A tale of the not so sympathetic nervous system

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1 A tale of the not so sympathetic nervous system A/Prof Markus Schlaich Neurovascular Hypertension & Kidney Disease Laboratory Alfred & Baker Hypertension Network Melbourne VIC, Australia

2 Department of Medicine 4 Nephrology & Hypertension University of Erlangen-Nuremberg in Erlangen Page 2: Baker IDI

3 Page 3: Baker IDI

4 Page 4: Baker IDI Neurovascular Hypertension & Kidney Disease

5 Page 5: Baker IDI Autonomic Nervous System

Kidney Heart Vein Arteriole Aggregatability Viscosity Na + retention

6 Sympathetic Nervous System Overactivity: Increased Risk of CV disease CNS (RVLM, I 1 -receptor) Epinephrine Adrenal medulla Page 6: Baker IDI Blood Kidney Heart Vein Arteriole Aggregatability Viscosity Na + retention Vasoconstriction Renin release Arrhythmias LVH, HR, SV hypertension vasoconstriction

7 Sympathetic Nervous System Overactivity: Effects on Metabolism CNS (RVLM, I 1 -receptor) Epinephrine Adrenal medulla Fat cell Liver Pancreas -cell Skeletal muscle Skeletal arteriole Lipolysis Gluconeogenesis Insulin release Slow to fast transition Rarefaction Page 7: Baker IDI

8 Cause Central Integration Consequence nnos Renal ischemia } Adenosine Contributing factors: Obesity Leptin Smoking Hypercapnia Hypercholesterolemia Oxidative stress Inflammation Endothelial factors NO RAAS Integration BP Aggravation of hypertension Growth (LVH) Arrhythmias Ischemia Heart Failure Growth Vasoconstriction Atherosclerosis Arterial compliance Sodium retention Hypervolemia RAAS Reduced Blood Flow Proteinuria Glomerulosclerosis Page 8: Baker IDI

9 Renal Sympathetic Efferent Nerve Activity Kidney as the Recipient of Sympathetic Signals Renal Efferent Nerves Renin release RAAS activation Sodium retention Renal Blood Flow Page 9: Baker IDI

Renal Afferent Sensory Nerve Activity Kidney as a driver of Central Sympathetic Outflow Vasoconstriction Atherosclerosis Hypertrophy Arrhythmia O 2 Consumption

10 Renal Afferent Sensory Nerve Activity Kidney as a driver of Central Sympathetic Outflow Vasoconstriction Atherosclerosis Hypertrophy Arrhythmia O 2 Consumption Heart Failure Renal Afferent Nerves Insulin Resistance Renal Injury Renal ischemia Renin release RAAS activation Sodium retention Renal Blood Flow Page 10: Baker IDI

11 The important role of SNS Activation in renal disease Experimental Evidence kidneys: dense afferent sensory and efferent sympathetic innervation origin and target of SNS activation subtotal nephrectomy subtotal nephrectomy + abrogation of afferent sensory signals (dorsal rhizotomy) Page 11: Baker IDI BP Campese V, Hypertension 1995 BP

12 Acute renal injury model Phenol Phenol + renal denervation BP NE secretion hypothalamus BP NE secretion hypothalamus Page 12: Baker IDI Ye S, Kidney Int 1997

13 Renal afferent denervation prevents hypertension in rats with CRF Page 13: Baker IDI Campese Vet al. Hypertension 1995; 25:

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15 ilateral nephrectomy reduces BP, vascular resistance and sympathetic nerve activity

16 SNS activation in ESRD Role of the diseased kidneys aemodialysis (HD) Patient Healthy Control HD Patient after renal Tx HD Patient after renal Tx + bilateral nephrectomy

17 Plasma NE predicts survival and incident CV events in patients with end-stage renal disease. r survival curves for all-cause death and cardiovascular events (fatal and nonfatal) in hemodialysis patients below

19 LVH develops in those hypertensive patients with high cardiac sympathetic nerve activity

20 ation between LVMI and cardiac sympathetic nerve activity

21 es of SCD by the baseline egfr category

22 Sympathetic activity in sheep after MI

27 mpathetic nerve activity is inversely related to egfr

30 - randomized, crossover design (pacebo / moxonidine 0.2mg bid over 3 weeks) - 15 normotensive,nonsmoking type 1 diabetic mellitus patients with good glycemic control - age 37.3± 6.6 yr; 9 men/6 women; - baseline urinary albumin excretion rates (AER) >20 µg/min in the run-in phase. Page 30: Baker IDI

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32 Therapeutic Implications (human studies) CRF + Hypertension n = 177 ACEI + diuretics nitrendipine 20 mg/d moxonidine 0.3 mg/d Adverse events (%) Creatinine Clearance (ml/min) ± ± 4.3 * S-Creatinine (µmol/l) ± ± 49.2 * Page 32: Baker IDI Vonend et al., J Hyp 2003

33 Catheter-Based Renal Denervation Symplicity Catheter System Ardian, Inc., Palo Alto, CA, USA 6F access Articulating tip with RF electrode Renal nerves lie in adventitia, encircling the renal arteries 4-6 focal 2-minute RF treatments along each renal artery Page 33: Baker IDI

$with refractory hypertension Study Sites: Melbourne & Newcastle, Australia; Krakow, Poland & Frankfurt, Germany Page 34: Baker IDI Krum et al. Lancet.$

34 Study Aims: To perform a first-in-man 12-month evaluation of the safety and blood pressurelowering efficacy of percutaneous renal sympathetic denervation in patients with refractory hypertension Study Sites: Melbourne & Newcastle, Australia; Krakow, Poland & Frankfurt, Germany Page 34: Baker IDI Krum et al. Lancet. 2009;373:

35 Baseline Patient Characteristics Patients Undergoing Procedure (N=45) Patients Anatomically Ineligible for Procedure (N=5) Age (years) 58 ± 9 51 ± 8 Gender (% female) Race (% non-caucasian) 4 0 Diabetes Mellitus II (%) CAD (%) Heart Rate (bpm) 72 ± ± 9 egfr (ml/min/1.73m 2 ) 81 ± ± 15 BP (mmhg) 177/101 ± 20/15 173/98 ± 8/9 Page 35: Baker IDI Lancet 2009; 373(9671):

36 Baseline Patient Characteristics Patients Undergoing Procedure (N=45) Patients Anatomically Ineligible for Procedure (N=5) Number of anti-htn meds (mean) 4.7 ± ± 0.5 ACE/ARB (%) Beta-blocker (%) Calcium channel blocker (%) Vasodilator (%) 18 0 Diuretic (%) Page 36: Baker IDI Lancet 2009; 373(9671):

37 Office BP: All Treated Patients Page n=45 37: Baker IDI Lancet 2009; 373(9671):

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43 0 Kidney Function SBP (mmhg) GFR (ml/min/year) r = 0.69; P <.05 RDN 12 month Average GFR = -3.1mL/min Avg SBP = 148 mmhg Predicted Trajectory for RDN Cohort Based on Baseline BP Parving HH, et al. Br Med J Moschio G, et al. N Engl J Med Viberti GC, et al. JAMA Bakris GL, et al. Kidney Int Klahr S, et al. N Eng J Med Bakris GL. Hypertension Hebert L, et al. Kidney Int The GISEN Group. Lancet Page Lebovitz 43: Baker H, et al. IDI Kidney Int Bakris et al. Am J Kidney Dis. 2000;36(3):

44 Page 44: Baker IDI Lancet Dec 4;376(9756):

45 Study Design Patient Population: - Adults (18-85yrs) - Office systolic BP 160 mmhg ( 150 mmhg with type 2 diabetes), - stable drug regimen of 3 antihypertensive medications Randomisation: Eligible patients were randomized 1:1 to either: - catheter-based renal denervation - control group (continuing medication alone), no intervention (Background anti-htn medication was held constant in both arms) Primary Endpoint: - Automated office systolic BP change from baseline to 6 months Page 45: Baker IDI Lancet Dec 4;376(9756):

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50 Renal parameters Renal denervation group Control group Patients Median change Patients Median change line and 38-3 (-1089 to 76) 37 1 (-538 to 227) p = 0.26 (Wilcoxon test) CR (mg/g)

51 ction, as assessed by serum creatinine, egfr, tin C concentrations were unchanged from in both groups at 6 months (table 2). During follow-up, no patient had a decrease of more in egfr, although two patients who underwent ervation and three controls had a more than ease in egfr. lated a paired baseline and 6-month urine o-creatinine ratio for 38 patients who underwent ervation and 37 controls. The median in urine albumin-to-creatinine ratio at was 3 mg/g (range 1089 to 76) for patients rwent renal denervation and 1 mg/g (range 27) for controls (p for signifi cance=0 26; test).

52 ffects of renal denervation on renal and total body NE spillover Mean office blood pressure 161/ /90 Renal Norepinephrine Spillover (ng/min) Baseline 30 days after bilateral denervation Left Kidney Right Kidney Totla Body Norepinephrine Spillover (ng/min)

53 of renal denervation on central sympathetic outflow (MSNA) Baseline 30 days FU 12 M FU sec

54 Medication at baseline: Tritace 10 mg Avapro 300 mg Zanidip 20 mg Noten 50 mg Minoxidil 5 mg ESRD patient (M; 37 yrs) ESRD (FSGS), RRT since 04/2006 Dry Weight: 81 kg no change in HD regimen NTx August 2008 Medication at 33 M FU: Noten 50 mg 180 Change in BP following bilateral denervation Blood Pressure (mmhg)

55 Meds: Tritace 10 mg Avapro 300 mg Zanidip 20 mg Noten 50 mg Minoxidil 5 mg ESRD patient (M; 37 yrs) ESRD (FSGS), RRT since 04/2006 Dry Weight: 81 kg no change in HD regimen Change in BP following bilateral denervation Blood Pressure (mmhg) systolic BP mmhg diastolic BP mmhg Page 55: Baker IDI 60 baseline 3 d FU 30 d FU 90 d FU Time

56 BW ESRD patient with MSNA over 33 months FU post bilateral denervation baseline MSNA: 46 burst/min Chart Window 12 Months FU MSNA: 21 burst/min Chart Window MSNA (V) MSNA (V) :20 8:25 8:30 8:35 8:40 18:20 18:25 18:30 18:35 18:40 18:45 3 Months FU MSNA: 33 burst/min Chart Window 33 Months FU MSNA: 19 burst/min Chart Window MSNA (V) MSNA (V) :45 20:50 20:55 21:00 1:15:20 1:15:25 1:15:30 1:15:35 Of note: normal MSNA between bursts/min

57 mpathetic activation in cardiorenal medicine

58 Symplicity HTN-1/2 Study Centers Australia, Europe, and USA e John Paul II Hospital, Krakow, Poland Jerzy Sadowski airie Education and Research Cooperative, Springfield, IL, USA Krishna Rocha-Singh iversitätsklinikum des Saarlandes, Homburg, Germany Michael Böhm modzielna Pracownia Hemodynamiczna, Warsaw, Poland Andrzej Januszewicz & Adam Witkowski e Alfred Hospital, Melbourne, Australia Henry Krum rdiovascular Center Frankfurt, Frankfurt, Germany Horst Sievert. Vincent s Hospital, Melbourne, Australia Robert Whitbourn iversitätsklinikum Düsseldorf, Düsseldorf, Germany Lars Christian Rump etrohealth System, Cleveland, OH, USA Mark Dunlap hn Hunter Hospital, Newcastle, Australia Suku Thambar rz-zentrum Bad Krozingen, Bad Krozingen, Germany Thomas Zeller uls Stradins Clinical University Hospital, Riga, Latvia Andrejs Erglis dinje Cardiovascular Institute, Belgrade, Serbia Boško Đukanović inikum Coburg, Coburg, Germany Johannes Brachmann iversitätsklinikum Hamburg-Eppendorf, Hamburg, Germany Gerhard Adam & Ulrich Wenzel nnepin County Medical Center, Minneapolis, MN, USA Bradley Bart

60 female, 63 yrs, obese (BMI 33.2kg/m 2 ) T2DM, HTN (4 drugs) anti-htn meds: Candesartan 32mg, HCT 25mg, Norvasc 10mg, Prazosin 5mg BD ABPM 164/93 mmhg, baseline creatinine 55 umol/l INAL ROUTINE BIOCHEMISTRY BGenA equest No: P P Date: 08/08/07 22/08/07 Time: 12:00 10:45 Units Ref Range ERUM/PLASMA pec.type Random Random a Conc'n mmol/l otassium mmol/l reatinine μmol/l rea mmol/l luc Serum 5.6 mmol/l /08/07 07P LUCOSE: f the patient is not known to have diabetes, consider erforming an OGTT in accordance with 1999 WHO criteria. National Evidence Based Guidelines For The Management Of ype 2 Diabetes Mellitus, Endorsed by the NHMRC ) 2/08/07 07P693528

61 female, 63 yrs, obese (BMI 33.2kg/m 2 ) T2DM, HTN (4 drugs) anti-htn meds: Candesartan 32mg, HCT 25mg, Norvasc 10mg, Prazosin 5mg BD ABPM 164/93 mmhg Renal Denervation 11/07/07 est No: P P P P Date:03/07/07 14/07/07 08/08/07 21/08/07 Time: 13:30 *UNK* 06:00 11:00 Units Ref Range E Type Random Random Random od Hrs me ml t Ex mmol/d t Cl 127 ml/min Ex mmol/d ogen Ex 4.5 g/l x H 283H 181 mmol/d mmol/d Ex 0.13 g/d <0.15 oalb mg/l NO-RANGE o Ex ug/min o DE mg/d 7/07 07P t:12/7/07 at 08:45 and finish:13/7/07 at 08:45. ICROALBUMIN EXCRETION *

62 Renal Noradrenaline Spillover Renal NA SO (ng/min) (Lander) Left kidney Right Kidney baseline int. right 2. baseline int. left 3. Baseline

63 LANCET proteinuria data

The ONTARGET Study l. N Engl J Med 2008; 358: 1547-1559.

64 The ONTARGET Study l. N Engl J Med 2008; 358: or ACE inhibitor were equi-effective at vascular events in high-risk patients. r, their combination at the doses trialed, d no extra benefit and was associated eased adverse events.

65 ONTARGET

ONTARGET CV Death, MI, HF or Stroke Results Ramipril and Telmisartan were equally effective at reducing primary outcomes RR = 1.01 [95% Cl, 1.01 (0.94 1.09)]. Additional BP reduction: Telmisartan (0.

66 ONTARGET CV Death, MI, HF or Stroke Results Ramipril and Telmisartan were equally effective at reducing primary outcomes RR = 1.01 [95% Cl, 1.01 ( )]. Additional BP reduction: Telmisartan (0.9/0.6 mmhg) vs Ramipril Combination (2.4/1.4 mmhg) vs Ramipril amipril Telmisartan Ramipril + Telmisartan Ramipril v combination therapy were equally effective at reducing primary outcomes RR =0.99 [95% Cl, ( )]. Conclusions In patients without HF but with pre-existing CVD co-morbidities the use of an ACEi in combination with an ARB does not reduce the primary outcomes compared to single drug therapy.

67 ONTARGET

71 Monotherapy vs ACEI/ARB combination in patients with high renal risk (low GFR and MAU) Page 71: Baker IDI Circulation 2011;123:

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74 Monotherapy vs ACEI/ARB combination in patients with high renal risk (low GFR and MAU) Combination Monotherapy Figure. Change of urinary albumin:creatinine ratio and blood pressure over time in patients with estimated <GFR 60 ml/min/1.73 m2 and macroalbuminuria in ONTARGET. Data are adapted from Tobe et al.19 The albumin:creatinine ratio was measured at a registration visit prior to the 6-week active run-in period. Dual therapy (ramipril and telmisartan) indicated by. Monotherapy (ramipril or telmisartan) indicated by. To convert the values of albumin:creatinine ratio to milligram per gram, multiply by Page 74: Baker IDI

75 Finally, the interpretation of the ONTARGET trial has led to the suggestion that albuminuria cannot be taken as a definitive marker for renal protection. 22 The current analysis of ONTARGET shows how careful one has to be with such interpretations. This article and the results in the online-only Data Supplement confirm what was known long before: if one is not able to reduce blood pressure or albuminuria in those with increased levels of albumin in the urine, one will fail to reduce the risk of renal or cardiovascular disease. Thus, ONTARGET actually shows that, next to blood pressure, effect on albuminuria is a good marker for renal protection. We need more on-target subanalyses of ONTARGET to fully understand why dual therapy had no additional effects on blood pressure and albuminuria in the patients at renal risk. Page 75: Baker IDI

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85 RF Ablation Approach to Renal Sympathetic Denervation Electrode Insulated arch wire Symplicity Catheter System, Ardian, Inc., Palo Alto, CA, USA Page 85: Baker IDI In the United States: Caution: Investigational Device. Limited by U.S. law to investigational use.

86 Symplicity Catheter System for selective renal denervation Ardian Inc., Palo Alto, CA, USA 6F access Articulating tip with RF electrode Renal nerves lie in adventitia, encircling the renal arteries 4-6 focal 2-minute RF treatments along each renal artery Page 86: Baker IDI

87 Anatomical Location of Renal Sympathetic Nerves Arise from T10-L1 Follow the renal artery to the kidney Primarily lie within the adventitia Vessel Lumen Media basket weave plexus (Page 1935) Adventitia Page 87: Baker IDI Renal Nerves

88 The Renal Nerves Nerves Lumen Endothelium Media Adventitia 3 mm Fat follow the renal artery to the kidney primarily within the adventitia Page 88: Baker IDI 88

89 Treatment by Renal RF Catheter

90 Multiple focal RF ablations

94 Focal ablations Multiple focal ablations Selective Renal Denervation: Symplicity Catheter System, Ardian, Inc., Palo Alto, CA, USA Renal Artery Treatments Kidney

100 First in Human Study Hypertension is a global public health problem of major magnitude Despite the availability of safe and effective pharmacological therapies, only ~50% of patients achieve adequate blood pressure control to guideline targets The sympathetic nervous system, in particular renal sympathetic efferent and afferent nerves, is recognized as critical in the hypertension disease process Disruption of renal sympathetic nerves has long been considered an attractive therapeutic target for this

101 Inclusion/Exclusion Criteria Inclusion Criteria Office SBP 160 mmhg despite 3+ anti-hypertensive medications (including diuretic), or confirmed intolerance to medications egfr (MDRD formula) of 45 ml/min/1.73m 2 Exclusion Criteria Known secondary cause of hypertension Type I diabetes mellitus Hemodynamically significant valvular disease Currently taking clonidine, moxonidine, or rilmenidine Renovascular abnormalities: significant renal artery stenosis, prior renal stenting or angioplasty, dual renal arteries

102 Procedure & Acute Procedural Safety rocedure time: median 38 (IQR 34-48) minutes ilateral procedure Average 4.2 (mode = 5) treatments in right renal artery Average 3.7 (mode = 4) treatments in left renal artery travenous narcotics & sedatives used to manage pain uring delivery of RF energy reatment delivered without complication in 43/45: 1 renal artery dissection during catheter delivery (prior to RF energy)

103 Chronic Procedural Safety o chronic vascular complications 18 patients with angiograms at days post-procedure 38 of 38 patients with CTA/MRA 6 months post-procedure o chronic renal ( egfr) complications 3 Month: 0.4 ml/min/1.73m 2 (95% CI: -4.2 to 4.9; N=31; p=0.87) 12 Month: -3.1 ml/min/1.73m 2 (95% CI: -9.0 to 2.8; N=28; p=0.31) o orthostatic or electrolyte disturbances ortality Cardiac death considered unrelated to the therapy - 6 months post

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105 Safety cedural and Device Safety or adverse events only : cute renal artery damage femoral artery pseudoaneurysm treated with manual compression early post-procedural drop in BP requiring reduction in medication yed Safety t patients have renal imaging available at 6 month follow-up. No frequency dosing related abnormalities detected (one Magnetic nance Angiogram indicates possible progression of a pre-existing l artery stenosis)

106 Conclusions ter-based renal denervation in patients with treatment-resistant tial hypertension results in very substantial reductions in BP rial affirms the crucial relevance of renal nerves in the maintenance vated BP echnique was applied without significant complications domized USA-based trial is in development UTURE: Application of the technique in patients with less severe tial hypertension is under consideration?

107 0 2 Kidney Function SBP (mmhg) r = 0.69; P < RDN 12 month Average GFR = -3.1mL/min Avg SBP = 148 mmhg Predicted Trajectory for RDN Cohort Based on Baseline BP

108 Where next? - Hypertension on-dippers n= ess severe forms of hypertension (controlled with 3-4 drugs) atients intolerant to antihypertensive drugs atients non-adherent/non-compliant to antihypertensive treatment

109 Where next? Metabolic Disorders athetic Nervous System Overactivity: Effects on Metabolism CNS (RVLM, I 1 -receptor) Epinephrine al lla Fat cell Liver Pancreas -cell Skeletal muscle Skeletal arteriole

110 Change in NE spillover after bilateral denervation Lean (BMI 27±2; n=5) Obese (BMI 37±3; n=12) renal whole body renal whole body % change in NE spillover

111 40 Change in BP after bilateral denervation Low BMI systolic High BMI systolic Low BMI diastolic High BMI diastolic 80 60

112 Baseline Characteristics All patients (n=47) Renal denervation (n=33) Control group (n=14) p Age 59.5 (1.4) 58.8 (1.6) 62.4 (3.3) 0.34 Sex (female) 15 (32%) 10 (30%) 5 (36%) 0.23 Type 2 diabetes mellitus 19 (40%) 14 (42%) 5 (36%) 0.48 on medication 15 (32%) 11 (33%) 4 (29%) 0.39 egfr (ml/min/1.72 m²) 65.0 (4.4) 67.5 (4.9) 56.9 (10.2) 0.36 Heart rate (bpm) 72 (2.1) 70 (2.1) 78 (5.7) 0.19 Blood pressure (mm Hg) 180/96 (3/2) 178/96 (3/3) 182/97 (7/5) 0.51 Number of antihypertensive drugs 5.5 (0.2) 5.6 (0.2) 4.9 (0.3) 0.11 Fasting glucose (mg/dl) 124 (3.7) 127 (4.5) 117 (6.9) 0.26 Glucose level 60-min, OGT (mg/dl) 217 (9) 225 (10) 191 (15) 0.07 Glucose level 120-min, OGT (mg/dl) 179 (11) 180 (13) 173 (19) 0.78 Impaired fasting glycemia, OGT (n) Impaired glucose tolerance, OGT (n) Diabetes mellitus, OGT (n) HbA1c (%) 5.9 (0.1) 5.9 (0.1) 6.2 (0.3) 0.37 Insulin (μiu/ml) 19.0 (2.4) 20.7 (2.8) 17.0 (5.2) 0.42 C-peptide (ng/ml) 4.6 (0.48) 5.1 (0.6) 3.9 (0.4) 0.09

113 ge in blood pressure and glucose metabolism at 1 and 3 months Treatment group Control group 1 month (n=33) p* 3 months (n=33) p** 1 month (n=14) p* 3 months (n=14) p** m Hg) -29/-10 (2/2)* <0.001/< /-10 (4/2)* 0.001/ /-4 (6/2) 0.274/ /-4 (6/2) 0.479/0.506 mg/dl) -6.8 (4.3) (3.3)* (8.0) (4.7) (0.1) (0.1) (0.1) (0.2) (3.1)* (3.3)* (7.2) (2.3) ) -2.0 (0.7)* (0.8)* (0.7) (0.5) (0.9)* (1.0)* (1.6) (0.9) (0.01)* (0.01)* (0.01) (0.02) min, OGT (mg/dl) (12)* (8) min, OGT (mg/dl) (12)* (11) glycemia, OGT (n) ±0 -

114 p<0.001 Change in blood pressure (mmhg) systolic 1 month 3 months diastolic 1 month 3 months p<0.001 p=0.274 p=0.479 p<0.001 p=0.366 p=0.002 p=0.506 Renal denervation (n=33) Control (n=14)

115 anges in glucose metabolism at 1 and 3 months compared to baseline 1 month 3 months p= month 3 months p= p=0.006 p=0.506 Renal denervation (n=33) Control (n=14) Change in fasting insulin (µiu/ml) p= p=0.033 p=0.404 Renal denervation (n=33) Control (n=14) 1 month 3 months p= month 3 months p= p= p=0.007 Renal denervation (n=33) Change in IR HOMA (ng/ml) p=0.308 p=0.037

116 Proportion of patients with DM, IGT, IFG, and NGT OGTT at baseline and after 3 months. Renal denervation (n=35) Control group (n=15) % 54% n=3 6% 51% 20% 47% n=1 27% Diabetes IGT, IFG, or both NGT 40 n=4 53% 20 31% 43% 33% n=2 20% 0

117 Changes in HbA1c following renal denervation t 0.3 6E

118 ct of bilateral renal denervation on insulin sensitivity (as assessed by euglycaemic hyperinsulinaemic clamp)

119 Renal denervation: a potential new treatment modality for polycystic ovary syndrome? B 100 MSNA (bursts/100hb) C Whole body NE spillover (ng/min) Baseline 12 weeks post renal denervation

120 Insulin sensitivity (mg/kg/min) C F Baseline 12 weeks post renal denervation UACR (mg/g creatinine)

121 ere next? CHF / Cardiorenal Syndrome SNS Activation

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123 Sympathetic activity in sheep after MI

124 Conclusions ercutaneous, catheter based, therapeutic renal sympathetic enervation is simple and safe ignificant and sustained reduction in sympathetic activity ssociated with substantial blood pressure reduction in patients with sistant hypertension otential benefit of selective renal denervation in various conditions haracterized by sympathetic activation

125 Acknowledgements BakerIDI, Alfred Hospital, Melbourne, AU: St Vincent s Hospital, Melbourne, AU: Cardiology Team Prof Murray Esler Dr Tony Walton Prof Henry Krum Cardiology Team A/Prof Rob Whitbourn John Hunter Hospital, Newcastle, AU: Cardiovascular Center Frankfurt, Germany: Jagiellonian University, Krakau, Poland: Ohio State University, Columbus, Ohio, USA: Cardiology Team Dr Suku Thambar Cardiology Team Prof Horst Sievert Cardiology Team Prof Jerzy Sadowski Dr Krzysztof Bartus Dr Boguslav Kapelak Prof William Abraham Prof Paul Sobotka

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127 of increased afferent g from the kidney to integrative structures Consequences of increased efferent sympathetic outflow to the kidney and other organs at can contribute to afferent signaling: - Therapeutic Options: 7Centrally acting sympatholytic agents 8 Renal denervation Growth (LVH) Arrhythmias Ischemia Heart Failure ia esterolemia stress ion l factors age 6 Blood pressure elevation 4 Growth Vasoconstriction Atherosclerosis Arterial compliance 1 Renal injury / Renal ischemia 5 Na + / H 2 O retention Reduced renal blood flow

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noradrenaline spillover and systemic blood pressure in patients with resistant hypertension

Effects of renal sympathetic denervation on noradrenaline spillover and systemic blood pressure in patients with resistant hypertension Markus Schlaich Neurovascular Hypertension & Kidney Disease Laboratory