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Eur J Heart Fail. 2016 Apr;18(4):362-71. doi: 10.1002/ejhf.465. Epub 2015 Dec 23.

Molecular and structural transition mechanisms in long-term volume overload.

Author information

1
Department of Cardiology and Pneumology, Georg-August-University, Goettingen, Germany.
2
DZHK (German Centre for Cardiovascular Research), Partner Site Goettingen, Germany.
3
Faculty of Medicine, Mansoura University, Egypt.
4
Department of Cardiovascular Physiology, Ruhr University Bochum, Germany.

Abstract

AIM:

We have previously reported that early phase (1 week) of experimental volume overload (VO) has an adaptive phenotype while wall stress-matched pressure overload (PO) is maladaptive. Here we investigate the transition from adaptation to heart failure (HF) in long-term VO.

METHODS AND RESULTS:

FVB/N wild-type mice were subjected to VO induced by aortocaval shunt, and were followed by serial echocardiography until in vivo left ventricular ejection fraction was below <50% (135 ± 35 days). Heart failure was evident from increased lung and liver weight and increased mortality compared with sham. Maladaptive remodelling resulted in significantly reduced sarcomeric titin phosphorylation (causing increased sarcomeric stiffness), whereas interstitial fibrosis was not increased. This was paralleled by re-expression of the fetal gene program, activation of calcium/calmodulin-dependent protein kinase II (CaMKII), decreased protein kinase B (Akt) phosphorylation, high oxidative stress, and increased apoptosis. Consistently, development of HF and mortality were significantly aggravated in Akt-deficient mice.

CONCLUSION:

Transition to HF in VO is associated with decreased Akt and increased CaMKII signalling pathways together with increased oxidative stress and apoptosis. Lack of interstitial fibrosis together with sarcomeric titin hypophosphorylation indicates an increased stiffness at the sarcomeric but not matrix level in VO-induced HF (in contrast to PO). Transition to HF may result from myocyte loss and myocyte dysfunction owing to increased stiffness.

KEYWORDS:

Akt signalling; Aortocaval shunt; Eccentric hypertrophy; Heart failure; Volume overload

Comment in

PMID:
26694078
PMCID:
PMC5064674
DOI:
10.1002/ejhf.465
[Indexed for MEDLINE]
Free PMC Article

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