1. Animal Models and Physiologic Models And Physiologic Assessment
Of Renal Denervation
Robert S. Schwartz, MD
Minneapolis Heart Institute and Foundation

2. Consulting: Covidien Scientific Advisory Board: ASI
Robert S. Schwartz, MD
Consulting: Covidien
Scientific Advisory Board: ASI

4. HTN and Renal Nerves: Background
Essential HTN is complex Problem
Polygenic control
multifactorial
Animal models have been useful to understand HTN
Will also prove essential for understanding treatments 4

5. Animal Models Several models share common features with human HTN
Models developed for example:
Excess Na Intake
Hyperactive RAAS
Genetic Factors 5

6. The Ideal Animal Model Feasible in small animals
Simple to perform and reproducible
Predict efficacy of various therapies
Comparable to human HTN 6

7. Types of human HTN Renovascular Dietary Endocrine Neurogenic
Psychogenic
Genetic
? Others 7

8. Specific Models
Renovascular Hypertension 8

9. Renovascular Model In Renovascular HTN – RAAS activation
Sympathetic NS key role
Both are activated by Renal A stenosis 9

10. Edward J. Johns et al. Compr Physiol 2011. DOI: 10.1002/cphy.c100043
Copyright © 2011 American Physiological Society

11. Renal Sympathetic Activity
Renin Release
Epi/Norepi release (adrenal)
Sodium Reabsorption
Renal Blood Flow and GFR

12. Images Courtesy Giuseppe Sangiorgi

13. Renovascular Hypertension
Decreased blood volume
Sympathetic Activation
Renin Secretion
AT to AT-1, then
AT-I to AT-II via ACE
AT II is potent vasoconstrictor
Also Aldosterone Release 13

14. Goldblatt Method - 1934 Renal Ischemia via RA constriction
Unilateral or bilateral
Dogs, Monkeys, rabbits, rats, pigs
HTN in the 160 – 190 mmHg range 14

15. Renal Artery Stenosis – many ways Also works with: Kidney compression
Goldblatt method
Renal Artery Stenosis – many ways
Also works with:
Kidney compression
Aortic coartation
Renal Mass ablation
Microsphere embolization 15

16. Renal Nerve Target: juxtaglomerular cells

17. Plasma and kidney norepinephrine (NE) levels, kidney angiotensin II (AngII) content, mRNA levels of angiotensinogen (AGT) and angiotensin type 1a (AT1a) receptor in renal cortical tissues, and urinary AGT excretion rate (UAGTV) in protocol 1.
Plasma and kidney norepinephrine (NE) levels, kidney angiotensin II (AngII) content, mRNA levels of angiotensinogen (AGT) and angiotensin type 1a (AT1a) receptor in renal cortical tissues, and urinary AGT excretion rate (UAGTV) in protocol 1. Plasma NE levels (A) and kidney tissue NE content (B) at 6 months after the sham or aortic regurgitation (AR) operation. AR rats have increased plasma and kidney NE levels. Treatment with olmesartan suppresses the increases in plasma and kidney NE levels in AR rats. Kidney AngII content (C), AT1a receptor mRNA levels (D), and AGT (E) mRNA levels in renal cortical tissues. AR rats have increased kidney AngII content and mRNA levels of AT1a receptor and AGT. Olmesartan suppresses the increases in AngII levels and the upregulation of AT1a receptor and AGT mRNA levels in AR rats. Real-time polymerase chain reaction data are expressed as fold changes compared with the sham group after normalization for the expression of GAPDH. F, UAGTV is augmented in AR rats compared with sham rats. The increase in UAGTV is suppressed by olmesartan in AR rats. *P<0.05, **P<0.01, ***P<0.005, ****P<0.001 vs sham; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.001 vs AR.
Rafiq K et al. Circulation 2012;125:
Copyright © American Heart Association

18. Specific Models: No Time to Discuss !
Dietary Hypertension
Endocrine
Genetic – SHR
Neurogenic 18

19. Renovascular Hypertension Lerman, Schwartz, Romero et al

20. Renovascular Hypertension Martin, Mika, Burkhoff, Schwartz

21. Renal Nerve Monitor

22. Overall Summary Multiple Models available
For Renal Denervation, need macroscopic
arteries to accommodate human catheter sizes
Renovascular HTN works well
Renal/Blood NE Levels for efficacy
Efficacy and Safety are easily evaluated

23. Animal Models and Physiologic Models And Physiologic Assessment
Of Renal Denervation
Robert S. Schwartz, MD
Minneapolis Heart Institute and Foundation