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\begin{document}

\title{Structural heart disease, not right ventricular pacing site, determines
QRS duration during right ventricular pacing}



\author[1]{Michio Ogano}%
\author[1]{Ippei Tsuboi}%
\author[2]{Yu-ki Iwasaki}%
\author[1]{Jun Tanabe}%
\author[2]{Wataru Shimizu}%
\affil[1]{Shizuoka Medical Center}%
\affil[2]{Nippon Medical School}%


\vspace{-1em}



  
  \date{May 23, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Introduction: Right ventricular (RV) pacing causes changes in the
heart's electrical and mechanical activation patterns. QRS duration is a
useful surrogate marker of electrical dyssynchrony; longer QRS duration
during RV pacing indicates poor prognosis. However, the mechanisms
underlying longer QRS duration during RV pacing remain unclear; hence,
we investigated factors predicting QRS prolongation during RV pacing.
Methods and Results: We enrolled 211 patients who underwent catheter
ablation for supraventricular tachyarrhythmia and showed no
bundle-branch-block. Three-dimensional mapping for QRS duration during
RV pacing from the RV outflow to RV apex was performed, and the
difference in QRS duration was analyzed. The predisposing factors
causing QRS \textgreater{}160 ms during RV apical pacing were also
analyzed. QRS durations at baseline and during RV pacing from the RV
outflow and at RV apex were 85.0\selectlanguage{ngerman}±7.5 ms, 163.7±17.1 ms, and 156.2±16.1
ms, respectively. With respect to QRS duration, there was a significant
correlation between RV outflow and RV apical pacing (r=0.658,
p\textless{}0.001). The difference in QRS duration between RV outflow
and apex in each patient was only 12.5±10.4 ms. Logistic multivariable
regression analysis identified baseline QRS duration {[}odds ratio (OR)
1.24, 95\% confidence interval (CI) 1.15 to 1.33, p\textless{}0.01{]},
interventricular septum thickness (OR 1.20, 95\% CI 1.02-1.40, p=0.025),
left atrial diameter (OR 1.08, 95\% CI 1.01-1.16, p=0.024), and E/e' (OR
1.23, 95\% CI 1.12-1.35, p\textless{}0.01) as significant predictors of
prolonged QRS duration during RV apical pacing. Conclusion: QRS duration
during RV pacing largely depends not on the pacing site, but on
underlying structural heart diseases.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Structural heart disease, not right ventricular pacing site,
determines QRS duration during right ventricular pacing}

Michio Ogano, MD+, Ippei Tsuboi, MD++, Yu-ki Iwasaki, MD\selectlanguage{ngerman}§, Jun Tanabe,
MD\selectlanguage{english}+, Wataru Shimizu MDSS

\selectlanguage{english}+Department of Cardiovascular Medicine

Shizuoka Medical Center, 762-1 Nagasawa, Shimizu, Sunto Shizuoka
4110906, Japan

\selectlanguage{english}++Department of Cardiovascular Medicine

Nippon Medical School Musasikosugi hospital, 1-396 Kosugi-cho,
Nakahar-ku, Kawasaki, Kanagawa 2118533, Japan

SSDepartment of Cardiovascular Medicine,

Nippon Medical School, 1-1-5 Sendagi, Bunkyo Tokyo 1138603, Japan

Funding: This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest: All authors have no conflicts of interest.

Address for correspondence and reprint requests: Michio Ogano, MD

Division of Cardiovascular Medicine, Shizuoka Medical Center,

762-1 Nagasawa, Shimizu, Sunto Shizuoka 4110906, Japan

Phone: +81-5-5975-2000, Fax: +81-5-5975-1999,
E-mail:\emph{m-ogano@nms.ac.jp}

Abstract

Introduction: Right ventricular (RV) pacing causes changes in the
heart's electrical and mechanical activation patterns. QRS duration is a
useful surrogate marker of electrical dyssynchrony; longer QRS duration
during RV pacing indicates poor prognosis. However, the mechanisms
underlying longer QRS duration during RV pacing remain unclear; hence,
we investigated factors predicting QRS prolongation during RV pacing.

Methods and Results: We enrolled 211 patients who underwent catheter
ablation for supraventricular tachyarrhythmia and showed no
bundle-branch-block. Three-dimensional mapping for QRS duration during
RV pacing from the RV outflow to RV apex was performed, and the
difference in QRS duration was analyzed. The predisposing factors
causing QRS \textgreater{}160 ms during RV apical pacing were also
analyzed. QRS durations at baseline and during RV pacing from the RV
outflow and at RV apex were 85.0+-7.5 ms, 163.7+-17.1 ms, and 156.2+-16.1
ms, respectively. With respect to QRS duration, there was a significant
correlation between RV outflow and RV apical pacing (r=0.658,
p\textless{}0.001). The difference in QRS duration between RV outflow
and apex in each patient was only 12.5+-10.4 ms. Logistic multivariable
regression analysis identified baseline QRS duration {[}odds ratio (OR)
1.24, 95\% confidence interval (CI) 1.15 to 1.33, p\textless{}0.01{]},
interventricular septum thickness (OR 1.20, 95\% CI 1.02-1.40, p=0.025),
left atrial diameter (OR 1.08, 95\% CI 1.01-1.16, p=0.024), and E/e' (OR
1.23, 95\% CI 1.12-1.35, p\textless{}0.01) as significant predictors of
prolonged QRS duration during RV apical pacing.

Conclusion: QRS duration during RV pacing largely depends not on the
pacing site, but on underlying structural heart diseases.

Keywords: Pacing, QRS duration, Heart Failure, Right ventricle,
Electrical dyssynchrony

Introduction

Right ventricular (RV) pacing results in non-physiological electrical
myocardial conduction and mechanical left ventricular (LV)
dyssynchrony\textsuperscript{1} and may cause LV systolic dysfunction
following heart failure even in patients without pre-existing systolic
dysfunction.\textsuperscript{2,3} The emergence of a permanent
physiological form of pacing such as His bundle pacing
(HBP)\textsuperscript{4} or left bundle branch
pacing\textsuperscript{5,6} as well as several beneficial
data\textsuperscript{4-6} suggest an alternative pacing management
compared to conventional RV pacing.

Although many patients may obtain much benefit from a physiological form
of pacing, successful placement of the HBP lead is only possible in
approximately 80\% of cases,\textsuperscript{7,8} and lead placement is
technically complex and has elevated capture
thresholds.\textsuperscript{9} Therefore, RV pacing remains the standard
of care in the pacing management by virtue of its accessibility and
relative stability over time. An additional reason is that most patients
can tolerate RV pacing without any cardiovascular events for a long
period.\textsuperscript{10}

Prolonged QRS duration on ECG is a simple marker of the quantity of
non-physiological electrical myocardial conduction and is an independent
predictor of cardiovascular events.\textsuperscript{11} Narrower QRS
after cardiac resynchronization therapy (CRT) predicts a good CRT
response.\textsuperscript{12} Furthermore, widening of the QRS duration
after CRT has been reported as an independent predictor of mortality or
progression to heart transplantation.\textsuperscript{13} Recently,
QRS-based CRT optimization was reported to be
effective.\textsuperscript{14}

A prolonged QRS duration during RV pacing has a detrimental effect on
long-term cardiac function.\textsuperscript{15} QRS duration during RVP
is a useful marker to identify patients who are at risk of heart failure
events. However, detailed background on differences in QRS duration
during RV pacing between patients is lacking. Our objective in this
study was to investigate the predictive factors of QRS prolongation
during RV pacing.

Methods

Patients

From a consecutive group of patients at a single hospital, 295 patients
who had undergone radiofrequency ablation for supraventricular
arrhythmias: atrial fibrillation, atrial flutter, atrial tachycardia,
atrioventricular reentrant tachycardia, and atrioventricular nodal
reentrant tachycardia were prospectively enrolled. Patients were
excluded if they had bundle branch block or native QRS duration longer
than 120 ms at baseline or if they had congenital heart disease,
frequent ventricular premature contraction or tachycardia, severe heart
failure (NYHA III or IV), or acute coronary syndrome.

The medical histories of all patients were analyzed, and all patients
underwent a baseline physical examination, a conventional 12-lead body
surface ECG, and echocardiography. Echocardiographic images were
obtained with a 3.5 MHz transducer in the left lateral decubitus
position using a commercially available system (Vivid Eight, General
Electric-Vingmed, Milwaukee, WI). Standard 2D triggered to the QRS
complex was saved in cine-loop format for offline analysis (EchoPac
6.06, GE Medical Systems, Horten, Norway). Echocardiographic parameters
included left ventricular end-systolic volume (LVESV), left ventricular
end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF),
intraventricular wall thickness (IVST), posterior wall thickness (PWT),
left atrial diameter (LAD), and the E/e' and E/A ratios. Ischemic
cardiomyopathy was defined in the presence of significant coronary
artery disease (\textgreater{}75\% stenosis in 1 or more of the major
epicardial coronary arteries) and/or history of myocardial infarction or
prior revascularization.

Antiarrhythmic drugs except beta-blockers were stopped \textgreater{}5
half-lives before the study. No patient received amiodarone in the 6
months before the study. All patients provided written informed consent
to participate, and the study was approved by our institutional ethics
committee (18-13) and conducted in accordance with the Declaration of
Helsinki.

Mapping during RV pacing

All patients entered into the electrophysiological laboratory in a
fasting state. The electrophysiological study and catheter ablation were
performed under deep sedation with intravenous propofol, pentazocine,
and hydroxyzine hydrochloride. After the conventional ablation procedure
was completed, the electrophysiological study of RV pacing was
performed. The RV around the septal site mainly at its apex and outflow
tracts was mapped with a 7.5 Fr, 3.5 mm open-irrigated-tip contact force
(CF)-sensing ablation catheter (Navistar ThermoCool, SmartTouch,
Biosense Webster, Diamond Bar, CA). Cardiac pacing was performed with a
programable stimulator with 5.0 V output. A three-dimensional mapping
system (CARTO 3, Biosense Webster) was used in real time with
electrophysiological information, color-coded and superimposed on the
anatomic map. The initial timing of the map was programmed to the pacing
artifact signal, and electroanatomical mapping was conducted based on
QRS duration during RV pacing: from the pacing artifact to the end of
the QRS wave (Figure 1). Around the His bundle or right bundle branch
area, careful pacing was conducted, and pure selective pacing of the His
bundle or right bundle branch (abrupt QRS narrowing compared neighboring
QRS duration) was excluded from the analysis.

Surface ECG was continuously monitored and stored on a computer-based
digital amplifier-recorder system with optical disk storage for offline
analysis. The 12 leads of the surface ECG were displayed in vertical
alignment on the screen. QRS duration was measured as the interval
between the earliest deflection of the ventricular complex in any of the
12 simultaneous leads and the latest offset in any lead by two
experienced investigators. Measurements were repeated at a screen
velocity of 50 mm/s.

During point acquisition, endocardial contact was facilitated by
CF-sensing and myocardium capture by pacing. The locations of the RV
outflow tract and RV apical site were identified based on the created
electroanatomical mapping and axis in frank leads: the inferior axis in
the RV outflow tract and superior axis in the RV apical site. The QRS
duration was defined as wide when it was longer than 160 ms during RV
apical pacing, which had previously shown a detrimental effect on
long-term cardiac function.\textsuperscript{14, 16, 17}

Statistical analysis

Continuous data are expressed as mean and standard deviation (SD), and
categorial data are summarized as frequencies and percentages. Fisher's
exact test and unpaired Student's t test were used to compare
categorical and continuous data, respectively. Correlation analysis was
performed to compare QRS duration during RV pacing and continuous
baseline variables using Spearman correlation coefficients.

Univariate and multivariate logistic regression analyses were performed
to identify possible predictors for wide QRS duration. The following
variables were investigated: sex, age, baseline QRS duration, atrial
fibrillation, hypertension, heart failure, ischemic cardiomyopathy,
LVEF, LVEDV, LVESV, IVST, PWD, LAD, E/e', A/E, and use of beta blockers.
The backward elimination method was applied. The multivariate models to
predict variables for wide QRS duration were selected based on the
univariate test results (p\textless{}0.1). Possible collinearity among
eligible variables was assessed using variance inflation factors with a
threshold equal to 5. To avoid statistical coupling of variables,
separate multivariate models were constructed that excluded parameters
derived from one another. Harrell's c-statistics were calculated for the
different models. The model with the marginally higher Harrell's
c-statistics was selected. A two-tailed probability P-value of 0.05
indicated statistical significance. Statistical analyses were calculated
using SPSS version 25 (IBM Corp., Armonk, NY).

Results

From November 2018 to October 2019, 295 patients were consecutively
enrolled. Of these patients, 72 patients with bundle branch block, 5
with severe heart failure (NYHA\textgreater{}III), 5 with hypertrophic
cardiomyopathy, and 2 with congenital heart disease were excluded. Data
of the remaining 211 patients were included in the analysis; 161 had
atrial fibrillation, 12 had atrial flutter, 20 had atrioventricular
nodal reentrant tachycardia, 10 had atrioventricular reentrant
tachycardia, and 8 had atrial tachycardia.

The average QRS duration at baseline, during RV outflow pacing, and
during RV apical pacing was 80.5+-7.5 ms, 163.7+-17.1 ms, and 156.2+-7.5
ms, respectively. Pure selective His bundle or right bundle branch
capture was not observed during pacing around the His or right bundle
branch areas. There was a significant correlation of QRS duration
between RV outflow pacing and RV apical pacing (r=0.658,
p\textless{}0.001) (Figure 2), signifying that patients with longer QRS
duration during RV outflow pacing were highly likely to have longer QRS
duration during RV apical pacing. The duration of QRS did not depend on
the RV pacing site in each patient. The difference in QRS duration
between RV outflow pacing and RV apical pacing in each patient was only
12.5+-10.4 ms (Figure 3). There were no significant color gradations of
CARTO mapping between the RV outflow and RV apex.

Demographic and clinical data of patients with QRS duration longer or
shorter than 160 ms during RV apical pacing are shown in Table 1. In
univariate logistic regression analysis, patients with QRS duration
longer than 160 ms during RV apical pacing were more likely to be male
{[}odds ratio (OR)=2.31; 95\% confidence interval (CI), 1.28-4.15,
p=0.005{]} and to have longer QRS duration at baseline (OR=1.02; 95\%
CI, 1.06-1.16, p\textless{}0.001), atrial fibrillation (OR=2.32; 95\%CI,
0.95-5.70, p=0.065), hypertension (OR=2.26; 95\%CI, 1.28-3.99, p=0.005),
heart failure (OR=2.12; 95\%CI, 0.97-4.94, p=0.061), lower LVEF
(OR=0.98; 95\%CI, 0.95-1.00, p=0.048), larger LVEDV (OR=1.02; 95\%CI,
1.01-1.03, p\textless{}0.001), larger LVESV (OR=1.03; 95\%CI 1.01-1.04,
p\textless{}0.001), higher IVST (OR=1.12; 95\%CI 0.98-1.27, p=0.088),
higher LAD (OR=1.14; 95\%CI 1.08-1.20, p\textless{}0.001), higher E/e'
(OR=1.13; 95\%CI 1.07-1.19, p\textless{}0.001), and beta-blocker
prescription (OR=2.12; 95\%CI 1.19-3.80, p=0.061).

To avoid statistical coupling of variance, separate multivariate models
were constructed that excluded coupled parameters (e.g., two separate
models were created for LVEDV and LVESV). The variance inflation factors
of LVEDV and LVESV were 5.47 and 5.12, respectively. A multivariate
model excluding LVESV showed marginally better c-statistics. A logistic
regression multivariate model combining male sex, baseline QRS duration,
atrial fibrillation, hypertension, heart failure, LVEF, LVEDV, IVST,
LAD, E/e', and use of beta blockers was tested and revealed that
baseline QRS duration (OR=1.24; 95\%CI 1.15-1.33, p\textless{}0.01),
IVST (OR=1.20; 95\%CI 1.02-1.40, p=0.025), LAD (OR=1.08; 95\%CI
1.01-1.16, p=0.024), and E/e' (OR=1.23; 95\%CI 1.12-1.35,
p\textless{}0.01) were independently associated with QRS
duration\textgreater{}160 ms during RV apical pacing (Table 2).

Discussion

In this study, we investigated predictive factors of QRS prolongation
during RV pacing. The present findings can be summarized as follows: (1)
The QRS duration during RV pacing varied among patients, and there was a
significant correlation of QRS duration during pacing between the RV
outflow and RV apex in each case, denoting that QRS duration during RV
pacing depends on the underlying heart condition, not on RV pacing
location. (2) Independent predictive factors for QRS duration longer
than 160 ms during RV apical pacing were longer QRS duration, LAD, IVST,
and higher E/e' at baseline. These factors suggested that cardiac
hypertrophy or diastolic dysfunction, not lower LVEF and larger LV
dimension, were associated with prolonged QRS duration during RV pacing.

RV apical pacing is known to generate non-physiological electrical and
mechanical dyssynchrony,\textsuperscript{1} and some patients with
permanent RV apical pacing experience adverse effects such as
deterioration of heart failure or occurrence of atrial
fibrillation.\textsuperscript{2,3}RV non-apical pacing sites were
considered alternative pacing sites to reduce adverse effect. However, a
randomized-controlled trial showed that non-apical pacing could not
provide a preventive effect on heart failure hospitalization, mortality,
and burden of atrial fibrillation.\textsuperscript{18} Delayed
contraction at the LV lateral site can be observed during RV pacing
irrespective of the pacing site, as RV pacing relies on slow cell to
cell conduction of the electrical wavefront. In our study, the
difference in QRS duration between RV outflow and RV apical pacing was
only 12.5+-10.4 ms, suggesting that selecting a non-apical pacing site in
RV to compensate for LV electrical dyssynchrony has large limitations.

Biventricular pacing can prevent delayed LV electrical activation and LV
lateral contraction. The BLOCK HF trial showed that biventricular pacing
reduced the rate of heart failure, hospitalization, and mortality
compared to conventional RV pacing in patients with atrioventricular
block, NYHA class I, II, or III heart failure, and LVEF of 50\% or
lower.\textsuperscript{19} Recent guidelines have recommended
biventricular pacing rather than conventional RV pacing for patients
with systolic heart failure who depend on chronic
pacing.\textsuperscript{20} However, the survival curve of the primary
outcome in the BLOCK HF trial showed steady decline even in the
biventricular pacing group, suggesting that even patients without
systolic heart failure can develop new-onset heart failure. Conflicting
preliminary data were reported by the Biventricular Pacing for
Atrioventricular Block to Prevent Cardiac Desynchronization Trial
investigators.\textsuperscript{21} Complications associated with the
implantation of biventricular pacing and high financial burden for
implantation make following the guidelines complicated. In the BLOCK HF
trial, 10.3\% of patients experienced events related to procedure and
device. Moreover, 4.9\% of patients had serious adverse events related
to biventricular pacing within 6 months. Additionally, biventricular
pacing implantation requires longer fluoroscopic times and, usually, the
use of contrast agents to define the coronary venous anatomy.
Biventricular pacing actually accounts for less than 10\% of implants in
the United States.\textsuperscript{22} Recently, His bundle pacing or
left bundle branch pacing has emerged as physiologic pacing
managements.\textsuperscript{4} Although several studies have already
shown that physiological pacing is superior to conventional RV pacing,
not many patients receive this management owing to procedural
difficulties, high pacing threshold, and
complications.\textsuperscript{7-9} Therefore, traditional RV pacing, in
which myocardial capture is achievable in virtually all patients, is
still common in clinical practice. We need to identify which patients
should receive physiological pacing management.

The QRS duration represents the time interval required for the whole
ventricle to be activated. A prolonged QRS duration indicates high risk
of morbidity and mortality.\textsuperscript{11} The baseline QRS
duration has been used as an indication for CRT as a representative for
LV electrical dyssynchrony, and electrical resynchronization reflected
by QRS narrowing is valuable to predict the CRT
response.\textsuperscript{12} A recent study showed that focusing on
narrowing QRS by intervening on the level of specialized conduction with
sequential LV pacing in peripheral myocardial areas activated later is
associated with a better CRT response.\textsuperscript{14} Therefore,
the QRS duration represents the degree of electrical dyssynchrony. A
prolonged QRS duration during RV pacing was also reported to constitute
high risk for heart failure events.\textsuperscript{15} However, the
underlying mechanism why some patients show prolonged QRS duration
during RV pacing remains to be elucidated.

In our study, independent predictive factors for QRS duration longer
than 160 ms during RV apical pacing were baseline longer QRS duration,
LAD, IVST, and higher E/e'. A longer baseline QRS duration indicates
slight intraventricular conductional disturbances. High IVST represents
cardiac hypertrophy, and high LAD and E/e' are widely used as signs of
cardiac diastolic failure.\textsuperscript{23} These factors indicate
that acquired cardiac disease such as diastolic dysfunction and
hypertrophy, not dilated ventricular dimension or lower systolic
function, are major determinants of prolonged QRS duration during RV
pacing. A recent study\textsuperscript{24} showed that LV size (i.e.,
LVEDV or LVESV) impacts prolongation of QRS duration during RV pacing.
In this study, the LV site was not a significant independent factor but
showed a trend to prolong QRS duration during RV pacing. This
discrepancy is attributed to the study design. Prior studies did not
include echocardiographic factors such as IVST, PWT, and E/e' in the
multivariate analysis. Moreover, patients with bundle branch block were
included. We speculate that electrical delay due to the effect of
hypertrophy or diastolic dysfunction surpasses spatial delay due to the
LV dimension to cause QRS prolongation. Fang et al reported that RV
apical pacing deteriorated cardiac function particularly in patients
with pre-existing LV diastolic dysfunction.\textsuperscript{25} Another
study showed that reduced cardiac function following atrioventricular
ablation and RV pacing was more often observed in patients with numerous
comorbidities.\textsuperscript{26,27} Conversely, in patients with
congenital atrioventricular block, long-term RV pacing did not develop
into heart failure.\textsuperscript{28}

Longer QRS duration is a sign of electrical dyssynchrony, which can
cause reduction of cardiac function. A prior study showed an association
between longer QRS duration of premature ventricular contractions (PVC)
and reduced cardiac function (i.e., PVC-induced
cardiomyopathy).\textsuperscript{29} QRS duration of PVC, not the PVC
origin or baseline LVEF, was found to be an independent predictor for
the recovery of LV function after ablation for
PVC.\textsuperscript{30}This finding is compatible with our results,
i.e., not the origin, but the underlying heart disease, which caused
electrical activation delay, strongly affected cardiac
function.\textsuperscript{31,32}

Study limitations

In this study, we enrolled patients planning to undergo radiofrequency
ablation, not pacemaker implantation. The results may be limited by
inclusion of a heterogeneous population. The potential for residual
confounding should be taken into account when interpreting data.
However, the aim of this study was to identify factors prolonging QRS
duration during RV pacing, and the average age or underlying
comorbidities of our patients were similar with those of patients
planning to undergo pacemaker implantation in another
study.\textsuperscript{15}

In our study, pure selective His bundle or right bundle branch capture
was not observed during pacing around the His or right bundle branch
area. We planned to exclude QRS measurement when pacing purely captured
the His bundle or right bundle branch. In attempting non-apical RV
pacing, His bundle or right bundle branch capture was accidentally
observed in a few patients. However, the incidence was exceedingly rare,
and pacing on these structures has already been reported to be superior
to conventional RV pacing.\textsuperscript{33} To examine the effect of
delayed activation not via the His bundle or right bundle branch, data
associated with narrowing QRS duration by RV pacing were excluded from
this study.

The selection of RV outflow and RV apex might depend on the discretion
of the operators. However, the general area of the RV outflow and RV
apex can be identified by 3D mapping, and the pacing electrical axis
(the inferior and superior axes signify the RV outflow and RV apical
pacing, respectively) can verify the location of the RV outflow and RV
apex. The RV pacing site is defined by both fluoroscopic imaging and the
electrocardiographic axis in clinical practice.

Our study was also limited by its single-center design and small study
population. Further multicenter studies including pacemaker implantation
with long-term follow-up and large numbers of patients are warranted to
confirm these findings.

Conclusion

The QRS duration during RV pacing depends on the underlying heart
disease, not on the RV pacing site. Cardiac hypertrophy and diastolic LV
dysfunction prolong electrical activation from the RV to LV lateral
sites. Physiological pacing management should be considered for patients
with obvious cardiac hypertrophy and diastolic LV dysfunction.

Acknowledgements

The authors thank Noboru Kitamura and Takeru Takada for technical
assistance and support during the pacing study.

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congestive heart failure. Am Heart J 2002;143:1085-1091.

12. Hsing JM, Selzman KA, Leclercq C, et al. Paced left ventricular QRS
width and ECG parameters predict outcomes after cardiac
resynchronization therapy: PROSPECT-ECG substudy. Circ Arrhythm
Electrophysiol 2011;4:851-857.

13. Iler MA, Hu T, Ayyagari S, et al. Prognostic value of
electrocardiographic measurements before and after cardiac
resynchronization device implantation in patients with heart failure due
to ischemic or nonischemic cardiomyopathy. Am J Cardiol
2008;101:359-363.

14. Trucco E, Tolosana JM, Arbelo E, et al. Improvement of reverse
remodeling using electrocardiogram fusion-optimized intervals in cardiac
resynchronization therapy: a randomized study. JACC Clin Electrophysiol
2018;4:181-189.

15. Chen S, Yin Y, Lan X, et al. Paced QRS duration as a predictor for
clinical heart failure events during right ventricular apical pacing in
patients with idiopathic complete atrioventricular block: results from
an observational cohort study (PREDICT-HF). Eur J Heart Fail
2013;15:352-359.

16. Shukla HH, Hellkamp AS, James EA, et al. Heart failure
hospitalization is more common in pacemaker patients with sinus node
dysfunction and a prolonged paced QRS duration. Heart Rhythm
2005;2:245-251.

17. Khurshid S, Liang JJ, Owens A, et al. Longer paced QRS duration is
associated with increased prevalence of right ventricular pacing-induced
cardiomyopathy. J Cardiovasc Electrophysiol 2016;27:1174-1179.

18. Kaye GC, Linker NJ, Marwick TH, et al. Effect of right ventricular
pacing lead site on left ventricular function in patients with
high-grade atrioventricular block: results of the Protect-Pace Study.
Eur Heart J 2015;36:856-862.

19. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for
atrioventricular block and systolic dysfunction. N Engl J Med
2013;368:1585-1593.

20. Normand C, Linde C, Singh J, Dickstein K. Indications for cardiac
resynchronization therapy: a comparison of the major international
guidelines. JACC Heart Fail 2018;6:308-316.

21. Beck H, Curtis AB. Right ventricular versus biventricular pacing for
heart failure and atrioventricular block. Curr Heart Fail Rep
2016;13:230-236.

22. Greenspon AJ, Patel JD, Lau E, et al. Trends in permanent pacemaker
implantation in the United States from 1993 to 2009: increasing
complexity of patients and procedures. J Am Coll Cardiol
2012;60:1540-1545.

23. Redfield MM. Heart failure with preserved ejection fraction. N Engl
J Med 2016;375:1868-1877.

24. Zweerink A, Bakelants E, Stettler C, Burri H. His bundle pacing to
avoid electrical dyssynchrony with traditional right ventricular pacing:
importance of heart size. Int J Cardiol 2020;311:54-57.

25. Fang F, Zhang Q, Chan JY, et al. Deleterious effect of right
ventricular apical pacing on left ventricular diastolic function and the
impact of pre-existing diastolic disease. Eur Heart J 2011;32:1891-1899.

26. Kiehl EL, Makki T, Kumar R, et al. Incidence and predictors of right
ventricular pacing-induced cardiomyopathy in patients with complete
atrioventricular block and preserved left ventricular systolic function.
Heart Rhythm 2016;13:2272-2278.

27. Chen L, Hodge D, Jahangir A, et al. Preserved left ventricular
ejection fraction following atrioventricular junction ablation and
pacing for atrial fibrillation. J Cardiovasc Electrophysiol
2008;19:19-27.

28. Sagar S, Shen WK, Asirvatham SJ, et al. Effect of long-term right
ventricular pacing in young adults with structurally normal heart.
Circulation 2010;121:1698-1705.

29. Del Carpio Munoz F, Syed FF, Noheria A, et al. Characteristics of
premature ventricular complexes as correlates of reduced left
ventricular systolic function: study of the burden, duration, coupling
interval, morphology and site of origin of PVCs. J Cardiovasc
Electrophysiol 2011;22:791-798.

30. Deyell MW, Park KM, Han Y, et al. Predictors of recovery of left
ventricular dysfunction after ablation of frequent ventricular premature
depolarizations. Heart Rhythm 2012;9:1465-1472.

31. Walters TE, Rahmutula D, Szilagyi J, et al. Left ventricular
dyssynchrony predicts the cardiomyopathy associated with premature
ventricular contractions. J Am Coll Cardiol 2018;72:2870-2882.

32. Huizar JF, Ellenbogen KA, Tan AY, Kaszala K. Arrhythmia-induced
cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol
2019;73:2328-2344.

33. Arnold AD, Shun-Shin MJ, Keene D, et al. His resynchronization
versus biventricular pacing in patients with heart failure and left
bundle branch block. J Am Coll Cardiol 2018;72:3112-3122.

\textbf{Table 1. Baseline patient characteristics}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Characteristics\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Total (N = 211)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
QRS duration \textgreater{} 160 ms (N = 82)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
QRS duration \textless{} 160 ms (N = 129)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
p-value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Male sex\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
124 (58.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
58 (70.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
66 (51.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.006\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age (years)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
66 \selectlanguage{ngerman}± 12\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
67 \selectlanguage{ngerman}± 10\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
66 \selectlanguage{ngerman}± 13\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.287\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Baseline ECG (ms)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
85.0 \selectlanguage{ngerman}± 7.5\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
88.2 \selectlanguage{ngerman}± 7.5\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
83.0 \selectlanguage{ngerman}± 6.8\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{} 0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Atrial fibrillation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
181 (85.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
75 (91.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
106 (82.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.007\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hypertension\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
108 (51.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
52 (63.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
56 (43.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.005\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Heart Failure\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (12.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15 (18.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
12 (9.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.089\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Ischemic cardiomyopathy\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11 (5.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6 (7.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5 (3.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.344\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LVEF (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
61.7 \selectlanguage{ngerman}± 10.6\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
59.9 \selectlanguage{ngerman}±12.2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
62.9 \selectlanguage{ngerman}± 9.3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.055\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LVEDV (ml)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
106.8 \selectlanguage{ngerman}± 35.0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
121.7 \selectlanguage{ngerman}± 39.8\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
97.4 \selectlanguage{ngerman}± 27.9\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{} 0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LVESV (ml)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
43.0 \selectlanguage{ngerman}± 26.2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
51.9 \selectlanguage{ngerman}± 34.1\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
37.3 \selectlanguage{ngerman}± 17.4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
IVST (mm)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10.1 \selectlanguage{ngerman}± 2.7\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10.6 \selectlanguage{ngerman}± 2.2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9.8 \selectlanguage{ngerman}± 3.0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.046\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
PWT (mm)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10.1 \selectlanguage{ngerman}± 6.8\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10.0 \selectlanguage{ngerman}± 1.6\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10.2 \selectlanguage{ngerman}± 8.6\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.782\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LAD (mm)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
38.3 \selectlanguage{ngerman}± 7.3\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
42.1 \selectlanguage{ngerman}± 6.1\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
36.7 \selectlanguage{ngerman}± 7.2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{} 0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
E/e'\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13.2 \selectlanguage{ngerman}± 6.5\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
15.9 \selectlanguage{ngerman}± 7.6\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11.5 \selectlanguage{ngerman}± 4.9\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{} 0.01\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\selectlanguage{greek}β \selectlanguage{english}blocker use\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
73 (34.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
37 (45.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
36 (27.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.012\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Data are presented as n (\%) and mean \selectlanguage{ngerman}± SD.

ECG = electrocardiogram, IVST = interventricular septum thickness, LAD =
left atrial dimension, LVEDV = left ventricular end-diastolic volume;
LVEF = left ventricular ejection fraction; LVESV = left ventricular
end-systolic volume; PWT = posterior left ventricular wall thickness

\textbf{Table 2. Univariate and multivariate logistic regression
analyses to predict wide QRS duration during RV pacing}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
& Univariate & Univariate & Univariate & Multivariate & Multivariate &
Multivariate\tabularnewline
\midrule
\endhead
& OR & 95\% CI & p Value & OR & 95\% CI & p Value\tabularnewline
Male sex & 2.31 & 1.28-4.15 & 0.005 & 1.05 & 0.43-2.56 &
0.91\tabularnewline
Age & 1.01 & 0.99-1.04 & 0.31 & & &\tabularnewline
Baseline QRS & 1.02 & 1.06-1.16 & \textless{} 0.001 & 1.24 & 1.15-1.33 &
\textless{} 0.001\tabularnewline
Atrial fibrillation & 2.32 & 0.95-5.70 & 0.065 & 0.63 & 0.12-2.14 &
0.46\tabularnewline
Hypertension & 2.26 & 1.28-3.99 & 0.005 & 1.84 & 0.77-4.39 &
0.17\tabularnewline
Heart Failure & 2.12 & 0.97-4.94 & 0.061 & 0.76 & 0.23-2.58 &
0.66\tabularnewline
Ischemic cardiomyopathy & 1.96 & 0.58-6.64 & 0.29 & & &\tabularnewline
LVEF & 0.98 & 0.95-1.00 & 0.048 & 1.00 & 0.98-1.01 & 0.77\tabularnewline
LVEDV & 1.02 & 1.01-1.03 & \textless{} 0.001 & 1.01 & 1.00-1.02 &
0.15\tabularnewline
LVESV & 1.03 & 1.01-1.04 & \textless{} 0.001 & & &\tabularnewline
IVST & 1.12 & 0.98-1.27 & 0.088 & 1.20 & 1.02-1.40 &
0.025\tabularnewline
PWT & 1.00 & 0.95-1.04 & 0.82 & & &\tabularnewline
LAD & 1.14 & 1.08-1.20 & \textless{} 0.001 & 1.08 & 1.01-1.16 &
0.024\tabularnewline
E/e' & 1.13 & 1.07-1.19 & \textless{} 0.001 & 1.23 & 1.12-1.35 &
\textless{} 0.001\tabularnewline
\selectlanguage{greek}β \selectlanguage{english}blocker use & 2.12 & 1.19-3.80 & 0.011 & 0.70 & 0.30-1.65 &
0.42\tabularnewline
\bottomrule
\end{longtable}

CI = confidence interval, IVST = interventricular septum thickness, LAD
= left atrial dimension, LVEDV = left ventricular end-diastolic volume,
LVEF = left ventricular ejection fraction, LVESV = left ventricular
end-systolic volume, OR = odds ratio, PWT = posterior left ventricular
wall thickness

Figure 1\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Creation of paced QRS (pQRS) mapping in the right ventricle. The initial
timing of QRS duration is set to the pacing artifact signal. The pQRS
duration is color coded and superimposed on the anatomic map.

Figure 2\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Relationship of paced QRS (pQRS) duration between the right ventricular
(RV) outflow and apex.

Figure 3\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Echocardiography, paced QRS map, and QRS duration during right
ventricular (RV) apex and RV outflow pacing are shown in a patient
without left ventricular (LV) hypertrophy and diastolic dysfunction (A)
and with LV hypertrophy and diastolic dysfunction (B). QRS duration
during RV pacing depends on the underlying heart disease, not the pacing
site.

\selectlanguage{english}
\FloatBarrier
\end{document}

