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RDN for hypertension: Physiological rationale. Dr.C.Venkata S.Ram. 0-2 2-4 4-6 6-8 8-10 10+. Prevalence Map of Raised Lesions of Right Coronary Artery by Age and Hypertension. Age. Normotensive. Hypertensive. 15-24. n=1067. n=185. 25 - 34.

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slide2

0-2 2-4 4-6 6-8 8-10 10+

Prevalence Map of Raised Lesions of Right

Coronary Artery by Age and Hypertension

Age

Normotensive

Hypertensive

15-24

n=1067

n=185

25-34

n=1134

n=233

Dr.C.Venkata S.Ram

slide3

86 Pts, 49 Months f/u

CV Events = 24.6%

13.6

9.5

CV Events/100 pt years

2.2

Low

Tertile

ADBP

Int

High

TEXAS BLOOD PRESSURE INSTITUTE

CVD Risk Is High In RH

(Redon HTN 1998;31:712)

Dr.C.Venkata S.Ram

slide4

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
Sympathetic Nervous System andAdrenergic 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

slide6

Ang II

Chemoreceptors

renin

Renal

afferents

Stress

NTS

vagal efferents

Baroreceptors

Ach

NE

Cardiac

afferents

NE

EPI

NE

sympathetic efferents

Dr.C.Venkata S.Ram

slide7

White Coat & Masked HTN

MSNA, b / 100hb

Grassi G et al., Hypertension 50:537, 2007

Dr.C.Venkata S.Ram

evidence for sympathetic activation in essential hypertension
Evidence for Sympathetic Activation in “Essential” Hypertension

Dr.C.Venkata S.Ram

consequences of sns activation
Consequences of SNS Activation

Dr.C.Venkata S.Ram

Mancia, G: http://www.sns-web.org/pdf/slideset_07.pdf

slide11

“RAUWOLFIA SERPENTINA TREATMENT OF HIGH BLOOD PRESSURE”

BY

RUSTOM JAL VAKIL

ACTA MEDICA SCANDINAVICA

1955;152:107-114

Dr.C.Venkata S.Ram

slide12

Long Term Effect of Renal Denervation in Human Hypertension

Am J Surg 75:48-68, 1948

Dr.C.Venkata S.Ram

slide13

Effects of Renal Sympathetic Nerve Activity on Renal Function

 Renin secretion rate

1 - adrenoceptor

Juxtaglomerular

granular cell: renin

 Tubular sodium reabsorption

1B - adrenoceptor

one nerve fiber

contacting

multiple effectors

 RSNA

 Renal blood flow

1A - adrenoceptor

Am J Physiol 279:R1517-1524, 2000

DiBona GF, Kopp UC. Physiol Rev 77:75-197, 1997

Dr.C.Venkata S.Ram

overactive sns is driver for r esistant htn
Overactive SNS is Driver for Resistant HTN

Significantly more nerves in hypertensive patients

nerves

G. Sangiorgi et al., TCT 2012

TZeller @ TCT2013

Dr.C.Venkata S.Ram

slide16

Renal Denervation by RF Ablation

Related Changes in Underlying Physiology

Baseline

161/107

72

79

600

0.3

719

1mo

141/90

37

20

348

0.15

1126

-48%

-75%

-42%

-50%

57%

OfficeBP

RenalNEspillover

-leftkidney

-rightkidney

TotalbodyNEspillover

PlasmaRenin

RenalPlasmaflow

(mmHg)

(ng/min)

(ng/min)

(µg/l/hr)

(ml/min)

LVMass(cMRI)dropped7%(from78.8to73.1g/m2)frombaselineto12months

Schlaichetal.NEJM.2009;36(9):932-934.

Dr.C.Venkata S.Ram

17

renal denervation preclinical efficacy and safety
Renal Denervation Preclinical Efficacy and Safety

P<0.0001

  • 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

P=1.0

Renal Tissue NE (pg/mg)

Data on file. Medtronic, Inc.

Dr.C.Venkata S.Ram

slide18

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

slide19

Renal DNX : prevents reflex induced renin secretion

Am J Physiol 232:H500-H507, 1977

Dr.C.Venkata S.Ram

slide20

Renal DNX : decreases renal renin content

  • Innervated
  •  Denervated

J Appl Physiol 33: 649-655, 1972

Dr.C.Venkata S.Ram

slide21

Assessing Sympathetic Activation 

Muscle Sympathetic Nerve Activity (MSNA)

EmmaHart

JulianPaton

Dr.C.Venkata S.Ram

slide22

Ablation of Renal Afferent Nerves: effect onmuscle

sympathetic nerve activity in a patient with

Resistant hypertension

Baseline

30 days FU

12 M FU

ECG

BP

MSNA

56 bursts/min

41 bursts/min

19 bursts/min

Schlaich et al. NEJM 2009;36:932-934

Dr.C.Venkata S.Ram

targeting renal nerves
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
Catheter-based RDN Therapy: Ardian and more

COV: One Shot STJ: EnligHTN RECOR BSX: Vessix KONA

and more…

TZeller @ TCT2013

Dr.C.Venkata S.Ram

the landmark trial symplicity htn 1
The Landmark Trial: SymplicityHTN-1

Reduction in Office BP is significant and sustained over 3 year follow up

M. Schlaich TCT 2012

TZeller @ TCT2013

Dr.C.Venkata S.Ram

porcine histology at 7 and 90 days
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 90 DAYS

TZeller @ TCT2013

Dr.C.Venkata S.Ram