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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, Vol. 309, No. 9, 11.2015, p. 1407-1418.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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 2015, 'A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction', AM J PHYSIOL-HEART C, vol. 309, no. 9, pp. 1407-1418. https://doi.org/10.1152/ajpheart.00542.2015

APA

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, B. M., Linke, W. A., Casadei, B., & Post, H. (2015). A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction. AM J PHYSIOL-HEART C, 309(9), 1407-1418. https://doi.org/10.1152/ajpheart.00542.2015

Vancouver

Schwarzl M, Hamdani N, Seiler S, Alogna A, Manninger M, Reilly S et al. A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction. AM J PHYSIOL-HEART C. 2015 Nov;309(9):1407-1418. https://doi.org/10.1152/ajpheart.00542.2015

Bibtex

@article{6de0c1b5dd384841add8103d51fce344,
title = "A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction",
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 = "Animals, Cardiomyopathies/etiology, Connectin/metabolism, Desoxycorticosterone Acetate/toxicity, Diet, Western, Dilatation, Pathologic/etiology, Disease Models, Animal, Female, Heart Atria/physiopathology, Heart Failure/etiology, Hyperlipidemias/chemically induced, Hypertension/chemically induced, Hypertrophy/etiology, Hypertrophy, Left Ventricular/etiology, Mineralocorticoids/toxicity, Myocytes, Cardiac/metabolism, Nitric Oxide Synthase/metabolism, Phosphorylation, Protein Isoforms/metabolism, Proto-Oncogene Proteins c-akt/metabolism, Stroke Volume, Superoxides/metabolism, Swine",
author = "Michael Schwarzl and Nazha Hamdani and Sebastian Seiler and Alessio Alogna and Martin Manninger and Svetlana Reilly and Birgit Zirngast and Alexander Kirsch and Paul Steendijk and Jochen Verderber and David Zweiker and Philipp Eller and Gerald H{\"o}fler and Silvia Schauer and Kathrin Eller and Heinrich Maechler and Pieske, {Burkert M} and Linke, {Wolfgang A} and Barbara Casadei and Heiner Post",
note = "Copyright {\textcopyright} 2015 the American Physiological Society.",
year = "2015",
month = nov,
doi = "10.1152/ajpheart.00542.2015",
language = "English",
volume = "309",
pages = "1407--1418",
journal = "AM J PHYSIOL-HEART C",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "9",

}

RIS

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 -