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.

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5-HT4 receptor agonist, cisapride, was widely used for the treatment of upper gastrointestinal diseases, but was withdrawn from the market because of arrhythmia with QT prolongation.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.

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.

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.

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.

Bundle branch re-entry ventricular tachycardia in a patient with myotonic dystrophy.

Bundle branch re-entry (BBR)-ventricular tachycardia (VT) is relatively rare with an incidence of about 6% in sustained monomorphic VT series. However, physicians unexpectedly encounter it in clinical practice. BBR-VT is associated with serious hemodynamic decompensation, and the clinical presentation in approximately 75% of patients with inducible BBR-VT is syncope or cardiac sudden death. Thus, precise mapping of His-Purkinje and bundle branch potentials is necessary for an accurate diagnosis and treatment of re-entrant mechanisms especially for BBR-VT. However, simultaneous recording of both the left-bundle (LB) and right-bundle (RB), as well as His-bundle (HB), potentials is often difficult during tachycardia. Here we report the clear documentation of the activation sequence of the His-Purkinje system during BBR-VT, which could be readily and completely treated by radiofrequency catheter ablation in a myotonic dystrophy patient.

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.

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.

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.

Waist circumference is the main determinant of elevated C-reactive protein in metabolic syndrome.

BACKGROUND: Metabolic syndrome (MetS) is known to increase the risk of cardiovascular disease. C-reactive protein (CRP) has been reported to be elevated in subjects with MetS. However, which component of MetS contributes mostly to the elevation has not been studied in detail. METHODS: We studied 628 apparently healthy Japanese subjects (men 262, women 366, age 19-85 years). Body mass index, waist circumference (WC), blood pressure, lipids, glucose, insulin and CRP were measured. MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III report. RESULTS: In partial correlation analysis, WC showed the strongest correlation with CRP among the variables related to MetS. CRP increased as the number of MetS components increased. The mean CRP value adjusted for demographic variables was higher in subjects with MetS than those without MetS, and further adjustments with variables related to MetS revealed that the significant difference between the two groups disappeared only when further adjustment was made for WC. In multiple linear regression analysis, the independent variable that most strongly explained the CRP level was WC, which was followed by HDL-cholesterol. Finally, comparison of the CRP levels in groups stratified by abdominal obesity and the number of MetS components revealed that those with abdominal obesity tended to show higher CRP levels compared with those without abdominal obesity regardless of the number of MetS components other than WC. CONCLUSIONS: Subjects with MetS showed higher levels of CRP and the main determinant of the CRP elevation was WC.

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.

Effects of ultrasound energy application on cardiac performance in open-chest Guinea pigs.

BACKGROUND: Although ultrasound (US) is widely used in cardiology, little is known about the effects of US energy on cardiac performance. This study aimed to investigate the mechanical effects of high-intensity continuous US energy (1.0 MHz with 3 different intensities) on cardiac performance. METHODS AND RESULTS: Either left ventricular (LV) pressure or aortic blood flow (ABF) was evaluated in open-chest guinea pigs (n=30) under surface ECG monitoring. LV systolic pressure and ABF increased significantly (ie, maximum percent increases in these parameters were 2.5%, 3.1% and 7.1% for LV systolic pressure and 9.4%, 4.9% and 8.8% for mean ABF at intensities of 0.06, 0.67 and 2.90 W/cm2, respectively). LV end-diastolic pressure was reduced significantly by US (5.3+/-0.9 to 4.8+/-0.8, 5.5 +/-1.3 to 4.8+/-1.0 and 5.8+/-2.0 to 5.0+/-1.2 mmHg, respectively), indicating positive inotropic and lusitropic effects and resultant ABF augmentation. Local temperature was not significantly changed. ECG showed neither chronotropic action nor arrhythmogenesis. CONCLUSIONS: Although the basic mechanisms of these phenomena remain unclear, this pilot study of the short-term effects of US energy on cardiac performance suggests the possibility of physical therapy for heart failure.

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.

[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.

A unipolar coronary sinus mapping study of patients with left-sided atrioventricular accessory pathways.

So-called unipolar 'PQS pattern' is widely accepted as a hallmark of successful catheter ablation of the left-sided atrioventricular accessory pathway. However, the unipolar nature of the electrogram and the site-dependent appearance of this characteristic pattern are poorly understood. Therefore, unipolar coronary sinus (CS) mapping was performed using a multipolar fine electrode in patients with Wolff-Parkinson-White (WPW) syndrome associated with an antegrade left-sided accessory pathway (case group) and those with a concealed left-sided accessory pathway or atrioventricular nodal reentrant tachycardia (control group) under sinus rhythm and fixed high right atrial, CS ostial, and distal pacing. In both groups, the unipolar CS atrial electrogram showed intrinsic negative deflection (initial positive followed by negative parts) with considerable variation depending on the recording site. This unipolar configuration of the atrial electrogram was not influenced by different activation sequences during pacing at various sites. The case group exhibited a unipolar 'PQS pattern' at successful ablation sites for the left lateral to anterolateral accessory pathway. However, this was not true for the left posteroseptal accessory pathway, possibly because the negative part of the atrial electrogram distorted the 'PQS pattern' as an intervening dip. In conclusion, the site-dependent variations of the unipolar CS atrial electrogram underlie the limited usefulness of the 'PQS pattern' in left posteroseptal accessory pathway localization.

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.

Successful treatment of tachycardia-induced cardiomyopathy with LVAD in a 12-year-old boy.

Tachycardia-induced cardiomyopathy is an unusual cardiac disease that is life-threatening if tachycardia is not controlled. We report a 12-year-old boy who suffered from ectopic left atrial tachyarrhythmia that was refractory to medications and caused tachycardia-induced cardiomyopathy with severe heart failure. The patient required a left ventricular assist device (ABIOMED BVS5000 [ABIOMED Inc, Danvers, MA]) as a bridge to recovery. Tachycardia was finally controlled with flecainide while the patient was on left ventricular assist device support. The device was successfully explanted after 28 days of support. The temporary use of a left ventricular assist device was necessary to maintain a good hemodynamic status during the treatment of pharmacological refractory tachycardia, and it allowed a successful bridge to recovery.