Catheter-Based Renal Sympathetic

Denervation in the Management of

Resistant Hypertension

Prof. Samir Morcos Rafla

Alexandria Univ.

1

The Renal

Sympathetic

Nervous System

3

4

The European Society of Cardiology (ESC)

has issued a consensus statement regarding

the use of catheter-based renal denervation for

the treatment of high blood pressure, stating

that the novel therapy can be considered a

therapeutic option in patients with drug-

resistant hypertension who cannot get to goal

with a combination of lifestyle and

pharmacologic therapy.

6

The data support the concept that the

radiofrequency ablation of the renal nerves

reduces blood pressure and improves blood-

pressure control in these difficult-to-treat

patients. The data supporting the treatment

now extend to 36 months

Mahfoud F, et al. Expert consensus document from the

European Society of Cardiology on catheter-based renal

denervation. Eur Heart J 2013; DOI:10.1093

7

Patients are eligible for renal denervation if they meet

the following criteria:

Office-based blood pressure >160 mm Hg (>150 mm Hg

in patients with type diabetes).

Use of three or more antihypertensive drugs in adequate

dosage and combination, including use of a diuretic.

Have attempted to modify blood pressure with lifestyle

changes.

Secondary hypertension has been excluded.

Pseudoresistance has been excluded with the use of

ambulatory blood-pressure monitoring.

Patients have preserved renal function (glomerular

filtration rate >45 mL/min/1.732).

Absence of polar or accessory arteries, no renal artery

stenosis, and no prior renal revascularization.

8

The ESC consensus statement acknowledges

that it is not yet clear how renal denervation

works, but the mechanism is likely the result of a

reduction in peripheral resistance, reduced renin

release, and favorable changes in water and salt

handling.

"The fact that renal denervation also reduces

whole-body sympathetic-nerve activity suggests

that this therapy may also be beneficial in other

clinical states characterized by sympathetic

nervous system activation—this may ultimately

lead to new indications,"

9

10

SYMPLICITY HTN-2 (Renal Denervation in Patients With Uncontrolled Hypertension)

• Background:

Renal sympathetic efferent and afferent nerves are crucial for the initiation and

maintenance of systemic hypertension

Denervation of the renal sympathetic nerve to reduce BP has been attempted,

unsuccessfully, by surgical means years ago

• Population and treatment:

106 patients with resistant hypertension (SBP >160 mm Hg, or >150 mm Hg for

those with type 2 diabetes, taking ≥ three antihypertensive drugs)

Randomized 1:1 to renal denervation + previous treatment (n=52) or previous

treatment alone (n=51)

• Primary outcome:

BP reduction at six months

MD Esler (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) American Heart Association 2010 Scientific Sessions

• Average office-based BP in the renal-denervation group was reduced 32/12 mm Hg

(average baseline 178/96 mm Hg) six months after the ablation

• Between-group differences in BP at six months were 33/11 mm Hg (p<0.0001)

• Of the patients in the ablation arm, 84% had a 10-mm-Hg or greater drop in SBP vs

35% of controls (p<0.0001)

• There did not appear to be any adverse events:

Imaging of renal arteries for damage showed no evidence of renal artery stenosis

or aneurysmal dilatation during the six-month follow-up

There were no changes in renal function, even in those with mild to moderate

renal failure

SYMPLICITY HTN-2: Results

SYMPLICITY HTN-2: Commentary*

*All comments from A revolutionary road for resistant hypertension? Renal denervation in Symplicity HTN-2 (http://www.theheart.org/article/1151787.do)

"This has the potential for really revolutionizing the way we treat resistant

hypertension, which is an enormous clinical need."

- Dr Suzanne Oparil

"I've never seen BP falls as big as this from any other treatment process, which

makes the possibility of cure realistic; it might be within reach."

- Dr Murray D Esler

"My only reservation about the study is that they have not compared the

denervation with the most effective add-on drug in patients with resistant

hypertension, which is spironolactone."

- Dr Peter Sever

Anatomical Location of Renal Sympathetic Nerves

• Arise from T10-L1 • Follow the renal artery to the kidney • Primarily lie within the adventitia

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

Adventitia

Renal Nerves

RF Ablation Approach to Renal Sympathetic Denervation

Electrode

Insulated arch wire

Symplicity® Catheter System, Ardian, Inc., Palo Alto, CA, USA

Placement of Renal RF Catheter

Treatment by Renal RF Catheter

Treatment by Renal RF Catheter

Treatment by Renal RF Catheter

Treatment by Renal RF Catheter

Treatment involves approximately 4 to 6

applications Using low-power (8 W)

radiofrequency energy. Treatments are

delivered in a helical fashion within the renal

artery by rotation of the catheter and

approximately 5 mm pullback between

ablations. The generator provides the

radiofrequency energy according to an

automated algorithm

For

dis

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where

the S

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renal denerv

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ppro

ved.

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for

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2012 M

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, In

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Hypertension Epidemiology

• Single largest contributor to death worldwide

• Every 20/10 mmHg increase in BP correlates with a doubling of 10-year cardiovascular mortality

• Dramatically increases risk of stroke, heart attack, heart failure, & kidney failure

• Only half of all treated hypertensives are controlled to established BP targets

• High prevalence:

• Affects 1 in 3 adults

• 1B people worldwide 1.6 B by 2025

35% Treated & Controlled

30% Untreated

35% Treated but Uncontrolled

Chobanian et al. Hypertension. 2003;42(6):1206–1252.

23

c

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where

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for

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. ©

2012 M

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, In

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rights

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Renal Sympathetic Activation: Efferent Nerves Kidney as Recipient of Sympathetic Signals

Renal Efferent

Nerves

↑ Renin Release RAAS activation

↑ Sodium Retention

↓ Renal Blood Flow

24

For

dis

trib

ution o

nly

in m

ark

ets

where

the S

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renal denerv

ation s

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for

dis

trib

ution in the U

SA

or

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Tra

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. ©

2012 M

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, In

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Hypertrophy

Arrhythmia

Oxygen Consumption

Vasoconstriction

Atherosclerosis

Insulin

Resistance

Renal Sympathetic Activation: Afferent Nerves Kidney as Origin of Central Sympathetic Drive

Renal Afferent

Nerves

↑ Renin Release RAAS activation

↑ Sodium Retention

↓ Renal Blood Flow

Sleep

Disturbances

25

For

dis

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ark

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where

the S

ymplic

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renal denerv

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yste

m i

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for

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SA

or

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Tra

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. ©

2012 M

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, In

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rights

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• Nerves arise from T10-L2 • The nerves arborize around the artery

and primarily lie within the adventitia

Renal Nerve Anatomy

Vessel Lumen

Media

Adventitia

Renal Nerves

26 26

For

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where

the S

ymplic

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renal denerv

ation s

yste

m i

s a

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Not

for

dis

trib

ution in the U

SA

or

Japan.

Tra

dem

ark

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. ©

2012 M

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Renal Nerve Anatomy Allows a

Catheter-Based Approach

27

• Renal artery access via standard interventional technique

• 4-6 two-minute treatments per artery • Proprietary RF generator

– Automated – Low power – Built-in safety algorithms

Spacing of

e.g. 5 mm.

For

dis

trib

ution o

nly

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ark

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where

the S

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renal denerv

ation s

yste

m i

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ppro

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for

dis

trib

ution in the U

SA

or

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Tra

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. ©

2012 M

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, In

c.

All

rights

reserv

ed. U

C201205567E

E

For

dis

trib

ution o

nly

in m

ark

ets

where

the S

ymplic

ity™

renal denerv

ation s

yste

m i

s a

ppro

ved.

Not

for

dis

trib

ution in the U

SA

or

Japan.

Tra

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nd a

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respective o

wners

. ©

2012 M

edtr

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, In

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All

rights

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ed. U

C201205567E

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Baseline Patient Characteristics (n=153)

29 Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Demographics Age (years) 57 ± 11

Gender (% female) 39%

Race (% non-Caucasian) 5%

Co-morbidities Diabetes Mellitus II (%) 31%

CAD (%) 22%

Hyperlipidemia (%) 68%

eGFR (mL/min/1.73m2) 83 ± 20

Blood Pressure Baseline BP (mmHg) 176/98 ± 17/15

Number of anti-HTN meds (mean) 5.1 ± 1.4

Diuretic (%) 95%

Aldosterone blocker(%) 22%

ACE/ARB (%) 91%

Direct Renin Inhibitor 14%

Beta-blocker (%) 82%

Calcium channel blocker (%) 75%

Centrally acting sympatholytic (%) 33%

Vasodilator (%) 19%

Alpha-1 blocker 19%

For

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ark

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where

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ymplic

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renal denerv

ation s

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m i

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dis

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SA

or

Japan.

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, In

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Brief Procedure with a Low Complication rate

(n=153)

• 38 minute median procedure time

– Average of 4 ablations per artery

• Intravenous narcotics & sedatives used to manage pain during delivery of RF energy

• No catheter or generator malfunctions

• No major complications

• Minor complications 4/153:

– 1 renal artery dissection during catheter delivery (prior to RF energy), no sequelae

– 3 access site complications, treated without further sequelae

30 Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

For

dis

trib

ution o

nly

in m

ark

ets

where

the S

ymplic

ity™

renal denerv

ation s

yste

m i

s a

ppro

ved.

Not

for

dis

trib

ution in the U

SA

or

Japan.

Tra

dem

ark

s m

ay

be r

egis

tere

d a

nd a

re t

he p

ropert

y o

f th

eir

respective o

wners

. ©

2012 M

edtr

onic

, In

c.

All

rights

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ed. U

C201205567E

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Symplicity HTN-1: BP Reductions through

3 years

BP change

(mmHg)

P<0.01 for ∆ from BL

for all time points

*Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

For

dis

trib

ution o

nly

in m

ark

ets

where

the S

ymplic

ity™

renal denerv

ation s

yste

m i

s a

ppro

ved.

Not

for

dis

trib

ution in the U

SA

or

Japan.

Tra

dem

ark

s m

ay

be r

egis

tere

d a

nd a

re t

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ropert

y o

f th

eir

respective o

wners

. ©

2012 M

edtr

onic

, In

c.

All

rights

reserv

ed. U

C201205567E

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• Therapeutic renal sympathetic denervation involves a brief,

simple percutaneous procedure

• No major complications were observed to either the renal

artery or the kidney

• Significant and sustained reductions in blood pressure were

achieved in patients with resistant hypertension

• Achievement of denervation supported by significant

reduction in renal norepinephrine spillover

Summary

Conclusions

Renal denervation offers a novel and safe

catheter-based approach for selective reduction

of renal sympathetic drive. We demonstrated for

the first time that selective denervation of the

renal sympathetic nerves has the potential to

improve glucose metabolism and blood pressure

control concurrently in patients with resistant

hypertension in the absence of significant

changes in body weight and alterations in lifestyle

or antihypertensive medication.

J Clin Hypertens . 2012;14:799–801. 2012

The Ohio State University, Columbus, OH;

35

Attenuation of sympathetic activity may have a

multitude of effects beyond those directly related to

hypertension. Increased sympathetic nervous

system activity, for example, is associated with

heightened risk of death among heart failure

patients. Further, salt and water retention in some

forms of heart failure may be mediated in large part

by renal sympathetic activity, and selective renal

denervation may play a role in treatment or

prevention of heart failure and the cardiorenal

syndrome. Recent reports in patients with insulin

resistance or type II diabetes mellitus,

polycystic ovary syndrome, and hypertension have

also suggested improved insulin resistance and

glycemic control with denervation therapy.

37

Multi-electrode renal-denervation device

appears safe

38

39

RD offers a novel and safe catheter-based approach

for selective reduction of renal sympathetic drive. We

demonstrate for the first time to our knowledge that

selective denervation of the renal sympathetic

nerves in addition to lowering peripheral BP

significantly reduces LV mass and improves diastolic

function in patients with resistant hypertension.

40

•Renal denervation has been shown to reduce

fasting plasma glucose, fasting plasma insulin,

insulin resistance, and haemoglobin A1C levels

in diabetic patients with resistant hypertension.

•In patients with obstructive sleep apnoea and

resistant hypertension, renal denervation

resulted in improvements in glucose profiles as

well as sleep apnoea symptoms.

•There is some evidence that renal denervation

exerts a renoprotective effect in diabetic

nephropathy. Excerpta Medica

Feb 19, 2013

Hints of renal-denervation side benefit:

Fewer ventricular arrhythmias Renal sympathetic denervation significantly reduces mean heart rate

and exerts a favorable effect on atrial and ventricular arrhythmias in

resistant hypertensives. American College of Cardiology 2013 Scientific

Sessions; March 9, 2013; San Francisco, CA. Abstract 1148-22.

41

Renal-artery denervation can help to reduce

the recurrence of atrial fibrillation in concert

with pulmonary-vein isolation (PVI) in

patients with drug-resistant hypertension.

A randomized comparison of pulmonary vein isolation with versus

without concomitant renal artery denervation in patients with refractory

symptomatic atrial fibrillation and resistant hypertension. J Am Coll Cardiol 2012; 05.036

42

Vascular lesions induced by renal nerve ablation as

assessed by optical coherence tomography: pre-

and post-procedural comparison with the

Simplicity(R) catheter system and the EnligHTN™

multi-electrode renal denervation catheter.

Eur Heart J Apr 2013;

43

CONCLUSION: Here we show that diffuse renal

artery constriction and local tissue damage at the

ablation site with oedema and thrombus formation

occur after RNA and that OCT (optical coherent

tomography) visualizes vascular lesions not apparent

on angiography. This suggests that dual antiplatelet

therapy may be required during RNA.

Expert Consensus Document From the European

Society of Cardiology on Catheter-Based Renal

Denervation. Eur Heart J 2013; Apr 25

1. Hypertension is one of the most frequent chronic

diseases worldwide. It is estimated that over the next

two decades, up to 50% of the adult population will be

diagnosed with hypertension.

2. Resistant hypertension, defined as uncontrolled blood

pressure that persists despite the use of three or more

antihypertensives of different classes, including a

diuretic, at maximal or the highest tolerated dose, is

present in 5-10% of patients with hypertension.

44

3. Renal denervation targeting both afferent and efferent

nerves has been demonstrated to reduce sympathetic

nerve activity, norepinephrine spillover, and blood

pressure in patients with resistant hypertension.

5. The renal artery needs to be at least 4 mm in

diameter and at least 20 mm in length for successful

denervation, and should be free of significant stenosis or

calcification.

6. Transient local de-endothelialization, acute cellular

swelling, connective tissue coagulation, and thrombus

formation have been demonstrated to occur after renal

denervation. Use of aspirin for 4 weeks is empirically

recommended based on these findings.

45

7. Improvement in blood pressure rarely occurs

immediately, and it often takes several weeks to

months before a notable blood pressure reduction

is evident. Further, a reduction in pill burden has

not been demonstrated in the currently completed

randomized trials, although consistent reduction

in blood pressure has been noted in both

randomized and observational studies.

46

8. Renal denervation results in a significant drop

in resting, maximum exercise, and recovery blood

pressure, whereas heart rate response during

exercise and oxygen uptake is well preserved.

9. Renal denervation is currently being evaluated

for heart failure and metabolic syndrome, with

small studies demonstrating promising results.

Further, the therapy has also been demonstrated

to reduce the occurrence of atrial fibrillation and

ventricular arrhythmias. 47