Physiological Pacing: Perspective I.E. O

I.E. O

Does Physiological Pacing Exist?

When introduced about 25 years ago, dual chamber pacing (DDD) was declared a ‘universal’ or ‘physiological’ mode of pacing. Lately, another defin- ition of DDD pacing has emerged: ‘true physiological pacing.’ If there is ‘true physiological pacing’, logically there should also be ‘false’ or ‘spurious’ physi- ological pacing.

Physiological pacing ‘may be achieved only by preserving, or, if that is impossible, by restoring or attempting to imitate the normal electrophysio- logical characteristics of the heart [i.e. normal chronotropism of cardiac rhythm with normal sino-atrial and atrioventricular (AV) activation] [1].

This paper will discuss current data regarding both kinds of ‘physiological’

pacing for patients with sinus node dysfunction.

The available ‘true’ physiological pacemaker is equipped with modern sophisticated diagnostic and therapeutic systems and features. However, even these sophisticated systems cannot support the requirements listed above for physiological pacing and provoke prolonged intra-atrial and intra- ventricular, interatrial and interventricular conduction time. This alterna- tion in conduction time may significantly modify synchronisation in the activation and contraction of the right and left heart and especially the left ventricle (LV) [1]. From the electrophysiological (EP) and haemodynamic points of view, a patient with DDD pacing is identical to the patient with ectopic right atrium (RA) rhythm originating from the location of the atrial lead and ectopic ventricular rhythm originating from the right ventricle (RV) apex. Consequences of permanent alterations in atrial conduction may lead to atrial arrhythmias such as atrial fibrillation (AF); RV apical pacing

Electrophysiology Laboratory, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel

leads to abnormal, retrograde depolarisation comparable with left bundle branch block (LBBB). As a result, DDD pacing leads to a combination of EP patterns of ectopic atrial and ectopic ventricular rhythm. When heart rate increases to more than 100 bpm, these rhythms should be classified as ectopic atrial tachycardia and ectopic ventricular tachycardia [1]. These EP alternations may lead to haemodynamic consequences. However, up to 10 years ago there was no solid evidence regarding adverse outcomes of ‘physio- logical’ pacing and the central subject for discussion was dual chamber ver- sus ventricular single chamber pacing (VVI/R). The initial assumption that DDD was superior to VVI was based on the intuition that the maintenance of AV synchrony afforded by DDD pacing is very important and is adequate to imitate normal EP patterns; later there were numerous retrospective studies which presented a significant body of evidence regarding the lower morbidi- ty and mortality associated with atrial-based versus ventricular pacing [1–4]. Over the last 10 years the results of several prospective trials have been published where, surprisingly, no difference in mortality appeared between physiological and non-physiological pacing (VVI/R), and the differ- ence in morbidity was significantly less [6–12]than had been previously believed [2–4]. The next period which significantly changed the credibility of

‘physiological’ pacing, was the beginning of the twenty-first century. In this period the studies tested the hypothesis that, even when AV synchrony is preserved, ventricular desynchronisation imposed by RV apical pacing increased the risk of congestive heart failure (CHF) and AF [13–17].

Physiological Pacing for Sinus Node Dysfunction

Sinus node dysfunction (SND) is the dominant indication for cardiac pacing in many countries [5]. The optimal pacing mode for treatment of sympto- matic SND has been debated for long time. A large number of observational studies have indicated that selection of pacing mode may be a factor in the clinical outcome for patients with symptomatic bradycardia in terms of development of AF, thromboembolism, CHF, mortality, and quality of life [2–4]. These retrospective studies were criticised for selection bias, and it was suggested that the only way to avoid this bias was to perform ran- domised controlled trials of pacing mode selection [2, 4]. The recent data from six randomised trials on mode selection in patients with SND will be discussed below.

The AAI vs VVI Trial

Ten years ago the AAI vs VVI trial, the first randomised trial comparing AAI

and VVI pacing in 225 consecutive patients with SND and normal AV con-

duction, was published by Andersen et al. [6]. After a mean follow-up of 40 months, 23% of the patients in the VVI group had AF compared with 14% in the AAI group (P = 0.12). Three years later, after an extended follow-up to a mean of 5.5 years, the differences in occurrence of AF between the AAI (24%) and VVI (35%) groups had increased substantially in favour of AAI pacing (P = 0.012) [7]. The Kaplan–Meier curves of freedom from AF diverged after 3 years of follow-up, indicating a delay after pacemaker implantation before the deleterious effect of VVI or the beneficial effect of AAI pacing becomes evident. In the VVI group NYHA functional class increased during follow-up (P < 0.001), and the use of diuretics increased.

These findings were associated with a decrease in LV fractional shortening and an excess dilatation of the left atrium (LA) in the VVI group as com- pared with the AAI group [8]. Total mortality was significantly less in the AAI group (P = 0.045), and the excess mortality in the VVI group was due to cardiovascular deaths [7].

The PASE Trial

In 1998 the Pacemaker Selection in the Elderly (PASE) Trial, the first ran- domised trial of VVIR versus DDDR pacing, was published [9, 10]. A total of 407 patients with SND, AV block, or other indications were included. Cross- over from VVIR to DDDR pacing because of pacemaker syndrome occurred in 26% of patients. The primary end-point was health-related quality of life, which did not differ between the two treatment groups at the end of follow- up. There was no significant difference in the incidence of AF between treat- ment groups.

The Italian Trial

At the same time Mattioli et al. reported a randomised trial [11] which included 210 patients with AV block and SND and with no history of prior AF. Patients received either VVI/VVIR, or a ‘physiological pacemaker’

(AAI/DDD/DDDR/VDD). Follow-up was up to 5 years. An increase in the incidence of chronic AF was observed in patients with SND who received VVI/VVIR pacing (P < 0.02).

The CTOPP Trial

This was the first large-scale randomised trial of pacing mode selection in

patients with SND and AV block, published in the year 2000 [12]; it included

1474 patients with VVI/VVIR pacemakers and 1094 patients with physiologi-

cal pacing (DDD/DDDR or AAI/AAIR). Mean follow-up was 3 years (range

2–5 years). No significant difference was observed in the primary end point

(st roke or cardiovascular death) b etween t reat ment g roups. The Kaplan–Meier curves of AF diverged after 2 years of pacing and an 18% risk reduction was observed in the physiologically paced group (P = 0.05). After an extended follow-up, (up to 6 years) still no significant difference between treatment groups was observed in regard to the primary end-point. AF remained more frequent in the VVIR group while the difference between groups significantly increased (P = 0.009) [13].

The MOST Trial

In the MOST trial, published in 2002 [14], 2010 patients with SND were included. All patients were implanted with a DDDR pacemaker, and after- wards the programming was randomly assigned to VVIR or DDDR pacing mode. A total of 313 patients (31%) crossed over from VVIR to DDDR.

Pacemaker syndrome was the reason for cross-over in 16% of VVIR patients.

At the end of follow-up AF was more frequent in the VVIR than in the DDDR group (P = 0.008). No differences were observed between groups in the pri- mary end-point death or non-fatal stroke or in the end-points all-cause mor- tality, cardiovascular death, stroke, or ‘death-stroke-or-hospitalisation for CHF’. Recently the MOST investigators have reported a correlation between cumulative percentage of ventricular pacing (Cum%VP) and an increasing risk of hospitalisation for heart failure [15]. Increasing Cum%VP was found to be clearly associated with an increasing incidence of AF both during VVIR and during DDDR pacing.

The AAIR vs DDDR Trial

In another Danish study [16], a total of 177 consecutive patients with SND,

normal AV conduction, and no bundle branch block were randomised to

treatment with AAIR and DDDR pacemakers programmed with a short AV

interval (DDDR-s) or DDDR pacemaker programmed with a long AV interval

(DDDR-l). Mean follow-up was 2.9 ± 1.1 years. In the AAIR group no signif-

icant changes were observed in such echocardiographic parameters as LA

and LV diameter and LV fractional shortening (LVFS) from baseline to last

follow-up (primary end-points). In both DDDR groups, LA diameter

increased significantly (P < 0.05), and in the DDDR-s group, LVFS also

decreased significantly (P < 0.01). AF was significantly less common in the

AAIR group, 7.4% vs. 23.3% in the DDDR-s group vs 17.5% in the DDDR-l

group (P = 0.03). The proportion of RV pacing was 90% in the DDDR-s

group and 17% in the DDDR-l group. The risk of developing AF in the AAIR

group compared to the DDDR-s group was significantly decreased after

adjustment for brady-tachy syndrome [relative risk 0.27 (95% CI 0.09–0.83),

Ongoing Trials

Two randomised trials of mode selection in SND are ongoing [18]. The DAN- PACE trial, comparing AAIR and DDDR pacing in 1900 patients, was started in 1999 in Denmark. Inclusion is expected to be completed in 2007. Mean fol- low-up will be 5.5 years. The primary end-point is all-cause mortality; AF is a secondary outcome event.

The Systematic Trial Of Pacing for Atrial Fibrillation (STOP-AF) [18] is designed to test VVI pacing vs. DDD or AAI pacing in 350 patients with regard to the incidence of chronic and paroxysmal AF.

Discussion

According to data available from randomised trials, VVI/R pacing is an unat- tractive therapy for patients with SND, increasing the incidence of AF, CHF, thromboembolism, and death compared with AAI/R pacing. DDDR also increased LA and LV size and decreased LV function, and probably as a result of these changes, patients with DDDR had increased incidence of CHF and AF compared with those with AAIR pacing. The lack of ventricular desynchronisation in the AAI/R mode may explain the remarkable benefit of atrial pacing compared with VVI/R and DDD/R pacing obtained by the Danish group in patients with SND, in a protocol where the investigation focused only on the role of AV synchrony. These findings are supported by data from the recent DAVID trial (The Dual Chamber and VVI Implantable Defibrillator trial) comparing ICDs with DDDR (70 bpm) and VVI (40 bpm) respectively [17]. Higher mortality and hospitalisation for new or worsened CHF were significantly more common in the DDDR group, most likely due to ventricular desynchronisation caused by RV pacing. The harm- ful consequences of RV pacing in the MOST trial also appeared related to non-physiological LV contraction [15]. The MOST study found a correlation between the cumulative percentage of RV pacing index and the development of AF.

The same mechanism probably explains the higher incidence of new or

worsened CHF in the ICD group than in the conventionally treated group in

the MADIT II trial [19]. The effect of RV apical pacing on LV activation pat-

terns and times is similar to that observed during LBBB [20, 21]. RV apical

pacing results in asynchronous ventricular activation and delayed LV activa-

tion time due to slow initial propagation of the electrical wavefront through

ventricular myocardium rather than through the His–Purkinje system. The

greater the mass of ventricular myocardium activated by muscle-to-muscle

conduction prior to activation of the Purkinje system, the longer the QRS

duration and the greater the ventricular asynchrony. It is therefore not sur-

prising that apical RV pacing is pathological and imposes acute and chronic adverse effects on ventricular haemodynamic function, myocardial perfu- sion, and cellular structure [20, 21]. These experimental data are validated by the above-mentioned clinical observations that chronic ventricular pacing in both the VVI/R and the DDD/R modes causes increased left heart size and reduced LV function compared with normal heart activation and atrial pac- ing, which presumably explains the adverse outcomes in the clinical trials cited previously. Furthermore, ventricular desynchronisation may explain why the difference between DDD/R and VVIR in the PASE, MOST, and CTOPP trials only was modest; the beneficial effect of preserving AV syn- chrony was partly outweighed by the harmful effect of ventricular desyn- chronisation. It should be emphasised that in none of the studies mentioned was AV interval optimised, which may compensate harmful outcome of RV pacing [1].

Conclusions

Significant outcomes of adverse effects of RV apical pacing are established.

In patients with SND, AAI/R pacing is preferable and its adverse effects are not yet widely accepted. This mode of pacing can be presently recognised as closest to physiological. Only in this pacing mode did outcomes of a ran- domised trial [6–8] support previous observational studies regarding mor- bidity and mortality. Despite this, the use of atrial pacing has been limited [22] by concern about the development of AV block. In patients with conduc- tion system disease and AV block, alternatives to RV apical pacing are need- ed to address the issue of ventricular synchrony [23].

Obviously, there is no one available physiological pacemaker for patients who need ventricular pacing. In patients with LV dysfunction, interventricu- lar synchrony is possibly more important than AV synchrony and can be restored by biventricular pacing. There is no study that demonstrates that optimal AV synchrony may neutralise ventricular asynchrony due to apical RV pacing. Meanwhile, for the patient who needs ventricular pacing, apical RV pacing should be minimised as much as clinically possible. The role of optimisation of AV interval and/or alternate site(s) for atrial and ventricular pacing have yet to be established. An alternative site may be at any location in the endocardium as well as in epicardium of one or both of the atria and the ventricles [21, 23].

Late note

In the January issue of Circulation (2005, 111:174–181) a paper by Rinfret et al. advo- cating the use of DDDR in patients with SND was published. Data in the paper are

based on 4-year follow-up of MOST patients. The authors concluded that for treating patients with SND, dual-chamber pacing is cost-effective in comparison with single chamber ventricular pacing.

So, for patients with SND, VVI/R is worst; dual chamber is better and AAI/R (if possible) is better than both.

References

1. Ovsyshcher IE (1997) Toward physiological pacing: optimization of cardiac hemodynamics by AV delay adjustment. Pacing Clin Electrophysiol 20:861–865 2. Connolly SJ, Kerr C, Gent M et al (1996) Dual-chamber versus ventricular pacing:

critical appraisal of current data. Circulation 94:578–583

3. Ovsyshcher I (1995) Matching optimal pacemaker to patient: do we need a large scale clinical trial of pacemaker mode selection? Pacing Clin Electrophysiol 18:1845–1852

4. Ovsyshcher IE, Hayes DL, Furman S (1998) Dual-chamber pacing is superior to ventricular pacing: fact or controversy? Circulation 97:2368–2370

5. Ovsyshcher IE, Furman S (2003) Determinants of geographic variations in pace- makers and implantable cardioverter defibrillators implantation rates. Pacing Clin Electrophysiol 26:474–478

6. Andersen HR, Thuesen L, Bagger JP et al (1994) Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome. Lancet 344:1523–1528 7. Andersen HR, Nielsen JC, Thomsen PE et al (1997) Long-term follow-up of

patients from a randomised trial of atrial versus ventricular pacing for sick sinus syndrome. Lancet 350:1210–1216

8. Nielsen JC, Andersen HR, Thomsen PE et al (1998) Heart failure and echocardio- graphic changes during long-term followup of patients with sick sinus syndrome randomized to single chamber atrial or ventricular pacing. Circulation 97:987–995 9. Lamas GA, Orav J, Stambler BS et al (1998) Quality of life and clinical outcomes in

elderly patients treated with ventricular pacing as compared with dual chamber pacing. N Engl J Med 338:1097–1104

10. Ellenbogen KA, Stambler BS, Orav EJ et al (2000) Clinical characteristics of patients intolerant to VVIR pacing. Am J Cardiol 86:59–63

11. Mattioli AV, Vivoli D, Mattioli G (1998) Influence of pacing modalities on the inci- dence of atrial fibrillation in patients without prior atrial fibrillation. A prospective study. Eur Heart J 19:282–286

12. Connolly SJ, Kerr CR, Gent M et al (2000) Effects of physiologic pacing versus ven- tricular pacing on the risk of stroke and death due to cardiovascular causes.

Canadian Trial of Physiologic Pacing Investigators. N Engl J Med 342:1385–1391 13. Kerr CR, Connolly SJ, Abdollah H et al (2004) Canadian Trial of Physiological

Pacing: effects of physiological pacing during long-term follow-up. Circulation 109:357–362

14. Lamas GA, Lee KL, Sweeney M et al (2002) Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N Engl J Med 346:1854–1862

15. Sweeney MO, Hellkamp AS, Ellenbogen KA et al (2003) Adverse effect of ventricu- lar pacing on heart failure and atrial fibrillation among patients with normal base- line QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunc- tion. Circulation 107:2932–2937

16. Nielsen JC, Kristensen L, Andersen HR et al (2003) A randomized comparison of atrial and dual-chamber pacing in 177 consecutive patients with sick sinus syndro- me: echocardiographic and clinical outcome. J Am Coll Cardiol 42:614–623 17. Wilkoff BL, Cook JR, Epstein AE et al (2002) Dual-chamber pacing or ventricular

backup pacing in patients with an implantable defibrillator: The Dual chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 288:3115–3123

18. Albertsen AE, Nielsen JC (2003) Selecting the appropriate pacing mode for patients with sick sinus syndrome: evidence from randomized clinical trials. Card Electrophysiol Rev 7:406–410

19. Moss AJ, Zareba W, Hall WJ et al (2002) Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 346:877–883

20. Vernooy K, Verbeek XAAM, Peschar M et al (2005) Left bundle branch block indu- ces ventricular remodelling and functional septal hypoperfusion. Eur Heart J 26:91–98

21. Vanagt WY, Verbeek XA, Delhaas T et al (2004) The left ventricular apex is the opti- mal site for pediatric pacing: correlation with animal experience. Pacing Clin Electrophysiol 27:837–843

22. Ector H, Ovsyshcher IE, Oto A et al (2003) The registry of the European Working Group on cardiac pacing: 2000–2001 (abstract). Europace 4:B100

23. Lieberman R, Grenz D, Mond HG et al (2004) Selective site pacing: defining and reaching the selected site. Pacing Clin Electrophysiol 27(6 Pt 2):883–886