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Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy.

Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany. University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland. Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany. Institute of Human Genetics, University Hospital Center Göttingen, Göttingen, Germany. Department of Cardiology, University of Heidelberg, Heidelberg, Germany. Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; Klinik für Innere Medizin II, University Medical Center Regensburg, Germany. Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany. Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany. Cologne Center for Genomics, University of Cologne, Cologne, Germany. Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany. Electronic address: kboemek@gwdg.de.

Journal of the American College of Cardiology. 2017;(8):975-991
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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 β-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 β-adrenergic signaling and TTS cardiomyocyte function. RESULTS 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. CONCLUSIONS 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).