Universität zu Köln

Borchert, Thomas, Huebscher, Daniela, Guessoum, Celina I., Lam, Tuan-Dinh D., Ghadri, Jelena R., Schellinger, Isabel N., Tiburcy, Malte, Liaw, Norman Y., Li, Yun, Haas, Jan, Sossalla, Samuel, Huber, Mia A., Cyganek, Lukas ORCID: 0000-0001-9120-1382, Jacobshagen, Claudius, Dressel, Ralf, Raaz, Uwe, Nikolaev, Viacheslav O., Guan, Kaomei ORCID: 0000-0002-0753-3083, Thiele, Holger, Meder, Benjamin, Wollnik, Bernd, Zimmermann, Wolfram-Hubertus, Luescher, Thomas F., Hasenfuss, Gerd, Templin, Christian and Streckfuss-Boemeke, Katrin (2017). Catecholamine-Dependent beta-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy. J. Am. Coll. Cardiol., 70 (8). S. 975 - 992. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1558-3597

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Abstract

BACKGROUND Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis. OBJECTIVES The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered b-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS. METHODS Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated beta-adrenergic signaling and TTS cardiomyocyte function. RESULTS Enhanced beta-adrenergic signaling in TTS-iPSC-CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate-dependent protein kinase A-mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by beta(1)-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function. CONCLUSIONS Enhanced beta-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621) (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Borchert, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Huebscher, Daniela UNSPECIFIED UNSPECIFIED UNSPECIFIED Guessoum, Celina I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lam, Tuan-Dinh D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ghadri, Jelena R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schellinger, Isabel N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tiburcy, Malte UNSPECIFIED UNSPECIFIED UNSPECIFIED Liaw, Norman Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Yun UNSPECIFIED UNSPECIFIED UNSPECIFIED Haas, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Sossalla, Samuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Huber, Mia A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cyganek, Lukas UNSPECIFIED orcid.org/0000-0001-9120-1382 UNSPECIFIED Jacobshagen, Claudius UNSPECIFIED UNSPECIFIED UNSPECIFIED Dressel, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Raaz, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Nikolaev, Viacheslav O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Guan, Kaomei UNSPECIFIED orcid.org/0000-0002-0753-3083 UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Meder, Benjamin UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmermann, Wolfram-Hubertus UNSPECIFIED UNSPECIFIED UNSPECIFIED Luescher, Thomas F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hasenfuss, Gerd UNSPECIFIED UNSPECIFIED UNSPECIFIED Templin, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Streckfuss-Boemeke, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-221566
DOI:	10.1016/j.jacc.2017.06.061
Journal or Publication Title:	J. Am. Coll. Cardiol.
Volume:	70
Number:	8
Page Range:	S. 975 - 992
Date:	2017
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1558-3597
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACUTE MYOCARDIAL-INFARCTION; STRESS CARDIOMYOPATHY; MOUSE MODEL; TAKO-TSUBO; CARDIOMYOCYTES; ISOPROTERENOL; PATHOGENESIS; DEFICIENCY; PATHWAY Multiple languages Cardiac & Cardiovascular Systems Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22156