DISCUSSION
In this paper, we report the first data for use of R2I2 and PERS as
markers of VA/death in patients with non-ischemic cardiomyopathy and we
also report the first data for PERS values in a normal control
population. As has been found previously, combining R2I2+PERS offered
the greatest discrimination of endpoint in this study population,
predicting VA/death (p=0.02) with a hazard ratio per positive component
marker of 3.2.11 R2I2 and PERS separately show trends
towards significantly higher values in patients reaching the endpoint of
VA/death than those not. This replicates the findings of our previous
work in ischemic cardiomyopathy using the same technique and cut-offs
for R2I2/PERS analysis and the same endpoints.11,12R2I2 and PERS appear to perform favourably compared to other surface ECG
markers, such as T wave alternans, QRS fragmentation, signal averaged
ECG and QRS-T angle, all of which have been shown to have a poor
positive predictive value.15
The underlying aetiology of the cohort was heterogeneous and
significantly more endpoints occurred in the ‘other conditions’ subgroup
compared to the dilated cardiomyopathy subgroup. Combined R2I2+PERS, was
independent of aetiology in predicting VA/death (p=0.04) with a hazard
ratio of 2.7 per positive component. This suggests that R2I2+PERS are
applicable to both dilated cardiomyopathy patients and patients with
‘other conditions’ but larger studies are needed to confirm the
relationship. In Kaplan Meier analysis (Figure 3) the rate of VA/death
at 5 years in patients positive for both R2I2≥1.03+PERS≥1.21 was 41%,
compared with 23% for patients positive for either, and 0% for
patients negative for both.
R2I2 was developed to quantify heterogeneity in APD restitution as a
measure of electrical instability. In silico modelling has shown
that heterogeneity of APD restitution leads to increased dispersion of
depolarisation and repolarisation times leading to wavebreak and the
substrate for ventricular arrhythmogenesis.5Heterogeneity in APD restitution has been clinically demonstrated with
both endocardial and epicardial approaches; using intracardiac catheters
and also with an epicardial sock of electrodes in patients undergoing
cardiac surgery, with significant differences seen between patients with
ischemic heart disease and aortic valve disease.16–18PERS is based on the original ‘restitution hypothesis’: a maximum APD
restitution curve gradient >1 magnifies oscillations of
APD/DI leading to wavebreak and ventricular fibrillation. Steep APD
restitution curves have been shown in silico and in animal
studies to convey increasing risk of VA.8,19,20
It is important and expected that R2I2 and PERS could be applied
successfully to patients without ischemic heart disease. Differences in
APD restitution heterogeneity have been demonstrated in studies in
cohorts of hypertrophic cardiomyopathy, Brugada syndrome, dilated
cardiomyopathy, valvular heart disease, cardiac sarcoidosis and ARVC
when compared to healthy controls.21–23 The
successful application to a non-ischemic population suggests that R2I2
and PERS measure a common underlying arrhythmogenic mechanism (i.e.
electrical restitution) rather than, for example, the effect of
infarction on ECG morphology.
R2I2 was found to be significantly higher in the study cohort compared
to the controls. PERS showed a non-significant trend to higher values in
the study group compared to controls. Both the DCM and the ‘other
conditions’ subgroups also had a significantly higher mean R2I2 than
controls with trends to higher PERS values. The study was underpowered
to test for a difference in R2I2/PERS values in relation to VA/death in
the study group aetiology subgroups but found trends to higher values.
Moderate positive correlation was seen between R2I2 and PERS values in
control patients. No correlation was seen between R2I2 and PERS values
in study patients.
It is of interest that correlation was seen between R2I2 and PERS in the
control group but not in the study group. Our previous study of R2I2 and
PERS found no correlation between the two parameters in an ischemic
cardiomyopathy population and this is anticipated since they are
intended to measure different APD restitution
properties.11 The R2I2 calculation uses mean and
standard deviations; it is a staple of the APD restitution research to
calculate mean and standard deviations of APD restitution slopes.
However, as the gradient of a slope steepens it increases exponentially
and hence the standard deviation of a steep slope is likely to be higher
than that of a shallow slope. It is possible that in a control
population with homogenous APD restitution this effect leads to a
relationship between PERS and R2I2 while in a population with high APD
restitution heterogeneity the heterogeneity effect predominates over the
standard deviation effect.
This study provides proof-of-principle that clinically relevant
biomarkers of electrical restitution curve heterogeneity and peak
electrical restitution curve slope can be measured using the 12 lead ECG
and be applied to a broad spectrum of patients at risk of sudden cardiac
death with a range of underlying etiologies. The annual incidence of
VA/death in patients with either/both R2I2≥1.03/PERS≥1.21 was over 7%
and all patients experiencing VA/death were positive for either
R2I2/PERS/both. A current limitation to wider use of R2I2 and PERS is
that their measurement requires a 5 min programmed stimulation protocol
delivered by transvenous pacing at the right ventricular apex, limiting
its use to patients in whom such a protocol can be instigated. Although
in the majority of patients, this currently requires an invasive study,
R2I2 and PERS can be investigated non-invasively in patients with ICDs
or pacemakers. This is currently being tested in a large prospective
multicentre trial of patients with ischaemic cardiomyopathy
(ClinicalTrials.gov Identifier: NCT03022487). We are also exploring
fully non-invasive methods of obtaining a spectrum of heart rates, such
as exercise and chronotropic medication to see if these methods provide
the same information as that from pacing.24
Amongst the limitations of this study was that the aetiology of the
study group was heterogeneous containing patients with dilated
cardiomyopathy and a range of other conditions. Importantly
R2I2≥1.03+PERS≥1.21 were independent of aetiology in predicting VA/death
but larger studies of homogenous populations are needed to support the
application of R2I2 and PERS in specific cohorts. This study was
marginally underpowered to find a difference in R2I2, reflected in the
non-significant trends seen; the results fit expectations from previous
work.11 Also, VA/death does not equate to SCD, the
combined endpoint is heterogeneous. The study is a single-centre study,
and before any clinical application, the association of the ECG markers
with VA/death should be replicated in a broader multicentre clinical
trial.
This study offers the first evidence to support application of two novel
electrical restitution markers R2I2≥1.03+PERS≥1.21 in assessment of
sudden cardiac death risk in patients with non-ischemic heart disease.
R2I2 and PERS have the potential to play an important role in SCD risk
stratification but their validity should be confirmed in a larger
multi-centre study before clinical trials are undertaken.