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Catheter-Based Renal Sympathetic Denervation in the Management of Resistant Hypertension
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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
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
reserv
ed. U
C201205567E
E
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
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
reserv
ed. U
C201205567E
E
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
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
reserv
ed. U
C201205567E
E
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
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
reserv
ed. U
C201205567E
E
• 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
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
reserv
ed. U
C201205567E
E
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
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
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
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
reserv
ed. U
C201205567E
E
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
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
reserv
ed. U
C201205567E
E
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
reserv
ed. U
C201205567E
E
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
he p
ropert
y o
f th
eir
respective o
wners
. ©
2012 M
edtr
onic
, In
c.
All
rights
reserv
ed. U
C201205567E
E
• 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