Beyond RDN Paul A. Sobotka, MD Professor of Medicine/Cardiology The Ohio State University Chief Medical Officer Cibiem, Inc.

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Consulting Fees/Honoraria Royalty Income Ownership/Founder/Salary Ardelyx Inc. Medtronic, Inc. Rox Medical, Inc. Ardian, Inc. Cibiem, Inc.

Next Generation Devices to Rebalance Sympathetic Activity Renal Denervation Clones Faster, smaller, more complete Smörgåsbord of Tools: Multi lead RF ablation, Ultrasound, Cryoablation Chemical Infusion Disruptive Technology- rebalancing central sympathetic & parasympathetic tone Baroreceptor stimulation Carotid body modulation

Control of Central Sympathetic Drive Vasoconstriction HTN & Insulin Resistance Renin, AngII, Aldo Sodium Retention Renal Blood Flow Dyspnea, Exercise Intolerance, Central Sleep Apnea Central Chemoreceptor Sensitivity Splanchnic Venous Capacitance Congestion Acute HF Obstructive Sleep Apnea Chemosensors carotid body Mechanosensors baroreceptor Hypertrophy Arrhythmia 4

Carotid Body in HF Both Increased Tonic and Chemosensitivity resting activity (21% FiO2) Schultz et al. ISH 2012

Carotid Body Function (CBF) is related to mortality in Heart Failure (CHF) Ponikowski et al. Circulation 2001;104:544-549 Gianonni, et al. Chemoreflex and Prognosis in HF. 2008

Therapeutic carotid body chemoreceptor denervation (CBD) reduces renal sympathetic nerve activity (RSNA) and arrhythmia incidence in congestive heart failure (CHF) Adult male New Zealand White Rabbits Paced into heart failure over the course of 3-4 weeks Carotid bodies ablated using a fine tip forceps dipped in liquid nitrogen Marcus, et al. Autonomic Society 2012

CBM normalizes RSNA in CHF Is the CB the sleep apnea link? * # Hypoxia increases RSNA in CHF CBM normalizes RSNA response to hypoxia in CHF

CBM Restores Sympathetic Balance in CHF CHF-CBD sham-sham CHF-sham 2.5 sec CBM reduces MSNA and normalizes RSNA in heart failure

CBM restores HRV B Schultz et al. ISH 2012

CBM normalizes Ve in CHF Hypoxia increases minute ventilation in CHF CBM normalizes minute ventilation response to hypoxia in CHF

Carotid Body Modulation in CHF Selective denervation of carotid body chemoreceptors reduces the elevation in RSNA observed in rabbit CHF. Arrhythmia incidence is increased in rabbit CHF, and is reduced by CBD. Surgical or device oriented ablation of carotid body chemoreceptors may reduce sympathetic outflow and restore autonomic balance to the heart in human CHF, which may in turn reduce incidence of arrhythmias.

CBM in Hypertension

Experimental Design SHR & Wistar rats 10 weeks of age 4 weeks of age carotid sinus nerve ablated 10 weeks of age left femoral artery cannulated 11 & 13 weeks of age ABP recorded during sleep McBryde et al. ISH 2012

CBM Reduces Renal Sympathetic Activity Days CBM (n=3) % Renal SNA Stress RSNA Days McBryde, Abdala et al. ISH 2012

Peripheral Chemoreceptor Afferent Drive is Pro-Hypertensive in SH Rats: Transient Inactivation 80 100 120 140 160 180 - 1 2 Time (min) MAP (mmHg) Wistar SHR H Y P E R O X I A * Air 3s 20mV RSA 100% O2 SHR – Renal Sympathetic -20 -15 -10 -5 5 ∆ MAP (mmHg) SHR Wistar * % RSA -120 -100 -80 -60 -40 -20 SHR Wistar * McBryde....Paton (2013)

Sympathetic Nerve Responses to RDN & Carotid Body Denervation in SH Rats Lumbar SNA (mV) -10 -5 5 10 Day -3 Day 10 -25 25 50 2s Renal Denervation Renal Carotid Body Denervation ↓22% ↓56% -50 McBryde..... Paton (2013)

Changes Evoked After Renal Denervation & Carotid Body Denervation in SH Rats -80 -60 -40 -20 MAP SNA (%) ** * # * p<0.05 within-subject * p<0.01 within-subject # p<0.01 between-group RD CBD MAP (mmHg) or SNA (%) McBryde..... Paton (2013)

Human Trials Positive Surgical Control Endovascular Trials- 2013 CHF (4 unilateral, 6 bilateral completed) FC III, IIIb; hyper chemosensitivity; optimal meds MSNA, Chemosens, Euglycemic Insulin Clamp, Sleep Study, Exercise parameters, ECHO morphology, BNP rHTN (4 unilateral completed) Office & ABPM proved rHTN MSNA, Chemo sens, Sleep Study, ABPM, oBP, HOMAir Endovascular Trials- 2013

The art of making a medical device Make it fool proof

Carotid Body Modulation (CBM) Restoring Sympathetic Balance CIBIEM, Inc.

Terminal Thoughts A final cautionary thought. I’ve been traveling through a lot of airline terminals lately. Here’s a diagram of several of them. Most people looking at this diagram will conclude there are many ways to build an airport. But I’m more cynical. I think it means we haven’t yet learned how to build one!