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Graded murine wire-induced aortic valve stenosis model mimics human functional and morphological disease phenotype

  • Sven Thomas NiepmannEmail author
  • Eva Steffen
  • Andreas Zietzer
  • Matti Adam
  • Julia Nordsiek
  • Isabella Gyamfi-Poku
  • Kerstin Piayda
  • Jan-Malte Sinning
  • Stephan Baldus
  • Malte Kelm
  • Georg Nickenig
  • Sebastian Zimmer
  • Christine Quast
Original Paper

Abstract

Aortic valve stenosis (AS) is the most common valve disease requiring therapeutic intervention. Even though the incidence of AS has been continuously rising and AS is associated with significant morbidity and mortality, to date, no medical treatments have been identified that can modify disease progression. This unmet medical need is likely attributed to an incomplete understanding of the molecular mechanism driving disease development. To investigate the pathophysiology leading to AS, reliable and reproducible animal models that mimic human pathophysiology are needed. We have tested and expanded the protocols of a wire-injury induced AS mouse model. For this model, coronary wires were used to apply shear stress to the aortic valve cusps with increasing intensity. These protocols allowed distinction of mild, moderate and severe wire-injury. Upon moderate or severe injury, AS developed with a significant increase in aortic valve peak blood flow velocity. While moderate injury promoted solitary AS, severe-injury induced mixed aortic valve disease with concomitant mild to moderate aortic regurgitation. The changes in aortic valve function were reflected by dilation and hypertrophy of the left ventricle, as well as a decreased left ventricular ejection fraction. Histological analysis revealed the classic hallmarks of human disease with aortic valve thickening, increased macrophage infiltration, fibrosis and calcification. This new mouse model of AS promotes functional and morphological changes similar to moderate and severe human AS. It can be used to investigate the pathomechanisms contributing to AS development and to test novel therapeutic strategies.

Keywords

Aortic valve stenosis Animal models Inflammation Calcification 

Notes

Acknowledgements

We thank Mrs. Theresa Schmitz, Mrs. Anna Flender, Dr. Sandra Adler and Mrs. Katharina Groll for excellent technical assistance. S.N. was funded by Else-Kröner-Fresenius-Foundation of the Medical Faculty of the University of Bonn.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

Supplementary material

392_2019_1413_MOESM1_ESM.pdf (40 kb)
Supplementary Figure 1: Long-term changes in aortic blood flow: Aortic valve blood flow of severe-injured mice over time (A). Aortic valve peak velocity of moderate and severe injured mice four weeks and twelve weeks after surgery (B) (PDF 39 KB)
392_2019_1413_MOESM2_ESM.pdf (995 kb)
Supplementary Figure 2: Histological analysis of human aortic valve specimens: Human aortic valve specimens were collected from patients who received surgical aortic valve replacement for either aortic valve stenosis (AS) or regurgitation (non AS). Representative images and quantitative analysis of hematoxylin and eosin (HE) (A, aortic valve thickness) and anti-CD68 immunofluorescence (B, macrophage infiltration) (PDF 994 KB)
392_2019_1413_MOESM3_ESM.pdf (5.3 mb)
Supplementary Figure 3: Apoptosis after moderate or severe wire injury: Representative images of TUNEL-stained aortic valves (PDF 5421 KB)
392_2019_1413_MOESM4_ESM.pdf (23 kb)
Supplementary Figure 4: Aortic valve blood flow of mice four weeks after severe aortic valve injury, comparison between two independent laboratories (PDF 22 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sven Thomas Niepmann
    • 1
    Email author
  • Eva Steffen
    • 1
  • Andreas Zietzer
    • 1
  • Matti Adam
    • 2
  • Julia Nordsiek
    • 1
  • Isabella Gyamfi-Poku
    • 3
  • Kerstin Piayda
    • 3
  • Jan-Malte Sinning
    • 1
  • Stephan Baldus
    • 2
  • Malte Kelm
    • 3
    • 4
  • Georg Nickenig
    • 1
  • Sebastian Zimmer
    • 1
  • Christine Quast
    • 3
  1. 1.Heart Center Bonn, Clinic for Internal Medicine IIUniversity Hospital BonnBonnGermany
  2. 2.Clinic for CardiologyUniversity Hospital CologneCologneGermany
  3. 3.Cardiovascular Research Laboratory, Division of Cardiology, Pulmonary Diseases and Vascular Medicine, Medical FacultyHeinrich-Heine UniversityDüsseldorfGermany
  4. 4.CARID, Cardiovascular Research Institute DüsseldorfDüsseldorfGermany

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