Reduced Left Ventricular Ejection Fraction Is a Risk for Sudden Cardiac Death in the Early Period After Hospital Discharge in Patients With Acute Myocardial Infarction.

BACKGROUND: The incidence of sudden cardiac death (SCD) after discharge in Japanese acute myocardial infarction (AMI) patients with reduced left ventricular ejection fraction (LVEF) treated with primary percutaneous coronary intervention (PCI) remains unknown.Methods and Results:The study population included 1,429 AMI patients (199 with LVEF ≤35% and 1,230 with LVEF >35%) admitted to the Hirosaki University Hospital, treated with primary PCI within 12 h after onset, and survived to discharge. LVEF was evaluated in all patients before discharge, and the patients were followed up for a mean of 2.6±0.8 years. The Kaplan-Meier survival curves revealed LVEF ≤35% was associated with all-cause death and SCD. The incidence of SCD was 2.6% at 1 year and 3.1% at 3 years in patients with LVEF ≤35%, whereas it was 0.1% at 1 year and 0.3% at 3 years in patients with LVEF >35%. Sixty-seven percent of SCDs in patients with LVEF ≤35% occurred within 4 months after discharge, and the events became less frequent after this period. A Cox proportional hazard model indicated LVEF ≤35% as an independent predictor for all-cause death and SCD. CONCLUSIONS: The incidence of SCD was relatively low in Japanese AMI patients treated with primary PCI, even in patients with LVEF ≤35% upon discharge. Careful management of patients with reduced LVEF is required to prevent SCD, especially in the early phase after discharge.

Characteristics and outcomes of unplanned intensive care unit admission after general anesthesia.

BACKGROUND: Unplanned ICU admission after surgery has been validated as a measure of a quality indicator of perioperative management because it may put surgical patients at risk of increased morbidity and mortality. Postoperative unscheduled admission to the ICU is usually determined either in the post-anesthesia care unit (PACU) or in the general surgical ward; however, it could be expected patient outcomes after ICU admission would be affected by the circumstances. The purpose of this retrospective observational study was to investigate the clinical characteristics and the outcome of unplanned admission to the ICU directly from the PACU or from the ward within 7 days after PACU discharge. METHODS: Forty-three thousand, five hundred fifty-three patients admitted to the PACU after general anesthesia were included in the study. Unplanned ICU admission was defined as the admission which was not anticipated preoperatively but was due to adverse events in the PACU (PACU group) or the ward after discharge from the PACU (Ward group). The following parameters were compared between the groups: patient characteristics, surgical characteristics, length of ICU and hospital stay, the principal adverse event for ICU admission, treatments in the ICU, and in-hospital mortality. The primary outcome was in-hospital mortality and the second was the length of ICU and hospital stay. RESULTS: Among 43,553 patients, 109 patients underwent unplanned ICU admission directly from the PACU (n= 73, 0.17%) or subsequently from the ward (n= 36, 0.08%). The length of both ICU and hospital stay was significantly longer in the Ward group than in the PACU group (1.4 and 19 days vs. 2.5 and 39 days, respectively). There was no significant difference in in-hospital mortality between the groups (4.1% vs. 8.3%, respectively). CONCLUSIONS: The incidence of unplanned ICU admission after PACU stay was low, however, delayed admission to the ICU from the ward may prolong the length of both ICU and hospital stay compared to those directly from the PACU.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma arising in patient with a history of EBV-positive mucocutaneous ulcer and EBV-positive nodal polymorphous B-lymphoproliferative disorder.

Elderly patients with Epstein-Barr virus (EBV) infection are at increased risk for developing B-cell lymphoproliferative disorder (B-LPD) due to immunosenescence. Here, we describe a case of a 75-year-old man who developed an EBV-positive (EBV+) mucocutaneous ulcer (EBVMCU) in the gingiva with spontaneous regression. Eighteen months after regression, he had a cervical lymph node enlargement that was diagnosed as EBV+ nodal polymorphous B-LPD, Ann Arbor stage IA. Clinicians decided to observe his clinical course without any treatment. Fourteen months later, the patient developed EBV-positive diffuse large B-cell lymphoma (DLBCL), Ann Arbor stage IIA, and received six courses of age-adjusted dose chemotherapy and achieved a complete remission. No evidence of a clonal relationship was found among these three lesions by standard polymerase chain reaction (PCR) analysis for immunoglobulin heavy chain. However, they all had expression of PD-L1 in the EBV+ large B-cells and Hodgkin Reed-Sternberg-like cells. This is the first case report of a PD-L1-positive (PD-L1+) EBVMCU and the development of multiple EBV-driven B-LPDs in the setting of immunosenescence within a 32-month period.

Novel Electrocardiographic Criteria for the Diagnosis of Left Ventricular Hypertrophy in the Japanese General Population.

Although there are several diagnostic criteria for left ventricular hypertrophy (LVH), their sensitivity remains low. A recent study reported that the sum of the amplitude of the deepest S wave in any lead (SD) and the S wave in lead V4 (SV4) (SD + SV4) improved sensitivity compared with commonly used criteria. To test whether this new formula improves sensitivity in the Japanese general population, we analyzed 12-lead electrocardiograms for Japanese residents participating in the Iwaki Health Promotion Project (n = 866). Left ventricular mass was calculated by echocardiography, indicating that 156 (18%) of the study population had LVH. In receiver operating characteristic analyses, the sum of the R wave in limb lead Ι (RLΙ) and the S wave in V4 (SV4) (RLΙ + SV4) showed a higher area under the curve (AUC = 0.76) than the Sokolow-Lyon voltage criteria (0.61) and the SD + SV4 criteria (0.63), and almost the same AUC as the Cornell voltage criteria (0.74) and the Cornell product criteria (0.76). The validation study also showed similar results. The cutoff values of RLΙ + SV4 criteria were ≥1.6 mV in men and ≥1.4 mV in women with a sensitivity of 39% and a specificity of 89%, whereas the sensitivity and specificity calculated based on SD + SV4 criteria were 21% and 94%, respectively. Thus, the diagnostic criterion of RLΙ + SV4 seems to be more useful than the previous criteria for diagnosing LVH in the Japanese general population.

Blood Pressure-Independent Effect of Olmesartan on Albuminuria in Mice Overexpressing Renin.

Enhanced renin-angiotensin activity contributes to hypertension, albuminuria, and glomerular hypertrophy. The angiotensin (Ang)-converting enzyme (ACE) 2/Ang (1-7)/Mas axis pathway acts against Ang II type 1 receptor (AT1R) signaling. We investigated whether olmesartan (Olm), an AT1R blocker, inhibits albuminuria independently of blood pressure and elucidated the potential mechanisms.Three- to 4-month-old male mice overexpressing renin in the liver (Ren-TG) were given olmesartan (5 mg/kg/day) or hydralazine (Hyd) (3.5 mg/kg/day) orally for 2 months. Ren-TG mice had higher systolic blood pressure (SBP) than wild-type (WT) mice (158.2 ± 6.3 versus 112.8 ± 8.8 mmHg, n = 3-4, P < 0.01). Ren-TG mice treated with Olm or Hyd for 2 months had lower SBP than untreated Ren-TG mice. Urinary albumin excretion (UAE) was significantly increased in Ren-TG mice compared with WT mice (78.2 ± 31.2 versus 28.6 ± 13.8 µg/day, n = 5-6, P < 0.01). Olm treatment for 2 months reduced UAE, whereas Hyd treatment did not. Olm treatment reversed decreased gene and protein expressions of ACE2 and Mas receptor (Mas 1) in the kidney of Ren-TG mice and inhibited enhanced NADPH oxidase (Nox) 4 expression, whereas Hyd treatment had no influence. Furthermore, increased reactive oxygen species (ROS) in the kidney of Ren-TG mice were decreased by Olm treatment but not by Hyd treatment.Olm treatment inhibits albuminuria and glomerular hypertrophy independently of blood pressure not only through its original AT1R blockade but also partly through the enhancement of the ACE2/Ang (1-7)/Mas axis and suppression of ROS generation.

Relationship Between Serum Eicosapentaenoic Acid Levels and J-Waves in a General Population in Japan.

We previously showed that J-waves were found more frequently in patients with low levels of serum eicosapentaenoic acid (EPA) in the acute phase of myocardial infarction, and were associated with the incidence of ischemia-related ventricular arrhythmias. However, the relationship between J-waves and serum EPA levels in a general population remains to be elucidated.The Iwaki Health Promotion Project is an ongoing community-based health promotion study in Iwaki, Hirosaki, which is in northern Japan. A total of 1,052 residents (mean age, 53.9 ± 15.4 years; 390 men) who participated in this project in 2014 were studied. A standard 12-lead electrocardiogram (ECG) was recorded and serum EPA levels were measured to evaluate the relationship between J-waves and serum EPA levels. J-waves were found in 52 (5%) subjects and were observed more frequently in male than female subjects (44 [11%] versus 8 [1%], P < 0.0001). More than half of the J-waves were the notched type (60%), and J-waves were detected most frequently in inferior leads on ECG (52%). The RR interval was longer and QTc duration shorter in subjects with J-waves than those without. No significant difference was found in serum EPA levels between subjects with and without J-waves (70 [49-116] versus 65 [41-106] µg/mL, P = 0.40). In multivariate analysis, male gender and RR interval were independent factors associated with the presence of J-waves.There was no significant relationship between J-waves and serum EPA levels in this general population in Japan. Various mechanisms for manifestation of the J-waves are suggested.

Questions of Mirror Symmetry at the Photoexcited and Ground States of Non-Rigid Luminophores Raised by Circularly Polarized Luminescence and Circular Dichroism Spectroscopy: Part 1. Oligofluorenes, Oligophenylenes, Binaphthyls and Fused Aromatics.

We report experimental tests of whether non-rigid, π-conjugated luminophores in the photoexcited (S1) and ground (S0) states dissolved in achiral liquids are mirror symmetrical by means of circularly polarized luminescence (CPL) and circular dichroism (CD) spectroscopy. Herein, we chose ten oligofluorenes, eleven linear/cyclic oligo-p-arylenes, three binaphthyls and five fused aromatics, substituted with alkyl, alkoxy, phenyl and phenylethynyl groups and also with no substituents. Without exception, all these non-rigid luminophores showed negative-sign CPL signals in the UV-visible region, suggesting temporal generation of energetically non-equivalent non-mirror image structures as far-from equilibrium open-flow systems at the S1 state. For comparison, unsubstituted naphthalene, anthracene, tetracene and pyrene, which are achiral, rigid, planar luminophores, did not obviously show CPL/CD signals. However, camphor, which is a rigid chiral luminophore, showed mirror-image CPL/CD signals. The dissymmetry ratio of CPL (glum) for the oligofluorenes increased discontinuously, ranging from ≈ -(0.2 to 2.0) × 10-3, when the viscosity of the liquids increased. When the fluorene ring number increased, the glum value extrapolated at [η] = 0 reached -0.8 × 10-3 at 420 nm, leading to (⁻)-CPL signals predicted in the vacuum state. Our comprehensive CPL and CD study should provide a possible answer to the molecular parity violation hypothesis arising due to the weak neutral current mediated by the Z°-boson.

Correction: Fujiki, M., et al. Questions of Mirror Symmetry at the Photoexcited and Ground States of Non-Rigid Luminophores Raised by Circularly Polarized Luminescence and Circular Dichroism Spectroscopy: Part 1. Oligofluorenes, Oligophenylenes, Binaphthyls and Fused Aromatics. Molecules, 2018, 23, 2606.

The authors wish to make the following correction to their paper [...].

Olmesartan Inhibits Cardiac Hypertrophy in Mice Overexpressing Renin Independently of Blood Pressure: Its Beneficial Effects on ACE2/Ang(1-7)/Mas Axis and NADPH Oxidase Expression.

Enhanced renin-angiotensin activity causes hypertension and cardiac hypertrophy. The angiotensin (Ang)-converting enzyme (ACE)2/Ang(1-7)/Mas axis pathway functions against Ang II type 1 receptor (AT1R) signaling. We investigated whether olmesartan (Olm), an AT1R blocker, inhibits cardiac hypertrophy independently of blood pressure, and evaluated the potential mechanisms. The 3- to 4-month-old male mice overexpressing renin in the liver (Ren-Tg) were given Olm (5 mg/kg/d) and hydralazine (Hyd) (3.5 mg/kg/d) orally for 2 months. Systolic blood pressure was higher in the Ren-Tg mice than in wild-type littermates. Olm and Hyd treatments lowered systolic blood pressure to the same degree. However, cardiac hypertrophy, evaluated by echocardiography, heart weight, cross-sectional area of cardiomyocytes, and gene expression, was inhibited by only Olm treatment, but not by Hyd. Olm treatment reversed decreased gene expressions of ACE2 and Mas receptor of Ren-Tg mice and inhibited enhanced NADPH oxidase (Nox)4 expression and reactive oxygen species, whereas Hyd treatment had no influence on them. These findings indicate that Olm treatment inhibits cardiac hypertrophy independently of blood pressure, not only through its original AT1R blockade but partly through enhancement of ACE2/Ang(1-7)/Mas axis and suppression of Nox4 expression.

Rapid and Easy Histological Evaluation of Alveolar Human Bone Quality at Dental Implant Sites Using a Nondecalcified Frozen Cryofilm Section Technique: A Technical Report.

INTRODUCTION: The evaluation of bone quality at the site of the alveolar bone for a dental implant is very important. This study presents an easy technique for direct evaluation of alveolar bone quality using nondecalcified cryofilm frozen sections on human alveolar bone core samples. MATERIALS AND METHODS: Core samples harvested from alveolar bone were immediately frozen in cooled hexanen and slowly cut using a disposable tungsten carbide blade; the sliced sections were collected with adhesive cryofilms. Staining was performed using von toluidine blue and von Kossa for microscopic observations. RESULTS: All core samples clearly showed bone structure components of cortical bone, trabecular bone, bone marrow, blood vessels, and bone-related cells. CONCLUSION: These results suggest the efficacy of a nondecalcified cryofilm frozen section technique for histological observation of surgical implant sites.

Reduced smoke-like echo and resolved thrombus in the left atrium with rivaroxaban therapy in an acute cardioembolic stroke patient.

We report a case of a nonvalvular atrial fibrillation (NVAF) patient with acute cardioembolic stroke in whom rivaroxaban, an oral direct factor Xa inhibitor, reduced a smoke-like echo in the left atrium and resolved a thrombus in the left atrial appendage. A 71-year-old man was admitted because of the sudden onset of right hemiplegia and aphasia and was diagnosed with acute cardioembolic stroke associated with NVAF. The patient had not been treated with warfarin before admission, and rivaroxaban therapy (15 mg once daily) was initiated. Transesophageal echocardiography was performed on day 8 and a mobile thrombus was found in the left atrial appendage, accompanied by a remarkable smoke-like echo in the left atrium. Notably, the thrombus was resolved and the smoke-like echo was reduced on day 40. No recurrent ischemic stroke occurred. We describe favorable effects of rivaroxaban on the reduction of a smoke-like echo and on the resolution of a thrombus in the left atrium in an NVAF patient with acute cardioembolic stroke.

The incidence of hypotension during general anesthesia: a single-center study at a university hospital.

BACKGROUND: Although intraoperative hypotension (IOH) has been emerging as a serious concern during general anesthesia, the incidence of IOH has not been demonstrated clearly in the Japanese population. METHODS: This single-center retrospective study investigated the incidence and the characteristics of IOH in non-cardiac surgery at a university hospital. IOH was defined as at least one fall of MAP during general anesthesia, which was categorized into the following groups: mild (65 to < 75 mmHg), moderate (55 to < 65 mmHg), severe (45 to < 55 mmHg), and very severe (< 45 mmHg). The incidence of IOH was calculated as a percentage of the number of events to the total anesthesia cases. Logistic regression analysis was performed to examine factors affecting IOH. RESULTS: Eleven thousand two hundred ten cases out of 13,226 adult patients were included in the analysis. We found moderate to very severe hypotension occurred in 86.3% of the patients for at least 1 to 5 min, and 48.5% experienced severe or very severe hypotension. The results of the logistic regression analysis indicated female gender, vascular surgery, American Society of Anesthesiologists physical status classification (ASA-PS) 4 or 5 in emergency surgery, and the combination with the epidural block (EDB) were significant factors of IOH. CONCLUSIONS: IOH during general anesthesia was very frequent in the Japanese population. Female gender, vascular surgery, ASA-PA 4 or 5 in emergency surgery, and the combination with EDB were independent risk factors associated with IOH. However, the association with patient outcomes were not elucidated.

Chiral sensing using an achiral europium(III) complex by induced circularly polarized luminescence.

[Eu(bda)(2)](-) (bda = 2,2'-bipyridine-6,6'-dicarboxylic acid) produces intense circularly polarized luminescence (CPL) in aqueous solutions in the presence of (S)-2-pyrrolidone-5-carboxylic acid upon UV irradiation, although the molecular structure of the europium(III) complex is achiral. The mechanism for the induction of CPL was preliminarily attributed to distortions induced by association with an amino acid to generate chirality in the achiral complex. The optical anisotropy factor (g(lum) value) for the (5)D(0) → (7)F(1) transition was 0.03 in the presence of 1.0 mol dm(-3) of the amino acid. Analysis of the CPL intensity as a function of the amino acid concentration gave an association constant between those of [Eu(bda)(2)](-) and the amino acid, K(aso) = 0.55 ± 0.09 mol(-1) dm(3). These results demonstrate the potential of [Eu(bda)(2)](-) to act as a luminescent chiral-sensing reagent in microscopic spectroscopy.

Evaluation of the effect of apixaban using a viscoelastic coagulation assay with Russell's viper venom reagent.

BACKGROUND: Conventional coagulation tests, such as prothrombin time and activated partial thromboplastin time, are not sensitive to anticoagulation by apixaban. We evaluated the antithrombotic effect of apixaban using a Russell viper venom (RVV) test for a patient who underwent posterior spine fusion surgery. CASE PRESENTATION: An 84-year-old man was scheduled for percutaneous posterior spine fusion. He continued apixaban until the night before surgery and resumed it on the first day after surgery. We performed an RVV test as point-of-care coagulation monitoring in combination with chromogenic anti-activated factor X (anti-Xa) activity, prothrombin time, and activated partial thromboplastin time. Clotting time with the RVV test was prolonged according to the anti-Xa activity of apixaban, which was in the therapeutic range during surgery. CONCLUSIONS: An RVV test might be useful as a point-of-care assay for estimation of the anti-Xa level induced by apixaban during the perioperative period.

In vitro selection and characterization of DNA aptamers specific for phospholamban.

Calcium transport across the membrane of the sarcoplasmic reticulum (SR) plays an important role in the regulation of heart muscle contraction and relaxation. The sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA) 2a is responsible for Ca(2+) up-take by this organelle and is inhibited in a reversible manner by phospholamban, another SR membrane protein. Thus, alleviation of phospholamban-mediated inhibition of SERCA2a is a potential therapeutic option for heart failure and cardiomyopathy. We have now applied the systematic evolution of ligands by exponential enrichment protocol to a library of single-stranded DNA molecules containing a randomized 40-nucleotide sequence to isolate aptamers that bind phospholamban. One of the obtained aptamers, designated Apt-9, was found to specifically bind to the cytoplasmic region of phospholamban in vitro with high affinity (dissociation constant, approximately 20 nM). Apt-9 increased the Ca(2+)-dependent ATPase activity of cardiac SR vesicles but not that of SR vesicles from skeletal muscle in a concentration-dependent manner. It also shifted the Ca(2+) concentration-response curve for this ATPase activity to the left. These effects of Apt-9 were not mimicked by an oligonucleotide with a scrambled version of the Apt-9 sequence. Thus, our results indicate that Apt-9 activates SERCA2a by alleviating the inhibitory effect of phospholamban on this ATPase, and they suggest that phospholamban-specific aptamers warrant further investigation as potential therapeutic agents for heart failure and cardiomyopathy.

A case of reversible ventricular tachycardia and complete atrioventricular block associated with primary cardiac B-cell lymphoma.

We report a long-term survival case of primary cardiac lymphoma with reversible ventricular tachycardia (VT) and complete atrioventricular block (C-AVB). A 65-year-old man with VT was treated by oral amiodarone administration. Later, a dual-chamber pacemaker was implanted because of C-AVB. Then, he was readmitted, as he complained of fever and chest pain. Echocardiography showed an enlarged cardiac mass and thus an open-chest biopsy was performed. He was then diagnosed with primary cardiac lymphoma. The chemotherapy and radiotherapy resulted in the disappearance of the mass. Complete remission has been maintained for 8 years after the therapy, and no VT or C-AVB has been detected.

Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease-Activated Receptor Pathway.

Background An enhanced renin-angiotensin system causes hypertensive renal damage. Factor Xa not only functions in the coagulation cascade but also activates intracellular signaling through protease-activated receptors ( PAR ). We investigated the effects of rivaroxaban, a factor Xa inhibitor, on hypertensive renal damage in hypertensive mice overexpressing renin (Ren-TG). Methods and Results The 12- to 16-week-old Ren-TG and wild-type mice were orally administered with or without 6 or 12 mg/kg of rivaroxaban for 1 or 4 months. Plasma factor Xa was significantly increased in the Ren-TG compared with the wild-type mice and was reduced by 12 mg/kg of rivaroxaban ( P<0.05). Urinary albumin excretion (UAE) was higher in the nontreated 8-month-old Ren-TG than in the wild-type mice (69.6±29 versus 20.1±8.2 µg/day; P<0.01). Treatment with 12 mg/kg of rivaroxaban for 4 months decreased the UAE to 38.1±13.2 µg/day ( P<0.01). Moreover, rivaroxaban treatment attenuated histologic changes of glomerular hypertrophy, mesangial matrix expansion, effacement of the podocyte foot process, and thickened glomerular basement membrane in the Ren-TG. The renal expression of PAR -2 was increased in the Ren-TG, but was inhibited with rivaroxaban treatment. In vitro study using the human podocytes showed that the expressions of PAR -2 and inflammatory genes and nuclear factor--κB activation were induced by angiotensin II stimulation, but were inhibited by rivaroxaban. PAR -2 knockdown by small interfering RNA also attenuated the PAR -2-related inflammatory gene expressions. Conclusions These findings indicate that rivaroxaban exerts protective effects against angiotensin II-induced renal damage, partly through inhibition of the PAR -2 signaling-mediated inflammatory response.

Physicochemical and pharmacokinetic characterization of water-soluble Coenzyme Q(10) formulations.

Coenzyme Q(10) (CoQ(10)) has been used as a drug for chronic heart failure. Furthermore, various biological effects of CoQ(10) have also been applied for food supplements and cosmetics. However, CoQ(10) was found to be poorly soluble in water, so that its bioavailability was low and variable depending on food intake. In the present investigation, a novel liquid (nano-emulsion, NE) and water-soluble powder formulations, including cyclodextrin-Q10 complex (CoQ(10)-CD) and dry-emulsion (DE), were prepared. The physicochemical properties of each formulation were characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM), powder X-ray diffractometry (PXRD), and differential scanning calorimetry (DSC). In all powder formulations prepared, CoQ(10) existed mainly as an amorphous form as determined by PXRD and DSC, and each powder formulation exhibited high solubility and dispersibility in water resulting in the formation of a nano-sized emulsion (NE; 60nm) and micron sized particles (DEs and CoQ(10)-CD; 0.77-2.4microm). The pharmacokinetic study of each dosage form, in comparison to a CoQ(10) crystal suspension, was also carried out in rats after a single oral dose. Although similar kinetic values were seen with T(max) of 1.5 and 1.7h, respectively, for NE and crystalline CoQ(10), NE exhibited ca 1.7-fold higher AUC and C(max) than the crystalline CoQ(10).