A Novel Cardiac Pacing Paradigm for A Novel Cardiac Pacing Paradigm for Atrial Fibrillation and Heart FailureAtrial Fibrillation and Heart Failure

PatientsPatients

George Emanuel Yanulis, D. EngGeorge Emanuel Yanulis, D. Eng

Atrial Fibrillation (AF) and heart failure (HF)Atrial Fibrillation (AF) and heart failure (HF)

Coupled Pacing (CP) and sustained CP applied to Coupled Pacing (CP) and sustained CP applied to persistent AFpersistent AF

Cardiac conduction pathwaysCardiac conduction pathways

Cardiac resynchronization therapy non-respondersCardiac resynchronization therapy non-responders

The CRT+CP pacing paradigmThe CRT+CP pacing paradigm

Simulation Studies (Great Cardiac Vein)Simulation Studies (Great Cardiac Vein)

ConclusionsConclusions

OutlineOutline

Atrial FibrillationAtrial Fibrillation

At age 40, remaining lifetime risks for AF were 26.0% At age 40, remaining lifetime risks for AF were 26.0% for men and 23.0% for women. for men and 23.0% for women.

From 1996 to 2001, hospitalizations with AF as the From 1996 to 2001, hospitalizations with AF as the first-listed diagnosis increased 34%.first-listed diagnosis increased 34%.

AF is an independent risk factor for ischemic stroke, AF is an independent risk factor for ischemic stroke, increasing risk about 4 to 5 fold. increasing risk about 4 to 5 fold.

Heart Disease and Stroke Statistics—2007 UpdateHeart Disease and Stroke Statistics—2007 Update

Clinical Correlates of AFClinical Correlates of AF

Overall 752 patients from the ALPHA Registry, Overall 752 patients from the ALPHA Registry, corresponding to a prevalence of 21.4% (95% CI corresponding to a prevalence of 21.4% (95% CI 20.0%–22.8%) were in AF. 20.0%–22.8%) were in AF.

The total proportion of HF patients with atrial The total proportion of HF patients with atrial fibrillation at any time is approximately 41% .fibrillation at any time is approximately 41% .

AF is more prevalent among HF patients with AF is more prevalent among HF patients with relatively preserved systolic function.relatively preserved systolic function.

European Journal of Heart. Volume 9, Issue 5, May 2007 European Journal of Heart. Volume 9, Issue 5, May 2007

Heart FailureHeart Failure

It has been estimated that 4.6 million persons have It has been estimated that 4.6 million persons have heart failure (HF).heart failure (HF).

An estimated 400,000 to 700,000 new cases develop An estimated 400,000 to 700,000 new cases develop each year.each year.

U.S. Hospital discharges for HF rose from 399,000 in U.S. Hospital discharges for HF rose from 399,000 in 1979 to 1,099,000 in 2004, an increase of 175% 1979 to 1,099,000 in 2004, an increase of 175% (National Hospital Discharge Survey).(National Hospital Discharge Survey).

HF is the primary diagnosis for 875,000 HF is the primary diagnosis for 875,000 hospitalizations annually, and it is the most common hospitalizations annually, and it is the most common diagnosis among hospitalized patients 65 years of diagnosis among hospitalized patients 65 years of age or older. age or older.

AHA 2007 Statistics Update AHA 2007 Statistics Update

Anatomical/Physiological ConsiderationsAnatomical/Physiological Considerations

Similar anatomical and physiological characteristics Similar anatomical and physiological characteristics between the canine and human cardiovascular between the canine and human cardiovascular systems.systems.

The canine model is a well-established model for The canine model is a well-established model for studying AF and chronic heart failure (CHF).studying AF and chronic heart failure (CHF).

And the ability to monitor canines in the conscious And the ability to monitor canines in the conscious state.state.

11stst Pacing Paradigm Pacing Paradigm

Coupled Pacing (CP)-rate control.Coupled Pacing (CP)-rate control.

CP is designed to improve cardiac function during CP is designed to improve cardiac function during atrial fibrillation (AF) and heart failure. atrial fibrillation (AF) and heart failure.

This pacing therapy both slows the rate of This pacing therapy both slows the rate of ventricular contraction and increases contractility. ventricular contraction and increases contractility.

CP first senses the intrinsic electrical activation of CP first senses the intrinsic electrical activation of the heart. Then a delayed stimulation coupled to this the heart. Then a delayed stimulation coupled to this intrinsic activation is applied, resulting in a second intrinsic activation is applied, resulting in a second electrical activation with minimal mechanical electrical activation with minimal mechanical contraction. contraction.

Schematic Representation of Cardiac Schematic Representation of Cardiac Conduction Pathways in the Human HeartConduction Pathways in the Human Heart

http://images.main.uab.edu/ http://images.main.uab.edu/

Concept of Coupled Pacing during AFConcept of Coupled Pacing during AF(Electrically Activating the Ventricles after a Specific Delay)(Electrically Activating the Ventricles after a Specific Delay)

Atrium

Ventricle

AVN

♥ ♥ ♥ ♥ ♥♥ ♥ ♥♥ ♥ ♥♥ ♥♥

♥ ♥ ♥ ♥ ♥♥ ♥ ♥

Atrium

Ventricle

AVN

AF can Lead to Ventricular TachycardiaAF can Lead to Ventricular Tachycardia

The AV node is not a perfect filter.The AV node is not a perfect filter.

During AF, rapid irregular ventricular contractions During AF, rapid irregular ventricular contractions can occur.can occur.

These ventricular contractions fail to eject bloodThese ventricular contractions fail to eject blood

CP blocks approximately one-half of the ventricular CP blocks approximately one-half of the ventricular activations leading to slower, stronger activations leading to slower, stronger contractionscontractions

Coupled Pacing vs. Paired StimulationCoupled Pacing vs. Paired Stimulation

Prior Coupled Pacing StudiesPrior Coupled Pacing Studies

Coupled pacing (CP) acutely does result in a Coupled pacing (CP) acutely does result in a sustained increasesustained increase in myocardial contractility. in myocardial contractility.

CP is different from paired stimulation in that it CP is different from paired stimulation in that it senses the intrinsic activation and then paces the senses the intrinsic activation and then paces the heart. heart.

And CP increases the And CP increases the mechanical efficiency during mechanical efficiency during acute AFacute AF and has a and has a positive inotropic effectpositive inotropic effect on the on the heart.heart.

Yamada H et al. Am J Physiol 287: H2016-H2022, 2004.Yamada H et al. Am J Physiol 287: H2016-H2022, 2004.

My Studies on Chronic Coupled PacingMy Studies on Chronic Coupled Pacing

AF is a prevalent cardiac arrhythmia.AF is a prevalent cardiac arrhythmia.

Are the effects of persistent coupled pacing (CP) Are the effects of persistent coupled pacing (CP) beneficial? beneficial?

Can the effects of chronic effects of CP be Can the effects of chronic effects of CP be sustained? sustained?

Placement of the Leads, Adapters, and Placement of the Leads, Adapters, and Pacemakers for the AF ModelPacemakers for the AF Model

Cingoz et al (2007). Cingoz et al (2007). The Annals of Thoracic SurgeryThe Annals of Thoracic Surgery, , 8383(5), 1858-1862.(5), 1858-1862.

Effects of Chronic AFEffects of Chronic AF

Significant tachycardia-mediated left ventricular (LV) Significant tachycardia-mediated left ventricular (LV) remodeling, resulting in both left atrial and left remodeling, resulting in both left atrial and left ventricular dilatation. ventricular dilatation.

The left ventricular end diastolic volume (LVEDV) The left ventricular end diastolic volume (LVEDV) increased from 62.3 increased from 62.3 ±± 4.78 mL to 75.5 4.78 mL to 75.5 ±± 6.65 mL (BL 6.65 mL (BL vs. AF, p<0.01).vs. AF, p<0.01).

And the left ventricular end systolic volume (LVESV) And the left ventricular end systolic volume (LVESV) increased from 30.7 increased from 30.7 ±± 2.57 mL to 51 2.57 mL to 51 ±± 4.57 mL 4.57 mL (p<0.001).(p<0.001).

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

0 1 2

AF1

23 4 5

0 1 2

CP1 2 3 4

0 1 2

SINUS1 2 3 4

ECG TracingsECG Tracings

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

Sinus Chronic AF Coupled Pacing0

10

20

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40

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60

#

6-8

LV

EF

(%

)

Effects of Chronic AF and CP on Cardiac Function

0

25

50

75

100

125

150

175

200

#

*

*

10-120

Time in weeks

VR

MC

(C/m

in)

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

Results of Sustained CP on LV Volumes- Results of Sustained CP on LV Volumes- Reversed RemodelingReversed Remodeling

The LVEDV decreased The LVEDV decreased from 75.5 from 75.5 ±± 6.65 mL to 6.65 mL to 65 65 ±± 3.22 mL (AF vs. 3.22 mL (AF vs. CP, p<0.0.5) .CP, p<0.0.5) .

The LVESV decreased The LVESV decreased from 51 from 51 ±± 4.57 mL to 4.57 mL to 34.5 34.5 ±± 2.41 mL 2.41 mL (p=0.001). (p=0.001).

Sinus Chronic AF Coupled Pacing0

20

40

60

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100

#

#

*

*

*

Volu

mes

(ml)

LVEDV LVESV LAV

Effects of Chronic AF and CP on Cardiac Volumes

Time in weeks

0 6-8 10-12

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

0

50

100 -3000

0

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-505

101520

0

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100 -3000

0

3000

-505

101520

ECG

RV electrogram

dp/dt (mmHg/s)

LV Pressure (mmHg)

Aortic Flow (L/min)

Coupled Pacing OFF

Coupled Pacing ON

Hemodynamic TracingsHemodynamic Tracings

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

My studies on Chronic Coupled PacingMy studies on Chronic Coupled Pacing

Are the effects of persistent coupled pacing (CP) Are the effects of persistent coupled pacing (CP) beneficial?beneficial?

Answer: Yes.Answer: Yes.

Can the effects of CP be sustained?Can the effects of CP be sustained?

Answer: Yes.Answer: Yes.

The 2The 2ndnd Pacing Paradigm (CRT+CP Pacing) Pacing Paradigm (CRT+CP Pacing)

Rather than CRT ending during episodes of AF, this Rather than CRT ending during episodes of AF, this new pacing regimen (CRT+CP) could be applied new pacing regimen (CRT+CP) could be applied desynchronized HF and AF patients.desynchronized HF and AF patients.

Briefly, CRT+CP, involves:Briefly, CRT+CP, involves:

The application of a 1st stimuli to the left ventricle and a The application of a 1st stimuli to the left ventricle and a 2nd stimuli to the right ventricle simultaneously in the same 2nd stimuli to the right ventricle simultaneously in the same manner as CRT is used clinically today manner as CRT is used clinically today

Thus, these first 2 stimulations will result in a more Thus, these first 2 stimulations will result in a more synchronized electrical activation and subsequent synchronized electrical activation and subsequent contraction of both ventricles contraction of both ventricles

And then a 3rd premature paced beat is applied to activate And then a 3rd premature paced beat is applied to activate both ventricles electrically but not mechanically for CP.both ventricles electrically but not mechanically for CP.

Atrial Fibrillation (AF) in Heart Failure Atrial Fibrillation (AF) in Heart Failure (HF) Patients(HF) Patients

AF and HF frequently coexist.AF and HF frequently coexist. HF promotes AF.HF promotes AF. And AF may cause or aggrevate HF.And AF may cause or aggrevate HF. 25% of HF patients also have AF25% of HF patients also have AF 34% of HF patients have LBBB.34% of HF patients have LBBB. 30% of above these patients also have AF.30% of above these patients also have AF.

Eur Heart J. 2002 Nov; 23(21): 1692-8.Eur Heart J. 2002 Nov; 23(21): 1692-8.

Electrical Activations of the Normal HeartElectrical Activations of the Normal Heart

www.physiome.org www.physiome.org

RV Apex PacingRV Apex Pacing Left Bundle Branch BlockLeft Bundle Branch Block

Prinzen et al, 2000Prinzen et al, 2000

Clinical Significance of CRTClinical Significance of CRT

CRT has been established as an effective pacing CRT has been established as an effective pacing therapy in most heart failure patients with left bundle therapy in most heart failure patients with left bundle branch block.branch block.

Heart failure patients with drug-refractory atrial Heart failure patients with drug-refractory atrial fibrillation may require ablation therapy to benefit fibrillation may require ablation therapy to benefit from CRT. from CRT.

Current Pacing TherapiesCurrent Pacing Therapies

Biventricular Pacing Biventricular Pacing (CRT) consists of:(CRT) consists of:

A pacemaker A pacemaker generator (#1)generator (#1)

A right atrial pacing A right atrial pacing wire (#2)wire (#2)

A right ventricular A right ventricular pacer wire (#3)pacer wire (#3)

And a coronary sinus And a coronary sinus (LV) pacing wire (#4).(LV) pacing wire (#4).

Circulation. 2005 Sep 27;112(13):e236-7. Circulation. 2005 Sep 27;112(13):e236-7.

AF in HF Patients with Left Bundle AF in HF Patients with Left Bundle Branch Block (LBBB)Branch Block (LBBB)

Cardiac resynchronization therapy (CRT) is effective Cardiac resynchronization therapy (CRT) is effective in many HF w/ LBBB.in many HF w/ LBBB.

CRT is not effective in some HF patients despite CRT is not effective in some HF patients despite resynchronization (non-responders) even during resynchronization (non-responders) even during sinus rhythm.sinus rhythm.

CRT can only be effective if the ventricular rate is CRT can only be effective if the ventricular rate is controlled during AF.controlled during AF.

CP added to CRT could be an effective means of rate CP added to CRT could be an effective means of rate control. control.

The CRT+CP Pacing ParadigmThe CRT+CP Pacing Paradigm

Our research to date has demonstrated that the Our research to date has demonstrated that the addition of a coupled paced beat significantly addition of a coupled paced beat significantly increased:increased:

The left ventricular ejection fraction (LVEF) The left ventricular ejection fraction (LVEF)

And the left ventricular strain as wellAnd the left ventricular strain as well

This pacing paradigm may improve overall This pacing paradigm may improve overall myocardial performance in HF and AF patients. myocardial performance in HF and AF patients.

Animal preparationAnimal preparation

RA electrodeRA electrode

RV electrode

Epicardial EchocardiographyEpicardial Echocardiography

LV electrodeLV electrode

Vagal electrodeVagal electrode

Baseline

N=6

Sinus Rhythm

Step 1

Experimental protocol

Atrial

Fibrillation

Step 2

Step 3

Step 4

Step 5

CRT+ CP

N=6

CRT-VS

N=3

CRT

N=6

RV pacing

N=6

Atrial pacing

N=6

Baseline

N=6

Sinus Rhythm

Step 1

Experimental protocol

Atrial

Fibrillation

Step 2

Step 3

Step 4

Step 5

CRT+ CP

N=6

CRT-VS

N=3

CRT

N=6

RV pacing

N=6

Atrial pacing

N=6

Right atrium

Right ventricle

VS

Left ventricle

CPCRT CPCRT

VS

RR

RV pacingHR=178bpm

Step 2

QRS=120msSD=16%

CRT+CPHR=110bpm

Step 4

QRS=90msSD=5%

CRT-VS HR=110bpm

Step 5

QRS=90msSD=3%

-12%-19%-7%-14%

BaselineHR=103bpm

Step 1

QRS=80msSD=5%

Atrial FibrillationSinus rhythm

Dog #176

CRTHR=197bpm

Step 3

QRS=90msSD=5%

-3%

Use of CRT+CP on CRT Non-respondersUse of CRT+CP on CRT Non-responders

CRT+CP may convert non-responders to responders CRT+CP may convert non-responders to responders in HF patients in sinus rhythm.in HF patients in sinus rhythm.

The addition of CP to CRT permits effective CRT to The addition of CP to CRT permits effective CRT to continue when AF and the subsequent rapid continue when AF and the subsequent rapid ventricular contractions occurs via its effective rate ventricular contractions occurs via its effective rate control mechanism.control mechanism.

Sensors to Control PacingSensors to Control Pacing

Presently measuring single site pressure, thoracic Presently measuring single site pressure, thoracic impedance, and the rate of cardiac electrical impedance, and the rate of cardiac electrical activation but not the rate of flow are used as activation but not the rate of flow are used as sensors to control cardiac pacemakers.sensors to control cardiac pacemakers.

Which parameter is best to use to control pacing?Which parameter is best to use to control pacing?

Simulation of Flow in the Great Cardiac VeinSimulation of Flow in the Great Cardiac Vein

I developed mock coronary venous circulatory I developed mock coronary venous circulatory circuits which tested whether the differential circuits which tested whether the differential pressure obtained in this system is representative of pressure obtained in this system is representative of flow.flow.

DATAQDATAQ®® software was used to acquire the raw data software was used to acquire the raw data obtained from my mechanical models.obtained from my mechanical models.

Then OriginThen Origin®® software was used to plot the software was used to plot the relationship between differential pressure and flow.relationship between differential pressure and flow.

Pressure Recording (Millar Sensors)Pressure Recording (Millar Sensors)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

30

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110

Change in Pressure (mmHg)

Flo

w (

ml/m

)

Trial #3-performed on 8-20-07

Mock II Circulatory Circuit Mock II Circulatory Circuit (Results)(Results)

Photograph of the Mock II Circulatory Photograph of the Mock II Circulatory Circuit Circuit

Conclusions of My Simulation StudiesConclusions of My Simulation Studies

My simulation results demonstrated that flow could My simulation results demonstrated that flow could be represented by measuring differential pressure.be represented by measuring differential pressure.

As flow is increased in the great cardiac vein, the As flow is increased in the great cardiac vein, the differential pressure (GCV1 – GCV2) would change differential pressure (GCV1 – GCV2) would change the balance of a Wheatstone bridge circuit the balance of a Wheatstone bridge circuit configuration, a low energy monitor.configuration, a low energy monitor.

This with this flow measurement and other cardiac This with this flow measurement and other cardiac measurements, optimizing the pacing paradigms measurements, optimizing the pacing paradigms such as CRT and or our novel pacing paradigm such as CRT and or our novel pacing paradigm (CRT+CP) could be achieved.(CRT+CP) could be achieved.

AcknowledgementsAcknowledgements

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