Development of nonfibrotic left ventricular hypertrophy in an ANG II-induced chronic ovine hypertension model.
Hypertension is a major risk factor for many cardiovascular diseases and leads to subsequent concomitant pathologies such as left ventricular hypertrophy (LVH). Translational approaches using large animals get more important as they allow the use of standard clinical procedures in an experimental setting. Therefore, the aim of this study was to establish a minimally invasive ovine hypertension model using chronic angiotensin II (ANG II) treatment and to characterize its effects on cardiac remodeling after 8 weeks. Sheep were implanted with osmotic minipumps filled with either vehicle control (n = 7) or ANG II (n = 9) for 8 weeks. Mean arterial blood pressure in the ANG II-treated group increased from 87.4 ± 5.3 to 111.8 ± 6.9 mmHg (P = 0.00013). Cardiovascular magnetic resonance imaging showed an increase in left ventricular mass from 112 ± 12.6 g to 131 ± 18.7 g after 7 weeks (P = 0.0017). This was confirmed by postmortem measurement of left ventricular wall thickness which was higher in ANG II-treated animals compared to the control group (18 ± 4 mm vs. 13 ± 2 mm, respectively, P = 0.002). However, ANG II-treated sheep did not reveal any signs of fibrosis or inflammatory infiltrates as defined by picrosirius red and H&E staining on myocardial full thickness paraffin sections of both atria and ventricles. Measurements of plasma high-sensitivity C-reactive protein and urinary 8-iso-prostaglandin F2α were inconspicuous in all animals. Furthermore, multielectrode surface mapping of the heart did not show any differences in epicardial conduction velocity and heterogeneity. These data demonstrate that chronic ANG II treatment using osmotic minipumps presents a reliable, minimally invasive approach to establish hypertension and nonfibrotic LVH in sheep.
Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany.
Niklas
N
Klatt
Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany.
Katharina
K
Scherschel
Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany.
Claudia
C
Schad
DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany Department of General and Interventional Cardiology, University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Denise
D
Lau
Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany.
Aline
A
Reitmeier
Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Pawel
P
Kuklik
Department of General and Interventional Cardiology, University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Kai
K
Muellerleile
Department of Diagnostic and Interventional Radiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Jin
J
Yamamura
DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany Department of General and Interventional Cardiology, University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Tanja
T
Zeller
Department of Cardiology and Cologne Cardiovascular Research Centre, Heart Centre University of Cologne, Cologne, Germany.
Daniel
D
Steven
Department of Cardiology and Cologne Cardiovascular Research Centre, Heart Centre University of Cologne, Cologne, Germany.
Stephan
S
Baldus
Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Benjamin
B
Schäffer
Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany.
Christiane
C
Jungen
Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Christian
C
Eickholt
German Heart Institute Berlin, Cardiovascular Pathology Unit, Berlin, Germany DZHK (German Centre for Cardiovascular Research), Partner Site, Berlin, Germany Department of Pathology, Rigshospitalet University Hospital of Copenhagen, Copenhagen, Denmark.
Katharina
K
Wassilew
DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Edzard
E
Schwedhelm
Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany.
Stephan
S
Willems
Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group University Heart Centre University Hospital Hamburg-Eppendorf, Hamburg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site, Hamburg/Kiel/Lübeck, Germany chr.meyer@uke.de.
Christian
C
Meyer
D000804:Angiotensin II / Q000009:adverse effects* / Q000378:metabolism; D000818:Animals; D001344:Autopsy; D005355:Fibrosis; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced* / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D023421:Models, Animal; D012307:Risk Factors; D012756:Sheep; D014662:Vasoconstrictor Agents / Q000009:adverse effects* / Q000378:metabolism; D020257:Ventricular Remodeling
D014662:Vasoconstrictor Agents; D000804:Angiotensin II
Angiotensin II; CMR; hypertension; left ventricular hypertrophy