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\begin{document}

\title{Intracardiac Echocardiography Guided Anatomical Ablation of the Arcuate
Ridge for Drug Refractory Inappropriate Sinus Tachycardia}



\author[1]{Juan Sebastian Cabrera}%
\author[1]{Carlos Tapias}%
\author[1]{Christian D. Adams}%
\author[1]{Boris Hernandez}%
\author[1]{William Bautista}%
\author[1]{Valentina Stozitzky}%
\author[2]{Alejandro Jimenez Restrepo}%
\author[1]{Luis Carlos Saenz}%
\affil[1]{Fundación Cardioinfantil Electrophysiology department}%
\affil[2]{Florida Electrophysiology Associates}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{INTRODUCTION:} Inappropriate sinus tachycardia (IST) is a common
condition with frequently not tolerated beta-blockers or ivabradine and
a high rate of complication in ablation strategy; we describe an
alternative anatomical approach of sinus node modulation.
\textbf{METHODOLOGY:} This retrospective study describes a case series
of 6 patients from two centers diagnosed with symptomatic IST undergoing
sinus node ablation. \textbf{RESULTS:} The mean age was 40.6 \selectlanguage{ngerman}± 13.9
years; five of the six patients were female, 100\% of patients reported
heart palpitations, and 66\% reported dizziness, the average HR on a
24-h Holter was 93.2 ±7.9 bpm. HR during the first stage of a stress
test using a standard Bruce protocol was 150 ±70 bpm, The average HR on
24-hour Holter post-ablation was 75 ± 5.6 bpm, the sinus rate HR during
stage 1 of a Bruce protocol exercise stress test was 120 ± 10 bpm.
\textbf{CONCLUSION:} This is the first case series reporting the acute
and long-term results of a novel anatomical approach for SNM to treat
IST targeting the AR under ICE guidance, The novel anatomic ICE-guided
catheter ablation approach aimed to identify the earliest activation at
the AR with an extension of RF lesions towards its septal region seems
effective and safe to modulate the SN in symptomatic patients with IST
refractory to medical treatment.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{INTRODUCTION}

Inappropriate sinus tachycardia (IST) is a common condition that causes
an abnormally high resting heart rate (HR) with an exaggerated
chronotropic response during exercise and/or stress, and is associated
with debilitating symptoms, exercise intolerance, and near
syncope\textsuperscript{1}. Pharmacological treatment with B-blockers,
calcium channel blockers and/ or Ivabradine are considered first-line
therapies for symptomatic patients\textsuperscript{2}. However, these
medications are frequently not tolerated due to side effects or are
ineffective in controlling patient's symptoms\textsuperscript{3}.
Radiofrequency catheter ablation (RFA) aimed at sinus node modulation
(SNM) has been proposed as an alternative therapy for refractory
patients, with success rates varying between 23\% and 85\% in the
published literature, and with a variable incidence of procedural
related complications (9.5 to 50\%) such as phrenic nerve (PN) injury,
pericarditis, superior vena cava (SVC) stenosis, cardiac tamponade and
iatrogenic sinus node (SN) dysfunction requiring pacemaker
implantation\textsuperscript{4}. The most common RFA approach for SNM is
based on the identification of the upper part (``head'') of the SN
complex that is activated during higher HR using 3D mapping and is
expected to be localized at the lateral aspect of the SVC-right atrium
(SVC-RA) junction, according to early anatomic descriptions of sinus
node myoarchitecture\textsuperscript{5}. In order to activate the higher
hierarchy of the SN cells, high doses of isoproterenol are used to
increase SN automaticity, and RFA is applied over the earliest
activation site. In most cases, additional RFA includes an extension of
the RF lesions towards the posteroinferior aspect of the SN complex
(``tail'') located along the superior aspect of the Crista Terminalis
(CT), to achieve clinically significant modulation of the SN activity
(Fig. 1a and 1b). An extensive RFA from the ``head'' to the ``tail'' in
this region could increase the risk for procedural complications from
collateral injury of structures such as the PN.

We describe the systematic use of an anatomical approach for SNM to
treat IST under intracardiac echography (ICE) guidance, aiming to
identify and ablate the earliest activation sites at the arcuate ridge
(AR) in the antero-superior SVC-RA junction, and extending the RFA
lesion set towards its more septal aspect, at the level of the
interatrial septum.

The presented approach is based on the following considerations: 1. ICE
is the most accurate real-time imaging technology to delineate the
SVC-RA junction\textsuperscript{6}. 2. In redo procedures, the extension
of ablation from the lateral SVC-RA junction to the AR was needed to
obtain final control of HR, as previously reported (Fig. 1c and
1d)\textsuperscript{7}. 3. The high doses of isoproterenol required to
increase the HR during the procedure are usually poorly tolerated,
affecting the accuracy of identifying the most anterosuperior and septal
extension of the upper SN region, target for RFA.

\textbf{LEARNING OBJECTIVES~}

\begin{itemize}
\tightlist
\item
  Describe the anatomical relationship between the SN and the AR, as an
  anatomical reference to guide SNM.
\item
  Showcase the use of ICE imaging to identify the relevant anatomy for
  RFA of IST.
\item
  Discuss the rationale for an anatomical approach that includes
  ablation of the earliest activation site at the AR, and RFA lesion
  extension to its more septal rather than lateral portion.
\item
  Present the results of this novel approach for SNM in a case series.
\end{itemize}

\textbf{METHODS}

\textbf{PATIENT CHARACTERISTICS}

This study describes a case series of 6 patients from two centers with a
diagnosis of symptomatic IST based on a 24-hour, 30-day cardiac rhythm
monitor and/or implantable cardiac rhythm monitor, and exercise
treadmill stress test, which failed pharmacological control of symptoms
and tachycardia, who underwent endocardial RFA using a novel anatomical
approach guided by ICE. The study was approved by the Institutional
Ethics Committees from all participating centers.

\textbf{PROCEDURE}

After obtaining informed consent, all patients underwent an invasive
electrophysiologic study (EPS) under moderate sedation with Midazolam
and Fentanyl. Programmed electrical stimulation and burst pacing from
the high right atrium, coronary sinus, His bundle region, and right
ventricle were used to evaluate atrioventricular conduction and exclude
other arrhythmias. 3D Electro-anatomic mapping (3DEAM) (Carto 3,
Biosense Webster OR EnSite Precision, Abbott) was used in all cases.
Femoral venous access was obtained under ultrasound guidance, and an ICE
catheter was advanced through femoral access into the RA.~ From the home
view position, the ICE probe was rotated clockwise to visualize the
interatrial septum, and then tilted posteriorly to obtain a long-axis
view of the SVC\textsuperscript{8} (Fig. 2). Slight adjustments using
clockwise and counter-clockwise rotation from this position allowed for
visualization of the lateral and septal aspects of the AR, identified as
a band of atrial myocardium in the region of the SVC--RA junction,
typically connecting the CT to the interatrial septum near its superior
limbus\textsuperscript{7} (Fig. 2). Incremental doses of isoproterenol
infusion were used to obtain sinus tachycardia. Once stable sinus
tachycardia at the highest tolerated isoproterenol dose (up to 10
mgc/min) was observed, 3DEAM of the SVC-RA region were created using a
high-definition multipolar catheter (PENTARAY NAV\selectlanguage{ngerman}®, Biosense Webster OR
Advisor HD Grid\textsuperscript{TM}, Abbott) advanced through a
deflectable sheath into the RA. In order to obtain accurate activation
points in the AR and avoid point extrapolation, manual annotation was
used as deemed necessary, to adjust tags under direct ICE visualization.
The course of the right PN was localized by pacing at high output (20
mA/1 ms) and tags were manually annotated on the 3DEAM under ICE
visualization when diaphragm stimulation was present (Fig. 3). Local
activation times were automatically defined from a stable reference
atrial electrogram (EGN), to the maximum negative dV/dT at the local
unipolar signal on the mapping catheter. RF applications were performed
at the earliest activation location in the AR, using an open
irrigated-tip catheter with contact force sensing capabilities
(THERMOCOOL SMARTTOUCH SF®, Biosense Webster OR
TactiCath\textsuperscript{TM}, Abbott). RF power was set at 30 to 40W,
with a contact force between 15-20 gm at the operator's discretion. Each
RF application was monitored for an impedance drop of at least 10 Ohms,
with elimination of local automaticity induced by RFA continued until a
50\% reduction in the amplitude of the local bipolar EGM was obtained.
The RF applications were anatomically extended from the earliest region
at the AR towards its septal aspect, until the elimination of
automaticity at this region and/or obtaining a decrease in HR of 25\% on
Isoproterenol infusion was achieved (Fig. 4 d,e) (usually coinciding
with a change of the P-wave axis on the horizontal plane of the ECG).
Anatomic extension of the RF lesions towards the septal AR was performed
on all study subjects, independent of the local activation times
recorded at this location. Repeat activation and voltage maps were
performed if a significant decrease in HR was not obtained with initial
RFA and additional RF applications were performed on the earliest site
at the AR with careful delineation of the PN on the new map.
Post-procedure, patients remained in the hospital overnight under
continuous ECG monitoring and were discharged the next day if no
complications occurred.

Follow-up included an exercise stress test at 3 months, a 24-hour
Holter, 30-day cardiac rhythm monitor or interrogation of an implanted
cardiac rhythm monitor at 3, 6, and 12 months, and longitudinal clinic
visits to assess symptom status and medication adjustments.

\textbf{STATISTICAL ANALYSIS}

Continuous variables are expressed as the mean ± SD values, and
categorical variables are expressed as the number and percentage of
patients. A Student t-test or Mann-Whitney U test was used, as
appropriate, to analyze the differences in the continuous variables, and
the chi-square test was used to analyze the differences in the
dichotomous variables. All statistical analyses were performed with R
version 4.1.0 software.

\textbf{RESULTS}

\textbf{Patient characteristics}

Six prospective patients from 2 centers were included. The mean age was
40.6 ± 13.9 years; five of the six patients were female, 100\% of
patients reported heart palpitations, and 66\% reported dizziness (Table
1). No patients presented with POTS and 2 patients had VVS. Other
prevalent diseases included systemic lupus erythematosus (n: 1, 16\%),
fibromyalgia (16,6\%) and anxiety disorder (16,6\%). No patients
reported other chronic diseases such as hypertension, diabetes or heart
failure. 3 patients had undergone previous ablations of other
supraventricular tachycardias (atrioventricular accessory pathway,
premature atrial contractions and AVNRT). Finally, two patients had
undergone previous SNM using the conventional method of high doses of
isoproterenol and ablation from the site of maximum precocity extending
laterally. Before the procedure, the average HR on a 24-h Holter was
93.2 ±7.9 bpm. HR during the first stage of a stress test using a
standard Bruce protocol was 150 ±70 bpm (Table 1).

\textbf{RESULTS}

\textbf{Procedural data}

The average procedural time was 213 ± 60.9 min, and an average radiation
dose of 5862,5 mGy. Baseline pre-ablation HR was 100 ± 8.5 bpm, and HR
at the maximal tolerated dose of Isoproterenol before RFA was 170 ± 19
bpm. Following RFA, average HR was 74.5 ± 6.5 bpm (p=0.035), and maximal
HR with the same pre-ablation Isoproterenol doses was 132 ± 23 bpm
(p=0.036). Average HR during 24 h Holter pre was 93.16 ± 7.08 and post
RFA 76.66 ± 4.92 (p=0.031).

The area of earliest activation was located at the AR (11 or 12 O'clock
landmark from a caudal view of the SVC-RA junction) in all patients.
Extension of the RF lesions from the earliest region at the AR towards
its more septal region was needed in all the included patients and
produced a transitory HR increment before obtaining a significant and
sustained HR drop of around 25\%. Notably, the activation recorded on
the septal aspect of the AR was later compared with the earliest site
from its lateral aspect. The mean distance between the RF applications
at the earliest region on the AR and the most septal ablated sites was 6
mm (Fig 4 d,e). The distance of the PN to the nearest RF application was
5mm (Fig 4 d,e).

\textbf{Clinical outcomes}

After a mean follow-up of 654 ± 417 days (Table 1), one patient required
reinitiating Ivabradine (at a lower dose than pre-ablation) for control
of symptoms, and one patient with a history of fibromyalgia complained
of mild exercise intolerance, despite no evidence of sinus node
dysfunction on post-ablation stress test and heart rhythm monitoring. No
patients reported heart palpitations or syncope during follow-up. The
average HR on 24-hour Holter post-ablation was 75 ± 5.6 bpm, the sinus
rate HR during stage 1 of a Bruce protocol exercise stress test was 120
± 10 bpm, and the chronotropic response was classified as normal by an
independent cardiologist in all the patients. (Table 1).

\textbf{DISCUSSION}

This is the first case series reporting the acute and long-term results
of a novel anatomical approach for SNM to treat IST targeting the AR
under ICE guidance. The main findings of our study are as follows: 1.
ICE allowed real-time visualization of the lateral and septal aspects of
the AR at the level of the SVC-RA junction; 2. RF applications at the AR
earliest activation site during maximally tolerated isoproterenol
infusion (up to 10 mcg/min), produced a suboptimal reduction of the HR
in all patients; 3. Extending the ablation lesion set from the earliest
site at the AR towards its septal region led to acute and long-term
modulation of the SN in all patients without the need to extend the
ablation lesion set towards the lateral/posteroinferior extension, thus
avoiding risk for PN damage or SN dysfunction.

The importance of the recognition of the AR for SNM by ICE was
previously described by Asirvatham et al. who reported a case of a
48-year-old woman with multiple failed ablation procedures for IST
performed at the high posterolateral RA earliest site of
activation\textsuperscript{7}. The patients underwent a repeat procedure
showing early activation at the lateral aspect of the SCV-RA. However,
detailed 3D mapping under ICE visualization demonstrated an even earlier
activation site in the AR area, where RFA was effective and led to
definitive control of the patient's arrhythmia and symptoms. In our
study, ICE also facilitated the identification of the AR early
activation sites, initially masked in all the patients during contact
activation mapping, by extrapolation of early activation sites between
the SCV and the RA. Our approach included correction of this
extrapolation based on tagged points on the surface of the AR, taken
with the ablation catheter under ICE guidance, and including those
activation points on the corrected anatomy, which included the AR. Based
on our case experience and anatomical understanding of this region, we
believe AR recognition by ICE increases procedure efficacy and safety,
by focusing the mapping and ablation efforts on the AR and preventing
unnoticed ablation inside the right atrial appendage. Notably, mapping
and ablation of the earliest activation sites alone did not produce the
desired HR reduction of around 25\%. However, an anatomic extension of
the ablation lesion set towards the septal aspect of the AR, performed
independently of the local activation times, produced a transient HR
increment followed by a significant HR reduction \textgreater{}25\% and
a change in the P wave axis. These findings suggest that part of the SN
complex was located in the septal region, but it was not identified by
the activation mapping under the isoproterenol effect. Notably, the
reduction of the HR was sustained during follow-up, measured by cardiac
monitoring and stress ECG, and associated with symptomatic relief.
Despite the encouraging results of this novel anatomic approach to
modulate the SN, our investigation does not provide insight into the
mechanistic role of the septal aspect of the AR on IST. Furthermore,
empirically extending the ablation target to the septal and not the
lateral region of the AR, may not achieve the desired HR modulatory
effect in some patients, owing to different characteristics in their SN
anatomy and extensions. Anatomical studies traditionally describe the SN
complex as a crescent-shape structure with a ``comma'' disposition, in
which the ``head'' lies subepicardial within the terminal groove, formed
by the lateral junction of the SCV with RA, and the ``tail'' extends
toward the posteroinferior aspect of the CT reaching the inferior vena
cava and RA junction\textsuperscript{9,10} (Fig. 1a). This usual
``comma'' depiction of the SN complex on anatomic drawings, has directed
efforts of mapping and ablation for SNM to the lateral SVC-RA junction
where the PN resides. Although the ``comma'' anatomical disposition is
the most prevalent, a ``horseshoe'' arrangement of the SN has also been
found in around 12\% of hearts\textsuperscript{9}. In the ``horseshoe''
arrangement, the SN complex is situated both medial (``head'') and
lateral (``tail'') to the mid-line of the SCV-RA junction at the
AR\textsuperscript{10} (Fig. 4 a, b). This anatomic variation of the SN
showing an extension towards the septal aspect of the SCV-RA junction
seems to be validated by the first ``in situ'' 3-D visualization of the
human cardiac conduction system performed by means of advanced imaging
tools of virtual CT dissection on human
cadavers\textsuperscript{11}(Fig. 4 c). Based on this anatomic
variation, it is plausible that the extension of RF ablation from the
earliest activation site at the AR towards its septal region could
explain the results of our proposed approach described in this study. As
mentioned previously, the usual target for SNM is defined as the
earliest activation site on the AR under the effect of Isoproterenol. A
concept based on physiological studies demonstrating shifting of
earliest activation from the ``tail'' to the ``head ``of the SN complex
under progressive HR increments\textsuperscript{4}. However, if patients
do not tolerate high doses of Isoproterenol during the procedure, it is
possible that the most anterosuperior aspect and septal extension of the
SN are not activated, and therefore not targeted, leading to suboptimal
results, unless extending the lesion empirically towards the septal AR
is performed (electro-anatomical approach). Coincidentally, an
electroanatomic analysis of the sinus impulse propagation in normal
human atria has shown that the area of earliest activation in the RA has
a ``spindle'' shape in 5 of 7 patients and a ``horseshoe'' shape in the
remaining 2 located between the SCV-RA junction, which could represent
the functional characterization of this anatomic SN
variation\textsuperscript{12}. Finally, it is possible that the
extension of RF delivery toward the septal aspect of the SCV-RA junction
at the AR in proximity to the interatrial groove could produce a
modification of the neural input of the SN with an additive
neuromodulatory effect. Interrupting autonomic nervous input to the
sinus node by isolating right pulmonary veins, superior vena cava, and
ablating fat tissue surrounding the sinus node is an integral part of
the surgical treatment of IST\textsuperscript{13}. A recently published
SN sparing hybrid ablation technique including RF bipolar clamp
isolation of the superior and inferior vena cava and lateral ablation
line across the Crista terminalis while sparing the SN region (plus
adjunct RF endocardial touch-up to complete lesion sets in 46\% of
cases); was compared to a conventional SNM approach (endocardial and/or
epicardial mapping and RF ablation at the site of earliest atrial
activation) in 100 consecutive patients (50 in each
group)\textsuperscript{14}. The SN sparing hybrid ablation group showed
a significant acute and long-term improvement in mean daily heart rate
and peak 6-minute walk heart rate\textsuperscript{15}. These results are
consistent with our small study population, but with a much more
simplistic approach. As mentioned previously, perhaps the anatomic
disposition of the SN complex with a ``horseshoe'' type and a regional
neuromodulatory effect explains why our conservative approach led to
excellent acute and long-term results.

Beyond the anatomical explanation of plausibility, it seems that the
neuromodulation could play an important role in our results. First, in
the body of the sinus node, there is a higher concentration of
sympathetic neurons compared to parasympathetic postganglionic
neurons\textsuperscript{16}. Since the target of our approach is the
body of the sinus node, the ratio of sympathetic neurons removed
compared to parasympathetic neurons would be greater, with a result of a
predominance of the parasympathetic ones. This is a simplistic
explanation; however. As we mentioned in our approach, ablation lesions
were extended towards the septal region of the AR where the dorsal right
atrial ganglionated subplexus (DRAsGP) is located. DRAsGP spread widely
into the dorsal and lateral right atrium, including the sinoatrial nodal
region and the superior surface of the right atrial
appendage\textsuperscript{17}. The ablation effect on sympathetic and
parasympathetic neurons may explain an improved regulatory effect over
the SN hyperactivity seen in IST patients, but this autonomic
interaction is more complex than a simple calculation of the number of
fibres or GPS ablated.

One question yet to be resolved is why, despite an inadvertent
parasympathetic ganglion modulation, a decrease in heart rate was
documented in our results. The answer to this question can be addressed
by a feature of the sinus node known as functional inhomogeneity, which
refers to the difference in the concentration of autonomic receptors
along the sinus node, and how 3 areas in the sinus node can be
discriminated that have a different response to neurohumoral influences.
When performing our ablation approach, the target would be the upper
part of the sinus node, leaving cells with a diminished response to
neurotransmitters as a guide for the pacemaker. On the contrary, if the
conventional ablation method is chosen, it is likely that the target
will be cells from the upper zone and transition, leaving cells with a
high sensitivity to adrenaline as a subsidiary pacemaker and it could
explain why patients could persist with tachycardia\textsuperscript{18}.

Finally, after explaining our findings from an anatomical and functional
point of view, another possible explanation could be the injury to the
sinus node artery. Scanavacca et al\textsuperscript{19} published a case
series, where they documented injury to the sinus node artery after
performing cardiac denervation procedures with a frequency of 4.76\%.
This was presented and confirmed by CT after performing ablation in the
area of \selectlanguage{english}\selectlanguage{english}the cavo-atrial junction and the area between the SVC and the
aorta, the latter is a target for ablation in our approach for
modulation of the sinus node, however in none of our patients presented
acute signs of sinus dysfunction.

\textbf{LIMITATIONS}

This study constitutes a small sample from 2 different centers.
Individuals were only considered for this anatomically based ablation
after exhausting all pharmacological and non-pharmacological
interventions for control of symptoms and HR. Therefore, our proposed
anatomical approach to guide SNM must be evaluated in a larger cohort of
patients to determine its reproducibility across a larger number of
patients. Nevertheless, our novel approach consistently showed acute and
long-term control of HR and proved to be reproducible in all patients,
with no complications and

\textbf{CONCLUSION}

The novel anatomic ICE-guided catheter ablation approach aimed to
identify the earliest activation at the AR with an extension of RF
lesions towards its septal region seems effective and safe to modulate
the SN in symptomatic patients with IST refractory to medical treatment.
This technique is reproducible and minimally invasive when compared to
more complex approaches such as epicardial SNM or surgical/ hybrid
ablation procedures. This approach however, needs to be tested in a
larger cohort of patients.

\textbf{REFERENCE}

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2. Olshansky B, Sullivan RM. Inappropriate sinus tachycardia. Europace.
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3. Ahmed A, Pothineni NVK, Charate R, Garg J, Elbey M, de Asmundis C, et
al. Inappropriate Sinus Tachycardia: Etiology, Pathophysiology,
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4. Rodriguez-Manero M, Kreidieh B, al Rifai M, Ibarra-Cortez S,
Schurmann P, Alvarez PA, et al. Ablation of Inappropriate Sinus
Tachycardia: A Systematic Review of the Literature. JACC Clin
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. Killu AM, Syed FF, Wu P, Asirvatham SJ. Refractory inappropriate sinus
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. Enriquez A, Saenz LC, Rosso R, Silvestry FE, Callans D, Marchlinski
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Circulation. 2018;137(21):2278--94.

. Anderson RH, Yen SH, Becker AE. The surgical anatomy of the conduction
tissues. Thorax. 1983; 38:408--20.

. Anderson' KR, Ho SY, Anderson2 RH. Location and vascular supply of
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. Kawashima T, Sato F. First in situ 3D visualization of the human
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1. de Ponti R, Ho Y, Salerno-Uriarte JA, Tritto M, Spadacini G.
Electroanatomic Analysis of Sinus Impulse Propagation in Normal Human
Atria. J Cardiovasc Electrophysiol. 2002;13(1):1--10.

. Khiabani AJ, Greenberg JW, Hansalia VH, Schuessler RB, Melby SJ,
Damiano RJ. Late Outcomes of Surgical Ablation for Inappropriate Sinus
Tachycardia. Ann Thorac Surg.2019;108(4):1162--8.

. de Asmundis C, Chierchia GB, Lakkireddy D, Romeya A, Okum E, Gandhi G,
et al. Sinus node sparing novel hybrid approach for treatment of
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2022;63(3):531--44.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Fig 1.} \textbf{a.} Illustration of the RA showing the usual
anatomic description of the SN complex represented as a crescent-shape
structure with a ``comma'' disposition in which its ``head'' is placed
at lateral SVC-RA junction and its ``tail'' extends toward the
posteroinferior aspect of the CT. \textbf{b} . 3-D activation map of a
patient who underwent SNM for IST in which the RF set of lesions was
extended from the earliest spot at the lateral SVC-RA junction towards
the posteroinferior aspect of the CT crossing next to the PN (dark
dots). Note the anatomic extrapolation between the SVC and
RA.\textbf{c.} 3-D voltage map of a patient who underwent previous SNM
for IST at the lateral SVC-RA junction (low voltage zone in green) where
earliest activation under isoproterenol was documented. Ablation at this
place did not control the HR with the need for an extension to the
posteroinferior CT with the same result. \textbf{d.} 3-D Activation map
of the same patient performed during redo procedure under isoproterenol
showing shifting of the earliest activation to the anterosuperior SVC-RA
junction at the AR (in red). RA: right atrium, CT: crista terminalis,
AR: arcuate ridge, SNM: Sinus Node Modulation, SVC: Superior Vena Cava,
IVC: Inferior Vena Cava, HR: Heart rate. PN: phrenic nerve, IST:
inappropriate sinus tachycardia. Reproduced from: Anderson RH, Yen SH,
Becker AE. The surgical anatomy of the conduction tissues. Thorax. 1983;
38:408--20.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Fig 2.} \textbf{a.} Cardiac anatomic specimen from a modified
left lateral view in which an oblique vertical transection passing
through the SVC posteriorly and the RV anteriorly has been performed to
show the lateral half of the SVC-RA junction. In this image, the CT
becomes the AR (white dotted line) at the anterosuperior SVC-RA
junction. \textbf{b.} Cardiac anatomic specimen from an anteroinferior
modified view in which the anterior RA and RAA have been removed to show
the CT becoming the AR (white dotted line). In this image, the tip of an
ICE tilted posteriorly is represented as a white circle from which clock
and counterclockwise rotation is performed to obtain a long view of the
SVC-RA junction to visualize the lateral, medial, and septal aspects of
the AR (represented as white transparent beams). \textbf{c.} Cardiac
anatomic specimen from a right lateral modified view in which part of
the SVC and the lateral half of the posterior RA wall have been removed
to show the septal extension of the AR (dotted white line) approaching
the interatrial septum next to the Ao. \textbf{d} . Long axis ICE view
of the SVC-RA junction showing the AR at its lateral portion. \textbf{e}
. Long axis ICE view of the SVC-RA junction showing the AR at its septal
portion (black dotted line) in which a small portion of the Ao is
viewed. RA: right atrium, LA: left atrium, AR: arcuate ridge, SVC:
Superior Vena Cava, IVC: Inferior Vena Cava, RAA: right atrial
appendage, RSPV and RIPV: right superior and inferior pulmonary veins,
FO: Foramen ovale, TV: Tricuspid valve, RV: right ventricle, AO: aorta,
CT: crista terminalis. Reproduced from: Shivkumar K, Editor Shumpei Mori
Kalyanam Shivkumar S. Anatomical basis of cardiac interventions, volume
1 cardiac anatomy. Vol. 1. 2022. 87--96 p.; McAlpine WA. Heart and
Coronary Arteries. Vol. 1, Heart, and Coronary Arteries. Springer Berlin
Heidelberg; 1975. 97--99 p.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Fig 3.} a. 3-D activation map during baseline SR showing
anatomic extrapolation between the SVC and the RA and a wide early zone
at the high anterolateral aspect of RA. \textbf{b.} Same 3-D activation
map showing shrinking of the early activation zone that shifted towards
a more posterior region after correction of the anatomic extrapolation.
The shell was shaved to see the white dots that correspond to anatomic
tags taken from the AR under ICE guidance. \textbf{c.} Long axis ICE
view of the SVC-RA junction showing an ablation catheter in contact with
the AR from where anatomical tags were taken. RA: right atrium, AR:
arcuate ridge, SVC: Superior Vena Cava, IVC: Inferior Vena Cava, RAA:
right atrial appendage, TV: Tricuspid valve.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Fig 4. a.} Illustration of the RA showing the ``horseshoe''
arrangement of the SN complex in which this structure is situated both
medial (``head'') and lateral (``tail'') to the mid-line of the SCV-RA
junction at the AR. \textbf{b.} Histological image of a transversal
section of the SVC-RA junction viewed from a cephalic view showing a
``horseshoe'' disposition of the SN complex with medial and lateral
extensions along the AR. \textbf{d.} 3-D ``in-situ'' visualization of
the human cardiac conduction system performed by means of advanced
imaging tools of virtual CT dissection on human cadavers showing
extension of the SN complex (in red) from the lateral to the septal
SVC-RAA junction. Note the septal extension of the SN coming to the
interatrial septum next to the Ao\textbf{. d., e.} 3-D activation map of
the RA during high HR from RAO and anterosuperior views, respectively.
Note the RF lesion set starting at the earliest activation (red ablation
dots) at the AR and extended towards its septal portion (pink ablation
dots) instead of going to the lateral SVC-RA junction that is relatively
next to the PN (dark dots). RA: right atrium, SVC: Superior Vena Cava,
IVC: Inferior Vena Cava, RAA: right atrial appendage, TV: Tricuspid
valve, PN: Phrenic nerve, Ao: aorta, AVCA: Atrioventricular conduction
system, RV: Right ventricle, LV: Left ventricle, PT: Pulmonary trunk.
Reproduced from: Kawashima T, Sato F. First in situ 3D visualization of
the human cardiac conduction system and its transformation associated
with heart contour and inclination. Sci Rep. 2021;11(1):1--15; Anderson
RH, Yen SH, Becker AE. The surgical anatomy of the conduction tissues.
Thorax. 1983; 38:408--20; Anderson KR, Ho SY, Anderson2 RH. Location and
vascular supply of sinus node in human heart. Br Heart J. 1979;
41:28--32.

Table 1.pre and post ablation heart rate variables in patients
undergoing SNM in our cohort.

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