{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T23:48:32Z","timestamp":1773100112516,"version":"3.50.1"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Multiple cardiac pathologies are accompanied by loss of tissue excitability, which leads to a range of heart rhythm disorders (arrhythmias). In addition to electronic device therapy (i.e. implantable pacemakers and cardioverter\/defibrillators), biological approaches have recently been explored to restore pacemaking ability and to correct conduction slowing in the heart by delivering excitatory ion channels or ion channel agonists. Using optogenetics as a tool to selectively interrogate only cells transduced to produce an exogenous excitatory ion current, we experimentally and computationally quantify the efficiency of such biological approaches in rescuing cardiac excitability as a function of the mode of application (viral gene delivery or cell delivery) and the geometry of the transduced region (focal or spatially-distributed). We demonstrate that for each configuration (delivery mode and spatial pattern), the optical energy needed to excite can be used to predict therapeutic efficiency of excitability restoration. Taken directly, these results can help guide optogenetic interventions for light-based control of cardiac excitation. More generally, our findings can help optimize gene therapy for restoration of cardiac excitability.<\/jats:p>","DOI":"10.1038\/srep17350","type":"journal-article","created":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T09:55:34Z","timestamp":1448963734000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Optogenetics-enabled assessment of viral gene and cell therapy for restoration of cardiac excitability"],"prefix":"10.1038","volume":"5","author":[{"given":"Christina M.","family":"Ambrosi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick M.","family":"Boyle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kay","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia A.","family":"Trayanova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilia","family":"Entcheva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,12,1]]},"reference":[{"key":"BFsrep17350_CR1","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1161\/CIRCRESAHA.111.252981","volume":"110","author":"L Tilemann","year":"2012","unstructured":"Tilemann, L., Ishikawa, K., Weber, T. & Hajjar, R. J. Gene therapy for heart failure. Circ Res 110, 777\u2013793 (2012).","journal-title":"Circ Res"},{"key":"BFsrep17350_CR2","doi-asserted-by":"publisher","first-page":"2128","DOI":"10.1634\/stemcells.2006-0722","volume":"25","author":"AB Rosen","year":"2007","unstructured":"Rosen, A. B. et al. Finding fluorescent needles in the cardiac haystack: tracking human mesenchymal stem cells labeled with quantum dots for quantitative in vivo three-dimensional fluorescence analysis. Stem Cells 25, 2128\u20132138 (2007).","journal-title":"Stem Cells"},{"key":"BFsrep17350_CR3","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1002\/jgm.1576","volume":"13","author":"KM Prasad","year":"2011","unstructured":"Prasad, K. M., Smith, R. S., Xu, Y. & French, B. A. A single direct injection into the left ventricular wall of an adeno-associated virus 9 (AAV9) vector expressing extracellular superoxide dismutase from the cardiac troponin-T promoter protects mice against myocardial infarction. J Gene Med 13, 333\u2013341 (2011).","journal-title":"J Gene Med"},{"key":"BFsrep17350_CR4","doi-asserted-by":"publisher","first-page":"S96","DOI":"10.1016\/j.hrthm.2013.03.027","volume":"10","author":"CM Ambrosi","year":"2013","unstructured":"Ambrosi, C. M. et al. Distribution of donor cells alters energy requirements for optogenetic control of the heart. Heart Rhythm 10, S96 (2013).","journal-title":"Heart Rhythm"},{"key":"BFsrep17350_CR5","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/gt.2010.105","volume":"18","author":"KM Prasad","year":"2011","unstructured":"Prasad, K. M., Xu, Y., Yang, Z., Acton, S. T. & French, B. A. Robust cardiomyocyte-specific gene expression following systemic injection of AAV: in vivo gene delivery follows a Poisson distribution. Gene Ther 18, 43\u201352 (2011).","journal-title":"Gene Ther"},{"key":"BFsrep17350_CR6","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1093\/cvr\/cvv004","volume":"106","author":"CC Vogt","year":"2015","unstructured":"Vogt, C. C. et al. Systemic gene transfer enables optogenetic pacing of mouse hearts. Cardiovasc Res 106, 338\u2013343 (2015).","journal-title":"Cardiovasc Res"},{"key":"BFsrep17350_CR7","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1161\/CIRCULATIONAHA.111.022889","volume":"124","author":"M Jessup","year":"2011","unstructured":"Jessup, M. et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2\u2009+\u2009-ATPase in patients with advanced heart failure. Circulation 124, 304\u2013313 (2011).","journal-title":"Circulation"},{"key":"BFsrep17350_CR8","doi-asserted-by":"publisher","first-page":"2369","DOI":"10.1001\/jama.2012.25321","volume":"308","author":"JM Hare","year":"2012","unstructured":"Hare, J. M. et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308, 2369\u20132379 (2012).","journal-title":"JAMA"},{"key":"BFsrep17350_CR9","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.jacc.2013.08.724","volume":"63","author":"K Malliaras","year":"2014","unstructured":"Malliaras, K. et al. Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction). J Am Coll Cardiol 63, 110\u2013122 (2014).","journal-title":"J Am Coll Cardiol"},{"key":"BFsrep17350_CR10","doi-asserted-by":"publisher","first-page":"128S","DOI":"10.2967\/jnumed.109.068239","volume":"51","author":"JC Wu","year":"2010","unstructured":"Wu, J. C., Abraham, M. R. & Kraitchman, D. L. Current perspectives on imaging cardiac stem cell therapy. J Nucl Med 51 Suppl 1, 128S\u2013136S (2010).","journal-title":"J Nucl Med"},{"key":"BFsrep17350_CR11","doi-asserted-by":"publisher","first-page":"13940","DOI":"10.1073\/pnas.1936192100","volume":"100","author":"G Nagel","year":"2003","unstructured":"Nagel, G. et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc Natl Acad Sci USA 100, 13940\u201313945 (2003).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep17350_CR12","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1126\/science.1195929","volume":"330","author":"AB Arrenberg","year":"2010","unstructured":"Arrenberg, A. B., Stainier, D. Y., Baier, H. & Huisken, J. Optogenetic control of cardiac function. Science 330, 971\u2013974 (2010).","journal-title":"Science"},{"key":"BFsrep17350_CR13","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1038\/nmeth.1512","volume":"7","author":"T Bruegmann","year":"2010","unstructured":"Bruegmann, T. et al. Optogenetic control of heart muscle in vitro and in vivo. Nat Methods 7, 897\u2013900 (2010).","journal-title":"Nat Methods"},{"key":"BFsrep17350_CR14","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1161\/CIRCEP.111.964247","volume":"4","author":"Z Jia","year":"2011","unstructured":"Jia, Z. et al. Stimulating cardiac muscle by light: cardiac optogenetics by cell delivery. Circ Arrhythm Electrophysiol 4, 753\u2013760 (2011).","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"BFsrep17350_CR15","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1016\/j.bpj.2011.08.004","volume":"101","author":"OJ Abilez","year":"2011","unstructured":"Abilez, O. J. et al. Multiscale computational models for optogenetic control of cardiac function. Biophys J 101, 1326\u20131334 (2011).","journal-title":"Biophys J"},{"key":"BFsrep17350_CR16","doi-asserted-by":"publisher","first-page":"e1003220","DOI":"10.1371\/journal.pcbi.1003220","volume":"9","author":"JC Williams","year":"2013","unstructured":"Williams, J. C. et al. Computational optogenetics: empirically-derived voltage- and light-sensitive channelrhodopsin-2 model. PLoS Comput Biol 9, e1003220 (2013).","journal-title":"PLoS Comput Biol"},{"key":"BFsrep17350_CR17","doi-asserted-by":"publisher","first-page":"H1179","DOI":"10.1152\/ajpheart.00432.2012","volume":"304","author":"E Entcheva","year":"2013","unstructured":"Entcheva, E. Cardiac optogenetics. Am J Physiol Heart Circ Physiol 304, H1179\u20131191 (2013).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"BFsrep17350_CR18","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1007\/978-1-4939-1047-2_19","volume":"1181","author":"CM Ambrosi","year":"2014","unstructured":"Ambrosi, C. M. & Entcheva, E. Optogenetic Control of Cardiomyocytes via Viral Delivery. Methods Mol Biol 1181, 215\u2013228 (2014).","journal-title":"Methods Mol Biol"},{"key":"BFsrep17350_CR19","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.pbiomolbio.2014.07.001","volume":"115","author":"CM Ambrosi","year":"2014","unstructured":"Ambrosi, C. M., Klimas, A., Yu, J. & Entcheva, E. Cardiac applications of optogenetics. Prog Biophys Mol Biol 115, 294\u2013304 (2014).","journal-title":"Prog Biophys Mol Biol"},{"key":"BFsrep17350_CR20","doi-asserted-by":"publisher","first-page":"6125","DOI":"10.1038\/srep06125","volume":"4","author":"SA Park","year":"2014","unstructured":"Park, S. A., Lee, S. R., Tung, L. & Yue, D. T. Optical mapping of optogenetically shaped cardiac action potentials. Sci Rep 4, 6125 (2014).","journal-title":"Sci Rep"},{"key":"BFsrep17350_CR21","doi-asserted-by":"publisher","first-page":"iv69","DOI":"10.1093\/europace\/euu250","volume":"16","author":"TV Karathanos","year":"2014","unstructured":"Karathanos, T. V., Boyle, P. M. & Trayanova, N. A. Optogenetics-enabled dynamic modulation of action potential duration in atrial tissue: feasibility of a novel therapeutic approach. Europace 16 Suppl 4, iv69\u2013iv76 (2014).","journal-title":"Europace"},{"key":"BFsrep17350_CR22","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.tcm.2014.10.004","volume":"25","author":"PM Boyle","year":"2015","unstructured":"Boyle, P. M., Karathanos, T. V. & Trayanova, N. A. \u201cBeauty is a light in the heart\u201d: the transformative potential of optogenetics for clinical applications in cardiovascular medicine. Trends Cardiovasc Med 25, 73\u201381 (2015).","journal-title":"Trends Cardiovasc Med"},{"key":"BFsrep17350_CR23","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.compbiomed.2015.04.036","volume":"65","author":"PM Boyle","year":"2015","unstructured":"Boyle, P. M., Karathanos, T. V., Entcheva, E. & Trayanova, N. A. Computational modeling of cardiac optogenetics: Methodology overview & review of findings from simulations. Comput Biol Med 65, 200\u2013208 (2015).","journal-title":"Comput Biol Med"},{"key":"BFsrep17350_CR24","doi-asserted-by":"publisher","first-page":"1934","DOI":"10.1016\/j.bpj.2015.03.032","volume":"108","author":"JC Williams","year":"2015","unstructured":"Williams, J. C. & Entcheva, E. Optogenetic versus Electrical Stimulation of Human Cardiomyocytes: Modeling Insights. Biophys J 108, 1934\u20131945 (2015).","journal-title":"Biophys J"},{"key":"BFsrep17350_CR25","doi-asserted-by":"publisher","first-page":"2370","DOI":"10.1038\/ncomms3370","volume":"4","author":"PM Boyle","year":"2013","unstructured":"Boyle, P. M., Williams, J. C., Ambrosi, C. M., Entcheva, E. & Trayanova, N. A. A comprehensive multiscale framework for simulating optogenetics in the heart. Nat Commun 4, 2370 (2013).","journal-title":"Nat Commun"},{"key":"BFsrep17350_CR26","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/S0167-5273(02)00554-5","volume":"90","author":"G Vassalli","year":"2003","unstructured":"Vassalli, G., Bueler, H., Dudler, J., Von Segesser, L. K. & Kappenberger, L. Adeno-associated virus (AAV) vectors achieve prolonged transgene expression in mouse myocardium and arteries in vivo: a comparative study with adenovirus vectors. Int J Cardiol 90, 229\u2013238 (2003).","journal-title":"Int J Cardiol"},{"key":"BFsrep17350_CR27","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1089\/hum.2008.123","volume":"19","author":"LT Bish","year":"2008","unstructured":"Bish, L. T. et al. Adeno-associated virus (AAV) serotype 9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7 and AAV8 in the mouse and rat. Hum Gene Ther 19, 1359\u20131368 (2008).","journal-title":"Hum Gene Ther"},{"key":"BFsrep17350_CR28","first-page":"4669","volume":"2011","author":"P Comtois","year":"2011","unstructured":"Comtois, P. & Nattel, S. Interactions between cardiac fibrosis spatial pattern and ionic remodeling on electrical wave propagation. Conf Proc IEEE Eng Med Biol Soc 2011, 4669\u20134672 (2011).","journal-title":"Conf Proc IEEE Eng Med Biol Soc"},{"key":"BFsrep17350_CR29","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1093\/biomet\/37.1-2.17","volume":"37","author":"PA Moran","year":"1950","unstructured":"Moran, P. A. Notes on continuous stochastic phenomena. Biometrika 37, 17\u201323 (1950).","journal-title":"Biometrika"},{"key":"BFsrep17350_CR30","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1007\/s11095-011-0647-7","volume":"29","author":"C Kilgus","year":"2012","unstructured":"Kilgus, C. et al. Local gene targeting and cell positioning using magnetic nanoparticles and magnetic tips: comparison of mathematical simulations with experiments. Pharm Res 29, 1380\u20131391 (2012).","journal-title":"Pharm Res"},{"key":"BFsrep17350_CR31","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1097\/FJC.0b013e3182588b00","volume":"60","author":"J Lu","year":"2012","unstructured":"Lu, J. et al. Improving cardiac conduction with a skeletal muscle sodium channel by gene and cell therapy. J Cardiovasc Pharmacol 60, 88\u201399 (2012).","journal-title":"J Cardiovasc Pharmacol"},{"key":"BFsrep17350_CR32","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1161\/01.CIR.0000059939.97249.2C","volume":"107","author":"J Qu","year":"2003","unstructured":"Qu, J. et al. Expression and function of a biological pacemaker in canine heart. Circulation 107, 1106\u20131109 (2003).","journal-title":"Circulation"},{"key":"BFsrep17350_CR33","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/nm1040","volume":"10","author":"JM Nygren","year":"2004","unstructured":"Nygren, J. M. et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 10, 494\u2013501 (2004).","journal-title":"Nat Med"},{"key":"BFsrep17350_CR34","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1161\/CIRCULATIONAHA.108.816058","volume":"120","author":"PV Johnston","year":"2009","unstructured":"Johnston, P. V. et al. Engraftment, differentiation and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 120, 1075\u20131083 1077 p following 1083 (2009).","journal-title":"Circulation"},{"key":"BFsrep17350_CR35","doi-asserted-by":"publisher","first-page":"12043","DOI":"10.1038\/srep12043","volume":"5","author":"IY Shadrin","year":"2015","unstructured":"Shadrin, I. Y., Yoon, W., Li, L., Shepherd, N. & Bursac, N. Rapid fusion between mesenchymal stem cells and cardiomyocytes yields electrically active, non-contractile hybrid cells. Sci Rep 5, 12043 (2015).","journal-title":"Sci Rep"},{"key":"BFsrep17350_CR36","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/nature05744","volume":"446","author":"F Zhang","year":"2007","unstructured":"Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633\u2013639 (2007).","journal-title":"Nature"},{"key":"BFsrep17350_CR37","doi-asserted-by":"publisher","first-page":"5295","DOI":"10.1128\/JVI.77.9.5295-5304.2003","volume":"77","author":"JD Evans","year":"2003","unstructured":"Evans, J. D. & Hearing, P. Distinct roles of the Adenovirus E4 ORF3 protein in viral DNA replication and inhibition of genome concatenation. J Virol 77, 5295\u20135304 (2003).","journal-title":"J Virol"},{"key":"BFsrep17350_CR38","doi-asserted-by":"crossref","first-page":"4805","DOI":"10.1128\/jvi.70.7.4805-4810.1996","volume":"70","author":"C Chartier","year":"1996","unstructured":"Chartier, C. et al. Efficient generation of recombinant adenovirus vectors by homologous recombination in Escherichia coli. J Virol 70, 4805\u20134810 (1996).","journal-title":"J Virol"},{"key":"BFsrep17350_CR39","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1177\/25.7.70454","volume":"25","author":"GW Zack","year":"1977","unstructured":"Zack, G. W., Rogers, W. E. & Latt, S. A. Automatic measurement of sister chromatid exchange frequency. J Histochem Cytochem 25, 741\u2013753 (1977).","journal-title":"J Histochem Cytochem"},{"key":"BFsrep17350_CR40","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1161\/CIRCRESAHA.110.223610","volume":"108","author":"NA Trayanova","year":"2011","unstructured":"Trayanova, N. A. Whole-heart modeling: applications to cardiac electrophysiology and electromechanics. Circ Res 108, 113\u2013128 (2011).","journal-title":"Circ Res"},{"key":"BFsrep17350_CR41","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.1161\/CIRCRESAHA.114.302240","volume":"114","author":"NA Trayanova","year":"2014","unstructured":"Trayanova, N. A. Mathematical approaches to understanding and imaging atrial fibrillation: significance for mechanisms and management. Circ Res 114, 1516\u20131531 (2014).","journal-title":"Circ Res"},{"key":"BFsrep17350_CR42","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1161\/01.RES.68.6.1501","volume":"68","author":"CH Luo","year":"1991","unstructured":"Luo, C. H. & Rudy, Y. A model of the ventricular cardiac action potential. Depolarization, repolarization and their interaction. Circ Res 68, 1501\u20131526 (1991).","journal-title":"Circ Res"},{"key":"BFsrep17350_CR43","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1016\/j.bpj.2008.10.026","volume":"96","author":"T Korhonen","year":"2009","unstructured":"Korhonen, T., Hanninen, S. L. & Tavi, P. Model of excitation-contraction coupling of rat neonatal ventricular myocytes. Biophys J 96, 1189\u20131209 (2009).","journal-title":"Biophys J"},{"key":"BFsrep17350_CR44","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/j.bbrc.2006.07.112","volume":"348","author":"D Zimmermann","year":"2006","unstructured":"Zimmermann, D. et al. Biophysical characterisation of electrofused giant HEK293-cells as a novel electrophysiological expression system. Biochem Biophys Res Commun 348, 673\u2013681 (2006).","journal-title":"Biochem Biophys Res Commun"},{"key":"BFsrep17350_CR45","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1109\/TBME.2010.2096425","volume":"58","author":"MJ Bishop","year":"2011","unstructured":"Bishop, M. J. & Plank, G. Representing cardiac bidomain bath-loading effects by an augmented monodomain approach: application to complex ventricular models. IEEE Trans Biomed Eng 58, 1066\u20131075 (2011).","journal-title":"IEEE Trans Biomed Eng"},{"key":"BFsrep17350_CR46","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.jelectrocard.2003.09.017","volume":"36","author":"EJ Vigmond","year":"2003","unstructured":"Vigmond, E. J., Hughes, M., Plank, G. & Leon, L. J. Computational tools for modeling electrical activity in cardiac tissue. J Electrocardiol 36 Suppl, 69\u201374 (2003).","journal-title":"J Electrocardiol"},{"key":"BFsrep17350_CR47","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.pbiomolbio.2007.07.012","volume":"96","author":"EJ Vigmond","year":"2008","unstructured":"Vigmond, E. J., Weber dos Santos, R., Prassl, A. J., Deo, M. & Plank, G. Solvers for the cardiac bidomain equations. Prog Biophys Mol Biol 96, 3\u201318 (2008).","journal-title":"Prog Biophys Mol Biol"},{"key":"BFsrep17350_CR48","doi-asserted-by":"publisher","first-page":"e59290","DOI":"10.1371\/journal.pone.0059290","volume":"8","author":"AD den Haan","year":"2013","unstructured":"den Haan, A. D. et al. Organ explant culture of neonatal rat ventricles: a new model to study gene and cell therapy. PLoS One 8, e59290 (2013).","journal-title":"PLoS One"},{"key":"BFsrep17350_CR49","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1109\/TBME.2013.2292320","volume":"61","author":"CM Costa","year":"2014","unstructured":"Costa, C. M. et al. An efficient finite element approach for modeling fibrotic clefts in the heart. IEEE Trans Biomed Eng 61, 900\u2013910 (2014).","journal-title":"IEEE Trans Biomed Eng"},{"key":"BFsrep17350_CR50","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1161\/01.RES.81.5.727","volume":"81","author":"RM Shaw","year":"1997","unstructured":"Shaw, R. M. & Rudy, Y. Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. Circ Res 81, 727\u2013741 (1997).","journal-title":"Circ Res"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep17350","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep17350.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep17350.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T19:42:44Z","timestamp":1672947764000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep17350"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,1]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,22]]}},"alternative-id":["BFsrep17350"],"URL":"https:\/\/doi.org\/10.1038\/srep17350","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,1]]},"assertion":[{"value":"29 June 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 October 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 December 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17350"}}