title: Reversibility of adverse, calcineurin-dependent cardiac remodeling.
abstract: BACKGROUND
  Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, in which genetic gain- and loss-of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet nothing is known about the effects of calcineurin when its activation commences in adulthood. Furthermore, despite the fact that ventricular hypertrophy is a well-established risk factor for heart failure, the relative pace and progression of these 2 major phenotypic features of heart disease are unknown. Finally, even though therapeutic interventions in adults are designed to slow, arrest, or reverse disease pathogenesis, little is known about the capacity for spontaneous reversibility of calcineurin-dependent pathological remodeling.
  
  
  OBJECTIVE
  We set out to address these 3 questions by studying mice engineered to harbor in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element.
  
  
  RESULTS
  Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Furthermore, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility.
  
  
  CONCLUSIONS
  Together, these data establish and define the deleterious effects of calcineurin signaling in the adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390-8573, USA.
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Berry
authors.forename: Vien
authors.initials: V
authors.lastname: Le
authors.forename: David
authors.initials: D
authors.lastname: Rotter
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Battiprolu
authors.forename: Bennett
authors.initials: B
authors.lastname: Grinsfelder
authors.forename: Paul
authors.initials: P
authors.lastname: Tannous
authors.forename: Jana S
authors.initials: JS
authors.lastname: Burchfield
authors.forename: Michael
authors.initials: M
authors.lastname: Czubryt
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D013997:Time Factors; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D019703:Calcineurin; D004318:Doxycycline