{"doi":"10.1161/hc4701.099578","title":"β-Adrenergic Receptor Blockers Restore Cardiac Calcium Release Channel (Ryanodine Receptor) Structure and Function in Heart Failure","abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Background</jats:italic>\n                </jats:bold>\n              </jats:italic>\n            </jats:bold>\n            β-Adrenergic receptor blockade is one of the most effective treatments for heart failure, a leading cause of mortality worldwide. The use of β-adrenergic receptor blockers in patients with heart failure is counterintuitive, however, because they are known to decrease contractility in normal hearts. The ryanodine receptor (RyR2) on cardiac sarcoplasmic reticulum is the key calcium release channel required for excitation-contraction coupling. In failing hearts, the stoichiometry and function of the RyR2 macromolecular complex is altered. Decreased levels of phosphatases (PP1 and PP2A) and hyperphosphorylation by protein kinase A result in dissociation of the regulatory protein FKBP12.6 and channels with increased open probability.\n          </jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Methods and Results</jats:italic>\n                </jats:bold>\n              </jats:italic>\n            </jats:bold>\n            Here, we show that systemic oral administration of a β-adrenergic receptor blocker reverses protein kinase A hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function in a canine model of heart failure.\n          </jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Conclusions</jats:italic>\n                </jats:bold>\n              </jats:italic>\n            </jats:bold>\n            These results may, in part, explain the improved cardiac function observed in heart failure patients treated with β-adrenergic receptor blockers.\n          </jats:p>","journal":"Circulation","year":2001,"id":680221,"datarank":0.779774554689874,"base_score":5.198497031265826,"endowment":5.198497031265826,"self_citation_contribution":0.779774554689874,"citation_network_contribution":0.0,"self_endowment_contribution":0.779774554689874,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":180,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":2,"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":1777256,"name":"Marta Gaburjakova","orcid":null,"position":1,"is_corresponding":false},{"id":1777257,"name":"Jana Gaburjakova","orcid":null,"position":2,"is_corresponding":false},{"id":1777258,"name":"Kun-lun He","orcid":null,"position":3,"is_corresponding":false},{"id":1777260,"name":"Alfonso Prieto","orcid":null,"position":4,"is_corresponding":false},{"id":1777262,"name":"Eva Becker","orcid":null,"position":5,"is_corresponding":false},{"id":1777263,"name":"Geng-hua Yi","orcid":null,"position":6,"is_corresponding":false},{"id":427738,"name":"Jie Wang","orcid":"0000-0002-2997-3450","position":7,"is_corresponding":false},{"id":230591,"name":"Daniel Burkhoff","orcid":"0000-0003-3995-2466","position":8,"is_corresponding":false},{"id":312237,"name":"Andrew R. Marks","orcid":"0000-0002-4316-5775","position":9,"is_corresponding":false},{"id":313220,"name":"Steven Reiken","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"β-Adrenergic Receptor Blockers Restore Cardiac Calcium Release Channel (Ryanodine Receptor) Structure and Function in Heart Failure","abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Background</jats:italic>\n                </jats:bold>\n              </jats:italic>\n            </jats:bold>\n            β-Adrenergic receptor blockade is one of the most effective treatments for heart failure, a leading cause of mortality worldwide. The use of β-adrenergic receptor blockers in patients with heart failure is counterintuitive, however, because they are known to decrease contractility in normal hearts. The ryanodine receptor (RyR2) on cardiac sarcoplasmic reticulum is the key calcium release channel required for excitation-contraction coupling. In failing hearts, the stoichiometry and function of the RyR2 macromolecular complex is altered. Decreased levels of phosphatases (PP1 and PP2A) and hyperphosphorylation by protein kinase A result in dissociation of the regulatory protein FKBP12.6 and channels with increased open probability.\n          </jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Methods and Results</jats:italic>\n                </jats:bold>\n              </jats:italic>\n            </jats:bold>\n            Here, we show that systemic oral administration of a β-adrenergic receptor blocker reverses protein kinase A hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function in a canine model of heart failure.\n          </jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Conclusions</jats:italic>\n                </jats:bold>\n              </jats:italic>\n            </jats:bold>\n            These results may, in part, explain the improved cardiac function observed in heart failure patients treated with β-adrenergic receptor blockers.\n          </jats:p>","is_dataset_classified":null,"base_score":5.198497031265826,"endowment":5.198497031265826,"datacite_reuse_total":2,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"11733405","pmcid":null,"openalex_id":"https://openalex.org/W2077319362","authors":[],"funders":[],"total_grants":0,"fwci":8.7518,"citation_percentile":0.98242544,"influential_citations":0,"citation_trend":[{"year":2012,"count":6},{"year":2013,"count":7},{"year":2014,"count":6},{"year":2015,"count":4},{"year":2016,"count":9},{"year":2017,"count":1},{"year":2018,"count":5},{"year":2019,"count":2},{"year":2020,"count":4},{"year":2021,"count":1},{"year":2022,"count":1},{"year":2023,"count":6},{"year":2024,"count":2},{"year":2025,"count":1},{"year":2026,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"https://www.ahajournals.org/doi/full/10.1161/hc4701.099578","host_type":"publisher"},{"url":"https://doi.org/10.1161/hc4701.099578","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/11733405","host_type":"repository"}],"fields_of_study":["Cardiac electrophysiology and arrhythmias","Ion channel regulation and function","Cardiac Fibrosis and Remodeling","Adrenergic beta-Antagonists","Animals","Binding, Competitive","Calcium","Cardiac Pacing, Artificial","Cyclic AMP-Dependent Protein Kinases","Dogs","Heart Failure","Immunoblotting","Metoprolol","Myocardium","Phosphorylation","Precipitin Tests","Ryanodine Receptor Calcium Release Channel"],"mesh_terms":["Adrenergic beta-Antagonists","Animals","Binding, Competitive","Calcium","Cardiac Pacing, Artificial","Dogs","Heart Failure","Metoprolol","Myocardium","Phosphorylation","Precipitin Tests","Immunoblotting","Cyclic AMP-Dependent Protein Kinases","Ryanodine Receptor Calcium Release Channel"],"keywords":["Ryanodine receptor 2","Ryanodine receptor","Hyperphosphorylation","Heart failure","Medicine","Internal medicine","Contractility","Endocrinology","Calcium channel","Receptor","Calcium","Cell biology","Biology","Kinase"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.24186170.v1","title":"Additional file 1 of Personalized medicine in the dish to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.24186170","title":"Additional file 1 of Personalized medicine in the dish to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes","publisher":"figshare","resource_type":"JournalArticle"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T14:38:48.993453Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}