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

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

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

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

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

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

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

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

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

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;586:1743-1754

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;86:1264-1272

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

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

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

Chemoreceptor sensitivity increases with worsening heart failure

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

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

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): 932-934. Schultz H D et al. Hypertension 2007;50:6-13

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

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

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. 2013 Jan 20;162(3):189-92

Blood pressure remains stable in CHF post-denervation REACH-Pilot, Davies JE, Francis DP et al. Int J Cardiol. 2013 Jan 20;162(3):189-92

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. 2013 Jan 20;162(3):189-92

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. 2013 Jan 20;162(3):189-92

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

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

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

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

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

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

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

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

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

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