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\begin{document}

\title{Rate-dependent pacing failure after pacemaker implantation:Novel
insights into the mechanism of using adenosine}



\author[1]{Hisaharu Ohe}%
\author[2]{Yasushi Oginosawa}%
\author[1]{Taro Miyamoto}%
\author[3]{Yamagishi Yasunobu}%
\author[1]{Keita Tsukahara}%
\author[4]{Ritsuko Kohno}%
\author[5]{Haruhiko Abe}%
\author[6]{Yutaka Otsuji}%
\affil[1]{University of Occupational and Environmental Health Japan}%
\affil[2]{Sangyo Ika Daigaku}%
\affil[3]{University of Occupational and Environmental Health Hospital}%
\affil[4]{University of Occupational and Environmental Health, Kitakyushu, Japan}%
\affil[5]{University of Occupational and Environmental Health, Japan}%
\affil[6]{University of Occupational and Environmental Health, Japan,}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
An 82-year-old woman received pacemaker implantation for sick sinus
syndrome. Two days after the implantation, electrocardiography showed
2:1 atrial pacing failure, followed by bradycardia-dependent increase in
the atrial pacing threshold during a pacemaker examination. However,
transient 1:1 atrial pacing capture recovered by adenosine triphosphate
(ATP) administration, which was performed to evaluate the
bradycardia-dependent pacing failure mechanism. We considered this
phenomenon to be caused by phase 4 depolarization and avoided replacing
this atrial lead. Three weeks later, the atrial pacing threshold had
improved. We report the potential role of phase 4 depolarization in
bradycardia-dependent increase in pacing threshold by using ATP.%
\end{abstract}%



\sloppy


\textbf{Introduction}

An acute increase in the pacing threshold early after pacemaker
implantation is occasionally a problem, even in the era of
steroid-eluting leads. In such cases, bradycardia-dependent increase in
the pacing threshold without apparent lead dislodgement has been
demonstrated to be responsible for micro-dislodgement or phase 4 block
and is expected to recover spontaneously\textsuperscript{1-2}. However,
the mechanism of this phenomenon has not been elucidated.

We herein report a case of a patient who underwent pacemaker
implantation for sick sinus syndrome (SSS), in whom the mechanism of
bradycardia-dependent increase in the pacing threshold was elucidated
using adenosine triphosphate (ATP).

\textbf{Case report}

An 82-year-old woman was referred to our hospital for the management of
SSS with lightheadedness. She had a history of lone atrial fibrillation
(AF), but was not taking any antiarrhythmic drugs. Holter
electrocardiography showed a total heart rate (HR) of about 50,000 beats
per day (minimum HR was 29 bpm), 8.3 seconds of cardiac arrest was
observed at the termination of AF. Consequently, we decided to implant a
dual-chamber pacemaker; a passive-fixation lead (INGEVITY MRI, Boston
Scientific, USA) and an active-fixation lead (INGEVITY MRI, Boston
Scientific, USA) were implanted in the right atrial appendage and right
ventricular mid-septum, respectively. The initial atrial pacing
threshold was 0.7 V at 0.4 ms at 60 bpm. The sensing threshold and
impedance values of the atrial lead were 2.1 mV and 638 \selectlanguage{greek}Ω, \selectlanguage{english}respectively.
The pacemaker was programmed to DDD 60-110 bpm with 3.5 V at a 0.4 ms
setting of atrial pacing output.

Two days after the implantation, electrocardiographic monitoring showed
2:1 ventricular pacing following atrial pacing spikes, without atrial
capture (Figure 1-A). The chest X-ray showed no apparent dislodgement of
either the atrial or ventricular leads. Pacemaker interrogation revealed
that atrial pacing capture was dependent on the interval of preceding
atrial sensing or captured pacing events (Figure 1-B). Therefore, we
evaluated the atrial pacing threshold by changing the pacing rate. The
atrial pacing threshold was then increased and was inversely correlated
with the pacing rate: 4.0 V at 0.4 ms at 50 bpm, 2.7 V at 0.4 ms at 60
bpm, 1.5 V at 0.4 ms at 70 bpm, and 1.0 V at 0.4 ms at 80 bpm (Figure
2-A). Although there was a slight decrease in the atrial pacing
threshold when the pulse width extended from 0.4 ms to 1.0 ms, the rate
dependency of the pacing threshold remained unchanged. The sensing and
impedance values were slightly decreased, but the decrease was not
significant, and it was acceptable. (sensing and impedance values were
1.3 mV and 582 \selectlanguage{greek}Ω, \selectlanguage{english}respectively).

The causes of such a bradycardia-dependent increase in the pacing
threshold without apparent lead dislodgement are considered as follows:
(1) fluctuation in the contact to the myocardium by lead
micro-dislodgement\textsuperscript{1}, and (2) phase 4 depolarization
and block in the injured myocardium\textsuperscript{2}. We assumed this
phenomenon to be associated with phase 4 depolarization in this patient,
because the relationship between the pacing threshold and pacing rate
indicated a sigmoid curve, which likely is a physiological phenomenon
(Figure 2-A). A pause-dependent paroxysmal atrioventricular block mostly
occurs in the presence of an injured His-Purkinje system and is known to
be responsible for gradual phase 4 depolarization\textsuperscript{3}. On
the other hand, Datino et al\textsuperscript{4} demonstrated that
adenosine could hyperpolarize canine pulmonary vein (PV) cardiomyocytes
by increasing the inward rectifier K\textsuperscript{+} current (IKAdo)
in which the resting membrane potential decreased by radiofrequency (RF)
application and this phenomenon could account for the ``dormant
conduction'' in PV isolation for AF. Therefore, we examined whether the
administration of ATP could restore the pacing capture in the damaged
atrial myocardium by hyperpolarization during phase 4. An intracardiac
electrogram (EGM) immediately after the administration of ATP during
atrial pacing under the subthreshold voltage, of 2.5 V at 0.4 ms at 50
bpm (the threshold was 3.5 V at 0.4 ms at 50 bpm), is shown in Figure
2-B. Since ATP administration resulted in 1:1 atrial capture
transiently, without a change in the pacing rate, we determined that her
bradycardia-dependent increase in the pacing threshold was related with
phase 4 depolarization. Some authors have already reported
bradycardia-dependent increase in the pacing threshold to improve
time-dependently\textsuperscript{2}; hence, we did not replace her
atrial lead and changed the pulse width from 0.4 ms to 1.0 ms, avoiding
pacing failure.

No improvement in the atrial pacing threshold was observed at the lower
pacing rate at seven days after the pacemaker implantation. However, two
more weeks later, the atrial pacing threshold was improved as follows:
1.0 V at 0.4 ms at 50 bpm, 0.7 V at 0.4 ms at 60 bpm, and 0.6 V at 0.4
ms at 70 bpm; this has been maintained for over two years. Informed
consent was obtained from the patient for the publication of this case
report.

\textbf{Discussions}

Even today, we may encounter patients with varying degrees of transient
increase in the pacing threshold after pacemaker implantation. Uehara et
al\textsuperscript{5} demonstrated an acute and transient, but not
persistent, rise in the capture threshold (TRACT) in 6\% of patients
undergoing dual-chamber pacemaker implantation, which most likely
occurred when the damaged atrial myocardium was associated with SSS.
Their colleagues also reported three similar TRACT cases of
bradycardia-dependent nature in which the involvement of a phase 4 block
was suggested\textsuperscript{2}. However, to the best of our knowledge,
this is the first report in which the potential role of phase 4
depolarization in bradycardia-dependent increase in the pacing threshold
was evaluated using ATP.

The resting membrane potential in the normal atrial myocardium is
usually at a steady negative level (about -80 mV), whereas in the
damaged atrial myocardium, it is expected to be decreased (becomes less
negative), such as in canine PV myocytes injured by RF application. As
the resting membrane potential decreases, the voltage-dependent
inactivation Na\textsuperscript{+} channel gradually closes and inward
Na\textsuperscript{+} current is reduced to a level at which action
potential cannot occur against external stimulations. On the other hand,
as described above, ATP could hyperpolarize damaged cardiomyocytes and
subsequently facilitate depolarization. Accordingly, we hypothesized
that the bradycardia-dependent increase in the pacing threshold observed
in the early phase after pacemaker implantation was associated with
phase 4 depolarization in the damaged myocardium, cause by factors such
as inflammation and edema due to lead-contact and could be improved by
the administration of ATP, which increases the resting membrane
potential and activates sufficient Na\textsuperscript{+} current (Figure
3). Indeed, Blazek et al\textsuperscript{6} suggested that
pacemaker-lead implantation-induced myocardial micro-damage, either with
an active or passive fixation lead, could be monitored by using the
high-sensitive troponin T level as an index.

Although further investigations are required, many cases of
bradycardia-dependent increase in the pacing threshold early after
pacemaker implantation could be due to phase 4 depolarization and ATP
could be useful for investigating the mechanism.

\textbf{Conclusion}

ATP injection transiently rectified rate-dependent pacing failure in the
acute phase after pacemaker implantation. This observation is concordant
with the effect of ATP on phase 4 depolarization. The evaluation of this
phenomenon using ATP could help in elucidating the mechanism and making
a decision regarding whether to perform re-intervention.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Katsumoto K, Niibori T, Watanabe Y. Rate-dependent threshold changes
  during atrial pacing: Clinical and experimental studies. Pacing Clin
  Electrophysiol. 1990;13:1009-1019.
\item
  Kimata A, Yoshida K, Takeyasu N, et al. Bradycardia-dependent rise in
  the atrial capture threshold early after cardiac pacemaker
  implantation in patients with sick sinus syndrome. Heart Rhythm Case
  Rep. 2015;2:27--31.
\item
  Shenasa M, Josephson ME, Wit AL, et al. Paroxysmal atrioventricular
  block: Electrophysiological mechanism of phase 4 conduction block in
  the His-Purkinje system: A comparison with phase 3 block. Pacing Clin
  Electrophysiol. 2017;40:1234-1241
\item
  Datino T, Macle L, Qi XY, et al. Mechanisms by which adenosine
  restores conduction in dormant canine pulmonary veins. Circulation.
  2010;121:963-972
\item
  Uehara Y, Yoshida K, Kimata A, et al. Underrecognized entity of the
  transient rise in the atrial capture threshold early after
  dual-chamber pacemaker implantation. Pacing Clin Electrophysiol.
  2017;40:1396--1404.
\item
  Blazek P, Ferri-Certic J, Vrazic H, et al. Pacemaker implantation
  associated myocardial micro-damage: A randomised comparison between
  active and passive fixation leads. Sci Rep. 2018;8:4870.
\end{enumerate}

\textbf{Figure legends}

Figure 1. A: Continuous ECG of lead II shows 2:1 wide QRS complexes
accompanied by ventricular pacing following the loss of atrial capture.
The pacemaker mode was DDD 60-110 bpm with a paced AV interval of 350
ms, 3.5 V at a 0.4 ms setting of atrial pacing output. B: Intracardiac
EGM strips during 2:1 atrial pacing failure. The middle portion
indicates the atrial EGM channel; the bottom indicates the ventricular
EGM channel. Because intrinsic atrial beats (indicated as PAC) were
observed after atrial pacing failure, but they were within the
post-ventricular atrial refractory period (PVARP), the pacemaker timing
cycle was not reset. A shorter coupling period (510 ms and 725 ms) of
atrial pacing, followed by the intrinsic atrial beat could capture the
atrial myocardium. A longer coupling period (1000 ms was the lower rate
interval) of atrial pacing could not capture the atrial myocardium.

Figure 2. A: Pacing threshold during atrial pacing is plotted against
each pacing rate. Larger output was required as a lower pacing rate. B:
Intracardiac EGM immediately after ATP 20 mg injection. Although the
first, second, fourth and fifth pacing could not capture the atrial
myocardium, the sixth, seventh, eighth, and ninth pacing could all
capture the atrial myocardium with 2.5 V at 0.4 ms where the threshold
before ATP injection was 3.5 V at 0.4 ms at 50 bpm, without changing the
pacing rate.

Figure 3. A proposed mechanism of ATP-induced transient improvement of
rate-dependent pacing failure. A. The resting membrane potential in the
normal atrial myocardium is steady negative and most of Na+ channels are
available for generating action potential (D: blue point). B.
Bradycardia-dependent pacing failure with myocardial injury after pacing
lead implantation can be explained by gradual depolarization during
phase 4, in a similar manner to rate-dependent phase 4 block. When
pacing with a shorter coupling interval (510 ms) from the preceding
depolarization, the Na\textsuperscript{+} channel fraction is available
enough to capture (D: yellow point). On the other hand, when pacing with
a longer coupling interval (1000 ms), a large fraction of the
Na\textsuperscript{+} channels is inactivated (D: red point), resulting
in pacing failure. C. Bolus ATP injection induces hyperpolarization
during phase 4 by increasing inward rectifier
K\textsuperscript{+}current (I\textsubscript{KAdo}). Consequently,
Na\textsuperscript{+}channel availability is restored (D: red point to
yellow point) and the myocardium is captured by pacing with a longer
coupling interval.

\textbf{Hosted file}

\verb`Figure 1.pptx`  available at \url{https://authorea.com/users/336035/articles/461844-rate-dependent-pacing-failure-after-pacemaker-implantation-novel-insights-into-the-mechanism-of-using-adenosine}

\textbf{Hosted file}

\verb`Figure 2.pptx`  available at \url{https://authorea.com/users/336035/articles/461844-rate-dependent-pacing-failure-after-pacemaker-implantation-novel-insights-into-the-mechanism-of-using-adenosine}

\textbf{Hosted file}

\verb`Figure 3.pptx`  available at \url{https://authorea.com/users/336035/articles/461844-rate-dependent-pacing-failure-after-pacemaker-implantation-novel-insights-into-the-mechanism-of-using-adenosine}

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