A5078177663- Neuroscience and Neural Engineering
- Cardiac electrophysiology and arrhythmias
- Pluripotent Stem Cells Research
- Cardiac pacing and defibrillation studies
- Tissue Engineering and Regenerative Medicine
- Microbial Inactivation Methods
- 3D Printing in Biomedical Research
- Microfluidic and Bio-sensing Technologies
- ATP Synthase and ATPases Research
- Mitochondrial Function and Pathology
- Immune cells in cancer
- Ion channel regulation and function
- CRISPR and Genetic Engineering
- Electrostatic Discharge in Electronics
- Health Systems, Economic Evaluations, Quality of Life
- Immune Response and Inflammation
- Computational Drug Discovery Methods
- Cytokine Signaling Pathways and Interactions
- Biomedical Ethics and Regulation
- ECG Monitoring and Analysis
- Advancements in Transdermal Drug Delivery
- Viral Infections and Immunology Research
- Muscle Physiology and Disorders
- Metabolomics and Mass Spectrometry Studies
- Neurotransmitter Receptor Influence on Behavior
United States Food and Drug Administration
2015-2024
Center for Devices and Radiological Health
2015-2024
Center for Drug Evaluation and Research
2017-2024
Office of Science
2016-2024
Universidad de Zaragoza
2017
Instituto de Investigación Sanitaria Aragón
2017
Karolinska Institutet
2017
Center for Biologics Evaluation and Research
2012-2014
National Heart Lung and Blood Institute
2003-2009
Energetics (United States)
2009
To assess the utility of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as an in vitro proarrhythmia model, we evaluated concentration dependence and sources variability electrophysiologic responses to 28 drugs linked low, intermediate, high torsades de pointes (TdP) risk categories using two commercial cell lines standardized protocols a blinded multisite study multielectrode array or voltage-sensing optical approaches. Logistical ordinal linear regression models...
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied effects 26 drugs 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye microelectrode-array assays CiPA initiative compared results with clinical QT prolongation torsade de pointes (TdP) risk. Concentration-dependent...
Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At same time, current regulatory paradigm for screening new causing is preventing reaching market, sometimes inappropriately. In this study, we report results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) calcium (diltiazem) blocking to counteract effects hERG potassium channel (dofetilide moxifloxacin). We demonstrate that both mexiletine lidocaine substantially...
Background: Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is potential side effect of many marketed and withdrawn medications. The contribution common genetic variants previously associated with baseline to drug-induced prolongation arrhythmias not known. Methods: We tested the hypothesis that weighted combination contributing at baseline, identified through genome-wide association studies, can predict individual response multiple...
The lifetimes of fluorescent components matrix NADH in isolated porcine heart mitochondria were investigated using time-resolved fluorescence spectroscopy. Three distinct resolved: 0.4 (63%), 1.8 (30%), and 5.7 (7%) ns (% total NADH). lifetime the emission wavelength short component consistent with free NADH. In addition to their longer lifetimes, remaining pools also had a blue-shifted spectrum immobilized On basis frequency data, contributed >80% fluorescence. steady-state kinetics...
Mitochondrial NADH fluorescence has been a useful tool in evaluating mitochondrial energetics both vitro and vivo. is enhanced several-fold the matrix through extended lifetimes (EFL). However, actual binding sites responsible for EFL are unknown. We tested hypothesis that to Complex I significant source of enhancement. To test this hypothesis, effect on efficiency was evaluated purified protein, native gels entire porcine heart mitochondria proteome. avoid oxidation these preparations, we...
Induced pluripotent stem cells (iPSCs) have shown promise in investigating donor-specific phenotypes and pathologies. The iPSC-derived cardiomyocytes (iPSC-CMs) could potentially be utilized personalized cardiotoxicity studies, assessing individual proarrhythmic risk. However, it is unclear how closely iPSC-CMs derived from healthy subjects can recapitulate a range of responses to drugs. It well known that QT-prolonging drugs induce subject-specific clinical response all do not necessarily...
Cardiac side-effects are one of the major reasons for failure drugs during preclinical development. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have been proposed as a model predicting drug-induced arrhythmias under Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm. Field potential duration (FPD) spontaneously beating iPSC-CMs is commonly corrected rate using formulas originally derived from clinical QT–RR relationship that not thoroughly validated use with...
Abstract Pulse electric field‐based (PEF) ablation is a technique whereby short high‐intensity fields inducing irreversible electroporation (IRE) are applied to various tissues. Here, we implemented standardized in vitro model compare the effects of biphasic symmetrical pulses (100 pulses, 1–10 μs phase duration (d), 10–1000 Hz pulse repetition rate (f)) using two different human cellular models: human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) and esophageal smooth...
Protein phosphorylation is a well-characterized regulatory mechanism in the cytosol, but remains poorly defined mitochondrion. In this study, we characterized use of (32)P-labeling to monitor turnover protein heart and liver mitochondria matrix. The (32)P labeling technique was compared contrasted Phos-tag fluorescent stain 2D isoelectric focusing. Of 64 proteins identified by MS spectroscopy Phos-Tag gels, over 20 were correlated with labeling. high sensitivity incorporation detected well...
Cardiac contractility modulation (CCM) is an intracardiac therapy whereby nonexcitatory electrical simulations are delivered during the absolute refractory period of cardiac cycle. We previously evaluated effects CCM in isolated adult rabbit ventricular cardiomyocytes and found a transient increase calcium contractility. In present study, we sought to extend these results human using induced pluripotent stem cell–derived (hiPSC-CMs) develop robust model evaluate vitro. HiPSC-CMs (iCell...
Buprenorphine is a μ-opioid receptor (MOR) partial agonist used to manage pain and addiction. QT C prolongation that crosses the 10 msec threshold of regulatory concern was observed at supratherapeutic dose in two thorough studies for transdermal buprenorphine product BUTRANS ® . Because can be associated with Torsades de Pointes (TdP), rare but potentially fatal ventricular arrhythmia, these results have led further investigation electrophysiological effects buprenorphine. Drug-induced TdP...
Introduction: Pulsed electric field (PEF) cardiac ablation has been recently proposed as a technique to treat drug resistant atrial fibrillation by inducing cell death through irreversible electroporation (IRE). Improper PEF dosing can result in thermal damage or reversible electroporation. The lack of comprehensive and systematic studies select parameters for safe effective IRE treatments hinders device development regulatory decision-making. Human induced pluripotent stem cell-derived...
Prostaglandin E2 (PGE2) is induced in vivo by bacterial products including TLR agonists. To determine whether PGE2 directly or via IL-1β, human monocytes and macrophages were cultured with LPS Pam3CSK4 presence of caspase-1 inhibitor, ZVAD, IL-1R antagonist, Kineret. agonists exclusively IL-1β-independent mechanisms. In contrast, ZVAD Kineret reduced production LPS-treated (but not Pam3CSK4-treated) monocytes, 30–60%. Recombinant IL-1β augmented COX-2 mPGES-1 mRNA LPS-pretreated but...
Cardiac contractility modulation (CCM) is a medical device therapy whereby non-excitatory electrical stimulations are delivered to the myocardium during absolute refractory period enhance cardiac function. We previously evaluated effects of standard CCM pulse parameters in isolated rabbit ventricular cardiomyocytes and 2D human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) monolayers, on flexible substrate. In present study, we sought extend these results 3D...
Abstract Introduction Cardiac contractility modulation (CCM) is a medical device‐based therapy delivering non‐excitatory electrical stimulations to the heart enhance cardiac function in failure (HF) patients. The lack of human vitro tools assess CCM hinders our understanding mechanisms action. Here, we introduce novel chronic (i.e., 2‐day) assay evaluate effects 3D microphysiological system consisting engineered tissues (ECTs). Methods Cryopreserved induced pluripotent stem cell‐derived...
Abstract Techniques that enable longitudinal tracking of cell fate after myocardial delivery are imperative for optimizing the efficacy cell-based cardiac therapies. However, these approaches have been underutilized in preclinical models and clinical trials, there is considerable demand site-specific strategies achieving long-term expression reporter genes compatible with safe noninvasive imaging. In this study, rhesus sodium/iodide symporter (NIS) gene was incorporated into macaque induced...