Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Schwarzl, M; Hamdani, N; Seiler, S; Alogna, A; Manninger, M; Reilly, S; Zirngast, B; Kirsch, A; Steendijk, P; Verderber, J; Zweiker, D; Eller, P; Höfler, G; Schauer, S; Eller, K; Maechler, H; Pieske, BM; Linke, WA; Casadei, B; Post, H.
A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction.
Am J Physiol Heart Circ Physiol. 2015; 309(9):H1407-18
Doi: 10.1152/ajpheart.00542.2015
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- Führende Autor*innen der Med Uni Graz
- Post Heiner
- Schwarzl Michael
- Co-Autor*innen der Med Uni Graz
- Albori Jochen
- Alogna Alessio
- Eller Kathrin
- Eller Philipp
- Höfler Gerald
- Kirsch Alexander
- Mächler Heinrich
- Manninger-Wünscher Martin
- Pieske Burkert Mathias
- Zirngast Birgit
- Zweiker David
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Cardiomyopathies - etiology, metabolism, pathology, physiopathology
- Connectin - metabolism
- Desoxycorticosterone Acetate - toxicity
- Diet, Western - administration & dosage
- Dilatation, Pathologic - etiology, physiopathology
- Disease Models, Animal - administration & dosage
- Female - administration & dosage
- Heart Atria - physiopathology
- Heart Failure - etiology, metabolism, pathology, physiopathology
- Hyperlipidemias - chemically induced, complications
- Hypertension - chemically induced, complications
- Hypertrophy - etiology, pathology
- Hypertrophy, Left Ventricular - etiology, metabolism, pathology, physiopathology
- Mineralocorticoids - toxicity
- Myocytes, Cardiac - metabolism, pathology
- Nitric Oxide Synthase - metabolism
- Phosphorylation - administration & dosage
- Protein Isoforms - metabolism
- Proto-Oncogene Proteins c-akt - metabolism
- Stroke Volume - administration & dosage
- Superoxides - metabolism
- Swine - administration & dosage
- Find related publications in this database (Keywords)
- heart failure with preserved ejection fraction
- hypertensive heart disease
- pressure-volume analysis
- titin
- oxidative stress