1. Renal Denervation for Atrial and Ventricular Arrhythmias
CRT 2015
Washington, DC, Feb 21-24, 2015
min
Renal Denervation for Atrial and Ventricular Arrhythmias
Vivek Y. Reddy, Horst Sievert
Mount Sinai Hospital, NYC, USA
CardioVascular Center Frankfurt – CVC, Frankfurt, Germany .

2. Disclosures Physician name Company Relationship Horst Sievert
Abbott, Access Closure, AGA, Angiomed, Aptus, Atrium, Avinger, Bard, Biosense Webster, Boston Scientific, Bridgepoint, Carag, Cardiac Dimensions, CardioKinetix, CardioMEMS, Cardiox, Celonova, CGuard, Coherex, Contego, Covidien, CSI, CVRx, EndoCross, ev3, FlowCardia, Gardia, Gore, GTIMD Medical, Guided Delivery Systems, Hemoteq, InSeal Medical, InspireMD, Lumen Biomedical, HLT, Lifetech, Lutonix, Maya Medical, Medtronic, NDC, Occlutech, Osprey, Ostial, PendraCare, pfm Medical, Recor, ResMed, Rox Medical, SentreHeart, Spectranetics, SquareOne, Svelte Medical Systems, Tendyne, Trireme, Trivascular, Valtech, Vascular Dynamics, Venus Medical, Veryan, Vessix
Consulting fees,
Travel expenses,
Study honoraria
Cardiokinetix, Access Closure, Velocimed, Lumen Biomedical,
Coherex, SMT
Cook, St. Jude Medical
Stock options,
Stocks
Grant Research Support

3. HTN and AF: Progressive Atrial Remodeling in an Ovine Model
Lau DH et al, Heart Rhythm 2010;7:1282–1290
Increasing Fibrosis over Time
Increasing Interstitial Collagen over Time
Electrical Remodeling over Time
Animal model of hypertension: in sheep, remove one kidney, and clamp 50% of other renal artery  causes spontaneous hypertension (top right graph shows increase in systolic/diastolic BP over course of 15 weeks)
Bottom left: concomitant with the increase in BP is an increase in interstitial collagen deposition over time (a hallmark of what happens in clinical AF)
Bottom right: also a change in the electrical properties of atria promoting AF (refractory periods, conduction velocity, AF inducibility and duration)
 overall a direct demonstration of the effects of HTN promoting AF

4. the Most Important Cause of Afib
Hypertension is
the Most Important Cause of Afib
ARIC Study: 14,598 for 17 yrs
57% of AF attributed to RFs:
HTN, Obesity, DM, Smoking, Prior cardiac disease
HTN accounts for 20% of all AF cases
 ~25% if borderline HTN also included
ARIC study: a longitudinal study of 14,595 middle-aged individuals  over 17 years of follow-up, 1520 cases of incident AF occurred (ie, AF development)
Overall, 57% of incident AF cases could be explained by having risk factors, of which HTN was the most important contributor….devleops more commonly with higher systolic (left graph) or diastolic BPs (right graph)
 shows important relationship between HTN and AF from an epidemiological perspective
Huxley et al, Circulation 123: (2011)
Grundvold et al. Hypertension 59: (2012)

5. Predictors of Recurrence After AF Ablation
Hypertension is Most Important Factor
Retrospective Analysis of 292 patients undergoing AF ablation
Most important risk factor predicting AF recurrence after ablation: HTN
Retrospective Analysis of 292 patients undergoing PVI for AF
Non-Dilated LA (<40mm) = 178 pts vs Dilated LA (>40mm) = 114 pts
Non-Dilated LA
Retrospective Analysis of 292 patients undergoing AF ablation
Most important risk factor predicting AF recurrence after ablation: Presence of history of HTN
 HTN important in AF recurrence after ablation
Takigawa et al. JRAS, DOI: / (2012)

6. Could Renal Denervation have a favorable effect on Atrial Fibrillation?

7. OSA-Related Atrial Arrhythmias
RDN Attenuates Increase in BP and Hormones
Porcine model of Obstructive Sleep Apnea
Tracheostomy and application of negative tracheal/thoracic pressure (NTP)
NTP (4 times per hour) x 4 hours
NTP without renal Denervation
Porcine model of sleep apnea: Application of negative tracheal pressure (NTP)
With sleep apnea (NTP): causes increase in blood pressure (B), and plasma renin (D) and aldosterone (E)
If perform Renal Denervation first, this prevents increase in BP (C), plasma renin (D) and aldosterone (E)
(see next slide for punchline regarding AF)
NTP with renal denervation first
D. Linz, Clin Res Cardiol, DOI /s (2014) 7

8. OSA-Related Atrial Arrhythmias
RDN Prevents Development of AF
Porcine model of Obstructive Sleep Apnea
Tracheostomy and application of negative tracheal/thoracic pressure (NTP)
NTP (4 times per hour) x 4 hours
programmed electrical stimulation
With sleep apnea (NTP): increase in PACs (A), development of AF (B), and AF duration (C)
If perform Renal Denervation first, all 3 (A-C) attenuated
Also, with programmed electrical stimulation (right figure): AF sustained in 0% of controls, 100% of sleep apnea/NTP animals
But while beta-blockers (atenolol) minimally affects AF induction (p=ns), RDN significantly attenuates AF induction (p=0001)
 RDN attenuates the development of AF in sleep apnea model of AF
Linz et al, Hypertension 62:767 (2013)
D. Linz, Clin Res Cardiol, DOI /s (2014) 8

9. Refractory HTN Patients with AF
RDN as Adjunctive Therapy to AF Ablation-1
Single-Center RCT: Effect of RDN on success of AF ablation
Patients with Refractory HTN (mean BP 179/96) + AF
AF ablation (PVI, n=14) vs AF ablation + RDN (n=13)
proof of concept
RCT of AF ablation alone (PVI) vs AF ablation + RDN (PVI + Renal)
Is a small (27pts total) study and single-center, but established proof of concept
Pokushalov et al, JACC (2012) 60:1163–1170

10. Refractory HTN Patients with AF
RDN as Adjunctive Therapy to AF Ablation-2
Extended patient cohort
Of course, most AF pts don’t have refractory hypertension.
Could RDN be beneficial in the majority of AF patients (who have milder/controlled hypertension)?
Same investigators have since extended their observation in a total of 80 AF patients with either refractory or moderately-refractory HTN  Similar outcomes
Pokushalov et al, Heart Rhythm (2014)

11. RDN as Upstream Therapy in AF?
HFIB Study
Single-Blind (Sham-RDN) RCT
AF + Controlled HTN:
AF ablation vs AF ablation+RDN
RDN with off-the-shelf RF catheter
Primary Endpoint: AF Recurrence
FDA Approval: IDE# G120025
PI: V.Reddy / Mount Sinai
Pilot (Enrollment of 50 pts/10 sites):
Safety Issues:
Renal Artery Dissection  3 pts
Renal Artery Stenosis  3 pts
Beneficial effect on AF recurrences (7 mo):
AF Ablation alone: 35%
AF Ablation + RDN: 15% (p=NS)
Plan for Full Study:
Use Dedicated RDN Catheter
H-FIB
AF + Hypertension
AF Ablation
Renal Angiogram R
Placebo
RSDN
HFIB RCT: (important): population is planned AF ablation patients with controlled hypertension (just taking at least one anti-HTN medication)
Used an off-the-shelf RF ablation catheter (an EP ablation catheter) to perform the RDN procedure
Despite the fact that we and others have shown this safe in single-center studies, in the HFIB pilot (50 pts/10 sites), there were important safety events (3 dissections during renal artery engagement, and even more importantly, 3 patients developed renal artery stenosis requiring angioplasty during follow-up)
BUT, efficacy data was very interesting (though small number of pts and not statistically significant)
Plan is to do the full trial (300 pts) using a dedicated RDN catheter (in negotiations with several companies as to which catheter to use…will decide in next month)
Follow-Up
AF Recurrences
H Ahmed / MA Miller / VY Reddy, JCE 25:503-9 (2013)

12. Ventricular Arrhythmias

13. Porcine Model of Ventricular Arrhythmias
RDN Decreases Incidence
First, Surgical RDN or Sham procedure in pigs
Then, Surgical ligation of the proximal LAD for 20 min  Reperfusion
Surgical model of ischemia-related ventricular arrhythmias
Left Figure: Lots of PVCs with arrhythmias (left), but lot fewer PVCs if first performed renal denervation (right)
Right Figure: Most animals have cardiac arrest with ischemia (dark bar), but not if first performed renal denervation (light bar)
 Thus, good reason to believe that RDN may have beneficial effect on development of ventricular arrhythmias
Linz et al, Heart Rhythm (2013) 13

14. RDN for Refractory VT Storm
Clinical Case Series
4 Patients / 3 Centers
2-NICM / 2-Isch Dz
Prior Ablations in all
2 – Endo Only
2 – Endo/Epi
RDN Performed in all
EP catheter (Irrigated or non-irrigated)
Follow-Up
8.8 ± 2.6 months (range 5–11 mo)
No hemodynamic deterioration
No change in renal function
Decrease in VT Episodes
11±4 episodes  0.3 ±0.1 episodes
Small case series (4 pts at 3 centers) of patients with structural heart disease and VT/ICD shocks refractory to VT ablation
RDN decreased number of subsequent VT episodes
 VERY small study (and no control group), but interesting proof-of-concept
Remo et al. Heart Rhythm 11:541 (2014)

15. 1º Prevention + Inducible VT
RDN for Ventricular Arrhythmias
Preventing Shocks in High-Risk ICD Patients
Single-Blind (Sham-RDN) RCT
ICD recipients:
Structural Heart Disease Patients
Secondary Prevention or Inducible Primary Prevention Populations
Primary Endpoint: ICD Therapy
FDA Approval: IDE# G120147
PI: V.Reddy / Mount Sinai
Protocol Design:
Pilot Phase: 20 Patients (Done)
Full Study: ~450 Patients
Trial Design Details:
Funding by Boston Scientific, Inc.
RDN Catheter: Vessix System
RESCUE-VT
2º Prevention
1º Prevention + Inducible VT
FDA Approval: IDE# G120147
ICD Implantation
Renal Angiogram R
This a single blind (sham RDN) RCT of Effect of RDN in ICD recipients
After ICD implantation, randomize to RDN vs sham procedure
Primary endpoint: ICD therapy
We completed 20-pt pilot study at 2 centers  was safe in this low EF population
 Full study submitted to FDA: we expect to start study next month (using Vessix RDN catheter)
Placebo
RSDN
Follow-Up
ICD Therapy

16. Conclusions Hypertension Atrial fibrillation: renal denervation
is a major cause of Afib
is a major cause of recurrence of Afib after ablation
Atrial fibrillation: renal denervation
reduces Afib in animal models
seems to reduce Afib recurrences after ablation in hypertensive patients
may reduce Afib recurrences in non-hypertensive patients
randomized study is planned
Ventricular arrhythmias: renal denervation
reduces PWCs and VF in an animal model
has reduced VF in small patient series
randomized study is planned in ICD patients