PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model

Background: The phosphoinositide 3-kinase (PI3K) signaling pathway is an interesting target in cancer treatment. The awareness of the proarrhythmic risk of PI3K inhibitors was raised because PI3K is also involved in regulating signaling toward cardiac ion channels. Canine cardiomyocytes treated with PI3K inhibitors show an increased action potential duration and reduced cardiac repolarizing currents. Now, the potential proarrhythmic effect of chronic treatment of PI3K/mTOR inhibitor GSK2126458 (omipalisib) was investigated in the atrioventricular (AV) block dog model. Methods: Purpose-bred Mongrel dogs received complete AV block by ablation of the bundle of His and their hearts were paced in the right ventricular apex at VDD-mode (RVA-VDD). In this way, sinus rhythm was maintained for 15 ± 1 days and thereby bradycardia-induced cardiac remodeling was prevented. Dogs received 1 mg/kg omipalisib once (n = 3) or twice (n = 10) a day via oral administration for 7 days. Under standardized conditions (anesthesia, bradycardia at 60 beats/min, and a dofetilide challenge), potential proarrhythmic effects of omipalisib were investigated. Results: Twice daily dosing of omipalisib increased accumulative plasma levels compared to once daily dosing accompanied with adverse events. Omipalisib prolonged the QT interval at baseline and more strongly after the dofetilide challenge (490 ± 37 to 607 ± 48 ms). The arrhythmic outcome after omipalisib resulted in single ectopic beats in 30% of dogs perpetuating in multiple ectopic beats and TdP arrhythmia in 20% of dogs. Isolated ventricular cardiomyocytes from omipalisib-treated dogs showed a diminished IKs current density. Conclusion: Chronic treatment of PI3K/mTOR inhibitor omipalisib prolonged the QT interval in a preclinical model under standardized proarrhythmic conditions. Furthermore, this study showed that electrical remodeling induced by omipalisib had a mild proarrhythmic outcome

National identity predicts public health support during a global pandemic

Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = −0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics.publishedVersio

PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model

Background: The phosphoinositide 3-kinase (PI3K) signaling pathway is an interesting target in cancer treatment. The awareness of the proarrhythmic risk of PI3K inhibitors was raised because PI3K is also involved in regulating signaling toward cardiac ion channels. Canine cardiomyocytes treated with PI3K inhibitors show an increased action potential duration and reduced cardiac repolarizing currents. Now, the potential proarrhythmic effect of chronic treatment of PI3K/mTOR inhibitor GSK2126458 (omipalisib) was investigated in the atrioventricular (AV) block dog model. Methods: Purpose-bred Mongrel dogs received complete AV block by ablation of the bundle of His and their hearts were paced in the right ventricular apex at VDD-mode (RVA-VDD). In this way, sinus rhythm was maintained for 15 ± 1 days and thereby bradycardia-induced cardiac remodeling was prevented. Dogs received 1 mg/kg omipalisib once (n = 3) or twice (n = 10) a day via oral administration for 7 days. Under standardized conditions (anesthesia, bradycardia at 60 beats/min, and a dofetilide challenge), potential proarrhythmic effects of omipalisib were investigated. Results: Twice daily dosing of omipalisib increased accumulative plasma levels compared to once daily dosing accompanied with adverse events. Omipalisib prolonged the QT interval at baseline and more strongly after the dofetilide challenge (490 ± 37 to 607 ± 48 ms). The arrhythmic outcome after omipalisib resulted in single ectopic beats in 30% of dogs perpetuating in multiple ectopic beats and TdP arrhythmia in 20% of dogs. Isolated ventricular cardiomyocytes from omipalisib-treated dogs showed a diminished IKs current density. Conclusion: Chronic treatment of PI3K/mTOR inhibitor omipalisib prolonged the QT interval in a preclinical model under standardized proarrhythmic conditions. Furthermore, this study showed that electrical remodeling induced by omipalisib had a mild proarrhythmic outcome

Flotillins in the intercalated disc are potential modulators of cardiac excitability

Background: The intercalated disc (ID) is important for cardiac remodeling and has become a subject of intensive research efforts. However, as yet the composition of the ID has still not been conclusively resolved and the role of many proteins identified in the ID, like Flotillin-2, is often unknown. The Flotillin proteins are known to be involved in the stabilization of cadherins and desmosomes in the epidermis and upon cancer development. However, their role in the heart has so far not been investigated. Therefore, in this study, we aimed at identifying the role of Flotillin-1 and Flotillin-2 in the cardiac ID. Methods: Location of Flotillins in human and murine cardiac tissue was evaluated by fluorescent immunolabeling and co-immunoprecipitation. In addition, the effect of Flotillin knockout (KO) on proteins of the ID and in electrical excitation and conduction was investigated in cardiac samples of wildtype (WT), Flotillin-1 KO, Flotilin-2 KO and Flotilin-1/2 double KO mice. Consequences of Flotillin knockdown (KD) on cardiac function were studied (patch clamp and Multi Electrode Array (MEA)) in neonatal rat cardiomyocytes (NRCMs) transfected with siRNAs against Flotillin-1 and/or Flotillin-2. Results: First, we confirmed presence in the ID and mutual binding of Flotillin-1 and Flotillin-2 in murine and human cardiac tissue. Flotillin KO mice did not show cardiac fibrosis, nor hypertrophy or changes in expression of the desmosomal ID proteins. However, protein expression of the cardiac sodium channel NaV1.5 was significantly decreased in Flotillin-1 and Flotillin-1/2 KO mice compared to WT mice. In addition, sodium current density showed a significant decrease upon Flotillin-1/2 KD in NRCMs as compared to scrambled siRNA-transfected NRCMs. MEA recordings of Flotillin-2 KD NRCM cultures showed a significantly decreased spike amplitude and a tendency of a reduced spike slope when compared to control and scrambled siRNA-transfected cultures. Conclusions: In this study, we demonstrate the presence of Flotillin-1, in addition to Flotillin-2 in the cardiac ID. Our findings indicate a modulatory role of Flotillins on NaV1.5 expression at the ID, with potential consequences for cardiac excitation

Bifurcation occlusions and endovascular treatment outcome in acute ischemic stroke

Background A thrombus in the M1 segment of the middle cerebral artery (MCA) can occlude this main stem only or extend into the M1-M2 bifurcation. The occlusion pattern may affect endovascular treatment (EVT) success, as a bifurcated thrombus may be more prone to fragmentation during retrieval. Objective To investigate whether bifurcated thrombus patterns are associated with EVT procedural and clinical outcomes. Methods Occlusion patterns of MCA thrombi on CT angiography from MR CLEAN Registry patients were classified into three groups: main stem occlusion, bifurcation occlusion extending into one M2 branch, and bifurcation occlusion extending into both M2 branches. Procedural parameters, procedural outcomes (reperfusion grade and embolization to new territory), and clinical outcomes (24-48 hour National Institutes of Health Stroke Scale [NIHSS FU ] score, change in NIHSS scores between 24 and 48 hours and baseline † [NIHSS], and 90-day modified Rankin Scale [mRS] scores) were compared between occlusion patterns. Results We identified 1023 patients with an MCA occlusion of whom 370 (36%) had a main stem occlusion, 151 (15%) a single branch, and 502 (49%) a double branch bifurcation occlusion. There were no statistically significant differences in retrieval method, procedure time, number of retrieval attempts, reperfusion grade, and embolization to new territory between occlusion patterns. Patients with main stem occlusions had lower NIHSS FU scores than patients with single (7 vs 11, p=0.01) or double branch occlusions (7 vs 9, p=0.04). However, there were no statistically significant differences in † NIHSS or in 90-day mRS scores. Conclusions In our population, EVT procedural and long-term clinical outcomes were similar for MCA bifurcation occlusions and MCA main stem occlusions

Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm

Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell-cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for CaV1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease

Standardization of Pathways to Adulthood? An Analysis of Dutch Cohorts Born Between 1850 and 1900

This article examines pathways to adulthood among Dutch cohorts born in the second half of the nineteenth century. Although largely overlooked by previous studies, theory suggests that life courses of young adults born during this period were already influenced by a process of standardization, in the sense that their life courses became more similar over time. Using data from a Dutch registry-based sample, we examine household trajectories: that is, sequences of living arrangements of young adults aged 15–40. Our study shows that for successive cohorts, household trajectories became more similar. We identified six types of trajectories: early death, life-cycle service, early family formation, late family formation, singlehood, and childless but with partner. Over time, early family formation gradually became the “standard” trajectory to adulthood. However, late family formation and singlehood, common pathways within the preindustrial western European marriage pattern, remained widespread among cohorts born in the late nineteenth century. Laboring class youths, farmers’ daughters, young people of mixed religious background, and urban-born youngsters were the nineteenth century forerunners of a standard pathway to adulthood