long term effects of rv pacing tehran arrhythmia center april 2006

Long Term Effects of RV Pacing

Tehran Arrhythmia CenterApril 2006

To Pace or not to Pace?

Pacing the right ventricle

Deleterious Effects of RV Apical Pacing

Altered left ventricular electrical and mechanical Altered left ventricular electrical and mechanical activationactivation

Altered ventricular functionAltered ventricular function Less work produced for given LVEDVLess work produced for given LVEDV Delayed papillary muscle activation Delayed papillary muscle activation Valvular insufficiency Valvular insufficiency

RemodelingRemodeling Modified regional blood flow patternsModified regional blood flow patterns Increased oxygen consumption without increase in blood flowIncreased oxygen consumption without increase in blood flow

60% change in blood flow between early and later activated regions60% change in blood flow between early and later activated regions

Abnormal thickening of LV wallAbnormal thickening of LV wall Cellular disarrayCellular disarray

Fibrosis (away from pacing lead location)Fibrosis (away from pacing lead location) Fat depositionFat deposition CalcificationCalcification Mitochondrial abnormalitiesMitochondrial abnormalities

Altered left ventricular mechanical activation

Potential detrimental effect of RV apical pacing in Potential detrimental effect of RV apical pacing in the form of pacing-induced LV dyssynchrony the form of pacing-induced LV dyssynchrony secondary to the abnormal activation sequencesecondary to the abnormal activation sequence

Pacing-induced abnormalities of myocardial Pacing-induced abnormalities of myocardial blood flowblood flow

RV apical pacing alters LV papillary muscle RV apical pacing alters LV papillary muscle function, changing the timing sequence of the function, changing the timing sequence of the mitral valve apparatus, thus causing mitral valve apparatus, thus causing MR.

Altered LV Electrical Activation Pattern

Two break-out locations on LV endocardiumTwo break-out locations on LV endocardiumInferior border of the mid-septumInferior border of the mid-septum

Superior basal aspect of free wallSuperior basal aspect of free wall Latest activationLatest activation

Base of the inferior posterior wallBase of the inferior posterior wall Muscular conduction (less Purkinje Muscular conduction (less Purkinje

fiber density)fiber density)

Cassidy DM, et al. Circ 1984;70:37-42 Single break-out location on LV endocardiumSingle break-out location on LV endocardium

Similar to left bundle branch blockSimilar to left bundle branch block Latest activationLatest activation

Similar to intrinsicSimilar to intrinsic

Inferioposterior baseInferioposterior base

Vassallo JA, et al. JACC 1986;7:1228-33

Normal Sinus Rhythm Right Ventricular Apical Pacing

Apical Pacing Histopathology

Karpawich (1990) – PediatricKarpawich (1990) – Pediatric Canine ModelCanine Model LV myofibril disarray was found after 4 months LV myofibril disarray was found after 4 months

of pacing from RV apexof pacing from RV apex 90 degree misalignment of adjacent fibers (stress related?)90 degree misalignment of adjacent fibers (stress related?)

Also noted appearance of prominent Purkinje Also noted appearance of prominent Purkinje cells in subendocardium, variable-sized cells in subendocardium, variable-sized mitochondria, and dystrophic calcificationmitochondria, and dystrophic calcification

Karpawich (1999) – Pediatric PatientsKarpawich (1999) – Pediatric Patients Myofibril hypertrophy, intracellular vacuolation, Myofibril hypertrophy, intracellular vacuolation,

degenerative fibrosis, and fatty deposits in the degenerative fibrosis, and fatty deposits in the LV after more than 3 years RV apical pacingLV after more than 3 years RV apical pacing

Independent of paced time, patient age, epi- or Independent of paced time, patient age, epi- or endocardial electrode placement, and modeendocardial electrode placement, and mode

Adomain (1986)Adomain (1986) Myofibril disarray was found in 75% of canine hearts after 3 months of pacing from Myofibril disarray was found in 75% of canine hearts after 3 months of pacing from

RV apexRV apex Greatest at base of left ventricular free wallGreatest at base of left ventricular free wall

25X: Karpawich PP, et al. Am Heart J 1990;119:1077-83

Clinical Studies of Adverse Effects of RV Pacing

Pace,Vol.29, March 2006

Clinical Studies of Adverse Effects of RV Pacing

Heart Rhythm, Vol 2, No 2, January 2005

Danish Study Overview

• Hypothesis:Hypothesis:In patients with SND, atrial pacing (AAI) will

result in less atrial fibrillation, thromboembolism, heart failure and overall mortality than ventricular pacing (VVI).

Study DesignStudy Design::

Single center, prospective, randomization of patients referred for first pacemaker implant

Primary:Primary:

--MortalityMortality

--Cardiovascular deathCardiovascular death Secondary:Secondary:

-Atrial fibrillation-Atrial fibrillation

-Thromboembolic events-Thromboembolic events

-Heart failure-Heart failure

-AV block-AV block

Danish Study Endpoints

Danish Study Patient Characteristics

AAl Group VVI Group

No. of PatientsNo. of Patients 110110 115115

Age, yAge, y 76 76 ++ 8 8 75 75 ++ 8 8

WomenWomen 7373 6969

MenMen 3737 4646

Sinus bradycardiaSinus bradycardia 1818 1818

Sino atrial blockSino atrial block 4949 4646

Brady-Tachy SyndromeBrady-Tachy Syndrome 4343 5151

Danish Study Patient Characteristics

AAl Group VVI Group

NYHA Class I 79 92

NYHA Class II 24 20

NYHA Class III 7 3

NYHA Class IV 0 0

Digoxin 22 11*

Beta Blocker 7 1

Calcium Blocker 13 11

Antiarrhythmic drugs 12 6

Furosemide, mg/d 32 + 51 23 + 39

Aspirin 48 46

Warfarin 6 1* P = 0.04, atrial versus ventricular group

Danish Study Overall survival by pacing mode

Andersen H, et al. Lancet 1997; 350: 1210-16.

p = 0.045

Atrialpacing

Ventricularpacing

Time (years)

0 2 4 6 8 10

0

0-2

0-4

0-6

0-8

1-0

Number of patients at riskduring follow-up

Atrial

Ventricular

110

115

102

103

97

96

92

91

82

80

59

56

38

29

86

85

13

12

Danish Study Cardiovascular death by pacing mode


Time (years)

p = 0.0065

Atrial pacing

Ventricular pacing

0 2 4 6 8 10

0

0-2

0-4

0-6

0-8

1-0C

um

ula

tive

su

rviv

al


Atrial

Ventricular

110

115

102

103

97

96

92

91

82

80

59

56

38

29

86

85

13

12

Danish Study Cumulative risk of PAF by pacing mode


0

0-2

0-4

0-6

0-8

1-0

p = 0.012

Atrialpacing

Ventricularpacing

Time (years)

0 2 4 6 8 10

Pro

port

ion

w

ith

ou

t A

F


Atrial

Ventricular

110 100 92 82 73 69 46 21 9

115 99 86 76 61 49 34 10 2

Danish Study Cumulative risk of chronic AF by pacing mode


p = 0.004

Atrialpacing

Ventricularpacing

Time (years)

0 2 4 6 8 10Pro

port

ion

wit

hou

t ch

ron

ic A

F

0

0-2

0-4

0-6

0-8

1-0


Atrial pacing

Ventricular pacing

110 102 96 91 80 74 49 26 10

115 102 92 84 75 65 41 18 5

Danish Study Mortality as a result of CHF


1,00

,80

,600 2 4 6 8 10

Atrial pacing

Ventricular pacing

p = 0.18

Time (years)

Su

rviv

al w

ith

ou

t d

eath

fro

m C

HF

AAI: 110 102 97 92 86 82 59 38 13VVI: 115 103 96 91 85 80 56 29 12

Danish Study CHF Analysis

NYHA classification was higher in the ventricular group NYHA classification was higher in the ventricular group vs. the atrial group (p=0.010) at long term follow up.vs. the atrial group (p=0.010) at long term follow up.

During follow up, NYHA class worsened in the ventricular During follow up, NYHA class worsened in the ventricular group vs. the atrial group (p<0.005)group vs. the atrial group (p<0.005)

Mean dose of diuretics increased in the ventricular group Mean dose of diuretics increased in the ventricular group vs. the atrial group (p=0.033)vs. the atrial group (p=0.033)

Danish StudyConclusions

In patients with SND, atrial pacing is In patients with SND, atrial pacing is associated with a significantly associated with a significantly

higher higher survival, less atrial fibrillation, survival, less atrial fibrillation, fewer fewer thromboembolic complications, thromboembolic complications, and and less heart failure compared to less heart failure compared to ventricular pacing.ventricular pacing.

Canadian Trial of Physiologic Pacing

CTOPP

CTOPP Study Overview

Hypothesis:Hypothesis:-Physiologic (DDDR or AAIR) pacing is superior to -Physiologic (DDDR or AAIR) pacing is superior to single-chamber (VVIR) pacing because it is single-chamber (VVIR) pacing because it is associated with lower risks of atrial fibrillation, stroke, associated with lower risks of atrial fibrillation, stroke, and death.and death.

Study Design:Study Design:-32 Canadian centers-32 Canadian centers

-Prospective, randomized-Prospective, randomized

CTOPP Study Endpoints

Primary:Primary:-Stroke or death due to cardiovascular causes-Stroke or death due to cardiovascular causes

Secondary:Secondary:-Death from any cause-Death from any cause

-Atrial fibrillation-Atrial fibrillation

-Hospitalization for heart failure-Hospitalization for heart failure

CTOPP Study ProtocolPatients undergoing

first IPG implant

n=2,568

Ventricular-Based Pacing

n = 1,474

Physiologic Pacing

n = 1,094

Follow for an average of 3 years and compare:

•Stroke or death due to cardiovascular causes

•Death from any cause

•Atrial fibrillation

•Hospitalization for HF

CTOPPCumulative Risk of Stroke or

Cardiovascular Death C

um

ula

tive R

isk

Years after Randomization

0 1 2 3 4

0

0.1

0.2

0.3

0.4

P = 0.33

Ventricular pacing

Physiologic pacing

Connolly S et al. N Engl J Med 2000; 342: 1385-91.

No. at risk:Ventricular pacing 1474 1369 1259 847 366Physiologic pacing 1094 1005 954 637 287

CTOPP Cumulative Risk of any AF

Cu

mu

lati

ve R

isk

0

0.1

0.2

0.3

0.4

0 1 3 4

Years after Randomization

P = 0.05

Ventricular pacing

Physiologic pacing

Connolly S et al. N Engl J Med 2000; 342: 1385-91.

No. at risk:Ventricular pacing 1474 1276 1127 731 303Physiologic pacing 1094 936 857 559 250

2

CTOPP Cumulative Risk of Chronic AF

Skanes A, et al. J Am Coll Cardiol 2001; 38: 167-72.

Cu

mu

lati

ve R

isk

Years Since Randomization

0 1 2 3 4

0.0

0.1

0.2

0.3

0.4

Number V 1474 1317 1180 779 331At Risk P 1094 975 906 601 269

P = 0.016

Ventricular pacing

Physiologic pacing

CTOPPConclusions

Physiologic pacing (dual-chamber or atrial) Physiologic pacing (dual-chamber or atrial) provides little benefit over ventricular pacing for provides little benefit over ventricular pacing for the prevention of stroke or death due to the prevention of stroke or death due to cardiovascular causes.cardiovascular causes.

Physiologic pacing does provide a reduction in Physiologic pacing does provide a reduction in the relative risk of paroxysmal and persistent the relative risk of paroxysmal and persistent AF.AF.

A Mode Selection Trial MOST Sub-Study

Effect of Pacing Mode and Cumulative Percent Time Ventricular Paced on Heart Failure and Atrial Fibrillation in Patients with Sinus Node

Dysfunction and Baseline QRS Duration <120 Milliseconds in MOST

Michael O. Sweeney, Anne S. Hellkamp, Arnold J. Greenspon, Robert Mittleman, Michael O. Sweeney, Anne S. Hellkamp, Arnold J. Greenspon, Robert Mittleman, John McAnulty, Kenneth Ellenbogen, Roger Freedman, Kerry L. Lee, Gervasio A. John McAnulty, Kenneth Ellenbogen, Roger Freedman, Kerry L. Lee, Gervasio A.

Lamas, for the MOST InvestigatorsLamas, for the MOST InvestigatorsCirculation 2003, in pressCirculation 2003, in press

MOST Sub-Study

Background:Background: DDDR pacing preserves AV synchrony and reduces DDDR pacing preserves AV synchrony and reduces

CHF compared to VVIR pacing in SND.CHF compared to VVIR pacing in SND. DDDR pacing results in prolonged QRS durations DDDR pacing results in prolonged QRS durations

(QRSd) due to ventricular desynchronization.(QRSd) due to ventricular desynchronization.

Hypothesis:Hypothesis: DDDR pacing often results in prolonged QRS DDDR pacing often results in prolonged QRS

duration (QRSd) due to ventricular desynchronization duration (QRSd) due to ventricular desynchronization in patients with normal baseline QRSd and may in patients with normal baseline QRSd and may increase risk of heart failure and atrial fibrillationincrease risk of heart failure and atrial fibrillation..

Sweeney MO, et al. Circulation 2003, in press

Methods:Methods: Baseline QRSd obtained from 12-lead EKG prior to Baseline QRSd obtained from 12-lead EKG prior to

IPG implant in MOST (a 2,010 patient, 6-year IPG implant in MOST (a 2,010 patient, 6-year randomized trial of DDDR vs. VVIR pacing in SND).randomized trial of DDDR vs. VVIR pacing in SND).

Cumulative % time ventricular paced was determined Cumulative % time ventricular paced was determined from stored pacemaker diagnostic data.from stored pacemaker diagnostic data.

Baseline QRSd <120 ms was observed in 1332 Baseline QRSd <120 ms was observed in 1332 patients; 702 were randomized to DDDR; 640 to VVIR.patients; 702 were randomized to DDDR; 640 to VVIR.

MOST Sub-Study


0

2

4

6

8

10

12

14

16

Rate

of H

eart

Failure

H

osp

italiza

tion

< 10% Cum VP >90% Cum VP

DDDR VVIR

MOST Sub-Study: Results Cum%VP was greater in DDDR (90%) vs. VVIR (51%). Cum%VP was greater in DDDR (90%) vs. VVIR (51%).

The rates of CHF hospitalization increased with Cum%VP:The rates of CHF hospitalization increased with Cum%VP:


0

1

2

3

4

5

6

7

0 20 40 60 80 100

Cum% VP

Ris

k o

f H

FH

rela

tive t

oD

DD

R p

ati

ent

wit

h C

um

%VP=

0


MOST Sub-study: Risk of HFH Relative to a DDDR Patient with

Cum % VP = 0•Risk of HFH increased between 0% and 40% Cum VP, but was level at Cum%VP above 40%.

•Risk can be reduced to about 2% if ventricular pacing is minimized.

0

1

2

3

4

5

6

7

0 20 40 60 80 100

Cum% VP

Ris

k o

f H

FH

rela

tiv

e t

o

VVIR

patie

nt w

ith C

um

%VP=

0


MOST Sub-Study: Risk of HFH Relative to a VVIR Patient with

Cum % VP = 0•Risk of CHF was constant between 0% and 80% Cum VP and increased by as much as 2.5-fold when Cum%VP exceeded 80%.

•Risk cannot be reduced regardless of minimization of ventricular pacing.

Cum% Vp at 30 days and subsequent HFH eventsDDDR/ Normal QRS

0.8

0.825

0.85

0.875

0.9

0.925

0.95

0.975

1

0 12 24 36 48

Months

Pro

port

ion e

vent-

free

Cum% Vp <= 40

Cum% Vp > 40

P=0.047


MOST Sub-Study

Cum% Vp at 30 days and subsequent HFH eventsVVIR/ Normal QRS

0.8

0.825

0.85

0.875

0.9

0.925

0.95

0.975

1

0 12 24 36 48

Months

Pro

port

ion e

vent-

free

Cum% Vp <= 80

Cum% Vp > 80

P=0.0046


MOST Sub-Study

Higher rates of CHF hospitalization were Higher rates of CHF hospitalization were associated with higher Cum% VP: associated with higher Cum% VP: - - Cum % VP<10% was associated with the lowest rates of

CHF hospitalization (DDDR 2%, VVIR 7%).- Cum % VP >90% was associated with the highest rates

of CHF hospitalization (DDDR 12%, VVIR 16%).

Ventricular pacing in the DDDR mode more than Ventricular pacing in the DDDR mode more than 40% confers a 3-fold increased risk of heart 40% confers a 3-fold increased risk of heart failure hospitalization but can be reduced to failure hospitalization but can be reduced to about 2% if ventricular pacing is minimized.about 2% if ventricular pacing is minimized.


MOST Sub-studyConclusions: CHF

0

1

2

3

4

0 20 40 60 80 100

Cum% VP

Ris

k o

f A

F re

lati

ve t

oD

DD

R p

ati

ent

wit

h C

um

%VP=

0

0

1

2

3

4

0 20 40 60 80 100

Cum% VPR

isk o

f A

F re

lati

ve t

o

VVIR

pati

ent

wit

h C

um

%VP=

0


Risk of AF increases linearly with Cum%VP up to 80-85% in both DDDR and VVIR

MOST Sub-study: AF Risk

Cum% Vp in first 30 days and subsequent AF eventsDDDR/ Normal QRS

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0 12 24 36 48

Months

Pro

port

ion e

vent-

free

%Vp <=40%%Vp 40-70%%Vp 70-90%



Cum% Vp in first 30 days and subsequent AF eventsVVIR/ Normal QRS

0.55

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0 12 24 36 48

Months

Pro

port

ion e

vent-

free

%Vp <=40%%Vp 40-70%%Vp 70-90%



• Relationship between risk of AF and CumRelationship between risk of AF and Cum%VP was similar between pacing modes:%VP was similar between pacing modes:

– Risk of AF showed a linearly increasing relationship with increased Cum%VP from 0% pacing up to 80-85% pacing in both pacing modes.

– Within this range, the risk of AF increased by 1% for each 1% increase in Cum%VP (DDDR hazard ratio 1.01 [1.004, 1.022] p=0.012; VVIR 1.01 [1.001, 1.01], p=0.025).Sweeney MO, et al. Circulation 2003, in press

MOST Sub-studyConclusions: AF

The adverse effects of forced ventricular desynchronization probably explain the difficulty in demonstrating a mortality and stroke benefit with physiologic (DDDR) compared to ventricular (VVIR) pacing in randomized trials.

These investigators concluded that RV pacing imposes ventricular dyssynchrony even when AV synchrony is preserved, thereby increasing the risk of heart failure and AF.


MOST Sub-Study:Overall Conclusions

Dual-Chamber and VVI Implantable Defibrillator

Trial

DAVID

DAVID Trial Overview

Hypothesis:Hypothesis:- - Aggressive management of LV dysfunction with optimized drug therapy and with dual chamber pacing could improve the combined endpoint of total mortality and hospitalization for heart failure, compared to similarly optimized drug therapy supported by ventricular backup pacing.

Study design:Study design:- - Single blind, multicenter, parallel group, randomized trial comparing DDDR (70 bpm lower rate) vs. VVI (40 bpm lower rate) pacing modes

Wilkoff B, et al. JAMA. 2002; 288: 3115-3123.

DAVID Trial Protocol

760 assessed for eligibility250 excluded 149 Did not meet Rx criteria 55 refused 46 Other

510 eligible4 Not randomized 2 Required pacing 1 Inadequate defibrillation threshold 1 Decided not to implant

506 randomized

VVI-40 (n=256) DDDR-70 (n= 250)

• 1 had pacing mode set to DDD• 1 LTF• 10 Discontinued intervention• 5 Bradycardia• 1 CHF and AF• 1 Brady induced Torsade• 1 Heart Tx workup• 1 AF w rapid V response• 1 multiple shocks due to double counting

• 3 had pacing mode set to VVI• 2 LTF• 5 Discontinued intervention• 1 Angina• 1 CHF and Lead Failure• 1 CHF Hospitalization• 1 Exacerbation of VT• 1 Lead Migration


DAVID Trial Results

VVI-40 DDDR-70 HR (p-value, adj.)

CHF Hospitalization or Death

16.1% 26.7% 1.61(p = 0.03)

CHF Hospitalization

13.3% 22.6% 1.54(p=0.07)

Death 6.5% 10.1% 1.61(p=0.15)


DAVID


VVI-40VVI-40 DDDR-70DDDR-70 P-valueP-value

6-month EKG:

SinusSinus 97.1%97.1% 42.0%42.0% <0.001<0.001

V-pacedV-paced 2.9%2.9% 55.7%55.7% <0.001<0.001

QRSdQRSd 117 117 ++ 29 ms 29 ms 134 134 ++ 39 ms 39 ms <0.001<0.001

Cum % VP:

3 months3 months 1.5% 1.5% ++ 8.0% 8.0% 57.9% 57.9% + + 35.8% 35.8% <0.001<0.001

6 months6 months 0.6% 0.6% ++ 1.7% 1.7% 59.6% 59.6% ++ 36.2% 36.2% <0.001<0.001

12 months12 months 3.5% 3.5% ++ 14.9% 14.9% 58.9% 58.9% ++ 36.0% 36.0% <0.001<0.001

DAVID Conclusions

Bradycardia pacing operation in dual-Bradycardia pacing operation in dual-chamber ICDs should be optimized for chamber ICDs should be optimized for individual patients.individual patients.-RV pacing in patients with LV dysfunction and no

bradycardia indication for pacing can be harmful.-Programming of dual chamber devices to backup

ventricular pacing is justified in this patient population.


Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation

(The PAVE Study)

The The PAVEPAVE study was a prospective, study was a prospective, patient-blinded, randomized, multicenter patient-blinded, randomized, multicenter clinical trial comparing chronic biventricular clinical trial comparing chronic biventricular to right ventricular pacing in patients with to right ventricular pacing in patients with chronic atrial fibrillation undergoing AV node chronic atrial fibrillation undergoing AV node ablation.ablation.

PAVE Study

(J Cardiovasc Electrophysiol, Vol. 16,pp. 1160-1165, November 2005)

PAVE Study

Ablation of the AV node was permitted up to 4 Ablation of the AV node was permitted up to 4 weeks post-implantationweeks post-implantation

Pacemaker was reprogrammed to a VVIR mode Pacemaker was reprogrammed to a VVIR mode with a lower rate of 80 ppm for the next 4 weeks with a lower rate of 80 ppm for the next 4 weeks so to mitigate the risk of polymorphic ventricular so to mitigate the risk of polymorphic ventricular tachycardia. All patients received rate-esponsive tachycardia. All patients received rate-esponsive pacing, with the sensor optimized 4 weeks after pacing, with the sensor optimized 4 weeks after implantationimplantation..

6-minute hallway walk distance


6-minute hallway walk distance

For patients with symptomatic heart failure For patients with symptomatic heart failure (NYHA Class II or III), the hallway walk (NYHA Class II or III), the hallway walk distance measured at 6 months was 53% distance measured at 6 months was 53% greater for patients randomized to greater for patients randomized to biventricular pacing in comparison to biventricular pacing in comparison to patients receiving right ventricular pacing patients receiving right ventricular pacing (78.9 ± 92.2 m vs 51.6 ± 86.2 m, P = 0.01).(78.9 ± 92.2 m vs 51.6 ± 86.2 m, P = 0.01).

LV ejection Fraction


NYHA Class


Mortality in PAVE Study

There were 13 deaths (8%) in the There were 13 deaths (8%) in the biventricular pacing group and 19 deaths biventricular pacing group and 19 deaths (18%) in the right ventricular pacing patients(18%) in the right ventricular pacing patients

Conclusion of PAVE Study

The findings of the PAVE study suggest that, in order to avoid the adverse effects of cardiac dyssynchrony generated by RV pacing, a biventricular pacing should be considered for patients who require AV node ablation for management of atrial fibrillation and who have a left ventricular ejection fraction ، 45ـ % or who have NYHA Class II or III symptoms.

Multicenter Automatic Defibrillator Trial II (MADIT II) study

During a 20-month follow-up, patients (n = 369) with ICD.During a 20-month follow-up, patients (n = 369) with ICD.

ICD programming was not standardized, the development ICD programming was not standardized, the development of new or worsened CHF was more common in the ICD of new or worsened CHF was more common in the ICD arm (19.9%) compared with the conventionally treated arm (19.9%) compared with the conventionally treated patients (14.9%) . patients (14.9%) .

The higher incidence of CHF in the ICD group was in all The higher incidence of CHF in the ICD group was in all likelihood due to ventricular desynchronization rather than likelihood due to ventricular desynchronization rather than myocardial injury from ICD shocksmyocardial injury from ICD shocks

MADIT II

Approximately 40% of the had dual chamber Approximately 40% of the had dual chamber units (mostly set at DDD 60 to 70 beats/min) and units (mostly set at DDD 60 to 70 beats/min) and 60% had single-chamber units (mostly set at VVI 60% had single-chamber units (mostly set at VVI 60 beats/min). 60 beats/min).

Patients with dual-chamber units paced the Patients with dual-chamber units paced the ventricle about 85% of the time, whereas those ventricle about 85% of the time, whereas those with single-chamber units paced the ventricle with single-chamber units paced the ventricle only 15% of the time. only 15% of the time.

MADIT II

During a 20-month follow-up, patients (n = 369) having high cumulative RV pacing (>50%), had a higher incidence of new or worsened heart failure and heart failure or death compared to patients with infrequent right ventricular pacing.

Conclusion of MADIT II study

The slightly increased occurrence of heart The slightly increased occurrence of heart failure was clearly associated with dual-failure was clearly associated with dual-chamber ICD units having a higher chamber ICD units having a higher frequency of ventricular pacing.frequency of ventricular pacing.

Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure

(COMPANION) trial

Cardiac resynchronization therapy with left Cardiac resynchronization therapy with left ventricular pacing decreased the combined ventricular pacing decreased the combined risk of death from any cause or first risk of death from any cause or first hospitalization in patients with advanced hospitalization in patients with advanced heart failure and prolonged QRS interval.heart failure and prolonged QRS interval.

COMPANION trial

These investigators concluded that These investigators concluded that reduction in the combined endpoints of reduction in the combined endpoints of death and heart failure hospitalizations was death and heart failure hospitalizations was primarily due to cardiac resynchronization primarily due to cardiac resynchronization therapy (CRT), since CRT and CRT with an therapy (CRT), since CRT and CRT with an ICD resulted in similar effects.ICD resulted in similar effects.

What are the lessons learned from clinical trials?

• Conventional RV apical pacing results in “forced” ventricular desynchronization, which mimics LBBB and has adverse effects on ventricular structure and function.

Goals and Strategies to Optimize Ventricular Pacing

The New Goals of Pacing Therapy

Several approaches have been Several approaches have been investigated:investigated:

Manipulation of DDDR timing cycles (AV Manipulation of DDDR timing cycles (AV delay) to minimize unnecessary RV pacingdelay) to minimize unnecessary RV pacing

Use of AAI or DDI/R pacing modesUse of AAI or DDI/R pacing modes Novel pacing algorithmsNovel pacing algorithms Alternate RV pacing sitesAlternate RV pacing sites

Long AV Delays During Dual Chamber Pacing

Long AV delays may reduce Long AV delays may reduce unnecessary ventricular pacing and unnecessary ventricular pacing and maintain normal ventricular activation maintain normal ventricular activation sequence but require reliable AV nodal sequence but require reliable AV nodal conduction.conduction.

Long AV Delays During Dual Chamber Pacing: An Incomplete Solution

Long AV delays may impose limitations on Long AV delays may impose limitations on optimal DDDR operation:optimal DDDR operation:-Reduced 2:1 block point due to increased TARP-Abandonment of mode-switching or significantly delayed AF

recognition-Susceptibility to endless loop tachycardias

Long AV delays do not sufficiently reduce ventricular pacing

Two approaches to programming long AV delays Two approaches to programming long AV delays to permit native ventricular activation:to permit native ventricular activation:

1. AV delays > resting PR intervals1• AV delays > resting PR intervals (22224 ms vs. 18423 ms)• Mean time Vp for all patients was 80%; > 50% for 88%

2. Long fixed AV delay (300 ms)2-3• Mean time Vp 17.7% overall but 39% in nearly 50% of patients• Resting PQ interval (17728 vs. 20438), atrial stimulus-Q

interval at 100 bpm (21340 vs. 22049) or AV delay (2993.2 vs. 28821) did not predict Vp

• High incidence of endless loop tachycardia• Can be reduced if rate-adaptive AV delays are used

1 Sgarbossa E et al PACE 1993; ;16:872A. 2 Nielsen JC et al PACE 1997:20:1574A. 3 Nielsen JC et al Europace 1999;1:113-120

AAI Pacing: Too Risky?

• AAI pacing preserves a normal ventricular AAI pacing preserves a normal ventricular activation sequence but requires stable long-activation sequence but requires stable long-term AV conduction and sinus rhythmterm AV conduction and sinus rhythm

• SND is a spectrum of electrical disorders that SND is a spectrum of electrical disorders that includes AF and AV blockincludes AF and AV block

• AAI pacing is ineffectual for ventricular AAI pacing is ineffectual for ventricular bradycardia duringbradycardia during– Paroxysmal and permanent AF– AV block

Development of Persistent (Complete) AV Block in Studies of Pacemaker Therapy for SND

Study Mean Follow-Up Time

Incidence of CHB

Annualized Incidence

Rosenqvist 1989Rosenqvist 1989(literature review)(literature review)

3 years3 years Median 2.1%Median 2.1%

Range: 0-11.9%Range: 0-11.9%

Median: 0.6%Median: 0.6%

Range: 0-4.5%Range: 0-4.5%

Andersen 1997Andersen 1997 8 years8 years 3.6%3.6% 0.6%0.6%

Brandt 1992Brandt 1992 5 years5 years 8.5%8.5% 1.8%1.8%

Sutton 1986Sutton 1986 3 years3 years 8.4%8.4% 2.8%2.8%

Rosenqvist 1986Rosenqvist 1986 2 years2 years 4.0%4.0% 2.0%2.0%

Rosenqvist 1985Rosenqvist 1985 5 years5 years 3.3%3.3% 0.7%0.7%

Hayes 1984Hayes 1984 3 years3 years 3.4%3.4% 1.1%1.1%

Development of Chronic AF in Studies of Pacemaker Therapy for SND and CHB

Study

Pacing Mode

Mean Follow-Up

Time

Incidence of AF

Annualized Incidence

Andersen 1997Andersen 1997 AAIAAI 5 years5 years 8.8%8.8% 1.8%1.8%

Sutton 1986Sutton 1986 AAIAAI 3 years3 years 4.5%4.5% 1.5%1.5%

Brandt 1992Brandt 1992 AAIAAI 5 years5 years 7.0%7.0% 1.4%1.4%

PASE 1998PASE 1998 DDDR DDDR onlyonly

18 months18 months 19.0%19.0% 12.7%12.7%

CTOPP 2000CTOPP 2000 DDDR/DDDR/

VVIRVVIR

3 years3 years 16.6%16.6% 5.5% 5.5% (DDDR)(DDDR)

DDIR Mode: A Limited Solution

Permits long AV delays without the possibility of Permits long AV delays without the possibility of upper rate limit tracking during AF (unlike DDDR).upper rate limit tracking during AF (unlike DDDR).-However, limitations of long AV delays in reducing ventricular pacing

still persist.

Unique limitations imposed by DDIR modeUnique limitations imposed by DDIR mode-Operationally VVIR during AV block if sinus rate exceeds lower rate

limit.-Competitive atrial pacing during sensor-modulation may

precipitate AF. Can be mitigated with a non-competitive atrial pacing algorithmCan be mitigated with a non-competitive atrial pacing algorithm

May be more applicable to the ICD populationMay be more applicable to the ICD population-Lower prevalence of AV block compared to conventional brady

pacing population.

Novel Pacing Algorithms to Optimize Ventricular Pacing

Current-generation devices have Current-generation devices have features that work to minimize features that work to minimize ventricular pacing in appropriate patient ventricular pacing in appropriate patient populations:populations:-Using Medtronic’s Search AV algorithm,27%

and 47.2% reductions in ventricular pacing have been observed by Silverman and Ellenbogen, respectively, in patients with 1:1 conduction.1,2

Silverman et al, NASPE 2000

Novel Pacing Algorithms toOptimize Ventricular Pacing

Minimal ventricular pacing modes can be used in Minimal ventricular pacing modes can be used in all patients, but are most effective in SND patients all patients, but are most effective in SND patients with reliable AV conduction and normal ventricular with reliable AV conduction and normal ventricular activation.activation.

Development will continue on new pacing Development will continue on new pacing algorithms which have been identified as an algorithms which have been identified as an important means of minimizing ventricular pacing.important means of minimizing ventricular pacing.

Novel Pacing Algorithms to Optimize Ventricular Pacing

Alternate Sites of Ventricular Pacing

Alternate site pacing :

- Other right ventricular sites (outflow or septal sites)

- Left ventricular sites in either unifocal or bifocal or biventricular modes.


Alternate Site Pacing

Ongoing Studies of Alternate Site Pacing


Right Ventricular Outflow Tract(RVOT) Pacing

A pooled analysis of nine prospective studies evaluating the hemodynamic effects of RVOT pacing in 217 patients indicated significant hemodynamic benefit compared with RV apical pacing.

Right Ventricular Outflow Tract(RVOT) Pacing

Among these studies, most of them reported acute hemodynamic effects, while only two studies reported long-term hemodynamic effects, with one indicating no difference between the two sites after 3 months of pacing and the other reporting a significant increase in left ventricular fractional shortening following 2 months of right ventricular outflow tract.

RV Septal Pacing

In an acute study of 14 patients receiving dual-chamber pacemaker for complete heart block, the septum was mapped to provide the narrowest QRS. The reduction of QRS duration obtained with right ventricular septal pacing correlated with homogenization of left ventricular contraction and improved systolic performance, albeit with minor differences in ejection fraction.

Shortest Distance to Purkinje Fibers?

Right Ventricular Outflow Tract (RVOT) and/or Right Ventricular Septum

Prevention of Remodeling with Septal Pacing

Karpawich (1991)Karpawich (1991)RV apical placement versus mid-RV apical placement versus mid-

septal placement septal placement Mid-septal lead position via Mid-septal lead position via

appearance of normal paced appearance of normal paced QRS (no bundle branch QRS (no bundle branch block)block)

FunctionFunction Near normal ventricular Near normal ventricular

conduction velocityconduction velocityHistologyHistology

4 month follow-up4 month follow-up No calcification, degenerative No calcification, degenerative

changes, or altered changes, or altered mitochondrial morphology in mitochondrial morphology in the septal paced groupthe septal paced group

Karpawich PP, et al. Am Heart J 1991;121:827-33

RV Apical Pacing RV Septal Pacing

LV Free Wall 4 months post Pacing

His Bundle Pacing

His bundle pacing has been shown to result in the same QRS duration and pressure development as sinus rhythm and atrial pacing and better hemodynamics than RV apex pacing.

Technical difficulties in applying such pacing relating to lead positioning, reliable capture, and long-term stability.

Need for an intact bundle branch conduction system may be a limiting factor.

His Bundle Pacing

A significant improvement in left ventricular performance was reported in 12 patients with a narrow QRS, chronic atrial fibrillation, and reduced ejection fraction (<40%).

The same investigators were successful in applying this pacing technique in 39 of 54 patients with cardiomyopathy, low ejection fraction (mean 23%), persistent atrial fibrillation, and normal QRS (<120 ms). After a mean follow-up of 42 months, 29 patients were alive with improved symptoms and ejection fraction (mean 33%).

Bifocal RV Pacing (apical and outflow tract)

Bifocal right ventricular (apical and outflow tract) pacing has been proposed for patients with heart failure where the coronary sinus approach to effect biventricular pacing turns out to be unsuccessful due to various reasons, such as failure to cannulate the os or to advance the lead.


The long-term (over a 22-month period) clinical response of 22 patients undergoing this approach has been favorable with ensuing clinical improvement.

In a subset of 50 patients with NYHA class II-III symptoms in the ROVA study, there was partial improvement reported with right ventricular bifocal pacing.


More data about the usefulness of bifocal right ventricular pacing will be provided by the ongoing, randomized, single blind, crossover study (BRIGHT), which is recruiting patients with NYHA class III heart failure, a left ventricular ejection fraction <35%, LBBB, and QRS complex ≥120 ms.

Biventricular or Left Ventricular Pacing

A few studies have compared RV apical pacing with LV or BiV pacing, which has now become the standard method to apply cardiac resynchronization therapy in patients with refractory heart failure .

Overall, patients treated with BiV pacing had significantly greater improvement in QRS duration, 6-minute walk test, and quality-of life scores compared to RV pacing therapy.


Preliminary data have indicated that there were no significant differences between single-site left ventricular pacing and biventricular pacing for cardiac resynchronization therapy suggesting that RV pacing may be redundant and left ventricular pacing alone might suffice.


Acute hemodynamic measurements in 27 patients with heart failure having an epicardial left ventricular lead indicated that left ventricular pacing alone was superior to right ventricular pacing, but also to biventricular pacing as well.

OPSITE, a prospective randomized trial, compared, in a single-blind, 3- month cross-over design, right ventricular and left ventricular pacing (phase 1) and right ventricular and biventricular pacing (phase 2). The study was performed in 56 patients affected by severely symptomatic permanent atrial fibrillation, uncontrolled ventricular rate, or heart failure. Primary endpoints were quality of life and exercise capacity, which were modestly improved mainly by biventricular, rather than left ventricular pacing.

Overall Conclusions

First, for those patients already having conventional pacing systems, particularly in the presence of LV dysfunction or heart failure, pacemaker programming should be employed to minimize RV pacing. IN patients with sinus node dysfunction but with normal atrioventricular conduction, by establishing functional AAIR pacing with use of the DDDR mode with a long atrioventricular delay (≥250 ms). However, it remains an inefficient way to reduce ventricular pacing in at least 17–32% .

Overall Conclusions

Manufacturers need to redesign their pacemakers to make such programming feasible or have the pacemakers search for atrioventricular conduction and withhold unnecessary ventricular pacing; automatic mode switching from AAIR to DDDR .

Overall Conclusions

IN patients with permanent AV block, we need to use alternate sites of pacing for those receiving new pacing systems.

For those patients who already have an implanted conventional pacemaker, either a dual-chamber pacing system in the presence of sinus rhythm or a single-chamber system in cases of permanent atrial fibrillation, we should seriously consider upgrading them to biventricular systems if moderate or severe left ventricular dysfunction is present.

The Donkey Analogy

Ventricular dysfunction limits a patient's ability to Ventricular dysfunction limits a patient's ability to perform the routine activities of daily living…perform the routine activities of daily living…

Digitalis CompoundsLike the carrot placed in front of the donkeyLike the carrot placed in front of the donkey

Diuretics, ACE InhibitorsReduce the number of sacks on the wagonReduce the number of sacks on the wagon

ß-BlockersLimit the donkey’s speed, thus saving energyLimit the donkey’s speed, thus saving energy

Cardiac Resynchronization Therapy

Increase the donkeyIncrease the donkey’s’s (heart) efficiency (heart) efficiency

Tehran Arrhythmia Clinic

www.IranEP. org

[email protected]

long term effects of rv pacing tehran arrhythmia center april 2006

Documents

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