1. Renal Denervation for Congestive Heart Failure
Dr Justin E Davies
Consultant Cardiologist
Hammersmith Hospital
Imperial College London
CRT, Washington 2015

2. Declaration of Interests
Justin Davies, MD, PHD
Consultant/Research Funding/Advisory Board:
Volcano Corporation
Medtronic
Intellectual property :

3. Sympathetic over activation
Adverse Effects of Systolic heart failure
Cardiac output
Sympathetic over activation

4. RDN for Heart Failure – Supporting Data
PNE Correlates With Mortality in Patients With HF
100 80 60 40 20
Cumulative Mortality (%) 18 30 42 60
Months 6 12 24 36 48 54
PNE >900 pg/ml
PNE >600 – ≤900 pg/ml
PNE ≤600 pg/ml
Two year
P<0.0001
Overall
Purpose:
To show the association of plasma norepinephrine levels and mortality in HF.
Key Points:
Plasma norepinephrine levels are elevated in patients with HF due to SNS hyperactivity
Level of PNE elevation correlates directly with mortality over 2 years
In this study, baseline PNE was measured in 743 patients with CHF
Patients were randomized to enalapril or hydralazine-isosorbide dinitrate
Patients were statified based on baseline PNE (≤600 pg/ml; >600- ≤900 pg/ml; >900 pg/mL)
Cumulative mortalitiy was significantly different between strata (P<0.0001), indicating that as PNE increased, mortality increased
Source:
Francis G, Cohn JN, Johnson G, et al. Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. Circulation. 1993;87:VI40-VI48.
PNE=plasma norepinephrine.
Source: Francis GS, et al. Circulation. 1993;87:VI40-VI48.
V-HeFT II

5. Cumulative Mortality (%)
RDN for Heart Failure – Supporting Data
PNE Correlates With Mortality in Patients With HF
100 80 60 40 20
Cumulative Mortality (%) 18 30 42 60
Months 6 12 24 36 48 54
PNE >900 pg/ml
PNE >600 – ≤900 pg/ml
PNE ≤600 pg/ml
Two year
P<0.0001
Overall
Purpose:
To show the association of plasma norepinephrine levels and mortality in HF.
Key Points:
Plasma norepinephrine levels are elevated in patients with HF due to SNS hyperactivity
Level of PNE elevation correlates directly with mortality over 2 years
In this study, baseline PNE was measured in 743 patients with CHF
Patients were randomized to enalapril or hydralazine-isosorbide dinitrate
Patients were statified based on baseline PNE (≤600 pg/ml; >600- ≤900 pg/ml; >900 pg/mL)
Cumulative mortalitiy was significantly different between strata (P<0.0001), indicating that as PNE increased, mortality increased
Source:
Francis G, Cohn JN, Johnson G, et al. Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. Circulation. 1993;87:VI40-VI48.
PNE=plasma norepinephrine.
Source: Francis GS, et al. Circulation. 1993;87:VI40-VI48.
V-HeFT II

6. Sympathetic over activation
Adverse Effects of Systolic heart failure
Arterial Vasoconstriction
Increased heart rate
Sympathetic over activation
Cardiac output
Fluid retention

7. Adverse Effects of Systolic heart failure
Arterial Vasoconstriction
Increased heart rate
Sympathetic over activation
Cardiac output
Fluid retention
Activation of central breathing systems “Chemoreceptors”

8. Sympathetic pathways returning to the brain modulate chemoreceptors
Exploring the symptoms of heart failure and where they arise from.
Breathing is under control of central nervous system
more specifically the central chemoreceptors
Sympathetic pathways returning to the brain modulate chemoreceptors

9. Sympathetic pathways returning to the brain modulate chemoreceptors
Exploring the symptoms of heart failure and where they arise from.
Breathing is under control of central nervous system
more specifically the central chemoreceptors
Sympathetic pathways returning to the brain modulate chemoreceptors

10. Sympathetic nerve activity discharge increases during exercise
REST
EXERCISE
O2 administration
O2 administration
Figure 1 Representative trace of a subject receiving hyperoxia at rest (top) and during exercise (bottom).
Stickland M K et al. J Physiol 2008;586:

11. Sympathetic nerve activity discharge increases in heart failure
SHAM
PACING
Pacing induces heart failure
Pacing increases sympathetic nerve discharge
Chart recordings of renal sympathetic nerve activity (RSNA), tidal volume (TV), arterial blood pressure (ABP), mean arterial blood pressure (MBP), HR, and breathing rate (BR) under normoxic and hypoxic conditions from a sham and a chronic hear failure (CHF) rabbit. CHF rabbit exhibited a higher level of baseline RSNA in normoxic state and an enhanced response to hypoxia in both RSNA and ventilation. Pa O 2 , arterial P O 2 .
Sun S et al. J Appl Physiol 1999;86:

12. Sympathetic activity increases with increased severity of induced CHF
Increased sympathetic discharge
More pronounced effects at lower oxygen tensions
Figure 1. A, Effect of chronic cardiac pacing on resting (21% O2) and hypoxia-activated RSNA in a conscious rabbit. RSNA obtained by chronic telemetric recording. Left ventricular fractional shortening, 77% of control after 1 week and 50% of control after 3 weeks of pacing. B, Carotid body CB chemoreflex function curves for RSNA before and during cardiac pacing. RSNA normalized among animals as percentage of maximal activity (evoked by the nasopharyngeal reflex). Left ventricular function for the group is listed in Table S1. n=4; *P<0.05 vs prepacing.
Schultz H D et al. Hypertension 2007;50:6-13

13. More breathlessness at lower levels of exercise intensity
Chemoreceptor up-regulation:
More breathlessness at lower levels of exercise intensity
Normal
Minute
volume
pCO2

14. More breathlessness at lower levels of exercise intensity
Chemoreceptor up-regulation:
More breathlessness at lower levels of exercise intensity
CHF
Normal
Minute
volume
pCO2

15. Chemoreceptor sensitivity increases with worsening heart failure

16. High chemoreceptor activation is associated with increased mortality
Ponikowski et al, Circulation 1999

17. High chemoreceptor activation is associated with increased mortality
Ponikowski et al, Circulation 1999

18. RDN provides a mechanism to reduce sympathetic nerve activity
Sympathetic activity with CHF induction
Sympathetic activity with RDN
Baseline
MSNA
56/min
1 month
MSNA
41/min
12 month
MSNA
19/min
Schlaich et al. NEJM. 2009; 36(9):
Schultz H D et al. Hypertension 2007;50:6-13

19. Adverse Effects of Systolic heart failure
Arterial Vasoconstriction
Beta-blockers
ACE inhibitors
A2 blockers
Increased heart rate
Sympathetic over activation
Cardiac output
Renal
Denervation?
Fluid retention
Diuretics
Activation of central breathing systems “Chemoreceptors”
No good therapy

20. Studies registered on ClinicalTrials.gov
Systolic CHF
Diastolic HF
Preserved EF
OLOMOUC
PRESERVE
Symplicity HF
REACH
RSD4CHF
DIASTOLE - UMC
RDT-PEF - RBH

21. REACH-Pilot1 Design 7 patient safety study
Chronic mod-severe heart failure
Maximal tolerated medical therapy
In-patient follow-up 5 day admission
Bilateral renal denervation
Aims
Safety of renal denervation
Follow-up for 6 months
Results
No procedural complications
No acute/medium term complication
Improvement in 6 min walk
REACH-Pilot, Davies JE, Francis DP et al. Int J Cardiol Jan 20;162(3):189-92

22. Blood pressure remains stable in CHF post-denervation
REACH-Pilot, Davies JE, Francis DP et al. Int J Cardiol Jan 20;162(3):189-92

23. Improvement in exercise capacity
Potential benefit of renal denervation in CHF
Improvement in exercise capacity
REACH-Pilot
Δ 27.1m
p=0.03
REACH-Pilot, Davies JE, Francis DP et al. Int J Cardiol Jan 20;162(3):189-92

24. Improvement in exercise capacity
Potential benefit of renal denervation in CHF
Improvement in exercise capacity
REACH-Pilot
Δ 27.1m
p=0.03
REACH-Pilot, Davies JE, Francis DP et al. Int J Cardiol Jan 20;162(3):189-92

25. Summary of drug changes
Loop diuretics were reduced or stopped in 4/7 patients
No patient had an increase in diuretic
Beta-blockers decrease in 2 and increased in 1.
A2 blocker decreased in 2 and increased in 1

26. Conclusion from REACH No acute, early or medium term adverse events
Potentially exciting trends
Small numbers

27. Caution Non-Blinded study Open label study Non-Randomised study
Needs exploration in more highly powered randomised clincial studies and in more severe CHF

28. Ongoing studies in heart failure
SYMPLICITY-HF
40 patients
NYHA II or III, EF<40%
GFR 30-75ml/min
Primary end point: Safety of renal denervation
Enrolment complete 2015
REACH
100 patient
Sham (3:2 randomisation)
Double blinded
Bilateral renal denervation in severe CHF
Primary endpoint: Symptom improvement
Reporting 2014

29. Ongoing studies in heart failure
SYMPLICITY-HF
40 patients
NYHA II or III, EF<40%
GFR 30-75ml/min
Primary end point: Safety of renal denervation
Enrolment complete 2015
REACH
100 patient
Sham (3:2 randomisation)
Double blinded
NYHA III, EF<40%
Bilateral renal denervation in severe CHF
Primary endpoint: Symptom improvement
Completion anticipated 2015

30. Summary
Mechanistic potential to expand denervation outside of resistant hypertension
Expand neuro-hormonal blockade offered by pharmacological therapies
Potential advantages to disruption of the over-activated afferent sympathetic system
Exciting field - many unanswered questions

31. Summary
Mechanistic potential to expand denervation outside of resistant hypertension
Expand neuro-hormonal blockade offered by pharmacological therapies
Potential advantages to disruption of the over-activated afferent sympathetic system
Exciting field - many unanswered questions

32. Summary
Mechanistic potential to expand denervation outside of resistant hypertension
Expand neuro-hormonal blockade offered by pharmacological therapies
Potential advantages to disruption of the over-activated afferent sympathetic system
Exciting field - many unanswered questions

33. Summary
Mechanistic potential to expand denervation outside of resistant hypertension
Expand neuro-hormonal blockade offered by pharmacological therapies
Potential advantages to disruption of the over-activated afferent sympathetic system
Exciting field - many unanswered questions

34. Summary
Mechanistic potential to expand denervation outside of resistant hypertension
Expand neuro-hormonal blockade offered by pharmacological therapies
Potential advantages to disruption of the over-activated afferent sympathetic system
Exciting field - many unanswered questions