Author + information
- Received February 4, 2014
- Revision received April 22, 2014
- Accepted April 23, 2014
- Published online October 1, 2014.
- Kenichi Sakakura, MD∗,
- Elena Ladich, MD∗,
- Elazer R. Edelman, MD†,
- Peter Markham, MS†,
- James R.L. Stanley, DVM†,
- John Keating, DVM†,
- Frank D. Kolodgie, PhD∗,
- Renu Virmani, MD∗ and
- Michael Joner, MD∗∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Michael Joner, CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, Maryland 20878.
Transcatheter ablation of renal autonomic nerves is a viable option for the treatment of resistant arterial hypertension; however, structured pre-clinical evaluation with standardization of analytical procedures remains a clear gap in this field. Here we discuss the topics relevant to the pre-clinical model for the evaluation of renal denervation (RDN) devices and report methodologies and criteria toward standardization of the safety and efficacy assessment, including histopathological evaluations of the renal artery, periarterial nerves, and associated periadventitial tissues. The pre-clinical swine renal artery model can be used effectively to assess both the safety and efficacy of RDN technologies. Assessment of the efficacy of RDN modalities primarily focuses on the determination of the depth of penetration of treatment-related injury (e.g., necrosis) of the periarterial tissues and its relationship (i.e., location and distance) and the effect on the associated renal nerves and the correlation thereof with proxy biomarkers including renal norepinephrine concentrations and nerve-specific immunohistochemical stains (e.g., tyrosine hydroxylase). The safety evaluation of RDN technologies involves assessing for adverse effects on tissues local to the site of treatment (i.e., on the arterial wall) as well as tissues at a distance (e.g., soft tissue, veins, arterial branches, skeletal muscle, adrenal gland, ureters). Increasing experience will help to create a standardized means of examining all arterial beds subject to ablative energy and in doing so enable us to proceed to optimize the development and assessment of these emerging technologies.
This paper would not have been possible without the support of the following companies: Biosense Webster, Medtronic, Kona Medical, and ReCor Medical. None of the mentioned companies provided financial support for the preparation of the current manuscript. However, this consensus document is based on studies that were conduced in cooperation with the above mentioned companies. CVPath Institute, Inc. provided full support for the work of Drs. Sakakura, Ladich, Kolodgie, Virmani, and Joner. Dr. Edelman was supported by grants from the National Institutes of Health including R01 GM49039. P. Markham, Dr. Keating, and Dr. Stanley were supported by CBSET, Inc., Lexington, Massachusetts. Dr. Sakakura is supported by a research fellowship from the Banyu Life Science Foundation International. Dr. Sakakura has received speaking honoraria from Abbott Vascular, Boston Scientific, and Medtronic CardioVascular. Dr. Virmani receives research support from 480 Biomedical, Abbott Vascular, Atrium, Biosensors International, Biotronik, Boston Scientific, CeloNova, Cordis J&J, GlaxoSmithKline, Kona, Medtronic, Microport Medical, OrbusNeich Medical, ReCor Medical, SINO Medical Technology, Terumo Corporation, and W.L. Gore; Dr. Virmani is a speaker for Merck; and receives honoraria from 480 Biomedical, Abbott Vascular, Biosense Webster, Biosensors International, Boston Scientific, Claret Medical, CeloNova, Cordis J&J, Lutonix, Medtronic, Terumo Corporation, and W.L. Gore; and is a consultant for 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. Dr. Joner is a consultant for Biotronik and Cardionovum; and has received speaker honoraria from Abbott Vascular, Biotronik, Cordis J&J, Medtronic, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received February 4, 2014.
- Revision received April 22, 2014.
- Accepted April 23, 2014.
- American College of Cardiology Foundation
- Animal Model Systems
- Porcine Renovascular Anatomy
- Norepinephrine Analysis
- Macroscopic 2,3,5-Triphenyltetrazolium Chloride Staining
- Histopathological and Immunohistochemical Stains
- Immunostaining of Perivascular Nerves and Scoring Criteria
- Histological Assessment of Renovascular Morphology
- Histological Assessment for Periarterial Tissues and Organs
- Advantage of the Combination of Various Stains
- Quadrant Analysis and Deepest Soft-Tissue Damage