Long Term Effects of RV Pacing

Long Term Effects of RV Pacing
Tehran Arrhythmia Center April 2006

Pacing the right ventricle
To Pace or not to Pace?

Deleterious Effects of RV Apical Pacing
Altered left ventricular electrical and mechanical activation Altered ventricular function Less work produced for given LVEDV Delayed papillary muscle activation  Valvular insufficiency Remodeling Modified regional blood flow patterns Increased oxygen consumption without increase in blood flow 60% change in blood flow between early and later activated regions Abnormal thickening of LV wall Cellular disarray Fibrosis (away from pacing lead location) Fat deposition Calcification Mitochondrial abnormalities This is a overview of some of the abnormalities that have been associated with RV apical pacing a couple of which will be discussed in more detail later in the presentation.

Altered left ventricular mechanical activation
Potential detrimental effect of RV apical pacing in the form of pacing-induced LV dyssynchrony secondary to the abnormal activation sequence Pacing-induced abnormalities of myocardial blood flow RV apical pacing alters LV papillary muscle function, changing the timing sequence of the mitral valve apparatus, thus causing MR.

Altered LV Electrical Activation Pattern
Normal Sinus Rhythm Right Ventricular Apical Pacing Electrical activation of the left ventricle differs when comparing sinus rhythm and RV apical pacing, the main difference being the presence of only a single break-out site on the LV endocardium with apical pacing. Cassidy DM, et al. Circ 1984;70:37-42 Vassallo JA, et al. JACC 1986;7: Single break-out location on LV endocardium Similar to left bundle branch block Latest activation Similar to intrinsic Inferioposterior base Two break-out locations on LV endocardium Inferior border of the mid-septum Superior basal aspect of free wall Latest activation Base of the inferior posterior wall Muscular conduction (less Purkinje fiber density)

Apical Pacing Histopathology
Adomain (1986) Myofibril disarray was found in 75% of canine hearts after 3 months of pacing from RV apex Greatest at base of left ventricular free wall Karpawich (1990) – Pediatric Canine Model LV myofibril disarray was found after 4 months of pacing from RV apex Also noted appearance of prominent Purkinje cells in subendocardium, variable-sized mitochondria, and dystrophic calcification 90 degree misalignment of adjacent fibers (stress related?) Karpawich (1999) – Pediatric Patients Myofibril hypertrophy, intracellular vacuolation, degenerative fibrosis, and fatty deposits in the LV after more than 3 years RV apical pacing Independent of paced time, patient age, epi- or endocardial electrode placement, and mode Similar to the previous slide, the altered strain patterns in the left ventricle can induce cellular and sub-cellular remodeling, as well as, fibrosis and calcification. Note: this occurs a distance from the pacing lead location. 25X: Karpawich PP, et al. Am Heart J 1990;119:

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: Study Design:
In patients with SND, atrial pacing (AAI) will result in less atrial fibrillation, thromboembolism, heart failure and overall mortality than ventricular pacing (VVI). Study Design: Single center, prospective, randomization of patients referred for first pacemaker implant

Danish Study Endpoints
Primary: -Mortality -Cardiovascular death Secondary: -Atrial fibrillation -Thromboembolic events -Heart failure -AV block

Danish Study Patient Characteristics
AAl Group VVI Group No. of Patients 110 115 Age, y 76 + 8 75 + 8 Women 73 69 Men 37 46 Sinus bradycardia 18 Sino atrial block 49 Brady-Tachy Syndrome 43 51

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 Digoxin 22 11* Beta Blocker 1 Calcium Blocker 13 11 Antiarrhythmic drugs 12 6 Furosemide, mg/d Aspirin 48 46 Warfarin * P = 0.04, atrial versus ventricular group

Danish Study Overall survival by pacing mode
Atrial pacing Ventricular Time (years) 2 4 6 8 10 0-2 0-4 0-6 0-8 1-0 Number of patients at risk during follow-up 110 115 102 103 97 96 92 91 82 80 59 56 38 29 86 85 13 12 After a mean follow-up of 3.3 years there was no difference in mortality or heart failure. Reanalysis after a mean follow-up of 5.5 years showed no difference in annualized mortality (6.4% AAI vs. 9.0% VVI) though overall mortality was less in the AAI group. Andersen H, et al. Lancet 1997; 350:

Danish Study Cardiovascular death by pacing mode
1-0 Atrial pacing 0-8 p = 0-6 Cumulative survival Ventricular pacing 0-4 Similarly, cardiovascular death was reduced in the AAI versus VVI group after 5 years of follow-up. 0-2 Time (years) 2 4 6 8 10 Number of patients at risk during follow-up Atrial Ventricular 110 115 102 103 97 96 92 91 82 80 59 56 38 29 86 85 13 12 Andersen H, et al. Lancet 1997; 350:

Danish Study Cumulative risk of PAF by pacing mode
0-2 0-4 0-6 0-8 1-0 p = 0.012 Atrial pacing Ventricular Time (years) 2 4 6 8 10 Proportion without AF Number of patients at risk during follow-up There was a lower incidence of electrocardiographically-documented paroxysmal AF in the AAI group. Andersen H, et al. Lancet 1997; 350:

Danish Study Cumulative risk of chronic AF by pacing mode
Atrial pacing Ventricular Time (years) 2 4 6 8 10 Proportion without chronic AF 0-2 0-4 0-6 0-8 1-0 Number of patients at risk during follow-up Atrial pacing Ventricular pacing After a mean follow-up of 3.3 years there was a higher incidence of chronic AF and stroke in the VVI group, however this difference was not statistically significant. Reanalysis after a mean follow-up of 5.5 years demonstrated less AF overall in AAI (24%) vs. VVI (35%) which was borderline significant (p=0.07). There were significantly fewer strokes overall in AAI (12%) vs. VVI (23%)(p=0.03) after mean follow-up of 5.5 years. Andersen H, et al. Lancet 1997; 350:

Danish Study Mortality as a result of CHF
1,00 ,80 ,60 2 4 6 8 10 Atrial pacing Ventricular pacing p = 0.18 Time (years) Survival without death from CHF AAI: VVI: Mortality as the result of congestive heart failure (CHF) during follow-up of patients randomised to atrial (AAI, N=110) or ventricular (VV I, N=115) pacing. Numbers below abscissa indicate number of patients at risk in the two treatment groups. Log-rank test was used in the comparison between groups. There was no significant difference in mortality due to heart failure between groups. Andersen H, et al. Lancet 1997; 350:

Danish Study CHF Analysis
NYHA classification was higher in the ventricular group vs. the atrial group (p=0.010) at long term follow up. During follow up, NYHA class worsened in the ventricular group vs. the atrial group (p<0.005) Mean dose of diuretics increased in the ventricular group vs. the atrial group (p=0.033) Though CHF mortality was not different between groups, CHF symptoms and diuretic usage were reduced in the AAI group.

Danish Study Conclusions
In patients with SND, atrial pacing is associated with a significantly higher survival, less atrial fibrillation, fewer thromboembolic complications, and less heart failure compared to ventricular pacing.

Canadian Trial of Physiologic Pacing CTOPP

CTOPP Study Overview Hypothesis: Study Design:
-Physiologic (DDDR or AAIR) pacing is superior to single-chamber (VVIR) pacing because it is associated with lower risks of atrial fibrillation, stroke, and death. Study Design: -32 Canadian centers -Prospective, randomized The Canadian Trial of Physiologic Pacing was a prospective, randomized comparison of VVI versus DDD pacing for all cause bradycardia in 2568 patients.

CTOPP Study Endpoints Primary: Secondary:
-Stroke or death due to cardiovascular causes Secondary: -Death from any cause -Atrial fibrillation -Hospitalization for heart failure The primary endpoints were stroke or cardiovascular death. The secondary endpoints were atrial fibrillation, all cause death, and hospitalization for CHF.

CTOPP Study Protocol Patients 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

CTOPP Cumulative Risk of Stroke or Cardiovascular Death
0.4 0.3 Ventricular pacing Cumulative Risk 0.2 P = 0.33 Physiologic pacing 0.1 There was no difference in annual rate of stroke or cardiovascular death between pacing modes (5.5%/year VVI vs. 4.9%/year DDD). Similarly, there was no significant difference in the annual rate of heart failure between pacing modes (3.5%/year VVI versus 3.1%/year DDD). 1 2 3 4 Years after Randomization No. at risk: Ventricular pacing Physiologic pacing Connolly S et al. N Engl J Med 2000; 342:

CTOPP Cumulative Risk of any AF
0.4 0.3 Cumulative Risk Ventricular pacing P = 0.05 0.2 Physiologic pacing 0.1 The reduction in the relative risk of atrial fibrillation was moderate (18%), and the absolute reduction was 3.9% over the course of the three-year average of the study. Thus, for every 100 patients treated for three years with DDD pacing rather than VVI pacing, the occurrence of atrial fibrillation would be prevented in 4 patients. The relatively late emergence of the benefit of DDD pacing with respect to the incidence of atrial fibrillation (after 2 years) suggests that a greater benefit could become evident after longer follow-up. The potential benefit of DDD pacing with respect to stroke was hypothesized to occur through a reduction in the incidence of AF. Several factors could explain the lack of effect of DDD pacing on stroke. The difference in the rates of AF between the 2 groups was small, and only a small fraction of patients with AF (5%) would be expected to have a stroke each year. Also, only about 1/3 of patients with AF received anticoagulation, which reduced the incidence of stroke. Therefore, the study did not have the power to detect a difference between the two pacing modes in their effect on stroke. 1 2 3 4 Years after Randomization No. at risk: Ventricular pacing Physiologic pacing Connolly S et al. N Engl J Med 2000; 342:

CTOPP Cumulative Risk of Chronic AF
0.4 0.3 P = 0.016 Cumulative Risk 0.2 Ventricular pacing 0.1 Physiologic pacing Similarly, there was a slight reduction in chronic AF in the DDD group, however, this effect was not observed until approximately 3 years of follow-up. 0.0 1 2 3 4 Years Since Randomization Number V At Risk P Skanes A, et al. J Am Coll Cardiol 2001; 38:

CTOPP Conclusions Physiologic pacing (dual-chamber or atrial) provides little benefit over ventricular pacing for the prevention of stroke or death due to cardiovascular causes. Physiologic pacing does provide a reduction in the relative risk of paroxysmal and persistent 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, John McAnulty, Kenneth Ellenbogen, Roger Freedman, Kerry L. Lee, Gervasio A. Lamas, for the MOST Investigators Circulation 2003, in press

MOST Sub-Study Background:
DDDR pacing preserves AV synchrony and reduces CHF compared to VVIR pacing in SND. DDDR pacing results in prolonged QRS durations (QRSd) due to ventricular desynchronization. Hypothesis: DDDR pacing often results in prolonged QRS duration (QRSd) due to ventricular desynchronization in patients with normal baseline QRSd and may increase risk of heart failure and atrial fibrillation. DDDR pacing preserves AV synchrony and reduces heart failure compared to VVIR pacing in SND in some, but not all prospective studies. DDDR pacing often results in prolonged QRS duration (QRSd) due to ventricular desynchronization in patients with normal baseline QRSd Effect of “forced” ventricular desynchronization on heart failure and AF during DDDR pacing in patients with normal baseline QRSd is unknown These studies suggest the possibility that cardiovascular mortality and congestive heart failure amongst DDDR patients with normal QRS duration and high frequency of ventricular pacing may be similar to DDDR patients with prolonged QRS duration (independent of frequency of ventricular pacing) and perhaps even VVIR patients. It is further possible that patients with a normal QRS duration and high frequency of ventricular pacing in the DDDR mode will have more heart failure and atrial fibrillation than similar patients with less frequent ventricular pacing. Sweeney MO, et al. Circulation 2003, in press

MOST Sub-Study Methods:
Baseline QRSd obtained from 12-lead EKG prior to IPG implant in MOST (a 2,010 patient, 6-year randomized trial of DDDR vs. VVIR pacing in SND). Cumulative % time ventricular paced was determined from stored pacemaker diagnostic data. Baseline QRSd <120 ms was observed in 1332 patients; 702 were randomized to DDDR; 640 to VVIR. The effect of forced ventricular desynchronization due to ventricular pacing in the DDDR mode among patients with normal baseline QRS duration was analyzed using the MOST study database. MOST was a 2010 patient, 6 year randomized trial of DDDR versus VVIR pacing in SND. Sweeney MO, et al. Circulation 2003, in press

MOST Sub-Study: Results
Cum%VP was greater in DDDR (90%) vs. VVIR (51%). The rates of CHF hospitalization increased with Cum%VP: Not unexpectedly, the cumulative percentage ventricular paced was significantly higher in the DDDR group compared to the VVIR group. The higher incidence of Cum%VP in the DDDR group is due to the overlap of baseline PR intervals with recommended programmed AV delays in the majority of patients. The overall percentage was 90% in the DDDR group versus 51% in the VVIR group. 50% of the patients in the DDDR group were ventricular paced continuously or near continuously, defined as greater than 90% of the time, compared to only 16% in the VVIR group. The relative incidence of heart failure hospitalization shows an increasing pattern with cumulative percent ventricular paced in both groups. The difference in incidence of heart failure hospitalization between pacing modes appears to be small. Sweeney MO, et al. Circulation 2003, in press

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. The shape of the relationship between Cum%VP and risk of HFH was different between DDDR and VVIR pacing modes. The risk was level above a certain Cum%VP (40%) in the DDDR mode and level below a certain percentage (80%) in the VVIR mode. These results imply that the risk of HFH in the DDDR mode does not increase with further increases in Cum%VP above 40%, but this risk might be reduced to about 2% if ventricular pacing is minimized. In contrast, the relative risk of HFH in the VVIR mode cannot be reduced regardless of minimization of ventricular pacing, and this risk is increased by as much as 2.5-fold when Cum%VP exceeds 80%. Sweeney MO, et al. Circulation 2003, in press

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. The shape of the relationship between Cum%VP and risk of HFH was different between DDDR and VVIR pacing modes. The risk was level above a certain Cum%VP (40%) in the DDDR mode and level below a certain percentage (80%) in the VVIR mode. These results imply that the risk of HFH in the DDDR mode does not increase with further increases in Cum%VP above 40%, but this risk might be reduced to about 2% if ventricular pacing is minimized. In contrast, the relative risk of HFH in the VVIR mode cannot be reduced regardless of minimization of ventricular pacing, and this risk is increased by as much as 2.5-fold when Cum%VP exceeds 80%. Sweeney MO, et al. Circulation 2003, in press

MOST Sub-Study P=0.047 This is a graphic representation of the effect of cumulative percent ventricular paced in the DDDR mode on subsequent incidence of heart failure hospitalization. Analysis showed that cumulative percent ventricular paced at 30 days correlated well with cumulative percent ventricular paced over all of follow-up. This plot shows time to heart failure hospitalization after 30 days, by cumulative percent ventricular paced groups using the binary cutoffs applied to the 30 day value for patients with normal QRS duration. The plot shows an early, sustained and increasing incidence of heart failure hospitalization amongst DDDR patients with cumulative percent ventricular paced >40% compared to <40%. Sweeney MO, et al. Circulation 2003, in press

MOST Sub-Study P=0.0046 A similar plot is shown for patients with normal QRS duration randomized to the VVIR mode. Again, time to heart failure hospitalization after 30 days, by cumulative percent ventricular paced groups using the binary cutoffs applied to the 30 day value for patients with normal QRS duration. The plot shows an early, sustained and increasing incidence of heart failure hospitalization amongst VVIR patients with cumulative percent ventricular paced >80% compared to <80%. Sweeney MO, et al. Circulation 2003, in press

MOST Sub-study Conclusions: CHF
Higher rates of CHF hospitalization were 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 40% confers a 3-fold increased risk of heart failure hospitalization but can be reduced to about 2% if ventricular pacing is minimized. Sweeney MO, et al. Circulation 2003, in press

MOST Sub-study: AF Risk
Ventricular pacing was also associated with an increased risk of AF. The best models demonstrated a linearly increasing risk of AF with Cum%VP in DDDR and VVIR modes up to approximately 80-85%. The magnitude of increased risk was approximately 1% for each 1% increase in Cum%VP and was similar between pacing modes. Risk of AF increases linearly with Cum%VP up to 80-85% in both DDDR and VVIR Sweeney MO, et al. Circulation 2003, in press

This is a graphic representation of the effect of cumulative percent ventricular paced in the DDDR mode on subsequent incidence of atrial fibrillation. Again, analysis showed that cumulative percent ventricular paced at 30 days correlated well with cumulative percent ventricular paced over all of follow-up. This plot shows time to atrial fibrillation after 30 days, by cumulative percent ventricular paced groups using cutoffs applied to the 30 day value for patients with normal QRS duration. Because there were no points of change in the slope of the risk relationship within the range of interest, groups of 40%, 40-70%, and 70-90% paced were chosen as dividing the range roughly into thirds. The plot shows an early, sustained and increasing incidence of atrial fibrillation amongst DDDR patients with increasing cumulative percent ventricular paced. Sweeney MO, et al. Circulation 2003, in press

A similar plot is shown for patients with normal QRS duration randomized to the VVIR mode. Again, time to atrial fibrillation after 30 days, by cumulative percent ventricular paced groups applied to the 30 day value for patients with normal QRS duration. The plot shows an early, sustained and increasing incidence of atrial fibrillation amongst VVIR patients with increasing cumulative percent ventricular paced. Sweeney MO, et al. Circulation 2003, in press

MOST Sub-study Conclusions: AF
Relationship between risk of AF and Cum%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-Study: Overall Conclusions
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. Sweeney MO, et al. Circulation 2003, in press

Dual-Chamber and VVI Implantable Defibrillator Trial DAVID

DAVID Trial Overview 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: - Single blind, multicenter, parallel group, randomized trial comparing DDDR (70 bpm lower rate) vs. VVI (40 bpm lower rate) pacing modes The hypothesis was based on the assumption that DDDR pacing mode with a lower rate of 70 bpm would provide rate support to increase cardiac output, suppress atrial and ventricular arrhythmias, and permit optimization of medications that can have a negative chronotropic and dromotropic effect. VVI could be programmed at a higher rate to provide rate support but would assure AV dysynchrony. Randomization occurred following successful implantation of a transvenous dual-chamber ICDs with a minimum safety margin of 10 Joules. Wilkoff B, et al. JAMA. 2002; 288:

DAVID Trial Protocol 760 assessed for eligibility 250 excluded
149 Did not meet Rx criteria 55 refused 46 Other 510 eligible 4 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 Wilkoff B, et al. JAMA. 2002; 288:

DAVID Trial Results VVI-40 DDDR-70 HR 16.1% 26.7% 1.61 (p = 0.03)
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% (p=0.15) P values adjusted for sequential monitoring. Log rank test p-values 95% CI for the HR for the primary endpoint was (95%CI: ) The increasing CHF hospitalizations appeared after the 6 th month; the mortality diverged early with more early deaths in the DDDR arm (5 vs 2) VVI-40 DDDR-70 Total Deaths CHF hospitalizations Crossovers were rare in both groups with only 5 DDDR patients and 10 in the VVI group having their pacing mode changes. Wilkoff B, et al. JAMA. 2002; 288:

DAVID VVI-40 DDDR-70 P-value 6-month EKG: Sinus 97.1% 42.0% <0.001 V-paced 2.9% 55.7% QRSd ms ms Cum % VP: 3 months 1.5% + 8.0% 57.9% % 6 months 0.6% + 1.7% 59.6% % 12 months 3.5% % 58.9% % Not surprisingly, the Cum%VP was significantly higher in the DDDR group throughout follow-up. This was manifest in a significantly prolonged QRSd on 6 month EKGs reflecting ventricular pacing. Note, however, that QRSd was prolonged in the VVI-40 group at 6 months as well. Percent RV Paced Beats was 1% in the VVI-40 group and 60% in the DDDR-70 group. Wilkoff B, et al. JAMA. 2002; 288:

DAVID Conclusions Bradycardia pacing operation in dual-chamber ICDs should be optimized for 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. Wilkoff B, et al. JAMA. 2002; 288:

Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation (The PAVE Study)
The PAVE study was a prospective, patient-blinded, randomized, multicenter clinical trial comparing chronic biventricular to right ventricular pacing in patients with chronic atrial fibrillation undergoing AV node ablation.

PAVE Study (J Cardiovasc Electrophysiol, Vol. 16,
pp , November 2005)

PAVE Study Ablation of the AV node was permitted up to 4 weeks post-implantation Pacemaker was reprogrammed to a VVIR mode with a lower rate of 80 ppm for the next 4 weeks so to mitigate the risk of polymorphic ventricular tachycardia. All patients received rate-esponsive pacing, with the sensor optimized 4 weeks after implantation.

6-minute hallway walk distance
(J Cardiovasc Electrophysiol, Vol. 16, pp , November 2005)

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

LV ejection Fraction (J Cardiovasc Electrophysiol, Vol. 16,
pp , November 2005)

NYHA Class (J Cardiovasc Electrophysiol, Vol. 16,
pp , November 2005)

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

Mortality in PAVE Study
There were 13 deaths (8%) in the biventricular pacing group and 19 deaths (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 ،ـ45% 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. ICD programming was not standardized, the development of new or worsened CHF was more common in the ICD arm (19.9%) compared with the conventionally treated patients (14.9%) . The higher incidence of CHF in the ICD group was in all likelihood due to ventricular desynchronization rather than myocardial injury from ICD shocks

MADIT II Approximately 40% of the had dual chamber units (mostly set at DDD 60 to 70 beats/min) and 60% had single-chamber units (mostly set at VVI 60 beats/min). Patients with dual-chamber units paced the ventricle about 85% of the time, whereas those with single-chamber units paced the ventricle 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 failure was clearly associated with dual-chamber ICD units having a higher frequency of ventricular pacing.

Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial
Cardiac resynchronization therapy with left ventricular pacing decreased the combined risk of death from any cause or first hospitalization in patients with advanced heart failure and prolonged QRS interval.

COMPANION trial These investigators concluded that reduction in the combined endpoints of death and heart failure hospitalizations was primarily due to cardiac resynchronization therapy (CRT), since CRT and CRT with an 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 investigated: Manipulation of DDDR timing cycles (AV delay) to minimize unnecessary RV pacing Use of AAI or DDI/R pacing modes Novel pacing algorithms Alternate RV pacing sites Recognition of the chronic adverse effects of RV apical pacing has stimulated interest in strategies to either attenuate these effects. Two approaches have been investigated. The first involves pacing at alternate sites in the right ventricle to reduce the QRS duration and, by extension, the adverse hemodynamic consequences of ventricular desynchronization. The second involves manipulation of DDDR timing cycles to minimize unnecessary ventricular pacing at the RV apex. The third involves using AAI or DDI pacing modes, while the fourth involves using novel pacing algorithms in an attempt to minimize ventricular pacing. To date, none of these strategies has proven to be 100% effective over a diverse patient population. In the interest of time, I will summarize by stating that carefully performed studies of alternate site RV pacing have shown no advantage to RV apical pacing relative to cardiac output, exercise duration, peak oxygen consumption, ejection fraction and functional status. Though direct His bundle pacing preserves native ventricular activation it is technically complex and does not address the development of infra-Hissian block.

Long AV Delays During Dual Chamber Pacing
Long AV delays may reduce unnecessary ventricular pacing and maintain normal ventricular activation sequence but require reliable AV nodal conduction. Long AV delays among patients with intact AV conduction may reduce unnecessary ventricular pacing in the DDDR mode. By operating in the functionally AAIR mode this may optimize hemodynamics by maintaining the normal ventricular activation sequence (in the absence of underlying bundle branch block). Optimal DDDR pacemaker programming among patients with intact but delayed AV conduction is problematic. Programming long pacemaker AV delay compromises upper rate behavior and atrial tachyarrhythmia detection. Programming short AV delays will result in "forced" ventricular desynchronization.

Long AV Delays During Dual Chamber Pacing: An Incomplete Solution
Long AV delays may impose limitations on 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 to permit native ventricular activation: 1. AV delays > resting PR intervals1 AV delays > resting PR intervals (22224 ms vs. 18423 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 (17728 vs. 20438), atrial stimulus-Q interval at 100 bpm (21340 vs. 22049) or AV delay (2993.2 vs. 28821) did not predict Vp High incidence of endless loop tachycardia Can be reduced if rate-adaptive AV delays are used Sgarbossa et al programmed long AV delays in 17 patients with intact AV conduction. Programmed AV delays were always longer than resting PR intervals (22224 ms vs. 18423 ms). During mean follow-up 4718 days, mean time of ventricular pacing for all patients was 80% and was greater than 50% for 15/17 (88%) patients. The majority of ventricular pacing followed atrial sensed events and mean time of ventricular pacing was higher among patients with adaptive AV delay programmed “on”. Nielsen et al programmed long AV delays (mean 29415 ms) in 18 patients with SND. Adaptive AV delays were programmed “off”. All patients had normal resting PQ intervals and Wenckebach point > 100 bpm. Overall, patients were paced a mean of 17.7% of the time in the ventricle. Ten patients were paced <3% of the time, and 8 patients were paced more than 15% (mean 38.7%). Resting PQ interval (17728 vs. 20438, p=0.10), atrial stimulus-Q interval at 100 bpm (21340 vs. 22049, p=0.77) or programmed AV delay (2993.2 vs. 28821, p=0.15) were not significantly different between the two groups and did not predict which patients were paced the most. 1 Sgarbossa E et al PACE 1993; ;16:872A Nielsen JC et al PACE 1997:20:1574A Nielsen JC et al Europace 1999;1:

AAI Pacing: Too Risky? AAI pacing preserves a normal ventricular activation sequence but requires stable long-term AV conduction and sinus rhythm SND is a spectrum of electrical disorders that includes AF and AV block AAI pacing is ineffectual for ventricular bradycardia during Paroxysmal and permanent AF AV block By definition, AAI pacing inherently will eliminate the possibility of RV apical pacing and will provide effective therapy for SND patients with intact AV conduction. However, this option carries with it too much risk, due to the possibility of patients developing Heart Block and/or AF over the life of their devices. In these cases, AAI pacing is both inappropriate and ineffective in treating the patients’ underlying bradycardia.

Development of Persistent (Complete) AV Block in Studies of Pacemaker Therapy for SND
Study Mean Follow-Up Time Incidence of CHB Annualized Incidence Rosenqvist 1989 (literature review) 3 years Median 2.1% Range: % Median: 0.6% Range: 0-4.5% Andersen 1997 8 years 3.6% 0.6% Brandt 1992 5 years 8.5% 1.8% Sutton 1986 8.4% 2.8% Rosenqvist 1986 2 years 4.0% 2.0% Rosenqvist 1985 3.3% 0.7% Hayes 1984 3.4% 1.1% Previous studies have demonstrated that intrinsic AV conduction remains relatively stable during long-term follow-up in the majority of patients with SND, but total prevalence risks of up to 11.9% have been reported. In aggregate, data from 28 different studies on atrial pacing for SND showed a median annual incidence of third degree AV block of 0.6% (0%-4.5%) with a total prevalence 2.1% (0-11.9%). There was no significant difference in follow-up time between studies that showed a low, compared to a high incidence of AV block. Variability in the reported incidence of persistent heart block likely relates to the exclusion of patients with bifascicular block or left bundle branch block in some studies with lower incidences and inclusion in others with higher incidences.

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 1997 AAI 5 years 8.8% 1.8% Sutton 1986 3 years 4.5% 1.5% Brandt 1992 7.0% 1.4% PASE 1998 DDDR only 18 months 19.0% 12.7% CTOPP 2000 DDDR/ VVIR 16.6% 5.5% (DDDR) Another important consideration in the application of AAI pacing is the development of chronic atrial fibrillation. This would render the therapy irrelevant and necessitate ventricular pacing if significant bradycardia accompanied persistent atrial fibrillation. The annual risk of atrial fibrillation in studies of pacemaker therapy has been reported and is dependent on the pacemaker mode. Brandt observed a 7% incidence of chronic atrial fibrillation amongst 213 patients with SND treated with AAI pacemakers. The mean follow-up was 5 years, yielding a 1.4% annualized incidence of chronic atrial fibrillation. This was identical to that reported by Sutton in a review of 410 SND patients treated with atrial pacing during a mean follow-up of 32.8 months. Andersen observed chronic atrial fibrillation in 8.8% SND patients treated with AAI pacing versus 21.6% SND patients treated with VVI pacing. These figures were based on an intention-to-treat analysis. In fact, 3/9 patients assigned to AAI pacing actually received VVI pacing systems, therefore the true incidence of chronic atrial fibrillation among patients who actually received AAI pacing was 6/102(5.9%). This yielded an 1.2% annualized incidence of chronic atrial fibrillation, also in alignment with the reports of Brandt and Sutton. In CTOPP the annual risk of AF (defined as at least one episode lasting at least 15 minutes) were 5.3% with DDDR pacemaker versus 6.6% for VVIR pacemaker, however, the study population was all-cause bradycardia (heart block and SND).

DDIR Mode: A Limited Solution
Permits long AV delays without the possibility of 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 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 algorithm May be more applicable to the ICD population -Lower prevalence of AV block compared to conventional brady pacing population. Higgins SL, et al. Am J Cardiol. 1998; 81 (11): Retrospective review of 122 ICD patients at Scripps Hospital, CA from 7/1/96-7/1/97. 35 patients (28.7%) met ACC/AHA Class I indications for pacemakers (including CHB) Geelen P, et al. PACE. 1997; 20 (1 part II): 139 consecutive ICD patients. 25 patients (18%) needed antibradycardia pacing—80% of these required DDD pacing. Iskos D, et al. Am J Cardiol. 1998; 82 (1): 250 consecutive patients received ICDs w/VVI pacing at U of MN, from 1/91-2/97. 35 Patients (14%) required adjunctive physiologic pacing. Iskos D, et al. PACE 1998; 21 (4, part II): 953. 398 patients received ICD w/VVI pacing. 22% of patients received, or were deemed indicated for, dual-chamber or atrial pacing. Intact or intermittent 1:1 conduction is found in ~83% of patients with sinus node dysfunction (Medtronic device registration; ). Programming in the DDI(R) mode: After an As, the mode will not provide a Vp unless no Vs occurs before reaching the lower rate After an Ap, which would only occur at the lower rate, a Vp will be provided (if needed) at the programmed PAV.

Novel Pacing Algorithms to Optimize Ventricular Pacing
Current-generation devices have features that work to minimize ventricular pacing in appropriate patient 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 R, Casavant D, et al. Atrioventricular Interval Search: A Dual Chamber Pacemaker Feature to Promote Intrinsic AV Conduction. A presentation at the NASPE 1999 Scientific Sessions. Data on file, Medtronic, Minneapolis. Ellenbogen K, Wood M, Gilligan D, et al. Validation of a New Algorithm for Maintenance of Intrinsic Ventricular Activation. Data on file, Medtronic, Minneapolis.

Silverman et al, NASPE 2000

Minimal ventricular pacing modes can be used in all patients, but are most effective in SND patients with reliable AV conduction and normal ventricular activation. Development will continue on new pacing algorithms which have been identified as an important means of minimizing 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 Pace,Vol.29, March 2006

Ongoing Studies of Alternate Site Pacing
Pace,Vol.29, March 2006

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) RV apical placement versus mid-septal placement Mid-septal lead position via appearance of normal paced QRS (no bundle branch block) Function Near normal ventricular conduction velocity Histology 4 month follow-up No calcification, degenerative changes, or altered mitochondrial morphology in the septal paced group RV Apical Pacing RV Septal Pacing LV Free Wall 4 months post Pacing Karpawich was the first to show that pacing from the RV septum preserved the myofibril architecture in the left ventricle. Karpawich PP, et al. Am Heart J 1991;121:827-33

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 perform the routine activities of daily living… Let’s compare our heart to this donkey, and our body to the wagon that this donkey has to pull every day. A healthy heart is like an energetic donkey, which without fatigue, pulls the wagon full of weights. Conversely, a diseased heart will have difficulty meeting metabolic demands (or pulling the wagon).

Digitalis Compounds Like the carrot placed in front of the donkey

Diuretics, ACE Inhibitors
Reduce the number of sacks on the wagon

ß-Blockers Limit the donkey’s speed, thus saving energy

Cardiac Resynchronization Therapy
Increase the donkey’s (heart) efficiency

Tehran Arrhythmia Clinic
org

Long Term Effects of RV Pacing

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Long Term Effects of RV Pacing

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