Differential cardiac remodeling in preload versus afterload.
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.
Toischer
Karl
K
Department of Cardiology and Pneumology, Georg-August-University Goettingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Rokita
Adam G
AG
Unsöld
Bernhard
B
Zhu
Wuqiang
W
Kararigas
Georgios
G
Sossalla
Samuel
S
Reuter
Sean P
SP
Becker
Alexander
A
Teucher
Nils
N
Seidler
Tim
T
Grebe
Cornelia
C
Preuss
Lena
L
Gupta
Shamindra N
SN
Schmidt
Kathie
K
Lehnart
Stephan E
SE
Krüger
Martina
M
Linke
Wolfgang A
WA
Backs
Johannes
J
Regitz-Zagrosek
Vera
V
Schäfer
Katrin
K
Field
Loren J
LJ
Maier
Lars S
LS
Hasenfuss
Gerd
G
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*
D035683:MicroRNAs; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium