lionheart. Compared with controls, deletion of the Lionheart in mice leads to decreased systolic function and a reduction in MYH6 protein levels following pressure overload. We reveal decreased MYH6 results from an interaction between Lionheart and Purine-rich element-binding protein A after pressure overload. Furthermore, human LIONHEART levels in left ventricular biopsy specimens positively correlate with cardiac systolic function. Our results demonstrate Lionheart plays a pivotal role in cardiac remodeling via regulation of MYH6.

We herein report a case of congenital long QT syndrome (LQTS) in which the QT interval was prolonged by Takotsubo syndrome (TTS), inducing ventricular fibrillation (VF). The patient was a 55-year-old woman who had been diagnosed with LQTS. Cardiopulmonary arrest occurred while coughing during sleep. VF was observed, and her heartbeat returned after two defibrillations. An electrocardiogram showed marked QT prolongation and large negative T waves. Echocardiography demonstrated hyperkinesis at the base of the left ventricle and akinesis at the apex. As there was no significant stenosis in the coronary artery, she was diagnosed with TTS.

Background: Fibroblast Growth Factor (FGF) 2 (also referred to as basic FGF) is a multifunctional growth factor that plays a pivotal role in the pro-survival, pro-migration and prodifferentiation of neurons., Method: Because alterations in FGF2 levels are suggested to contribute to the pathogenesis of schizophrenia, we investigated serum levels of FGF2 in the Gunn rat, a hyperbilirubinemia animal model of schizophrenic symptoms., Results: The enzyme-linked immunosorbent assay showed that the serum levels of FGF2 in Gunn rats were 5.09 ± 0.236 pg/mL, while those in the normal strain Wistar rats, serum levels were 11.90 ± 2.142 pg/mL. The serum FGF2 levels in Gunn rats were significantly lower than those in Wistar rats. We also measured serum levels of Unconjugated Bilirubin (UCB) and found a significant negative correlation between UCB and FGF2 in terms of serum levels in all the rats studied., Conclusion: Since it is known that FGF2 regulates dopaminergic neurons and have antineuroinflammatory effects, our finding suggests that low FGF2 levels may contribute to the pathogenesis of schizophrenia, in which imbalanced dopamin-ergic signaling and neuroinflammation are supposed to play certain roles., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Although growing evidence indicates that ECT affects astrocytes, the exact mechanisms of the therapeutic effect of ECT are still unknown. Astrocytic endfeet express the water channel aquaporin (AQP) 4 abundantly and ensheath brain blood vessels to form gliovascular units. It has been shown that the coverage of blood vessels by AQP4-immunostained endfeet is decreased in the prefrontal cortex (PFC) of patients with major depression. This study was made to determine whether ECT restores the astrocytic coverage of blood vessels with amelioration of depressive symptoms., Methods: After electroconvulsive shock (ECS) administration to rats, the forced swimming test (FST) and Y-maze test were performed. Subsequently, immunofluorescence analysis was conducted to measure the coverage of blood vessels by astrocytic endfeet in the PFC and hippocampus by using the endothelial cell marker lectin and anti-AQP4 antibody. We also performed Western blot to examine the effects of ECS on the hippocampal expression of AQP4 and the tight junction molecule claudin-5., Results: Gunn rats showed learned helplessness and impaired spatial working memory, compared to normal control Wistar rats. ECS significantly improved the depressive-like behavior. Gunn rats showed a decrease in astrocytic coverage of blood vessels, that was significantly increased by ECS. ECS significantly increased expression of AQP4 and claudin-5 in Gunn rats., Conclusions: ECS increased the reduced coverage of blood vessels by astrocytic endfeet in the mPFC and hippocampus with amelioration of depressive-like behavior. Therefore, therapeutic mechanism of ECT may involve restoration of the impaired gliovascular units by increasing the astrocytic-endfoot coverage of blood vessels., (Copyright © 2019. Published by Elsevier B.V.)

A reduction of GABAergic markers in postmortem tissue is consistently found in schizophrenia. Importantly, these alterations in GABAergic neurons are not global, which means they are more prevalent among distinct subclasses of interneurons, including those that express the calcium binding protein parvalbumin. A decreased expression of parvalbumin in the hippocampus is a consistent observation not only in postmortem human schizophrenia patients, but also in a diverse number of rodent models of the disease. Meanwhile, previously we reported that the congenital hyperbilirubinemia model rats (Gunn rats), which is a mutant of the Wistar strain, showed behavioral abnormalities, for instance, hyperlocomotor activity, deficits of prepulse inhibition, inappropriate social interaction, impaired recognition memory similar with several rodent models of schizophrenia. Several animal studies linked the importance of palvalbumin in relation to abnormal hippocampal activity and schizophrenia-like behavior. Here, we show that parvalbumin positive cell density was significantly lower in the CA1, CA3 and the total hippocampus of Gunn rats (congenital hyperbilirubinemia model rats) compared to Wistar control rats. The correlations between serum UCB levels and loss of PV expression in the hippocampus were also detected. The decreases in the PV-expression in the hippocampus might suggest an association of the behavioral abnormalities as schizophrenia-like behaviors of Gunn rats, compared to the Wistar control rats.

Objective: Recent studies demonstrate that microRNAs show promising potential, including angiogenesis, in therapeutic intervention. MicroRNA-126 (miR-126) is reported to regulate angiogenesis by blocking Sprouty-related EVH1 domain-containing protein 1 (SPRED1), an endogenous inhibitor of vascular endothelial cell growth factor. In this study, we investigated the angiogenic effects of the sustained release of miR-126 loaded with poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) in a murine hindlimb ischemia model., Methods: We induced mice hindlimb ischemia through femoral artery excision. We randomly assigned the mice to two groups and performed an intramuscular injection of miR-126-loaded PLGA NPs (miR-126) or scrambled miR-loaded PLGA NPs (control) shortly after induction of ischemia., Results: The miR-126 expression levels in the ischemic limb at 3 days after treatment were significantly higher in mice treated with miR-126-loaded PLGA NPs than in those with scrambled miR, indicating the fair efficiency of local miR transduction (control vs miR-126: 0.33 ± 0.12 vs 0.74 ± 0.42; P < .05; n = 6). Laser Doppler perfusion imaging revealed that limb blood flow in mice treated with miR-126-loaded PLGA NPs was significantly higher at 14 days after treatment (sham vs control vs miR-126: 0.62 ± 0.09 vs 0.58 ± 0.05 vs 0.72 ± 0.07; P < .001; n = 12). Immunohistochemical analysis indicated that CD31-positive cell density and α-smooth muscle actin-positive vessel density were significantly higher in miR-126-treated mice (control vs miR-126: 0.33 ± 0.12 vs 0.74 ± 0.42; P < .05; n = 6). SPRED1 messenger RNA expression levels were significantly lower in miR-126-treated mice (control vs miR-126: 1.00 ± 0.05 vs 0.81 ± 0.07; P < .05; n = 6). Western blotting indicated that protein levels of pERK/ERK mediated by SPRED1 were significantly higher in miR-126-treated mice (control vs miR-126: 0.29 ± 0.10 vs 0.54 ± 0.21; P < .05; n = 6)., Conclusions: This study suggests that sustained release of miR-126-loaded PLGA NPs might be an effective method in therapeutic angiogenesis for hindlimb ischemia., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Aim: Up to 60% of depressed patients do not obtain sufficient relief from a course of antidepressant therapy, and these treatment-resistant major depressive disorder (TRD) patients are at increased risk for relapse, chronicity, persistent psychosocial impairments, and suicide. Probiotics actively participate in treatment of neuropsychiatric disorders. However, the role of gut microbiota in brain disorders and depression remains unclear. We performed a prospective study to evaluate the effects of Clostridium butyricum MIYAIRI 588 (CBM588)., Methods: This was an 8-week open-label study to evaluate the efficacy and safety of CBM588 in combination with antidepressants in adult patients diagnosed with TRD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Forty antidepressant-treated inpatients were included. Patients were randomized to adjuvant treatment with CBM588 (n = 20) or control (n = 20). The primary endpoint was the change in the 17-item Hamilton Depression Rating Scale score from baseline to week 8. Secondary end points were changes in the Beck Depression Inventory and the Beck Anxiety Inventory scale scores from baseline to week 8. The Systematic Assessment of Treatment Emergent Events-General Inquiry was used to assess adverse effects., Results: CBM588 (60 mg/d) in combination with antidepressants (flvoxamine, paroxetine, escitalopram, duroxetine, and sertraline) provided significant improvement in depression. All patients completed the trial, and 70% responded to treatment; the remission rate was 35.0%. No serious adverse events occurred., Conclusions: These preliminary data suggest that CBM588 in combination with antidepressants is effective and well tolerated in the treatment of TRD. Further studies using a larger, double-blind, parallel-group design are warranted to confirm these findings.

Introduction: Recent studies imply that glial activation plays a role in the pathogenesis of psychiatric disorders, such as schizophrenia and major depression. We previously demonstrated that Gunn rats with hyperbilirubinemia show congenital gliosis and schizophrenia-like behavior., Methods: As it has been suggested that major depression involves glial activation associated with neuroinflammation, we examined whether Gunn rats show depression-like behavior using the forced swimming test (FST) and the tail suspension test (TST). In addition, we quantitatively evaluated both microgliosis and astrogliosis in the hippocampus of Gunn rats using immunohistochemistry analysis of the microglial marker ionized calcium-binding adaptor molecule (Iba) 1 and the astrocytic marker S100B., Results: Both the FST and TST showed that immobility time of Gunn rats was significantly longer than that of normal control Wistar rats, indicating that Gunn rats are somewhat helpless, a sign of depression-like behavior. In the quantification of immunohistochemical analysis, Iba1immunoreactivity in the dentate gyrus (DG), cornu ammonis (CA) 1, and CA3 and the number of Iba1-positive cells in the CA1 and CA3 were significantly increased in Gunn rats compared to Wistar rats. S100B immunoreactivity in the DG, CA1, and CA3 and the number of S100B-positive cells in the DG and CA3 were significantly increased in Gunn rats compared to Wistar rats., Conclusion: Our findings suggest that both microglia and astrocyte are activated in Gunn rats and their learned helplessness could be related to glial activation., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

The authors present the case of a 38-year-old man with schizophrenia and with severe insomnia, who attempted suicide twice during oral drug therapy with risperidone. The patient slept barely 2 or 3 h per night, and he frequently took half days off from work due to excessive daytime sleepiness. As a maladaptive behavior to insomnia, he progressively spent more time lying in bed without sleeping, and he repeatedly thought about his memories, which were reconstructed from his hallucinations. His relatives and friends frequently noticed that his memories were not correct. Consequently, the patient did not trust his memory, and he began to think that the hallucinations controlled his life. During his insomniac state, he did not take antipsychotic drugs regularly because of his irregular meal schedule due to his excessive daytime sleepiness. The authors started cognitive behavioral therapy for insomnia (CBT-i) with aripiprazole long acting injection (LAI). CBT-i is needed to be tailored to the patient's specific problems, as this case showed that the patient maladaptively use chlorpromazine as a painkiller, and he exercised in the middle of the night because he believed he can fall asleep soon after the exercise. During his CBT-i course, he learned how to evaluate and control his sleep. The patient, who originally wanted to be short sleeper, began to understand that adequate amounts of sleep would contribute to his quality of life. He finally stopped taking chlorpromazine and benzodiazepine as sleeping drugs while taking suvorexant 20 mg. Through CBT-i, he came to understand that poor sleep worsened his hallucinations, and consequently made his life miserable. He understood that good sleep eased his hallucinations, ameliorated his daytime sleepiness and improved his concentration during working hours. Thus, he was able to improve his self-esteem and self-efficacy by controlling his sleep. In this case report, the authors suggest that CBT-i can be an effective therapy for schizophrenia patients with insomnia to the same extent of other psychiatric and non-psychiatric patients.

Background: The main drawback of current available drug coated balloons (DCB) is that a certain percentage of the coated drug is lost in the bloodstream during its delivery to the target lesion. We integrated the nanoparticle-mediated drug delivery technology and polydimethylsiloxane (PDMS) as a new excipient to facilitate an efficient drug delivery and uptake by endothelial cells. The present study aimed to evaluate the efficacy of the new DCB., Method and Results: The novel DCB were coated with 5.6mg of paclitaxel-incorporated nanoparticles using PDMS. The efficacy of the new DCB was examined in rabbit iliac stent model (n=12) and in the swine in-stent restenosis model (n=8) by quantitative coronary angiography (QCA) and optical coherence tomography (OCT). At 28days follow-up in the swine in-stent restenosis model, the area stenosis was significantly lower in DCB group as compared with that of the control group in OCT analysis (0.31±0.05 vs 0.49±0.06, p=0.04) though there was no significant differences observed in the rabbit iliac stent model in QCA and OCT analysis., Conclusion: The study results indicated that the paclitaxel-incorporated nanoparticle-coated balloon using PDMS has an inhibitory effect for the proliferation of smooth muscle cell in a swine coronary in-stent restenosis model., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Abdominal aortic aneurysm (AAA) is an increasingly prevalent and ultimately fatal disease with no effective pharmacological treatment. Because matrix degradation induced by vascular inflammation is the major pathophysiology of AAA, attenuation of this inflammation may improve its outcome. Previous studies suggested that miR-33 (microRNA-33) inhibition and genetic ablation of miR-33 increased serum high-density lipoprotein cholesterol and attenuated atherosclerosis., Approach and Results: MiR-33a-5p expression in central zone of human AAA was higher than marginal zone. MiR-33 deletion attenuated AAA formation in both mouse models of angiotensin II- and calcium chloride-induced AAA. Reduced macrophage accumulation and monocyte chemotactic protein-1 expression were observed in calcium chloride-induced AAA walls in miR-33 -/- mice. In vitro experiments revealed that peritoneal macrophages from miR-33 -/- mice showed reduced matrix metalloproteinase 9 expression levels via c-Jun N-terminal kinase inactivation. Primary aortic vascular smooth muscle cells from miR-33 -/- mice showed reduced monocyte chemotactic protein-1 expression by p38 mitogen-activated protein kinase attenuation. Both of the inactivation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were possibly because of the increase of ATP-binding cassette transporter A1 that is a well-known target of miR-33. Moreover, high-density lipoprotein cholesterol derived from miR-33 -/- mice reduced expression of matrix metalloproteinase 9 in macrophages and monocyte chemotactic protein-1 in vascular smooth muscle cells. Bone marrow transplantation experiments indicated that miR-33-deficient bone marrow cells ameliorated AAA formation in wild-type recipients. MiR-33 deficiency in recipient mice was also shown to contribute the inhibition of AAA formation., Conclusions: These data strongly suggest that inhibition of miR-33 will be effective as a novel strategy for treating AAA., (© 2017 American Heart Association, Inc.)

The authors present the case of a 24-year-old male with treatment-resistant schizophrenia, with predominant severe delusion and hallucination, who received bone marrow transplantation (BMT) for acute myeloid leukemia. After BMT, he showed a remarkable reduction in psychotic symptoms without administration of neuroleptics. He also showed drastic improvement in social functioning. Follow-up evaluations 2 and 4 years after BMT showed persistent significant improvement of the psychotic state and social functioning. Recent findings show that the major underlying pathogenic mechanism of schizophrenia is immune dysregulation. Thus, conceptually, BMT, a cellular therapy, that facilitates the counteractive processes of balancing inflammation by immune regulation, could produce beneficial clinical effects in patients with treatment-resistant schizophrenia. Further studies are required to define the true benefits of BMT for the possible curative treatment of schizophrenia.

: Recurrent miscarriage can arise from a large diversity of causes and the factors responsible have not been fully clarified. The coagulation factor V R506Q (Leiden) mutation is a well known risk factor for recurrent miscarriage, although it has not been found in Japanese populations. We examined whether the factor V Nara and Hong Kong mutations, the factor V gene (F5) 16 single-nucleotide polymorphisms (SNPs), including the factor V R2 haplotype, and plasma factor V activity (FV:C) were risk factors for recurrent miscarriage. A cross-sectional study was conducted among 88 patients with a history of unexplained recurrent miscarriage and 95 fertile controls. None of the patients or controls was homozygous or heterozygous for the factor V Nara or Hong Kong mutation. In the 16 SNPs of F5, frequencies of the G/T and T/T genotypes at Ser156Ser were significantly lower in patients than in controls (OR 0.45, 95% CI 0.22-0.91, OR 0.32, 95% CI 0.14-0.72) and the allele frequency of C at Leu1288Leu was significantly higher in patients than that in controls (OR 1.66, 95% CI 1.02-2.71). The mean FV:C values were not significantly different between patients and controls. However, the prevalence of patients with a high or low FV:C (>95th or

Background: Despite recent progress with drug-eluting stents, restenosis and thrombosis after endovascular intervention are still major limitations in the treatment of cardiovascular diseases. These problems are possibly caused by inappropriate inhibition of neointimal formation and retardation of re-endothelialization on the surface of the stents. miR-126 has been shown to have the potential to enhance vascular endothelial cell proliferation., Methods and Results: We designed and constructed a 27-nt double strand RNA (dsRNA) conjugated to cholesterol, which has high membrane permeability, and formed mature miR-126 after transfection. For site-specific induction of miR-126, we utilized poly (DL-lactide-co-glycolide) nanoparticles (NPs). miR-126-dsRNA-containing NPs (miR-126 NPs) significantly reduced the protein expression of a previously identified miR-126 target, SPRED1, in human umbilical vascular endothelial cells (HUVECs), and miR-126 NPs enhanced the proliferation and migration of HUVECs. On the other hand, miR-126 NPs reduced the proliferation and migration of vascular smooth muscle cells, via the suppression of IRS-1. Finally, we developed a stent system that eluted miR-126. This delivery system exhibited significant inhibition of neointimal formation in a rabbit model of restenosis., Conclusions: miR-126 NP-conjugated stents significantly inhibited the development of neointimal hyperplasia in rabbits. The present study may indicate the possibility of a novel therapeutic option to prevent restenosis after angioplasty.

Background: Recently, it has been reported that specific microRNA (miRNA) levels are elevated in serum and can be used as biomarkers in patients with cardiovascular diseases. However, miRNAs expression profiles and their sources in pericardial fluid (PF) are unclear., Methods and Results: The purpose of this study was to identify the levels of miRNAs in PF in relation to those in the serum in patients undergoing cardiac surgery. Serum (S) and PF from patients undergoing coronary artery bypass graft (CABG) due to stable angina pectoris (sAP) and unstable AP (uAP) and aortic valve replacement due to aortic stenosis (AS) were analyzed for the detection of miRNAs. We named these samples S-sAP, S-uAP, S-AS, PF-sAP, PF-uAP, and PF-AS, respectively. We first measured the levels of miR-423-5p, which was recognized previously as a biomarker for heart failure. miR-423-5p levels were significantly higher in PF than serum. Although there was no difference in miR-423-5p levels among the PF-AS, PF-sAP, and PF-uAP, its levels were significantly elevated in S-uAP compared with those in S-AS and S-sAP. In order to clarify the source of miR-423-5p in PF, we measured the levels of muscle-enriched miR-133a and vascular-enriched miR-126 and miR-92a in the same samples. miR-133a levels were significantly higher in serum than in PF, and it was elevated in S-uAP compared with S-AS. miR-126 level was significantly increased in serum compared with PF, and the level of miR-92a the similar tendency. miR-423-5p is located in the first intron of NSRP1. There is another miRNA, miR-3184, encoded in the opposite direction in the same region. In vitro experiments indicated that the duplex of miR-423-5p and miR-3184-3p was more resistant to RNase than the duplex of miR-423-5p and miR-133-3p, which may help to stabilize miR-423-5p in the PF., Conclusions: Our results suggested that miR-423-5p is enriched in PF, and serum miR-423-5p may be associate with uAP. Its expression pattern was different to that of muscle- and vascular-enriched miRNAs, miR-133a, miR-126, and miR-92a.

Objective: To determine whether low HDL-C is a risk factor for adverse cardiovascular events in patients with known CAD., Methods: We evaluated 10,391 patients who underwent PCI from January 2005 to December 2007. In total, 3838 (36.9%) patients had low HDL-C (HDL-C <40 mg/dL in males and <50 mg/dL in females) and 6553 (63.1%) patients had normal HDL-C based on measurements on admission., Results: The unadjusted 5-year incidence of major adverse cardiac events (MACE: composite of cardiovascular death, myocardial infarction or stroke) was significantly higher in the low HDL-C group than in the normal HDL-C group (17.6% vs. 14.0%, P < 0.0001). However, after adjusting for confounders, low HDL-C was not associated with a higher risk of MACE (adjusted hazard ratio [HR] 1.07, 95% confidence interval (CI) 0.97-1.19; P = 0.19). There was no significant interaction between the effect of low HDL-C on MACE and several subgroup factors including age, sex, clinical presentation of CAD, statins use, serum low-density lipoprotein cholesterol level, and serum triglycerides level., Conclusion: Low HDL-C, as compared with normal HDL-C, was not associated with higher 5-year risk of MACE in patients who underwent PCI., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Rationale: In some patients with type 2 diabetes mellitus (DM) without hypertension, cardiac hypertrophy and attenuated cardiac function are observed, and this insult is termed diabetic cardiomyopathy. To date, microRNA (miRNAs or miR) functions in diabetic cardiomyopathy remain to be elucidated., Objective: To clarify the functions of miRNAs involved in diabetic cardiomyopathy caused by type 2 DM., Methods and Results: C57BL/6 mice were fed a high-fat diet (HFD) for 20 weeks, which induced obesity and type 2 DM. miRNA microarray analyses and real-time polymerase chain reaction revealed that miR-451 levels were significantly increased in the type 2 DM mouse hearts. Because excess supply of saturated fatty acids is a cause of diabetic cardiomyopathy, we stimulated neonatal rat cardiac myocytes with palmitic acid and confirmed that miR-451 expression was increased in a dose- and time-dependent manner. Loss of miR-451 function ameliorated palmitate-induced lipotoxicity in neonatal rat cardiac myocytes. Calcium-binding protein 39 (Cab39) is a scaffold protein of liver kinase B1 (LKB1), an upstream kinase of AMP-activated protein kinase (AMPK). Cab39 was a direct target of miR-451 in neonatal rat cardiac myocytes and Cab39 overexpression rescued the lipotoxicity. To clarify miR-451 functions in vivo, we generated cardiomyocyte-specific miR-451 knockout mice. HFD-induced cardiac hypertrophy and contractile reserves were ameliorated in cardiomyocyte-specific miR-451 knockout mice compared with control mice. Protein levels of Cab39 and phosphorylated AMPK were increased and phosphorylated mammalian target of rapamycin (mTOR) was reduced in cardiomyocyte-specific miR-451 knockout mouse hearts compared with control mouse hearts., Conclusions: Our results demonstrate that miR-451 is involved in diabetic cardiomyopathy through suppression of the LKB1/AMPK pathway., (© 2014 American Heart Association, Inc.)

MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33a located within the intron of sterol regulatory element-binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Primates, but not rodents, express miR-33b from an intron of SREBF1. Therefore, humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron, are required to address its function in vivo. We successfully established miR-33b knock-in (KI) mice and found that protein levels of known miR-33a target genes, such as ABCA1, ABCG1, and SREBP-1, were reduced compared with those in wild-type mice. As a consequence, macrophages from the miR-33b KI mice had a reduced cholesterol efflux capacity via apoA-I and HDL-C. Moreover, HDL-C levels were reduced by almost 35% even in miR-33b KI hetero mice compared with the control mice. These results indicate that miR-33b may account for lower HDL-C levels in humans than those in mice and that miR-33b is possibly utilized for a feedback mechanism to regulate its host gene SREBF1. Our mice will also aid in elucidating the roles of miR-33a/b in different genetic disease models.

Background: The Japan Atherosclerosis Society's 2007 Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases (JAS2007GL) advocate reducing LDL cholesterol (LDL-C) to target levels in patients with dyslipidemia, but achievement rates are frequently unsatisfactory even in the presence of lipid-lowering therapy. This multicenter, open-label, randomized, parallel-group study compared the efficacy of rosuvastatin and atorvastatin on JAS2007GL LDL-C goals in Japanese patients not achieving their target goal with atorvastatin treatment., Methods: The study involved 20 clinical institutes in Japan (Kishiwada Atherosclerosis Prevention Study [KAPS] Group). Patients with category II or III risk of coronary artery disease (CAD), or those with a history of CAD (secondary prevention), who had not achieved their JAS2007GL LDL-C goals during treatment with atorvastatin for at least 4 weeks were switched either to rosuvastatin 5 mg/day (from atorvastatin 10 mg/day) or rosuvastatin 10 mg/day (from atorvastatin 20 mg/day) (n = 75) or continued to receive atorvastatin (n = 77). The primary endpoint was achievement of LDL-C goals at 3 months. The main secondary endpoint was achievement of LDL-C goal + high-sensitivity C-reactive protein level <1.0 mg/L at 3 months., Results: Achievement rates for the primary endpoint were 49.3% in the rosuvastatin group and 31.7% in the atorvastatin group (P = 0.022). Achievement rates for the main secondary endpoint were 40.0% in the rosuvastatin group and 20.8% in the atorvastatin group (P = 0.010). Rosuvastatin and atorvastatin were both well tolerated in this study., Conclusions: Rosuvastatin is a useful treatment option for Japanese patients who are not achieving their JAS2007GL LDL-C goal with atorvastatin., (© 2014 John Wiley & Sons Ltd.)

MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports have indicated that miR-33, which is located within the intron of sterol regulatory element-binding protein (SREBP) 2, controls cholesterol homoeostasis and may be a potential therapeutic target for the treatment of atherosclerosis. Here we show that deletion of miR-33 results in marked worsening of high-fat diet-induced obesity and liver steatosis. Using miR-33(-/-)Srebf1(+/-) mice, we demonstrate that SREBP-1 is a target of miR-33 and that the mechanisms leading to obesity and liver steatosis in miR-33(-/-) mice involve enhanced expression of SREBP-1. These results elucidate a novel interaction between SREBP-1 and SREBP-2 mediated by miR-33 in vivo.

Background: Hyperinsulinemia and insulin resistance have been proposed as having a causal role in pathogenesis of atherosclerosis; however, the relationship between post-load insulin levels and long-term survival is not clear. We investigated whether post-load insulin response is a predictor of outcome in patients without previously recognized diabetes., Methods: Data from 933 Japanese patients who underwent both a 75 g oral glucose tolerance test and coronary angiography with suspected coronary artery disease were analyzed. The determinant factors in association with all-cause death or cardiovascular events, including reinfarction, heart failure or angina requiring re-hospitalization, and coronary revascularization were examined by multivariate Cox regression analysis., Results: The numbers of patients with normal glucose tolerance, impaired glucose regulation and diabetes were 326, 408 and 199, respectively. During the follow-up period (median 1113 days), death occurred in 37 patients including 13 cardiac causes. There were no significant differences in mortality or cardiovascular event incidence between glucose tolerance status. Kaplan-Meier curves indicated that the lower-response group of 2-hour insulin levels (<75.3 mU/L; median) was associated with higher mortality rates (Log-rank P=0.006). Multivariate Cox regression analysis revealed that 2-hour insulin level was an independent predictor of all-cause death (P=0.026) after adjustment for age, gender, number of stenosed vessels, ejection fraction, metabolic factors, and treatments., Conclusions: Post-load low insulin response is seen as a predictor of mortality rates for patients with no previous diagnosis of diabetes mellitus., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)