2. Newer and Future (Device) Therapies for Heart Failure William T. Abraham, MD, FACP, FACC, FAHA, FESC Professor of Medicine, Physiology, and Cell Biology Chair of Excellence in Cardiovascular Medicine Chief, Division of Cardiovascular Medicine Deputy Director, Davis Heart & Lung Research Institute The Ohio State University Columbus, Ohio Dr. Abraham has received consulting fees and/or research grants from Abbott Vascular, Cardiokinetix Inc., CardioMEMS, CVRx, Impulse Dynamics, Medtronic, and St. Jude Medical, and Sunshine Heart.

3. Current Evidence-Based Treatment of Chronic Systolic Heart Failure Control VolumeReduce Mortality Diuretics Digoxin  -Blocker ACEI or ARB Aldosterone Antagonist or ARB Treat Residual Symptoms CRT  an ICD* Hyd/ISDN* *For all indicated patients. Abraham WT, 2005.

4. Current Evidence-Based Treatment of Chronic Diastolic Heart Failure

5. Recommended Therapies for Routine Use: Treating known risk factors (e.g., hypertension) with therapy consistent with contemporary guidelines Ventricular rate control for all patients with AF Drugs for all patients Diuretics Drugs for appropriate patients ACEI ARBs Beta-Blockers Digitalis Coronary revascularization in selected patients Restoration/maintenance of sinus rhythm in appropriate patients Guideline Recommendations* for the Management of Diastolic Heart Failure *From ACC/AHA and HFSA heart failure guidelines; All of these recommendations based on consensus

6. Despite Current Therapies, Heart Failure Morbidity and Mortality Remain High 30% to 40% of patients are in NYHA class III or IV Re-hospitalization rates 2% at 2 days 25% at 1 month 50% at 6 months 5-year mortality ranges from 15% to more than 50% Asymptomatic LVD  15% Mild-moderate HF  35% Advanced HF >50%

7. Devices Under Investigation for the Treatment of Heart Failure Cardiac Contractility Modulation Cardiac Support Devices Ventricular Partitioning Devices Percutaneous Valve Repair Continuous Positive Airway Pressure Breathing (including ASV) Transthoracic Phrenic Nerve Pacing Ultrafiltration Devices

8. Devices Under Investigation for the Treatment of Heart Failure Newer Counter-pulsation Technologies Second and Third Generation LVADs Percutaneously-applied Ventricular Assistance Totally Implantable Artificial Hearts Fluid Monitors Implantable Hemodynamic Monitors Many others

9. Cardiac Contractility Modulation (CCM)

10. Optimizer II System

11. Early Studies of CCM Preclinical and early clinical studies showed that CCM: Increases cardiac contractility Reduces myocardial work Produces LV reverse remodeling Induces molecular changes (in genes, proteins and phosphorylation) indicative of improved calcium handling and contractile function These observations led to pivotal trials in Europe (FIX-HF-4) and the U.S. (Fix-HF-5)

12. Results of the FIX-HF-4 and FIX-HF-5 Studies In NYHA class III-IV heart failure patients, CCM improves Exercise capacity Quality of Life (MLWHFQ score) NYHA A subgroup of patients (EF ≥ 25, NYHA III) appears to benefit most from CCM* A prospective randomized controlled trial to confirm these observations (FIX-HF-5b) is ongoing in the U.S. *Abraham WT, et al. J Cardiac Failure 2011

13. Baroreflex Activation Therapy (BAT) Kidneys ↓ HR↑ Vasodilation ↓ Stiffness ↑ Diuresis ↓ Renin secretion Carotid Baroreceptor Stimulation Reduced blood pressure Reduced afterload, wave reflections and augmentation Reduced myocardial work and oxygen consumption Reduced neurohormonal stimulus Increased venous capacitance Heart Vessels Brain Autonomic Nervous System Inhibited Sympathetic Activity Enhanced Parasympathetic Activity Baroreflex Activation Lead Implantable Pulse Generator

14. Response to BAT is Prompt and Dose-Related ~ 4 min

15. BAT for Heart Failure Heart failure shares similar underlying mechanisms and drug treatments with hypertension BAT technology will be applied in the same way to treat heart failure patients Initial studies targeting heart failure with preserved LVEF 5.8 Million Heart Failure Patients in U.S.  Drugs  Drugs + Devices  No Approved Therapies Preserved EF Low EF

16. HOPE-4-HF Study Overview ≤ 100 patients at 15 sites FDA review on 30 Rheos patients followed for 3 mo 540 patients at 70 U.S. sites and 20 OUS sites Primary endpoint: CV death / HF event Follow-up until 270 primary endpoint events reached Enrollment uninterrupted Data counts toward endpoint First PhaseSecond Phase Rheos + Medical Management Implant/ Activate Medical Management Only Randomize 2:1

17. Spinal Cord Stimulation for Heart Failure SCS is approved for the treatment of chronic pain syndromes and has been used to treat intractable angina pectoris Current evidence suggests that thoracic SCS decreases sympathetic tone In a canine model, SCS caused vagal-like responses by slowing sinus rate and prolonging AV nodal conduction time and ventricular refractory period These effects may be beneficial in chronic heart failure

18. Clinical Response to SCS in a Canine Model of Heart Failure Lopshire JC, et al. Circulation 2009

19. Echocardiographic Response to SCS in a Canine Model of Heart Failure Lopshire JC, et al. Circulation 2009

20. Transvenous Phrenic Nerve Stimulation Respiratory Rhythm Management Unilateral phrenic nerve stimulation of the diaphragm Implantable stimulator with proprietary algorithm Implantable proprietary transvenous leads Stimulation algorithm restores natural breathing pattern, stabilizes gas exchange and decreases hypoxic episodes Inserted by cardiologist or EP using techniques similar to existing cardiac devices Currently stand-alone device, but can be combined with other cardiac therapies With Therapy

21. Acute Respiratory Rhythm Management Improves Sleep Indices *t-test Central Apnea Index % change = -91.0 p<0.0001* % change = -49.0 p=0.0006* *t-test % change = - 55.0 p=0.001* ODI 4 (%) % change = -51.0 p=0.0005* Arousal Index *t-test Oxygen Desaturation Index 4% Apnea Hypopnea Index Ponikowski P, ….. Abraham WT. Eur Heart J 2011

22. Implantable Hemodynamic Monitors LV Pressure Sensor PA Pressure Sensors RV Pressure Sensors LA Pressure Sensor

23. The Pulmonary Artery Pressure Measurement System Catheter-based delivery systemMEMS-based pressure sensor Home electronics PA Measurement database

24. CHAMPION Trial: Cumulative HF Hospitalizations Over Entire Randomized Follow-Up Period p < 0.001, based on Negative Binomial Regression Cumulative Number of HF Hospitalizations Days from Implant At Risk Treatment270262244209168130107812851 Control2802672522151791381056725100 Abraham et al., Lancet 2011

25. Secondary Efficacy Results Treatment (n=270) Control (n=280)p-Value Change from Baseline in Mean Pulmonary Artery Pressure at 6 Months Mean AUC -156330.008 Subjects Hospitalized for Heart Failure at 6 Months # (%) 54 (20)80 (29)0.022 Days Alive Outside Hospital at 6 Months Mean 174.4172.10.022 Minnesota Living with Heart Failure Questionnaire at 6 Months Mean 45510.024

26. CHAMPION: Putting It Altogether Pulmonary Artery Pressure Medication Changes On Basis of Pulmonary Artery Pressure P<0.0001 Pulmonary Artery Pressure Reduction P=0.008 Heart Failure Related Hospitalization Reduction P<0.0001 Quality of Life Improvement P=0.024 P values for Treatment Vs Control Group

27. Implantable LA Pressure Monitor Implantable Communications Module (ICM) Lead Sensor Module Proximal Anchor Distal Anchor Sensor Diaphragm ~ 3 mm Measures LAP IEGM Core Temp Implantable Sensor Lead (ISL)

28. PAM  Powers implant by RF  Atmospheric reference  Stores telemetry  Alerts patient to monitor  DynamicRX ™  Meds, activity, MD contact Handheld Patient Advisor Module (s) carvedilol(25mg),1 tab (s) lisinopril(20mg), 1 tab *(d) furosemide(40mg),1 tab

29. Physician-Directed, Patient-Self Management PAM LAP ≥28 … Very High… furosemide 80mg, call MD LAP 19-27 … High………. 40mg LAP 10-18 … Optimal…… 20mg LAP 6-9 … Low…………10mg LAP ≤ 5 … Very Low…. hold, increase fluid intake Remote (patient’s home) Direct USB (in-clinic) RF Telemetry Application Software Trends, Waveforms, Prescriptions PC or Web Based Optimal LAP makes it easier to up-titrate β-Blockers and ACE-I/ARBs

30. HOMEOSTASIS Trial Results Reduction in Heart Failure Hospitalizations PeriodAnnualized Event Rate P-values 12-mo period before enrollment 1.4 (1.1-1.9) 0.054 First 3 mo Observation Period 0.68 (0.33-1.4) <0.001 0.041 After mo 3 Titration/Stability Periods 0.28 (0.18-0.45) Ritzema J,..… Abraham WT. Circulation 2010 LAPTOP-HF, an adequately powered randomized controlled trial to assess clinical safety and effectiveness of this approach, is underway

31. New Approach to the Non-Invasive Assessment of Lung Water Proprietary RF monitoring and imaging technology As fluid replaces air, there is an increase in the dielectric coefficient Measurement is localized (lung-specific) as opposed to other modalities (e.g., bio- impedance) Enables non-invasive and continuous monitoring of lung fluid concentration

32. ReDS Correlation with CT and Pressure (Pre-Clinical Data) Inferior (Dependent) Lobes Superior Lobes Start of volume loading Diuretics CT + ReDS LVEDP, PAP Fluid concentration and pressures correlate during volume overload; a lag is observed during diuresis Interclass Correlation = 0.95

33. Left Ventricular Partitioning: Rationale Decrease LVEDV Decrease LVESV Reshape ventricle Decrease LV radius Reduce LV wall stress Increase contractility Prevent further remodeling/ reverse remodeling

34. Percutaneous Ventricular Partitioning Device: System Components 75mm & 85mm diameter Deliver via 14/16 French Catheter Nitinol struts ePTFE membrane Radiopaque Pebax polymer foot Cardiokinetix, Inc., Menlo Park, California, USA

35. PARACHUTE LVESV (ml) 0 50 100 150 200 Baseline 6 months 12 months 155.3 196.1 160.9 p<0.001 Efficacy Results: LVESV, Paired data, mean ± SEM Abraham et al., HFSA 2010 LBCT Presentation All 1yr, n=28

36. Cardiac Support Devices Primary goal is to reduces LV radius and transmural pressure, so that diastolic wall stress will fall Other properties (e.g., elasticity) of such devices may provide ancillary mechanisms of benefit First generation devices (e.g. CorCap™) required a major surgical procedure (i.e., sternotomy) Newer devices (e.g., HeartNet™) can be placed via a minimally invasive approach and has unique elastic properties

37. Minimally Invasive Approach to Ventricular Elastic Support Therapy Super elastic compliant nitinol structure Defibrillation, pacing compatible Delivered with special delivery system through minithoracotomy Self anchoring, self tensioning Pre sized based on echo measurements

38. Paracor HeartNet™ Compliance The elastic compliance allows the device to stretch and return to its original position

39. PEERLESS-HF CRT Subset Data P=0.036 HR=2.2

40. PEERLESS-HF CRT Subset Data P=0.06 HR=2.0

41. Extra-Aortic Counterpulsation Heart Fills - Cuff InflatesHeart Ejects - Cuff Deflates to body to heart reduce workload Increased Blood Flow: + 60% coronary flow; + 30% cardiac output; Reduced Heart Workload: - 30% pulmon. Pressure; -33% LV wall stress

42. C-Pulse for Moderate Heart Failure Patients ECG Sense Lead Extra-aortic Cuff Battery Pack Driver Interface Lead

43. Ventricular Assist Devices AHA estimates that  250,000 patients could benefit from long-term circulatory support Potential Opportunities Bridge to Transplant est. 7,000 patients annually Permanent Support or “Destination Therapy” est. 40,000 patients annually Bridge to Recovery est. > 200,000 patients annually

44. LVADs as Destination Therapy in End-Stage Heart Failure 100 80 60 40 20 0 0612182430 6838221151 612711430 No. at Risk LV Assist Device Medical Therapy Survival (%) Months LV Assist Device Medical Therapy Rose et al., NEJM 2001

45. LVADs as Destination Therapy in End-Stage Heart Failure 100 80 60 40 20 0 0612182430 6838221151 612711430 No. at Risk LV Assist Device Medical Therapy Survival (%) Months LV Assist Device Medical Therapy Rose et al., NEJM 2001

46. Generation II Devices (axial flow pumps) Characteristics: small, simple designs high rpm easy insertion/removal (minimally invasive techniques) durability risk/bearing Use (targeted): temporary support bridge to transplant bridge to recovery limited “permanent” use Ventricular Assist Devices

47. Heartmate II Axial Flow LVAD

48. Generation III Devices (magnetic bearings) Characteristics: high reliability fewer mechanical parts complex engineering closed loop systems (?) Use (targeted): temporary support bridge to transplant bridge to recovery “permanent” use Ventricular Assist Devices

49. HeartWare Ventricular Assist System Small implantable centrifugal pump Designed to be implanted in the pericardial space ?High rate of thrombotic complications

50. Micro-pumps: Short-Term Use Impela 2.5 Percutaneous Heart Pump Delivers 2.5 L/min of flow Unloads the ventricle Designed for Ease of Use (Cath Lab) 9 Fr Catheter 12 Fr micro-axial pump

51. Micro-pumps: Short-Term Use Impela 5.0 Requires arterial cutdown Delivers 5.0 L/min of flow Unloads the ventricle Surgical insertion 9 Fr Catheter 21 Fr micro-axial pump

52. Micro-pumps: Long-Term Use CircuLite Synergy Provides up to 4.25 liters/min of flow Size of a AA battery Small enough to be implanted subcutaneously in a "pacemaker-like" pocket through a minimally-invasive procedure CE Mark trial ongoing

53. Total Artificial Heart: Syncardia Rate of survival to transplantation with TAH was 79% versus 46% in controls (P<0.001) 1-year survival rate among the patients who received the artificial heart was 70%, as compared with 31 percent among the controls (P<0.001) Copeland JG, et al. NEJM 2004

54. Artificial Heart Driver Only FDA-approved driver for powering the artificial heart in the U.S. is the 418- lb hospital driver A portable driver, which would allow patients to be discharged from the hospital, is under investigation in an IDE study

55. The (Distant) Future of Heart Failure Therapies Xenotransplantation Gene therapies Cell therapies Myoblasts Stem cells Others