1. Denervacion Renal
Expandiendo las indicaciones
Dr.Juan Gaspar
Director Educacion Medica y Entrenamiento
Medtronic Cardiovascular LA
XI CONGRESO VENEZOLANO DE CARDIOLOGÍA
INTERVENCIONISTA - SOVECI 2013
XX JORNADAS REGIONALES SOLACI
Jueves, 21 de Febrero de 2013

2. Afferent and efferent sympathetic nerve fibers
Afferent
Renal ischemia
Adenosine 
Efferent
Renin secretion
Sodium retention
Proteinuria
Vasoconstriction
Atherosclerosis
LVH
Ischemia
Heart Failure
Gluconeogenesis ↑
Insulin resistance
Mahfoud F et al, DMW 2010

3. Local versus systemic effect?
?

4. Renal denervation reduces
renal and total body NE spillover
Krum et al., Lancet 2009. 373(9671):1275-81
Schlaich et al., N Engl J Med. 2009 Aug 27;361(9):932-4
Renal NE spillover
6 months (n=10)
0
25
-25
-50
-75
-47%
*
*significant reduction (p<0.05)
compared to baseline.

5. GLUCOSE
PolyCystic Ovary Syndrome
Atrial Fibrilation
Cardiac Heart Failure
Obstructive Sleep Apnea
Chronic Kidney Disease
THE NEW FRONTIER ?

6. • Spanish ABP Monitoring Registry
– N=68.045 patients
– Patients with resistant hypertension = 8.295 (12%)
• 63% true-resistance (ABPM sys >130 mmHg)
• 37% pseudo-resistance
De la Sierra, Hypertension 2011; 57:898-902

7. Patient‘s characteristics
Therapy resistant
N=5182
Age, a 64
Male, % 55
History of hypertension, a 11.4
Diabetes, % 35.1
LVH, % 18.5
Other CV diseases, % 19.1
>4 antihypertensives, % 38.3
De la Sierra, Hypertension 2011; 57:898-902

8. Patient‘s characteristics
Therapy resistant
N=5182
Age, a 64
Male, % 55
History of hypertension, a 11.4
Diabetes, % 35.1
LVH, % 18.5
Other CV diseases, % 19.1
>4 antihypertensives, % 38.3
De la Sierra, Hypertension 2011; 57:898-902

9. Huggett RJ. Circulation. 2003;108:3097-3101.
NT: normo tensive controls; DM: diabetes; HTN: hypertension; HTN+DM: hypertension+diabetes

10. Background
Sympathetic activity mediates vascular resistance
Blood flow is shifted from striated muscle (insulin
sensitive) to visceral tissue (insulin resistant)
Sympathetic drive
Resistant hypertension Insulin resistance

11. Obesity
Hyperinsulinemia
Sympathetic drive ↑
Sceletal blood flow ↓
Hypertension
Vasoconstriction
Insulin resistance
Hypertension and insulin resistance

12. • 50 patients (RD, 13 control)
• 59.7 ± 1.4 a
• BP 178/96 ± 3/2 mmHg
• antihypertensive drugs 5.6 ± 0.2
• fasting glucose 121 ± 4 mg/dl
• insulin 19.3 ± 2.5 μIU/ml
• HOMA-IR 5.7 ± 0.7
Mahfoud F et al., Circulation 2011

13. BP reduction after RD
-40
-35
-30
-25
-20
-15
-10
-5
0
1 month 3 months
systolic
3 months1 month
diastolic
Renal denervation (n=37)
Control (n=13)
-28 -8 -32 -5 -10 -4 -12 -3
Changeinbloodpressure(mmHg)
p<0.001
p=0.192
p<0.001
p=0.494
p<0.001
p<0.001
p=0.154
p=0.277
Mahfoud F et al., Circulation 2011

14. RD reduces fasting glucose
-17.5
-12.5
-7.5
-2.5
2.5
7.5
12.5
17.5
Changeinfastingglucose(mg/dl)
1 month 3 months
Renal denervation (n=37)
Control (n=13)
-8.9 -9.4
+3.9 +0.9
p=0.043 p=0.039
p=0.402
p=0.847
Mahfoud F et al., Circulation 2011

15. RD reduces fasting insulin
-15
-10
-5
0
5
10
15
Changeinfastinginsulin(µIU/ml)
1 month 3 months
Renal denervation (n=37)
Control (n=13)
-8.7 -11.6
+6.4 +0.5
p=0.036
p=0.006
p=0.129
p=0.984
Mahfoud F et al., Circulation 2011

16. RD reduces C-peptide
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
ChangeinfastingC-peptide(ng/ml)
1 month 3 months
Renal denervation (n=37)
Control (n=13)
-2.0 -2.3
+0.2 +0.2
p=0.006
p=0.002
p=0.699
p=0.776
Mahfoud F et al., Circulation 2011

17. RD improves insulin sensitivity
-5
-4
-3
-2
-1
0
1
2
3
4
5
ChangeinHOMA-IR(ng/ml)
1 month 3 months
Renal denervation (n=37)
Control (n=13)
-3.1 -3.7
+2.1 +0.3
p=0.008
p=0.001
p=0.085
p=0.734
Mahfoud F et al., Circulation 2011

18. Improves glucose tolerance
-9 -27*
-10
-20
-30
0
+10
-40
Reductioninglucoselevel(mg/dl)
60-min glucose level
120-min glucose level
*significant reduction (p<0.05)
compared to baseline
Glucose tolerance test, 75 g glucose per os
3 months
Renal denervation
Mahfoud F et al., Circulation 2011

19. PCOS is associated with
 increased sympathetic activity
 insulin resistance
 hypertension
Case report on 2 young patients with resistant
hypertension and PCOS with 3 months FU
Schlaich MP, J Hypertens 2011

20. RDN reduced BP and MSNA activity
Schlaich MP, J Hypertens 2011

21. Reduced fasting glucose and improved insulin
sensitivity
Schlaich MP, J Hypertens 2011

22. Symplicity inclusion and exclusion criteria
+ diagnosed OSA (AHI >5 per hour)
10 pts underwent RD
Follow-up: baseline, 3 and 6 months
Witkowski A, Hypertension 2011

23. Baseline 3 months 6 months
Improvement in AHI - 7/10 patients 8/10 patients
AHI, events/hr 30.7 ± 26.5 20.0 ± 25.3
(p=ns)
16.1 ± 22.2
(p=ns)
Epworth Sleepiness Scale
Score, points
9 6.5
(p=ns)
7
(p<0.05)
120 min glucose level
OGTT, mmol/l
8.4 ± 3.3 6.8 ± 2.5
(p=0.051)
6.8 ± 2.9
(p<0.05)
HbA1C, % 6.4 ± 0.8 6.0 ± 0.7
(p<0.05)
5.9 ± 0.7
(p<0.05)
Witkowski A, Hypertension 2011
Improved glucose metabolism
after RDN in patients with OSA

24. Open questions?
• Durability of the results remain to be
documented
• Renal, retinal and cardiovascular
consequences of these findings need to be
investiagated

25. baseline BP 174 ± 22/91 ± 16 mmHg
5.6 ± 1.3 antihypertensive drugs
Hering D et al, JASN 2012

26. RDN in CKD 3-4 – a pilot study
• 15 patients with CKD 3-4
• Baseline: mean GFR 31.2 ± 8.9 ml/min/1.73 m2
Hering D et al, JASN 2012

27. Renal sympathetic denervation for treatment of electrical storm: first-
in-man experience
Ukena et al, Clin Res Cardiol, 2012
2 patients with chronic heart failure, suffering from therapy resistant
electrical storm, underwent renal denervation
Ventricular tachyarrhytmias were reduced, blood pressure and
clinical status remained stable
Reduction of
ventricular
fibrillation
episodes in one
patient

28. 04.03.22

32. 04.03.23

33. 04.03.23

35. 04.03.23

36. 04.03.23

37. 04.03.23

38. 04.03.23

40. More news at EuroPCR 2013!!

41. Mahfoud F et al., unpublished data

42. Muchas gracias

43. Percutaneous renal denervation
Nonpharmacologic and optimized pharmacologic
treatment (encouragement of compliance)
Resistant hypertension
Who Is a Candidate for Renal Denervation?
Uncontrolled hypertension
Screening for secondary causes:
• OSA syndrome
• CKD
• Renal artery stenosis
• Primary hyperaldosteronism
• Pheochromocytoma
• Cushing’s syndrome
• Vasculitides
• Coarctation of the aorta
• Thyrotoxic crisis
Exclusion of
pseudo-
resistance
Identification of
reversible
lifestyle factors
Cessation of BP-
elevating
medications
Specific
therapy as
appropriate
CKD=chronic kidney disease; OSA=obstructive sleep apnea
Mahfoud F et al. Dtsch Arztebl Int. 2011;108:725-731.

44. Non-Response
No predictors of non-response (SBP <10 mmHg)
available
• Non-response rate 20%

45. RRI = (V max sys – V max endiast) / V max sys
Sobotka, Henry Krum, Bruno Scheller, Markus Schlaich, Ulrich Laufs and Michael Böhm
Dominik Linz, Roland Schmieder, Lars Christian Rump, Ingrid Kindermann, Paul Andrew
Felix Mahfoud, Bodo Cremers, Julia Janker, Britta Link, Oliver Vonend, Christian Ukena,
Denervation in PatientsWith Resistant Hypertension
Renal Hemodynamicsand Renal Function After Catheter-Based Renal Sympathetic
Print ISSN: 0194-911X. Online ISSN: 1524-4563
Copyright © 2012 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Hypertension
published online June 25, 2012;Hypertension.
http://hyper.ahajournals.org/content/early/2012/06/25/HYPERTENSIONAHA.112.193870
World Wide Web at:
The online version of this article, along with updated information and services, is located on the
Mahfoud F et al., Hypertension 2012

46. RRI at baseline and BP reduction –
Regression analysis
RRI at baseline was NOT associated with non-
response (SBP reduction >10 mmHg after 6
months)
• >0.70 (R=0.421, p=0.447)
• >0.75 (R=0.032, p=0.960)
• >0.80 (R=1.074, p=0.755)
• >0.85 (R=1.285, p=0.667)
Mahfoud F et al., Hypertension 2012

47. 0
120
140
160
180
200
220
240
0 25 50 75 100
% of maximum workload
Systolicbloodpressure(mmHg)
Baseline
3 months after RD
p<0.0001
p<0.0001
p<0.0001
p<0.0001
p<0.001
Ukena C, Mahfoud F et al, JACC 2011

48. No chronotropic incompetence after RDN
25 50 75 100
% of maximum work rate
Rest Recovery
0
20
40
60
80
100
120
140
p=0.028
p=0.006
p=0.121
p=0.074
p=0.141
p=0.001
Baseline
3 months after RD
Heartrate(bpm)
Ukena C, Mahfoud F et al, JACC 2011

49. Mean SBP and heart rate after drug provocation
Baseline
3 months
0
120
140
160
0
50
60
70
80
90
100
p=0.0592
heartrate[1/min]
Responder Non-Responder Responder Non-Responder
p=0.4509 p=0.9909 p=0.8300
SBP[mmHg]
Drug
provocation
Lenksi M, Mahfoud F, ESC 2012

50. Syncopes and presyncopes during tilt table
testing
Pre-syncope
Syncope
No symptoms
4 4
1
6 5
3 2
16 17
7 7
0
5
10
15
20
25
Baseline 3 Months Baseline 3 Months
Responder Non-Responder
[n]
30 n.s.
n.s.
Lenksi M, Mahfoud F, ESC 2012

51. BP
Change
ABPM reduction in Symplicity
Home BP
Change
(mmHg)
Systolic
Diastolic
Systolic
Diastolic
Symplicity HTN-2 Investigators.The Lancet. 2010.
p=0.006
p=0.014
p=0.51
p=0.75
Analysis on technically sufficient (>70% of readings)
paired baseline and 6-month

52. Real world data on ABPM –
patient characteristics
Mahfoud F, ESC 2012
N=80
Age (years) 58 ± 12
Gender (% female) 35%
Type 2 diabetes 44%
eGFR (MDRD, ml/min/1.73m2) 72 ± 13

53. Real world data on ABPM –
patient characteristics
Mahfoud F, ESC 2012
N=80
Age (years) 58 ± 12
Gender (% female) 35%
Type 2 diabetes 44%
eGFR (MDRD, ml/min/1.73m2) 72 ± 13
Antihypertensive drugs (#) 5.4 ± 1.5
SBP (mmHg) 169 ± 22
DBP (mmHg) 92 ± 15
HR (bpm) 69 ± 12
Mean SBP (mmHg) 151 ± 17
Mean DBP (mmHg) 85 ± 14

54. Real world experience – office BP reduction
ChangesinofficeBP(mmHg)
SBP
DBP
SBP
DBP
p<0.001
p<0.001
p<0.001
p<0.001
Mahfoud F, ESC 2012

55. ∆ from
Baseline
to
6 Months
(mmHg)
33/11 mmHg
difference between RDN and Control
(p<0.0001)
Systolic
Diastolic
Systolic Diastolic
Symplicity HTN-2 Investigators. Lancet. 2010.

56. Real world experience -
Changes in mean 24-hour BP
BPchanges(mmHg)
p=0.019
p=0.025
p=0.018
p=0.022
SBP
DBP
SBP
DBP
Mahfoud F, ESC 2012

57. BPchanges(mmHg)
p=0.019
p=0.025
p=0.018
p=0.022
SBP
DBP
SBP
DBP
Mahfoud F, ESC 2012
Real world experience -
Changes in mean 24-hour BP

58. Changes in daytime and nighttime BP
BPchanges(mmHg)
p=0.025
SBP
DBP
SBP
SBP
SBP
DBP
DBP
DBP
p=0.001
p=0.001
p=0.001
p=0.002
p=0.004
p=0.004
p=0.002
daytime
Mahfoud F, ESC 2012

59. Changes in daytime and nighttime BP
BPchanges(mmHg)
p=0.025
SBP
DBP
SBP
SBP
SBP
DBP
DBP
DBP
p=0.001
p=0.001
p=0.001
p=0.002
p=0.004
p=0.004
p=0.002
daytime nighttime
Mahfoud F, ESC 2012

60. RDN reduces maximum and minimum SBP
BPchanges(mmHg)
Max.
SBP
Max.
SBP
Min.
SBP Min.
SBP
p=0.009
p=0.003
p=0.013
p=0.011
Mahfoud F, ESC 2012

61. 24-hour BP changes are comparable to
spironolactone treatment – ASPIRANT study
Václavík J, et a. Hypertension. 2011;57:1069-75.

62. Mean ABP reductions in the subgroup of
patients treated with spironolactone (n=26)
SBP
DBP
DBP
SBP
Mahfoud F, ESC 2012
p=0.011
p=0.022
p=0.014
p=0.019