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

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

3. Local versus systemic effect?

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

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

6. Myocardial effects

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

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

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

10. 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 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

11. 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

12. 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):
Ferguson D, JACC 1990

13. 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:

14. 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

15. 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!

16. Atrial fibrillation

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

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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

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

27. 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

28. 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

29. 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

30. Thank you! Dr. Felix Mahfoud Klinik für Innere Medizin III
Universitätsklinikum des Saarlandes
Homburg/Saar, Germany
Tel
Fax