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\begin{document}

\title{A new clinical risk score for predicting the prevalence of low-voltage
areas in patients undergoing atrial fibrillation ablation}



\author[1]{Yasuhiro Matsuda}%
\author[1]{Masaharu Masuda}%
\author[1]{Mitsutoshi Asai}%
\author[1]{Osamu Iida}%
\author[1]{Shin Okamoto}%
\author[1]{Takayuki Ishihara}%
\author[1]{Kiyonori Nanto}%
\author[1]{Takashi Kanda}%
\author[1]{Takuya Tsujimura}%
\author[1]{Yosuke Hata}%
\author[1]{Hiroyuki Uematsu}%
\author[1]{Toshiaki Mano}%
\affil[1]{Kansai Rosai Hospital}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\selectlanguage{english}
\begin{abstract}
Introduction: Although the presence of left atrial low-voltage areas
(LVAs) is strongly associated with the recurrence of atrial fibrillation
(AF) after ablation, few methods are available to classify the
prevalence of LVAs. The purpose of this study was to establish a risk
score for predicting the prevalence of LVAs in patients undergoing
ablation for AF. Methods: We enrolled 1004 consecutive patients who
underwent initial ablation for AF (age, 68 \selectlanguage{ngerman}± 10 years old; female, 346
(34\%); persistent atrial fibrillation, 513 (51\%)). LVAs were deemed
present when the voltage map after pulmonary vein isolation demonstrated
low-voltage areas with a peak-to-peak bipolar voltage of \textless{}0.5
mV covering \selectlanguage{english}[?]5 cm2 of the left atrium. Results: LVAs were present in 206
(21\%) patients. The SPEED score was obtained as the total number of
independent predictors as identified on multivariate analysis, namely
female sex (odds ratio (OR) 3.4 {[}95\% confidence interval (CI)
2.2-5.2{]}, p \textless{}0.01), persistent AF (OR 1.8 {[}95\% CI
1.1-3.0{]}, p=0.02), age \selectlanguage{english}[?]70 years (OR 2.3 {[}95\% CI 1.5-3.4{]}, p
\textless{}0.01), elevated brain natriuretic peptide \selectlanguage{english}[?]100 pg/ml or
N-terminal pro-brain natriuretic peptide \selectlanguage{english}[?]400 pg/ml (OR 1.7 {[}95\% CI
1.02-2.8{]}, p=0.04), and diabetes mellitus (OR 1.8 {[}95\% CI
1.1-2.8{]}, p=0.02). LVAs were more frequent in patients with a higher
SPEED score, and prevalence increased with each additional SPEED score
point (OR 2.4 {[}95\% CI 2.0-2.8{]}, p \textless{}0.01). Conclusion: The
SPEED score accurately predicts the prevalence of LVAs in patients
undergoing ablation for AF.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy




\textbf{Introduction}

Catheter ablation has been established as an important therapy for
atrial fibrillation (AF). The prevalence of left atrial low-voltage
areas (LVAs) is strongly associated with the recurrence of atrial
tachyarrhythmias following catheter ablation, and the addition of guided
ablation of LVAs improves procedural outcomes compared to pulmonary vein
(PV) isolation alone. \textsuperscript{1,2,3,4}The ability to predict
the presence of LVAs in advance of ablation would be useful in
considering ablation indications and planning ablation methods. A
preliminary study investigated a risk score named
DR-FLASH,\textsuperscript{5} which is composed of several clinical risk
factors, including age \textgreater{}65 years and renal dysfunction
(estimated glomerular filtration rate \textless{}90
mL/min/1.73m\textsuperscript{2}). In countries with an aging society,
however, these cut-off values for elderly age (\textgreater{}65 years)
and renal dysfunction (estimated glomerular filtration rate
\textless{}90 mL/min/1.73m\textsuperscript{2}) appear so lenient that
the score does not appropriately represent the risk of LVA presence.
Hence, we sought a new risk score which allows the prediction of LVAs in
elderly patients and contemporary clinical settings. The objective of
this study was to explore predictors of LVA prevalence and establish a
new clinical risk score for predicting the prevalence of LVAs in
patients undergoing atrial fibrillation ablation.

\textbf{Methods}

\emph{Patients} From October 2014 to December 2018, 1004 consecutive
patients undergoing initial ablation for AF using Carto 3 (Biosense
Webster, Inc., Diamond Bar CA, USA), Ensite NavX (St. Jude Medical,
Inc., St. Paul MN, USA) or Rhythmia (Boston Scientific, Boston MA, USA)
were retrospectively enrolled at our hospital. Patients who could not
undergo voltage mapping were excluded. Other exclusion criteria were age
\textless{}20 years, left atrial thrombus, and prior catheter ablation
of AF. This study complied with the Declaration of Helsinki. Written
informed consent for ablation and the use of data in this study was
obtained from all patients, and the protocol was approved by our
institutional review board.\emph{Catheter ablation
procedure}Electrophysiological studies and catheter ablation were
performed under intravenous sedation with dexmedetomidine or propofol,
with the latter performed by four experienced operators (M.M, T.K, A.S,
Y.M). From October 2014 to March 2016, radiofrequency catheter ablation
was performed for all patients. From March 2016 to December 2018, in
general, cryoballoon ablation was performed for paroxysmal AF and for
persistent AF of short standing. Patients with common PVs or a large PV
diameter underwent radiofrequency catheter ablation. In cryoballoon
ablation, an Arctic Front Advance cryoballoon catheter with a 28-mm
balloon size (Medtronic, Inc., Minneapolis MN, USA) was passed into each
PV under guidance by fluoroscopy and the 3-D mapping system. After
confirming PV occlusion by pulmonary venography, cryoablation commenced
and continued for 180 s, during which individual PVs were isolated. If
LA--PV conduction persisted after cryoballoon ablation, an additional
touch-up ablation was performed using an open-irrigated Thermocool
SmartTouch (Biosense Webster) or FlexAbility (St. Jude Medical) linear
ablation catheter with a 3.5-mm tip. In radiofrequency catheter
ablation, circumferential ablation around both ipsilateral PVs was
performed using an open-irrigated Thermocool SmartTouch (Biosense
Webster) or FlexAbility (St. Jude Medical) linear ablation catheter via
an Agilis or Swartz Braided SL0 Transseptal Guiding Introducer Sheath
(St. Jude Medical). Radiofrequency energy was applied for 30 s at each
site using a maximum temperature of 42\selectlanguage{ngerman}°C, maximum power of 35 W, and
flow rate of 17 mL/min. PV isolation was considered complete when the
20-pole circular catheter no longer recorded any PV potentials.
Additional ablation was also performed for spontaneous atrial flutter or
flutter induced by atrial burst stimuli, and for any AF triggers
originating from non-PV foci induced by isoproterenol infusion.

\emph{Voltage mapping~}Following PV isolation, detailed voltage mapping
was performed using a bipolar 3.5-mm tip catheter or multi-electrode
mapping catheter during sinus rhythm or with pacing from the right
atrium. Mapping points were acquired to fill all color gaps on the
voltage map using the electroanatomical mapping system. Respective fill
and color interpolation thresholds were 15 mm and 23 mm using Carto 3
(Biosense Webster) and 20 mm and 7 mm using Ensite NavX (St. Jude
Medical). Using Rhythmia (Boston Scientific), interpolation threshold
was 5 mm and confidence mask was 0.03 mV. Sites at which LVAs were
recorded were then evaluated by high-density mapping to precisely
delineate their extent, using the confidence module with the Carto 3
system and Ensite Automap with Ensite NavX. Adequate endocardial contact
was confirmed by distance to the geometry surface and stable
electrograms. Each acquired point was classified according to the
peak-to-peak electrogram as follows: \textgreater{}0.5 mV, healthy;
\textless{}0.5 mV, LVAs, with the band pass filter was set at 30 to 500
Hz. LVAs were defined as regions with \selectlanguage{english}[?]5 cm\textsuperscript{2}
low-voltage points across the total surface area of the left atrium. The
target number of mapping points was \selectlanguage{english}[?]100 with the 3.5-mm tip catheter
and \selectlanguage{english}[?]1000 with the multi-electrode mapping catheter throughout the left
atrium.

\emph{Patient followup~}Rhythm outcomes were followed for 24 months.
Followup was performed as a part of routine visits, usually conducted
every 3 months. Each routine visit included 12-lead electrocardiogram,
while Holter electrocardiography was performed 6 months after the
procedure. AF recurrence was defined as atrial tachyarrhythmias lasting
\textgreater{}30 s at \selectlanguage{english}[?]90 d after the procedure.

\emph{Statistical methods~}Continuous data are expressed as mean +-
standard deviation. Categorical data are presented as absolute values
and percentages. Tests for significance were conducted using the
unpaired or paired \emph{t}-test for continuous variables and the
chi-squared test for categorical variables. Receiver operating
characteristic curve analysis was conducted between the clinical factors
and prevalence of LVAs. Kaplan-Meier analysis and the log-rank test were
used to investigate the association between the recurrence of atrial
tachyarrhythmia and prevalence of LVAs. Univariate and multivariate
logistic regression analyses were used to determine clinical factors
associated with the prevalence of LVAs, wherein variables with a P value
\selectlanguage{english}[?]0.05 in the univariate models were included in the multivariate
analysis. A new risk score was obtained as the total number of
independent predictors identified by multivariate analysis. All analyses
were performed using commercial software (SPSS \selectlanguage{english}, SPSS, Inc., Chicago
IL, USA).

\textbf{Results}

\emph{Patient characteristics~}One thousand and four patients undergoing
atrial fibrillation ablation were enrolled. PVI was successfully
completed in all patients, using Carto 3 in 822 (82\%), Ensite NavX in
159 (16\%) and Rhythmia in 23 (2\%). Patient characteristics are shown
in Table 1.

\emph{Voltage mapping} Left atrial voltage mapping was completed in all
cases, with a median of 681 (119-1222) acquired mapping points. LVAs
were identified in 206 (21\%) cases. Procedural characteristics between
the presence and absence of LVAs are compared in Table 2.

\emph{Predictors of LVAs prevalence~}Patients with LVAs were
significantly older, more frequently female, and had a higher prevalence
of persistent AF, diabetes mellitus, thromboembolism, and vascular
disease than those without. In addition, patients with LVAs had lower
hemoglobin, lower body mass index, lower estimated glomerular filtration
rate, higher brain natriuretic peptide, higher N-terminal pro-brain
natriuretic peptide, higher left ventricular mass index, higher left
atrial diameter, higher E/e', and longer deceleration time than those
without. On multivariate analysis, independent predictors of LVA
prevalence were female sex, persistent AF, age \selectlanguage{english}[?]70 years, elevated brain
natriuretic peptide \selectlanguage{english}[?]100 pg/ml or N-terminal pro-brain natriuretic
peptide \selectlanguage{english}[?]400 pg/ml, and diabetes mellitus (Table 3).

\emph{New clinical risk score for LVAs prevalence~}The total number of
independent predictors identified by multivariate analyses above -
female sex, persistent AF, age \selectlanguage{english}[?]70 years, elevated brain natriuretic
peptide \selectlanguage{english}[?]100 pg/ml or N-terminal pro-brain natriuretic peptide \selectlanguage{english}[?]400
pg/ml, and diabetes mellitus - was then used to devise a new clinical
risk score, which we termed the SPEED score. LVAs were more frequent in
patients who had a higher SPEED score (Figure 1, Figure 2), and the
prevalence of LVAs increased with each additional SPEED score point
(odds ratio 2.4 {[}95\% confidence interval 2.0-2.8{]}, p
\textless{}0.01). In patients with LVAs, the median total area of LVAs
classified by SPEED score were 2.6 (1.7-3.1) cm\textsuperscript{2} (0
point), 4.8 (2.4-15.3) cm\textsuperscript{2} (1 point), 5.4 (2.9-9.7)
cm\textsuperscript{2} (2 points), 7.3 (3.6-14.8) cm\textsuperscript{2}(3
points), 11.7 (6.0-21.9) cm\textsuperscript{2} (4 points) and 10.2
(6.9-25.6) cm\textsuperscript{2} (5 points). Receiver operating
characteristic curve analysis revealed that the SPEED score was a good
predictor of LVAs (Figure 3, area under the curve, 0.742).

\emph{AF recurrence in LVAs prevalence~}During the 24-month study
period, 277 (28\%) patients developed AF recurrence. Freedom from
recurrence was significantly lower in patients with LVAs than in those
without (Figure 4), and was significantly lower in patients with a high
SPEED score than in those with a low score (Figure 5).

\textbf{Discussion}

In this study of 1004 patients undergoing initial AF ablation, we found
that LVAs were present in 21\% of the total study population.
Independent predictors of LVAs were female sex, persistent AF, age \selectlanguage{english}[?]70
years, elevated brain natriuretic peptide \selectlanguage{english}[?]100 pg/ml or N-terminal
pro-brain natriuretic peptide \selectlanguage{english}[?]400 pg/ml, and diabetes mellitus. Using
the SPEED score, calculated as the total number of independent
predictors in each patient, LVAs were more frequent in patients with a
higher SPEED score. These findings suggest that the SPEED score
accurately predicts the prevalence of LVAs in patients undergoing
ablation for AF.

\emph{Predictors of LVAs prevalence~}We identified the following as
independent predictors of LVAs: female sex, persistent AF, age \selectlanguage{english}[?]70 years
old, elevated brain natriuretic peptide \selectlanguage{english}[?]100 pg/ml or N-terminal
pro-brain natriuretic peptide \selectlanguage{english}[?]400 pg/ml, and diabetes mellitus. The
association between these predictors and the prevalence of LVAs might be
explained by atrial fibrosis and decreased endocardial voltage.
Mechanisms underlying the sex differences in atrial fibrosis have been
identified.\textsuperscript{6} On histological analysis of atrial tissue
obtained during cardiac surgery, females showed stronger expression of
CX 40 than males, which indicates remodeling--induced change in
connexins.\textsuperscript{7} In addition, fibrosis-related genes were
upregulated in post-menopausal woman with AF.\textsuperscript{8}A number
of studies have shown that AF itself induces atrial
fibrosis.\textsuperscript{9,10} Conversely, atrial fibrosis is required
to sustain AF, and the structural changes induced by AF in the atrium
hinder termination of the arrhythmia.\textsuperscript{11,12} Although
the mechanisms of atrial fibrosis are not precisely known, assessment of
left atrial fibrosis by cardiac magnetic resonance imaging showed that
patients with persistent AF had more late gadolinium-enhanced segments
than those with paroxysmal AF.\textsuperscript{13}Aging is another
well-known factor associated with the promotion of myocardial fibrosis
and atrial remodeling.\textsuperscript{14} Senescence is associated with
interstitial fibrosis, which reduces the capacity to cope with cardiac
stress.\textsuperscript{15} In addition, deposition of collagen in the
ventricles of the heart with aging has been shown in animal models.
\textsuperscript{16,17} We set an age cut-off value of 70 years, which
was previously defined as the lower limit of middle
age.\textsuperscript{18}A previous study showed that atrial fibrosis
also occurred as a result of cardiac dysfunction, such as that which
occurs in dilated cardiomyopathy.\textsuperscript{19} Brain natriuretic
peptide levels are correlated with left ventricular end-diastolic
pressure and left atrial wall stress. \textsuperscript{20,21} Left
atrial wall stress is caused by elevated left atrial pressure, which
reflects volume or pressure overload in the left ventricle and atrium.
Left atrial wall stress can lead to left atrial fibrosis.
\textsuperscript{21} We set a cut-off value of brain natriuretic peptide
and N-terminal pro-brain natriuretic peptide of 100 pg/ml and 400 pg/ml,
respectively, based on Japanese guidelines for the diagnosis and
treatment of acute and chronic heart
failure.\textsuperscript{22}Diabetes mellitus is a cause of electrical
remodeling and changes in ionic currents, and additionally a cause of
atrial structural remodeling.\textsuperscript{23} Diabetes-related
cardiac fibrosis is associated with the accumulation of
collagen,\textsuperscript{24} and hyperglycemia may promote a fibrogenic
phenotype in cardiomyocytes and induce the synthesis and release of
growth factors and cytokines that induce fibroblast proliferation and
activation.\textsuperscript{25}\emph{New clinical risk score in LVA
prevalence}Based on our findings, we established a new clinical risk
score for predicting the prevalence of LVAs, which we named the SPEED
score. A previous clinical risk score named DR-FLASH was based on
diabetes mellitus, renal dysfunction (estimated glomerular filtration
rate \textless{}90 mL/min/1.73m\textsuperscript{2}), persistent form of
AF, left atrial diameter \textgreater{}45 mm, age \textgreater{}65
years, female sex, and hypertension.\textsuperscript{5} Although this
score was shown to be valuable, several limitations were noted. First,
the score consists of seven items, and scoring was complex. Second, two
of these seven items include the majority of patients, namely estimated
glomerular filtration rate \textless{}90 mL/min/1.73m\textsuperscript{2}
and age \textgreater{}65 years. Indeed, among our 1004 subjects, 958
(96\%) had an estimated glomerular filtration rate \textless{}90
mL/min/1.73m\textsuperscript{2}, and 670 (67\%) were older than 65
years. Having many items which most patients come under can hinder risk
stratification. Third, the only energy source of ablation used in the
DR-FLASH study cohort was radio frequency, and mapping catheter use was
limited. Finally, the cohort was relatively small, at about 240
patients. The SPEED score improves these limitations: it has only five
items and is simple to score; the criterion that included the most
patients - elevated brain natriuretic peptide \selectlanguage{english}[?]100 pg/ml or N-terminal
pro-brain natriuretic peptide \selectlanguage{english}[?]400 pg/ml - accounted for fewer of our
subjects than did an estimated glomerular filtration rate \textless{}90
mL/min/1.73m\textsuperscript{2} and age \textgreater{}65 years; the
study cohort included more than 1000 patients; and the score can be
adapted for ablation with various energy sources, types of 3-D mapping,
and mapping catheters. Additionally, receiver operating characteristic
curve analysis revealed that the SPEED score had a tendency to be better
predictor of LVAs (area under the curve, 0.742) than the DR-FLASH score
(area under the curve, 0.694) in our subjects.

\emph{Clinical implications~}Previous studies showed that LVAs increase
the risk of AF recurrence following catheter
ablation.\textsuperscript{4} Pre-procedural prediction of LVAs using the
SPEED score is simple and noninvasive. Precise prediction of LVAs may
influence indications for catheter ablation and allow the operator to
prepare for atrial ablation in addition to PV isolation.~

\emph{Limitations~}Several limitations of this study warrant mention.
First, since we performed voltage mapping using either bipolar 3.5-mm
tip catheters or multi-electrode mapping catheters, the distribution of
LVAs might have changed, given that multielectrode catheters produce
smaller LVA measurements than ablation catheters.\textsuperscript{26}
Second, our conduct of voltage mapping after the completion of PV
isolation and in the left atrium only might have influenced the
prevalence of LVAs. Third, LVA ablation was performed for only some
patients, so the association between SPEED score and AF recurrence could
not be assessed precisely. Finally, as this study was single center
study, the statistical analyses might have been influenced by the study
population.

\textbf{Conclusions}

The SPEED score, based on the total number of the independent predictors
of female sex, persistent AF, age \selectlanguage{english}[?]70 years, elevated brain natriuretic
peptide \selectlanguage{english}[?]100 pg/ml or N-terminal pro-brain natriuretic peptide \selectlanguage{english}[?]400
pg/ml, and diabetes mellitus, accurately predicts the prevalence of LVAs
in patients undergoing ablation for AF.

\textbf{Funding~}None declared

\textbf{Conflicts of Interest~}None declared

\textbf{Acknowledgements~}We thank Guy Harris DO from DMC Corp.
(\href{http://www.dmed.co.jp}{www.dmed.co.jp}
\textless{}\url{http://www.dmed.co.jp/}\textgreater{}) for editing
drafts of this manuscript.

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\end{enumerate}

\textbf{Figure legends}

\textbf{Figure 1.} SPEED score and prevalence of LVAs LVA prevalence
increased with increasing SPEED score. LVAs: low voltage areas, BNP:
brain natriuretic peptide, NT-proBNP: N-terminal pro-brain natriuretic
peptide~

\textbf{Figure 2.} Likelihood of the prevalence of LVAs at each point of
the SPEED score Odds ratio shows the likelihood for the prevalence of
LVAs in each point of the SPEED score. The prevalence of LVAs increased
for each additional point of the SPEED score. LVAs: low voltage areas,
AF: atrial fibrillation, BNP: brain natriuretic peptide, NT-proBNP:
N-terminal pro-brain natriuretic peptide, OR: odds ratio, CI: confidence
interval

\textbf{Figure 3.} Receiver operating characteristics curve analysis of
the association between SPEED score and LVA prevalence Receiver
operating characteristics curve analysis revealed that the SPEED score
was a good predictor of LVAs. LVAs: low voltage areas, AUC: area under
the curve

\textbf{Figure 4.} Freedom from AF recurrence in patients with and
without LVAs Freedom from AF recurrence was significantly lower in
patients with LVAs than in those without LVAs. AF: atrial fibrillation,
LVAs: low voltage areas

\textbf{Figure 5.} Freedom from AF recurrence in patients stratified by
SPEED score Freedom from AF recurrence was also significantly lower in
patients with a high SPEED score than in those with a low SPEED score.
AF: atrial fibrillation, LVAs: low voltage areas\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-SPEED/Figure-1-SPEED}

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

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

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4-SPEED/Figure-4-SPEED}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5-SPEED/Figure-5-SPEED}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`LVA_SPEED_tables JCE.docx`  available at \url{https://authorea.com/users/311170/articles/469547-a-new-clinical-risk-score-for-predicting-the-prevalence-of-low-voltage-areas-in-patients-undergoing-atrial-fibrillation-ablation}

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

