Spinal Cord Stimulation for Heart Failure Stuart P. Rosenberg, M.S. Senior Manager, Neuromodulation Research Implantable Electronic Systems Division St. Jude Medical

Disclosures I am an employee of St. Jude Medical. I will be discussing unapproved and/or investigational uses of medical devices. 2

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Cardiac Dysfunction Increased Sympathetic Outflow RAAS Activation Fluid Overload Heart failure is a progressive syndrome 4 HFSA Guidelines: Lindenfeld, J Card Fail, 2010 Schrier, NEJM, 1999 Shortness of breath Fatigue Susceptibility to arrhythmias Myocardial remodeling

Modern HF treatment paradigm: drugs ± device 5 AHA/ACC HF Guidelines: Hunt, Circ, 2009 Anti-Sympathetic Rx Implantable Cardioverter-Defibrillator (ICD)

6 Can we treat patients with heart failure using electrical neuromodulation?

SCS for refractory angina pectoris Promising clinical evidence from feasibility studies in man  Decreased frequency of anginal attacks 1-3  Decreased nitrate & morphine consumption 4-5  Improved functional class 6-7 and QoL 8,  Increased exercise capacity Stabilization of intrinsic cardiac nerves during ischemia in canine 7 Foreman, Cardiovasc Res, Greco, PACE, Hautvast, Clin Cardiol, De Jongste H, BHJ, Murphy, Pain, Andersen, Pain Clinic, TenVaarwerk. Heart, Sanderson, BMJ, Vulink, Intl Neurom, DeJongste, JACC, Hautvast, AHJ, Sanderson, EHJ, 1994 NOTE: SCS is not currently approved in the U.S. for use in treating angina pectoris

SCS directly affects the heart’s electrical properties in healthy canine 8 Increasing Sympathetic Stimulation Increasing Vagal Stimulation Effect of SCS on Sinus Cycle Length Olgin, J Cardiovasc Electrophysiol, 2002 Bernstein, Heart Rhythm, 2012 No SCS During SCS Effect of SCS on Atrial Effective Refractory Period (S1=400 ms) NOTE: SCS is not currently approved in the U.S. for use in treating cardiac arrhythmia

SCS improves LV function and reverse remodeling in canine HF 9 SCS SCS+MEDS MEDS CTRL Lopshire, Circ, 2009 LVEDD (cm) BSLN After 2Wk 5Wk 10Wk HF LVESD (cm) BSLN After 2Wk 5Wk 10Wk HF LVEDD (cm) BSLN After 2Wk 5Wk 10Wk HF LVESD (cm) BSLN After 2Wk 5Wk 10Wk HF LV Ejection Fraction (%) BSLN After 2Wk 5Wk 10Wk HF Serum BNP (pg/ml) Systolic function Reverse remodeling Neurohormonal biomarkers BSLN After 2Wk 5Wk 10Wk HF Serum Norepinepherine (pg/ml) BSLN After 2Wk 5Wk 10Wk HF Serum BNP (pg/ml) BSLN After 2Wk 5Wk 10Wk HF Serum Norepinepherine (pg/ml) Spontaneous arrhythmias (n) Ventricular tachyarrhythmias NOTE: SCS is not currently approved in the U.S. for use in treating heart failure

SCS improves LV contractility at reduced O 2 demand in porcine HF 10 HF (No SCS) During SCS Liu,J Cardiovasc Electrophysiol, 2012 NOTE: SCS is not currently approved in the U.S. for use in treating heart failure

SCS is promising at different stimulation durations in porcine HF 11 BSLNMIMI+HF2 Wk6 Wk10 Wk Systolic functionSerum Norepinephrine Tse, ESC Congress (abstract presentation), Aug 2012 LVEF (%) BSLN MI MI+HF 10 Wk BSLN MI MI+HF 10 Wk BSLN MI MI+HF 10 Wk Noerepinepherine (pg/mL) ControlSCS 12 hrSCS 24 hr NOTE: SCS is not currently approved in the U.S. for use in treating heart failure

Neurostimulation of Spinal Nerves that Affect the Heart SCS-HEARTDEFEAT-HFTAME-HF Sponsor The Methodist Hospital System (collaboration with SJM) SJMMDTSJM Principal Invest- igator Guillermo Torre- Amione Hung-Fat TseDoug Zipes, Heinz Theres Pierre Bordachar Sites Houston Methodist, USA ~5 sites: Hong Kong & Australia ~30 sites: USA and EU Bordeaux, FR # Patients Clinical Trial ID NCT NCT NCT not yet registered Several clinical trials are underway for SCS in HF 12 Neurostimulation of Spinal Nerves that Affect the Heart SCS-HEARTDEFEAT-HFTAME-HF Sponsor The Methodist Hospital System (collaboration with SJM) SJMMDTSJM Principal Invest- igator Guillermo Torre- Amione Hung-Fat TseDoug Zipes, Heinz Theres Pierre Bordachar Sites Houston Methodist, USA ~5 sites: Hong Kong & Australia ~30 sites: USA and EU Bordeaux, FR # Patients Clinical Trial ID NCT NCT NCT not yet registered ClinicalTrials.gov and internal data CAUTION ­­ Investigational device. Limited by Federal (or United States) law to investigational use.

Promising early experience with SCS in HF patients 13 Torre, Heart Failure Society of America (poster presentation), Sep 2012 CAUTION ­­ Investigational device. Limited by Federal (or United States) law to investigational use.

SCS for HF: What else do we need to know?  Mechanism of action  Target patient population and subgroup analyses  Duration, dosage, and other treatment parameters  Possible side effects and interactions with background therapies 14 NOTE: SCS is not currently approved in the U.S. for use in treating heart failure