Applications beyond hypertension management Renal Denervation @ CRT 2013 Applications beyond hypertension management Felix Mahfoud Klinik für Innere Medizin III Kardiologie, Angiologie und Internistische Intensivmedizin Universitätsklinikum des Saarlandes Germany

Felix Mahfoud, MD Medtronic, St. Jude, Vessix, ReCor, Cordis X Research contracts X Consulting fees

Local versus systemic effect?

(spikes per 100 hearts bearts) -37% Single unit MSNA (spikes per 100 hearts bearts) p<0.01 Hering D et al, Hypertension 2012

Effect of renal denervation on hypertensive endorgans and comorbities LVH Diastolic function Heart rate Arrhythmias Diabetes Renal function Renal hemodynamics Albuminuria

Myocardial effects

N=64 Brandt MC, Mahfoud F, et al, JACC 2012

Greater LV mass reduction in patients with LVH Brandt MC, Mahfoud F, et al, JACC 2012

Improvement in diastolic function Brandt MC, Mahfoud F, et al, JACC 2012

Change of heart rate (bpm) -12 -10 -8 -6 -4 -2 2 4 Change of heart rate (bpm) HR 1. Tertile HR ≤60 bpm HR 2. Tertile HR 61-71 bpm HR 3. Tertile HR ≥71 bpm p=0.035 p=0.113 p=0.008 p<0.0001 p=0.002 3 months 6 months ANOVA 3 months: p<0.0001 ANOVA 6 months: p<0.0001 n=120 Ukena C, Mahfoud F, et al, Int J Card 2012

No correlation between change of heart rate and change of SBP Response to SBP: reduction of ≥10 mmHg 40 30 20 10 Change of heart rate (bpm) Response to HR: reduction of ≥3 bpm -10 -20 r = 0.07 p = 0.455 -30 -40 -100 -80 -60 -40 -20 20 40 Change of SBP (mm Hg) Ukena C, Mahfoud F, et al, Int J Card 2012

Sympathetic activity correlates to NYHA class CHF is characterized by increased SNS activity proportional to severity of CHF Normal Subject NYHA functional class II NYHA functional class III NYHA functional class IV MSNA 10.4 bursts/min MSNA 18.8 bursts/min MSNA 67.4 bursts/min MSNA 99.4 bursts/min Higher functional class numbers reflect increasing functional disability and severity of disease Increasing SNS activity, as measured by microneurography (MSNA), correlated with functional class of HF patients In this study, SNS activity to muscle was measured by microneurography in 10 normal subjects (age 25 ± 2 years) and 29 patients with HF (age 49 ± 2 years) SNS activity was significantly higher in patients with HF than in normal subjects MSNA correlated with plasma norepinephrine level Source: Ferguson D, Berg WJ, Sanders JS. Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings. JACC. 1990;16(5):1125-1134. Ferguson D, JACC 1990

Cardiac and renal spillover in heart failure Spillover in patients with HF Indicating that the kidney is a main contributor to the pathophysiology Rundqvist B., Circulation 1997; 95:169-75.

REnAl DenervAtion in PatienTs with chronic heart failure – The RE-ADAPT-CHF study International, multicentre, randomized trial 50 Treatment Control Primary Endpoint 6M 12-36M Randomization Baseline SBP≥100 Following collection of the primary endpoint at 6-months, control patients permitted to cross-over 100

REnAl DenervAtion in PatienTs with chronic heart failure – The RE-ADAPT-CHF study Inclusion criteria 100 patients with CHF in NYHA class II-III LV-EF <40% eGFR >30 ml/min/1.73m2 Optimal and stable medical therapy I look really forward to participate in that study and I‘m curious about the results!

Atrial fibrillation

Higher sympathetic activity in patients with CHF+AF compared to CHF+SR Ikeda T et al, J Physiol 2012

Effect of RDN on postapneic blood pressure rises Linz D et al, Hypertension 2012

RDN reduces AF inducibility Normal breathing 2-min of NTP at -80mbar 2-min of NTP at -80mbar after Atenolol 2-min of NTP at -80mbar after RDN Linz D et al, Hypertension 2012

RDN reduces AF inducibility Normal breathing 2-min of NTP at -80mbar 2-min of NTP at -80mbar after Atenolol 2-min of NTP at -80mbar after RDN Linz D et al, Hypertension 2012

RDN reduces AF inducibility Normal breathing 2-min of NTP at -80mbar 2-min of NTP at -80mbar after Atenolol 2-min of NTP at -80mbar after RDN Linz D et al, Hypertension 2012

RDN reduces AF inducibility Normal breathing 2-min of NTP at -80mbar 2-min of NTP at -80mbar after Atenolol 2-min of NTP at -80mbar after RDN Linz D et al, Hypertension 2012

SHAM RDN Atrial CL (ms) SHAM Atrial Tachypacing ECG Atrial MAPs RDN p=0.002 Atrial CL (ms) SHAM n.s. Atrial Tachypacing Linz D et al, Hypertension 2012

SHAM RDN RDN Atrial CL (ms) SHAM Atrial Tachypacing RDN ECG Atrial MAPs RDN p=0.002 Atrial CL (ms) SHAM n.s. RDN Atrial Tachypacing RDN ECG SHAM Ventricular CL (ms) p=0.002 p=0.001 Atrial MAPs 1 sec. Atrial Tachypacing Linz D et al, Hypertension 2012

Key inclusion Randomization (n=27) Paroxysmal or persistent AF Resistant hypertension (SBP >160 mmHg) Randomization (n=27) 1:1 PVI alone vs. PVI + RDN

PVI + RDN in Afib – 12 months results RDN resulted in BP reduction -25/-10 mmHg 69% of patients after RDN were AF-free compared to 29% in the PVI-only group

Pleiotropic effects of renal denervation Efferent Afferent OSA Diabetes So, on the one hand we have a new and safe approach to reduce sympathetic drive and on the other hand we know that increased sympathetic activitiy contributes to the development or the progression of many cardiovascular diseases. The afferent sympathetic nerve fibers, which are activated by renal ischemia and high adenosine levels, connecting the kidneys with the hypothalamus. From animal models we know that the afferent sympathetic nerve activtiy is main contributor to the The other way round are efferent sympathetic fibers reaching from the hypothalamus to the organs. Activation of the efferent system induces glucogenesis and insulin resistance in the liver, trigger left ventricular hypertrophy and heart failure, vasoconstriction and atherosclerosis and at kidneys efferent sympathetic drive increases sodium and water retention, acitvates the renin-angiotensin-aldosterone-system and the renal gluconeogenesis. Linz D, Hypertension 2012 Witkowski A, Hypertension 2011 Mahfoud F, Circulation 2011 Schlaich M, J Hypertens 2011 Witkowski A, Hypertension 2011 Myocardial function Brandt MC, Mahfoud F, JACC 2012 Ukena C, Mahfoud F, Int J Card 2012 Linz D, Mahfoud F, Hypertension 2012 Davis J, Int J Card 2012 Pokushalov E, JACC 2012 Renal function Hering D, Mahfoud F, JASN 2012 Mahfoud F, Hypertension 2012

Hypertension Quo vadis... Arrhythmias Chronic heart failure Chronic kidney disease Obstructive sleep apnea So, ladies and gentleman I hope I could give you an insight into my understanding of potential new indications for renal denervation and I hope to arouse your enthusiam to the results of new studies! Chronic heart failure Insulin resistance and diabetes Arrhythmias Hypertension

Thank you! Dr. Felix Mahfoud Klinik für Innere Medizin III Universitätsklinikum des Saarlandes Homburg/Saar, Germany Tel. +49 6841-16-21346 Fax. +49 6841-16-13211 felix.mahfoud@uks.eu