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Renal denervation for
autonomic functions
modulation
Adam WitkowskiDept. of Interventional Cardiology and Angiology
Institute of Cardiology, Warsaw, PL
PINC, Kraków 09 May 2014
Presenter: Adam WitkowskiPresenter: Adam Witkowski
Consultancy and proctor fees from Medtronic
PA Sobotka et al: Curr Cardiol Rep 2012
NorepinephrineSpillover
Muscle SympatheticNerve Activity (MSNA)
Central SympatheticNerve Activity
Renal SympatheticNerve Activity
Proof of Principle
Reduction of Renal Contribution to Central Sympathetic Drive:MSNA (systemic muscle symphatetic nerve activity) in
Resistant Hypertension Patient
Baseline
1 mo
12 mo
MSNA(burst/min)
BP(mmHg)
56 161/107
41 (-27%) 141/90 (-20/-17)
19 (-66%) 127/81 (-34/-26)
* Improvement in cardiac baroreflex sensitivity after renal denervation (7.8 11.7 msec/mmHg)
* 59 year old male on 7 HTN meds
6
Schlaich et al. NEJM. 2009; 36(9): 932-934.
Staged Clinical Staged Clinical EvaluationEvaluation
First-in-Man
Series of Pilot studies
Symplicity HTN-2Initial Randomized Clinical Trial (enrollment closed)
Symplicity HTN-3US PMA Randomized Clinical Trial (upcoming)
Post-Market & New Indications
Symplicity HTN-1 Efficacy (+), Safety (+)
Efficacy (+), Safety (+)
Efficacy (-), Safety (+)
Global Simplicity RegistryEfficacy (+), Safety (+)
RationaleRationale
64% in RP Pedrosa et al, Hypertension 2011
Renal Denervation: areas of future research
Glucose metabolism
Background
Hypothesis
Baseline chracteristics
50 pts with resistant hypertension randomized
37 underwent RDN, 13 – controlBP 176/96±/2 mmHgAntihepertensive drugs: 5.6±0.2Diabetes type 2 – 20 (40%), oral treatement –
16
Mahfoud F et al. Circulation. 2011;123:1940–1946
BP Reduction after RDN
Mahfoud F et al. Circulation. 2011;123:1940–1946
Renal Denervation Improves Glucose Renal Denervation Improves Glucose
MetabolismMetabolism
Timepoint Fasting Glucose
(mg/dl)
Insulin
(mU/l)
C-peptide
(µg/l)
HOMA-IR
Baseline (n=25) 118 ± 20 22.3 ± 14.8 6.2 ± 3.6 6.2 ± 4.3
1 month (n=21) 113 ± 14 10.9 ± 7.3* 3.2 ± 1.5* 3.0 ± 1.8*
3 months (n=15) 102 ± 12* 8.4 ± 4.8* 3.0 ± 1.1* 2.1 ± 1.3*
6 months (n=7) 99 ± 18* 8.8 ± 4.6 3.1 ± 1.1 2.2 ± 1.4
*significant reduction (p<0.05) compared to baselineHOmeostasisModelAssessment-InsulinResistance (HOMA-IR) = (Insulin x Blood Glucose)/405
Mahfoud et al. Circulation. 2011;123:1940–1946.
Renal Denervation Improves Glucose Renal Denervation Improves Glucose
ToleranceTolerance
0 min 60 min 120 min
Glu
cose
co
nce
ntr
atio
n (
mg
/dl)
3 months (n=15)
*
*
*
*significant reduction (p<0.05) compared to baseline
270
6 months (n=7)
*
*
*Baseline (n=25)
250
230
210
180
150
120
90
Oral Glucose Tolerance Test (75 g)
Mahfoud et al. Circulation. 2011;123:1940–1946.
Diabetic controlDiabetic control
Mahfoud F et al. Circulation. 2011;123:1940–1946
3 years follow-up
unpublished data
P<0,05P<0,05 P<0,05P<0,05
6 months 3 years
Witkowski et al, Hypertension 2011; 58: 559-65 Witkowski et al, Hypertension 2011; 58: 559-65
Renal Denervation: areas of future research
Obstructive sleep apnea
Results (1): Mean ± standard deviation systolic and diastolic office BP before and at 3 and 6 months after
denervation.
Witkowski et al, Hypertension 2011; 58: 559-65 Witkowski et al, Hypertension 2011; 58: 559-65
Results (2): AHI before and at 3 and 6 months after denervation. Data of individual cases
AHI 3 and 6m (median): p=NS and 16.3 vs 4.5 (events/hour; ), p=0.059, respectively
AHI 3 and 6m (median): p=NS and 16.3 vs 4.5 (events/hour; ), p=0.059, respectively
Witkowski et al, Hypertension 2011; 58: 559-65 Witkowski et al, Hypertension 2011; 58: 559-65
3 years follow-up
unpublished data
The reduction in OSA severity was observed in 6 out of 10 patientsThe reduction in OSA severity was observed in 6 out of 10 patients
3 years follow-up
unpublished data
The possible mechanisms of interaction between renal denervation, resistant hypertension and sleep apnea
Resistant hypertension is characterized by significant fluid retention due to activation of sympathetic nervous system and RAA activation (1). Renal denervation reduces salt avidity by efferent sympathetic renal nerve disruption. It might reduce total body fluid, which is thought to contribute to obstructive episodes and may also reduce peripharyngeal fluid accumulation (rostral fluid shift at night) which predisposes to upper airway obstruction (2).
Venous capacitance remains under the control of the sympathetic nervous system. Thus it might be possible that renal denervation also affects venous capacitance and blood pooling (3).
Renal denervation in patients with resistant hypertension and OSA might attenuate the effects of sympathoactivation additionally and independently of CPAP treatment.
Fall in blood pressure may itself contribute to the attenuation of sleep apnea. This may be mediated by baroreflex deactivation inducing changes in chemoreflex modulation of breathing control, or by direct effects of lower blood pressure on central ventilatory or airway control mechanisms.
1. Gaddam K et al, Arch Intern Med 2008;168:1159-642. Gaddam K et al, J Hum Hypertens 2010;24:532-373. Pang CCY, Pharmacol Ther 2001;90:179-230
Renal Denervation: areas of future research
Heart Failure
Patients with congestive heart failure are characterized by an increase in sympathetic activity whose magnitude is proportional to the heart failure severitySympathetic activation that occurs in heart failure depends both on heart failure per se and on conditions such as obesity and hypertension that can induce sympathetic activation before heart failure
Sympathetic Activity, CHD and Cardio-Renal Syndrome
Francis GS et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990; 82:1724-9Hasking GJ et al. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 1986;73: 615-621
Ferguson et al .Circulation 1990
10.4 bursts/min15.3 bursts/100 beats
MSNA
18.8 bursts/min27.4 bursts/100 beats
MSNA
67.4 bursts/min95.7 bursts/100 beats
MSNA
99.4 bursts/min93.4 bursts/100 beats
MSNA
Sympathetic Activation Correlates with Functional Class of CHF
Normal Subject
NYHA functional class II
NYHA functional class III
NYHA functional class IV
Microneurographysystemic muscle sympathetic nerve activity (MSNA)
Resistance to diuretics in HFEarly exploration of the relation between
renal sympathetic activity and heart failure identified that increased renal sympathetic activity is associated with resistance to the natriuretic action of atrial natriuretic peptide
Increased RSNA causes Na+ retention and antagonizes the action of loop diuretics (Furosemid)
Pettersson A et al. Renal interaction between sympatheticactivity and ANP in rats with chronic ischaemic heart failure. ActaPhysiol Scand. 1989;135:487– 492.
Neurovascular Control of DyspneaMinute ventilation (dyspnea) response to pCO2 is
controlled by central chemoreceptorElevated sympathetic drive moves set point and gain
leftward, causing dyspnea
MV CHF Normal
pCO2
35 40
First-in-man safety evaluation of renal denervation for chronic systolic heart failure.Primary outcome from REACH-Pilot study
7 patients (mean age 69 years)with chronic systolic heart failure (NYHA III or IV, mean BP on referral 112/65 mm Hg) on maximal tolerated heart failure therapy underwent bilateral renal denervation
Davies JE et al, International Journal of Cardiology 2012
REACH-Pilot study: SBP and DBP
Davies JE et al, International Journal of Cardiology 2012
REACH-Pilot study: 6 minutes walk test
Davies JE et al, International Journal of Cardiology 2012
221±33 meters vs 249±34 meters; p=0.03