Experimentally-Based Computational Investigation into Beat-To-Beat Variability in Ventricular Repolarization and Its Response to Ionic Current Inhibition
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{"title"=>"Experimentally-based computational investigation into beat-to-beat variability in ventricular repolarization and its response to ionic current inhibition", "type"=>"journal", "authors"=>[{"first_name"=>"E.", "last_name"=>"Pueyo", "scopus_author_id"=>"7004512193"}, {"first_name"=>"C. E.", "last_name"=>"Dangerfield", "scopus_author_id"=>"35093693600"}, {"first_name"=>"O. J.", "last_name"=>"Britton", "scopus_author_id"=>"37033557900"}, {"first_name"=>"L.", "last_name"=>"Virág", "scopus_author_id"=>"7007076035"}, {"first_name"=>"K.", "last_name"=>"Kistamás", "scopus_author_id"=>"50161711100"}, {"first_name"=>"N.", "last_name"=>"Szentandrássy", "scopus_author_id"=>"6602625747"}, {"first_name"=>"N.", "last_name"=>"Jost", "scopus_author_id"=>"8838935100"}, {"first_name"=>"A.", "last_name"=>"Varró", "scopus_author_id"=>"7004541739"}, {"first_name"=>"P. P.", "last_name"=>"Nánási", "scopus_author_id"=>"45461224900"}, {"first_name"=>"K.", "last_name"=>"Burrage", "scopus_author_id"=>"7006145077"}, {"first_name"=>"B.", "last_name"=>"Rodríguez", "scopus_author_id"=>"35594111500"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84962190476", "scopus"=>"2-s2.0-84962190476", "issn"=>"19326203", "pui"=>"609350843", "doi"=>"10.1371/journal.pone.0151461", "pmid"=>"27019293"}, "id"=>"9738b60c-be55-3dc0-93f6-d74da0a4ae19", "abstract"=>"Beat-to-beat variability in repolarization (BVR) has been proposed as an arrhythmic risk marker for disease and pharmacological action. The mechanisms are unclear but BVR is thought to be a cell level manifestation of ion channel stochasticity, modulated by cell-to-cell differences in ionic conductances. In this study, we describe the construction of an experimentally-calibrated set of stochastic cardiac cell models that captures both BVR and cell-to-cell differences in BVR displayed in isolated canine action potential measurements using pharmacological agents. Simulated and experimental ranges of BVR are compared in control and under pharmacological inhibition, and the key ionic currents determining BVR under physiological and pharmacological conditions are identified. Results show that the 4-aminopyridine-sensitive transient outward potassium current, Ito1, is a fundamental driver of BVR in control and upon complete inhibition of the slow delayed rectifier potassium current, IKs. In contrast, IKs and the L-type calcium current, ICaL, become the major contributors to BVR upon inhibition of the fast delayed rectifier potassium current, IKr. This highlights both IKs and Ito1 as key contributors to repolarization reserve. Partial correlation analysis identifies the distribution of Ito1 channel numbers as an important independent determinant of the magnitude of BVR and drug-induced change in BVR in control and under pharmacological inhibition of ionic currents. Distributions in the number of IKs and ICaL channels only become independent determinants of the magnitude of BVR upon complete inhibition of IKr. These findings provide quantitative insights into the ionic causes of BVR as a marker for repolarization reserve, both under control condition and pharmacological inhibition.", "link"=>"http://www.mendeley.com/research/experimentallybased-computational-investigation-beattobeat-variability-ventricular-repolarization-re", "reader_count"=>16, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Student > Master"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Student > Master"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>3, "Unspecified"=>5, "Biochemistry, Genetics and Molecular Biology"=>1, "Mathematics"=>2, "Medicine and Dentistry"=>1, "Agricultural and Biological Sciences"=>2, "Chemistry"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>3}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>5}}, "reader_count_by_country"=>{"United Kingdom"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/4872919"], "description"=>"<p>Single AP traces obtained using the seventeen deterministic models, simulated with a BCL of 1000 ms under: control conditions (top left), complete I<sub>Kr</sub> inhibition (top right), complete I<sub>Ks</sub> inhibition (bottom left), complete I<sub>Ks</sub> and 90% I<sub>to1</sub> inhibition (bottom middle) and 95% I<sub>CaL</sub> inhibition (bottom right). Red vertical lines represent the maximum and minimum APD values derived from experimental data for the same simulation protocol. The blue dotted AP trace represents the Decker model without any rescaling of the ionic currents.</p>", "links"=>[], "tags"=>["arrhythmic risk marker", "inhibition", "BVR", "repolarization reserve", "ion channel stochasticity", "Partial correlation analysis", "Ito 1 channel numbers", "cell level manifestation", "rectifier potassium", "IK"], "article_id"=>3132610, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Evolutionary Biology", "Chemical Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Infectious Diseases"], "users"=>["E. Pueyo", "C. E. Dangerfield", "O. J. Britton", "L. Virág", "K. Kistamás", "N. Szentandrássy", "N. Jost", "A. Varró", "P. P. Nánási", "K. Burrage", "B. Rodríguez"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0151461.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Deterministic_model_single_AP_traces_/3132610", "title"=>"Deterministic model single AP traces.", "pos_in_sequence"=>3, "defined_type"=>1, "published_date"=>"2016-03-28 05:59:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4872997"], "description"=>"<p>Top: APD sequences of 30 beats for individual experiments and model realizations under control, illustrating cases associated with low (left) and high (right) temporal variability. Bottom: BVR measures in experiments (red crosses) and simulations (black open circles), calculated in mean over realizations, under control conditions. The BVR measures, from left to right, are as follows: ran<sub>APD</sub>, var<sub>APD</sub>, STV<sub>APD</sub> and LTV<sub>APD</sub>.</p>", "links"=>[], "tags"=>["arrhythmic risk marker", "inhibition", "BVR", "repolarization reserve", "ion channel stochasticity", "Partial correlation analysis", "Ito 1 channel numbers", "cell level manifestation", "rectifier potassium", "IK"], "article_id"=>3132676, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Evolutionary Biology", "Chemical Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Infectious Diseases"], "users"=>["E. Pueyo", "C. E. Dangerfield", "O. J. Britton", "L. Virág", "K. Kistamás", "N. Szentandrássy", "N. Jost", "A. Varró", "P. P. Nánási", "K. Burrage", "B. Rodríguez"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0151461.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Results_from_population_of_stochastic_models_under_control_conditions_/3132676", "title"=>"Results from population of stochastic models under control conditions.", "pos_in_sequence"=>5, "defined_type"=>1, "published_date"=>"2016-03-28 05:59:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4873051"], "description"=>"<p>A) Left: Poincaré plots for an individual experiment and a model realization under control and following I<sub>Kr</sub> inhibition. Right: BVR measures in experiments (red crosses) and simulations (black open circles), calculated in mean over realizations, under I<sub>Kr</sub> inhibition. The BVR measures, from left to right, are as follows: ran<sub>APD</sub>, var<sub>APD</sub>, STV<sub>APD</sub> and LTV<sub>APD</sub>. B) As in A) but following I<sub>Ks</sub> inhibition.</p>", "links"=>[], "tags"=>["arrhythmic risk marker", "inhibition", "BVR", "repolarization reserve", "ion channel stochasticity", "Partial correlation analysis", "Ito 1 channel numbers", "cell level manifestation", "rectifier potassium", "IK"], "article_id"=>3132709, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Evolutionary Biology", "Chemical Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Infectious Diseases"], "users"=>["E. Pueyo", "C. E. Dangerfield", "O. J. Britton", "L. Virág", "K. Kistamás", "N. Szentandrássy", "N. Jost", "A. Varró", "P. P. Nánási", "K. Burrage", "B. Rodríguez"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0151461.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Results_from_population_of_stochastic_models_under_I_sub_Kr_sub_and_I_sub_Ks_sub_inhibition_/3132709", "title"=>"Results from population of stochastic models under I<sub>Kr</sub> and I<sub>Ks</sub> inhibition.", "pos_in_sequence"=>6, "defined_type"=>1, "published_date"=>"2016-03-28 05:59:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4872961"], "description"=>"<p>Number of channels (left) and scaling factors for current conductances (right) in the seventeen models for I<sub>Kr</sub>, I<sub>Ks</sub>, I<sub>to1,</sub> I<sub>CaL</sub> and I<sub>K1</sub>.</p>", "links"=>[], "tags"=>["arrhythmic risk marker", "inhibition", "BVR", "repolarization reserve", "ion channel stochasticity", "Partial correlation analysis", "Ito 1 channel numbers", "cell level manifestation", "rectifier potassium", "IK"], "article_id"=>3132646, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Evolutionary Biology", "Chemical Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Infectious Diseases"], "users"=>["E. Pueyo", "C. E. Dangerfield", "O. J. Britton", "L. Virág", "K. Kistamás", "N. Szentandrássy", "N. Jost", "A. Varró", "P. P. Nánási", "K. Burrage", "B. Rodríguez"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0151461.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Channel_numbers_and_current_conductance_scaling_factors_/3132646", "title"=>"Channel numbers and current conductance scaling factors.", "pos_in_sequence"=>4, "defined_type"=>1, "published_date"=>"2016-03-28 05:59:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4873126"], "description"=>"<p>A) Bar graphs showing the mean and standard deviation of APD variability measurements across the set of models from simulations where all currents are stochastic and also when stochasticity is incorporated into each individual current, following I<sub>Kr</sub> inhibition. The measures of variability are ran<sub>APD</sub> (top left), var<sub>APD</sub> (top right), STV<sub>APD</sub> (bottom left) and LTV<sub>APD</sub> (bottom right). Insets: Partial correlation coefficients between variability measures and ion channel numbers, with black dots and open circles indicating significant and not significant correlation, respectively. B) As in A) but following I<sub>Ks</sub> inhibition.</p>", "links"=>[], "tags"=>["arrhythmic risk marker", "inhibition", "BVR", "repolarization reserve", "ion channel stochasticity", "Partial correlation analysis", "Ito 1 channel numbers", "cell level manifestation", "rectifier potassium", "IK"], "article_id"=>3132778, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Evolutionary Biology", "Chemical Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Infectious Diseases"], "users"=>["E. Pueyo", "C. E. Dangerfield", "O. J. Britton", "L. Virág", "K. Kistamás", "N. Szentandrássy", "N. Jost", "A. Varró", "P. P. Nánási", "K. Burrage", "B. Rodríguez"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0151461.g007", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Variability_in_APD_across_the_population_of_models_under_I_sub_Kr_sub_and_I_sub_Ks_sub_inhibition_/3132778", "title"=>"Variability in APD across the population of models under I<sub>Kr</sub> and I<sub>Ks</sub> inhibition.", "pos_in_sequence"=>8, "defined_type"=>1, "published_date"=>"2016-03-28 05:59:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4873096"], "description"=>"<p>Bar graphs showing the mean and standard deviation of APD variability measurements across the seventeen models from simulations where all currents are stochastic and also when stochasticity is incorporated into each individual current, under control conditions. The measures of variability are ran<sub>APD</sub> (top left), var<sub>APD</sub> (top right), STV<sub>APD</sub> (bottom left) and LTV<sub>APD</sub> (bottom right). Insets: Partial correlation coefficients between variability measures and ion channel numbers, with black dots and open circles indicating significant and not significant correlation, respectively.</p>", "links"=>[], "tags"=>["arrhythmic risk marker", "inhibition", "BVR", "repolarization reserve", "ion channel stochasticity", "Partial correlation analysis", "Ito 1 channel numbers", "cell level manifestation", "rectifier potassium", "IK"], "article_id"=>3132748, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Evolutionary Biology", "Chemical Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Infectious Diseases"], "users"=>["E. Pueyo", "C. E. Dangerfield", "O. J. Britton", "L. Virág", "K. Kistamás", "N. Szentandrássy", "N. Jost", "A. Varró", "P. P. Nánási", "K. Burrage", "B. Rodríguez"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0151461.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Variability_in_APD_across_the_population_of_models_under_control_conditions_/3132748", "title"=>"Variability in APD across the population of models under control conditions.", "pos_in_sequence"=>7, "defined_type"=>1, "published_date"=>"2016-03-28 05:59:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4872835", "https://ndownloader.figshare.com/files/4872847"], "description"=>"<div><p>Beat-to-beat variability in repolarization (BVR) has been proposed as an arrhythmic risk marker for disease and pharmacological action. The mechanisms are unclear but BVR is thought to be a cell level manifestation of ion channel stochasticity, modulated by cell-to-cell differences in ionic conductances. In this study, we describe the construction of an experimentally-calibrated set of stochastic cardiac cell models that captures both BVR and cell-to-cell differences in BVR displayed in isolated canine action potential measurements using pharmacological agents. Simulated and experimental ranges of BVR are compared in control and under pharmacological inhibition, and the key ionic currents determining BVR under physiological and pharmacological conditions are identified. Results show that the 4-aminopyridine-sensitive transient outward potassium current, I<sub>to1</sub>, is a fundamental driver of BVR in control and upon complete inhibition of the slow delayed rectifier potassium current, I<sub>Ks</sub>. In contrast, I<sub>Ks</sub> and the L-type calcium current, I<sub>CaL</sub>, become the major contributors to BVR upon inhibition of the fast delayed rectifier potassium current, I<sub>Kr</sub>. This highlights both I<sub>Ks</sub> and I<sub>to1</sub> as key contributors to repolarization reserve. Partial correlation analysis identifies the distribution of I<sub>to1</sub> channel numbers as an important independent determinant of the magnitude of BVR and drug-induced change in BVR in control and under pharmacological inhibition of ionic currents. Distributions in the number of I<sub>Ks</sub> and I<sub>CaL</sub> channels only become independent determinants of the magnitude of BVR upon complete inhibition of I<sub>Kr</sub>. These findings provide quantitative insights into the ionic causes of BVR as a marker for repolarization reserve, both under control condition and pharmacological inhibition.</p></div>", "links"=>[], "tags"=>["arrhythmic risk marker", "inhibition", "BVR", "repolarization reserve", "ion channel stochasticity", "Partial correlation analysis", "Ito 1 channel numbers", "cell level manifestation", "rectifier potassium", "IK"], "article_id"=>3132535, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Evolutionary Biology", "Chemical Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Infectious Diseases"], "users"=>["E. Pueyo", "C. E. Dangerfield", "O. J. Britton", "L. Virág", "K. Kistamás", "N. Szentandrássy", "N. Jost", "A. Varró", "P. P. Nánási", "K. Burrage", "B. Rodríguez"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0151461.s001", "https://dx.doi.org/10.1371/journal.pone.0151461.s002"], "stats"=>{"downloads"=>2, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Experimentally_Based_Computational_Investigation_into_Beat_To_Beat_Variability_in_Ventricular_Repolarization_and_Its_Response_to_Ionic_Current_Inhibition/3132535", "title"=>"Experimentally-Based Computational Investigation into Beat-To-Beat Variability in Ventricular Repolarization and Its Response to Ionic Current Inhibition", "pos_in_sequence"=>1, "defined_type"=>4, "published_date"=>"2016-03-28 05:59:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/4872886"], "description"=>"<p>Examples of simulated and experimental canine I<sub>CaL</sub> (top) and I<sub>Ks</sub> (bottom) traces, following voltage pulses from -40 mV to test potentials ranging from -35 to 55 mV in 5-mV increments in the case of I<sub>CaL</sub> and from -20 to 50 mV in 10-mV increments in the case of I<sub>Ks</sub>.</p>", "links"=>[], "tags"=>["arrhythmic risk marker", "inhibition", "BVR", "repolarization reserve", "ion channel stochasticity", "Partial correlation analysis", "Ito 1 channel numbers", "cell level manifestation", "rectifier potassium", "IK"], "article_id"=>3132580, "categories"=>["Biochemistry", "Cell Biology", "Genetics", "Molecular Biology", "Pharmacology", "Biotechnology", "Evolutionary Biology", "Chemical Sciences not elsewhere classified", "Developmental Biology", "Cancer", "Infectious Diseases"], "users"=>["E. Pueyo", "C. E. Dangerfield", "O. J. Britton", "L. Virág", "K. Kistamás", "N. Szentandrássy", "N. Jost", "A. Varró", "P. P. Nánási", "K. Burrage", "B. Rodríguez"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0151461.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Simulated_and_experimental_canine_I_sub_CaL_sub_and_I_sub_Ks_sub_traces_/3132580", "title"=>"Simulated and experimental canine I<sub>CaL</sub> and I<sub>Ks</sub> traces.", "pos_in_sequence"=>2, "defined_type"=>1, "published_date"=>"2016-03-28 05:59:41"}

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{"start_date"=>"2016-01-01T00:00:00Z", "end_date"=>"2016-12-31T00:00:00Z", "subject_areas"=>[]}
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