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

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 deoxycortic... Full description

Journal Title: American journal of physiology. Heart and circulatory physiology November 2015, Vol.309(9), pp.H1407-H1418
Main Author: Schwarzl, Michael
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1522-1539 ; DOI: 10.1152/ajpheart.00542.2015
Link: http://search.proquest.com/docview/1729349444/?pq-origsite=primo
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title: A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction.
format: Article
creator:
  • 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
subjects:
  • Animals–Etiology
  • Cardiomyopathies–Metabolism
  • Connectin–Pathology
  • Desoxycorticosterone Acetate–Physiopathology
  • Diet, Western–Metabolism
  • Dilatation, Pathologic–Toxicity
  • Disease Models, Animal–Etiology
  • Female–Physiopathology
  • Heart Atria–Physiopathology
  • Heart Failure–Etiology
  • Hyperlipidemias–Metabolism
  • Hypertension–Pathology
  • Hypertrophy–Physiopathology
  • Hypertrophy, Left Ventricular–Chemically Induced
  • Mineralocorticoids–Complications
  • Myocytes, Cardiac–Chemically Induced
  • Nitric Oxide Synthase–Complications
  • Phosphorylation–Etiology
  • Protein Isoforms–Pathology
  • Proto-Oncogene Proteins C-Akt
ispartof: American journal of physiology. Heart and circulatory physiology, November 2015, Vol.309(9), pp.H1407-H1418
description: 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.
language: eng
source:
identifier: E-ISSN: 1522-1539 ; DOI: 10.1152/ajpheart.00542.2015
fulltext: fulltext
issn:
  • 15221539
  • 1522-1539
url: Link


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titleA porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction.
creatorSchwarzl, 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
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ispartofAmerican journal of physiology. Heart and circulatory physiology, November 2015, Vol.309(9), pp.H1407-H1418
identifierE-ISSN: 1522-1539 ; DOI: 10.1152/ajpheart.00542.2015
subjectAnimals–Etiology ; Cardiomyopathies–Metabolism ; Connectin–Pathology ; Desoxycorticosterone Acetate–Physiopathology ; Diet, Western–Metabolism ; Dilatation, Pathologic–Toxicity ; Disease Models, Animal–Etiology ; Female–Physiopathology ; Heart Atria–Physiopathology ; Heart Failure–Etiology ; Hyperlipidemias–Metabolism ; Hypertension–Pathology ; Hypertrophy–Physiopathology ; Hypertrophy, Left Ventricular–Chemically Induced ; Mineralocorticoids–Complications ; Myocytes, Cardiac–Chemically Induced ; Nitric Oxide Synthase–Complications ; Phosphorylation–Etiology ; Protein Isoforms–Pathology ; Proto-Oncogene Proteins C-Akt
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descriptionHeart 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.
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titleA porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction.
authorSchwarzl, 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,...
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