Results
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 >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<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<0.001), while a lower proportion had
monomorphic VT (7.7% vs 46.0%, p<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%).
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<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.
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.
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).
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.