{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:37:50Z","timestamp":1792640270276,"version":"4.5.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,7,30]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Modeling of human arrhythmias with induced pluripotent stem cell\u2013derived cardiomyocytes has focused on single-cell phenotypes. However, arrhythmias are the emergent properties of cells assembled into tissues, and the impact of inherited arrhythmia mutations on tissue-level properties of human heart tissue has not been reported.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Here, we report an optogenetically based, human engineered tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia caused by mutation of the cardiac ryanodine channel and triggered by exercise. We developed a human induced pluripotent stem cell\u2013derived cardiomyocyte\u2013based platform to study the tissue-level properties of engineered human myocardium. We investigated pathogenic mechanisms in CPVT by combining this novel platform with genome editing.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              In our model, CPVT tissues were vulnerable to developing reentrant rhythms when stimulated by rapid pacing and catecholamine, recapitulating hallmark features of the disease. These conditions elevated diastolic Ca\n              <jats:sup>2+<\/jats:sup>\n              levels and increased temporal and spatial dispersion of Ca\n              <jats:sup>2+<\/jats:sup>\n              wave speed, creating a vulnerable arrhythmia substrate. Using Cas9 genome editing, we pinpointed a single catecholamine-driven phosphorylation event, ryanodine receptor\u2013serine 2814 phosphorylation by Ca\n              <jats:sup>2<\/jats:sup>\n              <jats:sup>+<\/jats:sup>\n              \/calmodulin-dependent protein kinase II, that is required to unmask the arrhythmic potential of CPVT tissues.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Our study illuminates the molecular and cellular pathogenesis of CPVT and reveals a critical role of calmodulin-dependent protein kinase II\u2013dependent reentry in the tissue-scale mechanism of this disease. We anticipate that this approach will be useful for modeling other inherited and acquired cardiac arrhythmias.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.119.039711","type":"journal-article","created":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T09:00:10Z","timestamp":1563354010000},"page":"390-404","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":133,"title":["Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue"],"prefix":"10.1161","volume":"140","author":[{"given":"Sung-Jin","family":"Park","sequence":"first","affiliation":[{"name":"Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghui","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, China (D.Z., Y.Q., P.Y., S.X.)."},{"name":"Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Qi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, China (D.Z., Y.Q., P.Y., S.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.)."},{"name":"Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu (Y.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keel Yong","family":"Lee","sequence":"additional","affiliation":[{"name":"Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassilios J.","family":"Bezzerides","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengcheng","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, China (D.Z., Y.Q., P.Y., S.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shutao","family":"Xia","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, China (D.Z., Y.Q., P.Y., S.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean L.","family":"Kim","sequence":"additional","affiliation":[{"name":"Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fujian","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco S.","family":"Pasqualini","sequence":"additional","affiliation":[{"name":"Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick H.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Geva","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre G.","family":"Kleber","sequence":"additional","affiliation":[{"name":"Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (A.G.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic J.","family":"Abrams","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T.","family":"Pu","sequence":"additional","affiliation":[{"name":"Harvard Stem Cell Institute (W.T.P., K.K.P.), Harvard University, Cambridge, MA."},{"name":"Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin Kit","family":"Parker","sequence":"additional","affiliation":[{"name":"Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, John A. Paulson School of Engineering and Applied Sciences (S.-J.P., K.Y.L., S.L.K., F.S.P., P.H.C., K.K.P.), Harvard University, Cambridge, MA."},{"name":"Harvard Stem Cell Institute (W.T.P., K.K.P.), Harvard University, Cambridge, MA."},{"name":"Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., V.J.B., X.L., F.L., J.G., A.E.R., D.J.A., W.T.P., K.K.P.)."},{"name":"Sogang-Harvard Research Center for Disease Biophysics, Sogang University, Seoul, South Korea (K.K.P.). Dr Park is currently at the Coulter Department of Biomedical Engineering, Georgia Institute of Technology, and Emory University School of Medicine, 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