title: Role of atrial tissue remodeling on rotor dynamics: an in vitro study.
abstract: The objective of this article is to present an in vitro model of atrial cardiac tissue that could serve to study the mechanisms of remodeling related to atrial fibrillation (AF). We analyze the modification on gene expression and modifications on rotor dynamics following tissue remodeling. Atrial murine cells (HL-1 myocytes) were maintained in culture after the spontaneous initiation of AF and analyzed at two time points: 3.1 ± 1.3 and 9.7 ± 0.5 days after AF initiation. The degree of electrophysiological remodeling (i.e., relative gene expression of key ion channels) and structural inhomogeneity was compared between early and late cell culture times both in nonfibrillating and fibrillating cell cultures. In addition, the electrophysiological characteristics of in vitro fibrillation [e.g., density of phase singularities (PS/cm(2)), dominant frequency, and rotor meandering] analyzed by means of optical mapping were compared with the degree of electrophysiological remodeling. Fibrillating cell cultures showed a differential ion channel gene expression associated with atrial tissue remodeling (i.e., decreased SCN5A, CACN1C, KCND3, and GJA1 and increased KCNJ2) not present in nonfibrillating cell cultures. Also, fibrillatory complexity was increased in late- vs. early stage cultures (1.12 ± 0.14 vs. 0.43 ± 0.19 PS/cm(2), P < 0.01), which was associated with changes in the electrical reentrant patterns (i.e., decrease in rotor tip meandering and increase in wavefront curvature). HL-1 cells can reproduce AF features such as electrophysiological remodeling and an increased complexity of the electrophysiological behavior associated with the fibrillation time that resembles those occurring in patients with chronic AF.
authors.affiliation: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; acliment@cardiovascularcelltherapy.com.
authors.forename: Andreu M
authors.initials: AM
authors.lastname: Climent
authors.affiliation: ITACA Institute, Universitat Politécnica de Valencia, Valencia, Spain;
authors.forename: María S
authors.initials: MS
authors.lastname: Guillem
authors.affiliation: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain;
authors.forename: Lucia
authors.initials: L
authors.lastname: Fuentes
authors.affiliation: Essel Research and Development, Toronto, Canada; Division of Cardiology, Toronto General Hospital, Toronto, Canada; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Lee
authors.affiliation: Sidra Medical and Research Center, Division of Cardiovascular Research, Doha, Qatar.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0002-6333-4791
authors.initials: C
authors.lastname: Bollensdorff
authors.affiliation: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain;
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Fernández-Santos
authors.affiliation: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain;
authors.forename: Susana
authors.initials: S
authors.lastname: Suárez-Sancho
authors.affiliation: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain;
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sanz-Ruiz
authors.affiliation: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain;
authors.forename: Pedro Luis
authors.initials: PL
authors.lastname: Sánchez
authors.affiliation: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain;
authors.forename: Felipe
authors.initials: F
authors.lastname: Atienza
authors.affiliation: Cardiology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain;
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernández-Avilés
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D064752:Atrial Remodeling / Q000187:drug effects; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008955:Models, Cardiovascular; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D000889:Anti-Arrhythmia Agents; C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D018031:Connexin 43; C543076:GJA1 protein, mouse; C497022:Kcnd3 protein, mouse; C489461:Kir2.1 channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024661:Potassium Channels, Inwardly Rectifying; C568321:Scn5a protein, mouse; D051672:Shal Potassium Channels
keywords: atrial fibrillation; optical mapping