1. Presenter Disclosure Information John F. Beshai, MD RethinQ Trial Results Disclosures Information: The following relationships exist related to this presentation: Consultant - St. Jude Medical, Atricure Research Grant - St. Jude Medical R Grimm : Speaker - St. Jude, Medtronic, GE Research Grant - GE S Nagueh: Speaker - Medtronic Consultant - St. Jude J Baker : no disclosures S Beau: no disclosures S Greenberg: Consultant - Medtronic, St. Jude, Boston Scientific L Pires: Consultant - St. Jude P Tchou: no disclosures

2. The Resynchronization Therapy in Normal QRS (RethinQ) Study John F. Beshai, MD, Richard A. Grimm, DO, Sherif F. Nagueh, MD, James H. Baker II, MD, Scott L. Beau, MD, Steven M. Greenberg, MD, Luis A. Pires, MD, Patrick J. Tchou, MD for the RethinQ study investigators Study Sponsored by St. Jude Medical

3. Background Currently, indications for cardiac resynchronization therapy (CRT) include QRS duration > 120ms, LVEF < 35% and NYHA Class III-IV. 20-30% of patients do not respond to CRT despite application of established selection criteria. Patients with normal conduction or a slightly prolonged QRS duration also exhibit mechanical abnormalities due to intraventricular dyssynchrony. Myocardial Tissue Doppler Imaging (TDI) allows both the velocity and timing of regional longitudinal motion to be measured. LV dyssynchrony may also be useful in predicting the benefit of CRT before implantation of the pulse generator.

4. Hypothesis We hypothesized that patients with NYHA class III, left ventricular ejection fraction less than or equal to 35%, narrow QRS duration < 130 ms, and evidence of mechanical dyssynchrony on echocardiography may benefit from cardiac resynchronization therapy.

5. Overall Objective Determine CRT safety and efficacy in patients who are candidates for an ICD with NYHA Class III, narrow QRS duration (<130 ms) and evidence of mechanical dyssynchrony as measured by echocardiography/Tissue Doppler Imaging Primary Endpoint Improvement in Peak VO 2 during CPET of at least 1.0ml/kg/min at 6 months. Secondary Endpoints Improvement in quality of life score at 6-months Improvement in NYHA classification at 6-months Study Design

6. Inclusion and Exclusion Criteria Inclusion Criteria NYHA class III HF LVEF ≤ 35% Evidence of mechanical dyssynchrony QRS duration < 130ms Exclusion Criteria NYHA class I, II, or IV Permanent Atrial Fibrillation Recent MI, unstable angina or cardiac revascularization Prior cardiac resynchronization therapy

7. Mechanical dyssynchrony considered present if either M-Mode - Septal posterior wall mechanical delay (SPWMD) ≥ 130 ms OR Tissue Doppler Imaging (TDI) of the basal ventricular segments in apical 4/2/3 chamber views - Septal to lateral delay ≥ 65ms OR - Antero-septal to posterior delay ≥ 65ms Echo Criteria for LV Dyssynchrony

8. Study Design

9. Results Baseline CharacteristicsControl (n = 85) CRT (n = 87) Age (yr), Mean ± SD58 ± 1460 ± 12 Male sex, n(%)49 (58%)62 (71%) NYHA III, n(%)84 (99%)87 (100%) QRS Duration (ms), Mean ± SD106 ± 13107 ± 12 Ischemic Cardiomyopathy, n(%)43 (51%)47 (54%) Left ventricular ejection fraction (%)26 ± 625 ± 5 Medications, n(%) ACE inhibitor or substitute§ Beta-Blocker Diuretic Antiarrhythmic 77 (91%) 79 (93%) 74 (87%) 10 (12%) 77 (89%) 84 (97%) 73 (84%) 7 (8%) § Includes ARBs and other ACE substitutes, including Hydralazine

10. Baseline Mechanical Dyssynchrony Mechanical Dyssynchrony Parameters Control ms CRT ms SPWMD - M-Mode Mean ± SD n = 12 165 ± 27 n = 9 151 ± 22 Septal to lateral - TDI Mean ± SD n = 69 99 ± 29 n = 67 96 ± 28 Antero-septal to posterior - TDI Mean ± SD n = 55 106 ± 29 n = 59 94 ± 23

11. Baseline Echocardiographic Data 0 20 40 60 80 Control n = 85 CRT n = 87 LV end diastolic diameter (mm) Mean +/- 1 SD p = 0.29 LV end systolic diameter (mm) Mean +/- 1 SD 0 20 40 60 80 p = 0.06 CRT n = 87 Control n = 85

12. Baseline Echocardiographic Data (Cont) 0 50 100 200 300 LV end diastolic volume (mL ) Mean +/- 1 SD p = 0.61 CRT n = 87 Control n = 85 0 50 100 200 300 LV end systolic volume (mL) Mean +/- 1 SD p = 0.43 CRT n = 87 Control n = 85

13. Baseline Evaluations 0 5 10 15 20 25 0 5 10 15 20 25 Peak VO 2 (ml/kg/min) Mean +/- 1 SD p = 0.85 Control n = 85 CRT n = 87 0 5 10 15 0 5 10 15 Exercise Duration (min) Mean +/- 1 SD p = 0.85 Control n = 85 CRT n = 87

14. Baseline Evaluations (Cont) 0 20 40 60 80 100 Quality of Life Score Mean +/- 1 SD p = 0.43 Control n = 85 CRT n = 87 0 100 200 300 400 0 100 200 300 400 Six-minute Hall Walk Distance (m) Mean +/- 1 SD p = 0.95 Control n = 85 CRT n = 87

15. Patient Flow Analysis 172 patients randomized (87 CRT and 85 control) 11 patients in CRT group and 5 patients in control group not included in endpoint analysis –< 6 months of follow up (7 patients) –Unable to complete CPET at 6 month visit for reason other than worsening HF (3 patients) –Death not due to worsening HF (3 patients) –Withdrawal prior to 6 month visit (3 patients) 156 patients (76 CRT and 80 control) were available for efficacy analysis

16. Results - Primary Endpoint 8 10 12 14 Baseline6-months Peak VO 2 (ml/kg/min) Median & 95% CI p = 0.75 Control (n = 80) CRT (n = 76 ) CRT n = 76 0 20 40 60 80 100 p = 0.63 41% 46% Control n = 80 % Improved in Peak VO2

17. Results - Secondary Endpoints ImprovedNo ChangeWorsened 0 20 40 60 80 100 29% 54% 64% 41% 8%5% NYHA Class p = 0.006 30 40 50 60 70 Baseline6-months Quality of Life Median & 95% CI p = 0.91 Control (n = 80) CRT (n = 76) Control (n = 80) CRT (n = 76)

18. Change in LVEDV/ LVESV Median & 95% CI -40 -20 0 10 p = 0.71 LVEDV p = 0.81 LVESV Change in LVEDD/ LVESD Median & 95% CI -4 -2 0 2 4 p = 0.49 LVEDD p = 0.34 LVESD Control CRT LV Volumes and Dimensions

19. Peak VO 2 by sub-group Peak VO2 (% improved from baseline) 0 20 40 60 80 100 QRS ≥ 120 ms p = 0.02 QRS < 120 ms p = 0.45 Control n = 25 CRT n = 17 Control n = 55 CRT n = 59 Peak VO2 (% improved from baseline) 0 20 40 60 80 100 Ischemic p = 0.82 Non-ischemic p = 0.25 Control n = 41 Control n = 39 CRT n = 40 CRT n = 36

20. Summary This prospective, multi-center, randomized trial was designed to evaluate the effectiveness of CRT therapy in a HF population with narrow QRS duration and evidence of mechanical dyssynchrony. There was no statistical significant difference in the change in Peak VO 2 between the treatment and control group during cardiopulmonary exercise testing. No improvement in other objective parameters including 6-minute walk test, LV reverse remodeling, and secondary endpoint - quality of life score.

21. Summary NYHA class improved to a greater extent in the treatment group than in the control group. Although numbers were small in the sub-group analysis, there was no statistically significant difference in the primary endpoint between ischemic and non-ischemic patients. Patients with QRS duration 120 - 130 ms demonstrated an improvement in peak VO2.

22. Conclusion CRT did not improve Peak VO 2 during exercise in patients with NYHA Class III heart failure, QRS duration <130ms, EF ≤ 35% and mechanical dyssynchrony as specified in this trial. While there was a statistically significant improvement of NYHA class, a secondary endpoint, there was no improvement in quality- of-life, 6-minute walking test, or echocardiographic measures of reverse LV remodeling A subgroup of patients with QRS duration between 120 ms and 130 ms demonstrated an improvement from CRT, however patients with QRS duration < 120 ms did not demonstrate improvement The subgroup of patients stratified on the basis of cardiomyopathy etiology did not demonstrate an improvement in peak VO2.