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 .

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

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

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 123:1501-1508 (2011) Grundvold et al. Hypertension 59:198-204 (2012)

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: 10.1177/1470320312446212 (2012)

Could Renal Denervation have a favorable effect on Atrial Fibrillation?

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 10.1007/s00392-014-0695-1 (2014) 7

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 10.1007/s00392-014-0695-1 (2014) 8

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

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)

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)

Ventricular Arrhythmias

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

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)

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

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