{"doi":"10.1093/cvr/cvab375","title":"Electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes","abstract":"<jats:title>Abstract</jats:title>\n               <jats:sec>\n                  <jats:title>Aims</jats:title>\n                  <jats:p>Cardiac electrophysiological heterogeneity includes: (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents in cells with similar AP durations (APDs). The aim of this study is to assess intra-regional AP waveform differences, to quantify the contribution of specific ion channels to the APD via drug responses and to generate a population of mathematical models to investigate the mechanisms underlying heterogeneity in rabbit ventricular cells.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results</jats:title>\n                  <jats:p>APD in ∼50 isolated cells from subregions of the LV free wall of rabbit hearts were measured using a voltage-sensitive dye. When stimulated at 2 Hz, average APD90 value in cells from the basal epicardial region was 254 ± 25 ms (mean ± standard deviation) in 17 hearts with a mean interquartile range (IQR) of 53 ± 17 ms. Endo-epicardial and apical-basal APD90 differences accounted for ∼10% of the IQR value. Highly variable changes in APD occurred after IK(r) or ICa(L) block that included a sub-population of cells (HR) with an exaggerated (hyper) response to IK(r) inhibition. A set of 4471 AP models matching the experimental APD90 distribution was generated from a larger population of models created by random variation of the maximum conductances (Gmax) of 8 key ion channels/exchangers/pumps. This set reproduced the pattern of cell-specific responses to ICa(L) and IK(r) block, including the HR sub-population. The models exhibited a wide range of Gmax values with constrained relationships linking ICa(L) with IK(r), ICl, INCX, and INaK.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion</jats:title>\n                  <jats:p>Modelling the measured range of inter-cell APDs required a larger range of key Gmax values indicating that ventricular tissue has considerable inter-cell variation in channel/pump/exchanger activity. AP morphology is retained by relationships linking specific ionic conductances. These interrelationships are necessary for stable repolarization despite large inter-cell variation of individual conductances and this explains the variable sensitivity to ion channel block.</jats:p>\n               </jats:sec>","journal":"Cardiovascular Research","year":2022,"id":670251,"datarank":0.5333022092234121,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"self_citation_contribution":0.5333022092234121,"citation_network_contribution":0.0,"self_endowment_contribution":0.5333022092234121,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1750668,"name":"Muhamad Hifzhudin Noor Aziz","orcid":"0000-0001-8888-1380","position":1,"is_corresponding":false},{"id":899845,"name":"Francis L. Burton","orcid":"0000-0002-6970-6250","position":2,"is_corresponding":false},{"id":963213,"name":"Niall Macquaide","orcid":"0000-0001-9026-0073","position":3,"is_corresponding":false},{"id":1946,"name":"Rachel C. Myles","orcid":"0000-0003-4670-361X","position":4,"is_corresponding":false},{"id":1750670,"name":"Radostin D Simitev","orcid":"0000-0002-2207-5789","position":5,"is_corresponding":false},{"id":725633,"name":"Godfrey L. 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The aim of this study is to assess intra-regional AP waveform differences, to quantify the contribution of specific ion channels to the APD via drug responses and to generate a population of mathematical models to investigate the mechanisms underlying heterogeneity in rabbit ventricular cells.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results</jats:title>\n                  <jats:p>APD in ∼50 isolated cells from subregions of the LV free wall of rabbit hearts were measured using a voltage-sensitive dye. When stimulated at 2 Hz, average APD90 value in cells from the basal epicardial region was 254 ± 25 ms (mean ± standard deviation) in 17 hearts with a mean interquartile range (IQR) of 53 ± 17 ms. Endo-epicardial and apical-basal APD90 differences accounted for ∼10% of the IQR value. Highly variable changes in APD occurred after IK(r) or ICa(L) block that included a sub-population of cells (HR) with an exaggerated (hyper) response to IK(r) inhibition. A set of 4471 AP models matching the experimental APD90 distribution was generated from a larger population of models created by random variation of the maximum conductances (Gmax) of 8 key ion channels/exchangers/pumps. This set reproduced the pattern of cell-specific responses to ICa(L) and IK(r) block, including the HR sub-population. The models exhibited a wide range of Gmax values with constrained relationships linking ICa(L) with IK(r), ICl, INCX, and INaK.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion</jats:title>\n                  <jats:p>Modelling the measured range of inter-cell APDs required a larger range of key Gmax values indicating that ventricular tissue has considerable inter-cell variation in channel/pump/exchanger activity. AP morphology is retained by relationships linking specific ionic conductances. These interrelationships are necessary for stable repolarization despite large inter-cell variation of individual conductances and this explains the variable sensitivity to ion channel block.</jats:p>\n               </jats:sec>","is_dataset_classified":null,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35020837","pmcid":"PMC9732512","openalex_id":"https://openalex.org/W4205383943","authors":[],"funders":[{"funder_name":"UK Engineering and Physical Sciences Research Council","grant_id":"EP/N014642/1","title":"EPSRC Centre for Multiscale Soft Tissue Mechanics - with application to heart &amp; cancer"},{"funder_name":"UK Engineering and Physical Sciences Research Council","grant_id":"EP/S030875/1","title":"SofTMech with MIT and POLIMI (SofTMechMP)"},{"funder_name":"Wellcome 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