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Am J Physiol Heart Circ Physiol. 2015 Nov;309(9):H1407-18. doi: 10.1152/ajpheart.00542.2015. Epub 2015 Sep 4.

A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction.

Author information

1
Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany;
2
Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany;
3
Division of General Medicine, Klinikum Starnberg, Starnberg, Germany;
4
Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
5
Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;
6
Department of Cardiothoracic Surgery, Medical University of Graz, Graz, Austria;
7
Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
8
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands;
9
Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
10
Department of Pathology, Medical University of Graz, Graz, Austria;
11
Division of Cardiology, Medical Department, Charité Berlin Campus Virchow, Berlin, Germany.
12
Division of Cardiology, Medical Department, Charité Berlin Campus Virchow, Berlin, Germany heiner.post@charite.de.

Abstract

Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs (n = 8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90-day-release subcutaneous depot) and a Western diet (WD) containing high amounts of salt, fat, cholesterol, and sugar for 12 wk. Compared with weight-matched controls (n = 8), DOCA/WD-treated pigs showed left ventricular (LV) concentric hypertrophy and left atrial dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship was markedly shifted leftward. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD-treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift toward the stiffer titin isoform N2B, and reduced total titin phosphorylation. LV superoxide production was increased, in part attributable to nitric oxide synthase (NOS) uncoupling, whereas AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large-animal model in which loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large-animal model.

KEYWORDS:

heart failure with preserved ejection fraction; hypertensive heart disease; oxidative stress; pressure-volume analysis; titin

PMID:
26342070
DOI:
10.1152/ajpheart.00542.2015
[Indexed for MEDLINE]
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