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\begin{document}

\title{Toward better risk stratification of asymptomatic Brugada Syndrome
patients?}



\author[1]{Najla Beydoun}%
\author[2]{Charbel Gharios}%
\author[3]{Marwan Refaat}%
\affil[1]{Tufts Medical Center}%
\affil[2]{Massachusetts General Hospital}%
\affil[3]{American University of Beirut Medical Center}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\textbf{Toward Better Risk Stratification of Asymptomatic Brugada
Syndrome Patients?}

Najla Beydoun MD\textsuperscript{1} , Charbel Gharios
MD\textsuperscript{2} , Marwan M. Refaat MD\textsuperscript{3}

\textsuperscript{1} Department of Anesthesiology and Perioperative
Medicine, Tufts Medical Center, Boston, MA

\textsuperscript{2} Cardiovascular Imaging Research Center,
Massachusetts General Hospital and Harvard Medical School, Boston, MA

\textsuperscript{3} Department of Internal Medicine, Division of
Cardiology, and Department of Biochemistry and Molecular Genetics,
American University of Beirut Faculty of Medicine and Medical Center,
Beirut, Lebanon

Short Title: Risk Stratification in Asymptomatic BrS

Word Counts: 602

\textbf{Conflict of Interests}

The authors declare no conflicts of interest

\textbf{Funding}

None

\textbf{Keywords}

Cardiac arrhythmias, Brugada Syndrome, risk stratification,
electroanatominal mapping, cardiovascular diseases, heart diseases

\textbf{Hosted file}

\verb`image1.emf`  available at \url{https://authorea.com/users/438593/articles/539755-toward-better-risk-stratification-of-asymptomatic-brugada-syndrome-patients}

The prognostic value of invasive electrophysiologic (EP) testing in
asymptomatic Brugada Syndrome (BrS) patients remains controversial. Even
though EP testing was recommended for the prognostication of
asymptomatic BrS patients in the 2005 consensus statement on
BrS\textsuperscript{1}, more recent guidelines have decreased the
emphasis on invasive testing for risk stratification. The 2013
HRS/EHRA/APHRS consensus statement notes that there is \emph{no
consensus} on the prognostic value of EP testing, and the more recent
2017 AHA/ACC/HRS guidelines mention that invasive testing \emph{may be
considered} in risk stratification of asymptomatic patients.
Specifically, the prognostic role of programmed ventricular stimulation
(PVS) for evaluation of ventricular arrhythmia inducibility has shown
inconsistent results.\textsuperscript{2, 3} However, EP testing with
myocardial substrate mapping has recently shown interesting results for
the assessment of arrhythmia inducibility. In 191 patients with BrS who
underwent EP testing, arrhythmogenic substrate size was an independent
predictor of inducibility, and substrate ablation prevented ventricular
arrhythmia re-inducibility.\textsuperscript{4}

In this issue of the \emph{Journal of Cardiovascular Electrophysiology}
, Letsas et. al suggest a potential role for high-density
electroanatomic mapping (HDEAM) in the risk stratification of BrS
patients. To this end, they characterize the differences in endocardial
abnormalities in the right ventricular outflow tract (RVOT) among
high-risk and asymptomatic BrS patients. Given that epicardial RVOT
abnormalities are believed to be the arrhythmogenic substrate in
BrS\textsuperscript{5, 6}, and given that endocardial unipolar HDEAM
helps in the localization of epicardial abnormalities\textsuperscript{7,
8}, the authors aimed to evaluate the clinical significance of looking
at abnormal endocardial substrate.

In their retrospective analysis of prospectively collected data from 54
patients with BrS, fourteen symptomatic patients with aborted sudden
cardiac death (SDC) underwent combined endocardial-epicardial HDEAM,
while 40 asymptomatic patients underwent endocardial HDEAM.
Comprehensive clinical evaluation and coronary angiography were
performed to rule out structural heart disease and coronary artery
disease, respectively. Unipolar and bipolar signals were recorded and
the duration, amplitude, presence of multiple components and relation to
surface QRS were analyzed. Abnormal endocardial findings were defined as
low-voltage areas (LVAs) \textgreater{} 1cm\textsuperscript{2} with
unipolar signals \textless{} 5.3 mV\textbf{.} This value was based upon
its 92.4\% specificity and 86.3\% sensitivity for the identification of
epicardial bipolar LVAs \textless{} 1mV. Moreover, all patients
underwent programmed ventricular stimulation (PVS) from the RV apex
and/or RVOT sites. In all cases, the endocardial unipolar LVAs were
found to be wider than endocardial bipolar LVAs, and the abnormalities
were mostly detected on the anterior wall of the RVOT. Interestingly,
endocardial unipolar LVAs were found colocalize with epicardial bipolar
LVAs. Importantly, symptomatic patients displayed wider endocardial
unipolar and bipolar LVAs in comparison to asymptomatic ones. Based on
receiver operatic characteristic (ROC) analysis, the presence of
unipolar LVAs \textgreater{} 14.5 cm\textsuperscript{2} as well as that
of bipolar LVAs \textgreater{} 3.68 cm\textsuperscript{2} significantly
discriminated symptomatic from asymptomatic individuals. Furthermore,
all symptomatic patients and one fourth of the asymptomatic patients
were inducible during PVS. Notably, wider areas of abnormal unipolar and
bipolar signals were found in inducible patients compared to
non-inducible ones.

These findings demonstrate that the size of endocardial abnormalities is
associated with VF inducibility. In fact, unipolar LVAs \textgreater{}
13.5 cm\textsuperscript{2} and bipolar LVAs \textgreater{} 2.97
cm\textsuperscript{2} significantly predicted VF inducibility. Finally,
all inducible patients with positive PVS received an implantable
cardioverter defibrillator (ICD).

The study is limited by the small number of high-risk patients and the
differences in catheter types and methods used to characterize the
abnormal substrates, given the retrospective nature of the study. These
results show different endocardial findings during HDEAM in high-risk
BrS patients compared to asymptomatic patients. Whether these findings
can be leveraged to better risk stratify asymptomatic BrS patients need
to be investigated in future larger prospective cohorts.



\textbf{References}

1. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome:
report of the second consensus conference: endorsed by the Heart Rhythm
Society and the European Heart Rhythm Association. \emph{Circulation} .
Feb 8 2005;111(5):659-70. doi:10.1161/01.Cir.0000152479.54298.51

2. Sroubek J, Probst V, Mazzanti A, et al. Programmed Ventricular
Stimulation for Risk Stratification in the Brugada Syndrome: A Pooled
Analysis. \emph{Circulation} . Feb 16 2016;133(7):622-30.
doi:10.1161/circulationaha.115.017885

3. Kusumoto FM, Bailey KR, Chaouki AS, et al. Systematic review for the
2017~AHA/ACC/HRS guideline for management of patients with
ventricular~arrhythmias and the prevention of sudden cardiac death: A
Report of the American College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines and the Heart Rhythm
Society.\emph{Heart Rhythm} . Oct 2018;15(10):e253-e274.
doi:10.1016/j.hrthm.2017.10.037

4. Pappone C, Ciconte G, Manguso F, et al. Assessing the Malignant
Ventricular Arrhythmic Substrate in Patients With Brugada
Syndrome.\emph{J Am Coll Cardiol} . Apr 17 2018;71(15):1631-1646.
doi:10.1016/j.jacc.2018.02.022

5. Frustaci A, Priori SG, Pieroni M, et al. Cardiac histological
substrate in patients with clinical phenotype of Brugada
syndrome.\emph{Circulation} . Dec 13 2005;112(24):3680-7.
doi:10.1161/circulationaha.105.520999

6. Pieroni M, Notarstefano P, Oliva A, et al. Electroanatomic and
Pathologic Right Ventricular Outflow Tract Abnormalities in Patients
With Brugada Syndrome. \emph{J Am Coll Cardiol} . Dec 4
2018;72(22):2747-2757. doi:10.1016/j.jacc.2018.09.037

7. Polin GM, Haqqani H, Tzou W, et al. Endocardial unipolar voltage
mapping to identify epicardial substrate in arrhythmogenic right
ventricular cardiomyopathy/dysplasia. \emph{Heart Rhythm} . Jan
2011;8(1):76-83. doi:10.1016/j.hrthm.2010.09.088

8. Venlet J, Piers SRD, Kapel GFL, et al. Unipolar Endocardial Voltage
Mapping in the Right Ventricle: Optimal Cutoff Values Correcting for
Computed Tomography-Derived Epicardial Fat Thickness and Their Clinical
Value for Substrate Delineation. \emph{Circ Arrhythm Electrophysiol} .
Aug 2017;10(8)doi:10.1161/circep.117.005175

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