D©nervation r©nale et stimulation carotidienne dans l’HTA ... D©nervation r©nale et stimulation

  • View
    215

  • Download
    0

Embed Size (px)

Text of D©nervation r©nale et stimulation carotidienne dans l’HTA ......

Dnervation rnale et stimulation carotidienne dans lHTA : physiopathologie

Pr Atul PATHAK

Service de Pharmacologie Clinique

Fdration des Services de Cardiologie

INSERM U1048

Equipe Physiopathologie et Pharmacologie du systme symapthique

Facult de Mdecine et CHU de Toulouse

Conflits dintrts

Pas de conflits dintrts relatifs au matriel prsent dans cette session.

Les vidences cliniques

Physiopathologie des maladies cardiomtaboliques: et hyperactivit sympathique

Svrit des pathologies cardiomtaboliques et hyperactivit sympathique

Traitement sympatholytique direct / indirect / non pharmacologique associ un bnfice sur la morbi mortalit dans le domaine cardiomtabolique

Pronostic

Freeman R. N Engl J Med 2008;358:615-624

Le Baroreflexe

Le point de dpart: les barorcepteurs

La conduction : les nerfs affrents

Lintegration: le noyau du tractus solitaire

La rponse cardiovasculaire

MS

NA

(U)

mm

Hg

Barorcepteurs

EC

G

La stimulation du barorcepteur est pression dpendante

Relation barorcepteur et reponse tensionnelle

Relation barorcepteur et reponse tensionnelle

Arterial

Pressure Baroreceptor

Carotid Sinus

Aortic Arch

Sinus Nerve

Vagus Nerve

Vasoconstrictor Center

Cardio-acceleratory Area

Cardio-inhibitory Area +

Peripheral Vascular Dilation

Heart Rate Contractility

Peripheral Resistance ( R)

Cardiac Output (Q) Arterial pressure decrease back towards normal

Modle exprimental

Chien normal

Enregistrement de la pression pendant plusieurs heures: PSA stable pas de variabilit

Chien dont le barorecepteur est dnerv

Variabilit exagre de la PSA

Chez lhomme: Baroreflex failure

Crise hypertensive chez un patient prsentant une insuffisance aigue du barorflexe (post chirurgicale)

Les bases de la stimulation du baroreflexe

Au cours de lhypertension perte de la sensibilit du baroreflexe (cause ou consquence ?) donc perte de linhibition autonome.

La stimulation du barorecepteur ou de ses affrences vont leurrer le cerveau (signal interprt comme une augmentation de pression) et induire une rponse autonome adapte.

Implantation of the Rheos System

BP and MSNA decrease acutely and remained suppressed throughout each stimulation period

Heusser et al. Hypertension. 2010;55:619

Acute arterial BP, MSNA and BRS changes with carotid baroreceptors stimulation

Heusser K. Hypertension. 2010;55:619 Heusser et al. Hypertension. 2010;55:619

Baroreflex Activation Therapy in Patients With Resistant Hypertension: a double blind RCT

1. Resistant HTN: at least 1 office SBP> 160 mm Hg with DBP > 80 mm Hg

2. at least 1 month of maximally tolerated Rx with > 3 appropriate AHT, including a diureJc.

3. 24-h ASBP >135 mm Hg

As part of ongoing subject medical management, invesJgators were not prevented from changing anJhypertensive medicaJons during the course of the trial

Bisognano et al. J Am Coll Cardiol 2011;58:765

Primary endpoint : acute BP at 6 months

-16 29

-9 29

% Responder pts Decrease in SBP (mmHg)

P = 0.08 P = 0.97

54 % 46 %

Bisognano et al. J Am Coll Cardiol 2011;58:765

proporJon of subjects that achieve at least a 10 mm Hg drop in SBP at Month 6

Summary of Adverse Events

Bisognano et al. J Am Coll Cardiol 2011;58:765

La suite, lavenir, lintrt

SBP drop of 26.13.3 mm Hg (p

Le Baroreflexe

Renal Sympathetic Efferent Nerve Activity

Renal Efferent Nerves

JG cell: renin Renin secretion rate

1-adrenoceptor

Tubular sodium reabsorption

1B-adrenoceptor

Renal blood flow 1A-adrenoceptor DiBona GF, Kopp UC. Physiol Rev 1997

Hypertrophy Arrhythmia Oxygen consumption Systolic HF HFPEF

Vasoconstriction

Insulin Resistance

Renal Sympathetic Afferent Activity

Renin Release RAAS activation Sodium Retention Renal Blood Flow

Renal Afferent Nerves

Krum H et al. Circulation 2011

Anatomy of Renal Artery

kidneys: dense afferent sensory and efferent sympathetic innervation

origin and target of SNS activation

subtotal nephrectomy

BP

subtotal nephrectomy + abrogation of afferent sensory signals

(dorsal rhizotomy)

BP Campese V, Hypertension 1995

Renal Denervation Delays or Prevents Development of Many Experimental Forms of Hypertension

Device-Based Approaches to Hypertension Management

Placement of Renal RF Catheter

Baseline 12 months FU 1 month FU

ECG

BP

MSNA

56 bursts/min 41 bursts/min 19 bursts/min

Schlaich M et al. NEJM 2009

Renal Sympathetic Denervation

Symplicity I: 36 Month Data

n=153 Symplicity I Investigators, ACC 2012

Change in Office BP vs Baseline

12-Mth Post-RDN Control

6-Mth Post-RDN

12-Mth Post-RDN

-24*

-8 -10

6-Mth Control

-12

+7 +1

* P

Symplicity HTN-3 Study

Symplicity HTN-2 Randomized,

Controlled Trial (N=106)

Symplicity HTN-1 First-in-Man & Expanded

Cohort (N=153)

SYMPLICITY HTN-3

Randomized, Blinded,

Controlled Trial (N~530)

= Planned follow up

= Partial cohort reports

= Primary endpoint

2015 2006 2010 2011 2012 2013 2014 2016 2007 2008 2009

Electrode RF Catheters and more

Vessix V2

St Jude EnLigHTN

Tout ne se rsume pas au baroreflexe et au sympathique rnale

SNS activation important contributor to HTN and end-organ disease esp. heart & kidney

Baroreflex and Renal sympathetic nerves long-standing therapeutic target in HTN and beyond

Interventional approaches have been developed to selectively disrupt sympathetic nerves

Multiple novel technologies have been employed to achieve this disruption

Development warrants better profiling, randomized clinical studies, head to head comparisons and morbidity / mortality data.

Conclusions / Perspectives