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Dénervation rénale et stimulation carotidienne dans l’HTA : physiopathologie
Pr Atul PATHAK
Service de Pharmacologie Clinique
Fédération des Services de Cardiologie
INSERM U1048
« Equipe Physiopathologie et Pharmacologie du système symapthique »
Faculté de Médecine et CHU de Toulouse
Les évidences cliniques
• Physiopathologie des maladies cardiométaboliques: et hyperactivité sympathique
• Sévérité des pathologies cardiométaboliques et hyperactivité sympathique
• Traitement sympatholytique direct / indirect / non pharmacologique associé à un bénéfice sur la morbi mortalité dans le domaine cardiométabolique
• Pronostic
Relation barorécepteur 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
Modèle expérimental
• Chien normal
• Enregistrement de la pression pendant plusieurs heures: PSA stable pas de variabilité
• Chien dont le barorecepteur est dénervé
• Variabilité exagérée de la PSA
Chez l’homme: « Baroreflex failure »
• Crise hypertensive chez un patient présentant une insuffisance aigue du baroréflexe (post chirurgicale)
Les bases de la stimulation du baroreflexe
• Au cours de l’hypertension perte de la sensibilité du baroreflexe (cause ou conséquence ?) donc perte de l’inhibition autonome.
• La stimulation du barorecepteur ou de ses afférences vont leurrer le cerveau (signal interprété comme une augmentation de pression) et induire une réponse autonome adaptée.
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
La suite, l’avenir, l’intérêt
SBP drop of 26.1±3.3 mm Hg (p<0.001) out to 6 months. Six of the 30 patients enrolled in this study had previously undergone renal denervation which was unsuccessful at controlling their resistant hypertension. These patients, on average, demonstrated a reduction in systolic BP of 22.3±9.8 mm Hg and diastolic of 11.3±8.1 mm Hg, despite starting with higher blood pressure at baseline
Renal Sympathetic Efferent Nerve Activity
Renal Efferent Nerves
JG cell: renin ↑ Renin secretion rate
β1-adrenoceptor
↑ Tubular sodium reabsorption
α1B-adrenoceptor
↓ Renal blood flow α1A-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
• 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
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<0.001 for SBP and DBP change from baseline
Symplicity HTN-2: Change in 6- & 12-Month Office Blood Pressure
-28*
Esler M et al. ACC 2012
∆ mmHg
∆ SBP
∆ DBP
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
• 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
Recommended