Development of a high-speed imaging system for real time evaluation and monitoring of cardiac engineered tissues.

Stem cell derived cardiac monolayers have high potential for tissue regeneration, drug testing and disease modeling. However, current differentiation protocols are still sub-optimal, resulting in cultures with variable yields and properties. We propose a high-speed lenseless imaging system, integrated with an electrical stimulation unit, to optimize the generation of these cultures.

Novel Analysis Method for Beating Cells Videomicroscopy Data: Functional Characterization of Culture Samples.

Cell culture of cardiac tissue analog is becoming increasingly interesting for regenerative medicine (cell therapy and tissue engineering) and is widely used for high throughput cardiotoxicity. As a cost-effective approach to rapidly discard new compounds with high toxicity risks, cardiotoxicity evaluation is firstly done requiring cells/tissue with physiological/pathological characteristics (close to properties). Studying multicellular electrophysiological and contractile properties is needed to assess drug effects.

In silico study of multicellular automaticity of heterogeneous cardiac cell monolayers: Effects of automaticity strength and structural linear anisotropy.

The biological pacemaker approach is an alternative to cardiac electronic pacemakers. Its main objective is to create pacemaking activity from added or modified distribution of spontaneous cells in the myocardium. This paper aims to assess how automaticity strength of pacemaker cells (i.

Noise-induced effects on multicellular biopacemaker spontaneous activity: Differences between weak and strong pacemaker cells.

Self-organization of spontaneous activity of a network of active elements is important to the general theory of reaction-diffusion systems as well as for pacemaking activity to initiate beating of the heart. Monolayer cultures of neonatal rat ventricular myocytes, consisting of resting and pacemaker cells, exhibit spontaneous activation of their electrical activity. Similarly, one proposed approach to the development of biopacemakers as an alternative to electronic pacemakers for cardiac therapy is based on heterogeneous cardiac cells with resting and spontaneously beating phenotypes.

Rate-Dependent Role of I in Human Atrial Repolarization and Atrial Fibrillation Maintenance.

The atrial-specific ultrarapid delayed rectifier K current (I) inactivates slowly but completely at depolarized voltages. The consequences for I rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed I inactivation dynamics. Here, we developed an updated formulation of I inactivation that accurately reproduces time-, voltage-, and frequency-dependent inactivation.

Potassium Channel Blockade Enhances Atrial Fibrillation-Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade.

Background: The development of effective and safe antiarrhythmic drugs for atrial fibrillation (AF) rhythm control is an unmet clinical need. Multichannel blockers are believed to have advantages over single-channel blockers for AF, but their development has been completely empirical to date. We tested the hypothesis that adding K(+)-channel blockade improves the atrium-selective electrophysiological profile and anti-AF effects of optimized Na(+)-channel blockers.

Wavelet analysis of cardiac optical mapping data.

Background: Optical mapping technology is an important tool to study cardiac electrophysiology. Transmembrane fluorescence signals from voltage-dependent dyes need to be preprocessed before analysis to improve the signal-to-noise ratio. Fourier analysis, based on spectral properties of stationary signals, cannot directly provide information on the spectrum changes with respect to time.

Spatiotemporal stability of neonatal rat cardiomyocyte monolayers spontaneous activity is dependent on the culture substrate.

In native conditions, cardiac cells must continuously comply with diverse stimuli necessitating a perpetual adaptation. Polydimethylsiloxane (PDMS) is commonly used in cell culture to study cellular response to changes in the mechanical environment. The aim of this study was to evaluate the impact of using PDMS substrates on the properties of spontaneous activity of cardiomyocyte monolayer cultures.

Atrial fibrillation promotion with long-term repetitive obstructive sleep apnea in a rat model.

Background: Obstructive sleep apnea (OSA) importantly contributes to the occurrence of atrial fibrillation (AF) in humans, but the mechanisms are poorly understood. Experimental research has provided insights into AF promotion by acute OSA episodes. However, patients with OSA usually have frequent nocturnal episodes for some time before manifesting AF.

Fibroblast electrical remodeling in heart failure and potential effects on atrial fibrillation.

Fibroblasts are activated in heart failure (HF) and produce fibrosis, which plays a role in maintaining atrial fibrillation (AF). The effect of HF on fibroblast ion currents and its potential role in AF are unknown. Here, we used a patch-clamp technique to investigate the effects of HF on atrial fibroblast ion currents, and mathematical computation to assess the potential impact of this remodeling on atrial electrophysiology and arrhythmogenesis.

Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs.

The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used.

Role for MicroRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure.

Background: Atrial tissue fibrosis is often an important component of the atrial fibrillation (AF) substrate. Small noncoding microRNAs are important mediators in many cardiac remodeling paradigms. MicroRNA-21 (miR-21) has been suggested to be important in ventricular fibrotic remodeling by downregulating Sprouty-1, a protein that suppresses fibroblast proliferation.

In silico optimization of atrial fibrillation-selective sodium channel blocker pharmacodynamics.

Atrial fibrillation (AF) is the most common type of clinical arrhythmia. Currently available anti-AF drugs are limited by only moderate efficacy and an unfavorable safety profile. Thus, there is a recognized need for improved antiarrhythmic agents with actions that are selective for the fibrillating atrium.

Interactions between cardiac fibrosis spatial pattern and ionic remodeling on electrical wave propagation.

Cardiac fibrosis is an important form of pathological tissue remodeling. Fibrosis can electrically-uncouple neighboring excitable cardiomyocytes thus acting as an obstacle to electrical propagation. In this study, we investigated the effects of fibrosis spatial pattern on electrical propagation in control, decreased maximum sodium conductance, and increased intracellular resistivity conditions.

Fluorescence-based system for measurement of electrophysiological changes in stretched cultured cardiomyocytes.

Acute or sustained stretch of cardiac tissue is known to play a key role in arrhythmogenesis. Using a fluorescence approach, we designed a system measuring calcium transients and transmembrane potential changes in monolayers of cultured cardiomyocytes under uniaxial elongation and electrical stimulation. Cardiac myocytes are seeded on a rectangular PDMS template held and stretched by a motorized linear guide system.

Differential effectiveness of pharmacological strategies to reveal dormant pulmonary vein conduction: a clinical-experimental correlation.

Background: Atrial fibrillation recurs in ∼30%-40% of patients after pulmonary vein (PV) isolation (PVI) procedures, often because of restored PV-left atrial (LA) conduction. Adenosine or isoproterenol are used clinically to reveal dormant PV conduction and guide additional ablation.

Objective: The purpose of this study was to assess the differential efficacy of adenosine and/or isoproterenol in revealing dormant PV conduction.

Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model.

Aims: Increasing evidence indicates that congenital long QT syndromes (LQTSs) promote atrial fibrillation. The atrial action potential (AP) has a short plateau, and whether LQTS atrial cardiomyocytes generate triggered activity via early afterdepolarizations (EADs) is unclear. Atrial cellular arrhythmia mechanisms have not been defined in congenital LQTS.

Role of T-type calcium channel subunits in post-myocardial infarction remodelling probed with genetically engineered mice.

Aims: Previous studies suggested that T-type Ca(2+)-current (I(CaT))-blockers improve cardiac remodelling, but all available I(CaT)-blockers have non-specific actions on other currents and/or functions. To clarify the role of I(CaT) in cardiac remodelling, we studied mice with either of the principal cardiac I(CaT)-subunits (Cav3.1 or Cav3.

Impact of tissue geometry on simulated cholinergic atrial fibrillation: a modeling study.

Atrial fibrillation (AF), arising in the cardiac atria, is a common cardiac rhythm disorder that is incompletely understood. Numerous characteristics of the atrial tissue are thought to play a role in the maintenance of AF. Most traditional theoretical models of AF have considered the atrium to be a flat two-dimensional sheet.

Mechanisms of atrial tachyarrhythmias associated with coronary artery occlusion in a chronic canine model.

Background: Coronary artery disease predisposes to atrial fibrillation (AF), but the effects of chronic atrial ischemia/infarction on AF-related substrates are unknown.

Methods And Results: Regional right atrial myocardial infarction (MI) was created in 40 dogs by ligating an artery that supplies the right atrial free wall and not the ventricles; 35 sham dogs with the same artery isolated but not ligated were controls. Dogs were observed 8 days after MI and subjected to open-chest study, in vitro optical mapping, and/or cell isolation for patch-clamp and Ca(2+) imaging on day 8.

The role of pulmonary veins vs. autonomic ganglia in different experimental substrates of canine atrial fibrillation.

Aims: Pulmonary vein (PV)-encircling ablation, which is effective in suppressing atrial fibrillation (AF), damages autonomic ganglia near the PV ostia. This study examined the effects of PV isolation (PVI) vs. peri-PV ganglionic plexus ablation (GPA) in two discrete canine AF models: ventricular tachypacing (240 bpm, 2 weeks)-induced congestive heart failure (CHF), and atrial tachypacing (400 bpm, 1 week)-induced atrial tachycardia remodeling (ATR).

Mechanisms by which adenosine restores conduction in dormant canine pulmonary veins.

Background: Adenosine acutely reconnects pulmonary veins (PVs) after radiofrequency application, revealing "dormant conduction" and identifying PVs at risk of reconnection, but the underlying mechanisms are unknown.

Methods And Results: Canine PV and left-atrial (LA) action potentials were recorded with standard microelectrodes and ionic currents with whole-cell patch clamp before and after adenosine perfusion. PVs were isolated with radiofrequency current application in coronary-perfused LA-PV preparations.