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In order to bridge the gap of information between the in silico model and human subjects, we evaluated torsadogenic risk of cisapride, dl -sotalol, bepridil and verapamil selected from 12 training compounds in the comprehensive in vitro proarrhythmia assay using the chronic atrioventricular block monkeys. Cisapride (0, 1, and 5 mg/kg, n  = 5 for each dose), dl -sotalol (0, 1, 3, and 10 mg/kg, n  = 5 for each dose), bepridil (0, 10, and 100 mg/kg, n  = 4 for each dose), verapamil (0, 1.5, 15, and 75 mg/kg, n  = 4 for each dose) were orally administered to the monkeys in conscious state. Five mg/kg of cisapride, 1, 3, and 10 mg/kg of dl -sotalol and 100 mg/kg of bepridil prolonged ΔΔQTcF, which was not observed by verapamil. Torsade de pointes was induced by 5 mg/kg of cisapride in 2 out of 5 animals, by 10 mg/kg of dl -sotalol in 5 out of 5 and by 100 mg/kg of bepridil in 2 out of 4, which was not induced by verapamil. These torsadogenic doses were normalized by their maximum clinical daily ones to estimate torsadogenic risk. The order of risk was dl -sotalol >bepridil ≥cisapride >verapamil in our study. Since the order was bepridil ≥ dl -sotalol >cisapride >verapamil in comprehensive in vitro proarrhythmia assay (CiPA) in silico mechanistic model validation, sympathetic regulation on the heart may play a pivotal role in the onset of torsade de pointes in vivo. [ABSTRACT FROM AUTHOR]

Oseltamivir has been shown to prolong the atrial conduction time and effective refractory period, and to suppress the onset of burst pacing-induced atrial fibrillation in vitro. To better predict its potential clinical benefit as an anti-atrial fibrillatory drug, we performed translational studies by assessing in vivo anti-atrial fibrillatory effect along with in vivo and in vitro electropharmacological analyses. Oseltamivir in intravenous doses of 3 (n = 6) and 30 mg/kg (n = 7) was administered in conscious state to the persistent atrial fibrillation model dogs to confirm its anti-atrial fibrillatory action. The model was prepared by tachypacing to the atria of chronic atrioventricular block dogs for > 6 weeks. Next, oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously administered to the halothane-anesthetized intact dogs to analyze its in vivo electrophysiological actions (n = 4). Finally, its in vitro effects of 10–1,000 μM on IK,ACh, IKur, IKr, INa and ICaL were analyzed by using cell lines stably expressing Kir3.1/3.4, KV1.5, hERG, NaV1.5 or CaV1.2, respectively (n = 3 for IK,ACh and IKr or n = 6 for IKr, INa and ICaL). Oseltamivir in doses of 3 and 30 mg/kg terminated the atrial fibrillation in 1 out of 6 and in 6 out of 7 atrial fibrillation model dogs, respectively without inducing any lethal ventricular arrhythmia. Its 3 and 30 mg/kg delayed inter-atrial conduction in a frequency-dependent manner, whereas they prolonged atrial effective refractory period in a reverse frequency-dependent manner in the intact dogs. The current assay indicated that IC50 values for IK,ACh and IKr were 160 and 231 μM, respectively, but 1,000 µM inhibited INa, ICaL and IKur by 22, 19 and 13%, respectively. The extent of INa blockade was enhanced at faster beating rate and more depolarized resting membrane potential. Oseltamivir effectively terminated the persistent atrial fibrillation, which may be largely due to the prolongation of the atrial effective refractory period and inter-atrial conduction time induced by IK,ACh and IKr inhibitions along with INa suppression. Thus, oseltamivir can exert a powerful anti-atrial fibrillatory action through its ideal multi-channel blocking property; and oseltamivir would become a promising seed compound for developing efficacious and safe anti-atrial fibrillatory drugs. [ABSTRACT FROM AUTHOR]

Non-bacterial thrombotic endocarditis (NBTE) is a condition that results in the development of vegetation on cardiac valves that are devoid of inflammation and bacteria. We herein report a 60-year-old man who transferred to our hospital because of a systemic embolism and heart failure. A mass in the right atrium and vegetation on the mitral valve were observed. He was first diagnosed with infectious endocarditis according to the Duke criteria. During treatment, however, the patient was diagnosed with antiphospholipid syndrome and cancer. After 4 weeks of antibacterial therapy, the patient underwent open chest surgery, and the postoperative histological diagnosis was NBTE.

Background: Effects of rapid electrical defibrillation and β-blockade on coronary ischemia/reperfusion-induced ventricular fibrillation (VF) during cardiopulmonary resuscitation (CPR) remain unknown.Methods and Results:After induction of VF by 30 min of ischemia followed by reperfusion, animals were treated with defibrillation alone (Group A, n=13), 2 min of open-chest cardiac massage followed by defibrillation (Group B, n=11), or the same therapy to Group B with propranolol (1 mg/kg, i.v.) treatment before ischemia/reperfusion (Group C, n=11). If return of spontaneous circulation (ROSC) was not attained, each therapy was repeated ≤3 times (Set-1). When ROSC was not obtained within Set-1, cardiac massage was applied to all animals followed by defibrillation, which was repeated ≤3 times (Set-2). ROSC after Set-1 was 8% in Group A, 82% in Group B and 82% in Group C, whereas that after Set-2 was 62% in Group A, 100% in Group B and 82% in Group C. Each animal with ROSC in Groups A (n=8) and B (n=11) showed sinus rhythm, whereas those in Group C (n=9) had sinus rhythm (n=5), atrial fibrillation (n=1), accelerated idioventricular rhythm (n=2) and atrioventricular block (n=1). Post ROSC heart rate and mean arterial pressure were significantly lower in Group C., Conclusions: Cardiac massage increased the likelihood of ROSC vs. rapid defibrillation, but β-blocker pretreatment may worsen hemodynamics and electrical stability after ROSC.

Contractility of the human heart increases as its beating rate is elevated, so-called positive force-frequency relationship; however, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been reported to exert a negative force-frequency relationship. We tested the hypothesis that the regulation of motion directions by electrical pacing and/or oxygen supply may improve the electro-mechanical properties of hiPSC-CMs monolayers. To better evaluate the spatial and temporal relationship between electrical excitation and contractile motion, we simultaneously observed the field potential and motion vector of hiPSC-CMs sheets. Under spontaneous contraction, although an electrical excitation originating from a region propagated unidirectionally over the cell sheet, contraction wave started from multiple sites, and relaxation wave was initiated from a geometric center of hiPSC-CMs sheet. During electrical pacing, contraction and relaxation waves were propagated from the stimulated site. Interestingly, the maximum contraction speed was more increased when the hiPSC-CMs sheet was stimulated at an area relaxation initiated under spontaneous condition. Furthermore, motion vector analysis demonstrated that "positive contraction velocity-frequency relationship" in contraction and "frequency-dependent enhancement of relaxation" were produced in the cell sheet by optimizing the direction and order of the contractile motion with pacing at the relaxation-initiating area. A close analysis of motion vectors along with field potential recording demonstrated that relaxation process consists of fast and slow phases, and suggest that intracellular Ca 2+ dynamics may be closely related to functions of Ca 2+ -ATPase pump and Na + -Ca 2+ exchangers. Namely, the slow relaxation phase occurred after the second peak of field potential, suggesting that the slow phase may be associated with extrusion of Ca 2+ by Na + -Ca 2+ exchangers during repolarization. Increase of oxygen concentration from 20 to 95% as well as β-adrenergic stimulation with isoproterenol accelerated the fast relaxation, suggesting that it could depend on Ca 2+ uptake via Ca 2+ -ATPase during the depolarization phase. The ratio of maximum contraction speed to field potential duration was increased by the β-adrenergic stimulation, indicating the elevated contraction efficiency per Ca 2+ -influx. Thus, these findings revealed potential ability of conventional monolayers of hiPSC-CMs, which will help apply them to translational study filling the gap between physiological as well as pharmacological studies and clinical practice., (Copyright © 2020 Izumi-Nakaseko, Chiba, Hagiwara-Nagasawa, Satsuka, Goto, Nunoi, Kambayashi, Matsumoto, Takei, Kanda, Naito and Sugiyama.)