Post*extrasystolic Potentiation as a Predictor of Ventricular Arrhythmias

Patients at increased risk for sudden cardiac death (SCD) caused by lethal
ventricular arrhythmias, may receive an implantable cardioverter defibrillator
(ICD). The primary criterion for ICD implantation is a left ventricular
ejection fraction (LVEF) *35%. Studies indicate that only 11-30% of ICD
carriers receive appropriate device therapy (ADT). Therefore, patient selection
for primary prevention ICD implantation needs refinement. Identification of new
parameters associated with SCD might lead to improved selection of patients.
Post-extrasystolic potentiation (PESP) may be a new risk marker for SCD. PESP
is defined as a temporary increase in contractility that follows an
extrasystolic beat (ESB) and is associated with myocardial calcium handling. In
heart failure, changes in calcium homeostasis may lead to afterdepolarisations
and thus predispose for SCD. PESP can be measured indirectly and non-invasively
as post-extrasystolic blood pressure potentiation (PESP-BP). Abnormal PESP-BP,
using spontaneous ESB, was found to be an independent predictor of increased
mortality in post-myocardial infarction patients with a reduced LVEF. However,
it is unknown if this increased mortality in heart failure patients with
abnormal PESP-BP is caused by SCD.
When using spontaneous ESB for assessment of PESP-BP, however, coupling
intervals between the ESB and both previous and subsequent beats are not
controlled and may vary substantially. These coupling intervals, as well as the
basic cycle length, are known to influence changes in contractility
significantly.
ICD patients offer the unique possibility to evoke atrial and ventricular ESB
in a reproducible manner. Basic cycle length and coupling intervals can be
controlled by cardiac stimulation using the ICD leads. Systolic BP change after
an ESB can reliably be assessed with a non-invasive continuous finger arterial
BP photoplethysmographic device. Using this reproducible assessment of PESP-BP,
different stimulation protocols can be evaluated and compared with PESP-BP of
spontaneous occurring ESB. This pilot study sets out to assess
stimulation-evoked PESP-BP using various stimulation protocols and to compare
outcomes with PESP-BP by spontaneous ESB. Moreover, we aim to derive a
stimulation protocol for PESP-BP assessment, which can be used in a larger
cohort of ICD patients to test PESP-BP as a new predictor for the occurrence of
ventricular arrhythmias. Please refer to chapter 1 of the protocol
(introduction and rationale)

This pilot study sets out to assess stimulation-evoked PESP-BP using various
stimulation protocols and to compare outcomes with PESP-BP by spontaneous ESB.
Moreover, we aim to derive a stimulation protocol for PESP-BP assessment, which
can be used in a larger cohort of ICD patients to test PESP-BP as a new
predictor for the occurrence of ventricular arrhythmias.

This pilot study has a stratified design.
Patients: 30 patients who are scheduled for ICD replacement/reposition or
pacemaker implantation/replacement/reposition will be included in this study;
(1) 10 ICD patients with LVEF < 35% who previously received ADT; (2) 10 ICD
patients with LVEF < 35% who are free from ADT and (3) 10 dual-chamber
pacemaker patients with normal LVEF (control group).
Intervention: During scheduled device implantation/replacement, ESB with
various extrasystolic and post-extrasystolic coupling intervals will be evoked
by electrical stimulation via the right atrial and ventricular device leads of
the patient. Throughout the stimulation study, blood pressure response will be
measured continuously and non-invasively, and a continuous electrocardiogram
will be recorded. Either before or after the procedure, patients will undergo a
30-minutes assessment of spontaneous ESB, again with blood pressure and ECG
recordings.
Comparator: 10 dual-chamber pacemaker patients without heart failure (control
group).
Outcome: Evoked PESP-BP (blood pressure differences between baseline, ESB and
post-ESB)
Time schedule: 15 minutes evoked PESP-BP assessment; 30 minutes spontaneous ESB
assessment; no follow-up necessary.

In this study, the intervention is the small EPS as previously described.

Subjects do not have a direct benefit from the study, as participation will not
change treatment or prognosis. The study will cause no harm to the subjects*
health. However, measurements will add a maximum of 15 minutes to the length of
the procedure.

A provoked atrial or ventricular ESB might have a pro-arrhythmic effect.
However, the chance that an ESB will provoke a ventricular arrhythmia very
small. Recently, we performed comprehensive electrophysiological tests for the
assessment of the excitability of VT/VF in 64 primary prevention ICD patients
within the No RisC Study (METc studynumber NL19680.029.08) . This stimulation
protocol consisted of a maximum 3 consecutive extrastimuli with different and
very short cycle lengths provoked in the right ventricular apex. During these
stimulation tests, 36 patients did not develop VT or VF, in 10 patients VT/VF
occurred after 2 consecutive extrastimuli and in 18 patients VT/VF occurred
after 3 consecutive extrastimuli. Furthermore, all VTs occurred after an ESI
below 300 msec. None of the patients developed VA based on one extrastimulus
[17]. Since the stimulation protocol of the A PRIORY STUDY will only provoke
one extra stimulus per cycle, with an ESI *300 msec, the chance of a developed
VA is very small. Furthermore, the study will be performed at the cardiac
catheterization laboratory, with a highly trained professionals and a crash car
directly available.