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. Methods and Results Afterload and preload were compared in mice with transversal aortic constriction (TAC) and aorto-caval shunt (Shunt). When compared to sham mice, six hours after surgery, systolic wall stress (afterload) was increased in TAC (+40%, P<0.05), diastolic wall stress (preload) was increased in Shunt (+277%, P<0.05) and TAC (+74%, P<0.05) and mean total wall stress was similarly increased in TAC (69%) and Shunt (67%) (TAC vs. Shunt: not significant (n.s.), each P<0.05 vs. Sham). At 1 week, left ventricular weight/tibia length was significantly increased by 22% in TAC and 29% in Shunt (n.s. TAC vs. Shunt). After 24 hours and 1 week, calcium/calmodulin dependent protein kinase II (CaMKII) signaling was increased in TAC. This resulted in altered calcium cycling, including increased L-type calcium current, calcium transients, fractional SR release and calcium spark frequency. In Shunt, Akt phosphorylation was increased. TAC was associated with inflammation, fibrosis and cardiomyocyte apoptosis. The latter was significantly reduced in CaMKIIδ-KO TAC mice. 157 mRNAs and 13 microRNAs were differentially regulated in TAC vs. Shunt. After 8 weeks, fractional shortening was lower and mortality higher in TAC Conclusions Afterload results in maladaptive fibrotic hypertrophy with CaMKII-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 which may require specific pharmacological interventions.

Rodent models of heart failure: an updated review

“…The timeline of disease progression depends on the selected species, age or gender, with mice subjected to TAC presenting LV hypertrophy as early as 7 days [294] and decompensate HF at 4 weeks [153], while rats present slower progression [16], as illustrated in Fig. 1.…”

Mechanical load‐dependent cardiac ER stress in vitro and in vivo: Effects of preload and afterload

“…We previously observed a similar degree of myocardial hypertrophy with both chronic volume and pressure overload [21]. Because protein synthesis [22] and thus also its associated challenge on the protein-folding capacity of the ER are increased in both volume and pressure overload, the induction of Grp78 and CRT does not appear to be an inevitable consequence of increased protein synthesis.…”

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

“…In contrast, however, cardiac atrophy is associated with reduced PLB phosphorylation, a reduced SR Ca 2+ content and a reduced SR Ca 2+ release. Each of these aspects could be expected to be increased in cardiac hypertrophy [5,9,31,47]. The remodelling of these SR-associated properties in cardiac atrophy therefore appears to be opposite to that in cardiac hypertrophy.…”

“…The remodelling of the resulting systolic Ca 2+ transients cannot be assigned to either concept. While cardiac hypertrophy is typically associated with an increased amplitude of systolic Ca 2+ transients [9,47], atrophic hearts have identical Ca 2+ transients as control hearts. Thus, the load-dependent remodelling of systolic Ca 2+ transients may follow a "rectification": while they are increased in response to an increased cardiac workload, they are conserved during states of decreased cardiac workload.…”

“…As a consequence, Ca 2+ content of the SR and systolic Ca 2+ release from the SR are enhanced [3,5,16,31,53]. Collectively, these alterations cause larger systolic Ca 2+ transients which are thought to allow adaptation to the increased cardiac workload in early hypertrophy [9,11,17,43,47]. We have previously reported a reduced phosphorylation of several phosphoproteins, including PLB, in cardiac atrophy [41].…”