D.
Michael Farmer, MD, N. A. Mark Estes, III, MD, Mark S. Link, MD
Tufts-New England Medical Center, Tufts
University School of Medicine, Boston, Massachusetts
Address for Correspondence: Mark S. Link, NEMC Box #197, Tufts-New
England Medical Center
750 Washington Street, Boston, MA 02111. Email:
Mlink@tufts-nemc.org
Abstract
After
implantation of a permanent pacemaker, patients may experience severe symptoms
of dyspnea, palpitations, malaise, and syncope resulting from pacemaker syndrome.
Although pacemaker syndrome is most often ascribed to the loss of atrioventricular
(A-V) synchrony, more recent data may also implicate left ventricular dysynchrony
caused by right ventricular pacing. Previous studies have not shown
reductions in mortality or stroke with rate-modulated dual-chamber (DDDR)
pacing as compared to ventricular-based (VVI) pacing. The benefits in A-V
sequential pacing with the DDDR mode are likely mitigated by the interventricular
(V-V) dysynchrony imposed by the high percentage of ventricular pacing commonly
seen in the DDDR mode. Programming DDDR pacemakers to encourage intrinsic
A-V conduction and reduce right ventricular pacing will likely decrease
heart failure and pacemaker syndrome. Studies are currently ongoing
to address these questions.
Keywords: VVI = ventricular-based, VVIR = rate modulated ventricular-based,
A-V = atrioventricular, V-V = interventricular, V-A = ventricular-atrial,
LBBB = left bundle branch block, LVEF = left ventricular ejection fraction,
DDDR = rate modulated dual-chamber, SND = sinus node dysfunction, AAI =
single-chamber atrial, AF = atrial fibrillation, LV = left ventricular,
RV= right ventricular
Introduction
Pacemaker
syndrome consists of the cardiovascular signs and symptoms of heart failure
and hypotension induced by right ventricular (RV) pacing. The reported
incidence of pacemaker syndrome likely approaches 20% in rate modulated
ventricular-based (VVIR) pacing
1.
Over the last three decades the understanding of pacemaker syndrome has evolved.
Initially described as only the sequela of A-V dysynchrony, pacemaker syndrome
may be highly influenced by RV-left ventricular (LV) dysynchrony as well.
The intricate interplay of these two factors along with autonomic and neurohormonal
changes cause the compilation of symptoms known as the pacemaker syndrome.
Pacemaker Syndrome
Pacemaker syndrome
was first described in 1969 by Mitsui et al. as a collection of symptoms
associated with right ventricular pacing
2.
Since its first discovery, there have been many definitions of pacemaker
syndrome, and the understanding of the cause of pacemaker syndrome is still
under investigation. In a general sense, pacemaker syndrome can be
defined as the symptoms associated with right ventricular pacing relieved
with the return of A-V and V-V synchrony.
The symptoms of
pacemaker syndrome included dyspnea on exertion, paroxysmal nocturnal dyspnea,
orthopnea, hypotension, pre-syncope, and even syncope
3,4,5.
Heart failure signs include elevated neck veins, rales, and pedal edema.
Physical exam can often reveal cannon A-waves. This sign occurs secondary
to ventricular-atrial (V-A) conduction and the contraction of the atria
against closed A-V valves. Although relatively uncommon, syncope has
been attributed to pacemaker syndrome. Syncope is usually associated
with systolic blood pressure declines of greater than 20 mm Hg that can occur
with the onset of pacing. Additional symptoms attributed to pacemaker
syndrome include easy fatigability, malaise, headache, and the sensation
of fullness and pulsations in the head and neck. Pacemaker syndrome
is most severe when intact V-A conduction is present
6. The elevated venous pressures associated
with the contraction against closed A-V valves causes a vagal afferent response
resulting in peripheral vasodilation and hypotension.
Incidence
The reported incidence
of pacemaker syndrome has ranged from 2%
7
to 83%
8. The wide range
of reported incidence is likely attributable to two factors. The first
is the criteria used to define pacemaker syndrome. In the Pacemaker
Selection in the Elderly (PASE) study, pacemaker syndrome was defined as
symptoms severe enough to warrant reprogramming from ventricular to dual-chamber
pacing
9. The Mode
Selection Trial (MOST) investigators defined pacemaker syndrome as occurring
if either one of two different criteria occurred
1.
The first criteria was new or worsened dyspnea, orthopnea, elevated jugular
venous pressure, rales, and edema with ventricular (VA) conduction during
ventricular pacing. The second criteria was symptoms of dizziness,
weakness, presyncope, or syncope, and a >20 mm Hg reduction of systolic
blood pressure when the patient had VVIR pacing compared with atrial pacing
or sinus rhythm. The second factor in the wide range of reported
incidence of pacemaker syndrome is the therapy used to resolve that diagnosis.
When surgical revision is required to upgrade a patient from VVIR pacing,
the incidence of pacemaker syndrome has been low. In the Canadian Trial
of Physiologic Pacing (CTTOP), surgical revision was required for the change
from VVIR to dual chamber pacing, and the incidence of pacemaker syndrome
was reported to be 2.7% at three years
10.
In other pacemaker mode trials, patients were implanted with dual chamber
devices and then either programmed to VVIR or DDDR pacing. In these
studies, patients complaining of symptoms consistent with pacemaker syndrome
could be easily upgraded to DDDR mode by simple pacemaker reprogramming.
In the PASE and MOST studies in which devices could be reprogrammed
from VVIR to DDDR mode, the incidence of pacemaker syndrome was higher
than in those studies that required an invasive intervention to change pacing
mode
9,11.
A-V vs. V-V dysynchrony
The majority of
the symptoms of pacemaker syndrome are likely attributable to the reduction
in cardiac output that is associated with right ventricular pacing
3,4,5.
Several studies have demonstrated the hemodynamic superiority and increase
in cardiac output of A-V sequential pacing over ventricular pacing
12. Other studies have shown that A-V
and V-V synchrony are independent contributors to the hemodynamic ramifications
of right ventricular pacing
13,14. Right ventricular pacing with or
without A-V synchrony induces a physiologic contraction similar to that caused
by left bundle branch block (LBBB). The effects of LBBB have been well
studied. LBBB leads to an asynchronous ventricular contraction leading
to altered diastolic filling time, increase in mitral regurgitation, as
well as a reduction in left ventricular ejection fraction (LVEF)
15,16,17.
Thus, the reduction in cardiac output and symptoms associated with pacemaker
syndrome are likely secondary to the loss of both A-V and V-V synchrony
that is associated with right ventricular apical pacing
18.
“Physiologic” vs. Ventricular pacing Trials
The physiologic
benefits of A-V sequential have caused DDDR pacing to become common practice
in most patients with sinus node dysfunction (SND). The results of
completed randomized clinical trials of pacemaker mode selection have been
somewhat conflicting. Overall, most trials have not shown reduction
in heart failure, reduction in mortality, or improvement in quality of life
with A-V sequential pacing (
Table 1).
Table 1: Clinical Trials of Pacemaker Mode Selection
In the first of
such trials, Anderson et al. compared single-chamber atrial (AAI) with VVI
pacing in 225 patients with SND, normal A-V conduction, and a narrow QRS
who had standard pacing indications
7.
The primary endpoints were frequency of atrial fibrillation (AF) and thromboembolic
events. The original study follow-up was 3.3 years with a subsequent
analysis at 5.5 years. Long term follow-up demonstrated persistent
reduction in the primary endpoints of AF, thromboembolic events, chronic
AF, and all cause mortality in the AAI paced group. At longer follow-up,
the VVI group had an increased incidence of heart failure, worsening echocardiographic
measurements of LV function, and increase in all-cause mortality.
These long-term results have not been reproduced by any other prospective,
randomized trial comparing solely atrial-based to ventricular-based pacing,
although the pacing mode in subsequent trials was mainly DDDR.
In the PASE study,
407 patients older than 65 years of age, in sinus rhythm, who required a
pacemaker for bradycardia, were randomized to VVIR or DDDR pacing
9. The primary end point was quality-of
life. Secondary endpoints included death from all causes, first nonfatal
stroke or death, first hospitalization for heart failure, development of
atrial fibrillation, and the development of pacemaker syndrome. At
quality of life evaluations at 3, 9 and 18 months, there were no differences
between the two pacing modes. There was a 26% crossover rate due to
the development of pacemaker syndrome. No differences in clinical outcomes
were observed. There were some trends that showed benefit in clinical
outcomes in the DDDR group, especially in the subset of patients with SND,
but none were of statistical significance.
As a result of
the conflicting data in the Anderson et al. trial and the PASE study, two
larger trials in pacemaker mode selection were performed. In the Canadian
Trial of Physiologic Pacing (CTOPP) trial, 2568 patients with symptomatic
bradycardia requiring pacing were randomized to atrial-based (AAI, AAIR,
DDD, or DDDR) or ventricular pacing (VVI or VVIR)
10. AAI and AAIR combined for only 5%
of the patients assigned to the atrial-based group. The remaining 95%
in the atrial-based group were either DDD or DDDR paced. The combined
endpoint of stroke or death due to cardiovascular causes after a 3-year follow-up
was not different between the two groups. The secondary endpoints of
AF and chronic AF were observed less commonly in the atrial-based group.
After an eight year follow-up, there were no significant differences in death
or stroke between the two groups
19.
In the Mode Selection
Trial in Sinus Node Dysfunction (MOST) study, 2020 patients with SND received
dual chamber pacemakers and were randomized to either VVIR or DDDR pacing
11. The mean follow-up was 33 months and the
primary endpoints were death and nonfatal stroke. There were no differences
in the primary endpoint between the two groups. The incidence of atrial
fibrillation was lower with dual-chamber pacing. Subsequent analyses
of the MOST data, has shown that the benefits of A-V sequential pacing are
likely attenuated by the ventricular pacing that occurs in the DDDR mode
20. Patients with a pre-paced
QRS duration less than 120 ms were analyzed for percentage of ventricular
pacing and clinical events. The percentage of ventricular pacing was
determined from stored pacemaker data. The percentage of ventricular pacing
was greater in the DDDR versus VVIR mode (90% vs. 58%). The percentage
of ventricular pacing was a strong predictor of heart failure hospitalization
in both pacing modes. The risk of AF increased linearly with percentage
of ventricular pacing in both groups. The authors concluded that ventricular
desynchronization imposed by ventricular pacing even when A-V synchrony
is preserved increases the risk of heart failure hospitalization and AF
in SND with normal baseline QRS duration. The analyses by Sweeney
et al. illustrate the fact that DDDR and DDD pacing is not physiologic.
The pacing mode that is most physiologic is AAI or AAIR. This fact can likely
explain the discrepancies between the study by Anderson et al. and the subsequent
studies in pacemaker mode selection. The benefit derived from A-V
sequential pacing in the CTTOP and MOST studies was likely counterbalanced
by the detrimental effects of right ventricular pacing seen in the DDDR
mode.
Several ongoing
trials are looking at the benefits of reduction in RV pacing in the DDDR
mode. The first is the Danish Multicenter Randomized Study of Atrial Inhibited
Versus Dual-Chamber Pacing in Sick Sinus Syndrome (DANPACE). This trial
is comparing AAI pacing and DDDR pacing with a short A-V delay. The
second is the Search A-V Extension for Promoting Atrioventricular Conduction
(SAVE-PACE) study. This study will evaluate the use of search hysteresis,
a pacemaker feature that allows the extension of the A-V delay to reduce
right ventricular pacing. The study investigators hypothesize that
the reduction in RV pacing will lead to a reduction in left ventricular remodeling
and AF.
Conclusion
Pacemaker syndrome
is a common problem faced by clinicians who implant pacemakers and for those
who take care of these patients. The syndrome is likely caused by
both the loss of A-V and V-V synchrony imposed by right ventricular pacing.
The studies on pacemaker mode selection have shown a high incidence of pacemaker
syndrome. Because of the high incidence of pacemaker syndrome in VVIR-paced
patients, atrial-based pacing is preferred.
These studies
have also showed that DDDR pacing as compared to VVIR pacing decreases the
incidence of AF, but does not affect stroke or mortality. The percentage
of beats ventricular paced in these studies in patients who received dual-chamber
pacemakers is likely to influence the incidence of pacemaker syndrome and
heart failure. The amount of ventricular pacing in the DDDR mode is
dependent on spontaneous A-V conduction and programmed A-V delay. Optimal
programming should seek to reduce ventricular pacing. The reduction
in the percentage of RV pacing in dual-chamber pacing modes will likely reduce
the incidence of pacemaker syndrome, heart failure, and possibly mortality.
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