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J Heart Lung Transplant. 2014 Feb;33(2):203-10. doi: 10.1016/j.healun.2013.10.006. Epub 2013 Oct 4.

Dynamic patterns of ventricular remodeling and apoptosis in hearts unloaded by heterotopic transplantation.

Author information

1
Department of Cardiac and Vascular Surgery, Inselspital University Hospital, Berne, Switzerland. Electronic address: henriette.brinks@insel.ch.
2
Cardiology, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
3
Department of Cardiac and Vascular Surgery, Inselspital University Hospital, Berne, Switzerland.
4
Institute of Physiology, University of Berne, Berne, Switzerland.
5
Center for Translational Medicine, Department of Pharmacology, Temple University, Philadelphia, Pennsylvania.
6
Center for Molecular and Translational Cardiology, Department of Internal Medicine III, University of Heidelberg, Germany.

Abstract

BACKGROUND:

Mechanical unloading of failing hearts can trigger functional recovery but results in progressive atrophy and possibly detrimental adaptation. In an unbiased approach, we examined the dynamic effects of unloading duration on molecular markers indicative of myocardial damage, hypothesizing that potential recovery may be improved by optimized unloading time.

METHODS:

Heterotopically transplanted normal rat hearts were harvested at 3, 8, 15, 30, and 60 days. Forty-seven genes were analyzed using TaqMan-based microarray, Western blot, and immunohistochemistry.

RESULTS:

In parallel with marked atrophy (22% to 64% volume loss at 3 respectively 60 days), expression of myosin heavy-chain isoforms (MHC-α/-β) was characteristically switched in a time-dependent manner. Genes involved in tissue remodeling (FGF-2, CTGF, TGFb, IGF-1) were increasingly upregulated with duration of unloading. A distinct pattern was observed for genes involved in generation of contractile force; an indiscriminate early downregulation was followed by a new steady-state below normal. For pro-apoptotic transcripts bax, bnip-3, and cCasp-6 and -9 mRNA levels demonstrated a slight increase up to 30 days unloading with pronunciation at 60 days. Findings regarding cell death were confirmed on the protein level. Proteasome activity indicated early increase of protein degradation but decreased below baseline in unloaded hearts at 60 days.

CONCLUSIONS:

We identified incrementally increased apoptosis after myocardial unloading of the normal rat heart, which is exacerbated at late time points (60 days) and inversely related to loss of myocardial mass. Our findings suggest an irreversible detrimental effect of long-term unloading on myocardium that may be precluded by partial reloading and amenable to molecular therapeutic intervention.

KEYWORDS:

apoptosis; atrophy; cardiac recovery; heterotopic heart transplantation; myocardial unloading

PMID:
24315785
PMCID:
PMC3946672
DOI:
10.1016/j.healun.2013.10.006
[Indexed for MEDLINE]
Free PMC Article

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