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

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

4. Heart failure is a progressive syndrome Fatigue Myocardial remodeling Shortness of breath Susceptibility to arrhythmias HFSA Guidelines: Lindenfeld, J Card Fail, 2010 Schrier, NEJM, 1999

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

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

7. SCS for refractory angina pectoris Promising clinical evidencefrom feasibility studies in man Stabilization of intrinsic cardiac nerves during ischemia in canine • Decreased frequency of anginal attacks1-3 • Decreased nitrate & morphine consumption4-5 • Improved functional class6-7 and QoL8, • Increased exercise capacity9-11 1 Greco, PACE, 1999 2 Hautvast, ClinCardiol, 1998 3 De Jongste H, BHJ, 1994 4 Murphy, Pain, 1987 5 Andersen,Pain Clinic, 1995 6 TenVaarwerk. Heart, 1999 7 Sanderson, BMJ, 1992 8 Vulink, Intl Neurom, 1999 9 DeJongste, JACC, 1994 10 Hautvast, AHJ, 1998 11 Sanderson, EHJ, 1994 Foreman, Cardiovasc Res, 2000 NOTE: SCS is not currently approved in the U.S. for use in treating angina pectoris

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

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

10. SCS improves LV contractility at reduced O2 demandin porcine HF HF (No SCS) During SCS Liu,JCardiovascElectrophysiol, 2012 NOTE: SCS is not currently approved in the U.S. for use in treating heart failure

11. SCS is promising at different stimulation durationsin porcine HF Systolic function Serum Norepinephrine LVEF (%) Noerepinepherine (pg/mL) Control SCS 12 hr SCS 24 hr BSLN BSLN BSLN BSLN MI MI MI MI MI+HF MI+HF MI+HF 10 Wk 10 Wk 10 Wk MI+HF 2 Wk 6 Wk 10 Wk Tse, ESC Congress (abstract presentation), Aug 2012 NOTE: SCS is not currently approved in the U.S. for use in treating heart failure

12. Several clinical trials are underway for SCS in HF ClinicalTrials.gov and internal data CAUTION ­­ Investigational device. Limited by Federal (or United States) law to investigational use.

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

14. 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 NOTE: SCS is not currently approved in the U.S. for use in treating heart failure