title: A mouse model reveals an important role for catecholamine-induced lipotoxicity in the pathogenesis of stress-induced cardiomyopathy.
abstract: OBJECTIVE
  Stress-induced cardiomyopathy (SIC), also known as takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular dysfunction (akinesia) involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC, but the pathomechanisms involved are unknown. We tested the hypothesis that excessive catecholamines cause perturbation of myocardial lipid metabolism and that cardiac lipotoxicity is responsible for the pathogenesis of SIC.
  
  
  RESULTS
  A single dose injection of isoprenaline (ISO; 400 mg/kg) induced SIC-like regional akinesia in mice. Oil red O staining revealed severe lipid accumulation in the heart 2 h post-ISO. Both intramyocardial lipid accumulation and cardiac function were normalized within 1 week post-ISO and no significant amount of fibrosis was detected. We found that gene expression of lipid importers and exporters (ApoB lipoprotein) was depressed 2 h post-ISO. These results were confirmed by similar findings in SIC patients and in ISO/patient serum-stressed HL-1 cardiomyocytes. Moreover, overexpression of ApoB in the heart was found to protect against the development of ISO-induced cardiac toxicity and cardiac dysfunction. We also found that ISO-induced intramyocardial lipid accumulation caused electrophysiological disturbance and stunning in ISO/patient serum-stressed HL-1 cardiomyocytes.
  
  
  CONCLUSIONS
  The present study demonstrates that lipotoxicity is closely associated with catecholamine-induced myocardial dysfunction, including neurogenic stunning, metabolic stunning, and electrophysiological stunning. Cardiac lipotoxicity may originate from direct inhibition of myocardial ApoB lipoprotein and subsequent decreased lipid export, caused by supraphysiological levels of catecholamines.
authors.affiliation: Wallenberg Laboratory at Sahlgrenska Academy, Göteborg University Göteborg, Sweden. shao.yangzhen@wlab.gu.se
authors.forename: Yangzhen
authors.initials: Y
authors.lastname: Shao
authors.forename: Björn
authors.initials: B
authors.lastname: Redfors
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.forename: Margareta Scharin
authors.initials: MS
authors.lastname: Täng
authors.forename: Azra
authors.initials: A
authors.lastname: Miljanovic
authors.forename: Helge
authors.initials: H
authors.lastname: Möllmann
authors.forename: Christian
authors.initials: C
authors.lastname: Troidl
authors.forename: Sebastian
authors.initials: S
authors.lastname: Szardien
authors.forename: Christian
authors.initials: C
authors.lastname: Hamm
authors.forename: Holger
authors.initials: H
authors.lastname: Nef
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Elmir
authors.initials: E
authors.lastname: Omerovic
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000235:genetics*; D001706:Biopsy; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007545:Isoproterenol / Q000633:toxicity; D050356:Lipid Metabolism / Q000235:genetics*; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D054549:Takotsubo Cardiomyopathy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D001055:Apolipoproteins B; D012313:RNA; D007545:Isoproterenol