title: Molecular and structural transition mechanisms in long-term volume overload.
abstract: We have previously reported that early phase (1 week) of experimental volume overload (VO) has an adaptive phenotype while wall stress-matched pressure overload (PO) is maladaptive. Here we investigate the transition from adaptation to heart failure (HF) in long-term VO.
  
  
  
  FVB/N wild-type mice were subjected to VO induced by aortocaval shunt, and were followed by serial echocardiography until in vivo left ventricular ejection fraction was below <50% (135 ± 35 days). Heart failure was evident from increased lung and liver weight and increased mortality compared with sham. Maladaptive remodelling resulted in significantly reduced sarcomeric titin phosphorylation (causing increased sarcomeric stiffness), whereas interstitial fibrosis was not increased. This was paralleled by re-expression of the fetal gene program, activation of calcium/calmodulin-dependent protein kinase II (CaMKII), decreased protein kinase B (Akt) phosphorylation, high oxidative stress, and increased apoptosis. Consistently, development of HF and mortality were significantly aggravated in Akt-deficient mice.
  
  
  
  Transition to HF in VO is associated with decreased Akt and increased CaMKII signalling pathways together with increased oxidative stress and apoptosis. Lack of interstitial fibrosis together with sarcomeric titin hypophosphorylation indicates an increased stiffness at the sarcomeric but not matrix level in VO-induced HF (in contrast to PO). Transition to HF may result from myocyte loss and myocyte dysfunction owing to increased stiffness.
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University, Goettingen, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Goettingen, Germany.|Faculty of Medicine, Mansoura University, Egypt.
authors.forename: Belal A
authors.initials: BA
authors.lastname: Mohamed
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University, Goettingen, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Schnelle
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University, Goettingen, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Goettingen, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Khadjeh
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University, Goettingen, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Goettingen, Germany.
authors.forename: Dawid
authors.initials: D
authors.lastname: Lbik
authors.affiliation: Department of Cardiovascular Physiology, Ruhr University Bochum, Germany.
authors.forename: Melissa
authors.initials: M
authors.lastname: Herwig
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University, Goettingen, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Goettingen, Germany.|Department of Cardiovascular Physiology, Ruhr University Bochum, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University, Goettingen, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Goettingen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.affiliation: Department of Cardiology and Pneumology, Georg-August-University, Goettingen, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Goettingen, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000601:surgery*; D017209:Apoptosis; D001166:Arteriovenous Shunt, Surgical; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D064211:Connectin / Q000378:metabolism; D004452:Echocardiography; D018507:Gene Expression Regulation, Developmental; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D009026:Mortality; D018384:Oxidative Stress; D010766:Phosphorylation; D011312:Pressure; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012518:Sarcomeres; D015398:Signal Transduction; D013314:Stress, Mechanical; D013318:Stroke Volume; D014682:Vena Cava, Inferior / Q000601:surgery*; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology*
chemical_list: D064211:Connectin; D051057:Proto-Oncogene Proteins c-akt; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Akt signalling; Aortocaval shunt; Eccentric hypertrophy; Heart failure; Volume overload