SARS-CoV-2 Seroprevalence among Healthcare Workers in General Hospitals and Clinics in Japan.

Coronavirus disease 2019 (COVID-19) has become a serious public health problem worldwide. In general, healthcare workers are considered to be at higher risk of COVID-19 infection. However, the prevalence of COVID-19 among healthcare workers in Japan is not well characterized. In this study, we aimed to examine the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies among 2160 healthcare workers in hospitals and clinics that are not designated to treat COVID-19 patients in Japan. The prevalence of SARS-CoV-2 immunoglobulin G was 1.2% in August and October 2020 (during and after the second wave of the pandemic in Japan), which is relatively higher than that in the general population in Japan (0.03-0.91%). Because of the higher risk of COVID-19 infection, healthcare workers should be the top priority for further social support and vaccination against SARS-CoV-2.

Safety, Tolerability, and Pharmacokinetics of Adrenomedullin in Healthy Males: A Randomized, Double-Blind, Phase 1 Clinical Trial.

BACKGROUND: Adrenomedullin (AM), an endogenous vasodilative peptide, has immunomodulative effects and acts as an accelerator of mucosal regeneration in the digestive tract. AM has shown beneficial effects in rodent models of inflammatory bowel disease and patients with ulcerative colitis. The present study aimed to evaluate the pharmacodynamic properties and safety of AM in healthy male adults in a phase 1 clinical trial. METHODS: This phase 1, randomized, double-blind, single-center study was conducted on healthy males aged 20-65 years. Subjects received either a placebo, 3 ng/kg/min AM, 9 ng/kg/min AM, or 15 ng/kg/min AM via continuous 12-h intravenous infusion. Other subjects received either placebo or 15 ng/kg/min AM for 8 h per day for 7 days. Adverse events (AEs), vital signs, physical examinations, laboratory tests, electrocardiograms (ECG), and pharmacokinetics were assessed. FINDINGS: All 24 subjects in the single-dose test completed the study. Of the 12 subjects in multiple dosing test, one from the AM group withdrew owing to a headache. No serious AEs were reported. Hemodynamic parameters were well maintained in all subjects. Slight ECG abnormalities were observed in the single-dose test. The plasma concentration of AM progressively increased in a dose-dependent manner and reached Cmax at the end of administration. Plasma AM rapidly returned to baseline concentrations after termination, with a T1/2 of under 60 min. INTERPRETATION: This is the first phase 1 trial in healthy men evaluating the safety of AM. Our results demonstrate the safety and tolerability of AM for subsequent Phase 2 trials.

Thorough QT/QTc Study Shows That a Novel 5-HT4 Receptor Partial Agonist Minesapride Has No Effect on QT Prolongation.

Minesapride (drug code: DSP-6952) is a potential gastrointestinal prokinetic agent with high selectivity for 5-hydroxytryptamine 4 (5-HT4 ) receptor that acts as a partial agonist. Although 5-HT4 receptor agonists are expected to show efficacy in patients with irritable bowel syndrome with constipation, only tegaserod is available for female patients, with limitations, in the United States. Previously, another 5-HT4 receptor agonist, cisapride, was widely used for the treatment of upper gastrointestinal diseases, but was withdrawn from the market because of arrhythmia with QT prolongation. Chemically, benzamide is one of the most common structures among 5-HT4 receptor agonists. Some benzamide derivatives, such as cisapride, are responsible for QT prolongation, while some, such as mosapride, are not. Thus, we planned a thorough QT/QTc study to investigate the effects of minesapride, a newly designed benzamide derivative, on the QT/QTc. This was a randomized, placebo-controlled, 4-arm, 4-period, crossover study conducted in healthy adults, with administration of single oral doses of minesapride (40 mg and 120 mg), placebo, and moxifloxacin in the fasted state. Minesapride and placebo were administered in a double-blind fashion, while the positive control moxifloxacin was administered in an open-label fashion. Japanese subjects (48 total: 24 males and 24 females) were randomized, and 47 subjects completed all treatment periods. A review of other electrocardiographic data revealed that neither therapeutic (40 mg) nor supratherapeutic (120 mg) doses of minesapride were associated with increased risk of prolonged QT interval.

Radio-frequency catheter ablation of atypical atrioventricular nodal reentrant tachycardia from a trans-aortic approach.

Radio-frequency catheter ablation (RFCA) was introduced for the treatment of reentrant tachyarrhythmias and has proven its usefulness, efficacy, and safety. It has gained the position of an early stage treatment option rather than being a 'last resort' option for certain groups of patients with supraventricular tachycardias including atrioventricular nodal reentrant tachycardia (AVNRT). The RFCA technique for AVNRT seems to have become established throughout these years and the right-side approach is considered to be the conventional method. However, in one percent of the patients with AVNRT it has been reported that they cannot be cured by the conventional method and a left-sided approach has been recommended. We experienced a case which presented with a fast/slow atypical AVNRT. We ultimately successfully treated the case with a left-sided (trans-aortic) RFCA approach. We believe the trans-aortic RFCA approach is a necessary alternative in the case of an unsuccessful RFCA via the right-sided approach even though the frequency of its need is very low.

Augmentation of pulmonary vein backflow velocity during left atrial contraction: a novel phenomenon responsible for progression of atrial fibrillation in hypertensive patients.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia showing disease progression. However, echocardiographic prediction of such progression remains incomplete. This study aimed to identify echocardiographic predictors of AF progression in hypertensive patients. METHODS: Hypertensive patients with paroxysmal AF were divided into two groups: patients with AF which became permanent (group A; n = 13) and those with AF which remained paroxysmal (group B; n = 46) during the same follow-up period (8.0 +/- 2.4 years). Clinical baselines showed no significant differences except for age. Transthoracic echocardiography was recorded 1-2 weeks after termination of the first-detected paroxysms of AF. RESULTS: Echocardiography showed greater left atrial (LA) dimension (p = 0.023) and late diastolic pulmonary vein (PV) backflow velocity (p < 0.001), and a lower LA fractional shortening (p = 0.008) in group A than in group B. Multilogistic regression analysis demonstrated that augmented PV backflow (p = 0.007) and reduced LA fractional shortening (p = 0.032) were independent predictors of the progression of AF. The receiver-operating characteristic curve demonstrated that PV backflow augmentation is the best predictor of future AF perpetuation. CONCLUSION: PV backflow leading to cyclic stretching of PV musculature contributes to AF progression.

Systemic chemotherapy of TS-1 and cisplatin for gastric signet-ring cell carcinoma presenting as cardiac tamponade.

A 59-year-old man complaining of dyspnea, anterior chest oppression, and hypotension was diagnosed to have cardiac tamponade due to massive pericardial effusion. A cytological analysis of the pericardial effusion disclosed adenocarcinoma. An endoscopic study revealed gastric cancer in the lesser curvature wall of the middle body of the stomach, and signet-ring cell carcinoma was confirmed histologically. The gastric cancer was complicated by malignant pericardial effusion, and metastasis to the mediastinal lymph nodes. The patient was treated with pericardiocentesis followed by systemic chemotherapy consisting of TS-1 and cisplatin (CDDP). After 5 months, pericardial effusion disappeared and the primary gastric tumor decreased in size. Our experience suggests that the systemic chemotherapy of TS-1 and CDDP may be effective for controlling advanced gastric signet-cell carcinoma accompanied by malignant pericardial effusion.

The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis.

The Polycomb-group (PcG) gene Rae28 is a mammalian homologue of the Drosophila gene polyhomeotic. PcG genes are known to maintain transcription states, once initiated, probably by regulating chromatin structure. Since homozygous Rae28-deficient (Rae28(-/-)) mice displayed cardiac anomalies similar to congenital heart diseases in humans, we examined the role of Rae28 in cardiac morphogenesis at the molecular level. In Rae28(-/-) embryos, expression of the cardiac selector gene Nkx2.5/Csx (Nkx2.5) was initiated properly but was not sufficiently sustained later in development. This impaired expression of Nkx2.5 in the maintenance phase proved to have a crucial effect on cardiac morphogenesis, as demonstrated by the results of a genetic complementation experiment in which the cardiac anomalies were suppressed by overexpression of human NKX2.5/CSX1 in Rae28(-/-) embryos. Ubiquitous expression of exogenous Rae28 likewise restored the impaired Nkx2.5 expression in Rae28(-/-) embryos, further supporting the notion that Rae28 sustains Nkx2.5 expression in cardiomyocytes. Thus, our data show that a mammalian PcG gene can play a key role in organogenesis by helping to maintain the expression of a selector gene.

Purified human hematopoietic stem cells contribute to the generation of cardiomyocytes through cell fusion.

To obtain insights into the cardiomyogenic potential of hematopoietic tissue, we intravenously (i.v.) injected purified hematopoietic stem/progenitor cells into newborn recipients that may fully potentiate the developmental plasticity of stem cells. Transplantation of mouse bone marrow (BM) lineage antigen-negative (Lin-) cells resulted in the generation of the cells that displayed cardiomyocyte-specific antigenic profiles and contractile function when transplanted into syngeneic newborn recipients. To clarify the mechanism underlying the cardiomyogenic potential, green fluorescent protein (GFP)-labeled BM Lin-ScaI+ hematopoietic progenitors were transplanted into neonatal mice constitutively expressing cyan fluorescence protein (CFP). Lambda image acquisition and linear unmixing analysis using confocal microscopy successfully separated GFP and CFP, and revealed that donor GFP+ cardiomyocytes coexpressed host-derived CFP. We further reconstituted human hemopoietic- and immune systems in mice by injecting human cord blood (CB)-derived Lin-CD34+CD38- hematopoietic stem cells (HSCs) into neonatal T cell(-)B cell(-)NK cell- immune-deficient NOD/SCID/IL2rgamma(null) mice. Fluoroescence in situ hybridization analysis of recipient cardiac tissues demonstrated that human and murine chromosomes were colocalized in the same cardiomyocytes, indicating that cell fusion occurred between human hematopoietic progeny and mouse cardiomyocytes. These syngeneic- and xenogeneic neonatal transplantations provide compelling evidence that hematopoietic stem/progenitor cells contribute to the postnatal generation of cardiomyocytes through cell fusion, not through transdifferentiation.

Case of paroxysmal atrial fibrillation improved after the administration of proton pump inhibitor for associated reflux esophagitis.

A 64-year-old man had demonstrated palpitations caused by paroxysmal atrial fibrillation (AF) documented by ambulatory electrocardiographic monitoring. Effectiveness of antiarrhythmic agent (disopyramide: 300 mg/day) was limited. Based on the gastrointestinal endoscopic findings, proton pump inhibitor (PPI: rabeprazole, 10 mg/day) was administered to eliminate heart burn due to reflux esophagitis. Symptoms of paroxysmal AF and reflux esophagitis were confusing due to the anatomical proximity of the diseased organs and concomitant occurrence in the evening and when in a supine position. After the additional PPI therapy, not only was reflux esophagitis improved subjectively and endoscopically but also paroxysms of AF markedly reduced. Because esophagus is attached to left atrial posterior wall and the role of inflammatory process on the development of AF is highlighted, amelioration of reflux esophagitis by PPI may have been followed by the remarkable reduction of paroxysms of AF.

Recapitulation of Clinical Individual Susceptibility to Drug-Induced QT Prolongation in Healthy Subjects Using iPSC-Derived Cardiomyocytes.

To predict drug-induced serious adverse events (SAE) in clinical trials, a model using a panel of cells derived from human induced pluripotent stem cells (hiPSCs) of individuals with different susceptibilities could facilitate major advancements in translational research in terms of safety and pharmaco-economics. However, it is unclear whether hiPSC-derived cells can recapitulate interindividual differences in drug-induced SAE susceptibility in populations not having genetic disorders such as healthy subjects. Here, we evaluated individual differences in SAE susceptibility based on an in vitro model using hiPSC-derived cardiomyocytes (hiPSC-CMs) as a pilot study. hiPSCs were generated from blood samples of ten healthy volunteers with different susceptibilities to moxifloxacin (Mox)-induced QT prolongation. Different Mox-induced field potential duration (FPD) prolongation values were observed in the hiPSC-CMs from each individual. Interestingly, the QT interval was significantly positively correlated with FPD at clinically relevant concentrations (r > 0.66) in multiple analyses including concentration-QT analysis. Genomic analysis showed no interindividual significant differences in known target-binding sites for Mox and other drugs such as the hERG channel subunit, and baseline QT ranges were normal. The results suggest that hiPSC-CMs from healthy subjects recapitulate susceptibility to Mox-induced QT prolongation and provide proof of concept for in vitro preclinical trials.

Cholesterol embolization treated with corticosteroids--two case reports.

Cholesterol embolization (CE) is a potentially serious complication associated with invasive arterial maneuvers, in which standard therapy has not been established. We experienced two cases of CE in patients with severe atherosclerosis whose renal function deteriorated within a few months after invasive arterial maneuvers. CE was confirmed either by renal biopsy (case 1) or skin biopsy (case 2). Oral administration of prednisolone at a daily dose of 30 mg (0.4 mg/kg) was effective to improve their renal function. Our observation suggests that corticosteroid therapy may be beneficial in some patients with CE.

[A case of metabolic syndrome with coronary artery disease advanced over 13 years. Case report].

A 61-year-old man was diagnosed with obesity, diabetes mellitus, and hyperlipidemia associated with insulin resistance in 1988. His condition was complicated with asymptomatic coronary artery disease in 1992. His coronary artery disease gradually progressed during the subsequent 13 years of observation, and he underwent percutaneous coronary intervention four times and also received a coronary artery bypass graft. This is a case of metabolic syndrome with multiple risk factors for arteriosclerosis as visceral obesity, insulin resistance, diabetes, hypertension and hyperlipidemia, in which the recent rapid progression of coronary artery disease might be associated with the discontinuation of statin after coronary artery bypass graft, accompanied with hyper-LDL-choleterolemia. Patients with metabolic syndrome require most comprehensive and strict therapies against multiple risk factors.

Bezold-Jarisch-like reflex during Brockenbrough's procedure for radiofrequency catheter ablation of focal left atrial fibrillation: report of two cases.

Brockenbrough's puncture technique has been widely conducted in the electrophysiologic laboratory. We report here two cases exhibiting a rare complication of this procedure, which arose during the conduct of catheter ablation using radiofrequency energy delivered to the pulmonary vein for the treatment of focal left atrial fibrillation. These cases exhibited marked sinus bradycardia and profound hypotension, suggestive of a Bezold-Jarisch-like reflex, observed immediately after Brockenbrough's procedure but before radiofrequency application. ST elevation in the inferior leads was also observed in spite of normal coronary angiograms. This unanticipated transient complication was treated by intravenous administration of atropine, which had no influence on the ablation procedure or prognosis. This is speculated to be attributable to the elevation of vagal tone caused by the mechanical effects of transseptal puncture on the interatrial vagal network.

Reentrant atrial tachycardia originating from the superior vena cava.

A 52-years old man with a previous pericardiotomy for idiopathic constrictive pericarditis underwent catheter ablation for drug-resistant atrial tachycardia (AT). The mechanism of the AT was considered as reentry because of resetting response and the entrainment phenomenon during AT. We introduced a 64-electrode basket catheter into the superior vena cava (SVC) during AT to obtain precise mapping. A fractionated potential preceding local atrial electrogram was recorded in the SVC. The earliest activation site of the potential was located at the anterior aspect of the SVC, 2 cm above the SVC-right atrium junction determined fluoroscopically. The fractionated potential at this site preceded the onset of the P wave by 115 msec. Radiofrequency catheter ablation at this site eliminated the tachycardia. At 6 months follow-up, the patient is free of AT. Reentrant AT involving the SVC is a candidate of RF ablation. Multielectrode basket catheter is useful for a detailed mapping of the SVC.

Recurrence of cervical carcinoma manifesting as cardiac metastasis three years after curative resection.

We report a rare case of cardiac metastasis from carcinoma of the uterine cervix. A 58-year-old woman presented with multiple pulmonary emboli, disseminated intravascular coagulation, and right heart failure 43 months after a curative resection of cervical carcinoma (stage IB1). Transthoracic echocardiography and computed tomography revealed large tumors in the right ventricle and right main pulmonary artery. No evidence of recurrence was obtained in the pelvis and abdomen. Surgical removal of the tumors remarkably improved her general condition, which had been declining progressively. The patient declined further treatment, including adjuvant chemotherapy, and was followed in the outpatient clinic. The right ventricular tumor recurred 4 months later and she died of heart failure. The possibility of late recurrence of cervical carcinoma in the heart should be considered even after curative resection.

Verapamil prevents impairment in filterability of human erythrocytes exposed to oxidative stress.

Effects of oxidative stress on intact human erythrocytes were investigated using tert-butyl hydroperoxide (tBHP). Exposure of erythrocytes to tBHP caused a marked decrease in filterability in a time-dependent manner. Erythrocytes exposed to tBHP also show an increase in mean corpuscular volume and a remarkable formation of methemoglobin (met-Hb) without any appearance of hemichromes that form Heinz bodies. High performance liquid chromatography demonstrated that the tBHP-treated erythrocytes exhibited an apparent decrease in the membrane phospholipid, phosphatidylethanolamine (PE). The decrease in PE was inhibited by pretreatment with ascorbate, but not with verapamil. SDS-polyacrylamide gel electrophoresis of the tBHP-treated erythrocyte membrane showed a degradation of spectrin, band 3, band 4.2, and band 4.5, accompanied by the appearance of low-molecular-weight products. The degradation of the membrane proteins was not prevented by pretreatment with verapamil or ascorbate. However, the pretreatment with verapamil but not with ascorbate revealed significant inhibition of the tBHP-induced impairment in filterability in the presence of extracellular Ca2+. Thus, the present study shows that verapamil, a potent drug in reperfusion therapy, plays an important role in protection against oxidative injury, based on a close linkage among decreased filterability, met-Hb formation, and impaired membrane integrity.

Surgical resection of malignant lymphoma in the right atrium after systemic chemotherapy.

A 74-year-old man was referred to us for evaluation of a tumor in the right atrium (RA). Transesophageal echocardiography (TEE) showed an unmovable 50x60 mm mass in the RA. Based on histological findings of subcutaneous tumors in the right abdominal wall, he was diagnosed as malignant lymphoma (ML), and treated with a THP-COP regimen. Upon completion of first THO-COP therapy, TEE showed marked regression of the mass and division into 3 masses, one of which showed marked floating movement with a small stalk. To prevent the risk of embolic events, surgical resection was performed. Resected tumors were necrotic tissues. Serial imaging of cardiac tumor and surgical resection is desirable to decrease the possibility of embolic complication.

Extracellular potassium dependent negative dromotropic action of nicorandil in guinea pig myocardium.

Although the antiarrhythmic action of nicorandil is drawing an increasing attention, dromotropic effect of this agent is unclear. Therefore, this was investigated by microelectrode technique to the superfused guinea pig papillary muscle to record the action potential and extracellular potential during conduction. The correlation of myocardial internal longitudinal resistance (r1) assumed to reflect the global gap junctional resistance, maximum rate of rise of the action potential upstroke (Vmax), and conduction velocity was examined under the alterations of external potassium concentrations ([K+]e; ranging from 3.0 to 12.0 mM) in the presence or absence of 100 microM nicorandil. In the minimum [K+]e, nicorandil caused significant (p < 0.05) hyperpolarization and reduction in Vmax. Negative dromotropic action of nicorandil was slight but significant (p < 0.05) in low (3.0 mM) [K+]e but was not evident in physiologic (5.4 mM) or elevated (9.0 to 12.0 mM)[K+]e. In conclusion, nicorandil exerts negative dromotropic action as [K+]e decreased, which was accounted for by the cable analysis and may contribute to the prevention of low [K+]e-induced arrhythmia.

Sick sinus syndrome disclosed by the successful radiofrequency catheter ablation of persistent common atrial flutter.

Sick sinus syndrome was disclosed in a 77 year-old man after a radiofrequency (RF) linear catheter ablation of cavotricuspid isthmus for persistent common atrial flutter. Prolongation of corrected sinus node recovery time, sinoatrial conduction time and AH interval, as observed after RF ablation, suggested binodal (sinus as well as atrioventricular node) dysfunction. Adams-Stokes syndrome due to sinus arrest was encountered on the day of RF ablation and a permanent DDD pacemaker was implanted consequently. Our experience indicates that careful observation is very important after the RF ablation when atrial flutter is associated with sick sinus syndrome. The present case suggests that binodal dysfunction underlies persistent atrial flutter and vice versa.

Evaluation of Assay Sensitivity and the Concentration-Effect Relationship of Moxifloxacin in a QT/QTc Study in Japan.

To investigate the potential for a QT/QTc study in Japan, a randomized, single-blind, crossover study was conducted using moxifloxacin in 64 healthy Japanese male volunteers. A 12-lead Holter electrocardiogram was used to test a relatively small population at each of 4 incorporated clinical research units to confirm the assay sensitivity and efficiency. Moxifloxacin (400 mg) significantly prolonged QT intervals, as previously reported, with small variations in this study. In addition, the placebo-adjusted mean QTcF changes from predose baseline showed that the lower bounds of the 1-sided 95% confidence interval exceeded 5 milliseconds at all of the clinical research units. The data also indicated statistically significant concentration-QT relationships in 3 of the 4 research units by separate analysis. These findings and the small amount of variability in this study suggest the feasibility of conducting a high-quality QT/QTc study in Japan.