Pathophysiological Mechanisms of Premature Ventricular Complexes

Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia. Despite the high prevalence, the cause of PVCs remains elusive in most patients. A better understanding of the underlying pathophysiological mechanism may help to steer future research. This review aims to provide an overview of the potential pathophysiological mechanisms of PVCs and their differentiation

Robotic magnetic navigation-guided catheter ablation establishes highly effective pulmonary vein isolation in patients with paroxysmal atrial fibrillation when compared to conventional ablation techniques

Introduction: Pulmonary vein isolation (PVI) is a pivotal part of ablative therapy for atrial fibrillation (AF). Currently, there are multiple techniques available to realize PVI, including: manual-guided cryoballoon (MAN-CB), manual-guided radiofrequency (MAN-RF), and robotic magnetic navigation-guided radiofrequency ablation (RMN-RF). There is a lack of large prospective trials comparing contemporary RMN-RF with the more conventional ablation techniques. This study prospectively compared three catheter ablation techniques as treatment of paroxysmal AF. Methods: This multicenter, prospective study included patients with paroxysmal AF who underwent their first ablation procedure. Procedural parameters (including procedural efficiency), complication rates, and freedom of AF during 12-month follow-up, were compared between three study groups which were defined by the utilized ablation technique. Results: A total of 221 patients were included in this study. Total procedure time was significantly shorter in MAN-CB (78 ± 21 min) compared to MAN-RF (115 ± 41 min; p &lt;.001) and compared to RMN-RF (129 ± 32 min; p &lt;.001), whereas it was comparable between the two radiofrequency (RF) groups (p =.062). A 3% complication rate was observed, which was comparable between all groups. At 12-month follow-up, AF recurrence was observed in 40 patients (19%) and was significantly lower in the robotic group (MAN-CB 19 [24%], MAN-RF 16 [23%], RMN-RF 5 [8%] AF recurrences, p =.045) (multivariate hazard ratio of RMN-RF on AF recurrence 0.32, 95% confidence interval: 0.12–0.87, p =.026). Conclusion: RMN-guided PVI results in high freedom of AF in patients with paroxysmal AF, when compared to cryoablation and manual RF ablation. Cryoablation remains the most time-efficient ablation technique, whereas RMN nowadays has comparable efficiency with manual RF ablation.</p

A simplified protocol for differentiation of electrophysiologically mature neuronal networks from human induced pluripotent stem cells

Progress in elucidating the molecular and cellular pathophysiology of neuropsychiatric disorders has been hindered by the limited availability of living human brain tissue. The emergence of induced pluripotent stem cells (iPSCs) has offered a unique alternative strategy using patient-derived functional neuronal networks. However, methods for reliably generating iPSC-derived neurons with mature electrophysiological characteristics have been difficult to develop. Here, we report a simplified differentiation protocol that yields electrophysiologically mature iPSC-derived cortical lineage neuronal networks without the need for astrocyte co-culture or specialized media. This protocol generates a consistent 60:40 ratio of neurons and astrocytes that arise from a common forebrain neural progenitor. Whole-cell patch-clamp recordings of 114 neurons derived from three independent iPSC lines confirmed their electrophysiological maturity, including resting membrane potential (−58.2±1.0 mV), capacitance (49.1±2.9 pF), action potential (AP) threshold (−50.9±0.5 mV) and AP amplitude (66.5±1.3 mV). Nearly 100% of neurons were capable of firing APs, of which 79% had sustained trains of mature APs with minimal accommodation (peak AP frequency: 11.9±0.5 Hz) and 74% exhibited spontaneous synaptic activity (amplitude, 16.03±0.82 pA; frequency, 1.09±0.17 Hz). We expect this protocol to be of broad applicability for implementing iPSC-based neuronal network models of neuropsychiatric disorders.Molecular Psychiatry advance online publication, 18 April 2017; doi:10.1038/mp.2017.56

A simplified protocol for differentiation of electrophysiologically mature neuronal networks from human induced pluripotent stem cells

Progress in elucidating the molecular and cellular pathophysiology of neuropsychiatric disorders has been hindered by the limited availability of living human brain tissue. The emergence of induced pluripotent stem cells (iPSCs) has offered a unique alternative strategy using patient-derived functional neuronal networks. However, methods for reliably generating iPSC-derived neurons with mature electrophysiological characteristics have been difficult to develop. Here, we report a simplified differentiation protocol that yields electrophysiologically mature iPSC-derived cortical lineage neuronal networks without the need for astrocyte co-culture or specialized media. This protocol generates a consistent 60:40 ratio of neurons and astrocytes that arise from a common forebrain neural progenitor. Whole-cell patch-clamp recordings of 114 neurons derived from three independent iPSC lines confirmed their electrophysiological maturity, including resting membrane potential (−58.2±1.0 mV), capacitance (49.1±2.9 pF), action potential (AP) threshold (−50.9±0.5 mV) and AP amplitude (66.5±1.3 mV). Nearly 100% of neurons were capable of firing APs, of which 79% had sustained trains of mature APs with minimal accommodation (peak AP frequency: 11.9±0.5 Hz) and 74% exhibited spontaneous synaptic activity (amplitude, 16.03±0.82 pA; frequency, 1.09±0.17 Hz). We expect this protocol to be of broad applicability for implementing iPSC-base

Vulnerability for Ventricular Arrhythmias in Patients with Chronic Coronary Total Occlusion

Introduction: The presence of a chronic total occlusion (CTO) is associated with an increased risk of ventricular arrhythmias. Areas covered: This review provides an overview of the relationship between CTO and ventricular arrhythmias, arrhythmogenic mechanisms, and the effect of revascularization. Expert opinion: Studies in recipients of an implantable cardioverter-defibrillator (ICD) have shown that a CTO is an independent predictor of appropriate ICD therapy. The myocardial territory supplied by a CTO is a pro-arrhythmogenic milieu

Visualization of Murine Intranasal Dosing Efficiency Using Luminescent Francisella tularensis: Effect of Instillation Volume and Form of Anesthesia

Intranasal instillation is a widely used procedure for pneumonic delivery of drugs, vaccine candidates, or infectious agents into the respiratory tract of research mice. However, there is a paucity of published literature describing the efficiency of this delivery technique. In this report we have used the murine model of tularemia, with Francisella tularensis live vaccine strain (FTLVS) infection, to evaluate the efficiency of pneumonic delivery via intranasal dosing performed either with differing instillation volumes or different types of anesthesia. FTLVS was rendered luminescent via transformation with a reporter plasmid that constitutively expressed the Photorhabdus luminescens lux operon from a Francisella promoter. We then used an IVIS Spectrum whole animal imaging system to visualize FT dissemination at various time points following intranasal instillation. We found that instillation of FT in a dose volume of 10 µl routinely resulted in infection of the upper airways but failed to initiate infection of the pulmonary compartment. Efficient delivery of FT into the lungs via intranasal instillation required a dose volume of 50 µl or more. These studies also demonstrated that intranasal instillation was significantly more efficient for pneumonic delivery of FTLVS in mice that had been anesthetized with inhaled (isoflurane) vs. parenteral (ketamine/xylazine) anesthesia. The collective results underscore the need for researchers to consider both the dose volume and the anesthesia type when either performing pneumonic delivery via intranasal instillation, or when comparing studies that employed this technique

Mathematical Modeling and Simulation of Ventricular Activation Sequences: Implications for Cardiac Resynchronization Therapy

Next to clinical and experimental research, mathematical modeling plays a crucial role in medicine. Biomedical research takes place on many different levels, from molecules to the whole organism. Due to the complexity of biological systems, the interactions between components are often difficult or impossible to understand without the help of mathematical models. Mathematical models of cardiac electrophysiology have made a tremendous progress since the first numerical ECG simulations in the 1960s. This paper briefly reviews the development of this field and discusses some example cases where models have helped us forward, emphasizing applications that are relevant for the study of heart failure and cardiac resynchronization therapy