1. Left Ventricular Pacing in the Early Post MI Period: Impact on LV Remodeling Eugene S.Chung, MD Director, Heart Failure Program, Director of Outcomes, The Christ Hospital and The Ohio Heart and Vascular Center Associate Professor of Clinical Medicine The Ohio State University Columbus, OH

2. Outline Impact of regional wall motion abnormality on LV remodeling Animal data: post MI LV pacing and remodeling Pilot human data with post MI LV biventricular pacing Multicenter trial of post MI, biventricular pacing

3. Infarct tissue changes  EF  Volume  Wall stress Compensatory dilatation and further wall stress

6. The H.E.A.R.T. Study Courtesy of Dr. Scott Solomon Apical Wall Stress and Remodeling

7. Post-MI Remodeling is Related to Regional Wall Stress

8. 7 dogs with RA, RV and LV pacing leads MRI imaging for strain and deformation analyses Result of different pacing sites studied Prinzen et al, J Am Coll Cardiol, 1999

10. ... apex base anterior posterior septum Atrial pace RV pace LV pace 0 (mJ/g) 8 Prinzen et al, J Am Coll Cardiol, 1999 Work Load is Reduced Near Pacing Site

11. Questions Can application of peri-infarct pacing reduce regional work/stress in a more clinical setting? Does this therapy offer protection for the infarcted region during a “vulnerable” period? Can this therapy offer cardiac structural and clinical benefits? Testing in human subjects

12. Effect of LV Pacing on Regional Stress Post MI Pre-excitation therapy 12 swine Lateral infarct LA lead for sensing LV peri-infarct lead LV pacing vs. no pacing for 60 days Sonomicrometer crystals and echocardiography Shuros, et al. Circulation. 2007 Sep 4;116(10):1162-9

13. d. e. f. Infarct Border Remote Wall Motion-Pre vs Post-MI Pressure/Segment Loop a. b. c. Increased lengthDisplacement of work Infarct Border Remote

14. Echocardiographic Data at 60 Days LV IDd, cm4.29±0.225.78±0.501.49±0.46 (0.0005)4.63±0.405.55±0.600.91±0.27 (0.0004) * LV IDs, cm3.43±0.254.22±0.430.79±0.38 (0.0039)3.48±0.344.22±0.380.74±0.21 (0.0003) FS, %20.0±4.926.8±6.86.8±10.3 (0.1664)25.0±3.923.8±4.4–1.2±5.7 (0.6186) IVS, cm0.94±0.151.00±0.050.06±0.14 (0.3402)0.81±0.150.96±0.100.15±0.09 (0.0099) PW, cm0.75±0.160.62±0.15–0.14±0.13 (0.0494)0.67±0.110.71±0.130.04±0.17 (0.6230) MR+1.50±1.233.17±0.821.67±0.61 (0.0011)2.08±0.671.67±1.63–0.42±1.20 (0.4341) LA, cm2.64±0.584.95±1.272.32±0.88 (0.0014)3.13±0.634.00±0.891.06±0.78 (0.0388) * Variable baseline 8 weeks change (p) baseline 8 weeks change (p) Control (n=6) Therapy (n=6) Adapted from Shuros, et al. Circulation. 2007 Sep 4;116(10):1162-9

15. Pacing the border regions for 60 days beginning post LCX ligation is associated with the follwing changes: Overall heart weight reduced by 11% Increase in LVID reduced by 39% Increase in LA dimension reduced by 54% MR was significantly reduced in therapy vs control animal Tricuspid regurgitation abolished in all therapy animals Electrical pre-excitation immediately post-MI appears safe Summary

16. Biventricular Pacing Post MI: A Human Study Acute –Pacing causes the region to contract early (pre-excited), against a lower ventricular pressure and at a reduced preload, –The pre-excited region does less external work and develops less stress Chronic –Chronic reduction of workload in the MI region via pacing will attenuate post-MI remodeling Pre-excitation (via pacing) can attenuate remodeling

17. Safety and Feasibility Pilot Study: Remodeling Prevention Therapy Chung ES, et al Congest Heart Fail. 2007 Jan-Feb;13(1):9-15. Goals: 1) Safety of post-MI biventricular pacing 2) Impact on ventricular remodeling

18. Patient Population Population: Acute STEMI All patients received device 30-45 days post-MI LVEF<30%, at least 2 segments with WMA QRS<120 ms RPT (N=8) vs. Control (N=6) Echocardiography interpreted by blinded independent observer Chung ES, et al Congest Heart Fail. 2007 Jan-Feb;13(1):9-15.

19. Therapy LV lead placed at infarct border if possible If not, standard lateral placement accepted Control = ICD: VVI-40, no pacing RPT = CRT-D: pacing Bi-V in all patients –AV-Delay programmed to 70% intrinsic at each visit –No implant failures or serious adverse events Chung ES, et al Congest Heart Fail. 2007 Jan-Feb;13(1):9-15.

20. Clinical Characteristics Chung ES, et al Congest Heart Fail. 2007 Jan-Feb;13(1):9-15. Control RPT

21. Baseline Characteristics ParameterControl (n=8) RPT (n=9) P Value LVEDV (ml)153 ± 38172 ± 300.46 LVESV (ml)109 ± 28126 ± 200.17 LVEDD (cm)5.5 ± 0.75.9 ± 0.50.31 LVESD (cm)4.6 ± 0.85.0 ± 0.60.47 QOL47 ± 1940 ± 250.36 6 MHW (m)382 ± 78331 ± 1060.36 Chung ES, et al Congest Heart Fail. 2007 Jan-Feb;13(1):9-15.

22. No detrimental effect on NYHA Class Baseline 6 month3 month1 month I II III IV ND 12 month RCT Control Baseline 6 month3 month1 month I II III IV ND 12 month RCT Control RPT Control Chung ES, et al Congest Heart Fail. 2007 Jan-Feb;13(1):9-15.

23. RPT May Attenuate Remodeling p=0.03* Chung ES, et al Congest Heart Fail. 2007 Jan-Feb;13(1):9-15.

24. Summary –Patients with low EF (<30%), recent MI (30-45 days), narrow QRS, and HF appear to remodel in presence of contemporary medical therapy –RPT appears safe and feasible in this patient population –RPT may have a beneficial effect on chronic ventricular remodeling at one year

25. Prevention of Myocardial ENlargement and Dilation after Myocardial Infarction (MENDMI) Goal: –Determine whether peri-MI pacing will attenuate remodeling in early post-MI patients with significant anterior MI Logistics: –Significant risk feasibility IDE study –30 US centers, 110 patients –80 randomized patients (1:1, RPT-D vs. Control) + 30 registry patients Sponsor: Boston Scientific

26. MendMI Study design Anterior AMI CK>2000 QRS<120 Registry No Tx N=10 Registry No Tx N=10 Registry No Tx N=10 Randomized ICD only N=40 Randomized RPT + ICD N=40 EF>40% EF≤40% WMA≤30% WMA>30%WMA≤30% WMA>30%

27. Technical Points The RV lead should preferably be placed in the peri-infarct region and should not be placed on the septal wall. The RV lead may be in the infarct as long as acceptable pace/sense parameters are obtained.

28. Data Collection Schedule

29. Current status of MENDMI Enrollment completed in Feb. 2008, last 6 month follow up in August 2008 Regarding adverse event rate, DSMB met in Sept 2006, May 2007, and Nov 2007 and recommended the study should "proceed without modification to the procedure“ Dataset complete spring of 2009

30. Conclusions LV pacing early (<14 days) of MI appears safe Preliminary data suggests favorable impact on remodeling Multicenter pilot study is completed and in follow-up phase Larger clinical endpoint driven study is needed

31. Future Considerations If LV / BIV pacing / RPT early post MI attenuates remodeling, what are the mechanisms? Would pacing in this setting enhance the viability of cell therapy post MI? Thank you