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