| Title |
Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy
|
|---|---|
| Published in |
JACC, August 2017
|
| DOI | 10.1016/j.jacc.2017.06.061 |
| Pubmed ID | |
| Authors |
Thomas Borchert, Daniela Hübscher, Celina I. Guessoum, Tuan-Dinh D. Lam, Jelena R. Ghadri, Isabel N. Schellinger, Malte Tiburcy, Norman Y. Liaw, Yun Li, Jan Haas, Samuel Sossalla, Mia A. Huber, Lukas Cyganek, Claudius Jacobshagen, Ralf Dressel, Uwe Raaz, Viacheslav O. Nikolaev, Kaomei Guan, Holger Thiele, Benjamin Meder, Bernd Wollnik, Wolfram-Hubertus Zimmermann, Thomas F. Lüscher, Gerd Hasenfuss, Christian Templin, Katrin Streckfuss-Bömeke |
| Abstract |
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. 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 β-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS. 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 β-adrenergic signaling and TTS cardiomyocyte function. Enhanced β-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 β1-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. Enhanced β-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). |
X Demographics
The data shown below were collected from the profiles of 198 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Spain | 31 | 16% |
| United States | 22 | 11% |
| Venezuela, Bolivarian Republic of | 15 | 8% |
| Mexico | 8 | 4% |
| United Kingdom | 8 | 4% |
| Argentina | 4 | 2% |
| Ecuador | 4 | 2% |
| Brazil | 3 | 2% |
| Australia | 3 | 2% |
| Other | 21 | 11% |
| Unknown | 79 | 40% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 139 | 70% |
| Practitioners (doctors, other healthcare professionals) | 30 | 15% |
| Scientists | 22 | 11% |
| Science communicators (journalists, bloggers, editors) | 7 | 4% |
Mendeley readers
The data shown below were compiled from readership statistics for 130 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 130 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 24 | 18% |
| Student > Ph. D. Student | 23 | 18% |
| Student > Bachelor | 12 | 9% |
| Student > Doctoral Student | 11 | 8% |
| Other | 10 | 8% |
| Other | 27 | 21% |
| Unknown | 23 | 18% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 49 | 38% |
| Biochemistry, Genetics and Molecular Biology | 22 | 17% |
| Agricultural and Biological Sciences | 14 | 11% |
| Pharmacology, Toxicology and Pharmaceutical Science | 7 | 5% |
| Nursing and Health Professions | 4 | 3% |
| Other | 2 | 2% |
| Unknown | 32 | 25% |
Attention Score in Context
This research output has an Altmetric Attention Score of 136. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 October 2023.
All research outputs
#312,969
of 25,878,862 outputs
Outputs from JACC
#714
of 16,978 outputs
Outputs of similar age
#6,582
of 331,874 outputs
Outputs of similar age from JACC
#22
of 191 outputs
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