Pugazhendhi Vijayaraman Cardiac Conduction System

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. -, NO.
-, 2023
ª 2023 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
STATE-OF-THE-ART REVIEW
Cardiac Conduction System Pacing

A Comprehensive Update
Pugazhendhi Vijayaraman, MD,a Mihal G. Chelu, MD, PHD,b Karol Curila, MD, PHD, MSC,c Gopi Dandamudi, MD,d
Bengt Herweg, MD,e Shumpei Mori, MD, PHD,f Marek Jastrzebski, MD, PHD,g Parikshit S. Sharma, MD, MPH,h
Kalyanam Shivkumar, MD, PHD,f Roderick Tung, MD,i Gaurav Upadhyay, MD,j Kevin Vernooy, MD, PHD,k
Allan Welter-Frost, MD, MPH,l Zachary Whinnett, MD,m Francesco Zanon, MD,n Kenneth A. Ellenbogen, MDo
ABSTRACT
The field of cardiac pacing has changed rapidly in the last several years. Since the initial description of His bundle pacing
targeting the conduction system, recent advances in pacing the left bundle branch and its fascicles have evolved. The
field and investigators’ knowledge of conduction system pacing including relevant anatomy and physiology has advanced
significantly. The aim of this review is to provide a comprehensive update on recent advances in conduction system
pacing. (J Am Coll Cardiol EP 2023;-:-–-) © 2023 by the American College of Cardiology Foundation.
T he field of cardiac pacing has changed rapidly

over the last several years. Since the initial
description of His bundle pacing (HBP) tar-
geting the conduction system, recent advances in
recent developments in CSP. This review highlights
topics and concepts discussed at the Sixth Annual
Physiology of Pacing Symposium
left bundle branch pacing (LBBP) and its fascicles NEW INSIGHTS INTO CARDIAC ANATOMY OF
has increased implant options for physiological pac- THE CONDUCTION SYSTEM
ing. New insights into conduction system pacing
(CSP), including relevant anatomy and physiology, Revisiting the clinical anatomy of the conduction
have made physiologic pacing a relevant choice for system 1 from the viewpoint of clinicians is a neces-
all pacing indications. The aim of this state-of-the sary step to appreciate the crucial and elegant dis-
art review is to provide a comprehensive update on covery made by Prof Sunao Tawara over a hundred
From the aGeisinger Heart Institute, Geisinger Commonwealth School of Medicine, Wilkes-Barre, Pennsylvania, USA; bDivision of
Cardiology, Baylor College of Medicine and Baylor St. Luke’s Medical Center and Texas Heart Institute, Houston, Texas, USA;
c
Cardiocenter, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Re-
public; dVirginia Mason Franciscan Health, Seattle, Washington, USA; eUniversity of South Florida Morsani College of Medicine,
Department of Cardiovascular Sciences, Tampa, Florida, USA; fUniversity of California Los Angeles (UCLA) Cardiac Arrhythmia
Center, UCLA Health System, David Geffen School of Medicine at UCLA, Los Angeles, California, USA; gFirst Department of
Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University, Medical College, Krakow, Poland;
h
Department of Cardiology, Rush University School of Medicine, Chicago, Illinois, USA; iDivision of Cardiology, University of
Arizona College of Medicine-Phoenix, Banner-University Medical Center, Phoenix, Arizona, USA; jDepartment of Cardiology,
Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, the Netherlands; kCenter for
Arrhythmia Care, Heart and Vascular Center, University of Chicago, Chicago, Illinois, USA; lCleveland Clinic Indian River Hospital,
m
Heart Vascular and Thoracic Institute, Vero Beach, Florida, USA; National Heart and Lung Institute, Imperial College, London,
United Kingdom; nSanta Maria della Misericordia Hospital, Rovigo, Italy; and the oDivision of Cardiology, Virginia Commonwealth
University School of Medicine, Richmond, Virginia, USA.
Michael Gold, MD, served as Guest Associate Editor for this paper. William Stevenson, MD, served as Guest Editor-in-Chief for this
paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received April 4, 2023; revised manuscript received May 10, 2023, accepted June 2, 2023.
ISSN 2405-500X/$36.00 https://doi.org/10.1016/j.jacep.2023.06.005

2 Vijayaraman et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. -, NO. -, 2023
Conduction System Pacing - 2023:-–-
ABBREVIATIONS years ago. Tawara discovered the atrioven-

AND ACRONYMS HIGHLIGHTS
tricular (AV) node and established the
concept of the AV conduction system as we HBP and the recent advances in LBBAP
3D = 3-dimensional
understand it now.2 His work proved the have increased the physiologic pacing
AV = atrioventricular
anatomic link from the AV node to the bundle options.
BVP = Biventricular pacing
of His (penetrating portion of the AV bundle),
CRT = cardiac New insights into the anatomy and
its division into the left and right bundle
resynchronization therapy physiology of conduction system pacing
branches, and Purkinje fibers. His assump-
CSP = conduction system are clinically relevant.
tion that the conduction velocity of excita-
pacing
ECGi = electrocardiographic
tion in the AV conduction system, except Confirmation of conduction system cap-
imaging within the AV node, would be fast has sub- ture and restoration of electrical syn-
e-DYS = electrical
sequently proven to be correct.2 His meticu- chrony is essential for successful CRT.
dyssynchrony lous micro- and macroscopic observations
Large-scale randomized clinical trials are
HBP = His bundle pacing eventually enabled him to “draw” one of his
necessary to establish the role of CSP in
HOT = His optimized classic illustrations (Figure 1).
the management of bradycardia and heart
IVCD = intraventricular
Following the discovery made by the pio-
failure.
conduction delay neering work of Purkinje, His, and Tawara,2
LBBB = left bundle branch numerous insights on the cardiac conduc-
especially in the human hearts but can be approxi-
block tion system have accumulated over the last
mated as shown in Figures 1 and 2.
LBBAP = left bundle branch century,3-7 revealing complexity and varia-
area pacing
tions of anatomy and function of the AV
LBBP = left bundle branch conduction system in mammalian hearts. HEMODYNAMICS OF CSP
pacing 8
The work of Dr Wallace A. McAlpine using
LOT = left bundle branch
pressure-perfused and fixed human hearts Acute hemodynamic measurements reflect acute
optimized
provides an excellent appreciation of anat- changes in cardiac function that can be quantified and
LV = left ventricle
omy for electrophysiologists. Another are therefore a useful tool in guiding the develop-
LVEF = left ventricular ejection
approach using micro–computed tomography ment of new pacing approaches.17 These measure-
fraction
also provides promising direction to demon- ments allow the immediate impact of pacing therapy
LVAT = left ventricular
activation time strate the clinically relevant anatomy of the to be evaluated, which allows different pacing ap-
LVSP = left ventricular septal conduction system. 9 McAlpine’s approach proaches to be compared within the same patient.
pacing allows us to dissect the central components Early studies of right ventricular pacing (RVP), in
ns = nonselective of the AV conduction system in the context of patients with severe bradycardia caused by complete
RBBB = right bundle branch the nondistorted heart (Supplemental heart block, observed large acute hemodynamic im-
block Figures 1 and 2).10 When removing epicar- provements. When cardiac resynchronization therapy
RV = right ventricle dial adipose tissue from the inferior pyrami- (CRT) with biventricular pacing (BVP) was developed,
RVP = right ventricular pacing dal space, 11 the inferoseptal process of the the observation of improvement in acute hemody-
s = selective left ventricle (LV) 8,10,12 and AV nodal artery namic measurements provided the justification for
SDAT = standard deviation of are unveiled. Here, the AV node can be chronic implantation and investigation in long-term
the ventricular activation time localized to the right side of the central outcome studies. 18,19
V6RWPT = V6 R-wave peak fibrous body (right fibrous trigone) before CSP using HBP or left bundle branch area pacing
time penetrating it (Figure 2), revealing the AV (LBBAP) has the potential to restore or preserve
VAT = ventricular activation node as an epicardial structure. The tendon normal physiological activation (Central Illustration).
time
of Todaro connecting to the central fibrous LBBAP includes both LBBP where there is clear evi-
UHF = ultra-high frequency
body can also be macroscopically dissected 8 dence of direct LBB capture and left ventricular septal
to show the real 3-dimensionality (3D) of the trian- pacing (LVSP) without direct capture of the LBB.
gle of Koch. 13-16 Histological data can be placed in the Acute hemodynamic studies have been used to
context of a nondistorted heart viewed from clinically compare CSP with RVP and BVP and to compare
familiar angles (Supplemental Figures 1 and 2). different methods for delivering CSP. The findings
Furthermore, these accumulated insights allow us to from these studies are summarized in this review.
digitally reconstruct a virtual AV conduction system Hemodynamic measures are not static; there are
in a 3D nondistorted heart,13 which is very useful to considerable natural variations caused by the
conceptualize CSP (Figure 2, Supplemental Figures 3 numerous biological phenomena, including respira-
and 4). Dissection and visualization of bundle tion and other autonomic phenomena. It is important
branches and Purkinje fibers remain challenging to take steps to minimize the impact of the
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. -, NO. -, 2023 Vijayaraman et al 3
- 2023:-–- Conduction System Pacing
F I G U R E 1 Tawara’s Illustration and Its 3D Reconstruction
Tawara’s classic illustration of the atrioventricular conduction system2 (A) was reconstructed on the three-dimensional (3D) field (B-D) created from the computed
tomographic data set obtained from a pressure-perfused and fixed heart.1 (B-D) Apical 2- (B), 3- (C), and 4-chamber (D) sections. These digital data sets can be used to
produce 3D printing models. Note that for the apical 4-chamber section (D), the paired piece of the one usually seen during transthoracic echocardiography is selected to
show the substantial portions of the conduction system.
spontaneous biological variability on the overall can adversely affect cardiac function in susceptible
findings, otherwise the results of the study may be individuals. 21 CSP aims to deliver more physiological
18
misleading. This can be done by keeping heart rate ventricular activation and thereby avoid the detri-
constant, averaging multiple beats, making a com- mental effects on cardiac function. The findings from
parison to a reference setting, and taking multiple acute hemodynamic studies 22-26 suggest that CSP
repeated measurements.19,20 achieves these objectives.
Keene et al22 performed a within patient compari-
CSP VS RVP: BRADYCARDIA INDICATIONS. RVP son of HBP and RVP in 18 patients with intermittent
produces nonphysiological ventricular activation that heart block and mean left ventricular ejection fraction
F I G U R E 2 Conduction System Pacing
Fluoroscopic images (A,B) show the His-bundle pacing (yellow arrowheads). White arrowheads indicate the stent placed in the distal right coronary artery. Virtual
simulation images viewed from the right anterior oblique direction (C,D) show the His-bundle pacing (red), and left bundle branch pacing (white, green). (C) The
estimated location of components of the atrioventricular conduction system (refer to Supplemental Figure 3A). (D) The relevant structures, including the membranous
septum and septal tricuspid leaflet, of the conduction system. From images C and D, it is reasonable to estimate that the potential risk of tricuspid regurgitation induced
by the mechanical interaction between active fixation leads and septal tricuspid leaflet, including impingement, perforation, and entrapment, will be minimized if the lead
(red) is fixed near the commissure between the septal and anterosuperior tricuspid leaflets, or if the lead (green) is fixed sufficiently distant from the tricuspid annulus.
Also, image D suggests the potential risk of perforation of the membranous septum during His-bundle pacing. (A,B) Images courtesy of Dr Chung Wei-Hsin. (C,D) Virtual
images were created using commercially available workstation (Ziostation2, version 2.9.8.4; AMIN Co, Ltd; Ziosoft Inc with post hoc modification using dedicated
volume-rendering software (SARA-Engine, pita4 mobile LLC).
(LVEF) of 44%. HBP delivered a shorter QRS duration P < 0 .0001) compared to RVP. 22 Zanon et al23 per-
(56 milliseconds; 95% CI: 67 to 46 milliseconds; formed a within-patient comparison of myocardial
P < 0 .0001) and improved acute systolic blood pres- perfusion, using scintigraphy with technetium 99m
sure by mean of 5.0 mm Hg (95% CI: 2.8-7.1 mm Hg; Tc-methoxy isobutyl isonitrile after 3 months of His
C E N T R A L ILL U ST R A T I O N Conduction System Pacing: Anatomic Location and ECG Responses of Conduction System
Pacing Are Shown
Vijayaraman P, et al. J Am Coll Cardiol EP. 2023;-(-):-–-.
bundle and RVP. They observed that myocardial global longitudinal strain and increase in peak sys-
perfusion during HBP was significantly better than tolic dispersion and left atrial volume index after
during RVP (0.44 0.5 vs 0.71 0.53, respectively; 6 months in patients receiving RVP. Whereas global
P ¼ 0.011).23 Michalik et al24 compared HBP and RVP longitudinal strain was unchanged and peak systolic
in patients with AV conduction disorders and pre- dispersion and left atrial volume index decreased in
served LVEF. They found that there was a decline in patients who received HBP.24 In contrast, however,
Wen et al 25 did not observe a difference in strain may occur in the proximal LBB, in which case the
measurements after 6 months in patients receiving conduction system needs to be targeted more distally
LBBAP and RV septal pacing.25 using LBBAP to restore normal LV activation. In pa-
tients with nonspecific intraventricular conduction
CSP VS BVP FOR CRT. Left bundle branch block
delay, VAT may be prolonged because of intra-
(LBBB) results in delayed and dyssynchronous acti-
myocardial disease with intact Purkinje activation,
vation of the LV, which is deleterious in patients with
and VAT is unlikely to be corrected with CSP.
heart failure. BVP improves the activation pattern,
Zweerink et al 28 evaluated the effectiveness of His
shortening left ventricular activation time (LVAT) and
bundle optimized (HOT)-CRT in 19 patients where
improving cardiac function. Long-term studies have
HBP failed to shorten QRS duration. The HOT-CRT
demonstrated substantial reduction in morbidity and
approach combines HBP with LV pacing using a cor-
mortality in patients with heart failure. However, it is
onary venous lead with pacing that is “optimized”
not always possible to implant a lead in the coronary
between the 2 leads to produce the narrowest fused
sinus, and BVP delivers only relatively modest im-
QRS width between the intrinsic conduction system
provements in QRS duration and VAT. AV delay
and LV epicardial stimulation. They recruited pa-
shortening in addition to ventricular resynchroniza-
tients with LV impairment and a range of different
tion appears to be an important mechanism through
ventricular conduction abnormalities. They found
which BVP delivers improvement in acute hemody-
that the HOT-CRT pacing configuration produced a
namic function. Supporting this hypothesis, it was
24% greater reduction in LVAT compared to BVP-CRT
shown that HBP delivered to retain native LBBB
(LVAT: 22 milliseconds; 95% CI: 33 to 10 milli-
activation (ie, without correction of LBBB) and
seconds; P ¼ 0.002). These findings suggesting that
delivered two-thirds of the hemodynamic improve-
HOT-CRT is a promising approach for patients in
ment delivered by BVP: 5.1 mm Hg (95% CI: 2.0-8.2;
which CSP alone fails to deliver ventricular
P ¼ 0.0026) and 7.1 mm Hg (95% CI: 3.6-10.7; P <
26 resynchronization.
0.001). CSP has therefore been investigated as an
alternative to BVP in cases of failure to implant an LV LBBAP VS BVP. LBBAP offers several potential tech-
lead via the coronary sinus, and also to determine nical advantages, compared to HBP using currently
whether it can provide more effective ventricular available tools, including low and stable thresholds,
resynchronization. the potential to treat more distal conduction system
disease, and potentially a faster learning curve.29
HBP BUNDLE CRT VS BVP-CRT. A within-patient
Liang et al 30 undertook an acute within-patient
comparison of the effects of His bundle CRT and
comparison of LBBAP with BVP in patients with
BVP-CRT, on ventricular activation (measured using
LBBB and LV impairment mainly caused by non-
electrocardiographic imaging [ECGi]) and acute he-
ischemic cardiomyopathy. They observed that LBBAP
modynamic function, was performed in patients with
produced a significantly greater reduction in QRS
heart failure and LBBB. In 18 of 23 patients, LVAT was
duration compared to BVP (11 milliseconds;
significantly shortened by HBP-CRT. In these pa-
95% CI: 17 to 4 milliseconds; P ¼ 0.003) and greater
tients, HBP-CRT delivered more effective ventricular
reduction in QRS area (85 m Vs; 95% CI: 113 to 56
resynchronization than BVP-CRT (LVAT: 26 milli-
mVs; P < 0.001). This improved ventricular resynch-
seconds; 95% CI: 41 to 21 milliseconds; P ¼ 0.002)
ronization was associated with a significantly greater
did.27 This translated into a significantly greater
acute hemodynamic improvement (LBBAP produced
improvement in acute hemodynamic response, with
a 6% greater increase in LV dP/dt (a measure of initial
an w60% increase in acute systolic blood pressure
velocity of myocardial contractile force) than BVP
compared to BVP-CRT (þ4.6 mm Hg; 95% CI: 0.2-
did; P ¼ 0.002). In a study powered for noninferiority,
9.1 mm Hg; P ¼ 0.04). These findings suggest that
Pujol-Lopez et al 31 randomized 70 patients to CSP
HBP-CRT has the potential to deliver more effective
(either HBP [4 of 35] or LBBAP) or BVP, the primary
ventricular resynchronization and improve cardiac
endpoint was change in LVAT measured using ECGi
function in patients when LBBB can be successfully
45 days postimplantation. Twenty-three percent of
corrected with HBP-CRT.
patients crossed over from CSP to BVP and 6% crossed
HOT-CRT VS BVP-CRT. Whereas HBP-CRT shows over from BVP to CSP. In the intention-to-treat anal-
considerable promise, it is not possible to achieve ysis, CSP was found to be noninferior to BVP ( D LVAT
ventricular resynchronization in all patients with an CSP: 28 26 milliseconds vs BVP: 21 20 milli-
LBBB pattern on the 12-lead ECG. Conduction block seconds; mean difference: 6.8 milliseconds; 95% CI:
–18.3 milliseconds to 4.6 milliseconds; P < 0.001 for LBBAP is to advance RV activation through anodal
noninferiority). CSP was found to deliver a signifi- capture. But there was uncertainty regarding the
cantly greater reduction in LVAT ( D LVAT: 36 19 mechanism by which early RV activation is achieved
milliseconds vs 16 23 milliseconds).31 (capture of right bundle or RV myocardial capture),
whether this produces hemodynamic benefit. These
HBP-CRT VS LBBAP-CRT. Whereas LBBAP offers
questions were addressed in a study of 21 patients
several technical advantages compared to HBP, a
using ECGi. The ventricular epicardial propagation
potential disadvantage is that it results in less phys-
maps demonstrated that RV septal myocardial cap-
iological biventricular activation, because RV activa-
ture, rather than right bundle capture, was the
tion typically does not occur via the conduction
32 mechanism for earlier RV activation. Whereas anodal
system. Ali et al performed a within-patient acute
capture produced a shorter QRS duration, it did not
hemodynamic study, comparing the 2 pacing modal-
produce additional hemodynamic benefit.36
ities, to establish whether the delayed RV activation
adversely affects cardiac function. The study BVP VS LV ENDOCARDIAL PACING. Several in-
included 19 patients with LBBB and LV impairment. 32 vestigators have previously demonstrated that LV
Noninvasive electrical mapping confirmed the endocardial pacing provides superior electrical
assumption that HBP produces more rapid biven- resynchronization compared to epicardial coronary
tricular activation compared to LBBAP ( D total VAT sinus pacing by rapidly engaging the Purkinje con-
HBP: 46 15 milliseconds, D total VAT LBBAP: 36 duction system. CSP using HBP or LBBAP may be the
17 milliseconds; P ¼ 0.03). But LBBAP was not purest form of LV endocardial pacing. Salden at al37
inferior to HBP with respect to reduction in LVAT compared LV endocardial pacing with BVP in pa-
( D LVAT HBP: 43 16 milliseconds, D LVAT tients with a CRT indication. They observed that
LBBAP: 45 17 milliseconds; P ¼ 0.65). Interestingly endocardial LVSP produced equivalent improve-
the delayed RV activation with LBBAP did not ments in LV dP/dt to that obtained with BVP (þ17
adversely affect hemodynamic response (P ¼ 0.8). 10% vs þ17 9%). Endocardial LVSP may be analo-
gous to deep septal pacing without confirmed LBB
HBP IN PATIENTS WITH ISOLATED LONG PR INTERVAL
capture and may provide insights into LBBAP. These
AND LV IMPAIRMENT. PR interval prolongation
findings are provocative suggesting that conduction
adversely affects ventricular filling and may lead to
system capture was neither required nor targeted
diastolic mitral regurgitation further reducing cardiac
during the delivery of endocardial LVSP.
output. Therefore, PR prolongation may represent an
electrical treatment target that can be corrected with
TECHNIQUES TO MEASURE VENTRICULAR
pacing therapy. Sohaib et al33 observed that
SYNCHRONIZATION
AV-optimized HBP improved acute hemodynamic
function when delivered to patients with a long PR
The urge to achieve synchronous ventricular activa-
interval, LV impairment, and normal QRS duration or
tion via the intrinsic conduction system led to the
right bundle branch block (RBBB). A mean 4.1 mm Hg
development of more physiological methods of pac-
improvement in systolic blood pressure was observed
ing, such as BVP, HBP, and LBBAP (LBBP or LVSP).
that represents w60% of the hemodynamic benefit
The most frequently encountered type of ventricular
achieved with BVP in patients with LBBB. 33 These
capture during LBBAP and HBP is the simultaneous
encouraging findings led to the HOPE-HF (His Opti-
capture of the conduction system and surrounding
mized Pacing Evaluated for Heart Failure) trial, which
ventricular myocardium (ie, nonselective [ns]HBP
was a double-blind crossover trial assessing the
and nsLBBP), which is responsible for creating 2
impact of AV-optimized HBP. Whereas the primary
different electrical wave fronts that activate the
outcome of peak oxygen uptake or the secondary
ventricles. The first wave front uses the conduction
endpoint of LVEF did not change significantly,
system, whereas His bundle capture results in rapid
symptomatic improvement (secondary endpoints of
activation of both ventricles, LBB capture results in
quality of life and symptomatic preference) was
rapid LV but delayed RV activation. Besides activa-
observed with this pacing approach in patients with
34,35
tion of the conduction system, a second wave front
long PR interval and LV impairment.
arises from the local activation of myocardium sur-
DOES PROGRAMMING ANODAL CAPTURE DURING rounding the pacing electrode. This local myocardial
LBBAP OFFER A HEMODYNAMIC BENEFIT? A pro- excitation is responsible for QRS widening by creating
posed solution to the delayed RV activation during a pseudo-delta wave. However, the effect of such
ventricular activation on ventricular synchrony was be some distance from the LBB and, on average, were
not known until recently. 3-mm shallower than pacing depths with nsLBBP.
The ventricular activation pattern during the In other studies, different ventricular dyssyn-
nsHBP, selective (s) HBP, and myocardial pacing of chrony measures were studied in patients with CSP.
the para-Hisian area was studied using an ultra-high- The standard deviation of the ventricular activation
frequency (UHF)-ECG by Curila et al.38 They showed time (SDAT) determined by using an ECG belt system
that although nsHBP led to a wider QRS duration than was used to compare LVSP with LBBP. The SDAT was
sHBP, ventricular synchrony measured using UHF- determined from 40 electrodes on the chest and was
ECG and expressed as electrical dyssynchrony used as a measure of ventricular e-DYS. The study
([e-DYS]; time difference between the first and last found no significant difference in SDAT between
activation under leads V 1-V 8) was the same LVSP and LBBP. However, the study was small and
(Figures 3A and 3B). It was also shown that both sHBP may have been underpowered to detect minor
and nsHBP resulted in ventricular synchrony similar SDAT differences. 45 Salden et al37 investigated the
to normal intrinsic rhythm of patients with narrow electrophysiological and hemodynamic effects of
QRS interval. On the other hand, myocardial pacing in LVSP and nsHBP in heart failure patients undergoing
the para-Hisian area significantly worsened ventric- CRT implantation; they showed that the SDAT during
ular dyssynchrony (Figure 3E). The comparable ef- LVSP was comparable to nsHBP. More recently, SDAT
fects of nsHBP and sHBP on ventricular activation and was also used to guide CRT implantation and opti-
contraction were confirmed by other studies using mization in a randomized trial in patients with non-
echocardiography, single-photon emission computed LBBB. However, SDAT could not predict the clinical
tomography, ECGi, and direct endo- and epicardial response to CRT, suggesting that SDAT may not be
activation measurement in animals. 39-41 Therefore, the best measure to study ventricular dyssynchrony
nsHBP may be more suitable for clinical practice than in different pacing strategies.46
sHBP because it does not worsen ventricular activa- Another well-studied measure of ventricular syn-
tion patterns and may be a safer pacing strategy. Few chrony is the QRS area. The QRS area is the sum of the
studies have included patients with bundle branch area under the QRS complex of the calculated vec-
block or intraventricular conduction delays (IVCDs), torcardiographic X, Y, and Z leads derived from a
so the effect of nsHBP on ventricular synchrony is still digital 12-lead ECG. It has been shown in several large
unclear in these patients. CRT cohorts to be a potential tool for predicting
Due to the limitations of HBP, direct pacing of the clinical and echocardiographic CRT response.47
LBB or LV septum has received increased interest in Moreover, it can also be used to guide LV lead im-
recent years as an alternative physiologic pacing plantation. Recently, the QRS area was studied in
method. Both LBBP and LVSP provide more physio- bradycardia patients undergoing LBBAP. During LVSP
logical ventricular activation than RVP despite without evidence of LBB capture, the QRS area was
delayed RV activation and a wider QRS interval, slightly higher than in LBBP; however, the absolute
which in V 1 has a pseudo- RBBB morphology. 42,43 A difference was small.48 In addition, in patients with
detailed study of ventricular activation patterns using normal ventricular activation, the QRS area during
a UHF-ECG44 showed that both nsLBBP and LVSP LBBAP was close to the values of the intrinsic QRS,
have, on average, the same QRS duration and are less which indicates that LBBAP maintains ventricular
physiological than nsHBP (Supplemental Figures 5A synchrony at near-physiologic levels. Moreover, this
and 5B). LVSP preserved the same absolute level of study showed improvement of ventricular synchrony
ventricular synchrony as nsHBP, but it led to a left-to- was achieved with each step of lead progression into
right activation pattern and less physiological LV the interventricular septum (Supplemental Figure 6).
lateral wall activation (ie, a broader depolarization Comparisons of the difference between LVSP and
map under V6 -V8 ) compared to LBBP and nsHBP. On LBBP were all affected by a lack of definition for
the other hand, nsLBBP preserved the same pattern of LVSP. In contrast to LBBP, where there is capture of
LV lateral wall activation as nsHBP, but it delayed RV the LBB, LVSP was defined more vaguely as deep
activation and worsened left-to-right interventricular septal pacing without the presence of LBB capture
dyssynchrony compared to both HBP and LVSP and with a QRS pattern of late r/R in V1 . However, this
(Supplemental Figure 5E). Notably, pacing locations late r/R can, be present at various depths of the pac-
referred to as LVSP in this study were often shown to ing lead inside the interventricular septum,49 which
F I G U R E 3 Ultra High Frequency ECG in HBP
QRS duration (A), electrical dyssynchrony (e-DYS) (B), and ventricular depolarization maps during selective (s) and nonselective (ns) His-bundle pacing (HBP), and
myocardial capture in the para-Hisian area (C to E) as visualized by ultra-high frequency electrocardiography. Ventricular activations are similar for e-DYS (time difference
between the first and last activation) during sHBP and nsHBP, respectively. In comparison, myocardial capture in the para-Hisian area, the e-DYS was 32 milliseconds.
may affect the resultant ventricular activation pattern deeper positions. The most physiological LV activa-
(Supplemental Figure 6). Also, UHF-ECG studies on tion pattern is observed during nsLBBP but at the
ventricular activation patterns showed that LVSP cost of increasing left-to-right interventricular
with a late r/R or rs in V 1, which occurred with pacing dyssynchrony.
at 66%-80% of the septal thickness, resulted in worse
LV activation than nsLBBP. In contrast, LVSP close to CRITERIA FOR CAPTURE OF THE LEFT
the LBB (ie, LVSP that is transitioned from nsLBBP CONDUCTION SYSTEM
during decremental output pacing) had LV activation
patterns that were similar to those of nsLBBP. An Confirmation of His bundle capture is generally quite
example of the change in the UHF-ECG pattern of straightforward because output-dependent transi-
ventricular activation while pacing the interventric- tions in QRS morphology are observed in >90% of
ular septum at various depths and 2 types of LVSP is cases. Capture of the left conduction system, either
shown in Figure 4. proximal LBB or its fascicles (left fascicular pacing) is
Moving the lead deeper into the interventricular considered as the optimal endpoint for LBBAP pro-
septum results in different levels of inter- and intra- cedure. At the usual pacing output (ie, >1.5-2.0 V at
ventricular synchrony. When pacing the RV septum, 0.4 milliseconds), LBBAP nearly always results in
the primary determinant of ventricular dyssynchrony capture of the septal myocardium, regardless of
is delayed LV lateral wall activation, which is reduced whether simultaneous LBB capture is present.
as the lead is progressed deeper into the septum. The Therefore, determination of LBB capture requires
best interventricular synchrony is achieved in pacing differentiation between LVSP only and nsLBBP,
locations when the first late r occurs in V 1 ; however, which is the simultaneous capture of septal myocar-
LV activation can be improved by pacing from dium and LBB.
F I G U R E 4 Transseptal Decrease in Ventricular Dyssynchrony When Pacing at Various Depths of the Interventricular Septum
(A) Right septal pacing resulted in an electrical dyssynchrony (e-DYS) of 30 milliseconds caused by delayed left ventricular lateral wall activation. Left ventricular lateral
wall delay and QRS duration (QRSd) were reduced when pacing at a depth of 8 mm (B), and the best interventricular synchrony with the shortest QRSd was observed at
a depth of 12 mm during left ventricular septal pacing 1 (LVSP1) with a small late r in V1 (C). Pacing at deeper positions during LVSP2 (which transited from nonselective
left bundle branch pacing during the decremental output pacing) and nonselective left bundle branch pacing resulted in QRSd prolongation caused by the increase in
left-to-right interventricular dyssynchrony with delayed right ventricular lateral wall activation (D,E).
Practical methods for determination of LBB cap- V 6 R-WAVE PEAK TIME. The most widely used QRS
ture are based on assessment of paced QRS characteristic to determine left conduction system
morphology and maneuvers that induce QRS transi- capture is paced V6 R-wave peak time (V6 RWPT) or
tion, which is the sudden change of QRS morphology peak LVAT in V6, a QRS measure that is related to the
related to the change in capture type from nsLBBP to local activation time of the lateral wall of the
either myocardial capture (LVSP) or sLBB capture.50 LV. Activation of the lateral wall of the LV is faster
Endocardial mapping of His bundle and fascicular during nsLBBP than during LVSP, resulting in an
potentials to prove LBB capture has application average difference in V 6RWPT of 20 milliseconds.
mainly for mechanistic investigation but can be of Change in V6 RWPT was empirically used to confirm
practical use if dual-lead implantation technique is LBB capture during the early days of LBBAP. Jastr-
employed. zebski et al51 studied 124 patients with confirmed
F I G U R E 5 Density Diagrams and ROC Curves for V6 RWPT During nsLBBP Capture and LVSP
(Top) Results for patients with narrow QRS interval or isolated right bundle branch block (RBBB). (Bottom) Results for patients with damaged
left conduction system: left bundle branch block (LBBB), nonspecific intraventricular conduction delay (NIVCD), wide escape rhythm, or
asystole. There is considerable overlap between V6 R-wave peak time (V6RWPT) values between nonselective left bundle branch (nsLBBP) and
left ventricular septal pacing (LVSP) especially in patients with damaged left conduction system. Modified with permission from Jastrzebski
et al.51 AUC ¼ area under the curve; ROC ¼ receiver-operating characteristic; SN ¼ sensitivity; SP ¼ specificity.
diagnosis of LBB capture (evidence for transition conduction slowing and/or multisite left conduction
from nsLBBP to sLBBP or LVSP during threshold system disease that is not corrected by LBBAP. To
testing or programmed stimulation) to develop more increase sensitivity of V 6 RWPT criterion in patients
objective criteria based on peak LVAT or RWPT. with LBBB/IVCD, RBBB with fascicular block or wide
V6 RWPT values <75 milliseconds are nearly 100% escape rhythm/asystole different cutoffs for diag-
specific for nsLBBP whereas values of 80-85 milli- nosis of LBB capture should be used: 80 milliseconds
seconds have the best balance of sensitivity/speci- for high specificity, and 90-100 milliseconds for
ficity. A major limitation of this criterion is low optimal overall diagnostic accuracy (Figure 5).51
sensitivity, especially for patients with heart failure, The V 6 RWPT criterion is more accurate when an
wide escape rhythms, LBBB, and IVCD. In such situ- individualized paced V6 RWPT cutoff value is used for
ations LV activation/V6 RWPT might be much longer diagnosis. This individualized value can be easily
despite LBB capture because there is widespread LV obtained during implantation by measuring the LBB
F I G U R E 6 LBB Capture
During nsLBBP capture, the interval from the LBB potential to the V6 R-wave peak during native conduction equaled the interval from the
stimulus to the V6 R-wave peak. During loss of LBB capture, resulting in only myocardial LVSP, the interval from the stimulus to the R-wave
peak was longer. Abbreviations as in Figures 4 and 5.
potential to V6 R-peak interval observed during con- bundle and fascicular potentials to prove LBB capture
ducted supraventricular beat with non-LBBB has application mainly as a research tool but can be of
morphology (Figure 6). When LBB is captured, these practical use if the dual-lead technique is used.
2 intervals are necessarily the same because the
activation pathways during pacing and intrinsic acti- V 6 -V 1 INTERPEAK INTERVAL. During LVSP, activa-
vation are the same. Endocardial mapping of His tion spreads from the septum to right and left
F I G U R E 7 Two LBBAP Sites in the Same Patient
In the first pacing site, lack of LBB potential and V6RWPT of 83 milliseconds (ie, over the 75 milliseconds cutoff) makes the diagnosis of LBB capture uncertain. Only
application of the V6-V1 criterion allows to make a firm diagnosis as values >44 milliseconds are nearly 100% specific for LBB capture. In the second position, illustrating
LVSP, R-wave peaks at V6 and V1 occur nearly simultaneously, resulting in V6-V1 interpeak interval during threshold testing of only 16 milliseconds, which is typical for
lack of LBB capture. Modified with permission from Jastrzebski et al.50 LBBAP ¼ left bundle branch area pacing; other abbreviations as in Figures 4 and 5.
ventricles resulting in similar delay of LV free wall interval will not be much effected. A value of V 6-V 1
and RV free wall. Consequently, paced R-wave peaks interpeak interval >44 milliseconds is highly specific
in V 1 and V 6 occur nearly simultaneously, and the V6 - for diagnosis of LBB capture, whereas values of 33-40
V1 interpeak interval is short. In contrast, during milliseconds show optimal sensitivity/specificity
nsLBBP, activation of RV is delayed in comparison to balance. Combined use of V 6RWPT and V6-V1 inter-
LV activation, hence the V 6–V 1 interval is longer peak criteria increases the diagnostic yield of ECG
(Figure 7). analysis.54,55
The paced V6 –V1 interval criterion addresses some
limitations of the V 6 RWPT criterion.52-54 Long DIAGNOSIS OF LBB CAPTURE BY DEMONSTRATION
V6 RWPT might be caused not only by lack of LBB OF QRS MORPHOLOGY TRANSITION. T h r e s h o l d
capture but also by initial latency, slower propagation t e s t . Perhaps the most straightforward and highly
via diseased HPS, substantial LV dilatation, or, often, specific diagnostic method is based on differences in
a combination of these factors. The V6-V1 interpeak capture threshold between left conduction system
interval is likely less influenced by these limitations. and septal myocardium. Unfortunately, this differ-
If there is substantial initial latency or slow conduc- ence is very often small or absent, resulting in lack of
tion through the myocardium, it will affect to a QRS transition and hence low sensitivity of this test
similar degree the timing of the activation of the RV (30%-70% during procedure, 15%-30% during follow-
and LV. Consequently, the R-wave peak will be up). Sensitivity can be increased by performing
delayed in both V1 and V 6, and the V 6-V 1 interpeak threshold test immediately after lead deployment
F I G U R E 8 Diagnostic QRS Transition During Threshold Test
(Left) Very subtle transition from nsLBBP to LVSP. There is diagnostic prolongation in V6 R-wave peak time, increase in R-wave amplitude in V2-V4 and change of
ST-segment from isoelectric to downsloping in V6. (Right) Obvious QRS transition from nsLBBP to sLBBP indicated by sudden prolongation of V1 R-wave peak time;
deepening of S waves in leads I, V5, and V6; prolongation of isoelectric interval after pacing stimulus; and appearance of discrete local potential on endocardial channel
(LBBP lead). Abbreviations as in Figures 4 and 5.
when the local trauma transiently increases myocar- prolong $10 milliseconds, and for nsLBBP / to
dial threshold and by performing threshold test s-LBBP there should be broadening of the V 1 R/r wave
multiple times during the procedure at different with increase in V 1RWPT and/or deepening of the S
pulse widths. wave in leads I, V 5, and V6; alternatively, there should
Threshold test should be conducted in unipolar be a sudden appearance/prolongation of latency in
pacing mode at a constant rate with output slowly surface ECG and discrete local potential on the
decreased until loss of capture. Simultaneously, 12- endocardial channel.
lead QRS morphology and endocardial recordings P r o g r a m m e d s t i m u l a t i o n . The refractory periods
are monitored for sudden QRS transition and change of the conduction system tissue and myocardium are
in local endocardial activation pattern (Figure 8). QRS different. Using programmed stimulation it is
change to be considered diagnostic of LBB capture possible to obtain capture of only one of these tissues,
needs to conform to some criteria for transition. For either conduction system (selective response)
nsLBBP / LVSP transition, the V 6 RWPT should or septal myocardium (myocardial response)
F I G U R E 9 Continuous Recording of ECG and Endocardial Channels From the HB and LBB
Continuous recording of electrocardiography (ECG) and endocardial channels from the His bundle (HB) and left bundle branch (LBB) leads
during lead rotation enables us to make a diagnosis of LBB capture already at the stage of lead deployment in the septum. After second QRS
interval, there is beat-to-beat QRS transition that indicates the moment of LBB capture. This moment can be recognized by sudden shortening
of V6 R-wave peak time by 10 milliseconds or more and by increase in V1 R-wave amplitude. HB recording, illustrating sudden appearance of
retrograde HB potential after the pacing stimulus, is not necessary to recognize diagnostic beat-to-beat QRS transition; it serves here as
additional evidence that the beat-to-beat QRS change was indeed related to the capture of the left conduction system.
(Supplemental Figures 7 and 8). Both these responses changes can be observed as the lead gets deeper into
are equivalent to QRS transition during threshold test the septum. This enables us to observe the moment of
and are diagnostic of LBB capture because they prove LBB capture, which is indicated by sudden V 6RWPT
that the QRS transition in question was a nonselective shortening and other morphologic changes in QRS
QRS transition (ns-LBBP), composed by simultaneous complex (normalization of repolarization in V5 and
depolarization of the 2 tissues. However, whereas V6; appearance of S waves in leads I, V 5, andV 6; and
selective response is 100% specific for LBB capture, sudden increase in r0 amplitude in lead V1
myocardial response must be differentiated from a (Figure 9). 56,57 This QRS transition is identical to the
similar, albeit nonspecific response that maybe seen QRS transition that can be observed during threshold
during LVSP. Dedicated pacing protocols, based on testing. The continuous pacing technique requires a
physiology of the His Purkinje system compared to rotational adapter that connects the distal pin of the
the RV make it possible to evoke both myocardial and pacing lead with the external pacemaker and at the
selective response in the same individual. Moreover, same time does not hamper lead rotations. Simple,
these dedicated protocols can augment the difference self-made, or commercial solutions are available for
in refractory periods between LBB and septal Medtronic SelectSecure MRI Surescan 3830 lead,
myocardium and hence increase the diagnostic yield whereas for stylet leads this can be easily achieved by
of programmed stimulation. Programmed stimulation connecting to the stylet. This technique requires use
is especially useful in patients with potentially long of an electrophysiology recording system because it is
V6 RWPT (eg, heart failure, LBBB) and lack of QRS often difficult to ascertain the moment of capture in
transition during thresholds test. real time. Confirming LBB capture during lead rota-
L e a d - p o s i t i o n – d e p e n d e n t Q R S t r a n s i t i o n . When tion often requires review of the moment of lead
continuous pacing technique is used during lead ro- deployment with careful assessment/measurement of
tations to achieve LBBAP, beat-to-beat–paced QRS several consecutive QRS complexes.
F I G U R E 1 0 Selective and Nonselective Pacing From Proximal LB and Distal Purkinje in a Patient With Narrow QRS Interval
Both QRS duration measurements are narrower during nonselective (NS) capture, where local ventricular electrogram is recruited immediately
after the pacing stimulus. In contrast, selective (S) capture of proximal (prox) left bundle branch shows preservation of local and surface
isoelectric segments with presystolic Purkinje activation before ventricular activation. During NS pacing, the basal right ventricle (His p, blue
dashed circle) is advanced earlier by direct septal capture, compared to late activation during S capture, which corresponds to the terminal R0 in
V1. S pacing more distally shows delayed retrograde activation of the His (H) and right bundle (RB), which occur after QRS onset, resulting in
less synchronization and wider QRS durations. Reproduced with permission from Sun et al.58 His d ¼ His distal; His p ¼ His proximal; LB ¼ left
bundle; LVAT ¼ left ventricular activation time; LVS ¼ left ventricular septal; LVS d ¼ left ventricular septal distal; LVS p ¼ left ventricular
septal proximal; other abbreviations as in Figure 5.
Influence of pacing site and capture selectivity characteristics during CSP. In a cohort of patients in
o n Q R S c h a r a c t e r i s t i c s a n d L V A T . It is important which paired analysis of selective and nonselective
to note that the type of capture has not been proven capture were available from multielectrode diag-
to translate into different clinical outcomes caused by nostic catheters, it was demonstrated that sLBBP
secondary rapid engagement of the His Purkinje sys- exhibited wider QRS durations than nsLBBP did. 58
tem with LVSP. On the other hand, 10-20 milliseconds Therefore, QRS narrowing during LBB capture is
may have a dramatic impact on remodeling in pa- predicated on recruitment of the basal septum and
tients undergoing CRT. To assess for differences in more rapid activation of the right bundle antegradely
LVSP vs LBBP in addition to differentiating between (Figure 10). This is in contradistinction to HBP, in
the type of pacing, it is important for us to acknowl- which nonselective capture exhibits a wider QRS
edge that we do not understand the determinants of narrowing than sHBP does. It is important to under-
clinical response to pacing. stand that LBB stimulation, which can achieve rapid
Direct pacing from the left conduction system of- His Purkinje recruitment results in interventricular
fers the ability to gain further understanding of QRS dyssychrony with incomplete or complete RBBB
pattern and narrow QRS interval is often achieved implantation include the His bundle and LBB. Due to
with AV fusion optimization with intrinsic RBB challenges related to implant technique, lower
activation. implant success rates, and reported increases in cap-
An important limitation of determining QRS dura- ture threshold with HBP, LBBAP has gained more
tion is whether to measure from the QRS onset or the popularity given better R-wave sensing and lower and
onset of stimulus artifact. There is more subjectivity stable capture thresholds. 60,61
when measuring from the earliest intrinsicoid
UPDATES IN IMPLANT TOOLS. With increasing
deflection, and intracardiac correlation reveals that
adoption of CSP, there have been various advances in
many pseudo delta waves during sLBB capture show
delivery sheaths for targeted lead implantation at the
little to no amplitude. However, when measuring
conduction system, for patients with normal cardiac
from stimulus, LBB capture is typically associated
anatomy as well as for specific situations such as
with QRS durations of >120 milliseconds, which is
right-sided implants and patients with enlarged and
counterintuitive for the achievement of electrical
dilated hearts. Table 1 highlights some of the newer
resynchronization.
delivery catheters for implantation. Zanon et al 62
Aside from QRS duration, peak LVAT or RWPT in V6
evaluated the comparative effectiveness of the C315
has been proposed to represent the time required to
preshaped delivery sheath (Medtronic Inc) with the
depolarize the bulk of the LV myocardium. Rapid
Selectra 3D sheath (Biotronik Inc) among 151 patients
conduction through the His-Purkinje system results
demonstrating a similar success rate for implantation.
in shorter V6 RWPT and, hence, is an indicator of
To date, there have been no dedicated leads
conduction system vs septal pacing. Whereas it has
designed for CSP. The most frequently used lead for
been proposed that LBBAP with conduction system
CSP has been the Medtronic 3830 lead, which is a
capture is defined by V6 RWPT <75 milliseconds in
4.1-F lumenless lead with a 1.8-mm exposed helix.
patients with narrow QRS interval and <85 millisec-
This lead has gained U.S. Food and Drug Adminis-
onds in patients with wide QRS interval, V 6RWPT >85
tration approval for both HBP and LBBAP. More
milliseconds can be observed during CSP. Impor-
recently, other active fixation stylet-driven leads
tantly, the site of stimulation is another unfactored
have been deployed successfully for CSP. However,
variable in the determination of peak LVAT or
only limited data are available on these leads.
V6 RWPT. Stimulation of a fascicle more distally from
De Pooter et al63 compared feasibility and success
a potential with shorter Purkinje-to-ventricle interval
rates of LBBAP among 50 patients and demonstrated
than a proximal site results in a shorter RWPT. This is
that the use of stylet-driven pacing leads was feasible
akin to S-QRS intervals in scar-related ventricular
(87% success) and yielded comparable implant suc-
tachycardia, in which sites closer to the exit have
cess to LBBAP with the lumenless 3830 lead (89%
shorter latency between the stimulus and myocardial
success). LBBAP thresholds were low and comparable
depolarization (in this case, the conduction system).
with both types of leads. However, the longer-term
Figure 11 shows the tradeoff between shorter RWPT
performance of stylet-driven leads need further
(LVAT) and wider QRS interval caused by distal
evaluation. Similar findings were observed in the
stimulation because synchronization with the right
observational study for LBBP by Zanon et al.62
bundle/RV is dependent on a longer path to retro-
gradely activate the His bundle or transseptal con-
UPDATES IN IMPLANT TECHNIQUES. With LBBP,
duction. Whether a shorter RWPT/LVAT or narrower
identifying the initial location for lead penetration
QRS interval is more optimal physiologically needs
through the muscular interventricular septum is
prospective assessment. In this context, shorter
usually performed by first identifying the His bundle
RWPT/LVAT may represent less intraventricular
and the using that as a landmark. However, in some
dyssynchrony with more interventricular dyssyn-
cases this can be challenging. More recently, Liu
chrony (wider QRS interval). Further studies are
et al 64 described a contrast-based visualization tech-
needed to assess for differences with LBBAP and sites
nique by defining the tricuspid valve in 60 patients
of stimulation (distal vs proximal).
undergoing LBBP. This technique decreased the pro-
cedural and fluoroscopic durations for LBBP implan-
CSP IMPLANT TECHNIQUES tation with fewer lead repositioning attempts. Jiang
et al65 described a novel 9-partition method to help
Conduction system pacing has been increasingly localize the region for successful HBP and LBBP
adopted in the real world over the past decade. 59 The among 70 patients. The region between the apex and
2 main sites along the conduction system for lead the ventricular contraction ring was divided into
F I G U R E 1 1 Impact of Pacing More Distally in the Left Conduction System on LVAT and QRS Duration
At more distal sites, the local Purkinje electrogram to ventricular interval is shorter, which results in shorter LVAT. However, because of a longer course of retrograde LB
activation into the RB, less synchronization yields a wider intrinsicoid QRS (QRSid) interval. The impact on QRS measured from stimulus interval is variable because the
LVAT shortens but QRS interval widens at more distal sites. Sequential pacing from more distal bipole pairs in a patient with normal QRS interval shortens LVAT
but results in widening of QRSid interval because of progressively delayed retrograde conduction into the RB. Reproduced with permission from Sun et al.58 Other
abbreviations as in Figures 5 and 10.
9 partitions using right anterior oblique fluoroscopic intraprocedural decision making regarding the type
views. HBP leads were distributed in the second of CRT: HBP, LBBAP, or BVP-CRT. If LVAT shortened
partition, and 94.3% (33 of 35) of LBBAP leads were in significantly with CSP, it suggested the patient had
the junctional area of second and fifth partitions. The true LBBB and CSP was used; if CSP failed, then BVP-
distance from the lead tip to the junction of the CRT was performed (Supplemental Figure 9).68
noncoronary cusp and right coronary cusp (using Left bundle branch pacing optimized (LOT)-CRT
computed tomography imaging) was 3.8 0.6 and combines LBBP with coronary vein pacing in patients
1.9 0.2 cm for LBBP and HBP, respectively. with wide QRS interval with incomplete correction
˛bski et al,66
The value of fixation beats by Jastrze ˛bski et al69 recently pub-
with LBBP alone. Jastrze
67
template and “M” beats by Ponnusamy et al dur- lished an international collaborative series demon-
ing rapid lead rotation through the interventricular strating an 81% success rate with LOT-CRT resulting
septum has added value in improving the negative in a dramatic QRS reduction from 182 25 millisec-
predictive value and the specificity of LBB capture, onds at baseline to 144 22 milliseconds (P < .0001)
respectively. and a modest improvement in LVEF.
ADVANCES IN CSP FOR CRT. Among patients with FLUOROLESS AND 3D-MAPPING TECHNIQUE. One of
LBBB/IVCD, Ravi et al68 demonstrated the use of a the critical points in CSP compared to standard apical
vision wire-guided lateral LVATs helped with pacing has been advocated as a longer exposure to
T A B L E 1 Specialized Delivery Catheters for CSP
Sheath C315 His C304 His C304 SSPC1 SSPC2 SSPC3 SSPC4 Selectra 3D
Company Medtronic Medtronic Medtronic Boston Boston Boston Scientific Boston Biotronik
Scientific Scientific Scientific
Shape Preshaped, septal curve Deflectable and Deflectable Preshaped, “C” Preshaped, Preshaped, Preshaped, Preshaped (3
preshaped multipurpose extended hook right-sided different shapes
available)
Introducer 7-F 9-F 9-F 8-F 8-F 8-F 8-F 9-F
Usable length, cm 43 43 40 40 40 40 40 32-39
Inner diameter 5.4-F 5.7-F 5.7-F 6.5-F 6.5-F 6.5-F 6.5-F 7.3-F
Outer diameter 7-F 8.4-F 8.4-F 8-F 8-F 8-F 8-F 8.7-F
Integrated valve Yes No No Yes Yes Yes Yes Yes
Hydrophilic coating Yes No No NA NA NA NA Yes
Braiding Yes, 16 16 Yes, 8 8 Yes, 8 8 NA NA NA NA Yes
Horizontal reach, 79 79 37 NA NA NA NA NA
mm
Vertical reach, mm 43 44 46 NA NA NA NA NA
Designed for RA and RV RA and RV septal RA and RV septal RA septal RA and RV Dilated RA and Right-sided RA and RV septal
septal location location location location septal location RV septal device location/Right side/
location implant DCM
Right-sided device Yes, can be reshaped for Designed for left- Designed for left- Designed for Designed for Designed for Yes Yes
implant better torque sided implant sided implant left-sided left-sided left-sided
transmission implant implant implant
DCM Sheath in sheath delivery Deflection can be Deflection can be See SSPC3 See SSPC3 Yes See SSPC3 Yes
used to increase used to increase
reach reach
Adopted from Ravi V, El Baba M, Sharma PS. His bundle pacing: tips and tricks. Pacing Clin Electrophysiol. 2021;44(1):26-34.
CSP ¼ conduction system pacing; DCM ¼ Dilated cardiomyopathy; NA ¼ not available; RA ¼ right atrial; RV ¼ right ventricular.
x-rays. Indeed, Zanon et al70 demonstrated that HBP LBBAP, the lead is moved toward the septum to a
is feasible using minimum or no fluoroscopy in 39 of previously tagged site. Three-dimensional electro-
41 patients with a success rate of 95% and selective anatomic mapping allowed the real-time visualiza-
capture in 59% of cases. The idea of this study was tion of the lead penetrating the septum. Switching
localizing the His bundle with mapping using a the connection from unipolar to bipolar, the whole
standard electrophysiology recording system. With bipole of the lead is visible to better evaluate the lead
this technique the operator is concentrating only on orientation and ensure it is perpendicular to the
the electrograms and the final HBP lead position was septum. Three-dimensional electroanatomic mapping
reached in 31 patients (79.4%) without fluoroscopy, also allows to measure the distance of the starting
only guided by electrograms. In 8 patients a minimal point from the His bundle cloud and the length of the
fluoroscopic approach (mean: 8 seconds) was used. penetrating part of the lead into the septum. More-
This experience has the limitation of being conducted over, some challenging anatomies such as congenital
in a highly experienced center with HBP implants; cardiac diseases or extremely enlarged right atria that
however, it highlights the concept of an electro- are usually associated with a high percentage of
physiologic procedure in contrast to an interven- implant failure may benefit from this combination of
tional/radiologic procedure. Similarly, Sharma et al71 technologies. 73
demonstrated the safety and feasibility of HBP
implant guided by 3D electroanatomic mapping sys- HYBRID APPROACHES TO CSP
tems with extremely low fluoroscopic exposure.
Similar outcomes have been reported by Richter Whereas conventional BVP has shown benefit in pa-
72
et al in 58 patients, indicating the feasibility and tients with heart failure and conduction system dis-
safety of routine electroanatomically guided HBP lead ease, there are limitations to its success, resulting in
implantation in a real-world cohort of patients with a widely variable clinical response. Several observa-
great reduction in radiation exposure. The potential tional and acute hemodynamic studies have demon-
advantage of this technique can be reflected in a strated improved electrical resynchronization and
precise localization of the His bundle with limited echocardiographic response with CSP or combined
fluoroscopy (Supplemental Figure 10). In case of sequential stimulation of the conduction system and
placement secondary to coronary venous anatomy

F I G U R E 1 2 Locations for Permanent Lead Placement and Possible CRT Strategies
Using CSP
also presents challenges. Furthermore, many pa-
tients have AV block, omitting delivery of fused
CRT, or an IVCD coexisting with bundle branch
block, complicating CRT delivery. In advanced car-
diomyopathy, coexisting LBBB and IVCD may
amplify LV dyssynchrony, because LV activation in
the setting of LBBB relies on prolonged myocardial
cell-to-cell conduction. Thus, coexistent IVCD
further delays activation of some myocardial seg-
ments. Therefore, CSP may paradoxically improve
the impact of a coexistent IVCD. In these circum-
stances, resynchronization may be more complete
when intervened on at the level of the specialized
Locations for permanent lead placement and possible cardiac resynchronization therapy conduction system followed by sequential epicardial
(CRT) strategies using conduction system pacing (CSP). BVP ¼ biventricular pacing; LV pacing in areas of late myocardial activation
HBP ¼ His bundle pacing; HOT ¼ His optimized; LBBP ¼ left bundle branch pacing;
(Figure 13). Many challenges of conventional CRT
LOT ¼ left bundle branch optimized.
have been overcome with VV-interval programma-
bility, device-based fusion optimization algorithms,
quadripolar LV leads allowing electronic reposi-
the epicardial LV via the coronary venous system tioning, multipoint stimulation, and targeted LV
(Figure 12). 74 HOT- or LOT-CRT are currently under pacing from the LV lateral base. CSP, alone or in
investigation. conjunction with LV epicardial pacing, may yield a
Currently, CRT by BVP is the only heart failure viable solution to some of the obstacles outlined
therapy that improves cardiac function, functional (Figure 14).
capacity, and survival while decreasing cardiac
workload and hospitalizations. Response to BVP is OBSERVATIONAL STUDIES ON HOT- OR LOT-CRT. In
variable, ranging from complete normalization of a small retrospective, observational multicenter
cardiac function to lack of benefit to worsening study, HOT-CRT was performed in a series of 27 pa-
heart failure. One obstacle for effective CRT de- tients with LBBB/IVCD where partial or insignificant
livery is slow impulse propagation and stimulus-to- QRS narrowing was achieved by HBP alone compared
QRS latency in severely diseased myocardium and with baseline (Supplemental Figure 11). All patients
myocardial scar. Suboptimal coronary venous lead had therapy-refractory NYHA functional class III-IV
F I G U R E 1 3 Pathophysiology of Coexistent LBBB and IVCD
(A) Intact His-Purkinje conduction in a patient with a small left ventricular scar. (B) With left bundle branch block (LBBB), left ventricular activation now relies on cell-to-
cell myocardial conduction through diseased myocardial tissue and scar amplifying the effective intraventricular conduction delay (IVCD). (C) A similar situation applies to
the scenario of atrioventricular block and right ventricular pacing amplifying the IVCD. (D) Management of coexistent LBBB and IVCD by His- or left bundle–optimized
cardiac resynchronization therapy.
F I G U R E 1 4 Ladder Diagrammatic Presentation of LBBB and IVCD and Their Management by Different Resynchronization Strategies
(A) Different presentations of IVCD. (B) Treatment of LBBB and coexistent IVCD by conventional CRT. (C) Treatment of LBBB and IVCD by
HOT- and LOT-CRT. AVB ¼ atrioventricular block; AVI ¼ AV interval; BiV ¼ biventricular; HV ¼ His - ventricular interval; L ¼ left; LBP ¼ left
bundle pacing; R ¼ right; RV ¼ right ventricular; RVP ¼ right ventricular pacing; other abbreviations as in Figures 5, 12, and 13.
heart failure symptoms and a baseline LVEF #35%. events, termination of device function, NYHA func-
HOT-CRT resulted in improved electrical resynchro- tional score, and a patient global assessment.
nization when compared to conventional BVP or HBP. The HOT-CRT (His-Purkinje Conduction System
The QRS duration was reduced from 183 27 to 120 Pacing Optimized Trial of Cardiac Resynchronization
16 milliseconds (34%) by HOT-CRT compared with Therapy; NCT04561778) trial is an ongoing random-
16218 milliseconds (11%) by BVP and 151 25 milli- ized, prospective, single-blinded trial of 100 patients
seconds (17%) by HBP alone (P < 0.05). Investigators investigating the overall success rate of HOT-CRT vs
observed significant echocardiographic and clinical BVP (Table 2, HOT-CRT section). In this trial, CSP first
improvement in patients with advanced heart failure arm will also evaluate the need for combining con-
who were treated with HOT-CRT. 28,75,76 duction system lead placement in patients with
A single center, prospective, nonrandomized incomplete electrical resynchronization. Acute out-
observational study investigated LOT-CRT compared comes include change in QRS duration and incidence
to BVP. Twenty-one patients with CRT indication and of major periprocedural complications. Primary out-
NYHA functional class II-IV were enrolled, 10 in the comes include improvement in LVEF at 6 months and
LOT-CRT group and 11 in the BVP group. In the LOT- freedom from major complications or need for CRT
CRT group, the QRS duration decreased from 158.0 lead revision at 6 months. Secondary outcomes
13.0 milliseconds at baseline to 132.0 4.5 milli- include heart failure hospitalizations, change in
seconds (16%) with BVP (P ¼ 0.019) and 123.0 5.7 NYHA functional class, LV end-systolic volume index
milliseconds (22%) with LBBP (P < 0.01) to 121.0 3.8 at 6 months, ventricular tachycardia or ventricular
milliseconds with LOT-CRT, which was not significant fibrillation requiring implantable cardioverter-
when compared to LBBP alone. LOT-CRT demon- defibrillator therapy, and change in quality-of-life
strated narrower QRS duration (121.0 3.8 millisec- scores. Currently, in absence of randomized
onds) compared to BVP (133.3 8.2 milliseconds; controlled clinical trial data, HOT-/LOT-CRT should
P ¼ 0.001). At 9-month follow-up, both groups be viewed as investigational. Whereas there are some
demonstrated improved LVEF, QRS duration, and data on the role of BVP in patients with non-LBBB,
NYHA functional class. The investigators concluded there are limited data on CSP in patients with non-
LOT-CRT was feasible in this patient cohort. There LBBB.
were no adverse events reported. 78
A multicenter observational study reported 112 CLINICAL TRIALS
patients with CRT indication undergoing LOT-CRT.
The implant success rate was 81%. LOT-CRT resul- There are 7 small (29-167 patients) published ran-
ted in improved electrical resynchronization when domized clinical trials examining the role of CSP (HBP
compared to conventional BVP or LBBP alone. The or LBBP) in patients with heart failure with reduced
QRS duration was reduced from 182 267 to 144 22 ejection fraction (LVEF <35%-40%) and different
milliseconds (21%) by LOT-CRT compared with underlying conduction abnormalities: left bundle
170 30 milliseconds (7%) by conventional BVP and branch block, atrial fibrillation with AV node ablation,
162 23 milliseconds (11%) by LBBP alone (P < 0.001). and prolonged PR (Table 3).79-83
LVEF and NYHA functional class improved from 28.5 In a crossover study by Lustgarten et al, 79 the QRS
9.9 to 37.2 12.0 (P < 0.001) and 2.9 0.6 to 1.9 duration was narrowed in the majority of patients
0.6 (P < 0.0001), respectively.69 with ischemic disease and only about one-half of the
The CSPOT (Conduction System Pacing Optimized nonischemic patients (21 of 29) with HBP. Quality of
Therapy) trial (NCT04905290) is an ongoing pro- life, NYHA functional class, 6-minute walk test, and
spective, observational, acute hemodynamic cross- LVEF were improved with the same degree by both
over trial comparing traditional BVP, LBBP, and BVP and HBP compared to baseline. In the HIS SYNC
LOT-CRT (Table 2, LOT-CRT section). At implanta- (His Bundle Pacing Versus Coronary Sinus Pacing for
tion, all subjects undergo an acute pacing protocol Cardiac Resynchronization Therapy) pilot trial of 40
comparing BVP, LBBP, and LOT-CRT, serving as their patients with indication for CRT, there was no sta-
own control. The primary outcomes include electrical tistically significant difference in the QRS duration
resynchronization response at time of implant and and LVEF change by both BVP and HBP compared to
hemodynamic response measured by LV dP/dtmax. baseline at 6 months, although numerical estimates
Secondary outcomes at 6-month follow-up include were higher in the HBP arm. 80 There was no observed
change in LVEF, LV end-systolic volume, and a clinic significant difference in CV hospitalization or death at
composite score based on mortality, heart failure 12 months between the 2 groups. Crossover from HBP
T A B L E 2 Cardiac Resynchronization Therapy
Success Follow-up Echocardiographic

Name, Year Design Indication N (%) (mo) Hemodynamic QRS Outcomes
HOT-CRT
Vijayaraman,75 Retrospective, HOT-CRT in LBBB 27 93 12 LVEF: 24%/38% Duration NYHA: 3.3/2.0
2019 multicenter, and IVCD with LVEDD: 65/59 mm, Baseline: 183 ms Reduced HF
observational QRS LVEDV: 225/200 mL, BiV: 162 ms hospitalizations
duration $140ms LVESV: 171/138 mL HBP: 151 ms Reduced loop
or AV block with Super-response: 28% HOT-CRT: 120 ms diuretic and
LBBB type escape aldosterone
antagonist doses
Zweerink,28 Prospective, CRT 19 NA Baseline LVEF: 31% Duration HOT-CRT acutely
2021 single-center, Baseline: 142 ms improves ventricular
observational HBP: 142 ms electrical synchrony
BiV: 154 ms compared to BiV
HOT-CRT: 126 ms and HBP
HOT-CRT reduced LVAT
by 21% compared to
HBP
Deshmukh,76 Retrospective, CRT indication in 21 100 32 LVEF 27%/41% Duration NYHA: 3/2
2021 single- center which His pacing Baseline: 170 ms HOT-CRT resulted in
did not result in HBP: 157 ms superior acute
resynchronization BiV: 141 ms electrical synchrony
HOT-CRT: 110 ms in this population
Vijayaraman, Randomized, CRT indication 100b 6 LVEF Duration change Improvement in LVEF
202377a prospective, LV chamber Freedom from major
double- dimensions complications
blinded, LV volumes HF hospitalizations
crossover LV end-systolic NYHA functional class
volume index Quality of life
LOT-CRT
Jastrzebski,78 Prospective, CRT indication or 112 81 3
3 LVEF: 29%/37% Duration LOT-CRT provides
2021 multicenter, nonresponders to (P < 0.0001) Baseline: 181 ms significantly greater
observational BiV CRT LVEDD: 62/59 mm LOT-CRT: 144 ms resynchronization
Super-response: 24% LBBP: 162 ms than LBBP or BiV
BVP: 170 ms CRT
NYHA: 2.9/1.9
Feng,79 2022 Prospective, CRT indication 21 90 9 LVEF Duration LOT-CRT
single-center, Atrial fibrillation BVP: 34%/46% BVP: 176/133 ms Feasible
observational excluded LOT-CRT: 32%/45% LOT-CRT: 158/121 ms Superior to BVP,
associated with
shorter QRS
duration
Improved NYHA
functional class and
LVEF during the
follow-up period of
9 mo
C-SPOT,a Prospective, CRT indication 60b 6 Change in LVEF Acute change in QRS Resynchronization
NCT04905290 observational, Change in LVESV duration response at
acute implantation
hemodynamic Hemodynamic response
study Change in NYHA
functional class
Vijayaraman,a Randomized, CRT indication 100 b
6 LVEF QRS duration change Improvement in
NCT04561778 Prospective, LVEDD, LVESD LVEF
double- LVEDV, LVESV Freedom from major
blinded, Cross LVESV index complications
Over HF Hospitalizations
NYHA functional
class
Quality of life
a
Not yet published. bEstimated.
AV ¼ atrioventricular; BiV ¼ biventricular; CRT ¼ cardiac resynchronization therapy; C-SPOT ¼ Conduction System Pacing Optimized CRT; HBP ¼ His bundle pacing; HOT ¼ His optimized; HF ¼ heart failure;
IVCD ¼ intraventricular conduction delay; LBBB ¼ left bundle branch block; LBBP ¼ left bundle branch pacing; LOT ¼ left bundle branch optimized; LVAT ¼ left ventricular activation time; LVEDD ¼ left
ventricular end-diastolic diameter; LVEDV ¼ left ventricular end-diastolic volume; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular end-systolic diameter; LVESV ¼ left
ventricular end-systolic volume; NA ¼ not available.
T A B L E 3 Randomized Clinical Trials for CSP
Other
Name, Year Treatments Size Population Primary Endpoint Endpoints Follow-up (mo) Country
Lustgarten et al,80 HBP vs BVP 29 CRT indication Feasibility QoL 12 USA

2015 QRSd >130 ms (28 LBBB, 1 RBBB) QRSd NYHA
6MWT
LVEF
His-SYNC,81 2019 HBP vs BVP 41 CRT indication QRSd 12 USA
LVEF #35% LVEF at 6 mo,
QRSd >120 ms CV hospitalization or
NYHA II-IV death at 12 mo
His-Alternative,82 HBP vs BVP 50 LVEF#35% LBBB His bundle lead QRSd 6 Denmark
2021 NYHA II-IV implant success LVEF
LVSV
NYHA
6MWT
NT-proBNP procedure time
fluoroscopy
time
radiation dose
lead measures
LBBP RESYNC,31 LBBP vs BVP 40 LVEF #40%, NICMP, LBBB, LVEF Echo measurements, NT- 6 China
2022 NYHA II-IV proBNP, NYHA, 6MWT,
QRSd, CRT response
LEVEL-AT,54 2022 CSP vs BVP 70 LVEF #35%, LBBB $130 ms or LVAT LVESV, death, or HFH 6 Spain
non-LBBB QRS $150 ms or AV
block
ALTERNATIVE HBP vs BVP 40 Persistent AF þ AVNA, LVEF 18 (crossover at China
AF,83 2022 LVEF #40%, , RSs <120 ms or 9 mo)
RBBB
NYHA II-IV
HOPE-HF,35 2022 HBP vs no 167 PR $200 ms, LVEF #40%, Peak VO2 QoL, LVEF, patients’ 12 (crossover at UK
pacing QRS #140 ms, or RBBB symptomatic preference 6 mo)
6MWT ¼ 6-minute walk test; AF ¼ atrial fibrillation; AVNA ¼ atrioventricular node artery; BVP ¼ biventricular pacing; CV ¼ cardiovascular; HFH ¼ heart failure hospitalization; His-Alternative ¼ His Pacing
Versus Biventricular Pacing in Symptomatic HF Patients With Left Bundle Branch Block; His-SYNC ¼ His Bundle Pacing versus Coronary Sinus Pacing for Cardiac Resynchronization therapy; HOPE-HF ¼ His
Optimized Pacing Evaluated for Heart Failure; LBBP RESYNC ¼ Left Bundle Branch Pacing Versus Biventricular Pacing for Cardiac Resynchronization Therapy; LEVEL-AT ¼ LEft VEntrucuLar Activation Time
Shortening With Physiological Pacing vs Biventricular Resynchronization Therapy; LVSV ¼ left ventricular stroke volume; NICMP ¼ nonischemic cardiomyopathy; NT-proBNP ¼ N-terminal pro–B-type
natriuretic peptide; NYHA ¼ NYHA functional class; PR ¼ PR interval; QoL ¼ quality of life; QRS ¼ QRS interval; QRSd ¼ QRS duration; QRSs ¼ QRS shortening; RBBB ¼ right bundle branch block; other
abbreviations as in Tables 1 and 2.
to BVP was high at 48% because of the requirement to and N-terminal pro–B-type natriuretic peptide at
achieve QRS narrowing by >20%, to QRS width 6 months compared to BVP in a small, randomized
of <130 milliseconds, correction thresholds <5 V at 1 study of 40 patients.82 There were comparable
millisecond, and enrollment of IVCD patients. changes in NYHA functional class, 6-minute walk
In a randomized study of 50 patients with LBBB distance, QRS duration, and rates of CRT response.
and LVEF <35%, HBP corrected the QRS duration in Similarly, in another randomized study of 70 patients,
96% of patients with LBBB (defined by Strauss there was no significant difference in LVAT at 45-day
criteria), suggesting that the conduction defect is at or QRS duration, LVEF, LV end-systolic volume,
the level of His in fibers committed to become the NYHA functional class, and combined endpoint of
LBB. Permanent HBP was feasible in 72% of patients mortality or heart failure hospitalizations at 6-month
randomized.81 QRS duration, LVEF, and clinical and follow-up compared to baseline between CSP or
physical parameters at 6 months were not signifi- BVP. 31
cantly different in an intention-to-treat analysis with In a population with symptomatic heart failure
HBP or BVP. However, LVEF was significantly (LVEF <40%), persistent atrial fibrillation, and
improved and LV end-systolic volume was signifi- requiring AV node ablation, HBP was found to
cantly lower at 6 months in patients with HBP improve LVEF by a statistically significant but modest
compared to BVP in a per-protocol analysis. Further- degree compared to BVP in a randomized, crossover
more, pacing thresholds were higher at implant and trial.83
6 months with HBP compared to BVP. In a randomized, double-blind, crossover trial of
The observed success of LBBAP is reported higher 167 patients with heart failure with reduced EF
than HBP. LBBAP was superior to BVP in LVEF (LVEF <40%), prolonged PR interval >200 and
improvement, reductions in LV end-systolic volume, relatively narrow QRS interval, or RBBB, HBP did not
T A B L E 4 Ongoing or Planned Clinical Trials for Conduction System for Bradyarrhythmias
Name NCT Other Follow-up

Status Treatments Size Population Primary Endpoint Endpoints (mo) Country
LEFT Bundle Pacing LBBP vs RVP 100 LVEF $50%, high-degree AVB LVESVi, implant CV death, HFH, death, LVEF, NT- 24 Canada
vs Standard with anticipated RVP >90% success, feasibility proBNP, AF progression, TR,
Right MR, lead parameters, QoL,
Ventricular safety
Pacing for Heart
Failure
NCT05015660
Recruiting
PHYSPAVB His/LBBP vs 200 LVEF >50%, AV block PICM LVESV, septal flash, AF, HFH, 12 Spain
NCT05214365 RVP NYHA
Recruiting 6MWT, NT-proBNP, QoL, safety
LEAP LVSP vs RVP 470 LVEF >35%, second or third AVB, Combined death, HFH, Death, HFH, combined death and 12 Netherlands
NCT04595487 or atrial arrhythmia with slow and LVEF HFH, AF, LVEF, QoL, Safety,
Recruiting VR, expected VP >20% QALY, CEA, BIA
PROTECT-SYNC LBBP vs RVP 450 Bradyarrhythmia with anticipated Composite, HFH, and Death, CV death, HFH, implant 24 South Korea
NCT05585411 RVP >40% upgrade to CRT success, safety, LVEF, AF,
Not recruiting cardiopulmonary exercise
parameters
LEAP-Block LBBP vs RVP 458 LVEF $50%, AVB patients with Composite death, HFH, Death and HFH, and upgrade to 24 China
NCT04730921 anticipated RVP > 40% and upgrade to CRT CRT, echo parameters, implant
Recruiting success, safety, device
parameters, atrial arrhythmias
OptimPacing LBBP vs RVP 683 LVEF >35%, NYHA I-III, second or Combined death, HFH, Echo parameters, NT-proBNP, 36 China
NCT04624763 third AV block or persistent or and PICM NYHA
Recruiting permanent AF with VR < 50 6MWT, QoL, safety
beats/min
PROTECT HF CSP vs RVP 2,600 LVEF >35%, high burden of VP Cardiovascular death, 48 UK, world
HFH, QOL, upgrade
AVB ¼ atrioventricular block; LEAP ¼ LVSP vs RVP in Patients With AV Conduction Disorders; LEAP-Block ¼ Impact of Left Bundle Branch Area Pacing vs Right Ventricular Pacing in Atrioventricular Block;
LVESVi ¼ left ventricular end systolic volume index; LVSP ¼ left ventricular septal pacing; MR ¼ mitral regurgitation; OptimPacing ¼ Protection of Cardiac Function With Left Bundle Branch Pacing in Patients
With Atrioventricular Block; PHYSPAVB ¼ Physiological Pacing for AV Block to Prevent Pacemaker-Induced Cardiomyopathy; PICM ¼ pacemaker induced cardiomyopathy; PROTECT-HF ¼ Physiological versus
Right ventricular pacing Outcome Trial Evaluated for Bradycardia Treatment - Heart Failure; PROTECT-SYNC ¼ Preventive Effect of Left Bundle Branch Area Pacing Versus Right Ventricular Pacing on All
Cause Death, Heart Failure Progression, and Ventricular Dyssynchrony in Patients With Substantial Ventricular Pacing; QALY ¼ quality-adjusted life-year; RVP ¼ right ventricular pacing; TR ¼ tricuspid
regurgitation; VP ¼ ventricular pacing; VR ¼ ventricular rate; other abbreviations as in Tables 2 and 3.
increase peak oxygen uptake but significantly LBBAP or both. This is likely caused by the limitations
improved quality of life and was symptomatically of HBP compared to LBBAP. The smaller studies have
preferred by a clear majority of patients. Importantly, surrogate primary endpoints and shorter follow-up
HBP did not adversely affect ventricular function at whereas larger clinical trials are powered to examine
6 months.35 clinically relevant outcomes such as mortality, heart
The planned and ongoing clinical trials cover most failure hospitalizations, and development of pacing-
of the clinical scenarios that require significant induced cardiomyopathy and have longer follow-up.
amounts of ventricular pacing either caused by high- The inclusion criteria include not only patients with
degree AV block (Table 4) or for CRT (Table 5). normal LVEF (>50%) but in some studies extend to
Furthermore, a number of trials examine CSP in spe- LVEF as low 35%. Comparison with RVP reflects
cific clinical scenarios such as atrial fibrillation in the different pacing practices in most countries for LVEF
context of slow ventricular rate or AV node ablation 35%-50%. In the United States, the favored modality
for rate control (Table 6) and after transaortic aortic is BVP for LVEF 35%-50% and high-degree AV block
valve replacement (Table 7). Many of those clinical based on current guidelines. Left vs Left (Table 3)
trials are powered to assess hard outcomes. In compares HBP/LBBAP to BVP in patients with LVEF
aggregate, these trials will enroll diverse patient 35%-50% and those with <35%. Whereas most trials
populations. are examining the efficacy and safety of CSP, the
Table 8 summarizes the advantages and disad- LEAP (LVSP vs RVP in Patients With AV Conduction
vantages of CSP vs BVP for CRT. Disorders) trial is unique in determining whether
LVSP is sufficient without a requirement to capture
CLINICAL TRIALS FOR BRADYARRHYTHMIAS. There the LBB. These studies will help establish the role of
are fewer trials that employ HBP alone compared to CSP for the appropriate patient population.
T A B L E 5 Ongoing or Planned Clinical Trials for CSP for CRT
Name NCT Other

Status Treatments Size Population Primary Endpoint Endpoints Follow-up (mo) Country
LIT-HF His/LBBP vs 50 NICMP, LVEF#35%, NYHA II- % with Health economics, LVEF, 18 China
NCT05572957 GDMT III, < 3 mo GDMT LVEF #35% LVESV, LVEDV, NT-
Recruiting SR, LBBB and/or VAs proBNP, NYHA, QoL,
safety
HIS-CRT HBP vs BVP 120 IIa, IIb indication for CRT-D, LVEF QRSd, LVESV, LVEDV, NT- 6 USA
NCT05265520 RBBB proBNP
Recruiting
HOT-CRT NCT04561778 HOT/LOT vs 100 LVEF #35%, LBBB QRSd LVEF, safety, HFH, death, VT/VF, crossover, 6 USA
Enrollment complete BVP >120 ms or LVEF #50%, success NYHA, QRSd, LVESVi, QoL
RVP > 40%, NYHA II-IV
REINVENT-CRT LBBP vs BVP 20 LVEF >35%, LBBB, NYHA I- IV MPI 6 USA
NCT05652218 (crossover
Not recruiting 3 mo)
HIS-alt_2 His/LBBP vs 125 LVEF #35%, NYHA II-IV, LVEF, QRS LVEF, 6MWT, NYHA, QoL, 6 Denmark
NCT04409119 BVP LBBB, or RVP > 90% narrowing QRSd, NT-proBNP, safety
Recruiting
LBBAP-AFHF LBBP vs BVP 60 Heart failure, LVEF <50%, LVEF Implant success, safety, echo 6 China
NCT05549544 NYHA II-IV, permanent AF, parameters, NT-proBNP,
Recruiting QRSd <130 ms, AVNA or death, and HFH
slow VR with anticipated
RVP $40%
CSP-SYNC His/LBBP vs 60 LVEF #35%, LBBB, NYHA II-III LV volume, Myocardial work 12 Slovenia
NCT05155865 BVP LVEF, NYHA, redistribution, QRSd,
Recruiting NT-ProBNP, arrhythmia, safety
6MWT, QoL
CONSYST-CRT His/LBBP vs 130 LVEF #35%, LBBB, Composite LVEF, LVESV, composite of 12 Spain
NCT05187611 BVP QRSd $130 ms or death, death, cardiac transplant,
Recruiting LVEF #35%, non-LBBB, cardiac HFH, QRSd, septal flash,
QRSd $150 ms or transplant, NYHA
LVEF <40%, AVB or HFH, LVEF
LVEF#35%, NYHA III-IV,
AF, QRSd $130 ms
Safety and Effectiveness of LBBP vs BVP 160 LVEF <50%, NYHA I-III, LVEF LVESV, implant success, death 12 China
Left Bundle Branch second or third AVB, or and HFH, safety, QRSd, TR
Pacing in Patients With RVP >40%
Cardiac Dysfunction and
AV Block
NCT05553626
Not recruiting
LeCaRT LBBP vs BVP 170 CRT indication, NYHA II-IV, Composite Procedure time, fluoroscopy 12 Belgium
NCT05365568 LBBB QRSd >130 ms or death, HFH, time, QRSd, 6MWT,
Recruiting non-LBBB QRSd, >150 ms, implant LVESV, ICD therapies
or wide paced QRSd failure, CIED
re-
intervention
LEFT-BUNDLE-CRT LBBP vs BVP 176 I or IIa indication for CRT, CRT response LVEF, clinical outcome, 12 Spain
NCT05434962 LBBB 6MWT, QoL, HFH, death,
Recruiting cardiac transplantation,
VAs, safety
PhysioSync-HF His/LBBP vs 304 LVEF #35%, LBBB, Composite Cost-effectiveness, QoL, 12 Brazil
NCT05572736 BVP QRSd $130 ms death, HFH, NYHA, 6MWT
Not recruiting LVEF NT-proBNP, LVEF
QRSd, CV death and HFH,
LVAT
Left vs Left His/LBBP vs 2,136 LVEF #50%, QRSd $130 ms Composite death QoL, death, HFH, and LVESVi 66 USA, Canada
NCT05650658 BVP or anticipated RVP >40% and HFH >15%, CV death, NYHA,
Not recruiting or upgrade to CRT because of 6MWT, NT-proBNP, AF,
RVP >40% ICD therapies, echo
parameters
CIED ¼ cardiac implantable electronic device; CONSYST-CRT ¼ Conduction System Pacing vs Biventricular Resynchronization Therapy in Systolic Dysfunction and Wide QRS; CRT-D ¼ cardiac resynchro-
nization therapy defibrillator; CSP-SYNC ¼ Conduction System Pacing Versus Biventricular Pacing for Cardiac Resynchronization; GDMT ¼ guideline directed medical therapy; HIS-alt_2 ¼ Direct His/LBB
Pacing as an Alternative to Biventricular Pacing in Patients With HFrEF and a Typical LBBB; HIS-CRT ¼ His-Bundle Corrective Pacing in Heart Failure; HOT-CRT ¼ His-Purkinje Conduction System Pacing
Optimized Trial of Cardiac Resynchronization Therapy; ICD ¼ implantable cardioverter-defibrillator; LBBAP-AFHF ¼ Clinical Efficacy of Left Bundle Branch Area Pacing for Patients With Permanent Atrial
Fibrillation and Heart Failure; LeCaRT ¼ Left Bundle Branch Area Pacing for Cardiac Resynchronization Therapy: A Randomized Study; LEFT-BUNDLE-CRT ¼ The Left Bundle Cardiac Resynchronization
Therapy Trial; Left vs Left ¼ Left vs Left Randomized Clinical Trial; LIT-HF ¼ LBBP as Initial Therapy in Patients With Nonischemic Heart Failure and LBBB; LVEDV ¼ left ventricular end diastolic volume;
MPI ¼ myocardial perfusion imaging; PhysioSync-HF ¼ Conduction System Pacing Versus Biventricular Resynchronization in Patients With Chronic Heart Failure; REINVENT-CRT ¼ Resynchronization
Comparison in LBBB and Normal or Mildly Reduced Ventricular Function With CRT; SR ¼ sinus rhythm; VA ¼ ventricular arrhythmia; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia; other ab-
breviations as in Tables 1-4.
T A B L E 6 Ongoing or Planned Trials for CSP for AF
Name NCT Other

Status Treatments Size Population Primary Endpoint Endpoints Follow-up Country
LBBAP-AFHF LBBP vs BVP 60 LVEF<50%, NYHA II-IV, LVEF Implant success, safety, echo 6 China
NCT05549544 permanent AF QRSd <130 ms, parameters, NT-proBNP, death,
Recruiting AVNA or slow VR with and HFH
anticipated RVP $40%
CONDUCT-AF His/LBBP vs BVP 82 LVEF <50%, QRSd # 120 ms, LVEF at 6 mo HFH, CV death, LVESV, LVEDV, NYHA, 24 Slovenia, Austria,
NCT05467163 perAF (>6 mo) refractory to 6MWT, QoL, NT-proBNP Bulgaria, Croatia,
Not recruiting AAD or failed CA and AVNA Romania
RAFT-P&A LBBP vs BVP 284 AF and AVNA, NYHA I-Iva, NT- NT-proBNP Composite HFH and death, QoL, 12 Canada
NCT05428787 proBNP > 600 or >400 if 6MWT, echo parameters
Not recruiting HFH within 12 mo
AAD ¼ antiarrhythmic drugs; CA ¼ catheter ablation; CONDUCT-AF ¼ Conduction System Pacing Versus Biventricular Pacing After Atrioventricular Node Ablation; perAF ¼ persistent atrial fibrillation; RAFT-
P&A ¼ Resynchronization in Patients With HF in AF Trial Undergoing Pace and AVNA Strategy With LBBAP Compared With BiV Pacing; other abbreviations as in Tables 1-5.
FUTURE PERSPECTIVES extraction from His bundle region and deep septal
location needs to be carefully evaluated. Early ob-
While we await the completion of larger randomized servations in case reports and small series support the
clinical trials on CSP, several important unanswered use of CSP in special populations such as painful
questions remain at the forefront of investigation: LBBB and LBBB-induced cardiomyopathy. Similarly,
others have explored the utility of leadless LV endo-
Is LBBAP as good as HBP?
cardial pacing for CRT. Advances in leadless pacing
What is the most optimal criteria for left conduc-
technology may lead to future possibilities of leadless
tion system capture?
CSP. Diligent scientific evaluation will likely usher in
Are there differences in clinical outcomes between
a promising future for CSP.
proximal and distal LBBAP?
Is LBB capture necessary to achieve maximal ben-
ACKNOWLEDGMENTS The authors thank those in-
efits in patients with bradycardia and patients
dividuals who have donated their bodies and tissues
requiring CRT (LBBP vs LVSP)?
for the advancement of education and research.
What is the clinical impact of delayed RV activation
Special thanks to organ procurement organization
with LBBAP, particularly in patients with heart
OneLegacy Foundation and the National Institutes of
failure?
Health SPARC Program, which formed the basis for
What is the clinical impact of CSP in patients with
obtaining donor hearts for research and for funding
diastolic heart failure and AV block or bundle
this effort. The authors appreciate Amiksha S. Gandhi
branch block?
for her dedication to support our projects. The au-
The long-term integrity of both lumenless vs thors are also grateful to all the staff members of the
stylet-driven leads and the feasibility of lead UCLA Donated Body Program, UCLA Translational
T A B L E 7 Ongoing or Planned Clinical Trials for CSP After TAVR
Name NCT Other

Status Treatments Size Population Primary Endpoint Endpoints Follow-up Country
PHYS-TAVI His/LBBP vs RVP 24 TAVR, AVB, LVEF> 50% Combined survival, LVEF, Septal flash, 6MWT, NYHA, MR, 12 Spain
NCT04482816 NYHA, 6MWT NT-proBNP, HFH, QRSd, QoL, GLS
Not recruiting
PLANET LBBP vs RVP 30 TAVR, LVEF $50%, second AVB, QRSd Death, CV death, HFH, LVEF, echo, 24 Germany
NCT05024279 third AVB bradycardic AF with NYHA, NT-proBNP, 6MWT, QoL,
Recruiting anticipated RVP >20% arrhythmias
Left Bundle LBBP vs RVP 46 TAVR, bradycardia or first AVB, GLS, LVEF, safety QoL, NYHA, 6MWT, HFH, death, 18 (crossover USA
BRAVE second AVB type I or II, high- endpoints NT-proBNP, echo parameters, at 9 mo)
NCT05541679 grade AVB, or third AVB device parameters
Not recruiting
GLS ¼ global longitudinal strain; Left Bundle BRAVE ¼ Comparison of Left Bundle Branch Area Versus Right Ventricular Septal Pacing in Patients With High-degree Conduction Disease After Transcatheter
Aortic Valve Replacement; PHYS-TAVI ¼ Physiological vs Right Ventricular Pacing in Patients With Normal Ventricular Function Post-TAVI; PLANET ¼ Left Bundle Branch Area Pacing in Patients After TAVR;
TAVR ¼ transcatheter aortic valve replacement; other abbreviations as in Tables 1-4.
Abbott, and Impulse Dynamics; and honoraria from Impulse Dy-

T A B L E 8 Advantages and Disadvantages of CSP vs BVP for CRT namics. Dr Curila has received consulting fees and honoraria from
Medtronic, Biotronik, and Abbott; has filed U.S. patent:
Advantages Disadvantages
US11,517,243B2: “Method of electrocardiographic signal processing
Comparable success rates (with LBBAP) Lower success rates
and apparatus for performing the method”; and is a shareholder of
(with HBP)
VDI Technologies. Dr Dandamudi has received honoraria and
Narrower paced QRSd Not ideal in patients
consulting fees from Medtronic; and served on advisory boards of
with IVCD
Medtronic, Biotronik, and Abbott. Dr Herweg has served as a
More physiological biventricular activation Lack of large-scale
speaker and consultant for Abbott; and has received speaking fees
randomized data
and fellowship support from Medtronic. Dr Jastrzebski has received
Better acute hemodynamics
honoraria and consulting fees from Medtronic and Abbott. Dr
a
Higher echocardiographic response rates
Sharma has received honoraria from Medtronic; and consulting fees
Higher clinical response rates in some patient from Medtronic, Abbott, Biotronik, and Boston Scientific. Dr Shiv-
groups, observational studiesa
kumar is a cofounder of NeuCures Inc. Dr Tung has received hon-
Possible lower HFH and mortality in some oraria and consulting fees from– Abbott. Dr Upadhyay has received
patient groupsa
honoraria from and served on advisory boards for Abbott, Bio-
tronik, Boston Scientific, Medtronic, Philips BioTel, and Zoll Medi-
a
Based on both small, single-center studies and larger-scale, multicenter obser-
cal. Dr Vernooy has received consulting fees from Biosense
vational data.
LBBAP ¼ left bundle branch area pacing; other abbreviations as in Tables 1 to 3.
Webster, Philips, Medtronic, and Abbott; honoraria from Microport;
and research and educational grants (paid to institution) from
Philips, Abbott, Medtronic, and Biosense Webster. Dr Whinnett has
received honoraria from Medtronic and Boston Scientific; and
Research Imaging Center (Department of Radiology), consulting fees from Medtronic and Abbott. Dr Zanon has received
and UCLA Translational Pathology Core Laboratory honoraria from Abbott, Biotronik, Boston Scientific, Medtronic, and
Microport. Dr Ellenbogen has received consulting fees from Med-
for their support for dissection, image acquisition,
tronic, Boston Scientific, Abbott, and Biotronik; and honoraria from
and histological preparation. Medtronic, Boston Scientific, and Biotronik. All other authors have
reported that they have no relationships relevant to the contents of
FUNDING SUPPORT AND AUTHOR DISCLOSURES this paper to disclose.
Work on anatomy was made possible by support from National In-

ADDRESS FOR CORRESPONDENCE: Dr Pugazhendhi
stitutes of Health grants OT2OD023848 (to Dr K Shivkumar) and from
the Tawara-McAlpine Festschrift (a component of the UCLA Amara- Vijayaraman, Geisinger Commonwealth School of
Yad Project). Dr Vijayaraman has received honoraria, consulting Medicine, Geisinger Heart Institute, MC 36-10 1000
fees, and research and fellowship support from Medtronic; honoraria
East Mountain Boulevard, Wilkes-Barre, Pennsylva-
from Biotronik and Boston Scientific; and consulting fees from
Abbott; and holds a patent for an HBP delivery tool. Dr Chelu has
nia 18711, USA. E-mail: [email protected]
received research support from PCORI, National Institutes of Health, OR [email protected].
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KEY WORDS cardiac resynchronization
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2020;17(10):1759–1767. tial His bundle and left ventricular pacing for version of this paper.

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JACC: CLINICAL ELECTROPHYSIOLOGY VOL. -, NO.

Cardiac Conduction System Pacing

T he ﬁeld of cardiac pacing has changed rapidly

ISSN 2405-500X/$36.00 https://doi.org/10.1016/j.jacep.2023.06.005

ABBREVIATIONS years ago. Tawara discovered the atrioven-

F I G U R E 1 Tawara’s Illustration and Its 3D Reconstruction

F I G U R E 2 Conduction System Pacing

Vijayaraman P, et al. J Am Coll Cardiol EP. 2023;-(-):-–-.

F I G U R E 3 Ultra High Frequency ECG in HBP

F I G U R E 7 Two LBBAP Sites in the Same Patient

F I G U R E 8 Diagnostic QRS Transition During Threshold Test

T A B L E 1 Specialized Delivery Catheters for CSP

placement secondary to coronary venous anatomy

F I G U R E 1 3 Pathophysiology of Coexistent LBBB and IVCD

T A B L E 2 Cardiac Resynchronization Therapy

Success Follow-up Echocardiographic

T A B L E 3 Randomized Clinical Trials for CSP

Lustgarten et al,80 HBP vs BVP 29 CRT indication Feasibility QoL 12 USA

T A B L E 4 Ongoing or Planned Clinical Trials for Conduction System for Bradyarrhythmias

Name NCT Other Follow-up

T A B L E 5 Ongoing or Planned Clinical Trials for CSP for CRT

Name NCT Other

T A B L E 6 Ongoing or Planned Trials for CSP for AF

Name NCT Other

T A B L E 7 Ongoing or Planned Clinical Trials for CSP After TAVR

Name NCT Other

Abbott, and Impulse Dynamics; and honoraria from Impulse Dy-

FUNDING SUPPORT AND AUTHOR DISCLOSURES this paper to disclose.

Work on anatomy was made possible by support from National In-

bundle branch capture. Europace. 2023;25(3): ˛bski M, Kiełbasa G, Moskal P, et al.

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