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A Swine Hind Limb Ischemia Model Useful for Testing Peripheral Artery Disease Therapeutics

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Abstract

Currently, there is no large animal model of sustained limb ischemia suitable for testing novel angiogenic therapeutics for peripheral artery disease (PAD) such as drugs, genes, materials, or cells. We created a large animal model suitable for efficacy assessment of these therapies by testing 3 swine hind limb ischemia (HLI) variations and quantifying vascular perfusion, muscle histology, and limb function. Ligation of the ipsilateral external and bilateral internal iliac arteries produced sustained gait dysfunction compared to isolated external iliac or unilateral external and internal iliac artery ligations. Hyperemia-dependent muscle perfusion deficits, depressed limb blood pressure, arteriogenesis, muscle atrophy, and microscopic myopathy were quantifiable in ischemic limbs 6 weeks post-ligation. Porcine mesenchymal stromal cells (MSCs) engineered to express a reporter gene were visualized post-administration via positron emission tomography (PET) in vivo. These results establish a preclinical platform enabling better optimization of PAD therapies, including cellular therapeutics, increasing bench-to-bedside translational success.

Graphical abstract

A preclinical platform for porcine studies of peripheral artery disease therapies including (1) a hind limb ischemia model and (2) non-invasive MSC viability and retention assessment via PET

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Abbreviations

ABI:

Ankle-brachial index

CT:

Computed tomography

EIA:

External iliac artery

FBS:

Fetal bovine serum

18F-MFBG:

18F-meta-fluorobenzylguanidine

GH:

Growth hormone

hNET:

Human norepinephrine transporter

IGF-1:

Insulin-like growth factor 1

IIA:

Internal iliac artery

mGFP:

mTag green fluorescent protein

MSC:

Mesenchymal stromal cell

MRI:

Magnetic resonance imaging

PAD:

Peripheral artery disease

PBS:

Phosphate-buffered saline

PET:

Positron emission tomography

TOF MRA:

Time-of-flight magnetic resonance angiography

HLI :

Hind limb ischemia

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Acknowledgements

We thank T3 Labs for swine experiment organization and technical expertise.

Funding

These data were generated with support of the Aronov Foundation, the Emory University Center for Systems Imaging Pilot Funding, the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under Award Numbers UL1TR002378 and TL1TR002382 (J.N.D), and R01HL140223 (R.D.L.). Experiments were performed in part using the Microscopy in Medicine Core (NIH grant P01HL095070) and the Emory Integrated Genomics Core (subsidized by the Emory University School of Medicine and additionally supported by NIH Award Number UL1TR002378). The content is solely the responsibility of the authors and does not necessarily represent the views of NIH.

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Authors and Affiliations

  1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA

    Juline N. Deppen, Sydney C. Ginn & John N. Oshinski

  2. Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Juline N. Deppen, Sydney C. Ginn, Na Hee Kim, Lanfang Wang & Rebecca D. Levit

  3. Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, USA

    Ronald J. Voll, Mark M. Goodman & John N. Oshinski

  4. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Steven H. Liang

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Contributions

Conceptualization: JND and RDL. Formal analysis: JND, SCG, and NHK. Funding acquisition: JND and RDL. Investigation: JND, SCG, NHK, LW, RJV, and JNO. Methodology: JND, RJV, SHL, MMG, JNO, and RDL. Project administration: MMG and RDL. Resources: LW, SHL, and MMG. Supervision: RDL. Visualization: JND and JNO. Writing—original draft preparation: JND. Writing—review and editing: JND, SCG, NHK, LW, RJV, MMG, JNO, and RDL.

Corresponding author

Correspondence to Rebecca D. Levit.

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No human studies were performed. All institutional and national guidelines for laboratory animal care and use were followed and approved by institutional committees at T3 Labs and Emory University for swine and rat studies, respectively.

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The authors declare no conflicts of interest.

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Deppen, J.N., Ginn, S.C., Kim, N.H. et al. A Swine Hind Limb Ischemia Model Useful for Testing Peripheral Artery Disease Therapeutics. J. of Cardiovasc. Trans. Res. 14, 1186–1197 (2021). https://doi.org/10.1007/s12265-021-10134-8

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