A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction
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A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction. / Schwarzl, Michael; Hamdani, Nazha; Seiler, Sebastian; Alogna, Alessio; Manninger, Martin; Reilly, Svetlana; Zirngast, Birgit; Kirsch, Alexander; Steendijk, Paul; Verderber, Jochen; Zweiker, David; Eller, Philipp; Höfler, Gerald; Schauer, Silvia; Eller, Kathrin; Maechler, Heinrich; Pieske, Burkert M; Linke, Wolfgang A; Casadei, Barbara; Post, Heiner.
in: AM J PHYSIOL-HEART C, Jahrgang 309, Nr. 9, 11.2015, S. 1407-1418.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction
AU - Schwarzl, Michael
AU - Hamdani, Nazha
AU - Seiler, Sebastian
AU - Alogna, Alessio
AU - Manninger, Martin
AU - Reilly, Svetlana
AU - Zirngast, Birgit
AU - Kirsch, Alexander
AU - Steendijk, Paul
AU - Verderber, Jochen
AU - Zweiker, David
AU - Eller, Philipp
AU - Höfler, Gerald
AU - Schauer, Silvia
AU - Eller, Kathrin
AU - Maechler, Heinrich
AU - Pieske, Burkert M
AU - Linke, Wolfgang A
AU - Casadei, Barbara
AU - Post, Heiner
N1 - Copyright © 2015 the American Physiological Society.
PY - 2015/11
Y1 - 2015/11
N2 - 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.
AB - 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.
KW - Animals
KW - Cardiomyopathies/etiology
KW - Connectin/metabolism
KW - Desoxycorticosterone Acetate/toxicity
KW - Diet, Western
KW - Dilatation, Pathologic/etiology
KW - Disease Models, Animal
KW - Female
KW - Heart Atria/physiopathology
KW - Heart Failure/etiology
KW - Hyperlipidemias/chemically induced
KW - Hypertension/chemically induced
KW - Hypertrophy/etiology
KW - Hypertrophy, Left Ventricular/etiology
KW - Mineralocorticoids/toxicity
KW - Myocytes, Cardiac/metabolism
KW - Nitric Oxide Synthase/metabolism
KW - Phosphorylation
KW - Protein Isoforms/metabolism
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Stroke Volume
KW - Superoxides/metabolism
KW - Swine
U2 - 10.1152/ajpheart.00542.2015
DO - 10.1152/ajpheart.00542.2015
M3 - SCORING: Journal article
C2 - 26342070
VL - 309
SP - 1407
EP - 1418
JO - AM J PHYSIOL-HEART C
JF - AM J PHYSIOL-HEART C
SN - 0363-6135
IS - 9
ER -