Cardiomyocyte? March 14 th 2013
|
|
- Liliana Paul
- 5 years ago
- Views:
Transcription
1 What Makes a Cardiomyocyte a Cardiomyocyte? Kyle Kolaja March 14 th 2013
2 What Makes a Cardiomyocyte a Cardiomyocyte? Shouldn t proliferate Should beat Should be fairly pure Should look like and express genes like a heart cell Should respond to cardioactive drugs 2
3 Cardiomyocyte a Cardiomyocyte Rationale from a toxicologist perspective Two schools of thought Bits and pieces look right Cell-based system responds like a heart Bits and Pieces Characterization Gene expression Channel activity/function Purity and impact on endpoints Cell-based systems Arrhythmia Hypertrophy Toxicity 3
4 icell Cardiomyocytes are more similar to Adult Human Heart Samples than Primary Cultures CDI cells d28 and d120 Primary Heart cultures Troponin I = at background = ES cell Babiarz et al Stem Cells Dev. Jan
5 icell Cardiomyocytes are more similar to Adult Human Heart Samples than Primary Cultures CDI cells d28 and d120 Primary Heart cultures Troponin I = at background = ES cell Babiarz et al Stem Cells Dev. Jan
6 Cardiomyocyte Manufacturing Process CREATE & MAINTAIN EXPAND DIFFERENTIATE FINSH & CRYOPRESERVE Cardiomyocyte y Production Quality Quantity Purity Purity and Morphology Differentiation with expression-based selection can yield >98% purity Cryopreservation makes easier for everyone Morphology with sarcomeres & striated myofibers
7 Confirmation of Cardiomyocyte Nature icell Cardiomyocytes Express major cardiac proteins Exhibit cardiac action potential wave forms Functionally active cardiac channels Respond as expected to channel blockers Ma et. al Am J Physiol Heart Circ Physiol. (2011) High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents 7
8 Impedance Detection of Cardiomyocyte Beating 96-well E-eplate Seconds 10 log) Cell Index ( Hours 8
9 Drug-induced changes in beat rate Indication of functional cardiac ion channels xcelligence: Impedance MEA: Electrical Field Control Na+ Channel Blocker Pace-maker Current Blocker Agonist of β- Adrenergic Receptor 9
10 Does impedance detect the physical beating or the electrical changes? Pre-drug Blebbistatin: Blocks myosin II in an actin-detached state 15 min MEA 15 min 0µM
11 In vitro Detection of Arrhythmias with Human icell Cardiomyocytes Pre-drug Post-drug 11
12 In vitro Detection of Arrhythmias using Human icell Cardiomyocytes E-4031 causes arrhythmia DMSO E-4031 Nifedipine rescues E-4031-induced arrhythmia DMSO + Nif E Nif Misner et al Br J Pharmacol Apr;165(8): Functional Rescue of Drug-induced Arrhythmia 12
13 Human Cardiomyocytes (hcar) Assay ips cell-derived human cardiomyocytes IB20= lowest tested concentration resulting in 20% irregular beats 13
14 hcar Assay Validation: 23 compounds with known in vivo effect 12 Pro-arrhythmic 11 Non-arrhythmic IB20 30 um One False Positive No False Negatives IB20= lowest tested concentration resulting in 20% i l b Drug IB20 Clinical herg QT (µm) arrhythmia Dofetilide (+) (+) (+) Ouabain 0.03 ( ) ( ) (+) Aconitine 0.03 ( ) ( ) (+) Cisapride 0.03 (+) (+) (+) E (+) (+) (+) Astemizole 0.03 (+) (+) (+) Terfenadine 0.3 (+) (+) (+) Flecainide 1 (+) (+) (+) Alfuzosin 1 ( ) (+) ( ) Thioridazine 3 (+) (+) (+) Quinidine 10 (+) (+) (+) Erythromycin 30 (+) (+) (+) Sotalol 30 (+) (+) (+) Fluoxetine >30 (+) (+) ( ) Verapamil >30 (+) (±) ( ) Moxifloxacin >100 (+) (+) (+) Amiodarone >100 (+) (+) (+) Ranolazine >100 (+) (+) ( ) Captopril >100 ( ) ( ) ( ) Rofecoxib >100 ( ) ( ) ( ) Amoxicillin >1000 ( ) ( ) ( ) irregular beats Aspirin >1000 ( ) ( ) ( ) Nifedipine >3 ( ) ( ) ( ) 14 Guo et al. Toxicol Sci Sep;123(1):281-9.
15 Human Cardiomyocytes (hcar) Assay Next Round of Validation 83 Compounds ~82% -- arrhy. prediction >90% -- QT prediction 30 Internal Compounds 80% -- arrhy. prediction 95% -- QT prediction 15
16 Hallmarks of Cardiac Hypertrophy Increased cell size Enhanced protein synthesis Higher organization of the sarcomere Re-activation of the fetal gene program Expression of B-type natriuretic protein (BNP) Normal Untreated + PE Kuwahara K et al. J Pharmacol Sci 2012;119: Cell Size Protein Synthesis BNP Expression Ac ctin Reorg Diseased Lister K et al. Cardiovasc Res 2006;70: Glenn D et al. Hypertension 2009;53:
17 Hypertrophy Application Suite BNP qpcr Measure activation of BNP gene (NPPB) ELISA Quantify levels of secreted BNP Flow Cytometry Detect BNP expression High Content Analysis Image BNP expression, Cell Size, Cell Thaw and Plate icell Cardiomyocytes Induce with ET-1 Detect BNP Coat Plate with Fibronectin Replace Medium
18 NHLBI Family Blood Pressure Program GWAS now icell Cardiomyocytes GWAS identification of associated SNPs with left Ventricular Hypertrophy Phenotyping through cardiovascular phenotypes and risk factors Family-based ascertainment NHLBI, Next Generation Genetic Association Studies, RFA-HL CDI will make pure ventricular cardiomyocytes from 250 different patients 100 most informative families derived from HyperGEN cohort Induce hypertrophy phenotype in vitro, perform molecular analyses Attempt to correlate GWAS findings with in vitro phenotype
19 CDI Grant Milestones You are here Grant Year Calendar Year Grant Phases Research Development Sample identification and Optimize parallel ips and CM production Cell Production Production Plan 25 donors completed or in progress donors donors donors
20 Example Pre and Post Selection Purity and Yield Sample ID O1144 Start of Selection (day 12) End of Selection (day 16) ctnt-33.0% ctnt-88.9% T CM yield (start of selection): 256M CM yield (end of selection): 280M QC Criteria at cryo (day 30) >90% purity (ctnt+) > 4.3 million viable cells per cryovial >50 million total yield (200M target) Mycoplasma negative Identity screen (STR) match Observed beating rate This will drift up to ~97% by day 30
21 Studying the mechanism of Sunitinib (Sutent) mediated cardiotoxicity Sutent multi-targeted (RTK) inhibitor for oncology indication Cardiac dysfunction and toxicity congestive heart failure and left ventricular systolic dysfunction Inhibits herg and causes arrhythmia Previous work done mostly with NRVMs Binds 150 kinases Inhibits proliferation/survival/angiogenesis VEGFR1-3, PDGFR(α and β), c-kit, FLT3, CSF1R, and RET AMP Kinase cellular gas gauge RSK ribosomal s6 kinase -downstream of ERK Aurora Kinase - cell prolif/, Chromatid seg., mitosis
22 Advancing the Understanding of Sutent Cardiotoxicity Sutent potently cytotoxic in icell CMs Confirmed the inhibition of AMPK by sutent but minimal protective effect seen by AMPK agonists Inhibit herg, Ca++ cycling and NaV1.5 -> arrhythmia RSK inhibitors not cardiotoxic icell CMs ideal RSK inhibitor inhibits herg and causes arrhythmia model to assess cardiotoxicity, Aurora Kinases electrophysiology and contractility tilit effects in parallel Multi-factorial combination of cytotoxicity, cardiac conduction abnormalities, hypoxia, pan- kinase inhibition leading to suppressed response/accommodation mechanisms 22
23 Jaspamide Cardiotoxicity Jaspamide (a cyclodepsipeptide isolated from the marine sponge Jaspis johnstoni ) a potential cancer therapeutic agent Pulmonary edema and cardiac hemorrhage and congestion in preclincal tox species Jaspamide (10 lm) inhibited Kv1.5 activity by 98.5%. And also inhibited Cav1.2, Cav3.2, and HCN2; but not herg icell CMs ideal model to assess cardiotoxicity, electrophysiology and contractility effects in parallel Affects actin binding to cytoskeleton 23
24 Opportunity for ips-derived Cardiomyocytes in Cardiac Research Functional aspects of PSC-derived cardiomyocytes highlight an improved in vitro tool for studying cardiotoxicity Gene expression Channel activity/function Purity and impact on endpoints Rhythmic beating and response to treatment Doesn t proliferate Maintain in culture for prolonged periods Example cell-based systems just beginning Arrhythmia and hypertrophy Mechanistic toxicity regulatory filings Continued validation through empirical testing 24
Assessment of pro-arrhythmic effects using Pluricyte Cardiomyocytes. on the ACEA xcelligence RTCA CardioECR
Assessment of pro-arrhythmic effects using Pluricyte Cardiomyocytes on the ACEA xcelligence RTCA CardioECR Application Note Version 2.1 / March 2018 Contents 1. Introduction 1 2. Assessment of pro-arrhythmic
More informationNcardia. Assessment of pro-arrhythmic effects in Pluricyte Cardiomyocytes. using the Axion BioSystems Maestro TM MEA system
Ncardia Stem cell experts Assessment of pro-arrhythmic effects in Pluricyte Cardiomyocytes using the Axion BioSystems Maestro TM MEA system Application note Version 2.0 Contents 1. Introduction 1 2. Assessment
More informationxcelligence Cardio Symposium 2014 Cardiotoxicity, QT Prolongation, and Arrhythmia Prediction Using icell Cardiomyocytes: Past, Present, and Future
xcelligence Cardio Symposium 2014 Cardiotoxicity, QT Prolongation, and Arrhythmia Prediction Using icell Cardiomyocytes: Past, Present, and Future Blake Anson Ph.D. Oct 18, 2014 Outline Proarrhythmia Testing
More informationMetrion Biosciences: the ion channel specialists
Metrion Biosciences: the ion channel specialists In depth profiling of human ipsc cardiomyocytes: From electrophysiology to phenotypic assays Saïd El-Haou, PhD 30 November 2017 www.metrionbiosciences.com
More informationWelcome to the Exhibitor Tutorial presented by
Welcome to the Exhibitor Tutorial presented by February 1, 217 1 Calcium Handling Assays with Human ipsc-derived Cell Types Coby Carlson, Ph.D. 7 February 217 Transformative Potential of ipsc Technology
More informationxcelligence RTCA Cardio Instrument Monitor Cardiomyocyte Beating in Real Time for Drug Discovery Research
xcelligence RTCA Cardio Instrument Monitor Cardiomyocyte Beating in Real Time for Drug Discovery Research xcelligence RTCA Cardio Instrument A new way to test for compound cardiotoxicity Cardiac liability
More informationMeasuring Cardiac Activity:
icell Cardiomyocytes 2 Application Protocol Measuring Cardiac Activity: Impedance Detection with xcelligence RTCA Cardio System Introduction icell Cardiomyocytes 2, human cardiomyocytes derived from induced
More informationEffects of reference compounds on impedance signals from stem cellderived human cardiomyocytes
Effects of reference compounds on impedance signals from stem cellderived human cardiomyocytes Herbert M. Himmel, Safety Pharmacology, Bayer Pharma AG, Wuppertal, Germany SPS Webinar Cardiac Safety Testing
More informationmesc Derived Cardiomyocytes and the RTCA Cardio Instrument - The Perfect Match for Screening Cardiac Effects
mesc Derived Cardiomyocytes and the RTCA Cardio Instrument - The Perfect Match for Screening Cardiac Effects Dr. Kristina Tressat, Axiogenesis AG ELRIG Drug Discovery II 7-8 Sep 2011, Manchester Challange
More informationAssessment of pro-arrhythmic effects using Pluricyte Cardiomyocytes on the ACEA xcelligence RTCA CardioECR
Assessment of pro-arrhythmic effects using Pluricyte Cardiomyocytes on the ACEA xcelligence RTCA CardioECR Version 1.2 CONTENTS Getting started... 3 Technical support and training... 3 1. Introduction...
More informationAssessment of pro-arrhythmic effects using Pluricyte Cardiomyocytes on the Axion Maestro system
Assessment of pro-arrhythmic effects using Pluricyte Cardiomyocytes on the Axion Maestro system Version 1.0 CONTENTS Getting started... 3 Technical support and training... 3 1. Introduction... 4 2. Workflow...
More informationAdvances in Safety Pharmacology: Utilizing ipsc-derived cardiomyocytes in early stage safety pharmacology investigations. Blake Anson, PhD.
Advances in Safety Pharmacology: Utilizing ipsc-derived cardiomyocytes in early stage safety pharmacology investigations Blake Anson, PhD. Presentation Outline I. Safety Pharmacology and in-vitro models
More informationWe ve crossed the Chasm and climbed out of the Trough. Advances and advantages with ipsc-derived cell types in drug discovery.
We ve crossed the Chasm and climbed out of the Trough. Advances and advantages with ipsc-derived cell types in drug discovery. Blake Anson Ph.D. Oct 31, 2014 Technology Hype Cycle The Chasm The Trough
More informationSuccesses and Evolving Challenges Posed by the Comprehensive In Vitro Proarrhythmia (CiPA) Initiative
Successes and Evolving Challenges Posed by the Comprehensive In Vitro Proarrhythmia (CiPA) Initiative Gary Gintant Dept. Integrative Pharmacology Integrated Sciences and Technology AbbVie For the CiPA
More informationxcelligence System RTCA Cardio Instrument
xcelligence System Application Note No. 15 January 2013 xcelligence System RTCA Cardio Instrument Preclinical Cardiac Safety Assessment using Human ipsc Derived icell TM Cardiomyocytes Introduction Over
More informationAssessment of pro-arrhythmic effects using Pluricyte Cardiomyocytes on the Axion BioSystems Maestro TM MEA system
Assessment of pro-arrhythmic effects using Pluricyte Cardiomyocytes on the Axion BioSystems Maestro TM MEA system Version 1.2 CONTENTS Getting started... 3 1. Introduction... 4 2. Workflow... 5 Important
More informationPerspectives on Evaluating and Managing Cardiovascular Safety Risk for Anticancer Drugs
Perspectives on Evaluating and Managing Cardiovascular Safety Risk for Anticancer Drugs DCTD/DTP/TPB Myrtle Davis, DVM, Ph.D. Chief, Toxicology and Pharmacology Branch Division of Cancer Treatment and
More informationMechanisms of Arrhythmogenesis: Focus on Long QT Syndrome (LQTS)
Mechanisms of Arrhythmogenesis: Focus on Long QT Syndrome (LQTS) Craig T. January, MD, PhD Division of Cardiovascular Medicine University of Wisconsin-Madison CSRC-HESI-FDA Rechanneling the Current Cardiac
More informationMultiparametric assessment of the effects of chemotherapeutic drugs on the (electro)physiology of Pluricyte Cardiomyocytes
Multiparametric assessment of the effects of chemotherapeutic drugs on the (electro)physiology of Pluricyte Cardiomyocytes Event Presenter Date Ncardia Workshop Tessa de Korte, MSc December 1, 2017 Page
More informationMeasuring Cardiac Activity:
icell Cardiomyocytes 2 Application Protocol Measuring Cardiac Activity: Impedance and Extracellular Field Potential Detection with CardioExcyte 96 System Introduction icell Cardiomyocytes 2, human cardiomyocytes
More informationMeasuring Cardiac Activity:
icell Cardiomyocytes Application Protocol Measuring Cardiac Activity: Intracellular Calcium Flux Detection on the FLIPR Tetra System Introduction icell Cardiomyocytes are human cardiomyocytes that recapitulate
More informationPluricyte Cardiomyocytes. Axion BioSystems Maestro TM MEA system
Pluricyte Cardiomyocytes Axion BioSystems Maestro TM MEA system User Guide Version 3.0 / March 2018 Contents 1. Introduction 2 2. Workflow 3 3. Important recommendations 4 4. Equipment, Materials and
More informationTdP Mechanisms and CiPA
TdP Mechanisms and CiPA Craig T. January, MD, PhD Division of Cardiovascular Medicine University of Wisconsin-Madison Cardiac Safety Research Consortium Hilton Washington DC December 6, 2016 Disclosures
More informationDiffering responses of human stem cell-derived cardiomyocytes to arrhythmogenic drugs, determined using impedance measurements
Fundamental Toxicological Sciences (Fundam. Toxicol. Sci.) Vol.3, No.2, 47-53, 2016 47 Letter Differing responses of human stem cell-derived cardiomyocytes to arrhythmogenic drugs, determined using impedance
More informationJapanese Stem Cell Efforts
Japanese Stem Cell Efforts Yuko Sekino, Ph. D. Organizer of JiCSA Head, Division of Pharmacology, National Institute of Health Sciences (NIHS) Pharmaceutical and Medical Safety Bureau NI HS Since 1874
More informationUse of hipsc derived Cardiomyocytes for Cardiac Safety Evaluation
Use of hipsc derived Cardiomyocytes for Cardiac Safety Evaluation Liang Gu, MD, Msc Sr. Principal Scientist/Lab Head, ADRD Investigative Toxicology March 14 th, 2018 (SOT Workshop) DEPARTMENT OF HEALTH
More informationHuman induced pluripotent stem cell derived cardiomyocytes are a more relevant model for assessing drug-induced effects on mitochondrial function
Human induced pluripotent stem cell derived cardiomyocytes are a more relevant model for assessing drug-induced effects on mitochondrial function than H9C2 cells 16 January 2013 SLAS2013 Presentation Outline
More informationAtrial Fibrillation: Rate vs. Rhythm. Michael Curley, MD Cardiac Electrophysiology
Atrial Fibrillation: Rate vs. Rhythm Michael Curley, MD Cardiac Electrophysiology I have no relevant financial disclosures pertaining to this topic. A Fib Epidemiology #1 Most common heart rhythm disturbance
More informationA New Comprehensive Translational Paradigm Using Human ipsc-derived Cardiomyocytes for Safety Assessment of Drug-Induced Arrhythmias
A New Comprehensive Translational Paradigm Using Human ipsc-derived Cardiomyocytes for Safety Assessment of Drug-Induced Arrhythmias Armando Lagrutta Safety & Exploratory Pharmacology (SEP) Department
More informationPreclinical Perspectives of QT Outlook from ICH Guidelines
Biometry in Early Clinical Research QT/QTc Interval Workshop in Heidelberg, November 17-19, 2005 Preclinical Perspectives of QT Outlook from ICH Guidelines Gerd Bode, M.D.,Ph.D. Frelance Consultant, e-mail
More informationhipsc Cardiomyocytes: Validation Study Results
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH OFFICE OF SCIENCE AND ENGINEERING LABORATORIES hipsc Cardiomyocytes: Validation Study Results Ksenia Blinova, PhD US Food and Drug Administration HESI-CSRC CiPA
More informationThe Application of Cell-Based Impedance Technology in Drug Discovery
The Application of Cell-Based Impedance Technology in Drug Discovery Yama A. Abassi, PhD Sr. Director Cell Biology and Assay Development ACEA Biosciences ACEA Biosciences Founded in early Located in San
More informationAssessment of pro-arrhythmic effects using Pluricyte Cardiomyocytes. on the ACEA xcelligence RTCA CardioECR
Assessment of pro-arrhythmic effects using Pluricyte Cardiomyocytes on the ACEA xcelligence RTCA CardioECR User Guide Version 3.0 / March 2018 Contents 1. Introduction 2 2. Workflow 3 3. Important recommendations
More informationWho Gets Atrial Fibrilla9on..?
Birmingham October 20 th 2013 AFA Pa9ents Day Symptoma9c Atrial Fibrilla9on What therapies are available? GENERAL BACKGROUND Andrew Grace Papworth Hospital and University of Cambridge Consultant: Medtronic
More informationIn Vitro Assessment to Replace the Clinical TQT Study: The Comprehensive In Vitro ProArrhythmia Assay (CiPA) Initiative
In Vitro Assessment to Replace the Clinical TQT Study: The Comprehensive In Vitro ProArrhythmia Assay (CiPA) Initiative Gary Gintant, AbbVie for the Comprehensive in Vitro ProArrhythmia Assay Group Hot
More informationQT prolongation and drug-drug interactions. Filip Josephson M.D., Ph.D Clinical Assessor Swedish Medical Products Agency
QT prolongation and drug-drug interactions Filip Josephson M.D., Ph.D Clinical Assessor Swedish Medical Products Agency Disposition Introduction to QT prolongation Three relevant DDI scenarios Concluding
More informationPluricyte Cardiomyocytes. using the Multiwell MEA System from Multi Channel Systems
Pluricyte Cardiomyocytes using the Multiwell MEA System from Multi Channel Systems User Guide Version 3.1 / March 2018 Contents 1. Introduction 2 2. Workflow 3 3. Important Recommendations 4 4. Equipment,
More informationThe QT Interval Safety Endpoint for DR- TB trials. Kelly Dooley & Gary Maartens (Disclaimer: I know very little cardiac electrophysiology)
The QT Interval Safety Endpoint for DR- TB trials Kelly Dooley & Gary Maartens (Disclaimer: I know very little cardiac electrophysiology) The ECG tracing Physiology of a cardiac myocyte Flow of ions (Na
More informationPerforming Bioenergetic Analysis: Seahorse XFe96 Analyzer
icell Cardiomyocytes 2 Application Protocol Performing Bioenergetic Analysis: Seahorse XFe96 Analyzer Introduction The myocardium is the most metabolically active tissue in the body and is highly sensitive
More informationInPulse: Development of an ipsc cardiomyocyte (ipsc-cm) platform to assess drug-induced contractility liabilities.
InPulse: Development of an ipsc cardiomyocyte (ipsc-cm) platform to assess drug-induced contractility liabilities. Sponsors: Arun Sridhar, Peter J. Clements, Brian Berridge, Drug induced contractility
More informationMultiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using ipsc Cells
457590JBXXXX10.1177/1087057112457590Jo urnal of Biomolecular ScreeningSirenko et al. 2012 Multiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using ipsc Cells Journal of
More informationThere are future perspectives in the pharmacological treatment of arrhythmias
There are future perspectives in the pharmacological treatment of arrhythmias George Andrikopoulos, MD, PhD, FESC, Cardiologist, Director, 1st Department of Cardiology/ Department of Electrophysiology
More informationDrugs Controlling Myocyte Excitability and Conduction at the AV node Singh and Vaughan-Williams Classification
Drugs Controlling Myocyte Excitability and Conduction at the AV node Singh and Vaughan-Williams Classification Class I Na Channel Blockers Flecainide Propafenone Class III K channel Blockers Dofetilide,
More informationThe mechanism of the cardiac arrhythmias Norbert Jost, PhD
The mechanism of the cardiac arrhythmias Norbert Jost, PhD Department of Pharmacology & Pharmacotherapy, University of Szeged Division for Cardiovascular Pharmacology, Hungarian Academy of Sciences Szeged,
More informationJay Simonson, MD, FACC, FHRS Medical Director, Cardiac Electrophysiology Park Nicollet Heart and Vascular Center
Jay Simonson, MD, FACC, FHRS Medical Director, Cardiac Electrophysiology Park Nicollet Heart and Vascular Center A-Fib Facts Yes, you may be able to blame your parents It is more of a nuisance than a
More informationBlocking the Late Sodium Current
Non-classical Targets in Antiarrhythmic Therapy Blocking the Late Sodium Current Luiz Belardinelli, MD SVP, Cardiovascular Therapeutics Gilead Sciences, CA, USA Madrid June 28, 2011 Disclosures: Full time
More informationDrugs Used in Heart Failure. Assistant Prof. Dr. Najlaa Saadi PhD pharmacology Faculty of Pharmacy University of Philadelphia
Drugs Used in Heart Failure Assistant Prof. Dr. Najlaa Saadi PhD pharmacology Faculty of Pharmacy University of Philadelphia Heart Failure Heart failure (HF), occurs when cardiac output is inadequate to
More informationComparison of Electrophysiological Data From Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes to Functional Preclinical Safety Assays
toxicological sciences 134(2), 412 426 2013 doi:10.1093/toxsci/kft113 Advance Access publication May 20, 2013 Comparison of Electrophysiological Data From Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes
More informationMEA assays using human ipsc-derived cardiomyocytes; challenges and opportunities
MEA assays using human ipsc-derived cardiomyocytes; challenges and opportunities Event Presenter Date EMA Workshop 2017 Tessa de Korte, MSc 2017, October 5 Page 1 Ncardia at a glance Foundation Ncardia
More information12/19/16. Disclosures
@atriumrx Don t Miss a Beat! Practical Tips on Managing Drug-Induced QTc Prolongation Sandeep Devabhakthuni, PharmD, BCPS- AQ Cardiology Assistant Professor University of Maryland School of Pharmacy Disclosures
More informationDevelopment and Use of Quantitative Adverse Outcome Pathways: Lessons Learned from Application to Cardiotoxicity
Development and Use of Quantitative Adverse Outcome Pathways: Lessons Learned from Application to Cardiotoxicity Chemicals Concentration 0.1 µm 1 µm 10 µm 100 µm Weihsueh A. Chiu, PhD Department of Veterinary
More informationArrhythmias. 1. beat too slowly (sinus bradycardia). Like in heart block
Arrhythmias It is a simple-dysfunction caused by abnormalities in impulse formation and conduction in the myocardium. The heart is designed in such a way that allows it to generate from the SA node electrical
More informationArrhythmias. Simple-dysfunction cause abnormalities in impulse formation and conduction in the myocardium.
Arrhythmias Simple-dysfunction cause abnormalities in impulse formation and conduction in the myocardium. However, in clinic it present as a complex family of disorders that show variety of symptoms, for
More informationMr. Eknath Kole M.S. Pharm (NIPER Mohali)
M.S. Pharm (NIPER Mohali) Drug Class Actions Therapeutic Uses Pharmacokinetics Adverse Effects Other Quinidine IA -Binds to open and inactivated Na+ -Decreases the slope of Phase 4 spontaneous depolarization
More informationFocus Application. Compound-Induced Cytotoxicity
xcelligence System Real-Time Cell Analyzer Focus Application Compound-Induced Cytotoxicity Featured Study: Using the Time Resolving Function of the xcelligence System to Optimize Endpoint Viability and
More informationANTI - ARRHYTHMIC DRUGS
ANTI - ARRHYTHMIC DRUGS CARDIAC ACTION POTENTIAL K Out Balance Ca in/k out Na in K Out GENERATION OF ARRHYTHMIAS Four mechanisms of arrhythmia generation; Increased normal automaticity Abnormal automaticity
More informationCan the Thorough QT Study Be Replaced? Norman Stockbridge Division of Cardiovascular and Renal Products FDA/CDER
Can the Thorough QT Study Be Replaced? Norman Stockbridge Division of Cardiovascular and Renal Products FDA/CDER Can the TQT study be replaced? Yes. Thank you. Any questions? Four genre of replacement
More informationRhythm Control: Is There a Role for the PCP? Blake Norris, MD, FACC BHHI Primary Care Symposium February 28, 2014
Rhythm Control: Is There a Role for the PCP? Blake Norris, MD, FACC BHHI Primary Care Symposium February 28, 2014 Financial disclosures Consultant Medtronic 3 reasons to evaluate and treat arrhythmias
More informationTCP Transl Clin Pharmacol
TCP 2018;26(4):145-149 https://doi.org/10.12793/tcp.2018.26.4.145 Five years of the CiPA project (2013 2018) - what did we learn? Dong-Seok Yim* Department of Clinical Pharmacology and Therapeutics, Seoul
More informationPatient Susceptibilities in Preclinical Drug Safety Assessment
Patient Susceptibilities in Preclinical Drug Safety Assessment B. R. Berridge GlaxoSmithKline ILAR Roundtable October, 2017 Animal studies represent an apical preclinical modeling system in drug development
More informationDuring exercise the heart rate is 190 bpm and the stroke volume is 115 ml/beat. What is the cardiac output?
The Cardiovascular System Part III: Heart Outline of class lecture After studying part I of this chapter you should be able to: 1. Be able to calculate cardiac output (CO) be able to define heart rate
More information2/1/2013. Poisoning pitfalls. The original pitfall
The original pitfall Poisoning pitfalls Craig Smollin MD Associate Medical Director, California Poison Control System - SF Division Assistant Professor of Emergency Medicine, UCSF What will we talk about?
More informationComparison of different proarrhythmia biomarkers in isolated rabbit hearts
Comparison of different proarrhythmia biomarkers in isolated rabbit hearts Summary of PhD Thesis Szabolcs Orosz, MSc Supervisor: Attila Farkas MD, PhD 2nd Dept. of Internal Medicine and Cardiology Centre
More informationHeart Failure (HF) Treatment
Heart Failure (HF) Treatment Heart Failure (HF) Complex, progressive disorder. The heart is unable to pump sufficient blood to meet the needs of the body. Its cardinal symptoms are dyspnea, fatigue, and
More informationRate and Rhythm Control of Atrial Fibrillation
Rate and Rhythm Control of Atrial Fibrillation April 21, 2017 춘계심혈관통합학술대회 Jaemin Shim, MD, PhD Arrhythmia Center Korea University Anam Hospital Treatment of AF Goal Reducing symptoms Preventing complication
More informationFocus Application. Compound-Induced Cytotoxicity
xcelligence System Real-Time Cell Analyzer Focus Application Compound-Induced Cytotoxicity For life science research only. Not for use in diagnostic procedures. Featured Study: Using the Time Resolving
More informationThe case for induced pluripotent stem cell-derived cardiomyocytes in pharmacological screening
BJP British Journal of Pharmacology DOI:10.1111/j.1476-5381.2012.02118.x www.brjpharmacol.org Themed Section: Regenerative Medicine and Pharmacology: A Look to the Future REVIEW The case for induced pluripotent
More informationDrug induced QT prolongation and Torsades de Pointes (TdP) Mark Friesen, PharmD March 13, 2013
Drug induced QT prolongation and Torsades de Pointes (TdP) Mark Friesen, PharmD March 13, 2013 None Conflict of Interest TdP: Learning objectives To review the pathophysiology of QT prolongation and TdP
More informationUse of Antiarrhythmic Drugs for AF Who, What and How? Dr. Marc Cheng Queen Elizabeth Hospital
Use of Antiarrhythmic Drugs for AF Who, What and How? Dr. Marc Cheng Queen Elizabeth Hospital Content i. Rhythm versus Rate control ii. Anti-arrhythmic for Rhythm Control iii. Anti-arrhythmic for Rate
More informationAtrial Fibrillation Etiologies and Treatment. Shawn Liu Learner Centered Learning Goal
Atrial Fibrillation Etiologies and Treatment Shawn Liu Learner Centered Learning Goal Pathophysiology Defined by the absence of coordinated atrial systole Results from multiple reentrant electrical waves
More informationDrugs, herg and sudden death
Cell Calcium 35 () 53 57 Drugs, herg and sudden death A.M. Brown a,b, a MetroHealth Campus, Case Western Reserve University, Cleveland, OH 8, USA b ChanTest, Inc., 656 Neo Parkway, Cleveland, OH 8, USA
More informationHow does the heart work? The heart is muscle whose main function is a pump; to push blood the rest of your body.
1 You have a condition called atrial fibrillation. I would like you to learn more about this condition. You should read about it below, and can also watch an Internet program about it. After reading about
More informationaxion Protocol Cell Culture on Microelectrode Arrays Cell Type: Cryopreserved Human ipsc-derived Neurons BioSystems v. 1.1
axion BioSystems Cell Culture on Microelectrode Arrays Cell Type: Cryopreserved Human ipsc-derived Neurons Protocol v. 1.1 Trademarks Axion BioSystems, Inc. and the logo are trademarks of Axion BioSystems,
More informationPluricyte Cardiomyocytes
Pluricyte Cardiomyocytes Manual Version 2.1 / March 2018 Contents 1. Introduction 2 2. Equipment, Materials and Reagents 3 3. Methods 4 3.1 Coating of tissue culture plates 4 3.2 Thawing Pluricyte Cardiomyocytes
More informationHYPERTENSION: Sustained elevation of arterial blood pressure above normal o Systolic 140 mm Hg and/or o Diastolic 90 mm Hg
Lecture 39 Anti-Hypertensives B-Rod BLOOD PRESSURE: Systolic / Diastolic NORMAL: 120/80 Systolic = measure of pressure as heart is beating Diastolic = measure of pressure while heart is at rest between
More informationGenetics of Sudden Cardiac Death. Geoffrey Pitt Ion Channel Research Unit Duke University. Disclosures: Grant funding from Medtronic.
Genetics of Sudden Cardiac Death Geoffrey Pitt Ion Channel Research Unit Duke University Disclosures: Grant funding from Medtronic Duke U N I V E R S I T Y Sudden Cardiac Death High incidence 50-100 per
More informationEindhoven University of Technology. Exam Modeling Cardiac Function (8W160)
Eindhoven University of Technology department of Biomedical Engineering group Cardiovascular Biomechanics Exam Modeling Cardiac Function (8W160) January 21, 2011, 14.00 17.00 h This exam consists of 6
More informationPHARMACOLOGY OF ARRHYTHMIAS
PHARMACOLOGY OF ARRHYTHMIAS Course: Integrated Therapeutics 1 Lecturer: Dr. E. Konorev Date: November 27, 2012 Materials on: Exam #5 Required reading: Katzung, Chapter 14 1 CARDIAC ARRHYTHMIAS Abnormalities
More informationAnti-HERG activity and the risk of drug-induced arrhythmias and sudden death
European Heart Journal (2005) 26, 590 597 doi:10.1093/eurheartj/ehi092 Clinical research Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death M.L. De Bruin 1,2 *, M. Pettersson
More informationModulating Glucose Uptake in Skeletal Myotubes: Insulin Induction with Bioluminescent Glucose Uptake Analysis
icell Skeletal Myoblasts Application Protocol Modulating Glucose Uptake in Skeletal Myotubes: Insulin Induction with Bioluminescent Glucose Uptake Analysis Introduction The skeletal muscle is one of the
More informationPreclinical Cardiovascular Safety in Oncology: Do We Need Plumbers, Electricians, or Strength Trainers?
Preclinical Cardiovascular Safety in Oncology: Do We Need Plumbers, Electricians, or Strength Trainers? Gary Gintant, Ph.D. Dept. Integrative Pharmacology Integrated Sciences & Technology, AbbVie CSRC
More informationSudden cardiac death: Primary and secondary prevention
Sudden cardiac death: Primary and secondary prevention By Kai Chi Chan Penultimate Year Medical Student St George s University of London at UNic Sheba Medical Centre Definition Sudden cardiac arrest (SCA)
More informationCardiac toxicity is a leading cause for drug attrition during. Molecular Cardiology
Molecular Cardiology Drug Screening Using a Library of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes Reveals Disease-Specific Patterns of Cardiotoxicity Ping Liang, MD, PhD*; Feng Lan, PhD*;
More informationIMPLEMENTATION OF NOVEL ECG BIOMARKERS
IMPLEMENTATION OF NOVEL ECG BIOMARKERS CSRC CiPA meeting May 21, 2018 Washington DC Borje Darpo, MD, PhD, FESC Chief Scientific Officer, Cardiac Safety, ERT 1 Disclosures I work as a consultant for ERT,
More informationMuscle tissues. Dr. Hersh Abdul Ham-Karim BVM&S, PG Dip, MSc and PhD
Muscle tissues Dr. Hersh Abdul Ham-Karim BVM&S, PG Dip, MSc and PhD Muscle tissue is a soft tissue that composes muscles in animal bodies, and gives rise to muscles' ability to contract. Muscle tissue
More informationCardiac Arrhythmias. For Pharmacists
Cardiac Arrhythmias For Pharmacists Agenda Overview of the normal Classification Management Therapy Conclusion Cardiac arrhythmias Overview of the normal Arrhythmia: definition From the Greek a-, loss
More informationIndex. cardiology.theclinics.com. Note: Page numbers of article titles are in boldface type.
Index Note: Page numbers of article titles are in boldface type. A AADs. See Antiarrhythmic drugs (AADs) ACE inhibitors. See Angiotensin-converting enzyme (ACE) inhibitors ACP in transseptal approach to
More informationEvolution of strategies to improve preclinical cardiac safety testing
OPINION Evolution of strategies to improve preclinical cardiac safety testing Gary Gintant, Philip T. Sager and Norman Stockbridge Abstract The early and efficient assessment of cardiac safety liabilities
More information4/14/15 HTEC 91. Topics for Today. Guess That Rhythm. Premature Ventricular Contractions (PVCs) Ventricular Rhythms
4/14/15 Topics for Today HTEC 91 Medical Office Diagnostic Tests Week 5 Ventricular Rhythms PVCs: Premature Ventricular Contractions VT: Ventricular Tachycardia VF: Ventricular Fibrillation Asystole Study
More informationProarrhythmia Risk Assessment in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Using the Maestro MEA Platform
TOXICOLOGICAL SCIENCES, 147(1), 2015, 286 295 doi: 10.1093/toxsci/kfv128 Advance Access Publication Date: June 27, 2015 Research Article Proarrhythmia Risk Assessment in Human Induced Pluripotent Stem
More information1. A method of selecting a treatment for congestive heart failure, in a subject with heart failure, comprising:
Diagnostic Methods Case Studies Instructions 1. Perform a Purposive Construction (PCon) of the claims: a. Identify the POSITA b. Identify the POSITA s CGK (in case study 2 this information has been specified
More informationInvasive and Medical Treatments for Atrial Fibrillation. Thomas J Dresing, MD Section of Electrophysiology and Pacing Cleveland Clinic
Invasive and Medical Treatments for Thomas J Dresing, MD Section of Electrophysiology and Pacing Cleveland Clinic Disclosures Fellow s advisory panel for St Jude Medical Speaking honoraria from: Boston
More informationMission Statement for our Arrhythmia Care
Mission Statement for our Arrhythmia Care We are dedicated to provide a compassionate and an outstanding care for patients with cardiac arrhythmias. We will be utilizing the cutting edge and the most advanced
More informationCan point of care cardiac biomarker testing guide cardiac safety during oncology trials?
Can point of care cardiac biomarker testing guide cardiac safety during oncology trials? Daniel J Lenihan, MD Professor, Division of Cardiovascular Medicine Director, Clinical Research Vanderbilt University
More informationDeclaration of conflict of interest. I have nothing to disclose.
Declaration of conflict of interest I have nothing to disclose. Left Bundle branch block in HF: DO GENETICS MATTER? Silvia Giuliana Priori Cardiovascular Genetics, Langone Medical Center, New York University
More informationDysrhythmias 11/7/2017. Disclosures. 3 reasons to evaluate and treat dysrhythmias. None. Eliminate symptoms and improve hemodynamics
Dysrhythmias CYDNEY STEWART MD, FACC NOVEMBER 3, 2017 Disclosures None 3 reasons to evaluate and treat dysrhythmias Eliminate symptoms and improve hemodynamics Prevent imminent death/hemodynamic compromise
More informationCase Report Suppression of Frequent Ventricular Ectopy in a Patient with Hypertrophic Heart Disease with Ranolazine: A Case Report
www.ipej.org 84 Case Report Suppression of Frequent Ventricular Ectopy in a Patient with Hypertrophic Heart Disease with Ranolazine: A Case Report David K. Murdock, MD 1,2 and Jeffrey W. Kaliebe, MT(ASCP),
More informationAF Today: W. For the majority of patients with atrial. are the Options? Chris Case
AF Today: W hat are the Options? Management strategies for patients with atrial fibrillation should depend on the individual patient. Treatment with medications seems adequate for most patients with atrial
More informationThe Role of Defibrillator Therapy in Genetic Arrhythmia Syndromes
The Role of Defibrillator Therapy in Genetic Arrhythmia Syndromes RHEA C. PIMENTEL, MD, FACC, FHRS UNIVERSITY OF KANSAS HOSPITAL MID AMERICA CARDIOLOGY AUGUST 19, 2012 Monogenic Arrhythmia Syndromes Mendelian
More informationAustralian Journal of Basic and Applied Sciences, 9(36) December 2015, Pages: ISSN: Journal home page:
ISSN:1991-8178 Australian Journal of Basic and Applied Sciences Journal home page: www.ajbasweb.com Role of Biochemical Tests Artery Disease (ANP, BNP) in the Evaluation of Patients with Coronary 1 Saad
More information