Transcript 1640_Venkata_Ram

RDN for hypertension:
Physiological rationale
Dr.C.Venkata S.Ram
Prevalence Map of Raised Lesions of Right
Coronary Artery by Age and Hypertension
Age
Normotensive
Hypertensive
15-24
n=1067
n=185
n=1134
n=233
25-34
0-2
Dr.C.Venkata S.Ram
2-4
4-6
6-8
8-10
10+
TEXAS BLOOD PRESSURE INSTITUTE
CVD Risk Is High In RH
CV Events/100 pt years
(Redon HTN 1998;31:712)
86 Pts, 49 Months f/u
CV Events = 24.6%
9.5
2.2
Low
Tertile
ADBP
Dr.C.Venkata S.Ram
13.6
Int
High
HYPERTENSION – WHY
INTERVENTIONAL THERAPIES ?
•
•
•
•
•
Chronic condition
Asymptomatic
Complications → serious
Poor compliance
Adverse effects:
* Diuretics
* β – blockers
* CCBs
* RAAS blockers
* Central α-agonists
* Hydralazine
* Minoxidil
• Cumulative costs
• Drug-drug interactions
• Intercurrent problems
Dr.C.Venkata S.Ram
Sympathetic Nervous System and
Adrenergic Excess
• The autonomic nervous system and its
sympathetic arm play an important role in the
regulation of BP
• Short term regulation of BP especially in
responses to transient changes in arterial BP
via baroreflex mechanisms is well known
• Role of SNS in longer term BP regulation has
been debated for many years
Dr.C.Venkata S.Ram
Stress
Ang II
Chemoreceptors
NTS
Baroreceptors
vagal efferents
Ach
renin
NE
Cardiac
afferents
NE
EPI
Renal
afferents
sympathetic efferents
Dr.C.Venkata S.Ram
NE
6
7
MSNA, b / 100hb
White Coat & Masked HTN
Grassi G et al., Hypertension 50:537, 2007
Dr.C.Venkata S.Ram
Dr.C.Venkata S.Ram
Dr.C.Venkata S.Ram
Consequences of SNS Activation
Dr.C.Venkata S.Ram
Mancia, G: http://www.sns-web.org/pdf/slideset_07.pdf
“RAUWOLFIA SERPENTINA
TREATMENT OF HIGH BLOOD
PRESSURE”
BY
RUSTOM JAL VAKIL
ACTA MEDICA SCANDINAVICA
1955;152:107-114
Dr.C.Venkata S.Ram
Long Term Effect of Renal Denervation in Human Hypertension
Dr.C.Venkata S.Ram
Am J Surg 75:48-68, 1948
Effects of Renal Sympathetic Nerve Activity on Renal Function
 Renin secretion rate
1 - adrenoceptor
one nerve fiber
 Tubular
sodium
contacting
reabsorption
multiple effectors
1B - adrenoceptor
Juxtaglomerular
granular cell: renin
 RSNA
 Renal blood flow
1A - adrenoceptor
Dr.C.Venkata S.Ram
Am UC.
J Physiol
279:R1517-1524,
2000
DiBona GF, Kopp
Physiol
Rev 77:75-197,
1997
Dr.C.Venkata S.Ram
Overactive SNS is Driver for Resistant HTN
Significantly more nerves in hypertensive patients
nerves
G. Sangiorgi et al., TCT 2012
Dr.C.Venkata S.Ram
10.20.2013
TZeller @ TCT2013
15
Renal Denervation by RF Ablation
Related Changes in Underlying Physiology
∆
Baseline
1 mo
161/107
141/90
- left kidney
72
37
-48%
- right kidney
79
20
-75%
Office BP
(mmHg)
Renal NE spillover
(ng/min)
Total body NE spillover
(ng/min)
600
348
-42%
Plasma Renin
(µg/l/hr)
0.3
0.15
-50%
Renal Plasma flow
(ml/min)
719
1126
57%
LV Mass (cMRI) dropped 7% (from 78.8 to 73.1 g/m2) from baseline to 12 months
Schlaich et al. NEJM. 2009; 36(9): 932-934.
Dr.C.Venkata S.Ram
17
• Extensive research in >300 swine
• Effectiveness:
Statistically significant
reduction in renal
tissue NE
• Safety:
–
Verification testing included
angiography, gross
pathology, histopathology, &
clinical pathology at 7, 30,
60, and 180 days
–
Intact endothelium by 7 days
–
Vascular healing observed
at 30 and 60 days; by 180
days, arteries were well
healed (no inflammatory
cells) – treatment sites were
considered sterile and stable
–
No stenosis or luminal
reduction seen in any
treated artery through
180 days
Renal Tissue NE (pg/mg)
–
P<0.0001
160
140
120
100
80
60
40
20
0
149
P=1.0
21
Untreated
Control
(N=24)
Data on file. Medtronic, Inc.
Dr.C.Venkata S.Ram
Catheter Denervation
(N=33)
14
Surgical Denervation
(N=4)
For distribution only in markets where the SymplicityTM renal denervation system is approved. Symplicity is a trademark of Medtronic, Inc. and is
registered in one or more countries of the world. Not for distribution in the USA or Japan. © 2012 Medtronic, Inc. All rights reserved. MKG025 3/12
Renal Denervation
Preclinical Efficacy and Safety
Renal NE Concentration After Renal DNX
Residual renal NE concentration 29%
of control at 24-32 days after DNX
Am J Physiol 238: R353-R358, 1980
Dr.C.Venkata S.Ram
Renal DNX : prevents reflex induced renin secretion
R e n in s e c re tio n , n g /m in
160
CO NTRO L
T IL T
120
80
40
R e n in s e c re tio n , n g /m in
0
200
160
CO NTRO L
F U R O S E M ID E
120
80
40
0
IN N
Dr.C.Venkata S.Ram
DNX
Am J Physiol 232:H500-H507, 1977
Renal DNX : decreases renal renin content
 Innervated
 Denervated
J Appl Physiol 33: 649-655, 1972
Dr.C.Venkata S.Ram
Assessing Sympathetic Activation
Muscle Sympathetic Nerve Activity (MSNA)
Emma Hart
Julian Paton
Dr.C.Venkata S.Ram
Ablation of Renal Afferent Nerves: effect on muscle
sympathetic nerve activity in a patient with
Resistant hypertension
Baseline
30 days FU
12 M FU
ECG
200
BP
150
100
50
MSNA
10 sec
56 bursts/min
41
bursts/min
Schlaich et al. NEJM 2009;36:932-934
Dr.C.Venkata S.Ram
19 bursts/min
Targeting Renal Nerves
• Nerves arise from T10-L2
• The nerves arborize around the
artery and primarily lie within
the adventitia
Vessel
Lumen
Media
Adventitia
Renal
Nerves
Dr.C.Venkata S.Ram
Catheter-based RDN Therapy: Ardian and more
COV: One Shot
STJ: EnligHTN
RECOR
BSX: Vessix
KONA
and more…
Dr.C.Venkata S.Ram
10.20.2013
TZeller @ TCT2013
Slide 24
The Landmark Trial: Symplicity HTN-1
Reduction in Office BP is significant and sustained over 3 year follow up
M. Schlaich TCT 2012
Dr.C.Venkata S.Ram
10.20.2013
TZeller @ TCT2013
Slide 25
Porcine Histology at 7 and 90 days
•
7-days: Circumferential nerve damage with minimal effect on artery; Less injury
with NW 2013 formulation
•
90-days: Nerves covered in fibrous connective tissue; arteries look healthy
7 DAYS
Dr.C.Venkata S.Ram
10.20.2013
TZeller @ TCT2013
90 DAYS
Slide 26
Dr.C.Venkata S.Ram