Left ventricular septal pacing: Potential application for Cardiac Resynchronization Therapy

Cardiac pump function depends on physiological electrical activation of the
ventricles. This normal activation is disturbed during artificial electrical
stimulation (pacing) of the right ventricle (RV), the common therapy to treat
symptomatic slow heart rate (*rate control*), as well as during electrical
dyssynchrony such as left bundle branch block (LBBB). As a consequence, RV
pacing and LBBB reduce cardiac pump function and increase cardiac morbidity and
mortality. During the last two decades cardiac resynchronization therapy (CRT)
has emerged as treatment to *resynchronize* ventricular electrical activation
by pacing the RV and left ventricular (LV) postero-lateral wall almost
simultaneously (*biventricular* (BiV) pacing).

Since initial approval of the therapy over 10 years ago, there have been
hundreds of thousands of implants worldwide. In the Netherlands currently more
than 2000 CRT devices are implanted each year. Large clinical trials have shown
that CRT improves LV systolic pump function, reverses structural remodeling,
improves quality of life and exercise tolerance, and decrease mortality.
However, a significant proportion of apparently suitable patients fail to
benefit. Depending on the definition used, the response to CRT is positive in
50-70% of treated patients, leaving 30-50% without significant effect. One of
the problems of CRT is proper positioning and fixation of the LV pacing lead in
the coronary vein.

Research in our laboratory revealed that in dogs with AV-block and in patients
with sinus node disease, pacing at the LV endocardial side of the
interventricular septum (LV septal pacing) provides near physiological
ventricular activation, near uniform distribution of workload, and near normal
pump function. Furthermore, pump function during LV septal pacing was also at
least as good as during BiV pacing. A recent study, with acute hemodynamic data
in dogs with LBBB and in a small group of patients with LBBB, further indicates
that LV septal pacing may be used for CRT, either as single site pacing or in
combination with pacing the RV. A weakness of the patient data is that these
patients were either non-responders to conventional CRT or patients where no
access to the coronary sinus was obtained. Therefore, this group may not be
representative for the entire CRT candidate population.

Two factors appear to determine the positive effect of LV septal pacing: the
slow impulse conduction across the interventricular septum and the fast impulse
conduction along the inner layers of the LV wall through superficial,
non-Purkinje fibers. Following this reasoning, we expect that the exact pacing
site at the septum is not critical. This would be of great advantage for future
applications in patients, since proper implantation of an LV lead in the
coronary sinus requires attention in order to position the lead in the latest
activated region.

The aim of the present study is to compare the electrophysiological and
hemodynamic effects of several modes and sites of LV septal pacing with those
of BiV pacing in patients. The results may have a larger impact on future
pacing therapy. The LV septum may become an alternative for BiV pacing, but
easier to apply, less invasive, and more cost-effective.

Primary objectives:
* To show non-inferiority in acute hemodynamic effect between the best LV
septal pacing side and conventional BiV pacing in heart failure patients who
are candidates for CRT. Conventional BiV pacing is defined by simultaneously
pacing the RV apical septum and LV epicardial postero-lateral wall. The acute
hemodynamic effect will be assessed by the invasive quantitative LVdP/dtmax
measurement.

Secondary objectives:
* Compare the differences in acute hemodynamic effect between the different LV
septal pacing sides and pacing the RV apical septum, His bundle, RV septum, LV
epicardial postero-lateral wall, and intrinsic ventricular activation.
* To investigate the effect of LV septal pacing on the sequence of LV
electrical activation assessed by 3-dimensional vectorcardiography (VCG) and
noninvasive body surface electrocardiographic mapping using the Verathon
Heartscape system (developed by Medtronic).

The present study will investigate the acute hemodynamic effect of LV septal
pacing. Thirty consecutive patients who have an indication for CRT according to
current international guidelines will be included.

Study measurements: during the study an extra pacemaker lead will be place on
either side of the septum (one in the LV and one in the RV). The positions of
the pacemaker lead will be varied and during the different locations of the
pacemaker leads various measurements will be performed. During each position,
the electrical activation of the heart will be measured using a
vectorcardiogram and the Verathon Heartscape system. Furthermore, the acute
hemodynamic response to CRT is assessed for each pace location using invasive
LV dP/dtmax.

Extra invasive acute hemodynamic measurements (LVdP/dtmax) measurements will be
performed during CRT implantation. The invasive measurements will be used to
compare different locations of LV septal pacing with conventional BiV pacing.

Invasive acute LVdP/dtmax measurements are performed with a PressureWire, which
is inserted via the femoral artery into the LV cavity using the retrograde
aortic approach. Using this same entry, the temporary LV pacing electrode or LV
steerable EP catheter is placed into the LV cavity. Local vascular
complications of femoral artery puncture like bleeding, infection or damage to
the vessel wall may occur but are rare. Complication rates have never been
published, but will likely not exceed the complication rate of 1.6% observed
after diagnostic cardiac catheterization. The LVdP/dtmax measurements by
themselves are not harmful for the patient.

The temporary EP catheter used to perform temporary His pacing and RV septum
pacing, uses the femoral vein as entry point. Since this entry point is very
close to the femoral artery used for the LV pacing electrode or LV steerable EP
catheter and PressureWire (as described above) no additional anaesthetics are
needed. Beside a possible haematoma at the inguinal, no other complications are
expected. The additional steps taking for the study are His pacing and RV
septal pacing. Cardiac complications of pacing the His or the RV with the EP
catheter have never been reported and is therefore not considered to carry any
risks for the patient.

The placement of the temporary RV septal steerable electrophysiology (EP)
catheter, the temporary LV pacing electrode or LV steerable EP catheter and the
PressureWire may require a longer fluoroscopy time than usual. During standard
CRT implantation patients are exposed to an average radiation dose of 400 mGy.
The extra radiation dose will be no more than 25% (100 mGy), which is
comparable to the average 1 year background radiation in the Netherlands.
Furthermore, the placement of the temporary RV septal steerable EP catheter,
the temporary LV pacing electrode or LV steerable EP catheter as well as the
intra-procedural measurements with VCG, Verathon Heartscape system, and
invasive LVdP/dtmax measurements will increase the total procedure time by a
maximum of 1 hour, thus increasing discomfort for the patient. There are no
direct benefits for the patient when participating in this study. However, if
the current study can validate the use of LV septal pacing in CRT candidates,
CRT becomes easier to apply, less invasive, and more cost-effective.
Furthermore, LV septal pacing in CRT candidates can also be performed in
patients with an inaccessible coronary sinus and/or in patients with phrenic
nerve stimulation.