{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:28:06Z","timestamp":1790148486302,"version":"4.0.1"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2011,10,28]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Cardiac tissue engineering should provide \u201crealistic\u201d in vitro heart muscle models and surrogate tissue for myocardial repair. For either application, engineered myocardium should display features of native myocardium, including terminal differentiation, organotypic maturation, and hypertrophic growth.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>To test the hypothesis that 3D-engineered heart tissue (EHT) culture supports (1) terminal differentiation as well as (2) organotypic assembly and maturation of immature cardiomyocytes, and (3) constitutes a methodological platform to investigate mechanisms underlying hypertrophic growth.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>We generated EHTs from neonatal rat cardiomyocytes and compared morphological and molecular properties of EHT and native myocardium from fetal, neonatal, and adult rats. We made the following key observations: cardiomyocytes in EHT (1) gained a high level of binucleation in the absence of notable cytokinesis, (2) regained a rod-shape and anisotropic sarcomere organization, (3) demonstrated a fetal-to-adult gene expression pattern, and (4) responded to distinct hypertrophic stimuli with concentric or eccentric hypertrophy and reexpression of fetal genes. The process of terminal differentiation and maturation (culture days 7\u201312) was preceded by a tissue consolidation phase (culture days 0\u20137) with substantial cardiomyocyte apoptosis and dynamic extracellular matrix restructuring.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>This study documents the propensity of immature cardiomyocytes to terminally differentiate and mature in EHT in a remarkably organotypic manner. It moreover provides the rationale for the utility of the EHT technology as a methodological bridge between 2D cell culture and animal models.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.111.251843","type":"journal-article","created":{"date-parts":[[2011,9,16]],"date-time":"2011-09-16T11:09:12Z","timestamp":1316171352000},"page":"1105-1114","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":114,"title":["Terminal Differentiation, Advanced Organotypic Maturation, and Modeling of Hypertrophic Growth in Engineered Heart Tissue"],"prefix":"10.1161","volume":"109","author":[{"given":"Malte","family":"Tiburcy","sequence":"first","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Didi\u00e9","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Boy","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Christalla","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"D\u00f6ker","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Naito","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bijoy Chandapillai","family":"Karikkineth","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"El-Armouche","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Grimm","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Nose","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Eschenhagen","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Zieseniss","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doerthe M.","family":"Katschinski","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazha","family":"Hamdani","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang A.","family":"Linke","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoke","family":"Yin","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Mayr","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); and King's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfram-Hubertus","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, Georg-August-University Goettingen, Germany (M.T., M.D., O.B., P.C., S.D., H.N., B.C.K., A.E.-A., W.-H.Z.); Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Germany (M.G., M.N., T.E.); the Department of Cardiovascular Physiology, Georg-August-University Goettingen, Germany (A.Z., D.M.K.); the Department of Cardiovascular Physiology, Institute of Physiology, Ruhr University Bochum, Germany (N.H., W.A.L.); 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