{"_id":"cJdo4Cx5mFuptwQ5W","bibbaseid":"adams-raisch-zhao-davalos-barrett-king-bain-coluccichang-etal-extracellularperinexalseparationisaprincipaldeterminantofcardiacconduction-2023","author_short":["Adams, W. P.","Raisch, T. B.","Zhao, Y.","Davalos, R.","Barrett, S.","King, D. R.","Bain, C. B.","Colucci-Chang, K.","Blair, G. A.","Hanlon, A.","Lozano, A.","Veeraraghavan, R.","Wan, X.","Deschenes, I.","Smyth, J. W.","Hoeker, G. S.","Gourdie, R. G.","Poelzing, S."],"bibdata":{"bibtype":"article","type":"Journal Article","author":[{"propositions":[],"lastnames":["Adams"],"firstnames":["W.","P."],"suffixes":[]},{"propositions":[],"lastnames":["Raisch"],"firstnames":["T.","B."],"suffixes":[]},{"propositions":[],"lastnames":["Zhao"],"firstnames":["Y."],"suffixes":[]},{"propositions":[],"lastnames":["Davalos"],"firstnames":["R."],"suffixes":[]},{"propositions":[],"lastnames":["Barrett"],"firstnames":["S."],"suffixes":[]},{"propositions":[],"lastnames":["King"],"firstnames":["D.","R."],"suffixes":[]},{"propositions":[],"lastnames":["Bain"],"firstnames":["C.","B."],"suffixes":[]},{"propositions":[],"lastnames":["Colucci-Chang"],"firstnames":["K."],"suffixes":[]},{"propositions":[],"lastnames":["Blair"],"firstnames":["G.","A."],"suffixes":[]},{"propositions":[],"lastnames":["Hanlon"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Lozano"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Veeraraghavan"],"firstnames":["R."],"suffixes":[]},{"propositions":[],"lastnames":["Wan"],"firstnames":["X."],"suffixes":[]},{"propositions":[],"lastnames":["Deschenes"],"firstnames":["I."],"suffixes":[]},{"propositions":[],"lastnames":["Smyth"],"firstnames":["J.","W."],"suffixes":[]},{"propositions":[],"lastnames":["Hoeker"],"firstnames":["G.","S."],"suffixes":[]},{"propositions":[],"lastnames":["Gourdie"],"firstnames":["R.","G."],"suffixes":[]},{"propositions":[],"lastnames":["Poelzing"],"firstnames":["S."],"suffixes":[]}],"title":"Extracellular Perinexal Separation Is a Principal Determinant of Cardiac Conduction","journal":"Circ Res","volume":"133","number":"8","pages":"658-673","note":"1524-4571 Adams, William P Orcid: 0000-0002-5601-663x Raisch, Tristan B Orcid: 0000-0002-6469-8570 Zhao, Yajun Orcid: 0000-0003-3029-0291 Davalos, Rafael Orcid: 0000-0003-1503-9509 Barrett, Sarah King, D Ryan Bain, Chandra B Orcid: 0000-0002-5308-5509 Colucci-Chang, Katrina Blair, Grace A Orcid: 0000-0002-5633-5497 Hanlon, Alexandra Lozano, Alicia Veeraraghavan, Rengasayee Wan, Xiaoping Orcid: 0009-0006-0417-3437 Deschenes, Isabelle Smyth, James W Hoeker, Gregory S Orcid: 0000-0002-3917-4791 Gourdie, Robert G Orcid: 0000-0001-6021-0796 Poelzing, Steven Orcid: 0000-0002-6979-1264 R01 HL094450/HL/NHLBI NIH HHS/United States R01 HL159097/HL/NHLBI NIH HHS/United States R01 HL132236/HL/NHLBI NIH HHS/United States R01 HL096962/HL/NHLBI NIH HHS/United States R35 HL161237/HL/NHLBI NIH HHS/United States R01 HL102298/HL/NHLBI NIH HHS/United States F31 HL140873/HL/NHLBI NIH HHS/United States R01 HL056728/HL/NHLBI NIH HHS/United States R01 HL138003/HL/NHLBI NIH HHS/United States R25 GM072767/GM/NIGMS NIH HHS/United States F31 HL147438/HL/NHLBI NIH HHS/United States R01 HL141855/HL/NHLBI NIH HHS/United States Journal Article United States 2023/09/08 Circ Res. 2023 Sep 29;133(8):658-673. doi: 10.1161/CIRCRESAHA.123.322567. Epub 2023 Sep 8.","abstract":"BACKGROUND: Cardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in the heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular resistance. By contrast, ephaptic theory is premised on the existence of a biphasic relationship between CV and the volume of specialized extracellular clefts within intercalated discs such as the perinexus. Our objective was to determine the relationship between ventricular CV and structural changes to micro- and nanoscale extracellular spaces. METHODS: Conduction and Cx43 (connexin43) protein expression were quantified from optically mapped guinea pig whole-heart preparations perfused with the osmotic agents albumin, mannitol, dextran 70 kDa, or dextran 2 MDa. Peak sodium current was quantified in isolated guinea pig ventricular myocytes. Extracellular resistance was quantified by impedance spectroscopy. Intercellular communication was assessed in a heterologous expression system with fluorescence recovery after photobleaching. Perinexal width was quantified from transmission electron micrographs. RESULTS: CV primarily in the transverse direction of propagation was significantly reduced by mannitol and increased by albumin and both dextrans. The combination of albumin and dextran 70 kDa decreased CV relative to albumin alone. Extracellular resistance was reduced by mannitol, unchanged by albumin, and increased by both dextrans. Cx43 expression and conductance and peak sodium currents were not significantly altered by the osmotic agents. In response to osmotic agents, perinexal width, in order of narrowest to widest, was albumin with dextran 70 kDa; albumin or dextran 2 MDa; dextran 70 kDa or no osmotic agent, and mannitol. When compared in the same order, CV was biphasically related to perinexal width. CONCLUSIONS: Cardiac conduction does not correlate with extracellular resistance but is biphasically related to perinexal separation, providing evidence that the relationship between CV and extracellular volume is determined by ephaptic mechanisms under conditions of normal gap junctional coupling.","keywords":"Animals Guinea Pigs *Dextrans/metabolism *Connexin 43/metabolism Myocytes, Cardiac/metabolism Sodium/metabolism Gap Junctions/metabolism Albumins/metabolism Mannitol/pharmacology/metabolism Action Potentials electrical conductivity electrophysiology gap junctions heart conduction system osmotic stress","issn":"0009-7330 (Print) 0009-7330","doi":"10.1161/circresaha.123.322567","year":"2023","bibtex":"@article{RN90,\n author = {Adams, W. P. and Raisch, T. B. and Zhao, Y. and Davalos, R. and Barrett, S. and King, D. R. and Bain, C. B. and Colucci-Chang, K. and Blair, G. A. and Hanlon, A. and Lozano, A. and Veeraraghavan, R. and Wan, X. and Deschenes, I. and Smyth, J. W. and Hoeker, G. S. and Gourdie, R. G. and Poelzing, S.},\n title = {Extracellular Perinexal Separation Is a Principal Determinant of Cardiac Conduction},\n journal = {Circ Res},\n volume = {133},\n number = {8},\n pages = {658-673},\n note = {1524-4571\nAdams, William P\nOrcid: 0000-0002-5601-663x\nRaisch, Tristan B\nOrcid: 0000-0002-6469-8570\nZhao, Yajun\nOrcid: 0000-0003-3029-0291\nDavalos, Rafael\nOrcid: 0000-0003-1503-9509\nBarrett, Sarah\nKing, D Ryan\nBain, Chandra B\nOrcid: 0000-0002-5308-5509\nColucci-Chang, Katrina\nBlair, Grace A\nOrcid: 0000-0002-5633-5497\nHanlon, Alexandra\nLozano, Alicia\nVeeraraghavan, Rengasayee\nWan, Xiaoping\nOrcid: 0009-0006-0417-3437\nDeschenes, Isabelle\nSmyth, James W\nHoeker, Gregory S\nOrcid: 0000-0002-3917-4791\nGourdie, Robert G\nOrcid: 0000-0001-6021-0796\nPoelzing, Steven\nOrcid: 0000-0002-6979-1264\nR01 HL094450/HL/NHLBI NIH HHS/United States\nR01 HL159097/HL/NHLBI NIH HHS/United States\nR01 HL132236/HL/NHLBI NIH HHS/United States\nR01 HL096962/HL/NHLBI NIH HHS/United States\nR35 HL161237/HL/NHLBI NIH HHS/United States\nR01 HL102298/HL/NHLBI NIH HHS/United States\nF31 HL140873/HL/NHLBI NIH HHS/United States\nR01 HL056728/HL/NHLBI NIH HHS/United States\nR01 HL138003/HL/NHLBI NIH HHS/United States\nR25 GM072767/GM/NIGMS NIH HHS/United States\nF31 HL147438/HL/NHLBI NIH HHS/United States\nR01 HL141855/HL/NHLBI NIH HHS/United States\nJournal Article\nUnited States\n2023/09/08\nCirc Res. 2023 Sep 29;133(8):658-673. doi: 10.1161/CIRCRESAHA.123.322567. Epub 2023 Sep 8.},\n abstract = {BACKGROUND: Cardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in the heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular resistance. By contrast, ephaptic theory is premised on the existence of a biphasic relationship between CV and the volume of specialized extracellular clefts within intercalated discs such as the perinexus. Our objective was to determine the relationship between ventricular CV and structural changes to micro- and nanoscale extracellular spaces. METHODS: Conduction and Cx43 (connexin43) protein expression were quantified from optically mapped guinea pig whole-heart preparations perfused with the osmotic agents albumin, mannitol, dextran 70 kDa, or dextran 2 MDa. Peak sodium current was quantified in isolated guinea pig ventricular myocytes. Extracellular resistance was quantified by impedance spectroscopy. Intercellular communication was assessed in a heterologous expression system with fluorescence recovery after photobleaching. Perinexal width was quantified from transmission electron micrographs. RESULTS: CV primarily in the transverse direction of propagation was significantly reduced by mannitol and increased by albumin and both dextrans. The combination of albumin and dextran 70 kDa decreased CV relative to albumin alone. Extracellular resistance was reduced by mannitol, unchanged by albumin, and increased by both dextrans. Cx43 expression and conductance and peak sodium currents were not significantly altered by the osmotic agents. In response to osmotic agents, perinexal width, in order of narrowest to widest, was albumin with dextran 70 kDa; albumin or dextran 2 MDa; dextran 70 kDa or no osmotic agent, and mannitol. When compared in the same order, CV was biphasically related to perinexal width. CONCLUSIONS: Cardiac conduction does not correlate with extracellular resistance but is biphasically related to perinexal separation, providing evidence that the relationship between CV and extracellular volume is determined by ephaptic mechanisms under conditions of normal gap junctional coupling.},\n keywords = {Animals\nGuinea Pigs\n*Dextrans/metabolism\n*Connexin 43/metabolism\nMyocytes, Cardiac/metabolism\nSodium/metabolism\nGap Junctions/metabolism\nAlbumins/metabolism\nMannitol/pharmacology/metabolism\nAction Potentials\nelectrical conductivity\nelectrophysiology\ngap junctions\nheart conduction system\nosmotic stress},\n ISSN = {0009-7330 (Print)\n0009-7330},\n DOI = {10.1161/circresaha.123.322567},\n year = {2023},\n type = {Journal Article}\n}\n\n","author_short":["Adams, W. P.","Raisch, T. B.","Zhao, Y.","Davalos, R.","Barrett, S.","King, D. R.","Bain, C. B.","Colucci-Chang, K.","Blair, G. A.","Hanlon, A.","Lozano, A.","Veeraraghavan, R.","Wan, X.","Deschenes, I.","Smyth, J. W.","Hoeker, G. S.","Gourdie, R. G.","Poelzing, S."],"key":"RN90","id":"RN90","bibbaseid":"adams-raisch-zhao-davalos-barrett-king-bain-coluccichang-etal-extracellularperinexalseparationisaprincipaldeterminantofcardiacconduction-2023","role":"author","urls":{},"keyword":["Animals Guinea Pigs *Dextrans/metabolism *Connexin 43/metabolism Myocytes","Cardiac/metabolism Sodium/metabolism Gap Junctions/metabolism Albumins/metabolism Mannitol/pharmacology/metabolism Action Potentials electrical conductivity electrophysiology gap junctions heart conduction system osmotic stress"],"metadata":{"authorlinks":{}}},"bibtype":"article","biburl":"https://bibbase.org/network/files/bdNBTZRXTsoHCgpbh","dataSources":["D4zENc4BfFNBwSYYJ","fJQsxtBoqymHQG6tL","LzxgEApraxMPkLTMn","Z2THpXfLYEJf3CB8p"],"keywords":["animals guinea pigs *dextrans/metabolism *connexin 43/metabolism myocytes","cardiac/metabolism sodium/metabolism gap junctions/metabolism albumins/metabolism mannitol/pharmacology/metabolism action potentials electrical conductivity electrophysiology gap junctions heart conduction system osmotic stress"],"search_terms":["extracellular","perinexal","separation","principal","determinant","cardiac","conduction","adams","raisch","zhao","davalos","barrett","king","bain","colucci-chang","blair","hanlon","lozano","veeraraghavan","wan","deschenes","smyth","hoeker","gourdie","poelzing"],"title":"Extracellular Perinexal Separation Is a Principal Determinant of Cardiac Conduction","year":2023}