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\begin{document}

\title{Diagnostic evaluation of unexplained ventricular tachyarrhythmias in
younger adults}



\author[1]{William J}%
\author[1]{Xiao X}%
\author[1]{Shirwaiker A}%
\author[1]{Patel HC}%
\author[1]{Sandeep Prabhu}%
\author[1]{Liang-Han Ling}%
\author[1]{Sugumar H}%
\author[1]{Justin Mariani}%
\author[1]{Peter  Kistler}%
\author[1]{Voskoboinik A}%
\affil[1]{The Alfred}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\emph{Background:} The diagnostic work-up for cardiac arrest from
ventricular tachyarrhythmias occurring in younger adults and
structurally normal hearts is variable and often incomplete.
\emph{Methods:} We reviewed records for all recipients of a secondary
prevention implantable cardiac defibrillator (ICD) younger than 60 years
at a single quaternary referral hospital from 2010-2021. Patients were
included if they had unexplained ventricular arrhythmias (UVA) and
absence of structural heart disease on echocardiogram, normal coronary
assessment and no clear diagnostic features on ECG. We specifically
evaluated the adoption rate of five modalities of `second-line' cardiac
investigations: cardiac magnetic resonance imaging (CMR), exercise ECG,
flecainide challenge, electrophysiology study (EPS) and genetic testing.
We also evaluated patterns of anti-arrhythmic drug therapy and
device-detected arrhythmias and compared them with secondary prevention
ICD recipients with a clear aetiology found on initial assessment.
\emph{Results:} 102 recipients of a secondary prevention ICD under the
age of 60 were analysed. 39 patients (38.2\%) were identified with UVA
and were compared with the remaining 63 patients with VA of clear
aetiology (61.8\%). UVA patients were younger (35.6 \selectlanguage{ngerman}± 13.0 years vs 46.0
± 8.6 years, p\textless{}0.001) and were more often female (48.7\% vs
28.6\%, p=0.04). CMR was performed in 32 patients with UVA (82.1\%),
whereas flecainide challenge, stress ECG, genetic testing and EPS were
only performed in a minority of patients. Overall, the use of a
second-line investigation suggested an aetiology in 17 patients with UVA
(43.5\%). Compared to patients with VA of clear aetiology, UVA patients
had lower rates of antiarrhythmic drug prescription (64.1\% vs 88.9\%,
p=0.003) and had a higher rate of device-delivered tachy-therapies
(30.8\% vs 14.3\%, p=0.045). \emph{Conclusion:} In this real-world
analysis of patients with UVA, the diagnostic work-up is often
incomplete. While CMR was increasingly utilized at our institution,
investigations for channelopathies and genetic causes appear to be
underutilized. Implementation of a systematic protocol for work-up of
these patients requires further study.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Diagnostic evaluation of unexplained ventricular
tachyarrhythmias in younger adults}

William J\textsuperscript{1}, Xiao X\textsuperscript{1}, Shirwaiker
A\textsuperscript{1}, Patel HC\textsuperscript{1}, Prabhu
S\textsuperscript{1,2}, Ling LH\textsuperscript{1}, Sugumar
H\textsuperscript{1}, Mariani J\textsuperscript{1}, Kistler
P\textsuperscript{1,2}, Voskoboinik A\textsuperscript{1,2}

\emph{\textsuperscript{1}Department of Cardiology, Alfred Health.}

\emph{\textsuperscript{2}Electrophysiology Research Group, Baker
Institute.}

\emph{Word Count}

Abstract (minus headings): 311 words

Manuscript (minus headings and figures): 4237 words

\emph{Address for Correspondence}

A/Prof Aleksandr Voskoboinik

Department of Cardiology, Alfred Hospital

55 Commercial Rd Melbourne VIC 3004, Australia

Tel: + 61 3 9076 3263

Email a.voskoboinik@alfred.org.au

\section*{Abstract.}

{\label{abstract.}}

Background: The diagnostic work-up for cardiac arrest from ventricular
tachyarrhythmias occurring in younger adults and structurally normal
hearts is variable and often incomplete.

Methods: We reviewed records for all recipients of a secondary
prevention implantable cardiac defibrillator (ICD) younger than 60 years
at a single quaternary referral hospital from 2010-2021. Patients were
included if they had unexplained ventricular arrhythmias (UVA) and
absence of structural heart disease on echocardiogram, normal coronary
assessment and no clear diagnostic features on ECG. We specifically
evaluated the adoption rate of five modalities of `second-line' cardiac
investigations: cardiac magnetic resonance imaging (CMR), exercise ECG,
flecainide challenge, electrophysiology study (EPS) and genetic testing.
We also evaluated patterns of anti-arrhythmic drug therapy and
device-detected arrhythmias and compared them with secondary prevention
ICD recipients with a clear aetiology found on initial assessment.

Results: 102 recipients of a secondary prevention ICD under the age of
60 were analysed. 39 patients (38.2\%) were identified with UVA and were
compared with the remaining 63 patients with VA of clear aetiology
(61.8\%). UVA patients were younger (35.6 \selectlanguage{ngerman}± 13.0 years vs 46.0 ± 8.6
years, p\textless{}0.001) and were more often female (48.7\% vs 28.6\%,
p=0.04). CMR was performed in 32 patients with UVA (82.1\%), whereas
flecainide challenge, stress ECG, genetic testing and EPS were only
performed in a minority of patients. Overall, the use of a second-line
investigation suggested an aetiology in 17 patients with UVA (43.5\%).
Compared to patients with VA of clear aetiology, UVA patients had lower
rates of antiarrhythmic drug prescription (64.1\% vs 88.9\%, p=0.003)
and had a higher rate of device-delivered tachy-therapies (30.8\% vs
14.3\%, p=0.045).

Conclusion: In this real-world analysis of patients with UVA, the
diagnostic work-up is often incomplete. While CMR was increasingly
utilized at our institution, investigations for channelopathies and
genetic causes appear to be underutilized. Implementation of a
systematic protocol for work-up of these patients requires further
study.

\section*{Introduction.}

{\label{introduction.}}

Ventricular tachyarrhythmia is a term used to describe a spectrum of
cardiac arrhythmias arising from the ventricular myocardium. It
comprises monomorphic ventricular tachycardia (VT), polymorphic VT,
ventricular fibrillation (VF) and ventricular
flutter\textsuperscript{1}. Sustained ventricular tachyarrhythmia is a
highly lethal arrhythmia and is implicated in an estimated 95\% of cases
of arrhythmic sudden cardiac death\textsuperscript{2}.

In the majority of cases, ventricular tachyarrhythmias are secondary to
either an identifiable structural heart abnormality (e.g., coronary
artery disease, non-ischaemic cardiomyopathy) or a primary
electrophysiological disease evident on baseline electrocardiography
(e.g., long QT syndrome, Brugada syndrome). However, an estimated 6-10\%
of patients who present with ventricular tachyarrhythmias have no clear
aetiology suggested by ECG, transthoracic echocardiography (TTE) or
coronary assessment\textsuperscript{3,4}. While data in these patients
with unexplained ventricular arrhythmia (UVA) is sparse, small case
series have shown that these patients are often
younger\textsuperscript{5} and have a higher risk of recurrent cardiac
arrest in the future\textsuperscript{6}.

Management of patients with UVA represents a clinical challenge, with
the diagnostic workup for these patients being poorly standardised and
often incomplete. Consensus guidelines published by the American College
of Cardiology/American Heart Association/Heart Rhythm Society
(ACC/AHA/HRS) on the evaluation of patients with ventricular
tachyarrhythmias provides a Class I recommendation for the use of a
baseline ECG, resting TTE and coronary angiography in the workup of
patients presenting with ventricular tachyarrhythmia\textsuperscript{7}.
Other investigations, such as cardiac magnetic resonance imaging (CMR),
electrophysiology study (EPS) and genetic testing, carry a Class II
recommendation. Exercise stress testing, provocative testing for Brugada
Syndrome (flecainide/ajmaline challenges) are not referenced in this
guideline. The relative yield of each of these modalities of testing in
the evaluation of UVA is uncertain.

\section*{Aims.}

{\label{aims.}}

The present study had three aims. First, we aimed to evaluate the
clinical characteristics of younger adults presenting with unexplained
ventricular arrhythmia (UVA), as compared with patients who have an
identifiable aetiology of ventricular tachyarrhythmia. Second, we aim to
examine the variability in diagnostic evaluation undertaken in this UVA
cohort. In particular, we will evaluate the adoption rate of five
`second-line' investigations: CMR, exercise stress ECG, flecainide
challenge, EP study and genetic testing. Third, we aimed to assess
differences in management and subsequent outcomes in patients with
unexplained ventricular arrhythmia compared to their counterparts with
an identified aetiological mechanism.

We hypothesised that the diagnostic workup in patients with UVA will be
heterogeneous and incomplete. We also hypothesised that these patients
with UVA will have lower rates of prescribed anti-arrhythmic drugs and a
higher rate of recurrent ventricular tachyarrhythmia, as failure to
identify a specific underlying aetiology may preclude appropriate
targeted therapy.

\section*{Methodology.}

{\label{methodology.}}

The study was approved by our institutional ethics committee (Alfred
Health Ethics Research Administration) as a low-risk project. Records
were reviewed for all patients under the age of 60 who underwent
implantation of a secondary prevention implantable cardiac defibrillator
(ICD) between January 2010 and July 2021 at a single quaternary
cardiology centre in Melbourne, Australia. Secondary prevention ICD was
defined in our study as a device implanted after a clinical presentation
with either 1) ventricular tachyarrhythmias resulting in syncope and/or
cardiac arrest, or 2) conscious sustained ventricular tachycardia. We
included patients receiving both subcutaneous ICDs and transvenous
devices, with the transvenous devices comprising single chamber ICDs,
dual chamber ICDs and biventricular ICDs.

Records were reviewed for all cardiac investigations performed as part
of the diagnostic evaluation in these device recipients, defined as
investigations performed either within 3 months prior to device implant
or within 6 months following device implant. Baseline ECGs were accessed
to record rhythm, cardiac axis, QT interval and the presence or absence
of the early repolarisation pattern. Transthoracic echocardiography
(TTE) records were accessed to collect both qualitative parameters
(overall left and right ventricular function, presence of segmental
hypokinesis, degree of valvular dysfunction) and quantitative parameters
(LV diastolic diameter and left ventricular ejection fraction).
Investigations for coronary artery disease, including invasive coronary
angiography and computerised tomographic coronary angiography (CTCA),
were accessed to record the presence of obstructive coronary artery
disease, defined as \textgreater{}70\% luminal stenosis, and requirement
for follow-on coronary revascularisation.

We then identified a cohort of patients with unexplained ventricular
arrhythmias (UVA, Group 1) in whom the aetiology for ventricular
arrhythmia remained unexplained after three `first-line' cardiac
investigations: TTE, ECG and coronary assessment (Table 1). More
specifically, patients with UVA were defined as those structurally
normal heart on TTE, absence of obstructive disease on coronary
assessment and no clear diagnostic features on ECG. Examples of clear
diagnostic features on ECG included long or short QT intervals, features
of arrhythmogenic right ventricular cardiomyopathy (ARVC), features of
Brugada syndrome or manifest pre-excitation.

We compared this UVA cohort of patients with patients having a confirmed
or strongly suspected aetiology of their ventricular arrhythmia on the
basis of 12-lead ECG, TTE and coronary assessment. This group was
labelled was labelled VA with clear aetiology (Group 2).

We then evaluated the adoption rate of five modalities of `second-line'
investigations for ventricular arrhythmia in both groups. These
second-line investigations included cardiac magnetic resonance imaging
(CMR), exercise stress ECG, flecainide challenge, electrophysiology
studies (EP) and genetic testing. Where these investigations were
available, we recorded whether the result elucidated the underlying
aetiology of the presenting ventricular arrhythmia.

Clinical discharge summaries were reviewed to determine which
antiarrhythmic drugs were prescribed to patients following presentation
with a ventricular arrhythmia. We recorded rates of prescription of beta
blockers, amiodarone, flecainide and sotalol.

Finally, we sought to evaluate outcome data for patients with respect to
future burden of ventricular arrhythmia and all-cause mortality. We
reviewed all available records from subsequent device interrogations for
the first five years following device implantation. In order to be
included for this phase of the analysis, patients were required to have
documentation of at least two device interrogation reports over this
five-year period. We assessed for the frequency of device-detected NSVT
and requirement for tachycardia therapies, including anti-tachycardia
pacing (ATP) and device-delivered shocks. Hospital records were reviewed
to assess for patient mortality up to 10 years following device implant.

\section*{Statistical analysis.}

{\label{statistical-analysis.}}

Differences between the two groups were assessed by the Student's
unpaired t-test for all parametric data, by the Mann-Whitney U test for
non-parametric data. These quantitative data were expressed as the mean
± standard deviation (SD). Differences between the two groups for
categorical data was performed using the Chi-Square test. These data are
represented as the number of patients in the category followed by the
percentage of the group total, as \emph{n (\%).} Statistical analysis
was performed using SPSS version 21 (IBM SPSS, Armonk, NY). A p-value
\textless{}0.05 was considered statistically significant.

\section*{Results}

{\label{results}}

\subsection*{Baseline characteristics}

{\label{baseline-characteristics}}

Records were reviewed for 287 recipients of a secondary prevention ICD
between January 2010 and July 2021 (Figure 1). Of these, 185 patients
were excluded on the basis of being \textgreater{}60 years of age. The
remaining 102 patients were included for further investigation. These
patients were dichotomised based on the criteria described in Table 1,
such that 39 patients (38.2\%) were identified with unexplained
ventricular arrhythmia (UVA, Group 1) and the remaining 63 patients
(61.8\%) were labelled VA with clear aetiology (Group 2). Of these 63
patients, the identified aetiologies of ventricular arrhythmia fit into
the following categories: 16 (25.3\%) had ischaemic cardiomyopathy, 38
(60.3\%) had non-ischaemic cardiomyopathy and 9 (14.3\%) had a primary
electrical aetiology which was evident on their resting baseline ECG.

The baseline characteristics for the patients in described in Table 2.
Patients with UVA were clinically distinct from their counterparts with
VA of clear aetiology. UVA patients were younger in age (35.6 ± 13.0
years vs 46.0 ± 8.6 years, p\textless{}0.001) and were more often female
(48.7\% vs 28.6\%, p=0.04). A lower proportion of the patients with UVA
had traditional cardiovascular risk factors, including hypertension
(10.3\% vs 30.2\%, p=0.02) and diabetes (2.6\% vs 15.9\%, p=0.04). A
greater proportion of UVA patients gave a history of prior syncope
compared to patients with VA of clear aetiology (20.5\% vs 9.5\%,
p=0.03).

When reviewing the culprit rhythm disorder which formed the indication
for ICD, a higher proportion of patients with UVA had ventricular
fibrillation compared to their counterparts with VA of clear aetiology
(87.2\% vs 50.8\%, p\textless{}0.001), while a lower proportion had
monomorphic VT (7.7\% vs 46.0\%, p\textless{}0.001). There was
consequently a trend towards a greater proportion of UVA patients
presenting in the context of a cardiac arrest (82.1\% vs 65.1\%,
p=0.06).

When reviewing the ICD subtype across the two groups, patients with UVA
were more likely to receive subcutaneous ICDs than their counterparts
with VA of clear aetiology (20.5\% vs 4.8\%, p=0.01). Both groups had
similar rates of implantation with single chamber and dual chamber
devices. No patients in the UVA group received a biventricular device
compared with 5 patients with VA of clear aetiology (7.9\%).

\subsection*{First-line cardiac
investigations}

{\label{first-line-cardiac-investigations}}

The results of baseline ECGs, transthoracic echocardiograms and coronary
assessments are shown in Table 3. All patients reviewed had a baseline
ECG available for analysis. Baseline ECG characteristics were similar
across the three groups, with the only significant difference being a
higher rate of axis deviation in patients with VA of clear aetiology
compared to those with UVA (28.6\% vs 10.3\%, p=0.02). Sinus rhythm was
the prevalent baseline rhythm in the majority of patients in both groups
(UVA: 97.4\%, VA of clear aetiology: 87.3\%, p=0.08). Of note, two
patients (5.1\%) in the UVA group exhibited the early repolarisation
pattern on their ECG (without additional diagnostic features of early
repolarisation syndrome), while no patients with VA of clear aetiology
exhibited this finding.

All patients analysed had a baseline transthoracic echocardiogram
available for review. In keeping with the criteria used to defined the
two groups, patients with UVAs had significantly lower rates of
structural heart disease compared with their counterparts with VA of
clear aetiology. Specifically, UVA patients had a higher LV ejection
fraction (59 ± 8.4\% vs 42.1 ± 15.3\%, p\textless{}0.001) and smaller LV
cavity size (50.8 ± 6.4mm vs 56.1 ± 11.0mm). By definition, no patients
in the UVA group exhibited impaired RV function, moderate-or-worse valve
dysfunction or segmental hypokinesis. These features were respectively
present in 30.2\%, 14.3\% and 30.2\% of the patients with VA of clear
aetiology.

Coronary assessments (either CTCA or invasive coronary angiography) were
widely performed in patients with UVA (87.2\%) and VA of clear aetiology
(84.1\%). By definition, no patients in the UVA group had obstructive
coronary disease, which in turn was present in 27.0\% of patients with
VA of clear aetiology. 14.3\% of patients with VA of clear aetiology
required follow-on revascularisation.

\subsection*{Second-line cardiac
investigations}

{\label{second-line-cardiac-investigations}}

Table 4 demonstrates the adoption rate of `second-line' investigations
for the workup of ventricular arrhythmia in patients with UVA and VA of
clear aetiology. Cardiac MRI was the most commonly utilised modality in
both groups, but was more commonly adopted in patients with UVA (82.1\%
vs 63.5\%, p=0.046). The remainder of the second-line investigations,
flecainide challenge, genetic testing, EP study and exercise stress ECG,
were only utilised in a minority of patients in both groups. Combined
workup with all five second-line investigations was only utilised in 3
patients, all of whom were patients with UVA.

The individual diagnoses that were identified as a result of second-line
investigations in patients with UVA is shown in Figure 2. CMR
facilitated diagnosis of an underlying aetiology of ventricular
arrhythmia in 8 patients. The late gadolinium enhancement (LGE) pattern
of ventricular scar was suggestive of a diagnosis in the majority of
these cases, including 2 cases of sarcoidosis, 1 case of old (inactive)
myocarditis and 1 case of transmural scar in a patient with
non-obstructive CAD (suggestive of a coronary embolic event).
Morphological analysis of the RV was suggestive of underlying
arrhythmogenic cardiomyopathy in 2 patients.

Flecainide challenge was performed in 8 patients (20.5\%) and revealed a
provokable ECG pattern suggestive of Brugada syndrome in 2 cases.
Genetic screening was performed in 10 patients; 8 of these patients
reported a family history of sudden cardiac death. A likely genetic
culprit was identified in 3 cases. One patient was found to have a
ryanodine receptor-2 mutation suggestive of catecholaminergic
polymorphic VT (CPVT), one patient was found to have a desmoglein-2
mutation suggestive of ARVC, and one patient was found to have a desmin
mutation signalling the presence of an underlying early NICM. An EP
study was performed in 6 patients (15.4\%). Focal VT originating from
the LV inferior septum and perimitral VT were found in one patient each.
In one case, the EP study demonstrated evidence of a right posterior
accessory pathway; suggesting that the malignant arrhythmia in question
may have been a pre-excited tachycardia rather than a ventricular
tachyarrhythmia. While exercise stress ECGs were performed in 8 patients
(20.5\%), no patients were identified to have catecholaminergic
polymorphic VT or congenital long QT syndrome.

Taken together, 17 patients in the UVA cohort (43.5\%) had a suggestive
aetiology for ventricular arrhythmia identified on one or more of the
five second-line investigations.

\subsection*{Prescribed anti-arrhythmic
therapy}

{\label{prescribed-anti-arrhythmic-therapy}}

Table 5 reviews the rates of prescription of antiarrhythmic therapies at
time of hospital discharge in each group. A lower proportion of patients
with UVA were prescribed at least one antiarrhythmic drug at time of
hospital discharge compared with their counterparts with VA of clear
aetiology (64.1\% vs 88.9\%, p=0.003). This was predominantly driven by
lower rates of prescription of beta blockers (51.3\% vs 81.0\%, p=0.002)
and amiodarone (5.1\% vs 34.9\%, p=0.001).

\subsection*{Device-detected arrhythmia
burden}

{\label{device-detected-arrhythmia-burden}}

Table 6 reviews the data collected from device interrogations in the
first 5 years post-device implantation. At least two device
interrogation reports were available for 34 patients with UVA (87.1\%)
and 51 patients with VA of clear aetiology (81.0\%). Reviewing these
records revealed a significantly greater requirement for
device-delivered tachy-therapies in the UVA group compared with the VA
of clear aetiology group (30.8\% vs 14.3\%, p=0.04). Rates of
device-detected NSVT were similar across the UVA and VA of clear
aetiology cohorts (43.6\% vs 38.1\%, p=0.58). 3 patients were found to
have died during follow-up: all three were in the VA of clear aetiology
cohort. 2 deaths resulted from end-stage systolic heart failure and one
death resulted from VT storm.

\section*{Discussion.}

{\label{discussion.}}

Our data provide important insights into the prevalence, clinical
features and diagnostic evaluation of patients with unexplained
ventricular arrhythmia in a real-world analysis. The key finding of this
study is that only a minority of patients with UVA underwent a
comprehensive assessment with an extended panel of investigations.
Furthermore, our data suggest that completing a more comprehensive
assessment in patients with UVA may allow for a significant proportion
of these patients to be assigned a more specific diagnosis with
subsequent targeted treatment.

\subsection*{Prevalence and clinical features of patients with
UVA}

{\label{prevalence-and-clinical-features-of-patients-with-uva}}

In the present study, 38\% of secondary prevention ICD recipients who
were evaluated met our criteria for UVA. This is a higher proportion of
UVA than has been demonstrated in existing research. In a retrospective
review of 717 survivors of sudden cardiac arrest by Waldmann et
al\textsuperscript{8}, the proportion of cases which remained
unexplained following assessment of baseline ECG, TTE and coronary
arteries was 12.3\%. We posit two reasons for this discrepancy. First,
our analysis was restricted to ICD recipients under the age of 60.
Younger patients are more likely to present at an earlier stage of their
cardiac pathology and are thus more likely to have subclinical
cardiomyopathies or only subtle baseline ECG changes at their time of
presentation. Second, our study only examined patients receiving
secondary prevention ICDs, rather than evaluating all-comers with
cardiac arrest or ventricular tachyarrhythmia. This excluded patients
who presented with ventricular tachyarrhythmias secondary to acute
ischaemia or other reversible causes, in whom an ICD would not be
implanted. Both features of our analysis may have led to a higher
representation of UVA.

Our data suggest that patients with UVA are clinically distinct from
their counterparts with ventricular tachyarrhythmias with manifest
structural or electrical heart disease. UVA patients in the present
study were significantly younger, more often female had a lower burden
of traditional cardiovascular risk factors. Our findings are largely in
keeping with previous research in this field, which has consistently
demonstrated that patients with unexplained or idiopathic ventricular
arrhythmia are of younger age at time of
presentation\textsuperscript{8,9}. Existing data on sex differences in
patients with UVA are more conflicted. While women account for a higher
proportion of overall presentations of ventricular arrhythmia with
structurally normal hearts\textsuperscript{10}, men account for a higher
percentage of patients presenting with unexplained sudden cardiac arrest
or death\textsuperscript{5,6}.

A history of a past episode of syncope preceding the acute presentation
with ventricular tachyarrhythmia was reported in 23\% of patients in the
UVA cohort of the present study. This high proportion of prior syncope
highlights the propensity for recurrent malignant arrhythmias in this
cohort. This is further supported by the fact that patients in the UVA
cohort more frequently required device delivered tachy-therapies during
follow-up compared to patients with VA of clear aetiology. This higher
risk for recurrent arrhythmia was also demonstrated in a previous review
of medium-term outcomes in 66 patients with idiopathic ventricular
fibrillation, in which recurrent ventricular arrhythmias were seen in
20\% of patients\textsuperscript{6}.

Significant differences in the pattern of prescribed therapies were
demonstrated between patients with UVA compared to those with VA of
clear aetiology. This may be due to the higher proportion of structural
heart disease in the VA of clear aetiology group, including coronary
artery disease and heart failure with reduced ejection fraction. Both of
these conditions represent an indication for beta blockade independent
of presentation with ventricular arrhythmia. However, amiodarone was
also prescribed at a lower rate to UVA patients. One reason for this may
be a reluctance to overprescribe medications to patients with
structurally normal heart and no clear diagnosis, particularly in
medicines with long-term toxicity such as amiodarone.

\subsection*{Diagnostic evaluation of UVA in current
practice}

{\label{diagnostic-evaluation-of-uva-in-current-practice}}

In this single-centre review, 12-lead ECG and transthoracic
echocardiogram data was acquired in all patients requiring a secondary
prevention ICD. Conversely, coronary evaluation was acquired in most,
but not all secondary prevention ICD recipients, and 13\% of patients in
the UVA cohort did not undergo any form of coronary assessment. Current
ACC/AHA provide a Class I recommendation for the use of either CT or
invasive coronary angiography in patients with unexplained cardiac
arrest\textsuperscript{7}. Potential reasons for patients with UVA not
being selected for coronary assessment in the present study include
younger age and lack of traditional cardiovascular risk factors.
However, non-atherosclerotic coronary disease remains an important cause
of ventricular arrhythmia in younger patients, and may be due to
anomalous coronary arteries\textsuperscript{11}, coronary embolic
events\textsuperscript{12} or coronary vasospasm\textsuperscript{13}.

In our analysed cohort of 39 patients with UVA, the utilisation of
second-line investigations was highly heterogenous. As the statewide CMR
quaternary referral centre for Victoria, CMR was the most commonly
utilised modality of testing, adopted in 82\% of participants. However,
other investigations were comparatively underutilised, including genetic
testing (26\%), flecainide challenge (21\%), exercise ECG (21\%) and EP
study (15.4\%). Such inconsistency in the evaluation of UVA has been
replicated in existing literature. Waldmann et al demonstrated that in a
cohort of 81 cases of unexplained cardiac arrest, while CMR was utilised
in 81\% of patients, other investigations including ajmaline challenge,
EP study and genetic testing were performed in only a minority of cases
(43\%, 25\% and 18\% respectively).

Reasons for this variability are uncertain, but several factors are
probably involved. First, standardised protocols for the evaluation of
UVA are not in place. Such a standardised assessment has been studied
and advocated for in the past\textsuperscript{9}, but has not gained
traction in current practice. Second, most of these second-line
investigations are usually completed in the outpatient setting, where it
can be more challenging to organise further investigations and perhaps
many patients with UVA may be lost to follow-up, particularly given
their younger age. One reason why the uptake of CMR is higher than other
modalities may be the impetus to complete this investigation as an
inpatient prior to the insertion of an ICD to allow for maximal
diagnostic yield.

\subsection*{Diagnostic yield of comprehensive assessment in
UVA}

{\label{diagnostic-yield-of-comprehensive-assessment-in-uva}}

In our study, 17 out of 39 patients (43\%) of patients with UVA had a
cause for ventricular arrhythmia suggested by one of the five
second-line investigations which were evaluated. This is in spite of the
highly variable nature of the work-up performed, and an even higher
proportion of patients may have had a diagnosis confirmed if complete
work-up was performed in all patients.

CMR had the highest diagnostic yield of all the investigations studied,
suggesting an underlying diagnosis in 8 patients. All diagnoses related
to structural heart disease initially not identified on transthoracic
echocardiography. This included diagnoses related to enhanced evaluation
of right ventricular function (ARVC diagnosed in 2 patients), better
visualisation of subtle structural anomalies (mitral annular disjunction
diagnosed in 1 patient), evaluation of tissue oedema (acute myocarditis
diagnosed in 1 patient) and patterns of late gadolinium enhancement
(cardiac sarcoidosis diagnosed in 2 patients, previous myocarditis
diagnosed in 1 patient, transmural scar suggestive of prior infarct
diagnosed in 1 patient). CMR is well understood to be more sensitive for
the diagnosis of cardiac sarcoid\textsuperscript{14},
myocarditis\textsuperscript{15} and ARVC\textsuperscript{16} compared to
echocardiography, all of which have a strong association with
ventricular arrhythmia.

Conversely, exercise ECG had the lowest diagnostic yield in this study,
with no additional information gained in 8 patients that underwent this
test. Part of this may be explained by the small number of patients who
underwent this investigation. While this study alone does not lend
support to the utility of exercise ECG in providing diagnostic clarity
in patients with UVA, previous research has shown that exercise testing
can unmask primary electrical disorders such as catecholaminergic
polymorphic VT\textsuperscript{17} and long QT
syndrome\textsuperscript{18}. Furthermore, a negative stress ECG may
provide value as a marker of improved prognosis and lower risk of
recurrent arrhythmia in patients with previous cardiac
arrest\textsuperscript{19}.

Ascertaining the underlying cause for unexplained ventricular arrhythmia
is of substantial clinical importance. First, it allows for targeted
therapies to be utilised, not only to prevent future arrhythmia but also
prevent the development of future structural heart disease. An example
of this is prescription of immunosuppressive therapy after diagnosis of
active sarcoidosis or myocarditis. Second, it allows for better risk
stratification and lifestyle modification advice. For instance, two
patients in our cohort were diagnosed with concealed Brugada syndrome
with the use of a flecainide challenge, and appropriate advice about
avoidance sodium channel blocking drugs and awareness of hyperthermia
was provided. Third, it has important implications for family screening,
particularly in cases of subclinical non-ischaemic cardiomyopathy (e.g.
ARVC) or channelopathies. Fourth, in certain cases, elucidation of the
underlying diagnosis may preclude the need for ICD therapy. An example
in our cohort was one patient who was found to have a right paraseptal
accessory pathway on EP study with malignant anterograde conduction
properties. Diagnosis and ablation of this pathway would effectively
prevent future pre-excited tachycardia and may have obviated the need
for a defibrillator.

\subsection*{Limitations and directions for future
research}

{\label{limitations-and-directions-for-future-research}}

Our analysis has a number of important limitations. First, this study is
limited by the small sample size. This is an inherent limitation of
studying ventricular arrhythmia and cardiac arrest in younger patients,
which remains a relatively infrequent, albeit important clinical entity.

Second, this was a single-centre retrospective review. The findings
relating to the adoption of certain diagnostic tests therefore only
reflects the practice at our own institution, and cannot be extrapolated
to the practice in the larger Australian or international cardiology
community. One important distinction was the high rate of utilisation of
CMR in this study, as access to CMR in varies significantly between
cardiac centres in Australia. However, it is notable that the adoption
rates for CMR, flecainide challenge and genetic testing in our study
were similar to the rates described in a previous European retrospective
review of patients with unexplained sudden cardiac
arrest\textsuperscript{8}. Both this limitation and the small sample
size could be mitigated by a multi-centre extension of the current
study.

Third, this study did not evaluate the role of early versus delayed
diagnosis in patients with UVA. A proportion of the patients in the UVA
cohort were diagnosed with an underlying aetiology for ventricular
arrhythmia early in their clinical course; for instance, patients who
underwent CMR prior to ICD implant while still an inpatient after
presenting with cardiac arrest. Such patients would therefore not have
had `unexplained' ventricular arrhythmia from this point onwards and
during their subsequent follow-up. In future research, this limitation
could be mitigated by evaluating patients who had a label of
`unexplained ventricular arrhythmia' at their time of hospital
discharge. In such an analysis, it would be interesting to measure the
time delay between the initial presentation with ventricular arrhythmia
and the eventual diagnosis being made.

Finally, our analysis was restricted to patients implanted with a
secondary prevention ICD. This was chosen as a practical method to
collect data on patients who had suffered from ventricular
tachyarrhythmias presenting to our institution. However, this fails to
capture patients presenting with ventricular arrhythmia in whom
defibrillators are not implanted, and those patients who die from sudden
cardiac arrest whose diagnoses may be made on post-mortem autopsy.
Future research in this field could instead review registry data for
patients with sudden cardiac arrest, to more widely explore the subject
of unexplained ventricular arrhythmia.

\section*{Conclusion.}

{\label{conclusion.}}

A substantial proportion of adults under the age of 60 who present with
ventricular tachyarrhythmia requiring an ICD will not have an apparent
diagnosis after baseline ECG, TTE and coronary assessment. Comprehensive
assessment with second-line investigations such as CMR, flecainide
challenge and genetic testing may provide an underlying diagnosis in
many of these patients, however the diagnostic evaluation in these
patients is highly variable and often incomplete. Implementation of a
systematic protocol for work-up of these patients requires further
study.

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