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

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

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

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

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

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

Specific Models Renovascular Hypertension 8

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

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

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

Images Courtesy Giuseppe Sangiorgi

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

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

Renal Artery Stenosis – many ways Also works with: Kidney compression Goldblatt method - 1934 Renal Artery Stenosis – many ways Also works with: Kidney compression Aortic coartation Renal Mass ablation Microsphere embolization 15

Renal Nerve Target: juxtaglomerular cells

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;125:1402-1413 Copyright © American Heart Association

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

Renovascular Hypertension Lerman, Schwartz, Romero et al

Renovascular Hypertension Martin, Mika, Burkhoff, Schwartz

Renal Nerve Monitor

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

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