Impact of KChIP2 on Cardiac Electrophysiology and the Progression of Heart Failure

Electrophysiological remodeling of cardiac potassium ion channels is important in the progression of heart failure. A reduction of the transient outward potassium current (Ito) in mammalian heart failure is consistent with a reduced expression of potassium channel interacting protein 2 (KChIP2, a KV4 subunit). Approaches have been made to investigate the role of KChIP2 in shaping cardiac Ito, including the use of transgenic KChIP2 deficient mice and viral overexpression of KChIP2. The interplay between Ito and myocardial calcium handling is pivotal in the development of heart failure, and is further strengthened by the dual role of KChIP2 as a functional subunit on both KV4 and CaV1.2. Moreover, the potential arrhythmogenic consequence of reduced Ito may contribute to the high relative incidence of sudden death in the early phases of human heart failure. With this review, we offer an overview of the insights into the physiological and pathological roles of KChIP2 and we discuss the limitations of translating the molecular basis of electrophysiological remodeling from animal models of heart failure to the clinical setting

High-Septal Pacing Reduces Ventricular Electrical Remodeling and Proarrhythmia in Chronic Atrioventricular Block Dogs

ObjectivesThis study was designed to analyze the relevance of ventricular activation patterns for ventricular electrical remodeling after atrioventricular (AV) block in dogs.BackgroundBradycardia is thought to be the main contributor to ventricular electrical remodeling after complete AV block. However, an altered ventricular activation pattern or AV dyssynchrony may also contribute.MethodsFor 4 weeks, AV block dogs were either paced from the high-ventricular septum near the His bundle at lowest captured rate (n = 9, high-septal pacing [HSP]) or kept at idioventricular rate without controlled activation (n = 14, chronic AV block [CAVB]). Multiple electrocardiographic and electrophysiological parameters were measured under anesthesia at 0 and 4 weeks. Proarrhythmia was tested at 4 weeks by IKrblock (25 μg/kg dofetilide intravenous).ResultsAt 0 weeks, the 2 groups were comparable, whereas after 4 weeks of similar bradycardia, QT duration at unpaced conditions had increased from 300 ± 5 to 395 ± 18 ms in CAVB (+32 ± 6%) and from 307 ± 8 ms to 357 ± 11 ms in HSP (+17 ± 4%; p < 0.05). Frequency dependency of repolarization was less steep in HSP compared to CAVB dogs after 4 weeks remodeling. Beat-to-beat variability of repolarization, a proarrhythmic parameter, increased only in CAVB from 0 to 4 weeks. Torsades de pointes arrhythmias were induced at 4 weeks in 44% HSP versus 78% CAVB dogs (p = 0.17). Cumulative duration of arrhythmias per inducible dog was 87 ± 36 s in CAVB and 30 ± 21 s in HSP (p < 0.05).ConclusionsHigh-septal pacing reduces the magnitude of ventricular electrical remodeling and proarrhythmia in AV block dogs, suggesting a larger role for altered ventricular activation pattern in the generation of ventricular electrical remodeling than previously assumed

Lay Bystanders' Perspectives on What Facilitates Cardiopulmonary Resuscitation and Use of Automated External Defibrillators in Real Cardiac Arrests

Background Many patients who suffer an out‐of‐hospital cardiac arrest will fail to receive bystander intervention (cardiopulmonary resuscitation [CPR] or defibrillation) despite widespread CPR training and the dissemination of automated external defibrillators (AEDs). We sought to investigate what factors encourage lay bystanders to initiate CPR and AED use in a cohort of bystanders previously trained in CPR techniques who were present at an out‐of‐hospital cardiac arrest. Methods and Results One‐hundred and twenty‐eight semistructured qualitative interviews with CPR‐trained lay bystanders to consecutive out‐of‐hospital cardiac arrest, where an AED was present were conducted (from January 2012 to April 2015, in Denmark). Purposive maximum variation sampling was used to establish the breadth of the bystander perspective. Twenty‐six of the 128 interviews were chosen for further in‐depth analyses, until data saturation. We used cross‐sectional indexing (using software), and inductive in‐depth thematic analyses, to identify those factors that facilitated CPR and AED use. In addition to prior hands‐on CPR training, the following were described as facilitators: prior knowledge that intervention is crucial in improving survival, cannot cause substantial harm, and that the AED will provide guidance through CPR; prior hands‐on training in AED use; during CPR performance, teamwork (ie, support), using the AED voice prompt and a ventilation mask, as well as demonstrating leadership and feeling a moral obligation to act. Conclusions Several factors other than previous hands‐on CPR training facilitate lay bystander instigation of CPR and AED use. The recognition and modification of these factors may increase lay bystander CPR rates and patient survival following an out‐of‐hospital cardiac arrest. </jats:sec

The Endo-Lysosomal System of Brain Endothelial Cells Is Influenced by Astrocytes In Vitro

Receptor- and adsorptive-mediated transport through brain endothelial cells (BEC) of the blood-brain barrier (BBB) involves a complex array of subcellular vesicular structures, the endo-lysosomal system. It consists of several types of vesicles, such as early, recycling, and late endosomes, retromer-positive structures, and lysosomes. Since this system is important for receptor-mediated transcytosis of drugs across brain capillaries, our aim was to characterise the endo-lysosomal system in BEC with emphasis on their interactions with astrocytes. We used primary porcine BEC in monoculture and in co-culture with primary rat astrocytes. The presence of astrocytes changed the intraendothelial vesicular network and significantly impacted vesicular number, morphology, and distribution. Additionally, gene set enrichment analysis revealedthat 60 genes associated with vesicular trafficking showed altered expression in co-cultured BEC. Cytosolic proteins involved in subcellular trafficking were investigated to mark transport routes, such as RAB25 for transcytosis. Strikingly, the adaptor protein called AP1-1B, important for basolateral sorting in epithelial cells, was not expressed in BEC. Altogether, our data pin-point unique features of BEC trafficking network, essentially mapping the endo-lysosomal system of in vitro BBB models. Consequently, our findings constitute a valuable basis for planning the optimal route across the BBB when advancing drug delivery to the brain.Peer reviewe