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.
METHODS AND 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.