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\begin{document}

\title{Isolated JUP Plakoglobin Gene Mutation with Left Ventricular Fibrosis in
Familial Arrhythmogenic Right Ventricular Cardiomyopathy}



\author[1]{Michael R. Sood}%
\author[1]{Daniel Zinkovsky}%
\affil[1]{Mount Sinai South Nassau}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
\let\center\flushleft
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\maketitle
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\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} Arrhythmogenic Right Ventricular Cardiomyopathy
(ARVC) is a rare inherited disorder usually affecting the \emph{right}
ventricle (RV), characterized by fibro-fatty tissue replacement of the
healthy ventricular myocardium. It often predisposes young patients to
ventricular tachycardia, heart failure, and / or sudden cardiac death.
However, recent studies have suggested predominantly \emph{left}
ventricle (LV) involvement with variable and / or atypical
manifestations. Cardiac Magnetic Resonance (CMR) imaging has emerged as
the non-invasive gold standard for the diagnosis of ARVC. \textbf{Case
summary:} A 21-year-old athletic male with a family history of unknown
ventricular arrhythmias, presented with near syncope, chest pain and
exertional palpitations. He had an initial work-up that was grossly
unremarkable including, electrocardiography (ECG), echocardiography and
CMR imaging. Six months later, he presented again with recurrent
symptoms during exercise and his ECG demonstrating a new epsilon wave.
He had markedly elevated cardiac biomarkers, (troponin I
\textgreater{}100 ng/dl, normal value \textless{} 0.04 ng/dl). A
subsequent coronary angiogram was performed, which was normal. Holter
monitoring further showed subsequent episodes of ventricular tachycardia
with a right bundle branch morphology. An endomyocardial biopsy was
performed, which was negative. A follow-up CMR demonstrated \emph{the
new development} and prominent \emph{left} ventricular epicardial scar
in the lateral wall. The patient underwent familial genetic testing,
which confirmed the presence of an isolated JUP gene mutation and showed
multiple genes consistent with ARVC in his mother. Thus, he manifested a
partial transmission of only one abnormal gene for ARVC and exhibited a
markedly different expression in his disease without evidence of typical
right-sided heart pathology. A third CMR study was performed, which
showed partial improvement in myocardial fibrosis after exercise
cessation. \textbf{Conclusion:} We present a case of a young male with a
newly diagnosed isolated JUP gene mutation and a genetically diagnosed
family history of ARVC. During his course, he demonstrated the
progression of a characteristic epsilon wave on ECG and the presence of
\emph{new, atypical, left} ventricular fibrosis on repeat CMR imaging.
This case demonstrates a complex interplay between variable genetic
penetrance, phenotypical heterogeneity, and lifestyle factors including
exercise, in his disease expression and provides insight on the natural
course of an isolated JUP mutation. Although rare, clinicians should
have a high threshold for the suspicion of ARVC or variants of this
disorder even in the absence of classic right sided pathologies and /or
an initially normal work-up.%
\end{abstract}%



\sloppy


\textbf{Isolated JUP Plakoglobin Gene Mutation with Left Ventricular
Fibrosis in Familial Arrhythmogenic}

\textbf{Right Ventricular Cardiomyopathy}

\textbf{An MRI based Case Report}

Daniel Zinkovsky, MD\textsuperscript{1,2}, Michael R. Sood, MD,
MS\textsuperscript{1-3}

\textsuperscript{1}Mount Sinai South Nassau, Oceanside, NY, 11572,
USA.\textsuperscript{2}Icahn School of Medicine at Mount Sinai, New
York, NY 10029, USA.\textsuperscript{3}Mount Sinai Heart -- Mount Sinai
South Nassau, Oceanside, NY, 11572, USA.

\textbf{Abstract:}

\textbf{Introduction:}

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a rare
inherited disorder usually affecting the \emph{right} ventricle (RV),
characterized by fibro-fatty tissue replacement of the healthy
ventricular myocardium. It often predisposes young patients to
ventricular tachycardia, heart failure, and / or sudden cardiac death.
However, recent studies have suggested predominantly
\emph{left}ventricle (LV) involvement with variable and / or atypical
manifestations. Cardiac Magnetic Resonance (CMR) imaging has emerged as
the non-invasive gold standard for the diagnosis of ARVC.

\textbf{Case summary:}

A 21-year-old athletic male with a family history of unknown ventricular
arrhythmias, presented with near syncope, chest pain and exertional
palpitations. He had an initial work-up that was grossly unremarkable
including, electrocardiography (ECG), echocardiography and CMR imaging.
Six months later, he presented again with recurrent symptoms during
exercise and his ECG demonstrating a new epsilon wave. He had markedly
elevated cardiac biomarkers, (troponin I \textgreater{}100 ng/dl, normal
value \textless{} 0.04 ng/dl). A subsequent coronary angiogram was
performed, which was normal. Holter monitoring further showed subsequent
episodes of ventricular tachycardia with a right bundle branch
morphology. An endomyocardial biopsy was performed, which was negative.
A follow-up CMR demonstrated \emph{the new development} and
prominent\emph{left} ventricular epicardial scar in the lateral wall.

The patient underwent familial genetic testing, which confirmed the
presence of an isolated JUP gene mutation and showed multiple genes
consistent with ARVC in his mother. Thus, he manifested a partial
transmission of only one abnormal gene for ARVC and exhibited a markedly
different expression in his disease without evidence of typical
right-sided heart pathology. A third CMR study was performed, which
showed partial improvement in myocardial fibrosis after exercise
cessation.

\textbf{Conclusion:}

We present a case of a young male with a newly diagnosed isolated JUP
gene mutation and a genetically diagnosed family history of ARVC. During
his course, he demonstrated the progression of a characteristic epsilon
wave on ECG and the presence of \emph{new, atypical, left} ventricular
fibrosis on repeat CMR imaging. This case demonstrates a complex
interplay between variable genetic penetrance, phenotypical
heterogeneity, and lifestyle factors including exercise, in his disease
expression and provides insight on the natural course of an isolated JUP
mutation. Although rare, clinicians should have a high threshold for the
suspicion of ARVC or variants of this disorder even in the absence of
classic right sided pathologies and /or an initially normal work-up.

\textbf{Author Disclosures and Consent:}

The authors have no conflicts of interest or financial disclosures to
report. Informed consent was obtained for publication and all images and
all patient information has been kept confidential.\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Appendix:} \emph{ACM: Arrhythmogenic Cardiomyopathy, AIVR:
Accelerated Idioventricular Rhythm, ARVC: Arrhythmogenic Right
Ventricular Cardiomyopathy, BP: Blood pressure, CRM: Cardiac Magnetic
Resonance, ECG: Electrocardiography, ED: Emergency Department, EMT:
Emergency Medical Technician, HR: Heart rate, ICD: Implantable
cardioverter defibrillator, JUP: Junctional Plakoglobin, LAD: Left
anterior descending, LBBB: Left bundle branch block, LGE}: \emph{Late
gadolinium enhancement,} \emph{LV: Left Ventricle, PVC: premature
ventricular contraction, RBBB: Right bundle branch block, RV: Right
Ventricle, SCD: Sudden Cardiac Death}\tabularnewline
\bottomrule
\end{longtable}

Keywords: Case report, Arrhythmogenic Right Ventricular Cardiomyopathy,
Arrhythmogenic Cardiomyopathy, Plakoglobin, JUP mutation, Cardiac
magnetic resonance

\textbf{Background:}

ARVC is a rare inherited disorder usually affecting the right ventricle,
characterized by fibro-fatty tissue substitution of healthy ventricular
myocardium. It often predisposes young patients to ventricular
tachycardia, heart failure, and sudden cardiac death. However, due to
multiple disease variants, it can involve both ventricles or
predominantly the left ventricle with atypical manifestations. Recent
post-mortem studies of patients with Arrhythmogenic Cardiomyopathy (ACM)
suggest left ventricular involvement in up to 87\% of
patients.\textsuperscript{1} Abnormal ECG findings and ventricular
arrhythmias may often precede abnormal imaging or structural findings.
To date fifteen genes have been identified to cause ARVC with a subset
encoding for desmosomal proteins including \emph{Plakoglobin (JUP).}
\textsuperscript{2} Phenotypic expression is highly variable, but some
evidence suggests young athletic males tend to have a more malignant
disease course in part due to their level of hormonal and or physical
activity, which in turn contributes a greater degree of mechanical
cardiac stress.\textsuperscript{3}

We present a case of a 21-year-old male with a genetically proven family
history of ARVC who presented to the hospital with near syncope and
through extensive workup, had no evidence of ARVC on initial imaging
(echo and CMR). Subsequently, he was found to have multiple episodes of
ventricular ectopy and tachycardia. During his second hospitalization,
work-up demonstrated atypical, predominantly left ventricular
dysfunction on echocardiogram with evidence of \emph{new,
left}ventricular fibrosis on repeat CMR study. A third CMR scan showed
interval improvement in myocardial fibrosis once exercise was limited.

\textbf{Case Report:}

Initial Presentation:

A 21-year-old physically fit male emergency medical technician trainee
with recurrent pre-syncope presented to our emergency department for an
episode of chest pain with near syncope in March 2021. He was in his
usual state of health when he began to experience transient substernal
chest pain while rigorously biking in cold weather with associated
lightheadedness, diaphoresis, and blurred vision. He reported similar
symptoms in the past with palpitations and dyspnea on exertion. He
denied any other toxic habits and urine toxicology screen was negative.
He notably reported a family history of ventricular tachycardia for
which his mother (at age 40) had received an implantable cardiac
defibrillator (ICD). He had seen a cardiologist prior where work up for
thyroid disease and holter monitoring were unremarkable.

On initial admission, his peak Troponin I was minimal (Table 1). ECG
showed normal sinus rhythm without any acute ST/T wave changes (Image
1). Transthoracic echocardiogram revealed normal diastolic filling
pattern, right sided pressures, and LV systolic function with an
Ejection Fraction (EF) 55-60\% and no regional wall motion
abnormalities. He had no events on telemetry. An exercise stress test
was performed but stopped due to hypotension (BP 70/50), sinus
tachycardia (190 bpm) and near syncope at Bruce stage 5 (maximal
exercise). There were no significant arrhythmias or evidence of ischemia
during exercise and very rare PVCs were noted in recovery. The patient
was subsequently discharged with outpatient telemetry monitoring, which
revealed infrequent ventricular ectopy/PVCs, with 2 episodes of brief
PVC in couplets and triplets.

The patient underwent a CMR scan (initial scan- three months from
initial presentation) which was a grossly normal study without evidence
of myocardial fibrosis, infiltrative disease, and did not meet criteria
for ARVC (Image 3).

Second Presentation:

Six-months after the initial presentation, the patient again presented
to the emergency department with severe, sharp, mid-substernal chest
pain with associated diaphoresis, and lightheadedness. He remained
physically active including frequent exercise. Physical exam including
orthostatic vitals was unremarkable. Electrocardiogram showed sinus
bradycardia at 40 bpm without ST elevation or depression and a right
ventricular conduction delay with an epsilon wave (Image 2), which were
new findings compared to prior. Troponins continued to rapidly and
markedly increase in addition to elevations of transaminases and
inflammatory markers (Table 1). Infectious work-up including covid-19
PCR was negative. Cardiac angiography revealed no coronary artery
disease but a very prominent mid LAD myocardial bridge with near
complete obliteration at resting HR in 70s. A repeat echocardiogram
showed a new reduction in EF to 40-45\% and diffuse hypokinesis of the
LV (in comparison to six months earlier).

A repeat CMR three months after the previous scan
(2\textsuperscript{nd}CMR study) revealed new findings of mildly reduced
LV systolic function with mild-moderate hypokinesis of the mid to apical
lateral wall, and prominent epicardial fibrosis and an area of small,
focal mid-myocardial fibrosis in a non-ischemic pattern with elevated
native T1 and T2 values on mapping, respectively (Image 4). Of note, the
study still did not meet any CMR criteria for ARVC. The patient
subsequently received an endomyocardial biopsy without any significant
histologic changes reported. Genetic testing demonstrated one pathogenic
variant in the JUP gene in our patient, along with multiple genetic
abnormalities for ARVC in his mother including abnormal JUP, NEBL and
ACTN2 genes. Given these genetic results along with his family history,
the patient was referred for an ICD implant for primary prevention of
sudden cardiac death along with exercise limitation. A follow-up
(3\textsuperscript{rd} CMR scan) was performed after 11 months after
initial CMR scan, which showed improvement in myocardial fibrosis (Image
5).

\textbf{Discussion}

ARVC is an inherited disorder, either autosomal dominant or rarely
autosomal recessive, that is predominantly believed to affect the right
ventricle, but a growing number of studies have noted involvement of
both or either ventricle.\textsuperscript{4} It is characterized by
fibro-fatty tissue substitution of healthy ventricular myocardium,
predisposing these patients to ventricular tachycardia, heart failure,
and sudden cardiac death. Its prevalence in the general population is
estimated at 1 in 5000, but closer to 1 in 2000 in select European
countries and constitutes up to 20\% of sudden cardiac death cases in
individuals under 30 years of age.\textsuperscript{5,6} In addition,
phenotypic expression in males differs, in which males have a more
malignant disease course and develop life threatening ventricular
arrhythmias at an earlier age, possibly due to differences in sex
hormones (testosterone) and increased level of physical activity, which
may contribute to a greater degree of mechanical cardiac
stress.\textsuperscript{7}

Due to an expanding phenotypic spectrum of arrhythmogenic
cardiomyopathy, from multi-gene variability in expression as well as
incomplete penetrance, the diagnosis has been challenging requiring
revisions to originally published criteria. The previously established
Task Force criteria for diagnosis of arrhythmogenic cardiomyopathy first
proposed in 1994, later revised in 2010, continues to evolve to include
left-sided variants and CMR findings of late-gadolinium
enhancement.\textsuperscript{8} The current criteria incorporate
electrical features (12 lead ECG), structural features (seen on
echocardiography and imaging), tissue characteristics (via biopsy) and
genetic familial evaluation (Figure 1). While most of the Task Force
criteria was originally developed from cohorts with predominantly right
ventricular involvement, this potentially missed those with left
ventricular dominant or biventricular disease. Pathological and imaging
studies have reported the prevalence of LV involvement ranging between
17-87\% of cases.\textsuperscript{9,10}

While ARVC can involve multiple genes and proteins, its primary genetic
defect involves proteins constituting desmosomes -- cell adhesion
structures -- which over time disrupt normal functioning of
intercellular junctions, as well as altering transcription to favor
adipogenesis/fibrogenesis over normal myocyte differentiation and
healthy cardiac development. Loss-of-function mutations in desmosomal
proteins such as plakophilin, desmoplakin, or desmoglein have been most
commonly described, but up to 13 other genes involved in ARVC have been
identified to date. Furthermore, cardiac biopsies have suggested an
immunological component of pathogenesis, noting the presence of
inflammatory infiltrates with T lymphocytes associated with myocyte
necrosis.\textsuperscript{11} As myocardial scarring develops,
ventricular arrhythmias may develop through macro-reentry mechanisms but
also due to gap-junction remodeling from the loss of desmosomal
integrity and resulting in alteration of sodium current.

Plakoglobin (JUP) gene and Arrhythmogenic Cardiomyopathy (ACM)

The Junction Plakoglobin (JUP) gene encodes for the protein plakoglobin,
found in cells of the heart and skin where it is part of adherens
junctions and desmosomes which help to hold neighboring cells together.
It also plays a role in cell signaling within the \emph{Wnt} pathway
involved in the normal development of the heart, skin, and
hair.\textsuperscript{12} Naxos disease, a cardio-cutaneous syndrome, is
an autosomal recessive condition involving a two base-pair deletion of
plakoglobin, characterized by effects on the heart (ARVC), skin
(palmoplantar keratosis) and hair (woolly hair).\textsuperscript{13} The
first case of isolated ARVC without cutaneous manifestations came from
the only known autosomal dominant mutation in JUP which was reported in
a proband in Germany in 2007. This mutation came from a three base pair
insertion causing an addition of a terminal serine residue in the
plakoglobin gene which affects the stability and degradation of
plakoglobin.\textsuperscript{14} In contrast, a rare but severe
phenotype associated with a homozygous JUP mutation with complete loss
of plakoglobin can cause diffuse skin erosion, a condition referred to
as lethal congenital epidermolysis bullosa
(LECEB).\textsuperscript{15}Of note, our patient, in contrast, was found
to have an isolated (heterozygous) JUP gene mutation, and appears to
have manifested much less severe phenotype, particularly without the
manifestation of any cutaneous symptoms. Moreover, to date, there has
not been any published cases on left sided or biventricular dysfunction
or fibrosis in patients with an isolated plakoglobin mutation.

Left-dominant Arrhythmogenic cardiomyopathy (LDAC)

Left-dominant Arrhythmogenic cardiomyopathy (LDAC) differs from ARVC in
more ways than only predominantly involving the LV. Ventricular
arrhythmias of typical ARVC are characterized by LBBB morphology,
whereas over 75\% of LDAC demonstrated RBBB morphology. Additionally,
findings of lateral and/or inferior T wave inversion found in LDAC
differ in pattern seen with ARVC which involves anterior T-wave
inversion and epsilon waves of the right precordial
leads.\textsuperscript{16} Epsilon waves are low-amplitude positive
signals following a QRS complex that arise from prolonged depolarization
in the affected part of the myocardium (as shown in our patient, Image
2). On echocardiography, 30\% of LDAC patients have LV dilation and/or
impairment with preserved RV volume and function. In the classic pattern
of ARVC, isolated RV dysfunction precedes LV involvement throughout the
disease course. In addition, there is general sparing of the septum in
late stage ARVC with LV involvement.\textsuperscript{17} It is
noteworthy that our patient manifested ventricular ectopy with RBBB
pattern (a typical characteristic of left ventricular involvement),
despite developing an epsilon wave, (which is similarly seen in typical
ARVC) along with other features of left sided involvement such as a
reduction in left ventricular function and the interval development of
left ventricular fibrosis seen on CMR.

CMR in diagnosis of Arrhythmogenic cardiomyopathy

As the diagnostic criteria evolved and studies over the decades have
uncovered more about the various phenotypic expression of ARVC, CMR
imaging has emerged as the noninvasive gold standard for ARVC workup. It
provides a useful tool to evaluate morphology, function, and tissue
characteristics. It can highlight myocardial fibrosis, fatty replacement
or identify wall motion abnormalities with high accuracy. The most
recent 2020 International diagnostic criteria of arrhythmogenic
cardiomyopathy relies on CMR to characterize the phenotype and aid with
the exclusion of other diagnoses. The new criterion adds the minor
criterion for the diagnosis of biventricular or left dominant variants
with the demonstration of LV systolic
dysfunction.\textsuperscript{18,19}

Late gadolinium enhancement (LGE) of the myocardium is often used to
assess myocardial fibrosis but has a limited role in the current
diagnostic criteria of ARVC. LGE is nonspecific and the differential
diagnosis can include sarcoidosis, myocarditis, amyloidosis, or dilated
cardiomyopathy.\textsuperscript{20} Furthermore, LGE is less useful in
classic ARVC where the thin RV wall makes the technique less useful, in
comparison to LDAC where LGE has been reported in up to 61\% of cases
presenting in a circumferential, mid-myocardial pattern extending to the
right side of the septum.\textsuperscript{21} Of note the
circumferential or mid-myocardial fibrosis pattern is seen in only left
dominant/biventricular ARVC. Autopsy studies of ARVC patients have
demonstrated fibro-fatty infiltration predominantly on the epicardial
surface leading to the understanding that the disease starts in the
epicardium with progression toward the endocardium. LV systolic
dysfunction can become more severe in advanced stages as there is
progression of transmural involvement. Our patient's second CMR study
reflected early yet significant changes with normal cavitary size/wall
thickness but mild-moderate hypokinesis of the mid to apical lateral
wall. Furthermore, he had predominately epicardial fibrosis in a
relatively circumferential pattern of the lateral wall with mid
myocardial fibrosis involving the septal walls.

Role of Testosterone and Physical Activity in ARVC Pathogenesis

Testosterone, the hormone generally found in higher amounts in males,
has been shown to have pro-arrhythmic effects, accelerate ARVC
pathogenesis including myocardial apoptosis and lipogenesis, independent
of age, BMI, ventricular function and desmosome mutation
status.\textsuperscript{22} Other concomitant factors that may have
accelerated his phenotypical expression, particularly with left sided
involvement, include (male) gender and the degree of physical activity
including strenuous exercise. The patient's rigorous exercise capacity
(evident by his exercise treadmill study reaching Bruce Stage 5) and
recent physical training for becoming a firefighter/EMT (which is
generally 18 weeks in duration), we feel, are likely to have progressed
his disease process in the short time with recurrent hospitalizations.
High intensity exercise is of particular importance in ARVC as it
increases wall stress, increases sympathetic stimulation, predisposes to
greater incidence of fatal ventricular arrhythmia, and is correlated
with reduced LV (and RV) function.\textsuperscript{23} Those with ARVC
are encouraged to avoid competitive sports, especially endurance or high
intensity sports due to the arrhythmic risk and accelerated disease
progression.\textsuperscript{24,25} Endurance training studies of
plakoglobin deficient mice (similar to the protein deficiency produced
by the JUP gene mutation in our patient), have demonstrated alterations
in \emph{right} ventricular dilation/dysfunction and
electrophysiological function (increased spontaneous ventricular
ectopy).\textsuperscript{26} To the best of our knowledge, we could not
find similar documented reports demonstrating structural
\emph{left}ventricular changes within such a short time period with this
isolated gene mutation. Ultimately, our recommendation for exercise
cessation may also help explain his improvement in scar/fibrotic burden
seen in his third CMR scan.

\textbf{Conclusion:}

We present a case of a young male with a family history of ventricular
arrhythmias, who had two separate hospitalizations for pre-syncope with
the manifestations of ARVC including the development of an epsilon wave
on ECG along with atypical, left sided myocardial dysfunction and the
development of left ventricular fibrosis on repeat CMR scan. He was
found to have an isolated JUP mutation with other family members having
multiple abnormal genes for ARVC. The timing and manifestations of these
findings over two separate hospitalizations have been seldom reported,
particularly with only any isolated JUP mutation. Since its discovery,
ARVC has undergone an evolution in diagnostic criterion due to it
variability in presentation and manifestations, as well as the discovery
of a broad spectrum and interplay of genes. Clinicians should recognize
the disease heterogeneity, as demonstrated in our case, particularly
where the initial cardiac work-up including his initial CMR study and
endomyocardial biopsy was unremarkable. Finally, this case provides
insight into the potential complex interplay in genotype and lifestyle
factors in the expression of an isolated JUP mutation, and its
involvement in various arrhythmogenic cardiomyopathies.

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  ventricular cardiomyopathy: \selectlanguage{greek}ε-\selectlanguage{english}waves and anterior T-wave
  inversion.~\emph{BMJ Case Rep} . 2011;2011:bcr0920103318. Published
  2011 May 16. doi:10.1136/bcr.09.2010.3318
\item
  Sen-Chowdhry S, Syrris P, Prasad SK, et al. Left-dominant
  arrhythmogenic cardiomyopathy: an under-recognized clinical
  entity.~\emph{J Am Coll Cardiol} . 2008;52(25):2175-2187.
  doi:10.1016/j.jacc.2008.09.019
\item
  Corrado D, Zorzi A, Cipriani A, et al. Evolving Diagnostic Criteria
  for Arrhythmogenic Cardiomyopathy.~\emph{J Am Heart Assoc} .
  2021;10(18):e021987. doi:10.1161/JAHA.121.021987
\item
  Corrado D, Perazzolo Marra M, Zorzi A, et al. Diagnosis of
  arrhythmogenic cardiomyopathy: The Padua criteria.~\emph{Int J
  Cardiol} . 2020;319:106-114. doi:10.1016/j.ijcard.2020.06.005
\item
  Manole S, Pintican R, Popa G, et al. Diagnostic Challenges in Rare
  Causes of Arrhythmogenic Cardiomyopathy-The Role of Cardiac
  MRI.~\emph{J Pers Med} . 2022;12(2):187. Published 2022 Jan 31.
  doi:10.3390/jpm12020187
\item
  te Riele AS, Tandri H, Bluemke DA. Arrhythmogenic right ventricular
  cardiomyopathy (ARVC): cardiovascular magnetic resonance
  update.~\emph{J Cardiovasc Magn Reson} . 2014;16(1):50. Published 2014
  Jul 20. doi:10.1186/s12968-014-0050-8
\item
  Ren J, Chen L, Zhang N, et al. Plasma testosterone and arrhythmic
  events in male patients with arrhythmogenic right ventricular
  cardiomyopathy.~\emph{ESC Heart Fail} . 2020;7(4):1547-1559.
  doi:10.1002/ehf2.12704
\item
  Saberniak J, Hasselberg NE, Borgquist R, et al. Vigorous physical
  activity impairs myocardial function in patients with arrhythmogenic
  right ventricular cardiomyopathy and in mutation positive family
  members.~\emph{Eur J Heart Fail} . 2014;16(12):1337-1344.
  doi:10.1002/ejhf.181
\item
  Gasperetti A, Dello Russo A, Busana M, et al. Novel risk calculator
  performance in athletes with arrhythmogenic right ventricular
  cardiomyopathy.~\emph{Heart Rhythm} . 2020;17(8):1251-1259.
  doi:10.1016/j.hrthm.2020.03.007
\item
  Zorzi A, Cipriani A, Bariani R, et al. Role of Exercise as a
  Modulating Factor in Arrhythmogenic Cardiomyopathy. \emph{Curr Cardiol
  Rep} . 2021 May 7;23(6):57. doi: 10.1007/s11886-021-01489-0.
\item
  Kirchhof P, Fabritz L, Zwiener M, et al. Age- and training-dependent
  development of arrhythmogenic right ventricular cardiomyopathy in
  heterozygous plakoglobin-deficient mice.~\emph{Circulation} .
  2006;114(17):1799-1806. doi:10.1161/CIRCULATIONAHA.106.624502
\end{enumerate}

\textbf{Images:}

\textbf{Image 1:} ECG 1 findings from 3/2021, below:\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Image 2:} ECG 2 from second hospitalization, (6 months from
prior) with intraventricular conduction delay changes, RBBB morphology,
QRS widening and possible Epsilon wave (red arrow). Prolonged S-wave
upstroke in V3 with QRS widening (green arrow)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Image 3 (Initial CMR scan):}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{ab}

Above, CMR, short axis gradient echo (a) and PSIR (b) , short axis and 3
chamber view post contrast WITHOUT any delayed gadolinium enhancement.
T1 maps were also normal (not shown).

\textbf{Image 4, Follow-up CMR scan- 3 months after
1\textsuperscript{st} study:}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image7/image7}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image8/image8}

\end{center}
\end{figure}

\textbf{a}

\textbf{b}

\textbf{c}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image9/image9}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image10/image10}

\end{center}
\end{figure}

\textbf{d}

\textbf{e}

Above, CMR, gradient echo, PSIR 3-chamber view with prominent epicardial
fibrosis of the infero-lateral wall (a), 2 chamber view showing
epicardial fibrosis of the basal anterior wall and inferior walls (b) ,
short axis view showing circumferntial epicardial enhancement of the
anterior, lateral and inferior walls (c), short axis-view with prominent
patchy epicardial anterior wall enhancement (d); T1 map with elevated
native values of the inferiro wall (1250 ms), (e)

\textbf{Image 5, (third CMR study, 11 months after the first scan):}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image11/image11}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image12/image12}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image13/image13}

\end{center}
\end{figure}

\textbf{a}

\textbf{b}

\textbf{c}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image14/image14}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image15/image15}

\end{center}
\end{figure}

\textbf{d}

\textbf{e}

CMR, above, gradient echo, PSIR short axis (a), 4-chamber (b), 2-chamber
(c), with improved myocardial fibrosis (arrows) T1 and T2 maps now
normal values (images d, e).

\textbf{Tables:}

\textbf{TABLE 1} Hospital course: Key findings from multiple admissions\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Hospital Course 1 (3/2021)}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Hospital Course 2 (9/2021)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Peak Troponin}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.207 ng/ml\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
128.44 ng/ml\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Peak CK with CK-MB}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
100 U/L\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
3194 U/L\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{BNP}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
16 pg/ml\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
13.9 pg/ml\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{TSH / FT4}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.2 ng/dL / 6.62 IU/mL\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
n/a\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{CRP}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.62mg/L\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
7.16mg/L\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{LFTs}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
AST 15 U/L, ALT 13 U/L\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
AST 251 U/L, ALT 50 U/L\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Na / K / Cr / CO2 / Ca}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Within normal limits\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Within normal limits\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textbf{ECG findings}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NSR, Normal ECG PR 146, QTc 409\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Sinus bradycardia with `incomplete RBBB'/Epsilon wave PR 142, QTc
392ms\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Echo}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
EF 55-60\%. Normal LV size /systolic function without regional wall
motion abnormalities.\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
EF 40-45\% with hypokinetic LV without wall motion abnormalities.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Cardiac MRI}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
6/21: LV has normal systolic function, (EF=55\%) and normal cavitary
size. There is normal wall thickness. There are no wall motion
abnormalities. There is no evidence of myocardial fibrosis, infiltrative
disease or arrhythmogenic right ventricular dysplasia.\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
9/2021: mildly reduced LV systolic function (EF=49\%) with normal
cavitary size/wall thickness but mild-mod hyperkinesis of the mid to
apical lateral wall. There was prominent epicardial fibrosis of the
basal anterior and entire lateral inferolateral, inferior, and
anterolateral and lateral walls. There is small focal mid-myocardial
fibrosis of the basal anterolateral wall and mid to apical infero-septal
walls. There is sparring of the sub-endocardium with all scar patterns
representing a non-ischemic pattern. There are elevated T1 and T2 values
on mapping suggesting inflammatory or edematous component which is
overlapping at areas of scar.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Normal Values:\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Troponin: \textless{} 0.031ng/mL} \emph{CK: 30-200 U/L} \emph{BNP:
\textless{}101.0 pg/mL} \emph{TSH: 0.8 -- 1.5 ng/dL}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{FT4: 0.4 -- 4.2 IU/mL} \emph{CRP: \textless{}5.1 mg/L} \emph{AST:
\textless{}36 U/L} \emph{ALT: \textless{}46 U/L}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Appendix:} ALT: Alanine Aminotransferase, AST: aspartate
aminotransferase, BNP: Brain Natriuretic Peptide, Ca: Calcium, CK:
Creatine Kinase, CK-MB: Creatine kinase-MB, CO2: Bicarbonate, Cr:
Creatinine, CRP: C Reactive Protein, ECG: Electrocardiogram, EF:
Ejection Fraction, FT4: Free Thyroxine, K: potassium, LV: Left
ventricle, Na: Sodium, NSR: Normal sinus rhythm, RBBB: Right bundle
branch block, TSH: Thyroid Stimulating Hormone\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Appendix:} ALT: Alanine Aminotransferase, AST: aspartate
aminotransferase, BNP: Brain Natriuretic Peptide, Ca: Calcium, CK:
Creatine Kinase, CK-MB: Creatine kinase-MB, CO2: Bicarbonate, Cr:
Creatinine, CRP: C Reactive Protein, ECG: Electrocardiogram, EF:
Ejection Fraction, FT4: Free Thyroxine, K: potassium, LV: Left
ventricle, Na: Sodium, NSR: Normal sinus rhythm, RBBB: Right bundle
branch block, TSH: Thyroid Stimulating Hormone\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Appendix:} ALT: Alanine Aminotransferase, AST: aspartate
aminotransferase, BNP: Brain Natriuretic Peptide, Ca: Calcium, CK:
Creatine Kinase, CK-MB: Creatine kinase-MB, CO2: Bicarbonate, Cr:
Creatinine, CRP: C Reactive Protein, ECG: Electrocardiogram, EF:
Ejection Fraction, FT4: Free Thyroxine, K: potassium, LV: Left
ventricle, Na: Sodium, NSR: Normal sinus rhythm, RBBB: Right bundle
branch block, TSH: Thyroid Stimulating Hormone\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Figures:

Figure 1: Diagnosis of arrhythmogenic cardiomyopathy (Int J Cardiol.
2020 Nov 15;319:106-114.)\textsuperscript{19}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image16/image16}

\end{center}
\end{figure}

Author Information:

The authors would like to thank the Department of Radiology and
Cardiology at Mount Sinai South Nassau, NY.

Daniel Zinkovsky, MD is the primary author.

Michael R. Sood, MD, MS, FACC, FACP, FSCMR is an additional primary and
corresponding author, who can be reached at mike.sood@gmail.com.

\selectlanguage{english}
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\end{document}

