Abstract
Hemodynamic load regulates myocardial function and gene expression. We tested the hypothesis that afterload and preload, despite similar average load, result in different phenotypes. 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. 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.
Highlights
Hemodynamic load regulates myocardial function and gene expression
Hemodynamic Function and Wall Stress Conductance catheter pressure volume analysis 6 hours after respective surgical procedures (Figure 1A) showed that left ventricular systolic pressure was increased in the transverse aortic constriction (TAC) group (ϩ41%; PϽ0.05), and left ventricular end-diastolic pressure and volume were increased in the shunt group (ϩ97%; PϽ0.05; Figure I in the online-only Data Supplement)
In the TAC group, midsystolic wall stress was increased by 40% (PϽ0.05; Figure IIB in the online-only Data Supplement), and end-diastolic wall stress was increased by 277% in the shunt group (PϽ0.05) and by 74% in the TAC group
Summary
A short description of Methods is given here. An expanded version can be found in the online-only Data Supplement.Animal Experiments and In Vivo CharacterizationThe investigation conforms to the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication No 85–23, revised 1996). A short description of Methods is given here. An expanded version can be found in the online-only Data Supplement. The investigation conforms to the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication No 85–23, revised 1996). In 12-week-old female mice, volume overload was induced by the creation of a shunt between the aorta and vena cava inferior. Female mice were used because of high mortality in male mice. Echocardiography, in vivo hemodynamic measurements, cardiomyocyte isolation, cardiomyocyte shortening, calcium measurements, and patch-clamp experiments were performed with standard protocols
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