Left ventricular septum pacing in patients by transvenous approach through the inter-ventricular septum - feasibility, long-term lead stability and safety

In the Netherlands each year, approximately 8000 patients receive a pacemaker
(PM) for bradycardia and 2000 patients receive a biventricular (BiV) PM for
cardiac resynchronization therapy (CRT).

Cardiac pacing is the only effective treatment for symptomatic bradycardia.
After the introduction of the implantable PM, the right ventricular apex (RVA)
has become the most frequently used ventricular pacing site. However, clinical
studies have shown that RVA pacing leads to left ventricular (LV) dyssynchrony,
and on the long run to adverse structural changes (remodeling), a higher risk
of developing atrial fibrillation and heart failure, and higher mortality.

CRT has become increasingly important for the treatment of heart failure when
accompanied by intraventricular conduction delay. Large clinical trials have
shown that CRT improves LV systolic pump function, reverses structural
remodelling, improves quality of life and exercise tolerance, and decreases
mortality. Unfortunately, problems encountered during positioning and fixation
of the LV pacing lead in the coronary vein result in suboptimal or loss of CRT
in at least a quarter of CRT candidates and require re-operation in 7% during
follow up.

Over the last years alternate pacing sites have been investigated to overcome
the adverse effects of RVA pacing and the limitations of BiV pacing. Recent
studies in animals have shown that pacing at the LV septum induces
significantly less ventricular dyssynchrony than RVA pacing and is able to
improve LV function to a similar degree as BiV pacing. In the animal
experiments the LV septum lead was permanently placed by introducing a custom
pacing lead with extended screw (Medtronic 09066 lead) transvenously into the
RV cavity and positioning it against the RV septum using a guiding catheter,
and then driving it from the RV side through the inter-ventricular septum into
the LV endocardial layer. This was shown to be a feasible and safe procedure
and lead stability was shown during four months of follow-up.

The Medtronic 09066 lead is derived from the market released Medtronic Select
Secure lead model 3830 and is placed by standard transvenous right ventricular
approach using a standard market released guiding catheter. The lead is
designed to provide the handling characteristics needed to screw the distal
portion of the lead into the LV septal wall starting from the RV side. For this
application the standard 3830 lead has been modified by extending the screw tip
of the lead from 2 to 4 mm. The further composition of the lead has been left
unchanged. In the animal study, 09066 leads were implanted in 11 canines as
described above. Trans-septal lead placement at the desired LV septal location
was shown to be a feasible and safe procedure. Except for insufficient lead tip
penetration in only one case, no other procedure- or lead related complications
(e.g. septum perforation/-rupture or lead-/screw dislocation/-fracture) were
observed during 16 weeks follow-up or at the post-mortem evaluation.
Furthermore, the leads remained mechanically and electrically stable during the
follow-up period in otherwise healthy and active canines. In addition, it was
shown that the 4 mm long screw has much better fixation than the standard 3830
2mm screw of which 4 out of 7 implanted dislocated within the first week of
follow-up.

The abovementioned adverse effects of RVA pacing, the limitations of BiV pacing
and the promising effects of LV septum pacing in preclinical studies have led
to the idea that LV septum pacing is an attractive alternative for treating
patients with a standard ventricular pacing indication, as well as patients
with an indication for BiV pacing. In the latter category, CRT could then be
performed using a single ventricular pacing lead, thus limiting the number of
lead implantations, and thereby reducing complication rate and implantation
costs as well as avoiding the difficult access route through the coronary
vein.

It is the aim of this study to translate the findings from preclinical studies
to the clinical situation by investigating in an initial phase 1 study the
feasibility, long-term lead stability and safety of LV septum pacing by
transvenous approach through the inter-ventricular septum in patients with a PM
indication.The results may have a large impact on future pacing therapy. The LV
septum may become the universal pacing site, being preferred for
anti-bradycardia therapy, and being an equal alternative for BiV pacing, but
easier to apply, less invasive and more cost-effective.

Primary objectives:
• To determine the feasibility of LV septum lead placement by transvenous
approach through the inter-ventricular septum in patients with sinus node
dysfunction (SND) and structurally normal hearts, as well as in patients with
heart failure and LBBB who are candidates for CRT.
• To determine the long-term (6 months) stability of the LV septum lead in
these patients.
• To evaluate the safety of the LV septum lead in these patients.

Secondary objectives:
• To investigate the acute hemodynamic effect of LV septum pacing on LV
systolic function, assessed by invasive quantitative LVdP/dtmax measurement and
non-invasive quantitative LV stroke volume measurement using Nexfin, as
compared to:
- RVA pacing and intrinsic ventricular activation in patients with SND.
- RVA pacing, LV only pacing, BiV pacing and intrinsic ventricular activation
in heart failure patients who are candidates for CRT.
• To investigate the effect of LV septum pacing on the sequence of LV
electrical activation assessed by ECG and 3-dimensional vectorcardiogaphy
(VCG).
• To investigate the effect of LV septum pacing on distribution of myocardial
strains, assessed by SPECKLE-tracking echocardiography.
• To correlate the non-invasively measured LV stroke volume using Nexfin and
the invasively determined LV dP/dt|max.

The present study is a prospective cohort study to investigate the feasibility,
long-term lead stability and safety of LV septum pacing by transvenous approach
through the inter-ventricular septum in patients with SND and CRT candidates.
In addition, the effects of LV septum pacing on LV systolic function, sequence
of LV electrical activation and distribution of myocardial strains in these
patients is evaluated.

Every patient who is enrolled in the study has a PM indication. Patients with
SND receive a standard dual chamber PM and CRT candidates receive a BiV PM.
Pacing leads are placed via standard transvenous approach by cephalic cut down
and/or subclavian puncture. The atrial lead and the LV lead used for BiV pacing
in CRT candidates are placed in the conventional positions. Subsequently, the
implantation procedure differs from a standard (BiV) PM implantation in the
following way: Instead of placing a pacing lead in the conventional RVA
position, a lead will be placed in the LV septum by driving a lead from the RV
to the LV side of the interventricular septum. For this purpose, we will use
the newly developped Medtronic lead model 09066, which is derived from the
market released Medtronic 3830 Select Secure lead. This lead which is fit with
a tip with an extended screw is positioned against the RV side of the
interventricular septum using a commercially available ventricular septum
delivery catheter which is inserted transvenously. Subsequently the pacing
electrode is advanced to the LV endocardial layer of the septum by driving the
lead through the inter-ventricular septum. Intracardiac echocardiography (ICE)
is used to guide LV septum lead placement. Proper position within the inner 1
mm of the septum is secured by fluoroscopy and by advancing the screw forward
until pacing thresholds increase, indicating that the electrode is entering the
LV cavity. Then the lead is slowly withdrawn until normal pacing thresholds are
achieved. After achieving adequate sensing values and pacing thresholds, the
leads are connected to a dual chamber PM in SND patients and a BiV PM in CRT
candidates, which is placed subcutaneously. Feasability of this implantation
method using the lead model 09066 has been previously demonstrated in canine
hearts. After implantation, the leads remained mechanically and electrically
stable in healthy and active animals during the follow-up period of 16 weeks.

This is the first application of this pacing method in patients. Therefore, the
risk of certain complications like inter-ventricular septum perforation or
-rupture or screw fracture is still unknown. However, the feasibility,
long-term lead stability and safety of trans-septal LV septum pacing has been
demonstrated in animal experiments and was comparable to conventional pacing
methods. Therefore, additional procedure- or lead related risks are not
expected for the study subjects.

Intracardiac echocardiography (ICE) will be used as an extra visualization tool
to guide lead implantation. Cardiac complications due to ICE have never been
reported. Therefore ICE by itself is not known to carry any risks for the
patients. The 8 F ICE catheter is introduced into the right ventricular (RV)
cavity via the femoral vein. Before femoral vein puncture, local anaesthetics
will be administered which may cause a burning sensation. Local vascular
complications due to femoral vein puncture like bleeding or infection may occur
but are very rare. Complication rates have never been published.

Following trans-septal LV septum lead placement, acute invasive hemodynamic
measurements are performed by inserting a RADI pressure wire via the femoral
artery into the LV cavity to determine maximal rate of LV pressure rise (LV
dP/dt|max) as a measure of LV systolic function2 during various pacing
configurations. Cardiac complications of the RADI pressure wire have never been
reported. Therefore the wire by itself is not known to carry any risks for the
patients. 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.

Subsequently, LV stroke volume measurements will be performed non-invasively
during the same pacing configurations using the Nexfin technique. Nexfin uses
an inflatable cuff that is placed around the mid-phalanx of the middle finger
to measure finger blood pressure in combination with calibrated volume-clamp
photoplethysmography. There are no risks involved with this procedure.

LV septum lead placement and all following invasive and non-invasive
hemodynamic measurements will increase the total PM implantation time by a
maximum of 1 hour.

ECG recordings, 3- dimensional QRS vector diagrams (VCG) and echocardiograms
are performed at 4-6 weeks follow-up during various pacing configurations.
These evaluations do not involve any risks for the patients, but require one
extra visit to the hospital.

PM check-ups to evaluate lead stability will be performed the first day after
implantation, 10 days (window: 5 - 15 days) after implantation, and 3 months
(window: 10 - 14 weeks) as well as 6 months (22 - 26 weeks) after implantation.
After 6 months, pacemaker check-up will be performed every 6 months, until
study closure. The PM check-up at 3 months post implantation is not part of
routine care and requires an extra visit to the hospital. Patients are not
exposed to any risks during the PM check-up.