Assessment of Proarrhythmic Potential of Drugs in Optogenetically Paced Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Cardiac side-effects are one of the major reasons for failure of drugs during preclinical development. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have been proposed as a model for predicting drug-induced arrhythmias under the Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm. Field potential duration (FPD) in spontaneously beating iPSC-CMs is commonly corrected for beating rate using formulas originally derived from the clinical QT-RR relationship that have not been thoroughly validated for use with iPSC-CMs.

Comparative analysis of media effects on human induced pluripotent stem cell-derived cardiomyocytes in proarrhythmia risk assessment.

Introduction: Cardiotoxicity assessment using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) forms a key component of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). A potentially impactful factor on iPSC-CM testing is the presence of serum in the experimental media. Generally, serum-free media is used to most accurately reproduce "free" drug concentration.

Role of suppression of the inward rectifier current in terminal action potential repolarization in the failing heart.

Background: The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. The inwardly rectifying K current (I) has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear.

Objective: The purpose of this study was to define the effect of I suppression on the cardiac AP and excitability in the normal and failing hearts.

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation.

Acute effects of nonexcitatory electrical stimulation during systole in isolated cardiac myocytes and perfused heart.

Application of electrical field to the heart during the refractory period of the beat has been shown to increase the force of contraction both in animal models and in heart failure patients (cardiac contractility modulation, or CCM). A direct increase in intracellular calcium during CCM has been suggested to be the mechanism behind the positive inotropic effect of CCM. We studied the effect of CCM on isolated rabbit cardiomyocytes and perfused whole rat hearts.

A novel approach to dual excitation ratiometric optical mapping of cardiac action potentials with di-4-ANEPPS using pulsed LED excitation.

We developed a new method for ratiometric optical mapping of transmembrane potential (V(m)) in cardiac preparations stained with di-4-ANEPPS. V(m)-dependent shifts of excitation and emission spectra establish two excitation bands (<481 and >481 nm) that produce fluorescence changes of opposite polarity within a single emission band (575-620 nm). The ratio of these positive and negative fluorescence signals (excitation ratiometry) increases V(m) sensitivity and removes artifacts common to both signals.

Altered calcium dynamics in cardiac cells grown on silane-modified surfaces.

Chemically defined surfaces were created using self-assembled monolayers (SAMs) of hydrophobic and hydrophilic silanes as models for implant coatings, and the morphology and physiology of cardiac myocytes plated on these surfaces were studied in vitro. We focused on changes in intracellular Ca(2+) because of its essential role in regulating heart cell function. The SAM-modified coverslips were analyzed using X-ray Photoelectron Spectroscopy to verify composition.

Development of a new arbitrary waveform defibrillator for cardiac electrophysiology research.

The innovative arbitrary waveform defibrillator for animal research presented in this paper is based on two power linear amplifiers in bridge configuration. It is capable of delivering 10 J shocks of arbitrary shape and duration. The system can be used to test new waveforms by comparing them to traditional ones, in in-vitro experiments.