United We Stand; Divided We Fibrillate?
2017; Lippincott Williams & Wilkins; Volume: 121; Issue: 12 Linguagem: Inglês
10.1161/circresaha.117.312176
ISSN1524-4571
Autores Tópico(s)Neuroscience and Neural Engineering
ResumoHomeCirculation ResearchVol. 121, No. 12United We Stand; Divided We Fibrillate? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBUnited We Stand; Divided We Fibrillate? Barry London Barry LondonBarry London From the Division of Cardiovascular Medicine, University of Iowa, Iowa City. Originally published8 Dec 2017https://doi.org/10.1161/CIRCRESAHA.117.312176Circulation Research. 2017;121:1302–1303The heart is an electric and biochemical syncytium with its cardiac myocytes coupled by gap junctions that allow the passage of both ionic current and small molecules.1 Electric coupling allows the rapid spread of depolarization through the atrium, ventricle, and specialized conduction system that is required for coordinated and efficient mechanical function. In addition, these low-resistance intercellular connections help to prevent arrhythmias in several ways. First, tight coupling leads to synchronization of repolarization across the cardiac chambers that decreases dispersion of repolarization and refractoriness and prevents functional reentry.2 Second, the flow of ions and metabolites minimizes the differences at the single cell level that could result from variations in ion channel expression and metabolic state, stabilizing electric propagation and preventing triggered activity. Third, if an aberrant action potential is triggered in a cell or small group of cells, the source–sink mismatch of the electric syncytium will often prevent propagation. In fact, both theoretical and experimental studies have estimated the number of synchronized myocytes required to initiate a premature ventricular beat.3,4Article, see p 1379Although coupling between cardiac myocytes is important, the absence of coupling is also critical in some circumstances. Electric isolation is required for pacemaker function in the sinoatrial and atrioventricular nodes, and limited coupling is required to overcome source–sink mismatch and prevent exit block as impulses leave the nodes.5 In addition, under pathophysiological conditions, such as myocardial infarction, damaged and dying myocytes must be isolated from the healthy tissue to prevent lethal arrhythmias.6Cardiac-specific deletion of connexin-43, the major cardiac connexin in gap junctions, increases arrhythmia susceptibility in mice.7 In experimental animal models and in humans, pathological conditions, such as heart failure, lead to gap junction remodeling and decreased intercellular conductance.8 Along with other types of electric remodeling, including decreased inward Na+ current (INa) leading to conduction slowing, increased late Na+ current (INa,L) leading to action potential duration prolongation, increased spontaneous Ca2+ release from the sarcoplasmic reticulum and increased expression of the sodium-calcium exchanger leading to increased transient inward current (Iti) and afterdepolarizations, and decreased inward rectifier current (IK1) leading to membrane depolarization, these changes increase the likelihood of both the initiation and propagation of ventricular arrhythmias.9The late Massachusetts Congressman and the 47th Speaker of the United States House of Representatives, Thomas Phillip (Tip) O'Neil, was famous for his statement that "All politics is local."10 For the heart's electric activity, this statement seems to hold some truth. In this issue of Circulation Research, Lang et al11 use high-resolution simultaneous voltage and calcium optical imaging to show that while hearts from wild mice have a small number of cells with spontaneous asynchronous calcium transients and no measurable depolarization, hearts from thoracic banded mice with heart failure have many more myocytes with both calcium waves and depolarization. They go on to show using calcein fluorescence recovery after photobleaching that cell-to-cell coupling is decreased in general in hearts from banded mice but to an even greater extent in myocytes with asynchronous calcium transients in those hearts. Finally, they show that multiple asynchronous Ca2+ transients can interact, that asynchronous Ca2+ transients can disrupt synchronous Ca2+ transients, and that asynchronous Ca2+ transients can trigger action potentials. Putting everything together, there seems to be a subpopulation of cardiac myocytes with abnormal intercellular coupling that are responsible for a significant portion of arrhythmia initiation in this mouse model.Several important questions remain. The specific mechanisms underlying the decrease in cellular coupling have not been ascertained in the affected population of cells. It is not clear whether the myocytes surrounding those with asynchronous transients have decreased coupling—that is are there actually islands of partially uncoupled cardiac myocytes, as the authors suggest? It is also not clear whether or to what extent the mechanisms underlying the increase in asynchronous Ca2+ transients are related to those underlying the change in coupling. Finally, there is no guarantee that all forms of heart failure will show the same electric phenotype or that the findings in mice will translate to large mammals including humans.I wonder, though, whether the study reported here has even more far reaching implications than the authors suggest. Both nonischemic cardiomyopathies and the decompensation phase of ischemic cardiomyopathies involve structural remodeling with the death/dropout of cardiac myocytes accompanied by replacement fibrosis.12 In the electrically and metabolically coupled heart, which myocytes die when stressed and why? It is possible that the subpopulation of partially electrically uncoupled cardiac myocytes with asynchronous Ca2+ transients that Lang et al11 have identified is, in fact, the population destined for dropout. If true, the study of that group of cells could provide invaluable insights, beyond the confines of electrophysiology, into the pathophysiology of heart failure progression. What is the molecular characterization of those cells, and why are they more vulnerable than others? Could we target treatments toward those cells to slow heart failure progression? Would increasing the coupling of those cells to their neighbors help to support them while other heart failure therapies take effect?The lyrics of a popular Rock-and-Roll song from the 1970s stated "You can go your own way, Go your own way, You can call it, Another lonely day."13 In the article by Lang et al,11 they seem to have identified a population of cardiac myocytes doing just that and increasing the electric vulnerability of the heart as a result. A major strength of the heart lies in its connectivity, mediated to a significant extent by gap junctions that can fail in the setting of diseases, such as heart failure. The whole is truly greater than the sum of its parts. Perhaps, a population of myocytes seceding from the syncytium has been identified, and now we can work to reunite and reconnect them for the benefit of the whole.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Barry London, MD, PhD, Division of Cardiovascular Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, E315-GH, 200 Hawkins Dr, Iowa City, IA 52242. E-mail [email protected]References1. Kanno S, Saffitz JE. The role of myocardial gap junctions in electrical conduction and arrhythmogenesis.Cardiovasc Pathol. 2001; 10:169–177.CrossrefMedlineGoogle Scholar2. Baker LC, London B, Choi BR, Koren G, Salama G. Enhanced dispersion of repolarization and refractoriness in transgenic mouse hearts promotes reentrant ventricular tachycardia.Circ Res. 2000; 86:396–407.LinkGoogle Scholar3. Xie Y, Sato D, Garfinkel A, Qu Z, Weiss JN. So little source, so much sink: requirements for afterdepolarizations to propagate in tissue.Biophys J. 2010; 99:1408–1415. doi: 10.1016/j.bpj.2010.06.042.CrossrefMedlineGoogle Scholar4. Myles RC, Wang L, Kang C, Bers DM, Ripplinger CM. Local β-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia.Circ Res. 2012; 110:1454–1464. doi: 10.1161/CIRCRESAHA.111.262345.LinkGoogle Scholar5. Nikolaidou T, Aslanidi OV, Zhang H, Efimov IR. Structure-function relationship in the sinus and atrioventricular nodes.Pediatr Cardiol. 2012; 33:890–899. doi: 10.1007/s00246-012-0249-0.CrossrefMedlineGoogle Scholar6. Wit AL, Peters NS. The role of gap junctions in the arrhythmias of ischemia and infarction.Heart Rhythm. 2012; 9:308–311. doi: 10.1016/j.hrthm.2011.09.056.CrossrefMedlineGoogle Scholar7. Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J, Chien KR, Stuhlmann H, Fishman GI. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43.Circ Res. 2001; 88:333–339.LinkGoogle Scholar8. Saffitz JE, Hames KY, Kanno S. Remodeling of gap junctions in ischemic and nonischemic forms of heart disease.J Membr Biol. 2007; 218:65–71. doi: 10.1007/s00232-007-9031-2.CrossrefMedlineGoogle Scholar9. Aiba T, Tomaselli GF. Electrical remodeling in the failing heart.Curr Opin Cardiol. 2010; 25:29–36. doi: 10.1097/HCO.0b013e328333d3d6.CrossrefMedlineGoogle Scholar10. O'Neil T, Gary H. All Politics Is Local: and Other Rules of the Game. Avon, MA: Adams Media Corporation; 1995:1–190.Google Scholar11. Lang D, Sato D, Jiang Y, Ginsburg KS, Ripplinger CM, Bers DM. Calcium-dependent arrhythmogenic foci created by weakly coupled myocytes in the failing heart.Circ Res. 2017; 121:1379–1391. doi: 10.1161/CIRCRESAHA.117.312050LinkGoogle Scholar12. Shah AM, Mann DL. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science.Lancet. 2011; 378:704–712. doi: 10.1016/S0140-6736(11)60894-5.CrossrefMedlineGoogle Scholar13. Fleetwood Mac. Go Your Own Way.Album Rumours. 1976.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetails December 8, 2017Vol 121, Issue 12 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.117.312176PMID: 29217706 Originally publishedDecember 8, 2017 Keywordsarrhythmias, cardiacgap junctionsheart failurecalcium signalingEditorialsconnexin 43optical imagingPDF download Advertisement SubjectsArrhythmiasCalcium Cycling/Excitation-Contraction CouplingHeart FailureIon Channels/Membrane Transport
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