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.
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
al8, 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
presentation8,9. 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 hearts10, men account for a higher
percentage of patients presenting with unexplained sudden cardiac arrest
or death5,6.
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 patients6.
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.
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
arrest7. 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 arteries11, coronary embolic
events12 or coronary vasospasm13.
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 past9, 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.
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 sarcoid14,
myocarditis15 and ARVC16 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 VT17 and long QT
syndrome18. 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
arrest19.
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.
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
arrest8. 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.