title: Dynamic patterns of ventricular remodeling and apoptosis in hearts unloaded by heterotopic transplantation.
abstract: BACKGROUND
  Mechanical unloading of failing hearts can trigger functional recovery but results in progressive atrophy and possibly detrimental adaptation. In an unbiased approach, we examined the dynamic effects of unloading duration on molecular markers indicative of myocardial damage, hypothesizing that potential recovery may be improved by optimized unloading time.
  
  
  METHODS
  Heterotopically transplanted normal rat hearts were harvested at 3, 8, 15, 30, and 60 days. Forty-seven genes were analyzed using TaqMan-based microarray, Western blot, and immunohistochemistry.
  
  
  RESULTS
  In parallel with marked atrophy (22% to 64% volume loss at 3 respectively 60 days), expression of myosin heavy-chain isoforms (MHC-α/-β) was characteristically switched in a time-dependent manner. Genes involved in tissue remodeling (FGF-2, CTGF, TGFb, IGF-1) were increasingly upregulated with duration of unloading. A distinct pattern was observed for genes involved in generation of contractile force; an indiscriminate early downregulation was followed by a new steady-state below normal. For pro-apoptotic transcripts bax, bnip-3, and cCasp-6 and -9 mRNA levels demonstrated a slight increase up to 30 days unloading with pronunciation at 60 days. Findings regarding cell death were confirmed on the protein level. Proteasome activity indicated early increase of protein degradation but decreased below baseline in unloaded hearts at 60 days.
  
  
  CONCLUSIONS
  We identified incrementally increased apoptosis after myocardial unloading of the normal rat heart, which is exacerbated at late time points (60 days) and inversely related to loss of myocardial mass. Our findings suggest an irreversible detrimental effect of long-term unloading on myocardium that may be precluded by partial reloading and amenable to molecular therapeutic intervention.
authors: Department of Cardiac and Vascular Surgery, Inselspital University Hospital, Berne, Switzerland. Electronic address: henriette.brinks@insel.ch.
authors: Henriette
authors: H
authors: Brinks
authors: Cardiology, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
authors: Marie-Noelle
authors: MN
authors: Giraud
authors: Department of Cardiac and Vascular Surgery, Inselspital University Hospital, Berne, Switzerland.
authors: Adrian
authors: A
authors: Segiser
authors: Department of Cardiac and Vascular Surgery, Inselspital University Hospital, Berne, Switzerland.
authors: Celine
authors: C
authors: Ferrié
authors: Department of Cardiac and Vascular Surgery, Inselspital University Hospital, Berne, Switzerland.
authors: Sarah
authors: S
authors: Longnus
authors: Institute of Physiology, University of Berne, Berne, Switzerland.
authors: Nina D
authors: ND
authors: Ullrich
authors: Center for Translational Medicine, Department of Pharmacology, Temple University, Philadelphia, Pennsylvania.
authors: Walter J
authors: WJ
authors: Koch
authors: Center for Molecular and Translational Cardiology, Department of Internal Medicine III, University of Heidelberg, Germany.
authors: Patrick
authors: P
authors: Most
authors: Department of Cardiac and Vascular Surgery, Inselspital University Hospital, Berne, Switzerland.
authors: Thierry P
authors: TP
authors: Carrel
authors: Department of Cardiac and Vascular Surgery, Inselspital University Hospital, Berne, Switzerland.
authors: Hendrik T
authors: HT
authors: Tevaearai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D053178:Caspase 6 / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D016027:Heart Transplantation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C505650:BNIP3 protein, rat; D015415:Biomarkers; C526316:CCN2 protein, rat; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; D016222:Fibroblast Growth Factor 2; D055513:Connective Tissue Growth Factor; D053178:Caspase 6
keywords: apoptosis; atrophy; cardiac recovery; heterotopic heart transplantation; myocardial unloading