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 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.
Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany;
Michael
M
Schwarzl
Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany;
Nazha
N
Hamdani
Division of General Medicine, Klinikum Starnberg, Starnberg, Germany;
Sebastian
S
Seiler
Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
Alessio
A
Alogna
Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
Martin
M
Manninger
Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;
Svetlana
S
Reilly
Department of Cardiothoracic Surgery, Medical University of Graz, Graz, Austria;
Birgit
B
Zirngast
Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
Alexander
A
Kirsch
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands;
Paul
P
Steendijk
Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
Jochen
J
Verderber
Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
David
D
Zweiker
Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
Philipp
P
Eller
Department of Pathology, Medical University of Graz, Graz, Austria;
Gerald
G
Höfler
Department of Pathology, Medical University of Graz, Graz, Austria;
Silvia
S
Schauer
Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria;
Kathrin
K
Eller
Department of Cardiothoracic Surgery, Medical University of Graz, Graz, Austria;
Heinrich
H
Maechler
Division of Cardiology, Medical Department, Charité Berlin Campus Virchow, Berlin, Germany.
Burkert M
BM
Pieske
Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany;
Wolfgang A
WA
Linke
Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;
Barbara
B
Casadei
Division of Cardiology, Medical Department, Charité Berlin Campus Virchow, Berlin, Germany heiner.post@charite.de.
Heiner
H
Post
D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D064211:Connectin / Q000378:metabolism; D064791:Desoxycorticosterone Acetate / Q000633:toxicity; D066273:Diet, Western; D004108:Dilatation, Pathologic / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006325:Heart Atria / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006949:Hyperlipidemias / Q000139:chemically induced / Q000150:complications; D006973:Hypertension / Q000139:chemically induced / Q000150:complications*; D006984:Hypertrophy / Q000209:etiology / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008901:Mineralocorticoids / Q000633:toxicity; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013318:Stroke Volume; D013481:Superoxides / Q000378:metabolism; D013552:Swine
D064211:Connectin; D008901:Mineralocorticoids; D020033:Protein Isoforms; D013481:Superoxides; D064791:Desoxycorticosterone Acetate; D019001:Nitric Oxide Synthase; D051057:Proto-Oncogene Proteins c-akt
heart failure with preserved ejection fraction; hypertensive heart disease; oxidative stress; pressure-volume analysis; titin