This document summarizes a novel cardiac pacing paradigm called CRT+CP for patients with atrial fibrillation (AF) and heart failure (HF). CRT+CP involves applying cardiac resynchronization therapy (CRT) followed by coupled pacing (CP) to control ventricular rate during AF episodes. Animal studies showed CRT+CP improved left ventricular function compared to other pacing methods. Simulations suggested measuring differential pressure in the great cardiac vein could help optimize pacing by monitoring cardiac flow. CRT+CP may help more HF patients benefit from CRT by controlling heart rate during AF.

1. A Novel Cardiac Pacing Paradigm for Atrial Fibrillation and Heart Failure Patients George Emanuel Yanulis, D.Eng.

2. Atrial Fibrillation (AF) and heart failure (HF) Coupled Pacing (CP) and sustained CP applied to persistent AF Cardiac conduction pathways Cardiac resynchronization therapy non-responders The CRT+CP pacing paradigm Simulation Studies (Great Cardiac Vein) Conclusions Outline

3. Atrial Fibrillation At age 40, remaining lifetime risks for AF were 26.0% for men and 23.0% for women. From 1996 to 2001, hospitalizations with AF as the first-listed diagnosis increased 34%. AF is an independent risk factor for ischemic stroke, increasing risk about 4 to 5 fold. Heart Disease and Stroke Statistics—2007 Update

4. Clinical Correlates of AF Overall 752 patients from the ALPHA Registry, corresponding to a prevalence of 21.4% (95% CI 20.0%–22.8%) were in AF. The total proportion of HF patients with atrial fibrillation at any time is approximately 41% . AF is more prevalent among HF patients with relatively preserved systolic function. European Journal of Heart. Volume 9, Issue 5, May 2007

5. Heart Failure It has been estimated that 4.6 million persons have heart failure (HF). An estimated 400,000 to 700,000 new cases develop each year. U.S. Hospital discharges for HF rose from 399,000 in 1979 to 1,099,000 in 2004, an increase of 175% (National Hospital Discharge Survey). HF is the primary diagnosis for 875,000 hospitalizations annually, and it is the most common diagnosis among hospitalized patients 65 years of age or older. AHA 2007 Statistics Update

6. Anatomical/Physiological Considerations Similar anatomical and physiological characteristics between the canine and human cardiovascular systems. The canine model is a well-established model for studying AF and chronic heart failure (CHF). And the ability to monitor canines in the conscious state.

7. 1 st Pacing Paradigm Coupled Pacing (CP)-rate control. CP is designed to improve cardiac function during atrial fibrillation (AF) and heart failure. This pacing therapy both slows the rate of ventricular contraction and increases contractility. CP first senses the intrinsic electrical activation of the heart. Then a delayed stimulation coupled to this intrinsic activation is applied, resulting in a second electrical activation with minimal mechanical contraction.

8. Schematic Representation of Cardiac Conduction Pathways in the Human Heart http://images.main.uab.edu/

9. Concept of Coupled Pacing during AF (Electrically Activating the Ventricles after a Specific Delay) Atrium Ventricle AVN                       Atrium Ventricle AVN

10. AF can Lead to Ventricular Tachycardia The AV node is not a perfect filter. During AF, rapid irregular ventricular contractions can occur. These ventricular contractions fail to eject blood CP blocks approximately one-half of the ventricular activations leading to slower, stronger contractions

11. Coupled Pacing vs. Paired Stimulation

12. Prior Coupled Pacing Studies Coupled pacing (CP) acutely does result in a sustained increase in myocardial contractility. CP is different from paired stimulation in that it senses the intrinsic activation and then paces the heart. And CP increases the mechanical efficiency during acute AF and has a positive inotropic effect on the heart. Yamada H et al. Am J Physiol 287: H2016-H2022, 2004.

13. My Studies on Chronic Coupled Pacing AF is a prevalent cardiac arrhythmia. Are the effects of persistent coupled pacing (CP) beneficial? Can the effects of chronic effects of CP be sustained?

14. Placement of the Leads, Adapters, and Pacemakers for the AF Model Cingoz et al (2007). The Annals of Thoracic Surgery , 83 (5), 1858-1862.

15. Effects of Chronic AF Significant tachycardia-mediated left ventricular (LV) remodeling, resulting in both left atrial and left ventricular dilatation. The left ventricular end diastolic volume (LVEDV) increased from 62.3  4.78 mL to 75.5  6.65 mL (BL vs. AF, p<0.01). And the left ventricular end systolic volume (LVESV) increased from 30.7  2.57 mL to 51  4.57 mL (p<0.001). Yanulis et al (2008). The Annals of Thoracic Surgery, 86(3), 984-987

16. ECG Tracings The top panel shows when the animal was in sinus rhythm. The number indicates the intrinsic electrical activations. The middle panel show when the animal was in persistent AF. The bottom panel shows coupled pacing.

17. Yanulis et al (2008). The Annals of Thoracic Surgery, 86(3), 984-987

18. Results of Sustained CP on LV Volumes- Reversed Remodeling The LVEDV decreased from 75.5  6.65 mL to 65  3.22 mL (AF vs. CP, p<0.0.5) . The LVESV decreased from 51  4.57 mL to 34.5  2.41 mL (p=0.001). Yanulis et al (2008). The Annals of Thoracic Surgery, 86(3), 984-987

19. Hemodynamic Tracings Marks above the left ventricular (LV) pressure tracings illustrate VRMC, and marks above the aortic flow tracings illustrate VREJ.

20. My studies on Chronic Coupled Pacing Are the effects of persistent coupled pacing (CP) beneficial? Answer: Yes. Can the effects of CP be sustained? Answer: Yes.

21. The 2 nd Pacing Paradigm (CRT+CP Pacing) Rather than CRT ending during episodes of AF, this new pacing regimen (CRT+CP) could be applied desynchronized HF and AF patients. Briefly, CRT+CP, involves: The application of a 1st stimuli to the left ventricle and a 2nd stimuli to the right ventricle simultaneously in the same manner as CRT is used clinically today Thus, these first 2 stimulations will result in a more synchronized electrical activation and subsequent contraction of both ventricles And then a 3rd premature paced beat is applied to activate both ventricles electrically but not mechanically for CP.

22. Atrial Fibrillation (AF) in Heart Failure (HF) Patients AF and HF frequently coexist. HF promotes AF. And AF may cause or aggrevate HF. 25% of HF patients also have AF 34% of HF patients have LBBB. 30% of above these patients also have AF. Eur Heart J. 2002 Nov; 23(21): 1692-8.

23. Electrical Activations of the Normal Heart www.physiome.org

24. RV Apex Pacing Left Bundle Branch Block Prinzen et al, 2000

25. Clinical Significance of CRT CRT has been established as an effective pacing therapy in most heart failure patients with left bundle branch block. Heart failure patients with drug-refractory atrial fibrillation may require ablation therapy to benefit from CRT.

26. Current Pacing Therapies Biventricular Pacing (CRT) consists of: A pacemaker generator (#1) A right atrial pacing wire (#2) A right ventricular pacer wire (#3) And a coronary sinus (LV) pacing wire (#4). Circulation. 2005 Sep 27;112(13):e236-7.

27. AF in HF Patients with Left Bundle Branch Block (LBBB) Cardiac resynchronization therapy (CRT) is effective in many HF w/ LBBB. CRT is not effective in some HF patients despite resynchronization (non-responders) even during sinus rhythm. CRT can only be effective if the ventricular rate is controlled during AF. CP added to CRT could be an effective means of rate control.

28. The CRT+CP Pacing Paradigm Our research to date has demonstrated that the addition of a coupled paced beat significantly increased: The left ventricular ejection fraction (LVEF) And the left ventricular strain as well This pacing paradigm may improve overall myocardial performance in HF and AF patients.

29. Animal preparation RA electrode RV electrode Epicardial Echocardiography LV electrode Vagal electrode

31. RV pacing HR=178bpm Step 2 QRS=120ms SD=16% CRT+CP HR=110bpm Step 4 QRS=90ms SD=5% CRT-VS HR=110bpm Step 5 QRS=90ms SD=3% -12% -7% -14% Baseline HR=103bpm Step 1 QRS=80ms SD=5% Atrial Fibrillation Sinus rhythm Dog #176 CRT HR=197bpm Step 3 QRS=90ms SD=5% -3% -19%

32. Use of CRT+CP on CRT Non-responders CRT+CP may convert non-responders to responders in HF patients in sinus rhythm. The addition of CP to CRT permits effective CRT to continue when AF and the subsequent rapid ventricular contractions occurs via its effective rate control mechanism.

33. Sensors to Control Pacing Presently measuring single site pressure, thoracic impedance, and the rate of cardiac electrical activation but not the rate of flow are used as sensors to control cardiac pacemakers. Which parameter is best to use to control pacing?

34. Simulation of Flow in the Great Cardiac Vein I developed mock coronary venous circulatory circuits which tested whether the differential pressure obtained in this system is representative of flow. DATAQ ® software was used to acquire the raw data obtained from my mechanical models. Then Origin ® software was used to plot the relationship between differential pressure and flow.

35. Pressure Recording (Millar Sensors) Mock II Circulatory Circuit (Results) Photograph of the Mock II Circulatory Circuit

36. Conclusions of My Simulation Studies My simulation results demonstrated that flow could be represented by measuring differential pressure. As flow is increased in the great cardiac vein, the differential pressure (GCV1 – GCV2) would change the balance of a Wheatstone bridge circuit configuration, a low energy monitor. This with this flow measurement and other cardiac measurements, optimizing the pacing paradigms such as CRT and or our novel pacing paradigm (CRT+CP) could be achieved.

37. Acknowledgements Don Wallick, Ph.D. Nolan Holland, Ph.D. George Chatzimavroudis, Ph.D. Christine Moravec, Ph.D. Walid Saliba, M.D. Brian Davis, Ph.D. Pascal Lim, M.D. Becky Laird Darlene Montgomery Shari Demarco, RVT Dana Frank, B.S.