title: Functional significance of the discordance between transcriptional profile and left ventricular structure/function during reverse remodeling.
abstract: To elucidate the mechanisms for reverse LV remodeling, we generated a conditional (doxycycline [dox] off) transgenic mouse tetracycline transactivating factor-TRAF2 (tTA-TRAF2) that develops a dilated heart failure (HF) phenotype upon expression of a proinflammatory transgene, TNF receptor-associated factor 2 (TRAF2), and complete normalization of LV structure and function when the transgene is suppressed. tTA-TRAF2 mice developed a significant increase in LV dimension with decreased contractile function, which was completely normalized in the tTA-TRAF2 mice fed dox for 4 weeks (tTA-TRAF2dox4W). Normalization of LV structure and function was accompanied by partial normalization (~60%) of gene expression associated with incident HF. Similar findings were observed in patients with dilated cardiomyopathy who underwent reverse LV remodeling following mechanical circulatory support. Persistence of the HF gene program was associated with an exaggerated hypertrophic response and increased mortality in tTA-TRAF2dox4Wmice following transaortic constriction (TAC). These effects were no longer observed following TAC in tTA-TRAF2dox8W, wherein there was a more complete (88%) reversal of the incident HF genes. These results demonstrate that reverse LV remodeling is associated with improvements in cardiac myocyte biology; however, the persistence of the abnormal HF gene program may be maladaptive following perturbations in hemodynamic loading conditions.
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Veli K
authors.initials: VK
authors.lastname: Topkara
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Kari T
authors.initials: KT
authors.lastname: Chambers
authors.affiliation: Department of Pharmacology, National Taiwan University School of Medicine, Taipei, Taiwan.
authors.forename: Kai-Chien
authors.initials: KC
authors.lastname: Yang
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Huei-Ping
authors.initials: HP
authors.lastname: Tzeng
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Evans
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Weinheimer
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.affiliation: Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Barger
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann