Abstract 810: Structural and Electrophysiological Maturation of Human iPSC-Derived Atrial Cardiomyocytes to Serve as a Platform to Model Atrial Fibrillation

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Olivia T Ly ◽  
Seock Won Youn ◽  
Grace Brown ◽  
Liang Hong ◽  
Arvind Sridhar ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Atrial Cardiomyocytes ◽  
Human Ipsc

Late Sodium Current in Atrial Cardiomyocytes Contributes to the Induced and Spontaneous Atrial Fibrillation in Rabbit Hearts

2020 ◽  
Vol 76 (4) ◽  
pp. 437-444
Author(s):  
Yanpeng Chu ◽  
Qiaomei Yang ◽  
Lu Ren ◽  
Shandong Yu ◽  
Zhipei Liu ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Sodium Current ◽  
Late Sodium Current ◽  
Atrial Cardiomyocytes

scholarly journals Defective regulation of L-type calcium currents by Src-kinase in atrial cardiomyocytes from patients with chronic atrial fibrillation

2002 ◽  
Vol 39 ◽  
pp. 104
Author(s):  
Maura Greiser ◽  
Christian R. Halaszovich ◽  
Marius Skasa ◽  
Christoph Stellbrink ◽  
Peter Hanrath ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Src Kinase ◽  
Chronic Atrial Fibrillation ◽  
Calcium Currents ◽  
Atrial Cardiomyocytes

scholarly journals Late Sodium Current in Human Atrial Cardiomyocytes from Patients in Sinus Rhythm and Atrial Fibrillation

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0131432 ◽  
Author(s):  
Claire Poulet ◽  
Erich Wettwer ◽  
Morten Grunnet ◽  
Thomas Jespersen ◽  
Larissa Fabritz ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Sinus Rhythm ◽  
Sodium Current ◽  
Late Sodium Current ◽  
Atrial Cardiomyocytes

The Role of OSM and Reg3β for Dedifferentiation of Atrial Cardiomyocytes in Human Patients with Atrial Fibrillation

2015 ◽  
Vol 21 (10) ◽  
pp. S178
Author(s):  
Sokichi Kamata ◽  
Manfred Richter ◽  
Thomas Kubin ◽  
Yoshiki Sawa ◽  
Thomas Walter ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Atrial Cardiomyocytes

scholarly journals In-silico analysis of aging mechanisms of action potential remodeling in human atrial cardiomyocites

2020 ◽  
Vol 22 ◽  
pp. 01025
Author(s):  
Tatyana Nesterova ◽  
Dmitry Shmarko ◽  
Konstantin Ushenin ◽  
Olga Solovyova
Keyword(s):  
Experimental Data ◽  
Atrial Fibrillation ◽  
Action Potential ◽  
In Silico ◽  
Antiarrhythmic Drugs ◽  
Model Parameters ◽  
Experimental Conditions ◽  
Human Cardiomyocytes ◽  
Atrial Cardiomyocytes ◽  
Age Related

Electrophysiology of cardiomyocytes changes with aging. Agerelated ionic remodeling in cardiomyocytes may increase the incidence and prevalence of atrial fibrillation (AF) in the elderly and affect the efficiency of antiarrhythmic drugs. There is the deep lack of experimental data on an action potential and transmembrane currents recorded in the healthy human cardiomyocytes of different age. Experimental data in mammals is also incomplete and often contradicting depending on the experimental conditions. In this in-silico study, we used a population of ionic models of human atrial cardiomyocytes to transfer data on the age- related ionic remodeling in atrial cardiomyocytes from canines and mice to predict possible consequences for human cardiomyocyte activity. Based on experimental data, we analyzes two hypotheses on the aging effect on the ionic currents using two age-related sets of varied model parameters and evaluated corresponding changes in action potential morphology with aging. Using the two populations of aging models, we analyzed the agedependent sensitivity of atrial cardiomyocytes to Dofetilide which is one of the antiarrhythmic drugs widely used in patients with atrial fibrillation.

Modelling of atrial fibrillation at physiologically relevant scales enabled by massive expansion of native human atrial cardiomyocytes

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
N Harlaar ◽  
SO Dekker ◽  
J Zhang ◽  
MJ Schalij ◽  
RJM Klautz ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Conduction Velocity ◽  
Lentiviral Vector ◽  
Troponin T ◽  
Simian Virus 40 ◽  
T Antigen ◽  
Atrial Cardiomyocytes ◽  
Cardiomyogenic Differentiation ◽  
Electrical Pacing ◽  
Human Atrial Fibrillation

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): LUMC Background Current in vitro models of atrial fibrillation have limited translational potential due to a lack of relevant human physiology or the inability to reach the high activation frequencies present in human atrial fibrillation. Absence of relevant models is the result of a general deficit of readily available and standardized sources of well-differentiated human atrial cardiomyocytes. Therefore, we aimed to immortalize native human atrial cardiomyocytes to produce natural and standardized lines of these cells. Methods Human fetal atrial cardiomyocytes were transduced with a lentiviral vector directing myocyte-specific and doxycycline-inducible expression of simian virus 40 large T antigen. Addition of doxycycline to the culture medium pushed cardiomyocytes towards a highly proliferative phenotype (proliferation up to 10^12 cells). These cells were labelled hiAMs (human immortalised Atrial Myocytes). After differentiation upon doxycycline removal, hiAM cells were characterized using various molecular, biological and electrophysiological assays. Results Following cardiomyogenic differentiation, hiAMs no longer expressed the proliferation marker Ki67, revealed striated α-actinin and troponin T staining patterns and displayed synchronous contractions. Optical voltage mapping of hiAM monolayers revealed excitable cells showing homogeneous spreading of action potentials at 22.5 ± 3.1 cm/s with a mean APD80 of 139 ± 22 ms. Addition of flecainide (10 µM) to hiAM monolayers decreased the conduction velocity by 35% and increased the APD80 by 107%. Dofetilide (10 nM) addition had no effect on the conduction velocity, but did increase the APD80 by 81%. Due to their scalability, monolayers of hiAMs as big as 10 cm2 showing homogenous action potential propagation could easily be created. Following high-frequency electrical pacing, rotors could be induced with an average activation frequency of 7.5 ± 0.9 Hz. Infusion of flecainide during arrhythmic activity resulted in termination of the rotor in 18 of 24 attempts (75%), whereas addition of 0.1% DMSO (vehicle control) did not result in termination in any of the attempts. Dofetilide infusion did not result in termination. However, it did lower the average activation frequency to 2.1 ± 0.7 Hz. Conclusion We have generated first-of-a-kind lines of human atrial cardiomyocytes, allowing massive cell expansion under proliferation conditions and robust formation of cross-striated, contractile and excitable cardiomyocytes after differentiation. These characteristics allow, for the first time, the modelling, at a large-scale, of human atrial arrhythmias with frequencies similar to human atrial fibrillation. With the generation of hiAMs, a user-friendly, clinically-relevant and much-anticipated human atrial research model has been produced. Abstract Figure. hiAM AF Model

scholarly journals Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation

2020 ◽  
Vol 127 (8) ◽  
pp. 1036-1055 ◽  
Author(s):  
Jordi Heijman ◽  
Azinwi Phina Muna ◽  
Tina Veleva ◽  
Cristina E. Molina ◽  
Henry Sutanto ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Patch Clamp ◽  
Protein Expression ◽  
Postoperative Atrial Fibrillation ◽  
Interleukin 1Β ◽  
Right Atrial ◽  
Open Probability ◽  
Atrial Cardiomyocytes ◽  
Increased Risk ◽  
Tissue Homogenates

Rationale: Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown. Objective: To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery. Methods and Results: Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca 2+ ] i -recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca 2+ -transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca 2+ -release events and L-type Ca 2+ -current alternans occurred more frequently. CaMKII (Ca 2+ /calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca 2+ -content was unchanged in POAF despite greater SR Ca 2+ -leak, with a trend towards increased SR Ca 2+ -ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1β caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca 2+ -release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca 2+ -uptake are sufficient to reproduce the Ca 2+ -handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β. Conclusions: Preexisting Ca 2+ -handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca 2+ -releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.

Dedifferentiation of atrial cardiomyocytes in cardiac valve disease: unrelated to atrial fibrillation

2008 ◽  
Vol 17 (3) ◽  
pp. 156-165 ◽  
Author(s):  
Mien-Cheng Chen ◽  
Jen-Ping Chang ◽  
Shun-Chen Huang ◽  
Hsueh-Wen Chang ◽  
Chien-Jen Chen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cardiac Valve ◽  
Valve Disease ◽  
Atrial Cardiomyocytes ◽  
Cardiac Valve Disease

Bioengineering approaches to mature induced pluripotent stem cell-derived atrial cardiomyocytes to model atrial fibrillation

2021 ◽  
pp. 153537022110091
Author(s):  
Olivia T Ly ◽  
Grace E Brown ◽  
Yong Duk Han ◽  
Dawood Darbar ◽  
Salman R Khetani
Keyword(s):  
Atrial Fibrillation ◽  
3D Culture ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Pharmacologic Therapy ◽  
Mature Adult ◽  
Culture Techniques ◽  
Atrial Cardiomyocytes ◽  
Induced Pluripotent ◽  
Parenchymal Cells

Induced pluripotent stem cells (iPSCs) serve as a robust platform to model several human arrhythmia syndromes including atrial fibrillation (AF). However, the structural, molecular, functional, and electrophysiological parameters of patient-specific iPSC-derived atrial cardiomyocytes (iPSC-aCMs) do not fully recapitulate the mature phenotype of their human adult counterparts. The use of physiologically inspired microenvironmental cues, such as postnatal factors, metabolic conditioning, extracellular matrix (ECM) modulation, electrical and mechanical stimulation, co-culture with non-parenchymal cells, and 3D culture techniques can help mimic natural atrial development and induce a more mature adult phenotype in iPSC-aCMs. Such advances will not only elucidate the underlying pathophysiological mechanisms of AF, but also identify and assess novel mechanism-based therapies towards supporting a more ‘personalized’ (i.e. patient-specific) approach to pharmacologic therapy of AF.

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