Mechanistic insight in left ventricular septal and left bundle branch pacing.

The efficiency of cardiac pump function depends on synchronous electrical
activation of the ventricles. The normal, synchronous activation sequence is
disturbed during conduction system disease like left bundle branch block (LBBB)
and during artificial electrical stimulation (= pacing) of the right ventricle
(RV). RV pacing is, despite the known detrimental effects, the common therapy
to treat symptomatic slow heart rate. The RV pacing site has become the
preferred site as it is easily accessible and because it yields chronically
stable lead performance. However, as a consequence of disturbed electrical
activation, RV pacing and LBBB reduce cardiac pump function and increase
cardiac morbidity and mortality.(2, 3) RV pacing in combination with left
ventricular (LV) pacing (RV + LV pacing = cardiac resynchronization therapy;
CRT) is the common therapy to treat patients with RV pacing or LBBB who develop
heart failure.
Under normal, physiological conditions the electrical impulse generated in the
sinus node exits the fast-conducting Purkinje system at sites located at the LV
endocardial surface of the septum.(4, 5) It was therefore hypothesized that
pacing near these sites results in better systolic and diastolic function
compared to RV pacing. Animal studies in our lab confirmed that LV function was
maintained at normal level during ventricular septal pacing on the left side of
the interventricular septum (LV septal pacing; LVsP).(6) In these experiments
the LVsP lead was permanently implanted by introducing a adapted pacing lead
transvenously into the RV and driving it from the RV side through the
interventricular septum (IVS) to the left side of the septum. This was shown to
be a feasible and safe procedure, and leads remained mechanically and
electrically stable during 4-month follow-up.(7) Furthermore, cardiac pump
function during LVsP was at least as good as during BiV pacing (BVP),
indicating that LVsP could be applied in CRT. Subsequently a first-in-man
study performed in our center demonstrated the feasibility of permanently
implanting a LVsP lead in symptomatic sinus node disease patients using a
transvenous approach through the interventricular septum.(8)

More recently, it was observed in a patient with heart failure and LBBB that in
LVsP the left bundle branch (LBB) could be stimulated. In this patient, pacing
the LBB completely resolved the conduction block.(9) At 1-year follow-up the
left ventricular ejection fraction (LVEF) increased from 32% to 62% and LV
end-diastolic volume decreased from 76 mm to 42 mm. These results were
confirmed by Zhang and colleagues who demonstrated mechanical as well as
electrical resynchronization in eleven consecutive patients with heart failure
(HF), reduced LVEF and LBBB.(10) At a mean follow-up period of 7 months, NYHA
functional class, BNP plasma level, LV end diastolic diameter, and LVEF were
significantly improved. This new pacing technique has also been investigated in
bradycardia patients without heart failure. In a study of 33 patients with
atrioventricular block (AVB), Li et al.(11) reported that LBB pacing had
slightly improved cardiac function and left ventricular synchronization by
2-dimensional echocardiographic strain imaging at the 3-month follow-up
compared with that at baseline. These results were confirmed in a larger study
performed in 56 patients with normal cardiac function, where all patients
survived without any symptoms of heart failure during a mean follow-up of 5*±*2*
months. LVEF, LV end systolic diameter, and LV end diastolic diameter remained
unchanged during follow-up.(12)
However, the LBB is not always captured and reported success rates range from
81%(13) to 93%(14). Despite the many recent publications regarding LBB pacing,
there are still many unknowns that need to be investigated. Three main unknowns
are 1) optimal septal lead depth , 2) the effect of additional LBB capture, and
3) long-term clinical benefits.

LVsP/LBB pacing has great potential in future cardiac pacing therapy with
possibly a wide application. It is, therefore, of importance to obtain more
mechanistic insight in this therapy.


References:
1. Rademakers LM, van Hunnik A, Kuiper M, Vernooy K, van Gelder B, Bracke FA,
et al. A possible role for pacing the LV septum in cardiac resynchronization
therapy. JACC Clin Electrophysiol. In press.
2. Nielsen JC, Kristensen L, Andersen HR, Mortensen PT, Pedersen OL, Pedersen
AK. A randomized comparison of atrial and dual-chamber pacing in 177
consecutive patients with sick sinus syndrome: echocardiographic and clinical
outcome. J Am Coll Cardiol. 2003;42(4):614-23.
3. Sweeney MO, Hellkamp AS, Ellenbogen KA, Greenspon AJ, Freedman RA, Lee KL,
et al. Adverse effect of ventricular pacing on heart failure and atrial
fibrillation among patients with normal baseline QRS duration in a clinical
trial of pacemaker therapy for sinus node dysfunction. Circulation.
2003;107(23):2932-7.
4. Durrer D, van Dam RT, Freud GE, Janse MJ, Meijler FL, Arzbaecher RC. Total
excitation of the isolated human heart. Circulation. 1970;41(6):899-912.
5. Myerburg RJ, Nilsson K, Gelband H. Physiology of canine intraventricular
conduction and endocardial excitation. Circ Res. 1972;30(2):217-43.
6. Peschar M, de Swart H, Michels KJ, Reneman RS, Prinzen FW. Left ventricular
septal and apex pacing for optimal pump function in canine hearts. J Am Coll
Cardiol. 2003;41(7):1218-26.
7. Mills RW, Cornelussen RN, Mulligan LJ, Strik M, Rademakers LM, Skadsberg ND,
et al. Left ventricular septal and left ventricular apical pacing chronically
maintain cardiac contractile coordination, pump function and efficiency. Circ
Arrhythm Electrophysiol. 2009;2(5):571-9.
8. Mafi-Rad M, Luermans JG, Blaauw Y, Janssen M, Crijns HJ, Prinzen FW, et al.
Feasibility and Acute Hemodynamic Effect of Left Ventricular Septal Pacing by
Transvenous Approach Through the Interventricular Septum. Circ Arrhythm
Electrophysiol. 2016;9(3):e003344.
9. Huang W, Su L, Wu S, Xu L, Xiao F, Zhou X, et al. A Novel Pacing Strategy
With Low and Stable Output: Pacing the Left Bundle Branch Immediately Beyond
the Conduction Block. Can J Cardiol. 2017;33(12):1736 e1- e3.
10. Zhang W, Huang J, Qi Y, Wang F, Guo L, Shi X, et al. Cardiac
resynchronization therapy by left bundle branch area pacing in patients with
heart failure and left bundle branch block. Heart Rhythm. 2019;16(12):1783-90.
11. Li X, Li H, Ma W, Ning X, Liang E, Pang K, et al. Permanent left bundle
branch area pacing for atrioventricular block: Feasibility, safety, and acute
effect. Heart Rhythm. 2019;16(12):1766-73.
12. Hou X, Qian Z, Wang Y, Qiu Y, Chen X, Jiang H, et al. Feasibility and
cardiac synchrony of permanent left bundle branch pacing through the
interventricular septum. Europace. 2019;21(11):1694-702.
13. Li Y, Chen K, Dai Y, Li C, Sun Q, Chen R, et al. Left bundle branch pacing
for symptomatic bradycardia: Implant success rate, safety, and pacing
characteristics. Heart Rhythm. 2019;16(12):1758-65.
14. Vijayaraman P, Subzposh FA, Naperkowski A, Panikkath R, John K, Mascarenhas
V, et al. Prospective evaluation of feasibility and electrophysiologic and
echocardiographic characteristics of left bundle branch area pacing. Heart
Rhythm. 2019;16(12):1774-82.

To demonstrate superiority of left ventricular septal pacing over right
ventricular pacing and to investigate the additional effect of capturing the
left bundle branch in left ventricular septal pacing (LVsP). This will be done
by studying differences in electrophysiological effects, measured by
electrocardiogram (ECG), vector cardiogram (VCG) and the ECG-Belt (Medtronic
product), of different LV septal pacing lead penetration depths.

The study is a multicentre prospective interventional cohort study performed in
the Maastricht UMC+ and Radboudumc to investigate the electrophysiological and
hemodynamic effects of different LV septal lead penetration depths.
Forty consecutive patients referred for pacemaker implantation will be
included. The aim is to include approximately 20 patients referred for
pacemaker implantation with structurally normal heart and approximately 20
patients referred for pacemaker implantation with reduced LV ejection fraction.

All patients eligible for study participation have a clinical indication for
permanent cardiac pacing and will receive a standard (CRT-)pacemaker
implantation whether they decide to participate in the study or not. Patients
will be recruited from the outpatient pacemaker/ICD clinic and from the
cardiology ward. Prior to implantation, they will be asked informed consent to
undergo extra measurements at the time of implantation.

Forty study participants referred for pacemaker implantation will be included.
Participants will consist of patients with structurally normal hearts
(bradycardia indication) and patients with heart failure and LBBB (CRT
indication). In both patient groups the atrial lead is positioned in the right
atrial appendage according to routine clinical practice. The LV septal pacing
lead (Medtronic 3830 lead) is positioned via transvenous approach at the right
side of the interventricular septum and advanced (screw-in) in on average 4
steps to the endocardial border of the left ventricular septum with the aim to
obtain left bundle branch capture. Electrical and hemodynamic measurements are
performed when pacing at different inter-ventricular septum penetration depths
of the pacing electrode, starting at the RV side of the inter-ventricular
septum (= baseline measurement) and advancing to mid-septum, left side of
septum and finally near the left bundle branch.

Atrio-ventricular pacing will be performed with relative short AV-delay of 80
ms ensuring ventricular capture.
Left bundle branch capture will be defined as following: 1) paced right bundle
branch block (RBBB) QRS morphology, 2) stable and short stimulus to LV
activation time (LVAT; R in V5) at high and low pacing output and 3) recorded
LBB potential.
Once the lead is positioned in an adequate stable position the lead will remain
in position and is connected to the pacemaker.
When the implantation is completed, an echocardiogram will be performed
evaluating the global and regional LV and RV contractions patterns during
intrinsic rhythm and during LV septal pacing.
Patients will undergo a routine pacemaker follow-up at 2 weeks and 3 months to
evaluate the sensing and pacing threshold values of the implanted LV septal
pacing lead and echocardiography will be performed immediately after as well as
6 months after the implantation procedure to evaluate LV dimensions.

All study participants have a clinical indication for permanent cardiac pacing
and will receive left ventricular septal pacemaker implantation as part of
their routine medical care. The intra-procedural measurements with VCG,
Verathon Heartscape system, and the invasive blood pressure measurements are
not part of routine medical care. The burden and risks of these study
procedures are described below:

1. Blood pressure is invasively measured via the femoral artery by connecting
the femoral sheath directly to the standard blood pressure measurement system
as is standard practice in coronary angiography (CAG) procedures. Local
vascular complications of the arterial 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. Heparin will be administered
as part of standard procedure.

2. VCGs are constructed post-procedure from the routine 12-lead ECGs using the
Kors matrix and will therefore not require any additional action.

3. Verathon Heartscape system (*ECG-Belt)* measurements are performed using a
55-electrode body surface mapping system developed by Medtronic. The belt is
placed prior to the procedure and the patient has to wear this belt during the
procedure. Since the measurements are of non-invasive nature and that they are
not diagnostic, they do not expose the patient to any risks.

Performing all measurements during the implantation including will lengthen
procedure time by a maximum 30 minutes, this increasing the burden for the
patient.