Publications by authors named "Shigeru Saito"

886 Publications

Intraoperative transesophageal echocardiography reveals diastolic mitral regurgitation caused by an aortic regurgitation jet.

J Echocardiogr 2022 Jun 24. Epub 2022 Jun 24.

Anesthesiology, Cardiovascular Surgery, and Cardiology, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-0083, Japan.

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http://dx.doi.org/10.1007/s12574-022-00579-4DOI Listing
June 2022

Two cases of successful transcatheter aortic valve implantation in patients with quadricuspid aortic valve stenosis.

Cardiovasc Interv Ther 2022 Jun 21. Epub 2022 Jun 21.

Department of Cardiology, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa, 247-8533, Japan.

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http://dx.doi.org/10.1007/s12928-022-00871-1DOI Listing
June 2022

Rare Complications of Pseudoaneurysms of the Superior Vena Cava After Transvenous Lead Extraction.

JACC Case Rep 2022 Apr 6;4(7):443-448. Epub 2022 Apr 6.

Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan.

Superior vena cava laceration has been reported as a catastrophic complication that requires immediate surgical intervention during transvenous lead extraction. Hereby, we present 2 cases of pseudoaneurysm formation at the superior vena cava after transvenous lead extraction, which were successfully managed without invasive treatment. ().
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http://dx.doi.org/10.1016/j.jaccas.2022.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9175205PMC
April 2022

Pseudo-intestinal obstruction after transsphenoidal surgery for craniopharyngioma.

J Surg Case Rep 2022 May 31;2022(5):rjac254. Epub 2022 May 31.

Department of Anesthesiology, Gunma University Graduate School of Medicine, Maebashi City, Japan.

Craniopharyngioma surgery is frequently associated with the occurrence of central diabetes insipidus, and oral rehydration therapy is reliable for postoperative management if the patient's thirst is normal. A 61-year-old Japanese male patient underwent extended endoscopic transsphenoidal surgery for craniopharyngioma. He was undergoing acute treatment for postoperative central diabetes insipidus and hypopituitarism in the intensive care unit. Two days after the surgery, he started to vomit occasionally, despite receiving oral rehydration therapy for central diabetes insipidus. Despite increasing the dose of parenteral hydrocortisone, the periodic vomiting persisted during fasting periods and progressed to aspiration pneumonia and severe sepsis. Abdominal computed tomography was performed to identify the cause of persistent vomiting and revealed the presence of a pseudo-intestinal obstruction extending from the small to large intestine. When oral rehydration therapy for central diabetes insipidus is accompanied by vomiting symptoms suggestive of hypopituitarism, a holistic evaluation of the gastrointestinal system is advisable.
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http://dx.doi.org/10.1093/jscr/rjac254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9156015PMC
May 2022

Device Failure in Bicuspid Aortic Stenosis Following Transcatheter Aortic Valve Implantation.

Am J Cardiol 2022 Aug 25;176:96-104. Epub 2022 May 25.

Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.

Recent studies showed the favorable outcomes of transcatheter aortic valve implantation (TAVI) in patients with bicuspid aortic valve (BAV) stenosis. However, data on the relation between BAV morphology and optimal transcatheter heart valve (THV) selection are limited. This study sought to evaluate the determinants of device performance in patients with BAV who underwent TAVI. Consecutive patients with BAV who underwent TAVI with the SAPIEN 3 from multicenters were evaluated. Outcomes were the incidence and predictors of device failure. Device failure was defined as peak aortic velocity >3.0 m/s, mean pressure gradient >20 mm Hg, moderate or severe paravalvular leakage and/or procedure mortality. A total of 187 patients with BAV were identified, aged 77 years, and 38.0% were women. A total of 37 patients (19.8%) were treated with 23-mm valve, 58 (31.0%) with 26-mm valve, and 92 (49.2%) with 29-mm valve. Predischarge echocardiogram demonstrated 37 patients (19.8%) with device failure. BAV with excessive leaflet calcification plus calcified raphe (EC-BAV) (OR 16.7, 95% CI 1.99 to 39.6) and smaller THV (OR 4.41, 95% CI 1.43 to 13.6) were independently associated with increased risk of device failure. In addition, 4.0%, 5.1%, and 11.1% of device failures were observed in patients without EC-BAV who underwent TAVI with 23-, 26- and 29-mm THV (p = 0.47), respectively, and 91.7%, 31.6% and 23.2% in those with EC-BAV, respectively (p <0.001). In conclusion, EC-BAV morphology was the major determinant of a device failure after TAVI. Moreover, TAVI in patients with EC-BAV requiring small SAPIEN 3 could be challenging. Further data on device and treatment selection in patients with BAV are still warranted.
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http://dx.doi.org/10.1016/j.amjcard.2022.04.037DOI Listing
August 2022

Hypoxia-Reoxygenation Impairs Autophagy-Lysosomal Machinery in Primary Human Trophoblasts Mimicking Placental Pathology of Early-Onset Preeclampsia.

Int J Mol Sci 2022 May 18;23(10). Epub 2022 May 18.

Department of Pediatrics, Women & Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI 02905, USA.

We have previously described that placental activation of autophagy is a central feature of normal pregnancy, whereas autophagy is impaired in preeclampsia (PE). Here, we show that hypoxia-reoxygenation (H/R) treatment dysregulates key molecules that maintain autophagy-lysosomal flux in primary human trophoblasts (PHTs). Ultrastructural analysis using transmission electron microscopy reveals a significant reduction in autophagosomes and autolysosomes in H/R-exposed PHTs. H/R-induced accumulation of protein aggregates follows a similar pattern that occurs in PHTs treated with a lysosomal disruptor, chloroquine. Importantly, the placenta from early-onset PE deliveries exhibits the same features as seen in H/R-treated PHTs. Taken together, our results indicate that H/R disrupts autophagic machinery in PHTs and that impaired autophagy in the placenta from early-onset PE deliveries mimics the events in H/R-treated PHTs. Notably, assessment of key regulators at each stage of autophagic processes, especially lysosomal integrity, and verification of autophagic ultrastructure are essential for an accurate evaluation of autophagy activity in human trophoblasts and placental tissue from PE deliveries.
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http://dx.doi.org/10.3390/ijms23105644DOI Listing
May 2022

Changes in Antithrombotic Therapy Over Time and Durability of a Prasugrel WOEST-Like Regimen for Percutaneous Coronary Intervention Patients With Atrial Fibrillation - Post Hoc Analysis of the PENDULUM Mono and PENDULUM Registries.

Circ Rep 2022 May 21;4(5):194-204. Epub 2022 Apr 21.

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center Tokyo Japan.

Previously published randomized atrial fibrillation (AF) percutaneous coronary intervention (PCI) trials have demonstrated the safety and efficacy of a WOEST-like regimen (oral anticoagulant [OAC] plus P2Y inhibitor) in patients with AF PCI within 1 year. However, the efficacy of this regimen in real-world practice has not been fully confirmed, especially the efficacy of the WOEST-like regimen using the approved dose of prasugrel in Japan. This post hoc analysis included 186 and 220 patients from the PENDULUM mono and PENDULUM registries, respectively. Endpoints were the cumulative incidences of clinically relevant bleeding (CRB) and major adverse cardiac and cerebrovascular events (MACCE) at 12 months after PCI. Differences in the enrollment period led to an increase in OAC prescriptions (from 64.7% to 81.2%) and a reduction in the median duration of triple antithrombotic therapy (from 203.0 to 32.0 days) in the PENDULUM vs. PENDULUM mono registries, respectively. After adjustment by the inverse probability of treatment method, in patients with OAC, PENDULUM mono AF significantly reduced CRB without increasing MACCE compared with PENDULUM AF. A WOEST-like regimen with prasugrel may reduce CRB, without increasing MACCE, in Japanese patients with AF and high bleeding risk undergoing PCI.
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http://dx.doi.org/10.1253/circrep.CR-22-0032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072101PMC
May 2022

Distal Versus Conventional Radial Access for Coronary Angiography and Intervention: The DISCO RADIAL Trial.

JACC Cardiovasc Interv 2022 Jun 17;15(12):1191-1201. Epub 2022 May 17.

Department of Cardiology, Shonan Kamakura General Hospital, Kanagawa, Japan.

Background: Currently, transradial access (TRA) is the recommended access for coronary procedures because of increased safety, with radial artery occlusion (RAO) being its most frequent complication, which will increasingly affect patients undergoing multiple procedures during their lifetimes. Recently, distal radial access (DRA) has emerged as a promising alternative access to minimize RAO risk. A large-scale, international, randomized trial comparing RAO with TRA and DRA is lacking.

Objectives: The aim of this study was to assess the superiority of DRA compared with conventional TRA with respect to forearm RAO.

Methods: DISCO RADIAL (Distal vs Conventional Radial Access) was an international, multicenter, randomized controlled trial in which patients with indications for percutaneous coronary procedure using a 6-F Slender sheath were randomized to DRA or TRA with systematic implementation of best practices to reduce RAO. The primary endpoint was the incidence of forearm RAO assessed by vascular ultrasound at discharge. Secondary endpoints include crossover, hemostasis time, and access site-related complications.

Results: Overall, 657 patients underwent TRA, and 650 patients underwent DRA. Forearm RAO did not differ between groups (0.91% vs 0.31%; P = 0.29). Patent hemostasis was achieved in 94.4% of TRA patients. Crossover rates were higher with DRA (3.5% vs 7.4%; P = 0.002), and median hemostasis time was shorter (180 vs 153 minutes; P < 0.001). Radial artery spasm occurred more with DRA (2.7% vs 5.4%; P = 0.015). Overall bleeding events and vascular complications did not differ between groups.

Conclusions: With the implementation of a rigorous hemostasis protocol, DRA and TRA have equally low RAO rates. DRA is associated with a higher crossover rate but a shorter hemostasis time.
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http://dx.doi.org/10.1016/j.jcin.2022.04.032DOI Listing
June 2022

Early P2Y Inhibitor Single Antiplatelet Therapy for High-Bleeding Risk Patients After Stenting - PENDULUM Mono 24-Month Analysis.

Circ J 2022 May 17. Epub 2022 May 17.

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center.

Background: In PENDULUM mono, Japanese patients with high bleeding risk (HBR) received short-term dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy (SAPT) with prasugrel after percutaneous coronary intervention (PCI). One-year data from PENDULUM mono showed better outcomes with prasugrel monotherapy after short-term DAPT compared with matched patients in the PENDULUM registry with longer DAPT durations according to guidelines at that time. This study presents 2-year results.Methods and Results: We compared 24-month data from PENDULUM mono (n=1,107; de-escalation strategy group) and the PENDULUM registry (n=2,273; conventional strategy group); both were multicenter, non-interventional, prospective registry studies, using the inverse probability of treatment weighting (IPTW) method. In the PENDULUM mono group, the cumulative incidence of clinically relevant bleeding (CRB) at 24 months post-PCI (primary endpoint) was 6.8%, and that of major adverse cardiac and cerebrovascular events (MACCE) was 8.9%. After IPTW adjustment, the cumulative incidence of CRB was 5.8% and 7.2% in PENDULUM mono and the PENDULUM registry, respectively (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.57-1.04; P=0.086), and that of MACCE was 8.0% and 9.5%, respectively (HR 0.77; 95% CI 0.59-1.01; P=0.061).

Conclusions: Japanese PCI patients with HBR prescribed prasugrel SAPT after short-term DAPT had a lower ischemic event risk than those prescribed long-term DAPT, and this was particularly relevant for ischemic events after 1 year.
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http://dx.doi.org/10.1253/circj.CJ-21-1004DOI Listing
May 2022

Retained products of conception (RPOC) following delivery without placenta previa: Which patients with RPOC show postpartum hemorrhage?

Placenta 2022 06 10;124:12-17. Epub 2022 May 10.

Department of Obstetrics and Gynecology, Mie University School of Medicine, Mie, Japan.

Introduction: To clarify the perinatal outcome of retained products of conception (RPOC) after 22 weeks or more.

Methods: The retrospective cohort study reviewed medical records of patients with RPOC without placenta previa at 186 Japanese perinatal centers.

Results: Of the 323 patients with RPOC, pregnancies after assisted reproductive technology (ART) accounted for 43%. Transfusion at delivery was required in 33% of the patients. Logistic regression analyses revealed that transfusion was significantly required in the following situations: ART pregnancy (aOR: 6.0, 95%CI: 2.3-16, P < 0.001), and RPOC length ≥4 cm (aOR: 5.3, 95%CI: 2.1-13, P < 0.001). Transarterial embolization (TAE) and/or hysterectomy for subsequent RPOC-related bleeding was performed in 60 patients with RPOC. Logistic regression analysis revealed that additional interventions were significantly required in the following situations: multiparity (aOR: 6.1, 95%CI: 2.1-17.2, P < 0.001), and hypervascular RPOC (aOR: 12.8, 95%CI: 3.2-51.1, P < 0.001). TAE and/or hysterectomy was also frequently employed in ART pregnancy, although this was not significant (aOR: 2.8, 95%CI: 0.9-8.2, P = 0.063).

Discussion: Patients with RPOC were significantly more likely to require transfusion at delivery in the presence of large RPOC and ART. They were also more likely to require hemostatic procedures for subsequent bleeding in the presence of hypervascular RPOC and ART.
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http://dx.doi.org/10.1016/j.placenta.2022.05.004DOI Listing
June 2022

Clinical Outcomes After Percutaneous Coronary Intervention in East Asian Patients - 30-Month Results of the PENDULUM Registry.

Circ J 2022 May 13. Epub 2022 May 13.

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center.

Background: The 12-month results of the PENDULUM registry showed that after implantation of second-generation drug-eluting stents (DES), high P2Yreaction unit (HPR) were independently associated with ischemic but not bleeding events.Methods and Results: This study analyzed cumulative incidences of major adverse cardiac and cerebrovascular events (MACCE) and major bleeding (Bleeding Academic Research Consortium type 3 and 5) at 30 months after index percutaneous coronary intervention (PCI) (primary endpoints). Of 6,422 patients undergoing PCI with DES, 5,796 completed the 30-month follow up. The continuation rate of dual antiplatelet therapy decreased to 59.3% at 12 months and 26.4% at 30 months. At 30 months, the cumulative incidence of MACCE increased linearly and reached 9.5% (95% confidence interval 8.8-10.2) and that of major bleeding had the inflection point at 12 months and was 4.4% (3.9-5.0). MACCE and bleeding events were higher in HPR patients (unadjusted P value). After covariate adjustment, P2Yreactivity units measured immediately after index PCI was not an independent risk factor for MACCE or major bleeding at 30 months.

Conclusions: MACCE consistently increased after 12 months post-PCI, whereas the increase in major bleeding events slowed down after 12 months in Japanese PCI patients in a real-world clinical setting. HPR patients had increased MACCE and bleeding complications, but HPR was not an independent risk factor of events at 30 months.
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http://dx.doi.org/10.1253/circj.CJ-21-0991DOI Listing
May 2022

Predictors of conduction disturbances after transcatheter aortic valve implantation with balloon-expandable valve for bicuspid aortic valve stenosis.

J Cardiovasc Electrophysiol 2022 May 11. Epub 2022 May 11.

Department of Cardiology, Heart and Lung Center, Helsinki University and Helsinki University Central Hospital, Helsinki, Finland.

Introduction: Implantation depth and membranous septum (MS) length have been established as the predictors of new-onset conduction disturbance (CD) after transcatheter aortic valve replacement (TAVR) for tricuspid aortic valve (TAV) stenosis. However, little is known about the predictors with bicuspid aortic valve (BAV). This study investigated the role of MS length and implantation depth in predicting CD following TAVR with a balloon-expandable valve in patients with BAV.

Methods: This retrospective study analyzed 169 patients who underwent TAVR for BAV with balloon-expandable valve, and TAV cohort was established as a control group using propensity score (PS) matching. The primary endpoints were in-hospital new permanent pacemaker implantation (PPI) and new-onset CD (the composite outcome of new-onset left bundle branch block and new PPI).

Results: PPI developed in 14 patients (8.3%) and new-onset CD in 37 patients (21.9%) in the BAV cohort. Multivariate analysis revealed severe left ventricle outflow tract (LVOT) calcification (odds ratio [OR]: 5.83, 95% confidence interval [CI]: 1.08-31.5, p = .0407) and implantation depth-MS length (OR: 1.30, 95% CI: 1.12-1.51, p = .0005) as the predictors of new-onset CD within the BAV cohort. The matched comparison between BAV and TAV groups showed similar MS length (3.0 vs. 3.2 mm, p = .5307), but valves were implanted more deeply in the BAV group than in the TAV group (3.9 vs. 3.0 mm, p < .0001). New-onset CD was more frequent in patients who had BAV (22.3% vs. 13.9%, p = .0458).

Conclusion: The implantation depth-MS length, and severe LVOT calcification predicted new-onset CD following TAVR in BAV with balloon-expandable valve. Among BAV patients, valves were implanted more deeply compared to TAV patients. High deployment technique could be considered to avoid new-onset CD in BAV anatomy.
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http://dx.doi.org/10.1111/jce.15525DOI Listing
May 2022

Novel super-neutralizing antibody UT28K is capable of protecting against infection from a wide variety of SARS-CoV-2 variants.

MAbs 2022 Jan-Dec;14(1):2072455

Department of Clinical Laboratory and Molecular Pathology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.

Many potent neutralizing SARS-CoV-2 antibodies have been developed and used for therapies. However, the effectiveness of many antibodies has been reduced against recently emerging SARS-CoV-2 variants, especially the Omicron variant. We identified a highly potent SARS-CoV-2 neutralizing antibody, UT28K, in COVID-19 convalescent individuals who recovered from a severe condition. UT28K showed efficacy in neutralizing SARS-CoV-2 in an assay and prophylactic treatment, and the reactivity to the Omicron strain was reduced. The structural analyses revealed that antibody UT28K Fab and SARS-CoV-2 RBD protein interactions were mainly chain-dominated antigen-antibody interactions. In addition, a mutation analysis suggested that the emergence of a UT28K neutralization-resistant SARS-CoV-2 variant was unlikely, as this variant would likely lose its competitive advantage over circulating SARS-CoV-2. Our data suggest that UT28K offers potent protection against SARS-CoV-2, including newly emerging variants.
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http://dx.doi.org/10.1080/19420862.2022.2072455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103358PMC
May 2022

Prevalence and outcomes of stent thrombosis with in-stent calcified nodules: substudy from the REAL-ST registry.

EuroIntervention 2022 Apr 8. Epub 2022 Apr 8.

Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: The relationship between in-stent calcified nodules (IS-CN) and second-generation drug-eluting stent (G2-DES) stent thrombosis (ST) remains uncertain.

Aims: We aimed to evaluate the prevalence, clinical demographic and long-term clinical outcomes after G2-DES ST with IS-CN.

Methods: The prespecified substudy of the REAL-ST registry (a retrospective, multicentre registry of patients with definite ST after first- and G2-DES implantation) enrolled patients who experienced definite G2-DES ST and who underwent pre-intervention intravascular ultrasound imaging at index ST events.

Results: IS-CN was observed in 15 out of 118 (13%) definite G2-DES ST cases. The multiple logistic regression model demonstrated that haemodialysis (odds ratio [OR] 12.27, 95% confidence interval [CI]: 1.56-94.54; p=0.02), proximal or mid-right coronary artery lesions (OR 12.79, 95% CI: 1.78-92.13; p=0.01) and severe calcification (OR 13.01, 95% CI: 1.18-142.94; p=0.04) were independently associated with ST with IS-CN. The cumulative 5-year incidence of target lesion revascularisation (TLR) after ST was significantly higher in the IS-CN group than in the non-IS-CN group (p=0.02). Independent predictors of TLR after the index ST events were female sex (hazard ratio [HR] 3.05, 95% CI: 1.20-7.74; p=0.02), diabetes mellitus (HR 3.26, 95% CI: 1.26-8.41; p=0.01) and IS-CN (HR 3.07, 95% CI: 1.16-8.14; p=0.02).

Conclusions: IS-CN may be one of the underlying mechanisms of G2-DES ST. Notably, IS-CN was associated with a higher TLR rate after the index ST events, suggesting the need for careful clinical follow-up of ST patients with IS-CN.
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http://dx.doi.org/10.4244/EIJ-D-21-00976DOI Listing
April 2022

Practice Patterns and Outcomes of Transcatheter Aortic Valve Replacement in the United States and Japan: A Report From Joint Data Harmonization Initiative of STS/ACC TVT and J-TVT.

J Am Heart Assoc 2022 03 4;11(6):e023848. Epub 2022 Mar 4.

Department of Cardiovascular Surgery Osaka University Hospital Osaka Japan.

Background The practice pattern and outcome of medical devices following their regulatory approval may differ by country. The aim of this study is to compare postapproval national clinical registry data on transcatheter aortic valve replacement between the United States and Japan on patient characteristics, periprocedural outcomes, and the variability of outcomes as a part of a partnership program (Harmonization-by-Doing) between the 2 countries. Methods and Results The patient-level data were extracted from the US Society of Thoracic Surgeons /American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) and the J-TVT (Japanese Transcatheter Valvular Therapy) registry, respectively, to analyze transcatheter aortic valve replacement outcomes between 2013 and 2019. Data entry for these registries was mandated by the federal regulators, and the majority of variable definitions were harmonized to allow direct data comparison. A total of 244 722 transcatheter aortic valve replacements from 646 institutions in the United States and 26 673 transcatheter aortic valve replacements from 171 institutions in Japan were analyzed. Median volume per site was 65 (interquartile range, 45-97) in the United States and 28 (interquartile range, 19-41) in Japan. Overall, patients in J-TVT were older (United States: mean-age, 80.1±8.7 versus Japan: 84.4±5.2; <0.001), were more frequently women (45.9% versus 68.1%; <0.001), and had higher median Society of Thoracic Surgeons Predicted Risk of Mortality (5.27% versus 6.20%; <0.001) than patients in the United States. Japan had lower unadjusted 30-day mortality (1.3% versus 3.2%; <0.001) and composite outcomes of death, stroke, and bleeding (17.5 versus 22.5%; <0.001) but had higher conversion to open surgery (0.94% versus 0.56%; <0.001). Conclusions This collaborative analysis between the United States and Japan demonstrated the feasibility of international comparison using the national registries coded under mutual variable definitions. Both countries obtained excellent outcomes, although the Japanese had lower 30-day mortality and major morbidity. Harmonization-by-Doing is one of the key steps needed to build global-level learning to improve patient outcomes.
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http://dx.doi.org/10.1161/JAHA.121.023848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075277PMC
March 2022

The efficacy of duloxetine depends on spinal cholinergic plasticity in neuropathic pain model rats.

IBRO Neurosci Rep 2022 Jun 12;12:188-196. Epub 2022 Feb 12.

Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan.

Antidepressants, such as duloxetine, are widely used to treat chronic pain, including neuropathic pain; however, their efficacy is unsatisfactory. In our previous studies, we showed that in a spinal nerve ligation (SNL) rat model, the descending noradrenergic inhibitory system, which involves in the anti-hypersensitivity mechanism of antidepressants, decrease its activity over time following peripheral nerve injury. In this study, we hypothesized that the analgesic effects of duloxetine may diminish following the attenuation of the descending noradrenergic inhibitory system. The analgesic effects of duloxetine in SNL model rats at the early (SNL2W) and chronic (SNL6W) phases following spinal nerve ligation were compared. Male Sprague-Dawley rats were randomly assigned to the SNL2W or SNL6W groups and used to evaluate the anti-allodynic effects of duloxetine using the von Frey filament test. The anti-allodynic effects of duloxetine at a dose of 10 mg/kg were lower in SNL6W rats than in SNL2W rats. Basal noradrenaline concentrations in rat spinal dorsal horns were higher in the SNL6W group than in the SNL2W group, and there was no difference in the increase in spinal noradrenaline concentrations between the 2 groups following duloxetine administration. In addition, we found that duloxetine-induced acetylcholine (ACh) release and choline acetyltransferase (ChAT) expression in the spinal dorsal horn decreased in SNL6W rats. At a dose of 30 mg/kg, duloxetine showed anti-allodynic effects even in SNL6W rats and induced ACh release in the spinal cord. Furthermore, these anti-allodynic effects were completely inhibited by intrathecal atropine (muscarinic antagonist) administration. Moreover, 5 daily intraperitoneal injections of the TrkB agonist, 7,8-dihydroxyflavone (5 mg/kg), not only restored ChAT expression, but also decreased the anti-allodynic effects of duloxetine. These findings suggest that the attenuation of the anti-allodynic effects of duloxetine at the chronic phase of SNL may be due to impaired spinal acetylcholine-mediated analgesia. In addition, the activation of BDNF-TrkB signaling may be beneficial in reversing this impairment.
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http://dx.doi.org/10.1016/j.ibneur.2022.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8881419PMC
June 2022

Complex vs. non-complex percutaneous coronary intervention with newer-generation drug-eluting stents: an analysis from the randomized BIOFLOW trials.

Clin Res Cardiol 2022 Feb 25. Epub 2022 Feb 25.

Heart Center Bad Segeberg, Segeberger Kliniken GmbH, Am Kurpark 1, 23795, Bad Segeberg, Germany.

Background: Patients undergoing complex percutaneous coronary intervention (PCI) are at higher risk of adverse outcomes, but data are scarce in the era of newer-generation coronary stents.

Aim: We sought to compare the clinical outcomes after complex PCI with a bioresorbable-polymer sirolimus-eluting stent (BP-SES) versus a durable-polymer everolimus-eluting stent (DP-EES).

Methods: Patients (n = 2350) from BIOFLOW-II, -IV, and -V randomized trials were categorized into non-complex PCI vs. complex PCI. Complex PCI had at least one of the following criteria: multi-vessel PCI, ≥ 3 lesions treated, ≥ 3 stents implanted, total stent length ≥ 60 mm. Endpoints were target lesion failure (TLF: cardiac death, target-vessel myocardial infarction [TV-MI], or target lesion revascularization [TLR]) and probable/definite stent thrombosis (ST) at three years.

Results: Patients with complex PCI (n = 348) were older and presented more often with acute coronary syndrome than non-complex PCI patients (n = 2002). Complex PCI lesions were more often type B2/C and bifurcation lesions and required more pre- and post-dilatation. Complex PCI patients had higher rates of TLF (14.6% vs. 8.1%; aHR 1.89, 95% CI [1.31-2.73], p = 0.001), TV-MI (10.2% vs. 4.4%, aHR 2.17, 95% CI [1.40-3.37], p = 0.001), and ST (1.5% vs. 0.4%, p = 0.025) as compared with non-complex PCI. TLF was not lower with BP-SES as compared to DP-EES in complex PCI (12.6% vs 18.2%, p = 0.16).

Conclusion: Patients undergoing complex PCI with the newer-generation DES still sustain a higher risk of TLF, TV-MI and stent thrombosis as compared with non-complex PCI. This adverse outcome was not significantly modified by the stent platform (BP-SES vs. DP-EES).

Clinical Trial Registration: Clinicaltrial.gov NCT01356888, NCT01939249, NCT02389946, https://clinicaltrials.gov/show/NCT01356888 ; https://clinicaltrials.gov/show/NCT01939249 ; https://clinicaltrials.gov/show/NCT02389946 .
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http://dx.doi.org/10.1007/s00392-022-01994-4DOI Listing
February 2022

Progress in the understanding of the pathophysiology of immunologic maladaptation related to early-onset preeclampsia and metabolic syndrome related to late-onset preeclampsia.

Am J Obstet Gynecol 2022 02 5;226(2S):S867-S875. Epub 2022 Jan 5.

Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.

Among mammalian species, human reproduction has 2 outstanding features. The human hemochorial placentation is characterized by a very deep endovascular trophoblast invasion in the spiral arteries, reaching deep into the myometrium. This requires an agonistic direct cell-cell interaction between the maternal immune system and semiallogeneic trophoblast. The second feature is preeclampsia, a heterogeneous syndrome, a uniquely human condition. The human female is one of the few mammals exposed to her partner's semen on multiple occasions before conception. Regulatory T cells, especially paternal antigen-specific regulatory T cells, play an important role in the maintenance of pregnancy. Sexual intercourse increases the number of dendritic cells in the uterus that play an important role in the induction of paternal antigen-specific regulatory T cells. Paternal antigen-specific regulatory T cells maintain pregnancy by inducing tolerance. In the decidua basalis of preeclamptic cases, clonal regulatory T cells are reduced; these would normally monoclonally expand to recognize fetal or paternal antigens. Programmed cell death-1 expressed on T cells regulate cytotoxic T-cell activity and protect the fetus against maternal rejection. Programmed cell death-1 expression on clonal cytotoxic T cells is reduced in preeclampsia especially in early-onset preeclampsia, making the fetus and placenta vulnerable to attack by cytotoxic T cells. These phenomena can explain the epidemiologic phenomenon that preeclampsia is more common in couples using condom contraception, with shorter cohabitation periods, first pregnancies, first pregnancies in multiparous women when they change partner, and pregnancies after assisted reproduction using donated gametes. In contrast to its importance in early-onset preeclampsia, shallow trophoblast invasion does not play a role in the development of preeclampsia, that is, immune maladaptation does not seem to be involved. Late-onset preeclampsia (>34 weeks' gestation), representing 80% to 90% of preeclampsia in most developed countries with a "Western lifestyle," is strongly associated with maternal cardiometabolic variables (metabolic syndrome). Although the underlying pathophysiology might be quite different, syncytiotrophoblast stress is the final common pathway leading to the maternal syndrome among the subtypes of preeclampsia by causing an imbalance between proangiogenic factors (placental growth factor and vascular endothelial growth factor) and antiangiogenic factors (soluble fms-like tyrosine kinase-1 and soluble endoglin). Low-dose aspirin, started before 16 week's gestation, will prevent up to 60% of early-onset preeclampsia but will not prevent late-onset preeclampsia. Optimizing prepregnancy weight and controlling gestational weight gain may be the most effective ways to prevent preeclampsia.
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http://dx.doi.org/10.1016/j.ajog.2021.11.019DOI Listing
February 2022

Probiotics including Clostridium butyricum, Enterococcus faecium, and Bacillus subtilis may prevent recurrent spontaneous preterm delivery.

J Obstet Gynaecol Res 2022 Mar 26;48(3):688-693. Epub 2022 Jan 26.

Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan.

Aim: A large cohort study of Japanese women reported that the rate of recurrent spontaneous preterm delivery (sPTD) in the next pregnancy was 22.3%; therefore, it is important to prevent recurrent sPTD. The present study investigated the rate of recurrent sPTD in pregnant women treated with probiotics.

Methods: This was a retrospective study. Fifty-one pregnant women with a history of sPTD and who had been taking probiotics before 14 weeks of gestation were selected. The rate of sPTD in the next pregnancy among 255 pregnant women with a history of sPTD who had not taken probiotics was compared with that in the probiotics group.

Results: The rate of recurrent sPTD was 9.8% (5/51), which was lower than previously reported values. Furthermore, the rate of recurrent sPTD was significantly lower in the probiotics group (9.8%) than in the nonprobiotics group (31.0% [79/255]; p = 0.002).

Conclusions: Probiotics may reduce the rate of recurrent sPTD.
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http://dx.doi.org/10.1111/jog.15166DOI Listing
March 2022

The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice.

Pregnancy Hypertens 2022 Mar 9;27:148-169. Epub 2021 Oct 9.

Department of Women and Children's Health, School of Life Course Sciences, King's College London, UK.

All units managing hypertensive pregnant women should maintain and review uniform departmental management protocols and conduct regular audits of maternal & fetal outcomes. The cause(s) of pre-eclampsia and the optimal clinical management of the hypertensive disorders of pregnancy remain uncertain; therefore, we recommend that every hypertensive pregnant woman be offered an opportunity to participate in research, clinical trials and follow-up studies.
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http://dx.doi.org/10.1016/j.preghy.2021.09.008DOI Listing
March 2022

Sex-related differences in plaque characteristics and endothelial shear stress related plaque-progression in human coronary arteries.

Atherosclerosis 2022 02 26;342:9-18. Epub 2021 Dec 26.

Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background And Aims: Clinical atherosclerosis manifestations are different in women compared to men. Since endothelial shear stress (ESS) is known to play a critical role in coronary atherosclerosis development, we investigated differences in anatomical characteristics and endothelial shear stress (ESS)-related plaque growth in human coronary arteries in men compared to women.

Methods: 1183 coronary arteries (male/female: 944/239) from the PREDICTION study were studied for differences in artery/plaque and ESS characteristics, and ESS-related plaque progression (6-10 months follow-up) among men and women and after stratification for age. All characteristics were derived from IVUS-based vascular profiling and reported per 3 mm-segments (13,030 3-mm-segments (male/female: 10,465/2,565)).

Results: Coronary arteries and plaques were significantly smaller in females compared to males; but no important differences were observed in plaque burden, ESS and rate of plaque progression. Change in plaque burden was inversely related to ESS (p<0.001) with no difference between women versus men (β: -0.62 ± 0.13 vs -0.68 ± 0.05, p=0.62). However, stratification for age demonstrated that ESS-related plaque growth was more marked in young women compared to men (<55 years, β: -2.02 ± 0.61 vs -0.33 ± 0.10, p=0.007), reducing in magnitude over the age-categories up till 75 years.

Conclusions: Coronary artery and plaque size are smaller in women compared to men, but ESS and ESS- related plaque progression were similar. Sex-related differences in ESS-related plaque growth were evident after stratification for age. These observations suggest that although the fundamental processes of atherosclerosis progression are similar in men versus women, plaque progression may be influenced by age within gender.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.12.013DOI Listing
February 2022

Characteristics of anatomical difficulty for cryoballoon ablation: insights from CT.

Open Heart 2022 01;9(1)

Cooperative Major in Advanced Biomedical Sciences, Joint Graduate School of Tokyo Women's Medical University and Waseda University, Waseda University, Shinjuku-ku, Tokyo, Japan

Background: The limited availability of balloon sizes for cryoballoon leads to anatomical limitations for pulmonary vein (PV) isolation. We conducted a comprehensive systematic analysis on procedural success rate, atrial fibrillation (AF) recurrence rate and complications of cryoballoon ablation in association with the anatomy of the left atrium and PV based on preprocedural CT to gain insights into proper treatments of patients with AF using cryoballoon.

Method: A systematic search of literature databases, including PubMed, Web of Science and Cochrane Library, from the inception of each database through February 2021 was conducted. Search keywords included 'atrial fibrillation', 'cryoballoon ablation' and 'anatomy'.

Results: Overall, 243 articles were identified. After screening, 16 articles comprising 1396 patients were included (3, 5 and 8 for acute success, AF recurrence and complications, respectively). Regarding acute success and AF recurrences, thinner width of the left lateral ridge, higher PV ovality, PV ostium-bifurcation distance, shorter distance from the non-coronary cusp to inferior PVs, shallower angle of right PVs against the atrial septum and larger right superior PV (RSPV) were associated with poor outcomes. Regarding complications, shorter distance between the RSPV ostium and the right phrenic nerve, larger RSPV-left atrium angle, larger RSPV area and smaller right carina width were associated with incidences of phrenic nerve injury.

Conclusion: This study elucidated several key anatomical features of PVs possibly affecting acute success, AF recurrence and complications in patients with AF using cryoballoon ablation. CT analysis has helped to describe benefits and anatomical limitations for cryoballoon ablation.
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http://dx.doi.org/10.1136/openhrt-2021-001724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739445PMC
January 2022

Relationship between platelet aggregation and stroke risk after percutaneous coronary intervention: a PENDULUM analysis.

Heart Vessels 2022 Jun 1;37(6):942-953. Epub 2022 Jan 1.

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan.

In patients undergoing percutaneous coronary intervention (PCI) with a stent, high on-treatment platelet reactivity may be associated with an increased risk of stroke. This post hoc analysis of the PENDULUM registry compared the risk of post-PCI stroke according to on-treatment P2Y reaction unit (PRU) values. Patients aged ≥ 20 years who underwent PCI were stratified by baseline PRU (at 12 and 48 h post-PCI) as either high (HPR, > 208), optimal (OPR, > 85 to ≤ 208), or low on-treatment platelet reactivity (LPR, ≤ 85). The incidences of non-fatal ischemic and non-ischemic stroke through to 12 months post-PCI were recorded. Almost all enrolled patients (6102/6267 [97.4%]) had a risk factor for ischemic stroke, and most were receiving dual antiplatelet therapy. Of the 5906 patients with PRU data (HPR, n = 2227; OPR, n = 3002; LPR, n = 677), 47 had a non-fatal stroke post-PCI (cumulative incidence: 0.68%, ischemic; 0.18%, non-ischemic stroke). Patients with a non-fatal ischemic stroke event had statistically significantly higher post-PCI PRU values versus those without an event (P = 0.037). The incidence of non-fatal non-ischemic stroke was not related to PRU value. When the patients were stratified by PRU ≤ 153 versus > 153 at 12-48 h post-PCI, a significant difference was observed in the cumulative incidence of non-fatal stroke at 12 months (P = 0.044). We found that patients with ischemic stroke tended to have higher PRU values at 12-48 h after PCI versus those without ischemic stroke.Clinical trial registration: UMIN000020332.
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http://dx.doi.org/10.1007/s00380-021-02003-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114031PMC
June 2022

Impact of GAD65 and/or GAD67 deficiency on perinatal development in rats.

FASEB J 2022 02;36(2):e22123

Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan.

GABA is a major neurotransmitter in the mammalian central nervous system. Glutamate decarboxylase (GAD) synthesizes GABA from glutamate, and two isoforms of GAD, GAD65, and GAD67, are separately encoded by the Gad2 and Gad1 genes, respectively. The phenotypes differ in severity between GAD single isoform-deficient mice and rats. For example, GAD67 deficiency causes cleft palate and/or omphalocele in mice but not in rats. In this study, to further investigate the functional roles of GAD65 and/or GAD67 and to determine the contribution of these isoforms to GABA synthesis during development, we generated various kinds of GAD isoform(s)-deficient rats and characterized their phenotypes. The age of death was different among Gad mutant rat genotypes. In particular, all Gad1 ; Gad2 rats died at postnatal day 0 and showed little alveolar space in their lungs, suggesting that the cause of their death was respiratory failure. All Gad1 ; Gad2 rats and 18% of Gad1 ; Gad2 rats showed cleft palate. In contrast, none of the Gad mutant rats including Gad1 ; Gad2 rats, showed omphalocele. These results suggest that both rat GAD65 and GAD67 are involved in palate formation, while neither isoform is critical for abdominal wall formation. The GABA content in Gad1 ; Gad2 rat forebrains and retinas at embryonic day 20 was extremely low, indicating that almost all GABA was synthesized from glutamate by GADs in the perinatal period. The present study shows that Gad mutant rats are a good model for further defining the role of GABA during development.
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http://dx.doi.org/10.1096/fj.202101389RDOI Listing
February 2022

Periodontal Disease as a Potential Risk Factor of Cardiovascular Disease.

Circ J 2022 04 25;86(5):819-820. Epub 2021 Dec 25.

Department of Cardiology, Shonan Kamakura General Hospital.

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http://dx.doi.org/10.1253/circj.CJ-21-1008DOI Listing
April 2022

Ischemic and Bleeding Events in PENDULUM Patients With High Bleeding Risk and High Platelet Reactivity.

Circ J 2022 04 8;86(5):763-771. Epub 2021 Dec 8.

Division of Cardiovascular Medicine, Toho University Ohashi Medical Center.

Background: The balance between thrombotic and bleeding risk is of great concern in high bleeding risk (HBR) patients. This study evaluated the relationship between perioperative antiplatelet reactivity and thrombotic and bleeding events in patients at HBR undergoing percutaneous coronary intervention (PCI).Methods and Results: In this post hoc analysis of the PENDULUM (Platelet rEactivity in patieNts with DrUg eLUting stent and balancing risk of bleeding and ischeMic event) registry, patients undergoing PCI were categorized as HBR or non-HBR, and stratified as having high platelet reactivity (HPR; P2Yreaction unit [PRU] >208) or non-HPR (PRU ≤208). Cumulative incidences of cardiovascular and cerebrovascular events (Journal of the American College of Cardiology expert definitions) and bleeding events (Bleeding Academic Research Consortium criteria) were assessed 12 months after index PCI. The incidence of ischemic and bleeding events was ~3-fold higher in HBR vs. non-HBR patients. Thrombotic/ischemic events were significantly more common in the HPR subgroup in HBR patients (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.11-2.28; P=0.012), but there was no difference in non-HBR patients. After adjustment for covariates, HPR in HBR patients remained an independent factor for thrombotic and ischemic events (HR: 1.69; 95% CI: 1.13-2.54; P=0.011), but not for bleeding events (HR: 1.56; 95% CI: 0.78-3.11; P=0.210).

Conclusions: Maintaining adequate PRU levels during PCI is an important factor in improving clinical outcomes, especially for HBR patients.
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http://dx.doi.org/10.1253/circj.CJ-21-0717DOI Listing
April 2022

Duration of Dual Antiplatelet Therapy for Patients at High Bleeding Risk Undergoing PCI.

J Am Coll Cardiol 2021 11;78(21):2060-2072

Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

Background: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) among patients at high bleeding risk (HBR) is unknown.

Objectives: The purpose of this analysis was to compare 1 vs 3 months of DAPT in HBR patients undergoing drug-eluting stent implantation.

Methods: The XIENCE Short DAPT program comprised 3 prospective, multicenter, single-arm studies of HBR patients treated with a short DAPT course followed by aspirin monotherapy after PCI with a cobalt-chromium everolimus-eluting stent. In this exploratory analysis, patients who received 1-month DAPT (XIENCE 28 USA and 28 Global) were compared with those on 3-month DAPT (XIENCE 90) using propensity score stratification. Ischemic and bleeding outcomes were assessed between 1 and 12 months after index PCI.

Results: A total of 3,652 patients were enrolled and 1,392 patients after 1-month DAPT and 1,972 patients after 3-month DAPT were eligible for the analyses. The primary endpoint of all-cause mortality or myocardial infarction was similar between the 2 groups (7.3% vs 7.5%; difference -0.2%; 95% CI: -2.2% to 1.7%; P = 0.41). The key secondary endpoint of BARC (Bleeding Academic Research Consortium) type 2-5 bleeding was lower with 1-month DAPT compared with 3-month DAPT (7.6% vs 10.0%; difference -2.5%; 95% CI: -4.6% to -0.3%; P = 0.012). Major BARC type 3-5 bleeding did not differ at 12 months (3.6% vs 4.7%; difference -1.1%; 95% CI: -2.6% to 0.4%; P = 0.082), but was lower with 1-month DAPT at 90 days (1.0% vs 2.1%; P = 0.015).

Conclusions: Among HBR patients undergoing PCI, 1 month of DAPT, compared with 3 months of DAPT, was associated with similar ischemic outcomes and lower bleeding risk. (XIENCE 90 Study; NCT03218787; XIENCE 28 USA Study; NCT03815175; XIENCE 28 Global Study; NCT03355742).
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http://dx.doi.org/10.1016/j.jacc.2021.08.074DOI Listing
November 2021
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