Infolding of Evolut PRO+ during transcatheter aortic valve implantation and bailout by post-balloon dilation: A case report.

An 89-year-old man with symptomatic severe aortic stenosis underwent transcatheter aortic valve implantation due to old age and a history of coronary artery bypass grafting. Computed tomography showed a tricuspid aortic valve and severe calcification at the aortic valve annulus, with a perimeter of 88.7 mm. The 34-mm Evolut PRO+ (Medtronic Inc., Minneapolis, MN, USA) was selected. After balloon aortic valvuloplasty, deployment of the Evolut PRO+ was attempted, but significant expansion failure was observed. Upon retraction and removal of the Evolut PRO+ from the body, frame deformation was observed. A new Evolut PRO+ was tried again, but a similar finding was noted as a magatama-like infolding on transesophageal echocardiography. Fortunately, the patient's hemodynamics were relatively stable. Post-dilation was performed using a 25 mm Z-MED II (NuMED, Inc., Montreal, Canada) for reshaping. Learning objective: In self-expanding transcatheter aortic valves (TAVs), bending of the TAV frame is widely known as one of the key problems. However, this is rare and infrequently encountered. In this case, TAV frame infolding occurred repeatedly, and the morphology of the infolding was evaluated in vitro and in vivo. Furthermore, we report that some TAVs can be reshaped by post-dilation.

One-Month Dual Antiplatelet Therapy Followed by P2Y12 Inhibitor Monotherapy After Biodegradable Polymer Drug-Eluting Stent Implantation　- The REIWA Region-Wide Registry.

BACKGROUND: The safety and feasibility of using 1-month dual antiplatelet therapy (DAPT) followed by P2Y12inhibitor monotherapy for patients after percutaneous coronary intervention (PCI) with thin-strut biodegradable polymer drug-eluting stents (BP-DES) in daily clinical practice remain uncertain.Methods and Results: The REIWA region-wide registry is a prospective study conducted in 1 PCI center and 9 local hospitals in northern Japan. A total of 1,202 patients who successfully underwent final PCI using BP-DES (Synergy: n=400; Ultimaster: n=401; Orsiro: n=401), were enrolled in the registry, and received 1-month DAPT followed by P2Y12inhibitor (prasugrel 3.75 mg/day or clopidogrel 75 mg/day) monotherapy. The primary endpoint was a composite of cardiovascular and bleeding events at 12 months, including cardiovascular death, myocardial infarction (MI), definite stent thrombosis (ST), ischemic or hemorrhagic stroke, and Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding. Based on the results of a previous study, we set the performance goal at 5.0%. Over the 1-year follow-up, the primary endpoint occurred in 3.08% of patients, which was lower than the predefined performance goal (Pnon-inferiority<0.0001). Notably, definite ST occurred in only 1 patient (0.08%) within 1 year (at 258 days). No differences were observed in the primary endpoint between stent types. CONCLUSIONS: The REIWA region-wide registry suggests that 1-month DAPT followed by P2Y12inhibitor monotherapy is safe and feasible for Japanese patients with BP-DES.

Detailed Lipid Profiles and Lipid-related Residual Risk after 12-week 10 mg Rosuvastatin Treatment for Acute Myocardial Infarction.

Objective We aimed to reveal detailed on-treatment lipid profiles, lipid-related surrogate markers, and factors predicting failure to achieve the guideline-recommended lipid management goal following guideline-recommended statin treatment in Japanese patients with acute myocardial infarction (AMI). Methods and Results Sixty AMI patients who underwent coronary intervention and had received rosuvastatin 10 mg/day since the start of their hospitalization were assessed for on-treatment lipid-related profiles, including high-sensitivity C-reactive protein, small dense low-density lipoprotein cholesterol (sd LDL-C), and lipoprotein (a), at the 12-week follow-up. Patients who failed to achieve the guideline-recommended lipid management at 12 weeks were defined as the "unachieved group." Univariate and multivariate logistic regression analyses were performed to evaluate the predictors of inclusion in the unachieved group after high-dose statin treatment. Despite the use of high-dose rosuvastatin, 61.7% of the enrolled AMI patients were included in the unachieved group. In addition, the unachieved group had higher sd LDL-C and lipoprotein (a) levels than the achieved group. Logistic regression analyses demonstrated that low baseline high-density lipoprotein cholesterol (HDL-C) levels and the absence of diabetes were predictors of inclusion in the unachieved group. Conclusion More than half of the Japanese AMI patients treated with rosuvastatin 10 mg/day did not achieve the guideline-recommended goal of lipid management and still had lipid-related residual risk at 12 weeks. Particular attention should be paid to patients with low baseline HDL-C levels and those without diabetes with regard to their on-treatment lipid profiles.

Impella device in fulminant myocarditis: Japanese Registry for Percutaneous Ventricular Assist Device (J-PVAD) registry analysis on outcomes and adverse events.

AIMS: Given that fulminant myocarditis, characterized by unstable haemodynamics, is a significant clinical challenge and that traditional pharmacological treatments have limitations, evaluating alternatives such as the Impella device is a crucial focus of this study. Further, this study presents pioneering large-scale registry data on its use in managing fulminant myocarditis. METHODS AND RESULTS: Data from the Japanese Registry for Percutaneous Ventricular Assist Devices (J-PVAD) were analysed to assess Impella's role in managing fulminant myocarditis from February 2020 to December 2021. The primary outcome was 30-day mortality for those treated with Impella. Of the 269 patients treated with Impella, 107 used Impella standalone, and 162 used ECPELLA (Impella combined with extracorporeal membrane oxygenation). The average age was 54 years, with 42.8% females. Overall, 74.3% survived at 30 days. Specifically, the success rate was 68.5% for the ECPELLA group and 83.2% for the Impella standalone group. Cox regression highlighted that lower estimated glomerular filtration rate and pre-Impella systolic blood pressure increased adverse event risk, while Swan-Ganz catheterization use reduced it. Adverse events were noted in 48.7% of patients, such as bleeding (32.0%) and deteriorating renal function (8.6%). CONCLUSION: Impella's use in fulminant myocarditis demonstrates encouraging short-term outcomes, albeit with significant adverse events. These findings align with previous mechanical circulatory support studies, emphasizing caution regarding haemorrhagic issues. Further studies are essential to enhance patient selection and treatment approaches.

Risk of Coronary Occlusion Due to Sinus Sequestration by Redo Transcatheter Aortic Valve Implantation in Japanese Patients With SAPIEN 3.

Background: Transcatheter aortic valve (TAV)-in-TAV is an attractive treatment for degenerated TAV. The risk of coronary artery occlusion due to sequestration of the sinus of Valsalva (SOV) in TAV-in-TAV has been reported, but the risk in Japanese patients is unknown. This study aimed to investigate the proportion of Japanese patients who are expected to experience difficulty with the second TAV implantation (TAVI) and evaluate the possibility of reducing the risk of coronary artery occlusion. Methods and Results: Patients (n=308) with an implanted SAPIEN 3 were divided into 2 groups: a high-risk group, which included patients with a TAV-sinotubular junction (STJ) distance <2 mm and a risk plane above the STJ (n=121); and a low-risk group, which included all other patients (n=187). The preoperative SOV diameter, mean STJ diameter, and STJ height were significantly larger in the low-risk group (P<0.05). The cut-off value for predicting the risk of SOV sequestration due to TAV-in-TAV in the difference between the mean STJ diameter and area-derived annulus diameter was 3.0 mm (sensitivity 70%; specificity 68%; area under the curve 0.74). Conclusions: Japanese patients may have a higher risk for sinus sequestration caused by TAV-in-TAV. The risk of sinus sequestration should be assessed before the first TAVI in young patients who are likely to require TAV-in-TAV, and whether TAVI is the best aortic valve therapy must be carefully decided.

CRISPR/Cas9 and AAV mediated insertion of ß2 microglobulin-HLA-G fusion gene protects mesenchymal stromal cells from allogeneic rejection and potentiates the use for off-the-shelf cell therapy.

Introduction: Mesenchymal stromal cells (MSCs) hold the potential for application as cellular therapy products; however, there are many problems that need to be addressed before the use in clinical settings, these include the heterogeneity of MSCs, scalability in MSC production, timing and techniques for MSC administration, and engraftment efficiency and persistency of administered MSCs. In this study, problems regarding immune rejection caused by human leukocyte antigen (HLA) mismatches were addressed. Methods: Umbilical cord-derived MSCs (UC-MSCs) were gene-edited to avoid allogeneic immunity. The HLA class I expression was abrogated by the knock-out of the beta-2-microglobulin (B2M) gene; instead, the B2M-HLA-G fusion gene was knocked-in using the CRISPR/Cas9 system in combination with adeno-associated virus (AAV). Results: Cell surface markers on gene-edited UC-MSCs were not different from those on primary UC-MSCs. The gene-edited UC-MSCs also retained the potential to differentiate into adipocytes, osteoblasts, and chondrocytes. B2M gene knock-out alone protected cells from allogeneic T cell immune responses but were vulnerable to NK cells. B2M gene knock-out in combination with B2M-HLA-G knock-in protected cells from both T cells and NK cells. The B2M-HLA-G knock-in MSCs retained a good immunosuppressive ability and the addition of these cells into the mixing lymphocyte reaction showed a significant inhibition of T cell proliferation. Conclusions: The results of this study demonstrated the possibility that the CRISPR/Cas9 system combined with AAV can be used to effectively disrupt/introduce any gene into UC-MSCs. Our findings suggest that the gene-edited cell line produced here using this method may have a higher ability to escape the cytotoxic activity of immune cells than primary cells, thereby being more advantageous for long-term graft survival.

Pharmacokinetics of lanoconazole in human skin after repeated topical application.

Drug disposition after topical application to the skin has not been fully elucidated, especially after repeated application. We conducted a clinical trial to evaluate the pharmacokinetics in the stratum corneum of healthy adults after repeated application of lanoconazole cream as a model drug. We applied 25 mg of 1% lanoconazole cream onto the pre-specified areas on the participants' back once daily for 5 days. The stratum corneum was sampled twice on each study day using a standardized tape-stripping method, and the amount of lanoconazole contained in the samples was quantified using the tandem mass spectrometry method. The obtained data were used to evaluate lanoconazole pharmacokinetics in the stratum corneum. The amount of lanoconazole in the stratum corneum after once daily repeated administration reached a steady state on day 3, and it was eliminated from the stratum corneum with a half-life of approximately 11 h after discontinuing application.

Safety and feasibility of retrograde INOUE-BALLOON for balloon aortic valvuloplasty without rapid ventricular pacing during transcatheter aortic valve replacement.

Rapid ventricular pacing (RVP) is commonly employed during transcatheter aortic valve replacement (TAVR); however, frequent TAVR is associated with worse prognoses. The retrograde INOUE-BALLOON® (IB) allows balloon aortic valvuloplasty (BAV) without RVP. The aim of this study was to evaluate the feasibility of retrograde IB for TAVR preparation. The study population included 178 consecutive patients (mean age, 84 ± 5 years; male, 47%) who underwent retrograde BAV before prosthetic valve replacement via the transfemoral approach. Patients were divided into a retrograde IB group without RVP (n = 74) and a conventional balloon (CB) group with RVP (n = 104). The primary endpoint was prolonged hypotension after BAV (reduced systolic pressure < 80 mmHg for over 1 min or vasopressor drug requirement). The incidence of prolonged hypotension after BAV was significantly lower in the IB group compared with the CB group (4% vs. 16%, p = 0.011). Balloons were able to penetrate and expand the aortic valve in both groups. RVP was used less for total TAVR in the IB group compared with the CB group. The aortic valve area-index after BAV was not significantly different between the two groups (0.72 ± 0.14 cm2/m2 vs. 0.71 ± 0.12 cm2/m2; p = 0.856). Multivariate analysis demonstrated that IB use was associated with avoidance of prolonged hypotension (OR, 0.27 [0.059-0.952]; p = 0.041). In conclusion, BAV using retrograde IB without RVP is both safe and feasible. More stable hemodynamics were achieved using retrograde IB by avoiding RVP during TAVR.

Inhibition of low-density lipoprotein uptake by Helicobacter pylori virulence factor CagA.

Helicobacter pylori (H. pylori) infection mainly causes gastroduodenal diseases, including chronic gastritis, peptic ulcer disease and gastric cancer. In recent years, several studies have demonstrated that infection with H. pylori, especially strains harboring the virulence factor CagA (cytotoxin-associated gene A), contribute to the development of non-gastric systemic diseases, including hypercholesterolemia and atherosclerotic cardiovascular diseases. However, mechanisms underlying this association has not been defined. In this study, we carried out a large-scale genetic screen using Drosophila and identified a novel CagA target low-density lipoprotein receptor (LDLR), which aids in the clearance of circulating LDL. We showed that CagA physically interacted with LDLR via its carboxy-terminal region and inhibited LDLR-mediated LDL uptake into cells. Since deficiency of LDLR-mediated LDL uptake has been known to increase plasma LDL and accelerate atherosclerosis, our findings may provide a novel mechanism for the association between infection with CagA-positive H. pylori and hypercholesterolemia leading to atherosclerotic cardiovascular diseases.

Proton transfer pathway from the oxygen-evolving complex in photosystem II substantiated by extensive mutagenesis.

We report a structure-based biological approach to identify the proton-transfer pathway in photosystem II. First, molecular dynamics (MD) simulations were conducted to analyze the H-bond network that may serve as a Grotthuss-like proton conduit. MD simulations show that D1-Asp61, the H-bond acceptor of H2O at the Mn4CaO5 cluster (W1), forms an H-bond via one water molecule with D1-Glu65 but not with D2-Glu312. Then, D1-Asp61, D1-Glu65, D2-Glu312, and the adjacent residues, D1-Arg334, D2-Glu302, and D2-Glu323, were thoroughly mutated to the other 19 residues, i.e., 114 Chlamydomonas chloroplast mutant cells were generated. Mutation of D1-Asp61 was most crucial. Only the D61E and D61C cells grew photoautotrophically and exhibit O2-evolving activity. Mutations of D2-Glu312 were less crucial to photosynthetic growth than mutations of D1-Glu65. Quantum mechanical/molecular mechanical calculations indicated that in the PSII crystal structure, the proton is predominantly localized at D1-Glu65 along the H-bond with D2-Glu312, i.e., pKa(D1-Glu65) > pKa(D2-Glu312). The potential-energy profile shows that the release of the proton from D1-Glu65 leads to the formation of the two short H-bonds between D1-Asp61 and D1-Glu65, which facilitates downhill proton transfer along the Grotthuss-like proton conduit in the S2 to S3 transition. It seems possible that D1-Glu65 is involved in the dominant pathway that proceeds from W1 via D1-Asp61 toward the thylakoid lumen, whereas D2-Glu312 and D1-Arg334 may be involved in alternative pathways in some mutants.

Sex-Related Differences in Cardiac Remodeling and Reverse Remodeling After Transcatheter Aortic Valve Implantation in Patients with Severe Aortic Stenosis in a Japanese Population.

Left ventricular (LV) remodeling with aortic stenosis (AS) appears to differ according to sex, but reverse remodeling after transcatheter aortic valve implantation (TAVI) has not been elucidated in a Japanese population. This study aims to determine whether any sex-related differences in LV or reverse remodeling after TAVI exist in the context of severe AS.Of 208 patients who received TAVI for severe AS in our institution, 100 (men, 42; mean age, 83.0 ± 4.9 years) underwent transthoracic echocardiography before and 3 months after TAVI. Despite similar valvular gradients, women with severe AS had lower indexed LV mass (LVMi) than did men (152.3 ± 35.4 versus 173.2 ± 44.6 g/m2, P = 0.005), with smaller indexed LV end-diastolic (LVEDVi) (50.2 ± 13.3 versus 61.4 ± 20.7 mL/m2, P = 0.001) and end-systolic (LVESVi; 17.9 ± 8.7 versus 24.3 ± 13.8 mL/m2, P = 0.006) volumes. After TAVI, women (-6.0% ± 14.4%) had higher reduction in the rate of change of relative wall thickness (RWT) than did men (4.4% ± 19.0%, P = 0.003). Men (-8.9% ± 3.9%) had higher reduction in the rate of change of LVEDVi than did women (1.5% ± 3.3%, P = 0.045). Incidence of LV reverse remodeling defined as a reduction in LVESV of >15% was significantly higher in men (50%) than in women (26%, P = 0.013).In addition to sex differences in the pattern of LV remodeling with AS, reverse LV remodeling after TAVI also differed between sexes.

Parotid gland atrophy after conservative treatment of a post-traumatic parotid fistula in a two-year-old boy.

A parotid fistula is a rare complication following parotid gland and duct injury. A two-year-old boy with a previous parotid fistula after parotid injury due to a dog bite was successfully treated with pressure-dressing therapy, which is generally non-invasive and tolerable by young children. During follow-up, ultrasonography revealed atrophy of the parotid gland. This finding is consistent with the healing mechanism previously assumed in adult patients with a parotid fistula. Consideration should be paid to the possibility of oral environmental changes associated with reduced saliva secretion from parotid gland atrophy after conservative treatment of parotid fistula.

Comparison of Archival Angiographic Findings in Patients Later Developing Acute Coronary Syndrome or Stable Angina.

Acute coronary syndrome (ACS) can develop in patients with mildly to moderately stenotic lesions. However, the angiographic characteristics of lesions in patients who will later develop ACS have not been systematically investigated. For this reason, we examined the earlier angiographic findings of such patients in a retrospective study.The study population consisted of 45 consecutive ACS and 45 stable angina (SA) patients who require revascularization. All of them had received cardiac catheterization within 5 years prior to onset, for different reasons. The detailed parameters of the earlier coronary angiographies at the culprit site the whole culprit vessel, and all three vessels were compared between the two groups.Mild-to-moderate stenosis was present exclusively at the culprit site in the earlier angiographies, both in ACS and SA patients. Lesions associated with ACS progression were significantly shorter in length than those associated with SA progression (11.5 ± 5.5 versus 16.1 ± 10.5 mm, P = 0.02) and were more eccentric (eccentricity index: 0.5 ± 0.3 versus 0.7 ± 0.3, P = 0.04). Percent diameter stenosis was similar (42.2 ± 14.5 versus 44.0 ± 13.8%, P = 0.5). The mean grading scores for plaque extension and size (1-3) were significantly lower in ACS than in SA (1.4 ± 0.6 versus 1.8 ± 0.6, P = 0.01, and 1.3 ± 0.6 versus 1.7 ± 0.7, P = 0.01, respectively). Residual SYNTAX scores were significantly lower in ACS (12.5 ± 7.4 versus 16.4 ± 8.6, P = 0.03).Despite equivalent degrees of stenosis in previous angiographies, ACS occurred more frequently in patients with more focal and eccentric lesions but with less diseased coronary arteries than SA.

ß-Silicon-effect-promoted intermolecular site-selective C(sp3)-H amination with dirhodium nitrenes.

A dirhodium-catalyzed, ß-selective C-H amination of organosilicon compounds has been developed. Primary C(sp3)-H bonds of silylethyl groups and secondary C(sp3)-H bonds of silacycloalkanes can be selectively converted to C-N bonds at the ß-position of the silicon atoms. The experimental data and theoretical calculations indicate that the strong σ-donor ability of the carbon-silicon bonds is responsible for the ß-selectivity. Kinetic isotope effects clearly demonstrate that the C-H bond cleavage step is not turnover-limiting, but selectivity-determining.

Synthesis of 4-Deoxy Pyranosides via Catalyst-Controlled Site-Selective Toluoylation of Abundant Sugars.

A two-step procedure was developed for the synthesis of 4-deoxy pyranosides from the parent pyranosides with four hydroxy groups via organocatalytic site-selective acylation and reductive deacyloxylation.

Chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating expression of ephrin-B1.

Advanced solid tumors are exposed to hypoxic conditions over longer periods of time as they grow. Tumor hypoxia is a major factor that induces malignant progression, but most previous studies on tumor hypoxia were performed under short-term hypoxia for up to 72 hours and few studies have focused on tumor response to chronic hypoxic conditions. Here we show a molecular mechanism by which chronic hypoxia promotes invasive behavior in prostate cancer cells. We found that an epithelial-mesenchymal transition (EMT)-driving transcription factor, slug, is specifically upregulated under chronic hypoxia and promotes tumor cell migration and invasion. Unexpectedly, processes associated with EMT, such as loss of E-cadherin, are not observed under chronic hypoxia. Instead, expression of ephrin-B1, a ligand of Eph-related receptor tyrosine kinases, is markedly induced by slug through E-box motifs and promotes cell migration and invasion. Furthermore, slug and ephrin-B1 are highly coexpressed in chronic hypoxic cells of human prostate adenocarcinoma tissues after androgen deprivation, which is known to cause tumor hypoxia. Taken together, these results indicate that chronic hypoxia-induced slug promotes invasive behavior of prostate cancer cells by activating the expression of ephrin-B1. In addition, ephrin-B1 may be a novel therapeutic target in combination with androgen deprivation therapy for aggressive prostate cancer.

The membrane-bound O-acyltransferase Ale1 transfers an acyl moiety to newly synthesized 2-alkyl-sn-glycero-3-phosphocholine in yeast.

To elucidate the mechanism of acyl chain remodeling at the sn-1 position of phosphatidylcholine (PC), we investigated acyl chain introduction using a newly synthesized 1-hydroxy-2-hexadecyl-sn-glycero-3-phosphocholine (HHPC) in Saccharomyces cerevisiae. HHPC is incorporated into yeast cells and converted to a PC species containing acyl residues of 16 or 18 carbons. The efficiency of palmitoleic acid introduction to HHPCin vitro is lower in the reaction with the extract from the deletion mutant of ALE1, which encodes a membrane-bound O-acyltransferase, than in that with extracts from the wild-type strain. In addition, deletion of ALE1 causes reductions in the molecular species containing acyl residues in HHPC. These results reveal that ALE1 is involved in acyl chain transfer to the sn-1 position of HHPC in yeast.