{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T06:47:45Z","timestamp":1775630865810,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1007572","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T00:00:00Z","timestamp":1593043200000}}],"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T00:00:00Z","timestamp":1591315200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005956","name":"Kavli Institute for Theoretical Physics, University of California, Santa Barbara","doi-asserted-by":"publisher","award":["via NSF PHY-1748958 NIH-R25GM067110 and Gordon and Betty Moore Foundation 2919.01"],"award-info":[{"award-number":["via NSF PHY-1748958 NIH-R25GM067110 and Gordon and Betty Moore Foundation 2919.01"]}],"id":[{"id":"10.13039\/100005956","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010198","name":"Ministerio de Econom\u00eda, Industria y Competitividad, Gobierno de Espa\u00f1a","doi-asserted-by":"publisher","award":["SAF2017-88019-C3-2-R"],"award-info":[{"award-number":["SAF2017-88019-C3-2-R"]}],"id":[{"id":"10.13039\/501100010198","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["PGC2018-095456-B-I00"],"award-info":[{"award-number":["PGC2018-095456-B-I00"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL R01-119095"],"award-info":[{"award-number":["HL R01-119095"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1007572","type":"journal-article","created":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T13:54:28Z","timestamp":1591365268000},"page":"e1007572","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5917-2673","authenticated-orcid":true,"given":"David","family":"Conesa","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0503-1781","authenticated-orcid":true,"given":"Blas","family":"Echebarria","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0162-2851","authenticated-orcid":true,"given":"Angelina","family":"Pe\u00f1aranda","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0070-8979","authenticated-orcid":true,"given":"Inmaculada R.","family":"Cantalapiedra","sequence":"additional","affiliation":[]},{"given":"Yohannes","family":"Shiferaw","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6824-6857","authenticated-orcid":true,"given":"Enrique","family":"Alvarez-Lacalle","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2020,6,5]]},"reference":[{"issue":"2","key":"pcbi.1007572.ref001","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/0921-8009(95)00066-6","article-title":"Making economic growth more sustainable","volume":"15","author":"M Munasinghe","year":"1995","journal-title":"Ecological Economics"},{"key":"pcbi.1007572.ref002","doi-asserted-by":"crossref","first-page":"147","DOI":"10.2307\/1907242","article-title":"Mr. Keynes and the \u201cclassics\u201d; a suggested interpretation","author":"JR Hicks","year":"1937","journal-title":"Econometrica: journal of the Econometric Society"},{"key":"pcbi.1007572.ref003","doi-asserted-by":"crossref","DOI":"10.1007\/978-94-010-0658-3","volume-title":"Excitation-contraction coupling and cardiac contractile force","author":"D Bers","year":"2001"},{"issue":"1-3","key":"pcbi.1007572.ref004","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ejphar.2004.07.013","article-title":"Force\u2013frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance","volume":"500","author":"M Endoh","year":"2004","journal-title":"European journal of pharmacology"},{"issue":"5","key":"pcbi.1007572.ref005","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1172\/JCI114611","article-title":"Role of intracellular calcium handling in force-interval relationships of human ventricular myocardium","volume":"85","author":"J Gwathmey","year":"1990","journal-title":"The Journal of clinical investigation"},{"issue":"5","key":"pcbi.1007572.ref006","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.yjmcc.2007.08.012","article-title":"Determinants of frequency-dependent contraction and relaxation of mammalian myocardium","volume":"43","author":"PM Janssen","year":"2007","journal-title":"Journal of molecular and cellular cardiology"},{"issue":"3","key":"pcbi.1007572.ref007","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1113\/jphysiol.2002.025619","article-title":"Mechanisms underlying the frequency dependence of contraction and [Ca2+] i transients in mouse ventricular myocytes","volume":"543","author":"G Antoons","year":"2002","journal-title":"The Journal of physiology"},{"issue":"2","key":"pcbi.1007572.ref008","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/j.1469-7793.2001.00535.x","article-title":"Minimal force-frequency modulation of inotropy and relaxation of in situ murine heart","volume":"534","author":"D Georgakopoulos","year":"2001","journal-title":"The Journal of Physiology"},{"issue":"4","key":"pcbi.1007572.ref009","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1161\/01.RES.87.4.275","article-title":"Calcium fluxes involved in control of cardiac myocyte contraction","volume":"87","author":"DM Bers","year":"2000","journal-title":"Circulation research"},{"issue":"15","key":"pcbi.1007572.ref010","doi-asserted-by":"crossref","first-page":"4193","DOI":"10.1113\/JP272011","article-title":"The calcium\u2013frequency response in the rat ventricular myocyte: an experimental and modelling study","volume":"594","author":"S Gattoni","year":"2016","journal-title":"The Journal of physiology"},{"issue":"12","key":"pcbi.1007572.ref011","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1006\/jmcc.2000.1252","article-title":"Differences in Ca2+-handling and sarcoplasmic reticulum Ca2+-content in isolated rat and rabbit myocardium","volume":"32","author":"LS Maier","year":"2000","journal-title":"Journal of molecular and cellular cardiology"},{"key":"pcbi.1007572.ref012","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.yjmcc.2012.11.017","article-title":"Calcium flux balance in the heart","volume":"58","author":"D Eisner","year":"2013","journal-title":"Journal of molecular and cellular cardiology"},{"issue":"11","key":"pcbi.1007572.ref013","doi-asserted-by":"crossref","first-page":"H1540","DOI":"10.1152\/ajpheart.00515.2013","article-title":"Are SR Ca content fluctuations or SR refractoriness the key to atrial cardiac alternans?: insights from a human atrial model","volume":"306","author":"CA Lugo","year":"2014","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"issue":"2","key":"pcbi.1007572.ref014","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1161\/CIRCRESAHA.117.310230","article-title":"Calcium and excitation-contraction coupling in the heart","volume":"121","author":"DA Eisner","year":"2017","journal-title":"Circulation research"},{"issue":"12","key":"pcbi.1007572.ref015","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1161\/CIRCRESAHA.117.310083","article-title":"Calcium signaling and cardiac arrhythmias","volume":"120","author":"AP Landstrom","year":"2017","journal-title":"Circulation research"},{"issue":"1-3","key":"pcbi.1007572.ref016","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.pbiomolbio.2015.11.003","article-title":"The link between abnormal calcium handling and electrical instability in acquired long QT syndrome\u2013does calcium precipitate arrhythmic storms?","volume":"120","author":"J N\u011bmec","year":"2016","journal-title":"Progress in biophysics and molecular biology"},{"issue":"2","key":"pcbi.1007572.ref017","doi-asserted-by":"crossref","first-page":"e55042","DOI":"10.1371\/journal.pone.0055042","article-title":"Dependency of calcium alternans on ryanodine receptor refractoriness","volume":"8","author":"E Alvarez-Lacalle","year":"2013","journal-title":"PloS one"},{"key":"pcbi.1007572.ref018","article-title":"Cardiac gene therapy with adeno-associated virus-based vectors","author":"K Chamberlain","year":"2017","journal-title":"Current opinion in cardiology"},{"issue":"2","key":"pcbi.1007572.ref019","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.cmet.2015.01.005","article-title":"Altered myocardial calcium cycling and energetics in heart failure-a rational approach for disease treatment","volume":"21","author":"PA Gorski","year":"2015","journal-title":"Cell metabolism"},{"issue":"4","key":"pcbi.1007572.ref020","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.3390\/ijms19041086","article-title":"Correcting Calcium Dysregulation in Chronic Heart Failure Using SERCA2a Gene Therapy","volume":"19","author":"T Samuel","year":"2018","journal-title":"International journal of molecular sciences"},{"issue":"3","key":"pcbi.1007572.ref021","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.cardfail.2009.01.013","article-title":"Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1\/2 clinical trial","volume":"15","author":"BE Jaski","year":"2009","journal-title":"Journal of cardiac failure"},{"issue":"3","key":"pcbi.1007572.ref022","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1161\/CIRCULATIONAHA.111.022889","article-title":"Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID) a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure","volume":"124","author":"M Jessup","year":"2011","journal-title":"Circulation"},{"issue":"21","key":"pcbi.1007572.ref023","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1093\/eurheartj\/ehw019","article-title":"Gene therapy for the treatment of heart failure: promise postponed","volume":"37","author":"JS Hulot","year":"2016","journal-title":"European heart journal"},{"issue":"10","key":"pcbi.1007572.ref024","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.3390\/ijms20102386","article-title":"Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart","volume":"20","author":"S Hamilton","year":"2019","journal-title":"International journal of molecular sciences"},{"issue":"3","key":"pcbi.1007572.ref025","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1161\/CIRCRESAHA.119.315891","article-title":"The Control of Diastolic Calcium in the Heart: Basic Mechanisms and Functional Implications","volume":"126","author":"A. Eisner D.","year":"2020","journal-title":"Circulation Research"},{"issue":"2","key":"pcbi.1007572.ref026","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1161\/01.RES.88.2.195","article-title":"Coordinated control of cell Ca2+ loading and triggered release from the sarcoplasmic reticulum underlies the rapid inotropic response to increased L-type Ca2+ current","volume":"88","author":"A Trafford","year":"2001","journal-title":"Circulation research"},{"issue":"2","key":"pcbi.1007572.ref027","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1529\/biophysj.106.98160","article-title":"A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates","volume":"94","author":"A Mahajan","year":"2008","journal-title":"Biophysical journal"},{"issue":"3","key":"pcbi.1007572.ref028","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1085\/jgp.113.3.469","article-title":"Local control models of cardiac excitation\u2013contraction coupling: a possible role for allosteric interactions between ryanodine receptors","volume":"113","author":"M. D. Stern","year":"1999","journal-title":"The Journal of general physiology"},{"issue":"9","key":"pcbi.1007572.ref029","doi-asserted-by":"crossref","first-page":"093928","DOI":"10.1063\/1.5000709","article-title":"Minimal model for calcium alternans due to SR release refractoriness","volume":"27","author":"I. R. Cantalapiedra","year":"2017","journal-title":"Chaos: An Interdisciplinary Journal of Nonlinear Science"},{"issue":"10","key":"pcbi.1007572.ref030","doi-asserted-by":"crossref","first-page":"108101","DOI":"10.1103\/PhysRevLett.114.108101","article-title":"Calcium alternans is due to an order-disorder phase transition in cardiac cells","volume":"114","author":"E Alvarez-Lacalle","year":"2015","journal-title":"Physical review letters"},{"issue":"13","key":"pcbi.1007572.ref031","doi-asserted-by":"crossref","first-page":"e008724","DOI":"10.1161\/JAHA.118.008724","article-title":"Size matters: Ryanodine receptor cluster size affects arrhythmogenic sarcoplasmic reticulum calcium release","volume":"7","author":"S Galice","year":"2018","journal-title":"Journal of the American Heart Association"},{"issue":"2","key":"pcbi.1007572.ref032","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.pbiomolbio.2016.05.005","article-title":"Electron tomography of rabbit cardiomyocyte three-dimensional ultrastructure","volume":"121","author":"EA Rog-Zielinska","year":"2016","journal-title":"Progress in biophysics and molecular biology"},{"issue":"3","key":"pcbi.1007572.ref033","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1093\/cvr\/cvv231","article-title":"Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation enhance calcium release","volume":"108","author":"N Macquaide","year":"2015","journal-title":"Cardiovascular research"},{"issue":"41","key":"pcbi.1007572.ref034","doi-asserted-by":"crossref","first-page":"10195","DOI":"10.1073\/pnas.1814207115","article-title":"Ryanodine receptor cluster size sets the tone in cerebral smooth muscle","volume":"115","author":"C Soeller","year":"2018","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"1","key":"pcbi.1007572.ref035","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0006-3495(94)80500-4","article-title":"Effects of rapid buffers on Ca2+ diffusion and Ca2+ oscillations","volume":"67","author":"J. Wagner","year":"1994","journal-title":"Biophysical Journal"},{"issue":"6","key":"pcbi.1007572.ref036","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1016\/S0006-3495(96)79824-7","article-title":"Validity of the rapid buffering approximation near a point source of calcium ions","volume":"70","author":"G. D. Smith","year":"1996","journal-title":"Biophysical Journal"},{"issue":"6","key":"pcbi.1007572.ref037","doi-asserted-by":"crossref","first-page":"3666","DOI":"10.1016\/S0006-3495(03)74784-5","article-title":"Model of intracellular calcium cycling in ventricular myocytes","volume":"85","author":"Y. Shiferaw","year":"2003","journal-title":"Biophysical journal"},{"issue":"5","key":"pcbi.1007572.ref038","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1529\/biophysj.104.047449","article-title":"A mathematical treatment of integrated Ca dynamics within the ventricular myocyte","volume":"87","author":"TR Shannon","year":"2004","journal-title":"Biophysical journal"},{"key":"pcbi.1007572.ref039","volume-title":"Synergetics: introduction and advanced topics","author":"H Haken","year":"2013"},{"key":"pcbi.1007572.ref040","doi-asserted-by":"crossref","first-page":"35625","DOI":"10.1038\/srep35625","article-title":"A unified theory of calcium alternans in ventricular myocytes","volume":"6","author":"Z. Qu","year":"2016","journal-title":"Scientific reports"},{"issue":"2","key":"pcbi.1007572.ref041","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.bpj.2010.04.032","article-title":"Ca2+ alternans in a cardiac myocyte model that uses moment equations to represent heterogeneous junctional SR Ca2+","volume":"99","author":"MA Huertas","year":"2010","journal-title":"Biophysical journal"},{"issue":"1","key":"pcbi.1007572.ref042","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/S0006-3495(00)76595-7","article-title":"Reverse mode of the sarcoplasmic reticulum calcium pump and load-dependent cytosolic calcium decline in voltage-clamped cardiac ventricular myocytes","volume":"78","author":"T. R. Shannon","year":"2000","journal-title":"Biophysical Journal"},{"key":"pcbi.1007572.ref043","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-70344-2","volume-title":"The general theory of employment, interest, and money","author":"JM Keynes","year":"2018"},{"issue":"5","key":"pcbi.1007572.ref044","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1161\/01.RES.0000240542.03986.e7","article-title":"Spatially discordant alternans in cardiac tissue: role of calcium cycling","volume":"99","author":"D Sato","year":"2006","journal-title":"Circulation research"},{"key":"pcbi.1007572.ref045","doi-asserted-by":"crossref","DOI":"10.1093\/cvr\/cvs155","volume-title":"Intracellular Ca2+ waves, afterdepolarizations, and triggered arrhythmias","author":"Y Shiferaw","year":"2012"},{"key":"pcbi.1007572.ref046","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.yjmcc.2012.11.014","article-title":"Ca2+ waves in the heart","volume":"58","author":"LT Izu","year":"2013","journal-title":"Journal of molecular and cellular cardiology"},{"issue":"10","key":"pcbi.1007572.ref047","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1114\/1.1616930","article-title":"Ion channel basis for alternans and memory in cardiac myocytes","volume":"31","author":"M Li","year":"2003","journal-title":"Annals of biomedical engineering"},{"key":"pcbi.1007572.ref048","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.jtbi.2019.06.016","article-title":"Complex patterns of subcellular cardiac alternans","volume":"478","author":"J. Veasy","year":"2019","journal-title":"Journal of Theoretical Biology"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1007572","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T00:00:00Z","timestamp":1593043200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1007572","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T14:04:14Z","timestamp":1593093854000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1007572"}},"subtitle":[],"editor":[{"given":"Andrew D.","family":"McCulloch","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2020,6,5]]},"references-count":48,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1007572","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/861997","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,5]]}}}