scholarly journals An Augmented Negative Force-Frequency Relationship and Slowed Mechanical Restitution Are Associated With Increased Susceptibility to Drug-Induced Torsade de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog

2018 ◽  
Vol 9 ◽  
Author(s):  
David J. Sprenkeler ◽  
Alexandre Bossu ◽  
Jet D. M. Beekman ◽  
Marieke Schoenmakers ◽  
Marc A. Vos
Keyword(s):  
Atrioventricular Block ◽  
Torsade De Pointes ◽  
Force Frequency ◽  
Drug Induced ◽  
Mechanical Restitution ◽  
Frequency Relationship ◽  
Increased Susceptibility

Effects of Pacing Rate on Mechanical Restitution Within the In vivo Canine Heart: Study of the Force?Frequency Relationship

2007 ◽  
Vol 18 (2) ◽  
pp. 212-217 ◽  
Author(s):  
SARAH E. AHLBERG ◽  
CRYSTAL M. RIPPLINGER ◽  
NICHOLAS D. SKADSBERG ◽  
PAUL A. IAIZZO ◽  
LAWRENCE J MULLIGAN
Keyword(s):  
Canine Heart ◽  
Force Frequency ◽  
Mechanical Restitution ◽  
Heart Study ◽  
Frequency Relationship

scholarly journals Sensitivity of the acute atrioventricular block rabbit as a novel model for detecting drug-induced Torsade de Pointes arrhythmias

2018 ◽  
Vol WCP2018 (0) ◽  
pp. PO3-11-6
Author(s):  
Yoshinobu Nagasawa ◽  
Mihoko Hagiwara-Nagasawa ◽  
Seiji Shibuta ◽  
Kazuhiro Takada ◽  
Ryuichi Kambayashi ◽  
...  
Keyword(s):  
Atrioventricular Block ◽  
Torsade De Pointes ◽  
Drug Induced ◽  
Novel Model

scholarly journals P448Augmented contractile remodeling is associated with increased susceptibility to drug-induced torsade de pointes arrhythmias in the chronic AV-block dog model

EP Europace ◽  
2018 ◽  
Vol 20 (suppl_1) ◽  
pp. i87-i87
Author(s):  
D J Sprenkeler ◽  
A Bossu ◽  
HDM Beekman ◽  
M Schoenmakers ◽  
M A Vos
Keyword(s):  
Torsade De Pointes ◽  
Av Block ◽  
Drug Induced ◽  
Dog Model ◽  
Increased Susceptibility

scholarly journals The anaesthetized rabbit with acute atrioventricular block provides a new model for detecting drug-induced Torsade de Pointes

2017 ◽  
Vol 174 (15) ◽  
pp. 2591-2605 ◽  
Author(s):  
Mihoko Hagiwara ◽  
Seiji Shibuta ◽  
Kazuhiro Takada ◽  
Ryuichi Kambayashi ◽  
Misako Nakajo ◽  
...  
Keyword(s):  
Atrioventricular Block ◽  
Torsade De Pointes ◽  
Drug Induced ◽  
New Model ◽  
Anaesthetized Rabbit

The pharmacovigilance-center FAKOS – Detection of drug induced agranulocytosis, immune thrombocytopenia, hepatitis, pancreatitis, LongQT-Syndrome and Torsade de pointes

2010 ◽  
Vol 72 (08/09) ◽  
Author(s):  
E Bronder ◽  
H Kurtal ◽  
A Klimpel ◽  
F Andersohn ◽  
W Haverkamp ◽  
...  
Keyword(s):  
Immune Thrombocytopenia ◽  
Torsade De Pointes ◽  
Drug Induced ◽  
Pharmacovigilance Center

Reproducible Induction of Early Afterdepolarizations and Torsade de Pointes Arrhythmias by d -Sotalol and Pacing in Dogs With Chronic Atrioventricular Block

Circulation ◽  
1995 ◽  
Vol 91 (3) ◽  
pp. 864-872 ◽  
Author(s):  
Marc A. Vos ◽  
S. Cora Verduyn ◽  
Anton P.M. Gorgels ◽  
Gyorgyi C. Lipcsei ◽  
Hein J.J. Wellens
Keyword(s):  
Atrioventricular Block ◽  
Torsade De Pointes ◽  
Early Afterdepolarizations

Strain Rate in Children and Young Piglets Mirrors Changes in Contractility and Demonstrates a Force-Frequency Relationship

2017 ◽  
Vol 30 (8) ◽  
pp. 797-806 ◽  
Author(s):  
Silvia V. Alvarez ◽  
Etienne Fortin-Pellerin ◽  
Mohammed Alhabdan ◽  
Jesus S. Lomelin ◽  
Michal Kantoch ◽  
...  
Keyword(s):  
Strain Rate ◽  
Force Frequency ◽  
Frequency Relationship

Abstract 15596: Maturation of Hipsc-cm Electrophysiological and Contractile Function for Enhanced Sensitivity of Cardiac Safety Assays

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Heather B Hayes ◽  
Anthony M Nicolini ◽  
Colin Arrowood ◽  
Daniel Millard
Keyword(s):  
Contractile Function ◽  
Induced Pluripotent Stem Cell ◽  
Force Frequency ◽  
Cardiac Safety ◽  
Electrophysiological Response ◽  
Mechanical Conditioning ◽  
Enhanced Sensitivity ◽  
Frequency Relationship ◽  
Positive Force

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have significantly advanced in vitro cardiac safety and disese modeling, yet remain an immature representation of human myocytes. Electrical or mechanical conditioning of hiPSC-CMs facilitates functional maturation, as measured by a positive force-frequency relationship, but current in vitro protocols require 2-4 weeks of conditioning. Using array-based contractility and local electrical stimulation, we detected functionally mature phenotypes and compound responses in hiPSC-CMs after only 48 hours of chronic pacing. To mature cardiomyocytes, hiPSC-CMs were cultured on 24- and 96-well MEA plates with a dedicated stimulation electrodes. Later, hiPSC-CMs were electrically or optically paced at 2Hz for 48 hours. Multimodal measures quantified contractile and electrophysiological responses to varied pacing rates and compound addition. After 48 hours of pacing, hiPSC-CMs displayed shortened repolarization timing compared to before chronic pacing (baseline: 423 +/- 21 ms; matured: 316 +/- 15 ms), without significant beat period changes (baseline: 1255 +/- 40 ms; matured: 1314 +/- 84 ms). Contractile beat amplitude was measured using array-based impedance during spontaneous beating and at increasing pacing rates (1, 1.2, 1.5, 2, and 2.5 Hz). Before chronic pacing, beat amplitude decreased with increasing pacing rate; after chronic pacing, the same wells displayed increased beat amplitudes with increasing pacing rate. The matured wells also showed enhanced sensitivity to positive inotropes, such as isoproterenol, digoxin, omecamtiv mecarbil, and dobutamine. Local extracellular action potentials (LEAP) further revealed altered electrophysiological response to ranolazine, a multichannel blocker. Unpaced control wells exhibited dose-dependent APD90 prolongation in response to ranolazine, whereas matured wells showed no APD90 change. Similar results were seen with 48 hour of optogenetic pacing at 2 Hz. Overall, hiPSC-CMs chronically paced for only 48 hours exhibited more mature functional phenotypes, including a positive force-frequnecy relationship, enhanced ionotrope sensitivity, and altered compound response.

Positive inotropic responses in cardiac muscles: influence of stimulation frequency and species

1982 ◽  
Vol 60 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Peter K. S. Siegl ◽  
John H. McNeill
Keyword(s):  
Right Ventricular ◽  
Species Difference ◽  
Extracellular Calcium ◽  
Stimulation Frequency ◽  
Force Frequency ◽  
Papillary Muscles ◽  
Drug Induced ◽  
Cardiac Muscles ◽  
Inotropic Responses ◽  
Isolated Rat

Inotropic responses to cumulative additions of methoxaminc (10−7 to 3 × 10−4 M), isoproterenol (10−9 to 10−5 M), or calcium (2 to 32 mM) were measured in isolated rat left atria and papillary muscles and rabbit right ventricular papillary muscles at three stimulation frequencies. Cardiac muscles were incubated in oxygenated Chenoweth–Koelle solution (2 mM calcium) at 37 °C. The basal developed force (BDF) before and maximum developed force (MDF) after challenge with methoxamine and isoproterenol were inversely related to stimulation frequency in rat preparations. BDF was directly related to stimulation rate in rabbit papillary muscles while MDF was independent of the rate. Drug-induced increases in force (MDF – BDF) were independent of stimulation frequency in rat and inversely related to stimulation frequency in rabbit. Responses to calcium were similar to the observed adrenergic responses. Also, force–frequency relationships of the rat and rabbit preparations were not similar in the absence and presence of these agonists. These data show that inotropic responses by rat and rabbit hearts are not affected similarly by stimulation frequency and this may reflect a species difference in the utilization of extracellular calcium for contraction.

scholarly journals Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

2021 ◽  
Author(s):  
Yangyang Lin ◽  
Sam Z. Grinter ◽  
Zhongju Lu ◽  
Xianjin Xu ◽  
Hong Zhan Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Therapeutic Efficacy ◽  
Torsade De Pointes ◽  
Computational Prediction ◽  
Chemical Library ◽  
Drug Induced ◽  
Voltage Dependent ◽  
Life Threatening ◽  
Approved Drugs

AbstractCardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD) either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs, a slowly activating K+ current plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage sensing domain (VSD) of the IKs channel. Here we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.Significance statementC28, identified by in silico screening, specifically facilitated voltage dependent activation of a cardiac potassium ion channel, IKs. C28 reversed drug-induced prolongation of action potentials, but minimally affected the normal action potential at the same dosage. This outcome supports a computational prediction of modulating IKs activation as a potential therapy for all forms of action potential prolongation, and could expand therapeutic efficacy of many currently approved drugs that may trigger arrhythmias.

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