title: Differential cardiac remodeling in preload versus afterload.
abstract: BACKGROUND
  Hemodynamic load regulates myocardial function and gene expression. We tested the hypothesis that afterload and preload, despite similar average load, result in different phenotypes.
  
  
  RESULTS
  Afterload and preload were compared in mice with transverse aortic constriction (TAC) and aortocaval shunt (shunt). Compared with sham mice, 6 hours after surgery, systolic wall stress (afterload) was increased in TAC mice (+40%; P<0.05), diastolic wall stress (preload) was increased in shunt (+277%; P<0.05) and TAC mice (+74%; P<0.05), and mean total wall stress was similarly increased in TAC (69%) and shunt mice (67%) (P=NS, TAC versus shunt; each P<0.05 versus sham). At 1 week, left ventricular weight/tibia length was significantly increased by 22% in TAC and 29% in shunt mice (P=NS, TAC versus shunt). After 24 hours and 1 week, calcium/calmodulin-dependent protein kinase II signaling was increased in TAC. This resulted in altered calcium cycling, including increased L-type calcium current, calcium transients, fractional sarcoplasmic reticulum calcium release, and calcium spark frequency. In shunt mice, Akt phosphorylation was increased. TAC was associated with inflammation, fibrosis, and cardiomyocyte apoptosis. The latter was significantly reduced in calcium/calmodulin-dependent protein kinase IIdelta-knockout TAC mice. A total of 157 mRNAs and 13 microRNAs were differentially regulated in TAC versus shunt mice. After 8 weeks, fractional shortening was lower and mortality was higher in TAC versus shunt mice.
  
  
  CONCLUSIONS
  Afterload results in maladaptive fibrotic hypertrophy with calcium/calmodulin-dependent protein kinase II-dependent altered calcium cycling and apoptosis. Preload is associated with Akt activation without fibrosis, little apoptosis, better function, and lower mortality. This indicates that different loads result in distinct phenotype differences that may require specific pharmacological interventions.
authors: Department of Cardiology and Pneumology, Georg-August-University Goettingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
authors: Karl
authors: K
authors: Toischer
authors: Adam G
authors: AG
authors: Rokita
authors: Bernhard
authors: B
authors: Unsöld
authors: Wuqiang
authors: W
authors: Zhu
authors: Georgios
authors: G
authors: Kararigas
authors: Samuel
authors: S
authors: Sossalla
authors: Sean P
authors: SP
authors: Reuter
authors: Alexander
authors: A
authors: Becker
authors: Nils
authors: N
authors: Teucher
authors: Tim
authors: T
authors: Seidler
authors: Cornelia
authors: C
authors: Grebe
authors: Lena
authors: L
authors: Preuss
authors: Shamindra N
authors: SN
authors: Gupta
authors: Kathie
authors: K
authors: Schmidt
authors: Stephan E
authors: SE
authors: Lehnart
authors: Martina
authors: M
authors: Krüger
authors: Wolfgang A
authors: WA
authors: Linke
authors: Johannes
authors: J
authors: Backs
authors: Vera
authors: V
authors: Regitz-Zagrosek
authors: Katrin
authors: K
authors: Schäfer
authors: Loren J
authors: LJ
authors: Field
authors: Lars S
authors: LS
authors: Maier
authors: Gerd
authors: G
authors: Hasenfuss
mesh_terms: D000818:Animals; D001011:Aorta / Q000503:physiopathology; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D055106:Genome-Wide Association Study; D006333:Heart Failure / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D006439:Hemodynamics / Q000502:physiology*; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D035683:MicroRNAs; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium