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

2. Outline
 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

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 Pacing Paradigm
st
 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
AVN
Ventricle
♥ ♥ ♥ ♥ ♥♥ ♥ ♥ ♥ ♥ ♥♥ ♥
♥
Atrium
AVN
Ventricle
♥ ♥♥ ♥ ♥♥ ♥♥

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
SINUS
1 2 3 4
0 1 2
1
AF
3 4 5
2
0 1 2
CP
2 4
1 3
0 1 2
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. Effects of Chronic AF and CP on Cardiac Function
60 200
50 * 175
#
150
40
VRMC (C/min)
125
LVEF (%)
* #
30 100
75
20
50
10
25
0 0
Sinus Chronic AF Coupled Pacing
0 6-8 10-12
Time in weeks
Yanulis et al (2008). The Annals of Thoracic Surgery, 86(3), 984-987

18. Results of Sustained CP on LV Volumes-
Reversed Remodeling
Effects of Chronic AF and CP on Cardiac Volumes
 The LVEDV decreased
from 75.5 ± 6.65 mL to
65 ± 3.22 mL (AF vs.
100
LVEDV
LVESV
80 * LAV CP, p<0.0.5) .
#
60
*
Volumes (ml)
 The LVESV decreased
*
from 51 ± 4.57 mL to
40
#
20 34.5 ± 2.41 mL
0
(p=0.001).
Sinus Chronic AF Coupled Pacing
0 6-8 10-12
Time in weeks
Yanulis et al (2008). The Annals of Thoracic Surgery, 86(3), 984-987

19. Hemodynamic Tracings
ECG
RV electrogram
dp/dt
(mmHg/s)
LV Pressure
(mmHg)
Aortic Flow
(L/min)
Coupled Pacing Coupled Pacing
OFF ON
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 2nd 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
LV electrode
Vagal electrode
RV electrode
Epicardial Echocardiography

30. Experimental protocol
Sinus
Right atrium Left ventricle
Rhythm Baseline VS
N=6 Right ventricle
Step 1
Atrial
Fibrillation Atrial pacing
N=6
RV pacing
Step 2
N=6
Step 3 CRT
N=6
CRT+ CP
Step 4 N=6 CRT CP
RR
CRT-VS
Step 5 N=3 VS

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

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)
Trial #3-performed on 8-20-07
110
100
90
80
Flow (ml/m)
70
60
50
40
30
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8
Change in Pressure (mmHg)
Photograph of the Mock II Mock II Circulatory Circuit
Circulatory Circuit (Results)

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.