Objective According to consensus guidelines, eosinophilic esophagitis (EoE) is defined as a clinicopathological entity whose symptoms and histology must always be considered together. However, ...endoscopic findings typical of EoE are often seen in asymptomatic esophageal eosinophilia (aEE). We aimed to clarify the clinicopathological features of aEE. Methods We retrospectively compared cases of aEE and those of symptomatic EoE. Materials We reviewed 146 patients who underwent upper gastrointestinal endoscopy and were confirmed histopathologically to have esophageal eosinophil infiltration of at least 15 eosinophils per high-power field. They were divided into the aEE group (n=75) and the EoE group (n=71). Patients' clinicopathological findings were then collected and examined. Results The EoE group experienced dysphagia (47.9%), heartburn (40.8%), food impaction (40.8%), chest pain (16.9%), and other symptoms (8.5%). There was no significant difference between the two groups with regard to age, sex, current smoking status, or alcohol consumption. The aEE group had a significantly higher body mass index (p<0.01) and significantly lower frequency of concurrent allergic diseases (p<0.01) than the EoE group. No significant differences were found between the two groups with regard to the mean peripheral blood eosinophil count, non-specific immunoglobulin E concentration, peak eosinophil infiltration in the biopsy specimens, EoE histology scoring system, phenotype and location of typical endoscopic findings of EoE, or thickness of the esophagus wall or the mucosal and submucosal layer as measured by endoscopic ultrasonography. Two patients in the aEE group who were followed up without treatment subsequently developed esophageal symptoms. Conclusion aEE and EoE may have the same clinicopathological features.
Background: We investigated the relationship between intraprocedural angiographic and echocardiographic AR severity after TAVI, and the clinical robustness of angiographic assessment. Methods and ...Results: In 74 consecutive patients, the echocardiographic circumferential extent (CE) of the paravalvular regurgitant jet was retrospectively measured and graded based on the VARC-2 cut-points; and angiographic post-TAVI AR was retrospectively quantified using contrast videodensitometry (VD) software that calculates the ratio of the contrast time-density integral in the LV outflow tract to that in the ascending aorta (LVOT-AR). Seventy-four echocardiograms immediately after TAVI were analyzable, while 51 aortograms were analyzable for VD. These 51 echocardiograms and VD were evaluated. Median LVOT-AR across the echocardiographic AR grades was as follows: none-trace, 0.07 (IQR, 0.05–0.11); mild, 0.12 (IQR, 0.09–0.15); and moderate, 0.17 (IQR, 0.15–0.22; P<0.05 for none-trace vs. mild, and mild vs. moderate). LVOT-AR strongly correlated with %CE (r=0.72, P<0.0001). At 1 year, the rate of the composite end-point of all-cause death or HF re-hospitalization was significantly higher in >mild AR patients compared with no-mild AR on intra-procedural echocardiography (41.5% vs. 12.4%, P=0.03) as well as in patients with LVOT-AR >0.17 compared with LVOT-AR ≤0.17 (59.5% vs. 16.6%, P=0.03). Conclusions: VD (LVOT-AR) has good intra-procedural inter-technique consistency and clinical robustness. Greater than mild post-TAVI AR, but not mild post-TAVI AR, is associated with late mortality.
Dantrolene binds to the Leu601-Cys620 region of the N-terminal domain of cardiac ryanodine receptor (RyR2), which corresponds to the Leu590-Cys609 region of the skeletal ryanodine receptor, and ...suppresses diastolic Ca2+ leakage through RyR2.
We investigated whether the chronic administration of dantrolene prevented left ventricular (LV) remodeling and ventricular tachycardia (VT) after myocardial infarction (MI) by the same mechanism with the mutation V3599K of RyR2, which indicated that the inhibition of diastolic Ca2+ leakage occurred by enhancing the binding affinity of calmodulin (CaM) to RyR2.
A left anterior descending coronary artery ligation MI model was developed in mice. Wild-type (WT) were divided into four groups: sham-operated mice (WT-Sham), sham-operated mice treated with dantrolene (WT-Sham-DAN), MI mice (WT-MI), and MI mice treated with dantrolene (WT-MI-DAN). Homozygous V3599K RyR2 knock-in (KI) mice were divided into two groups: sham-operated mice (KI-Sham) and MI mice (KI-MI). The mice were followed for 12 weeks.
Survival was significantly higher in the WT-MI-DAN (73%) and KI-MI groups (70%) than the WT-MI group (40%). Echocardiography, pathological tissue, and epinephrine-induced VT studies showed that LV remodeling and VT were prevented in the WT-MI-DAN and KI-MI groups compared to the WT-MI group. An increase in diastolic Ca2+ spark frequency and a decrease in the binding affinity of CaM to the RyR2 were observed at 12 weeks after MI in the WT-MI group, although significant improvements in these values were observed in the WT-MI-DAN and KI-MI groups.
Pharmacological or genetic stabilization of RyR2 tetrameric structure improves survival after MI by suppressing LV remodeling and proarrhythmia.
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•Dantrolene, a stabilizer of RyR2, prevented diastolic Ca2+ leakage from RyR2 by enhancing the binding affinity of calmodulin (CaM) to RyR2 in MI.•The mutation V3599K of RyR2 inhibited the diastolic Ca2+ leakage by enhancing the binding affinity of CaM to RyR2 in MI.•Pharmacological or genetic stabilization of tetrameric RyR2 improved survival after MI by suppressing LV remodeling and proarrhythmia.
Background:An association between atrial high-rate episode (AHRE) and stroke has been reported, although data for the Asian population are limited. This study aimed to investigate the role of AHRE in ...ischemic and major bleeding events in patients who underwent a cardiac implantable electronic device (CIED) procedure.Methods and Results:This single-center historical cohort study included 710 patients (age: 78±11 years, 374 women) who underwent a CIED-related procedure between October 2009 and September 2019 at Shimane Prefectural Central Hospital (median follow-up period: 4.5 2.5, 7 years, 3439 person-years). Based on the maximum AHRE burden, patients were divided into: (1) <6 min; (2) ≥6 min to 24-h; and (3) ≥24-h groups. The cumulative incidence of ischemic (ischemic stroke, systemic embolism, and transient ischemic attack) and major bleeding (≥3 Bleeding Academic Research Consortium bleeding criteria) events after the procedure were compared. Uni- and multivariate analyses were performed to identify factors associated with these events. The incidence of both events increased with the rising AHRE burden, being significantly higher in the ≥24-h group than in the <6 min group. Multivariate analysis found age ≥85 years to be the only independent factor associated with both events.Conclusions:Longer AHRE duration is associated with a high number of major bleeding and ischemic events. Monitoring these bleeding risks is mandatory when clinicians are considering anticoagulation therapy for such patients.
Abstract Objectives The NIPPON (Nobori Dual Antiplatelet Therapy as Appropriate Duration) study was a multicenter randomized investigation of the noninferiority of short-term versus long-term dual ...antiplatelet therapy (DAPT) in patients with implantation of the Nobori drug-eluting stent (DES) (Terumo, Tokyo, Japan), which has a biodegradable abluminal coating. Background The optimum duration of DAPT for patients with a biodegradable polymer-coated DES is unclear. Methods The subjects were 3,773 patients with stable or acute coronary syndromes undergoing Nobori stent implantation. They were randomized 1:1 to receive DAPT for 6 or 18 months. The primary endpoint was net adverse clinical and cerebrovascular events (NACCE) (all-cause mortality, myocardial infarction, stroke, and major bleeding) from 6 to 18 months after stenting. Intention-to-treat analysis was performed in 3,307 patients who were followed for at least 6 months. Results NACCE occurred in 34 patients (2.1%) receiving short-term DAPT and 24 patients (1.5%) receiving long-term DAPT (difference 0.6%, 95% confidence interval CI: 1.5 to 0.3). Because the lower limit of the 95% CI was inside the specified margin of −2%, noninferiority of short-term DAPT was confirmed. Mortality was 1.0% with short-term DAPT versus 0.4% with long-term DAPT, whereas myocardial infarction was 0.2% versus 0.1%, and major bleeding was 0.7% versus 0.7%, respectively. The estimated probability of NACCE was lower in the long-term DAPT group (hazard ratio: 1.44, 95% CI: 0.86 to 2.43). Conclusions Six months of DAPT was not inferior to 18 months of DAPT following implantation of a DES with a biodegradable abluminal coating. However, this result needs to be interpreted with caution given the open-label design and wide noninferiority margin of the present study. (Nobori Dual Antiplatelet Therapy as Appropriate Duration NIPPON; NCT01514227 )
Extranodal natural killer (NK)/T‐cell lymphoma, nasal type, and aggressive NK‐cell leukemia are rare, and their standard therapy has not been established. They are Epstein–Barr virus‐associated ...lymphoid malignancies, and tumor cells express P‐glycoprotein leading to multidrug resistance of the disease. Patients with stage IV, relapsed or refractory diseases have a dismal prognosis, with survival measured in months only. To develop an efficacious chemotherapeutic regimen, we conducted a dose‐escalation feasibility study of a new chemotherapeutic regimen, SMILE, comprising the steroid dexamethasone, methotrexate, ifosfamide, l‐asparaginase, and etoposide. The components of SMILE are multidrug resistance‐unrelated agents and etoposide. Etoposide shows both in vitro and in vivo efficacy for Epstein–Barr virus‐associated lymphoproliferative disorders. Eligible patients had newly diagnosed stage IV, relapsed or refractory diseases after first‐line chemotherapy, were 15–69 years of age, and had satisfactory performance scores (0–2). Four dose levels of methotrexate and etoposide were originally planned to be evaluated. At level 1, six patients with extranodal NK/T‐cell lymphoma, nasal type, were enrolled. Their disease status was newly diagnosed stage IV (n = 3), first relapse (n = 2), and primary refractory (n = 1). All of the first three patients developed dose‐limiting toxicities, and one of them died of sepsis with grade 4 neutropenia. A protocol revision stipulating early granulocyte colony‐stimulating factor administration was made. Two out of three additional patients developed dose‐limiting toxicities that were all manageable and transient. For the six enrolled patients, the overall response rate was 67% and the complete response rate was 50%. Although its safety and efficacy require further evaluation, we recommend a SMILE chemotherapy dose level of 1 for further clinical studies. (Cancer Sci 2008; 99: 1016–1020)
Background:The clinical robustness of contrast-videodensitometric (VD) assessment of aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) has been demonstrated. Correct ...acquisition of aortic root angiography for VD assessment, however, is hampered by the opacified descending aorta and by individual anatomic peculiarities. The aim of this study was to use preprocedural multi-slice computed tomography (MSCT) to optimize the angiographic projection in order to improve the feasibility of VD assessment.Methods and Results:In 92 consecutive patients, post-TAVI AR (i.e., left ventricular outflow tract LVOT AR) was assessed on aortic root angiograms using VD software. The patients were divided into 2 groups: The first group of 54 patients was investigated prior to the introduction of the standardized acquisition protocol; the second group of 38 consecutive patients after implementation of the standardized acquisition protocol, involving MSCT planning of the optimal angiographic projection. Optimal projection planning has dramatically improved the feasibility of VD assessment from 57.4% prior to the standardized acquisition protocol, to 100% after the protocol was implemented. In 69 analyzable aortograms (69/92; 75%), LVOT-AR ranged from 3% to 28% with a median of 12%. Inter-observer agreement was high (mean difference±SD, 1±2%), and the 2 observers’ measurements were highly correlated (r=0.94, P<0.0001).Conclusions:Introduction of computed tomography-guided angiographic image acquisition has significantly improved the analyzability of the angiographic VD assessment of post-TAVI AR.
Increased endoplasmic reticulum (ER) stress is strongly associated with the phenotypic switching of vascular smooth muscle cells (VSMCs) in atherosclerosis. Depletion of the ER Ca2+ content is one of ...the leading causes of increased ER stress in VSMCs. The ryanodine receptor (RyR) is a major Ca2+ release channel in the sarcoplasmic reticulum membrane. Calmodulin (CaM), which binds to RyR (CaM-RyR), stabilizes the closed state of RyR in the resting state in normal cells. Defective CaM-RyR interactions can cause abnormal Ca2+ leakage through RyR, resulting in decreased Ca2+ content, indicating that defective CaM-RyR interactions may be a cause of increased ER stress. Herein, we used a mouse VSMCs to assess whether CaM-RyR plays a pivotal role in VSMCs phenotypic switching, which is caused by ER stress, and whether dantrolene, which enhances the binding affinity of CaM to RyR, affects VSMCs phenotypic switching.
Tunicamycin was used to mimic ER stress in vitro. Tunicamycin-induced ER stress caused CaM to dissociate from the RyR and translocate to the nucleus, which stimulated phenotypic switching through the activation of MEF2 and KLF5. Dantrolene suppressed tunicamycin-induced apoptosis, ER stress (restoring ER Ca2+ content), and phenotypic switching of VSMCs. Suramin, which directly unbinds CaM from RyR, promoted nuclear CaM accumulation with parallel VSMCs phenotypic switching, and dantrolene prevented these effects.
We observed that ER stress causes CaM translocation to the nucleus and drives the phenotypic switching of VSMCs. Thus, restoration of the binding affinity of CaM to RyR may be a therapeutic target for atherosclerosis.
•Tunicamycin-induced ER stress promotes cell death by causing apoptosis, but this tunicamycin-driven apoptosis can be inhibited by dantrolene.•Dantrolene suppresses the expression of GRP78 and CHOP by restoring the ER Ca2+ content.•Tunicamycin-induced ER stress promotes MEF2 and KLF5 expression in the nucleus, which promotes the phenotypic switching of VSMCs, but dantrolene reduces the nuclear MEF2 and KLF5 expressions, suggesting that dantrolene prevents the phenotypic switching of VSMCs.•Tunicamycin-induced ER stress reduces the CaM-RyR binding and accelerates the translocation of CaM to the nucleus.•Direct displacement of CaM from RyR by suramin promotes both the nuclear accumulation of CaM and the nuclear expression of KLF5, leading to the phenotypic switching of VSMCs.•Treatment with dantrolene suppresses the formation of atherosclerotic plaque in ApoE−/− mice.
Sudden cardiac death (SCD) is the major cause of death in cardiac sarcoidosis (CS). We aimed to identify the prognostic markers for sustained ventricular tachycardia (sVT) and SCD in patients with ...CS.
We performed a prospective observational cohort study for patients with CS diagnosed according to the Japanese or Heart Rhythm Society guidelines between June 2008 and March 2020 in our hospital. The primary endpoint was a composite of the first sVT and SCD. The levels of urinary 8-hydroxy-2'-deoxyguanosine (U-8-OHdG), a marker of oxidative DNA damage that reflects the inflammatory activity of CS, other biomarkers, and indices of cardiac function and renal function were measured on admission.
Eighty-nine consecutive patients with CS were enrolled; 28 patients with no abnormal
F-fluorodeoxyglucose (
F-FDG) accumulation in the heart were excluded and 61 patients with abnormal
F-FDG accumulation were followed up for a median of 46 months (IQR: 20-84). During the follow-up period, 15 of 61 patients showed sVT (n=12) or SCD (n=3). A Cox proportional hazard model showed that U-8-OHdG concentration and presence of ventricular aneurysm (VA) were independent predictors of first sVT/SCD. The cut-off U-8-OHdG concentration for predicting first sVT/SCD was 14.9 ng/mg·Cr. Patients with U-8-OHdG concentration ≥14.9 ng/mg·Cr and VA showed a significantly increased risk of sVT/SCD.
U-8-OHdG and presence of VA were powerful predictors of first sVT/SCD in patients with CS, facilitating the stratification of cardiac events and providing relevant information about the substrates of ventricular tachycardia.
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